WO2017121700A1 - Dérivés de 1h-pyrazolo[3,4-b]pyridine 1,3-disubstitués et leur utilisation en tant que stimulateurs de la guanylacte cyclase soluble - Google Patents

Dérivés de 1h-pyrazolo[3,4-b]pyridine 1,3-disubstitués et leur utilisation en tant que stimulateurs de la guanylacte cyclase soluble Download PDF

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WO2017121700A1
WO2017121700A1 PCT/EP2017/050326 EP2017050326W WO2017121700A1 WO 2017121700 A1 WO2017121700 A1 WO 2017121700A1 EP 2017050326 W EP2017050326 W EP 2017050326W WO 2017121700 A1 WO2017121700 A1 WO 2017121700A1
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formula
compound
alkyl
group
amino
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PCT/EP2017/050326
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German (de)
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Markus Follmann
Johannes-Peter Stasch
Nils Griebenow
Jens Ackerstaff
Niels Lindner
Gorden Redlich
Andreas Knorr
Frank Wunder
Volkhart Min-Jian Li
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Bayer Pharma Aktiengesellschaft
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present application relates to novel, substituted 5-Ringheteroaryl derivatives and their use, processes for their preparation, their use alone or in combinations for the treatment and / or prophylaxis of diseases and their use for the preparation of medicaments for the treatment and / or prophylaxis of diseases , in particular for the treatment and / or prophylaxis of cardiovascular diseases.
  • cyclic guanosine monophosphate cGMP
  • NO nitric oxide
  • the guanylate cyclases catalyze the biosynthesis of cGMP from guanosine triphosphate (GTP).
  • GTP guanosine triphosphate
  • the previously known members of this family can be divided into two groups according to both structural features and the nature of the ligands: the particulate guanylate cyclases stimulable by natriuretic peptides and the soluble guanylate cyclases stimulable by NO.
  • the soluble guanylate cyclases consist of two subunits and most likely contain one heme per heterodimer, which is part of the regulatory center. This is central to the activation mechanism. NO can bind to the iron atom of the heme and thus significantly increase the activity of the enzyme. On the other hand, heme-free preparations can not be stimulated by NO. Carbon monoxide (CO) is also able to bind to the central iron atom of the heme, with stimulation by CO being markedly lower than by NO.
  • CO Carbon monoxide
  • guanylate cyclase plays a crucial role in various physiological processes, in particular in the relaxation and proliferation of smooth muscle cells, platelet aggregation and adhesion, neuronal signaling and diseases based on a disturbance of the above operations.
  • the NO / cGMP system may be suppressed, which may, for example, lead to hypertension, platelet activation, increased cell proliferation, endothelial dysfunction, arteriosclerosis, angina pectoris, heart failure, myocardial infarction, thrombosis, stroke and sexual dysfunction.
  • a NO-independent treatment option for such diseases which is aimed at influencing the cGMP pathway in organisms, is a promising approach on account of the expected high efficiency and low side effects.
  • soluble guanylate cyclase only compounds such as organic nitrates have been used, whose action is based on NO. This is formed by bioconversion and activates the soluble guanylate cyclase by attack on the central iron atom of the heme.
  • the development of tolerance is one of the decisive disadvantages of this type of treatment.
  • WO 00/06568 and WO 00/06569 disclose fused pyrazole derivatives and WO 03/095451 discloses carbamate-substituted 3-pyrimidinyl-pyrazolopyridines. 3-Pyrimidinyl-pyrazolopyridines with phenylamide substituents are described in E.M. Becker et al, BMC Pharmacology, 2001, 1 (13).
  • WO 2004/009590 describes pyrazolopyridines with substituted 4-aminopyrimidines for the treatment of CNS diseases.
  • WO 2010/065275 and WO 2011/149921 disclose substituted pyrrolo and dihydropyridopyrimidines as sGC activators.
  • WO 2012/004259 As sGC stimulators, in WO 2012/004259, WO2013 / 131923, WO 2014/131760 and WO 2014/131741 fused aminopyrimidines, in WO 2015/004105 fused triazines and in WO 2012/004258, WO 2012/143510 and WO 2012/152629 Pyrimidines and triazines described.
  • WO 2012/28647 discloses pyrazolopyridines with various azaheterocycles for the treatment of cardiovascular diseases.
  • the object of the present invention is to provide novel substances which act as potent stimulators of soluble guanylate cyclase, are therefore suitable for the treatment and / or prophylaxis of cardiovascular diseases, and have the same or improved physicochemical and / or therapeutic profile.
  • the present invention relates to compounds of the general formula (I)
  • a 1 , A 2 and A 3 are each independently O or S,
  • D 1 , D 2 , D 3 and D 4 are each independently CR 13 or N,
  • R 13 is hydrogen, halogen or (Ci-C i) -alkyl, with the proviso that a maximum of two of the groups D 1 , D 2 , D 3 and D 4 are N, E 1 , E 2 , E 3 and E 4 are each independently CR 14 or N,
  • L is a group * -CR 15A R 15B, - (CR 16A R 16B) P - ** is wherein
  • * represents the point of attachment to the group G
  • ** represents the point of attachment to the triazole ring
  • p stands for a number 0, 1 or 2
  • R 15A is hydrogen, fluorine, (Ci-C alkyl or hydroxy
  • R 15B is hydrogen, fluorine, (Ci-C i) -alkyl or trifluoromethyl, or
  • R 15A and R 15B together with the carbon atom to which they are attached form an oxo group, a 3- to 6-membered carbocycle or a 4- to 6-membered heterocycle,
  • R 16A is hydrogen, fluorine, (Ci-C i) -alkyl or hydroxy
  • R 16B is hydrogen, fluorine, (C 1 -C 4 ) -alkyl or trifluoromethyl,
  • R 3 is (C 1 -C 6) -alkyl, (C 3 -C 4) -cycloalkyl, amino, aminocarbonyl, 4- to 7-membered heterocyclyl, phenyl or pyridyl, wherein (C 1 -C 6) -alkyl has from 1 to 3 substituents independently selected from the group halogen, difluoromethyl, trifluoromethyl, (C3-Cv) -cycloalkyl, di-fluoromethoxy, trifluoromethoxy, (Ci-C4) alkoxy, hydroxycarbonyl, (C1-C4) - alkoxycarbonyl, (Ci-C4) alkoxycarbonylamino , (C 1 -C 4) -alkoxycarbonyl- (C 1 -C 4) -alkylamino, amino, mono- (C 1 -C 4) -alkylamino, di- (C 1 -C 4) -alkylamin
  • R 10 is amino or (C 1 -C 4) -alkoxycarbonylamino
  • R 11 is mono (Ci-C4) alkylamino, aminocarbonyl, or mono- (Ci-C4) alkylamino carbonyl group,
  • R 12 is (C 1 -C 4 ) -alkyl, in which (C 1 -C 4 ) -alkyl having 1 to 3 substituents independently of one another selected from the group consisting of halogen, difluoromethyl, trifluoromethyl, (C 3 -C 4) -cycloalkyl, di-fluoromethoxy, Trifluoromethoxy, (C 1 -C 4) -alkoxy, hydroxycarbonyl, (C 1 -C 4) -alkoxycarbonyl, (C 1 -C 4) -alkoxycarbonylamino, (C 1 -C 4) -alkoxycarbonyl- (C 1 -C 4) -alkylamino, amino, mono (Ci -C4) -alkylamino, di (Ci-C4) -alkylamino, aminocarbonyl, mono- (Ci-C4) -alkylaminocarbonyl, di- (Ci-C4)
  • R 1 is hydrogen or fluorine
  • R 2 is (C 1 -C 6 ) -alkyl or benzyl, where (C 1 -C 6 ) -alkyl is substituted by one substituent trifluoromethyl, where (C 1 -C 6 ) -alkyl may be substituted by 1 to 3 substituents of fluorine, and wherein benzyl is substituted by 1 to 3 substituents fluorine, and their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.
  • Compounds according to the invention are the compounds of the formula (I) and their salts, solvates and solvates of the salts comprising the compounds of the formulas below and their salts, solvates and solvates of the salts and of the formula (I) encompassed by formula (I), hereinafter referred to as exemplary compounds and their salts, solvates and solvates of the salts, as far as the compounds of formula (I), the compounds mentioned below are not already salts, solvates and solvates of the salts.
  • Salts used in the context of the present invention are physiologically acceptable salts of the compounds according to the invention. Also included are salts which are themselves unsuitable for pharmaceutical applications but can be used, for example, for the isolation or purification of the compounds of the invention.
  • Physiologically acceptable salts of the compounds of the invention include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, e.g. Salts of hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, ethanesulfonic, toluenesulfonic, benzenesulfonic, naphthalenedisulfonic, formic, acetic, trifluoroacetic, propionic, lactic, tartaric, malic, citric, fumaric, maleic and benzoic acids.
  • Salts of hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, ethanesulfonic, toluenesulfonic, benzenesulfonic, naphthalenedisulfonic formic, acetic, trifluoroacetic, propionic, lactic, tartaric, malic, citric, fumaric, maleic and benzoic
  • Physiologically acceptable salts of the compounds according to the invention also include salts of customary bases, such as, by way of example and by way of preference, alkali metal salts (for example sodium and potassium salts), alkaline earth salts (for example calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines having 1 to 16 carbon atoms, such as, by way of example and by way of illustration, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine and N-methylpiperidine.
  • customary bases such as, by way of example and by way of preference, alkali metal salts (for example sodium and potassium salts), alkaline earth salts (for example calcium and magnesium salts
  • Solvates in the context of the invention are those forms of the compounds according to the invention which form a complex in the solid or liquid state by coordination with solvent molecules. Hydrates are a special form of solvates that coordinate with water. As solvates, hydrates are preferred in the context of the present invention.
  • the compounds according to the invention may exist in different stereoisomeric forms, ie in the form of configurational isomers or optionally also as conformational isomers (enantiomers and / or diastereomers, including those in the case of atropisomers). The present invention therefore encompasses the enantiomers and diastereoisomers and their respective mixtures.
  • the stereoisomerically uniform components can be isolated in a known manner; Preferably, chromatographic methods are used for this, in particular HPLC chromatography on achiral or chiral phase.
  • the present invention encompasses all tautomeric forms.
  • the present invention also includes all suitable isotopic variants of the compounds of the invention.
  • An isotopic variant of a compound according to the invention is understood to mean a compound in which at least one atom within the compound according to the invention is exchanged for another atom of the same atomic number but with a different atomic mass than the atomic mass that usually or predominantly occurs in nature.
  • isotopes which can be incorporated into a compound of the invention are those of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as 2 H (deuterium), 3 H (tritium), 13 C, 14 C, 15 N, 17 0, 18 0, 32 P, 33 P, 33 S, 34 S, 35 S, 36 S, 18 F, 36 Cl, 82 Br, 123 I, 124 I, 129 I and 131 I.
  • isotopic variants of a compound of the invention such as, in particular, those in which one or more radioactive isotopes are incorporated, may be useful, for example, for the study of the mechanism of action or drug distribution in the body; Due to the comparatively easy production and detectability, compounds labeled with 3 H or 14 C isotopes are particularly suitable for this purpose.
  • isotopes such as deuterium may result in certain therapeutic benefits as a result of greater metabolic stability of the compound, such as prolonging the body's half-life or reducing the required effective dose;
  • Such modifications of the compounds of the invention may therefore optionally also constitute a preferred embodiment of the present invention.
  • Isotopic variants of the compounds according to the invention can be prepared by the processes known to the person skilled in the art, for example by the methods described below and the rules given in the exemplary embodiments, by using appropriate isotopic modifications of the respective reagents and / or starting compounds.
  • the present invention also includes prodrugs of the compounds of the invention.
  • prodrugs refers to compounds which are themselves biologically active or may be inactive, but during their residence time in the body to be converted into compounds of the invention (for example, metabolically or hydrolytically).
  • R 4 is hydrogen
  • R 5 is hydrogen
  • R 6 may also be in the respective tautomeric forms (see Scheme 1 below); the tautomeric forms are expressly encompassed by the present invention.
  • alkyl is a linear or branched alkyl radical having in each case the number of carbon atoms specified.
  • alkyl is a linear or branched alkyl radical having in each case the number of carbon atoms specified.
  • alkyl is a linear or branched alkyl radical having in each case the number of carbon atoms specified.
  • Cycloalkyl or carbocycle in the context of the invention is a monocyclic, saturated alkyl radical having 3 to 7 or 3 to 6 carbon atoms. Examples which may be mentioned by way of example include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • Alkoxy in the context of the invention is a linear or branched alkoxy radical having 1 to 4 carbon atoms. Examples which may be mentioned by way of example include: methoxy, ethoxy, n-propoxy, isopropoxy, 1-methylpropoxy, n-butoxy, isobutoxy and tert. Butoxy.
  • Alkoxycarbonyl in the context of the invention are a linear or branched alkoxy radical having 1 to 4 carbon atoms and an oxygen-bonded carbonyl group.
  • alkoxycarbonyl in the context of the invention are a linear or branched alkoxy radical having 1 to 4 carbon atoms and an oxygen-bonded carbonyl group.
  • Alkoxycarbonylamino in the context of the invention represents an amino group having a linear or branched alkoxycarbonyl substituent which has 1 to 4 carbon atoms in the alkyl chain and is linked via the carbonyl group to the nitrogen atom.
  • alkoxycarbonylamino represents an amino group having a linear or branched alkoxycarbonyl substituent which has 1 to 4 carbon atoms in the alkyl chain and is linked via the carbonyl group to the nitrogen atom.
  • Mono-alkylamino in the context of the invention represents an amino group having a linear or branched alkyl substituent which has 1 to 4 carbon atoms. Examples which may be mentioned are: methylamino, ethylamino, n-propylamino, isopropylamino and tert-butylamino.
  • Di-alkylamino in the context of the invention represents an amino group having two identical or different linear or branched alkyl substituents, each having 1 to 4 carbon atoms.
  • Mono-alkylaminocarbonyl in the context of the invention represents an amino group which is linked via a carbonyl group and which has a linear or branched alkyl substituent having 1 to 4 carbon atoms.
  • methylamino carbonyl methylamino carbonyl, ethylaminocarbonyl, n-propylaminocarbonyl, isopropylaminocarbonyl, n-butylaminocarbonyl and ferric butylaminocarbonyl.
  • Di-alkylaminocarbonyl is in the context of the invention an amino group which is linked via a carbonyl group and which has two identical or different linear or branched alkyl substituents each having 1 to 4 carbon atoms. Examples which may be mentioned are: N, N-dimethylaminocarbonyl, N, N-diethylaminocarbonyl, N-ethyl-N-methylaminocarbonyl, N-methyl-N-n-propylaminocarbonyl, N-n-butyl-N-methylaminocarbonyl and N-tert. - butyl-N-methylaminocarbonyl.
  • Alkylsulfonyl in the context of the invention is a linear or branched alkyl radical having 1 to 4 carbon atoms, which is bonded via a sulfonyl group.
  • a sulfonyl group By way of example and preferably its name: methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, iso-propylsulfonyl, n-butylsulfonyl and tert. -Butylsulfonyl.
  • Alkylsulfonylamino in the context of the invention is an amino group having a linear or branched alkylsulfonyl substituent which has 1 to 6 carbon atoms and is linked via the sulfonyl group to the N-atom.
  • Mono-alkylaminosulfonyl in the context of the invention represents an amino group which is linked via a sulfonyl group and which has a linear or branched alkyl substituent having 1 to 4 carbon atoms.
  • the following may be mentioned by way of example and by way of preference: methylamino-sulfonyl, ethylaminosulfonyl, n-propylaminosulfonyl, isopropylaminosulfonyl, n-butylaminosulfonyl and tert-butylaminosulfonyl.
  • Di-alkylaminosulfonyl in the context of the invention is an amino group which is linked via a sulfonyl group and which has two identical or different linear or branched alkyl substituents each having 1 to 4 carbon atoms. Examples which may be mentioned are: N, N-dimethylaminosulfonyl, N, N-diethylaminosulfonyl, N-ethyl-N-methylaminosulfonyl, N-methyl-N-n-propylaminosulfonyl, N-n-butyl-N-methylaminosulfonyl and N-tert. - butyl-N-methylaminosulfonyl.
  • Heterocycle or heterocyclyl in the context of the invention is a saturated heterocycle having a total of 4 to 7 ring atoms which contains one or two ring heteroatoms from the series N, O and / or S and via a ring carbon atom or optionally a ring nitrogen - atom is linked.
  • Examples include: azetidinyl, pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl and Thiomorpholinyl.
  • Preferred are azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl and morpholinyl.
  • An oxo group in the context of the invention is an oxygen atom which is bonded via a double bond to a carbon atom.
  • Halogen is in the context of the invention for fluorine, chlorine, bromine and iodine.
  • radicals are substituted in the compounds according to the invention, the radicals can, unless otherwise specified, be monosubstituted or polysubstituted. In the context of the present invention, the meaning is independent of each other for all radicals which occur repeatedly. Substitution with one, two or three identical or different substituents is preferred. In the context of the present invention, preference is given to compounds of the formula (I) in which Q is a group of the formula
  • a 2 is O
  • a 3 stands for S
  • D 1 is CR 13 or N
  • R 13 is hydrogen
  • D 2 , D 3 and D 4 are each independently CH, E 1 , E 3 and E 4 are each independently CH, E 2 is CR 14 ,
  • L is a group * -CR 15A R 15B - (CR 16A R 16B ) P - **, where * is the point of attachment to the group G,
  • ** represents the point of attachment to the triazole ring
  • p stands for a number 0 or 1
  • R 15A is hydrogen or methyl
  • R 15B is hydrogen or methyl
  • R 16A is hydrogen
  • R 16B is hydrogen
  • R 3 is (Ci-C i) -alkyl, cyclopropyl, cyclobutyl, amino, aminocarbonyl, phenyl or pyridyl, wherein (Ci-C i) -alkyl having 1 or 2 substituents independently selected from the group fluorine, trifluoromethyl, cyclopropyl , Cyclobutyl,
  • Trifluoromethoxy, (Ci-C i) alkoxy and pyrrolidin-2-one-l -yl may be substituted, and wherein phenyl and pyridyl may be substituted with 1 or 2 substituents independently selected from the group fluorine, methyl, amino and hydroxymethyl .
  • R 4 is hydrogen, (Ci-C 4 ) -alkyl or benzyl, wherein (Ci-C i) -alkyl having 1 or 2 substituents independently selected from the group fluorine, trifluoromethyl, cyclopropyl, cyclobutyl, trifluoromethoxy, methoxy, ethoxy , Methoxycarbonyl and ethoxycarbonyl, and wherein benzyl may be substituted with 1 or 2 substituents independently selected from the group of fluorine and methyl,
  • R 5 is hydrogen, methyl or ethyl, in which methyl and ethyl may be substituted by 1 substituent selected from among fluorine, trifluoromethyl, cyclopropyl, cyclobutyl, trifluoromethoxy, methoxy, ethoxy, hydroxycarbonyl, methoxycarbonyl and ethoxycarbonyl,
  • R 6 represents hydrogen, methyl or ethyl, in which methyl and ethyl may be substituted by 1 substituent selected from among fluorine, trifluoromethyl, cyclopropyl, cyclobutyl, trifluoromethoxy, methoxy, ethoxy, hydroxycarbonyl, methoxycarbonyl, ethoxycarbonyl and piperidin-1-yl,
  • R 7 is amino, methoxycarbonylammo or methoxycarbonyl-N-methylamino
  • R 8 is methyl or ethyl
  • R 9 is (C 1 -C 12) -alkyl, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, methylaminocarbonyl or ethylaminocarbonyl,
  • R 10 is amino, Methoxycarbonylammo or ethoxycarbonylamino
  • R 11 is methylamino, ethylamino or aminocarbonyl
  • R 12 is (C 1 -C 4 ) -alkyl, in which (C 1 -C 4 ) -alkyl having 1 substituent selected from the group consisting of fluorine, trifluoromethyl, cyclopropyl, cyclobutyl, trifluoromethoxy, methoxy, ethoxy, hydroxycarbonyl, methoxycarbonyl, ethoxycarbonyl, amino, Methylamino, ethylamino, methylaminocarbonyl and ethylaminocarbonyl, in which methylaminocarbonyl and ethylaminocarbonyl in turn may be substituted with 1 substituent trifluoromethyl,
  • R 1 is hydrogen or fluorine
  • R 2 is 2-fluorobenzyl, and their salts, solvates and solvates of the salts.
  • Q is a group of the formula
  • D 1 is CR 13 or N
  • R 13 is hydrogen
  • D 2 , D 3 and D 4 are each independently CH,
  • E 1 , E 3 and E 4 are each independently CH,
  • E 2 is CR 14 ,
  • R 14 is chlorine
  • p is a number 0 or 1
  • R 15A is hydrogen or methyl
  • R 15B is hydrogen or methyl
  • R 16A is hydrogen
  • R 16B is hydrogen, R 1 is hydrogen or fluorine, R 2 is 2-fluorobenzyl, and their salts, solvates and solvates of the salts.
  • # is the point of attachment to the pyrazolopyridine, A 2 is O, A 3 is S,
  • R 3 is methyl, cyclopropyl, cyclobutyl or amino
  • R 4 is hydrogen, methyl or ethyl, in which methyl and ethyl may be substituted by 1 or 2 substituents independently of one another selected from the group trifluoromethyl, methoxy, methoxycarbonyl and ethoxycarbonyl, is hydrogen, amino, methoxycarbonylamino or methoxycarbonyl-methylamino is methyl,
  • R io stands for amino
  • R 11 is methylamino
  • R 1 is hydrogen
  • R 2 is 2-fluorobenzyl, and their salts, solvates and solvates of the salts.
  • D 1 , D 2 , D 3 and D 4 are each independently CR 13 or N, wherein
  • R 13 is hydrogen, fluorine, chlorine or methyl, with the proviso that at most one of the groups D 1 , D 2 , D 3 and D 4 is N, E 1 , E 2 , E 3 and E 4 are each independently are CR 14 or N, in which
  • L represents a group * -CR 15A R 15B - (CR 16A R 16B ) P - ** wherein
  • * represents the point of attachment to the group G
  • ** represents the point of attachment to the triazole ring
  • p stands for a number 0 or 1
  • R 15A is hydrogen, fluorine, methyl or hydroxy
  • R 15B is hydrogen, methyl or trifluoromethyl
  • R 15A and R 15B together with the carbon atom to which they are attached form an oxo group, a cyclopropyl, cyclobutyl or cyclopentyl ring or an azetidinyl or oxetanyl ring,
  • R 16A is hydrogen
  • R 16B is hydrogen
  • their salts, solvates and solvates of the salts are hydrogen
  • R 7 is amino, methoxycarbonylamino or methoxycarbonyl-N-methylamino
  • R 8 is methyl or ethyl, and their salts, solvates and solvates of the salts.
  • # is the point of attachment to the pyrazolopyridine, is (Ci-C i) -alkyl, cyclopropyl, cyclobutyl, amino, aminocarbonyl, phenyl or pyridyl, wherein (Ci-C i) -alkyl having 1 or 2 substituents independently selected from the group fluorine, trifluoromethyl, cyclopropyl, cyclobutyl, trifluoromethoxy, (Ci-C i) -alkoxy and pyrrolidin-2-one-l -yl may be substituted, and wherein phenyl and pyridyl having 1 or 2 substituents independently selected from the group Fluorine, methyl, amino and hydroxymethyl, is hydrogen, (Ci-C i) -alkyl or benzyl, wherein (Ci-C i) -alkyl having 1 or 2 substituents independently selected from the group fluorine, trifluoromethyl, Cy
  • R 3 is methyl, cyclopropyl, cyclobutyl or amino, and their salts, solvates and solvates of the salts.
  • R 4 is hydrogen, methyl or ethyl, wherein methyl and ethyl may be substituted with 1 or 2 substituents independently selected from the group trifluoromethyl, methoxy, methoxycarbonyl and ethoxycarbonyl, and their salts, solvates and solvates of the salts.
  • R 7 is amino, methoxycarbonylammo or methoxycarbonyl-N-methylamino
  • R 8 is methyl or ethyl
  • # is the point of attachment to the pyrazolopyridine, A 2 is O, A 3 is S,
  • R 3 is methyl, amino or aminocarbonyl
  • R 4 is hydrogen or methyl, wherein methyl may be substituted with 1 substituent trifluoromethyl
  • R 5 is 2,2,2-trifluoroethyl
  • R 6 is hydrogen or 2,2,2 Trifluoroethyl
  • R 7 is amino, methoxycarbonylamino or methoxycarbonyl-N-methylamino
  • R 8 is methyl
  • R 10 is amino or methoxycarbonylamino
  • R 11 is methylamino
  • their salts, solvates and solvates of the salts
  • # is the point of attachment to the pyrazolopyridine
  • R 5 is 2,2,2-trifluoroethyl
  • R 6 is hydrogen or 2,2,2-trifluoroethyl
  • # is the point of attachment to the pyrazolopyridine, A 2 is O, A 3 is S,
  • R 10 is amino or methoxycarbonylamino
  • R 11 is methylamino
  • their salts, solvates and solvates of the salts are also replaced by residue definitions of other combinations, regardless of the particular combinations of the residues indicated.
  • the invention further provides a process for the preparation of the compounds of the formula (I) according to the invention which comprises reacting a compound of the formula (II)
  • R 3A is (Ci-C 6 ) -alkyl, (C 3 -C 7 ) -cycloalkyl, 4- to 7-membered heterocyclyl, phenyl or pyridyl, wherein (Ci-Ce) alkyl having 1 to 3 substituents independently selected from the group consisting of halogen, difluoromethyl, trifluoromethyl, (C 3 -C 4) -cycloalkyl, di-fluoromethoxy, trifluoromethoxy, (C 1 -C 4) -alkoxy, hydroxycarbonyl, (C 1 -C 4) -alkoxycarbonyl, (C 1 -C 4) -alkoxycarbonylamino , (C 1 -C 4) -alkoxycarbonyl- (C 1 -C 4) -alkylamino, amino, mono- (C 1 -C 4) -alkylamino, di- (C 1 -C 4)
  • R 1 , R 2 and R 3A each have the meanings given above, or
  • T 1 is hydrogen or (C 1 -C 4 ) -alkyl, in an inert solvent with hydrazine carbothioamide to form a compound of formula (IC)
  • R is amino, or a compound of formula (V) in an inert solvent hydrazmcarboximidamide to a compound of formula (I-Dl)
  • R is (C 1 -C 4 ) -alkyl or benzyl, wherein (Ci-C i) alkyl having 1 to 3 substituents independently selected from the group halogen, difluoromethyl, trifluoromethyl, (C3-Cv) -cycloalkyl, di-fluoromethoxy, trifluoromethoxy, (Ci-C i) alkoxy, hydroxycarbonyl , (C 1 -C 4) -alkoxycarbonyl, (C 1 -C 4) -alkoxycarbonylamino, (C 1 -C 4) -alkoxycarbonyl- (C 1 -C 4) -alkylamino, amino, mono- (C 1 -C 4) -alkylamino, di- (C 1 -C 4) -alkylamino, C 4) -alkylamino, amino-carbonyl, mono- (C 1 -C 4) -alkylamino,
  • halogen in particular chlorine or bromine, mesylate or tosylate,
  • R 1 , R 2 , R 3D and R 4D in each case have the meanings given above, or
  • R 7E is amino, cyclized, or [F] a compound of the formula (V) in an inert solvent in the presence of a suitable coupling reagent with a compound of the formula (IX)
  • R, R, D, D, D and D are each as defined above, cyclized, or a compound of the formula (X) in an inert solvent in the presence of a suitable base and hydroxylammonium chloride with a compound of the formula (XII)
  • T 2 is (C 1 -C 4 ) -alkyl, to give a compound of the formula (XIII)
  • R, R 2 and T 2 in each case have the meanings indicated above, and then these in an inert solvent with ammonia compound of the formula (IH)
  • R 1 and R each have the meanings given above, or
  • R 1, R 2 and R 6 are each as defined above, cyclized, or
  • T 3 is hydrogen or (C 1 -C 4 ) -alkyl, in an inert solvent in the presence of a suitable base with or without coupling reagent in a compound of formula (IJ)
  • T 4 is (C 4 -C 9 ) -alkyl, to give a compound of the formula (XX)
  • E 1 , E 2 , E 3 , E 4 , R 1 and R 2 in each case have the meanings given above, and these in the following in an inert solvent in the presence of a suitable acid with sodium nitrite in a compound of formula (IK )
  • E 1 , E 2 , E 3 , E 4 , R 1 and R 2 in each case have the meanings given above, and optionally cleaving protective groups present according to methods known to the person skilled in the art, and / or optionally the resulting compounds of the formula ( IA), (IB), (IC), (I-D1), (I-D2), (IE) (IF), (IG), (IH), (II), (IJ) and (IK) optionally with the appropriate (i) solvents and / or (ii) acids or bases in their solvates, salts and / or solvates of the salts.
  • the compounds of the formula (IA), (IB), (IC), (I-D1), (I-D2), (IE) (IF), (IG), (IH), (II), (IJ) and (IK) belong to the group of the compound of the formula (I) according to the invention.
  • Inert solvents for the reaction (II) + (III) - > (IA) are, for example, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, ethers such as diethyl ether, dioxane, tetrahydrofuran, Glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbon Substances such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as dimethylformamide (DMF), dimethyl sulfoxide (DMSO), NN'-dimethylpropyleneurea (DMPU), dimethylacetamide, N-methylpyrrolidone (NMP), pyridine, acetonitrile or sulfolane. It is likewise possible to use mixtures of the solvents mentioned. Preferred is DMSO
  • Suitable bases for process step (II) + (III) -> (I-A) are the customary inorganic or organic bases. These include preferably alkali metal hydroxides such as lithium, sodium or potassium hydroxide, alkali metal or alkaline earth metal carbonates such as lithium, sodium, potassium, calcium or cesium carbonate, alkali alcoholates such as sodium or potassium, sodium or potassium or sodium or Potassium tert-butoxide, alkali metal hydrides such as sodium or potassium hydride or amides such as sodium amide, lithium or potassium bis (trimethylsilyl) amide or lithium diisopropylamide. Cesium carbonate is preferably used.
  • alkali metal hydroxides such as lithium, sodium or potassium hydroxide
  • alkali metal or alkaline earth metal carbonates such as lithium, sodium, potassium, calcium or cesium carbonate
  • alkali alcoholates such as sodium or potassium, sodium or potassium or sodium or Potassium tert-butoxide
  • alkali metal hydrides such as sodium
  • Suitable copper (I) species for the process step (II) + (III) -> ⁇ (IA) are inorganic copper (I) salts such as copper (I) bromide or copper (I) iodide , see also Nagasawa, H. et al, J. Am. Chem. Soc. 2009, 131, 15080-15081.
  • the reaction (II) + (III) -> (IA) is generally carried out in a temperature range from + 80 ° C to + 180 ° C, preferably at + 100 ° C to + 150 ° C, optionally in a microwave.
  • the reaction can be carried out at normal, elevated or at reduced pressure (for example from 0.5 to 5 bar). Generally, one works at normal pressure.
  • Inert solvents for process step (II) + (IV) -> ⁇ (IB) are for example ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as Dimethylformamide (DMF), dimethyl sulfoxide (DMSO), NN'-dimethyl propyleneurea (DMPU), dimethylacetamide, N-methylpyrrolidone ( ⁇ ), pyridine, acetonitrile or sulfolane. It is likewise possible to use mixtures of the solvents mentioned. Preferred is DMF.
  • Suitable bases for the reaction (II) + (IV) -> ⁇ (IB) are the usual inorganic or organic bases. These include preferably alkali metal hydroxides such as, for example, lithium, sodium or potassium hydroxide, alkali metal or alkaline earth metal carbonates such as lithium, sodium, potassium, calcium or cesium carbonate, alkali metal alcoholates such as sodium or potassium methoxide, sodium or potassium ethoxide or sodium or potassium hydroxide.
  • alkali metal hydroxides such as, for example, lithium, sodium or potassium hydroxide
  • alkali metal or alkaline earth metal carbonates such as lithium, sodium, potassium, calcium or cesium carbonate
  • alkali metal alcoholates such as sodium or potassium methoxide, sodium or potassium ethoxide or sodium or potassium hydroxide.
  • alkali metal hydrides such as sodium or potassium hydride
  • amides such as sodium amide, lithium, sodium or potassium bis (trimethylsilyl) amide or lithium diisopropylamide
  • organic amines such as triethylamine, N-methylmorpholine, N- Methylpiperidine, N, N-diisopropylethylamine, pyridine, l, 5-diazabicyclo [4.3.0] non-5-ene (DBN), 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) or l, 4- diazabicyclo [2.2.2] octane (DABCO ®).
  • DBN non-5-ene
  • DBU 1,8-diazabicyclo [5.4.0] undec-7-ene
  • DBU 4- diazabicyclo [2.2.2] octane
  • reaction (II) + (IV) -> (IB) may optionally be carried out in the presence of a dialkyl azodicarboxylate such as azodiethylodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), di-tert-butyl azodicarboxylate, NNN'N'- Tetramethylazodicarboxamide (TMAD), 1 '- (azodicarbonyl) -dipiperidine (ADDP) or 4,7-dimethyl-3,5,7-hexahydro-l, 2,4,7-tetrazocine-3,8-dione (DHTD ).
  • a dialkyl azodicarboxylate such as azodiethylodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), di-tert-butyl azodicarboxylate, NNN'N'- Tetramethylazodicarboxamide (TMAD), 1
  • the reaction (II) + (IV) -> (I-B) is generally carried out in a temperature range of -20 ° C to + 80 ° C, preferably at + 10 ° C to + 40 ° C, optionally in a microwave.
  • the reaction may be carried out at normal, elevated or reduced pressure (e.g., from 0.5 to 5 bar). Generally, one works at normal pressure.
  • Inert solvents for the reactions (V) - » ⁇ (IC) and (V) -» ⁇ (I-Dl) are alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, ethers such as Diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N, N'-dimethylpropyleneurea (DMPU), dimethylacetamide, N-methylpyrrolidone ( ⁇ ), pyridine, acetonitrile or sulfolane. It is likewise possible to use mixtures of the solvents mentioned. Preference
  • Suitable bases are alkali metal hydroxides such as lithium, sodium or potassium hydroxide, alkali metal or alkaline earth metal carbonates such as lithium, sodium, potassium, calcium or cesium carbonate, alkali metal alcoholates such as sodium or potassium, sodium or potassium or sodium or Potassium tert-butylate, alkali metal hydrides such as sodium or potassium hydride, amides such as sodium amide, lithium, sodium or potassium bis (trimethylsilyl) amide or lithium diisopropylamide, or organic amines such as triethylamine, N-methylmorpholine, N-methylpiperidine, NN Diisopropylethylamine, pyridine, 1,5-diazabicyclo [4.3.0] non-5-ene (DBN), l, 8-diazabicyclo [5.4.0] undec
  • alkali metal hydroxides such as lithium, sodium or potassium hydroxide
  • alkali metal or alkaline earth metal carbonates such as lithium, sodium, potassium, calcium
  • Suitable coupling reagents are, for example, carbodiimides such as N, N'-diethyl, NN'-dipropyl, N, N'-diisopropyl, N, N'-dicyclo- hexylcarbodiimide (DCC) or N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride (EDC), phosgene derivatives such as NN'-carbonyldiimidazole (CDI), 1,2-oxazolium compounds such as 2-ethyl-5-phenyl-1 , 2-oxazolium-3-sulphate or 2-ferric-butyl-5-methylisoxazolium perchlorate, acylamin
  • the reactions (V) -> (IC) and (V) -> (I-Dl) are generally in a temperature range from 0 ° C to + 120 ° C, preferably at + 10 ° C to + 80 ° C, optionally in a microwave, performed.
  • the reaction can be carried out at normal, elevated or at reduced pressure (for example from 0.5 to 5 bar). Generally, one works at normal pressure
  • Inert solvents for the reactions (V) - > (VII) and (I-Dl) + (VI) - > ⁇ (I-D2) are ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, xylene , Toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as dimethylformamide (DMF), dimethyl sulfoxide (DMSO), NN'-dimethyl propyleneurea (DMPU), dimethylacetamide, N-methylpyrrolidone (NMP), pyridine, acetonitrile, or sulfolane. It is likewise possible to use mixtures of the solvents mentioned. Preference is given to tetrahydrofuran or DMF.
  • Suitable bases for the reactions (V) - > (VII) and (I-Dl) + (VI) - > ⁇ (I-D2) are the usual inorganic or organic bases. These include preferably alkali metal hydroxides such as lithium, sodium or potassium hydroxide, alkali metal or alkaline earth metal carbonates such as lithium, sodium, potassium, calcium or cesium carbonate, alkali alcoholates such as sodium or potassium, sodium or potassium or sodium or Potassium tert-butoxide, alkali metal hydrides such as sodium or potassium hydride, amides such as sodium amide, lithium, sodium or potassium bis (trimethylsilyl) amide or lithium diisopropylamide, or organic amines such as triethylamine, N-methylmorpholine, N-methylpiperidine, NN Diisopropylethylamine, pyridine, 1,5- Diazabicyclo [4.3.0] non-5-ene (DBN), l, 8-diazabicyclo [5.4.0
  • the reactions (V) -> (VII) and (I-Dl) + (VI) -> (I-D2) are generally carried out in a temperature range of -78 ° C to + 100 ° C.
  • the reaction (V) -> (VII) is preferably carried out generally in a temperature range of -78 ° C to + 20 ° C.
  • the reaction (I-Dl) + (VI) -> (TD2) is generally carried out in a temperature range of + 50 ° C to + 80 ° C.
  • the reactions may be at normal, elevated or reduced pressure (e.g., from 0.5 to 5 bar). Generally, one works at normal pressure.
  • Inert solvents for the cyclization (VII) + (VIII) - > ⁇ (IE) are alcohols, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol or n-pentanol, ethers, such as diethyl ether, Dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as dimethylformamide (DMF), dimethylsulfoxide (DMSO), NN'-dimethylpropyleneurea (DMPU), dimethylacetamide, N-methylpyrrolidone ( ⁇ ), pyridine, acetonitrile or sulfolane.
  • alcohols such as methanol, ethanol, n
  • reaction (VII) + (VIII) -> (IE) is generally carried out in a temperature range of + 50 ° C to + 160 ° C, preferably carried out in a temperature range of + 100 ° C to + 150 ° C.
  • the reaction can be carried out at normal, elevated or at reduced pressure (for example from 0.5 to 5 bar). Generally, one works at normal pressure.
  • Suitable Kupplungsreagezien for implementation (V) + (IX) - » ⁇ (IF) include carbonyl diimides such as N, N'-diethyl, N, N'-dipropyl, N, N'-diisopropyl, N, N'-dicyclohexylcarbodiimide (DCC ) or N- (3-dimethylaminoisopropyl) -N'-ethylcarbodiimide hydrochloride (EDC), phosgene derivatives such as NN'-carbonyldiimidazole (CDI), 1, 2-oxazolium compounds such as 2-ethyl-5-phenyl-1, 2 oxazolium-3-sulphate or 2-tert.-butyl-5-methylisoxazolium perchlorate, acylamino compounds such as 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, or isobutyl chloroformate, propane
  • Suitable bases for the reaction (V) + (IX) -> ⁇ (IF) are the usual inorganic or organic bases. These include preferably alkali metal hydroxides such as, for example, lithium, sodium or potassium hydroxide, alkali metal or alkaline earth metal carbonates such as lithium, sodium, potassium, calcium or cesium carbonate, alkali alcoholates such as sodium or potassium methoxide, sodium or potassium ethanolate or sodium or potassium hydroxide.
  • alkali metal hydroxides such as, for example, lithium, sodium or potassium hydroxide
  • alkali metal or alkaline earth metal carbonates such as lithium, sodium, potassium, calcium or cesium carbonate
  • alkali alcoholates such as sodium or potassium methoxide, sodium or potassium ethanolate or sodium or potassium hydroxide.
  • alkali metal hydrides such as sodium or potassium hydride
  • amides such as sodium amide, lithium, sodium or potassium bis (trimethylsilyl) amide or lithium diisopropylamide
  • organic amines such as triethylamine, N-methylmorpholine, N-methylpiperidine, N, N-diisopropylethylamine, Pyridine, l, 5-diazabicyclo [4.3.0] non-5-ene (DBN), 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) or l, 4-diazabicyclo [2.2.2] octane (DABCO ®).
  • DBN non-5-ene
  • DBU 1,8-diazabicyclo [5.4.0] undec-7-ene
  • DBU 4-diazabicyclo [2.2.2] octane
  • Benzotriazol-1-yloxy-tris (pyrrolidino) phosphonium hexafluorophosphate (PyBOP) is preferably used in combination with N, N-diisopropylethylamine.
  • the reaction (V) + (IX) -> (I-F) is generally carried out in a temperature range of 0 ° C to + 140 ° C, preferably carried out in a temperature range of + 20 ° C to + 120 ° C.
  • the reaction may be carried out at normal, elevated or reduced pressure (e.g., from 0.5 to 5 bar). Generally, one works at normal pressure.
  • Inert solvents are alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol or 1, 2-ethanediol, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, Trichlorethylene, chlorobenzene or 1, 2-dichlorobenzene, hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, or other solvents such as acetone, methyl ethyl ketone, ethyl acetate,
  • reaction (X) + (XI) -> (IG) is generally carried out in a temperature range from + 50 ° C to + 200 ° C, preferably from + 100 ° C to + 160 ° C.
  • the reaction can be carried out at normal or elevated pressure (for example in the range from 0.5 to 5 bar). Generally one works at elevated pressure or normal pressure.
  • the reaction (X) + (XI) -> (IG) takes place in the presence of a suitable copper species such as, for example, copper (I) chloride, copper (I) bromide, copper (I) iodide, copper ( II) bromide, copper (II) iodide or copper (II) acetate, with the addition of 3,4,7,8-tetramethyl-l, 10-phenanthroline and zinc (II) iodide, see also Nagasawa, H. et al, J. Am. Chem. Soc. 2009, 131, 15080-15081.
  • a suitable copper species such as, for example, copper (I) chloride, copper (I) bromide, copper (I) iodide, copper ( II) bromide, copper (II) iodide or copper (II) acetate, with the addition of 3,4,7,8-tetramethyl-l, 10-phenanthroline and zinc (II) iodide,
  • reaction (X) + (XII) -> (XIII) proceeds in a one-pot variant initially with the formation of the hydroxyimidamide, followed by reaction with the compound (XII) to give the 1,2,4-oxadiazole.
  • the formation of the Hydroxyimidamids takes place in an inert solvent such as alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol or 1,2-ethanediol, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, or other solvents such as acetone, methyl ethyl ketone, ethyl acetate, acetonitrile, N, N-dimethylformamide, dimethyl sulfoxide, N, N-dimethylpropyleneurea (DMPU), N-methylpyrrolidone (II), sulfolane or pyridine, preferably in ethanol.
  • alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol,
  • Suitable bases for the formation of the Hydroxyimidamids are the usual inorganic or organic bases. These include preferably alkali metal or alkaline earth metal carbonates, such as lithium, sodium, potassium, calcium or cesium carbonate, alkali metal alcoholates, such as sodium or potassium methoxide, sodium or potassium ethoxide or sodium or potassium tert-butoxide. Preference is given to potassium carbonate.
  • alkali metal or alkaline earth metal carbonates such as lithium, sodium, potassium, calcium or cesium carbonate
  • alkali metal alcoholates such as sodium or potassium methoxide, sodium or potassium ethoxide or sodium or potassium tert-butoxide. Preference is given to potassium carbonate.
  • Hydroxyimidamids generally takes place at a temperature of + 50 ° C to + 120 ° C.
  • the conversion of the carboxylic acid ester (XIII) into the amide (IH) is carried out under the conditions known to the person skilled in the art, for example with ammonia in ethanol at a temperature of + 40 ° C. to + 80 ° C., optionally in a microwave.
  • the reaction (XIV) - > (XV) takes place in a solvent which is inert under the reaction conditions.
  • Inert solvents are alcohols, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol or 1,2-ethanediol, ethers, such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, halohydrocarbons, such as dichloromethane, trichloromethane, Tetrachloromethane, trichlorethylene, chlorobenzene or 1, 2-dichlorobenzene, hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, or other solvents such as acetone, methyl ethyl ketone, ethyl acetate, acetonitrile, N, N-dimethylformamide, dimethyl sulfoxide, N,
  • Suitable bases for this reaction are the usual inorganic or organic bases. These include preferably alkali metal hydroxides such as lithium, sodium or potassium hydroxide, Alkalioder Erdalkalicarbonate such as lithium, sodium, potassium, calcium or cesium carbonate, alkali alcoholates such as sodium or potassium, sodium or potassium or sodium or potassium tert.
  • alkali metal hydroxides such as lithium, sodium or potassium hydroxide
  • Alkalioder Erdalkalicarbonate such as lithium, sodium, potassium, calcium or cesium carbonate
  • alkali alcoholates such as sodium or potassium, sodium or potassium or sodium or potassium tert.
  • alkali metal hydrides such as sodium or potassium hydride
  • amides such as sodium amide, lithium, sodium or potassium bis (trimethylsilyl) amide or lithium diisopropylamide
  • organic amines such as triethylamine, N-methylmorpholine, N-methylpiperidine, N, N-diisopropylethylamine, Pyridine, l, 5-diazabicyclo [4.3.0] non-5-ene (DBN), 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) or l, 4-diazabicyclo [2.2.2] octane (DABCO ®).
  • triethylamine is used.
  • the process step (XIV) -> (XV) is carried out in the presence of a suitable palladium and / or copper catalyst.
  • a suitable palladium catalyst for example, palladium on activated carbon, palladium (II) acetate, tetrakis (triphenylphosphine) palladium (0), bis (triphenylphosphine) palladium (II) chloride, bis (acetonitrile) palladium (II ) chloride and [ ⁇ , - bis (diphenylphosphino) ferrocene] dichloropalladium (II) -dichloromethane complex, optionally in combination with additional phosphine ligands such as (2-biphenyl) di-tert.
  • Suitable copper catalysts are, for example, copper bronze, copper (I) iodide or copper (I) bromide.
  • reaction (XIV) -> (XV) is generally carried out in a temperature range from + 20 ° C to + 180 ° C, preferably at + 50 ° C to + 120 ° C, optionally in a microwave.
  • the reaction can be carried out at normal, elevated or at reduced pressure (for example from 0.5 to 5 bar). Generally, one works at normal pressure.
  • the process step (XV) -> (XVI) takes place in a solvent which is inert under the reaction conditions.
  • Inert solvents are alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol or 1, 2-ethanediol, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, Trichlorethylene, chlorobenzene or 1, 2-dichlorobenzene, hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, or other solvents such as acetone, methyl ethyl ketone, ethyl acetate, acetonitrile, N, N-dimethylformamide, dimethyl sulfoxide, N, N-d
  • the reaction (XV) -> (XVI) takes place in the presence of a suitable base.
  • Suitable bases for this reaction are the usual inorganic or organic bases. These include preferably alkali metal hydroxides such as, for example, lithium, sodium or potassium hydroxide, alkalis or alkaline earth metal carbonates such as lithium, sodium, potassium, calcium or cesium carbonate, alkali alcoholates such as sodium or potassium methoxide, sodium or potassium ethoxide or sodium or potassium hydroxide.
  • alkali metal hydrides such as sodium or potassium hydride
  • amides such as sodium amide, lithium, sodium or potassium bis (trimethylsilyl) amide or lithium diisopropylamide
  • organic amines such as triethylamine, N-methylmorpholine, N-methylpiperidine, NN- Diisopropylethylamine, pyridine, 1,5-diazabicyclo [4.3.0] non-5-ene (DBN), 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) or 1,4-diazabicyclo [2.2. 2] octane (DABCO ®).
  • potassium carbonate is used.
  • the reaction (XV) -> (XVI) is generally carried out in a temperature range from + 0 ° C to + 80 ° C, preferably at + 20 ° C to + 50 ° C, optionally in a microwave.
  • the reaction can be carried out at normal, elevated or at reduced pressure (for example from 0.5 to 5 bar). Generally, one works at normal pressure.
  • the cyclization (XVI) - > (II) takes place in a solvent which is inert under the reaction conditions.
  • Inert solvents are alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol or 1, 2-ethanediol, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, Trichlorethylene, chlorine benzene or 1, 2-dichlorobenzene, hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, or other solvents such as acetone, methyl ethyl ketone, ethyl acetate, acetonitrile, N, N-dimethylformamide, dimethyl sulfoxide, N, N-d
  • the cyclization (XVI) - » ⁇ (II) is carried out under copper-catalyzed conditions, preferably using copper (II) sulfate pentahydrate and sodium ascorbate [see. eg Sharpless B. et al., Angew. Chem. Int. Ed. 2002, Vol. 41, 14, 2596-2599].
  • the reaction (XVI) -> (II) is generally carried out in a temperature range of + 0 ° C to + 80 ° C, preferably at + 20 ° C to + 50 ° C, optionally in a microwave.
  • the reaction can be carried out at normal, elevated or at reduced pressure (for example from 0.5 to 5 bar). Generally, one works at normal pressure.
  • Inert solvents for the reaction (I-D2-1) -> (IJ) are alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N, N'-dimethylpropyleneurea (DMPU), dimethylacetamide, N-methylpyrrolidone (II), Pyridine, acetonitrile or sulfolane. It is likewise possible to use mixtures of the solvents mentioned. Preferred is DMSO or DMF.
  • Suitable bases are alkali metal hydroxides such as, for example, lithium, sodium or potassium hydroxide, alkali metal or alkaline earth metal carbonates such as lithium, sodium, potassium, calcium or cesium carbonate, alkali alcoholates such as sodium or potassium methoxide, sodium or potassium ethanolate or sodium or potassium hydroxide.
  • alkali metal hydrides such as sodium or potassium hydride
  • amides such as sodium amide, lithium, sodium or potassium bis (trimethylsilyl) amide or lithium diisopropylamide
  • organic amines such as triethylamine, N-methylmorpholine, N-methylpiperidine, N, N-diisopropylethylamine, Pyridine, l, 5-diazabicyclo [4.3.0] non-5-ene (DBN), 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU) or l, 4-diazabicyclo [2.2.2] octane (DABCO ®).
  • DBU 1-diazabicyclo [4.3.0] non-5-ene
  • DBU 1, 8-diazabicyclo [5.4.0] undec-7-ene
  • l 4-diazabicyclo [2.2.2] octane
  • DBU 4-diazabicyclo [2.2.2]
  • Suitable coupling reagents are, for example, carbodiimides such as NN'-diethyl, NN'-dipropyl, NN-diisopropyl, NN'-dicyclohexylcarbodiimide (DCC) or N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride (EDC), phosgene derivatives such as NN'-carbonyldiimidazole (CDI), 1,2-oxazolium compounds such as 2-ethyl-5-phenyl-1, 2-oxazolium-3-sulphate or 2-ferric-butyl-5-methylisoxazolium perchlorate, acylamino compounds such as 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline
  • the reaction (I-D2-1) -> (I-J) are generally carried out in a temperature range from + 50 ° C to + 180 ° C, preferably at + 100 ° C to + 150 ° C, optionally in a microwave.
  • the reaction may be carried out at normal, elevated or reduced pressure (e.g., from 0.5 to 5 bar). Generally, one works at normal pressure
  • Inert solvents are alcohols, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol or 1,2-ethanediol, ethers, such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, halohydrocarbons, such as dichloromethane, trichloromethane, Tetrachloromethane, trichlorethylene, chlorobenzene or 1, 2-dichlorobenzene, hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, or other solvents such as acetone, methyl ethyl, ethers, such as ethersulfate, n-propanol, isopropanol, n-butanol, tert
  • Suitable Lewis acids for process step (XVII) + (XVIII) + (XIX) -> (XX) are boron trifluoride-diethyl ether complex, cerium (IV) ammonium nitrate (CAN), tin (II) chloride, lithium Perchlorate, zinc (II) chloride, indium (III) chloride, indium (III) bromide or Scaniumtrifluormethan- sulfonate.
  • scium trifluoromethanesulfonate is used.
  • the reaction (XVII) + (XVIII) + (XIX) -> (XX) is generally in a temperature range from 0 ° C to + 80 ° C, preferably at + 20 ° C to + 50 ° C, optionally in a microwave , carried out.
  • the reaction may be carried out at normal, elevated or reduced pressure (e.g., from 0.5 to 5 bar). Generally, one works at normal pressure
  • the cleavage of the group T 4 in process step (XX) -> (XXI) is carried out by the methods known in the art, for example using trifluoroacetic acid in dichloromethane at a temperature of 0 ° C to + 40 ° C.
  • Suitable acids for the reaction (XXI) - » ⁇ (IK) are, for example, inorganic acids such as hydrochloric acid / hydrochloric acid, sulfuric acid or phosphoric acid and organic acids such as methanesulfonic acid, toluenesulfonic acid or trifluoroacetic acid.
  • Inert solvents for the reaction (XXI) - » ⁇ (IK) are, for example, water or alcohols such as methanol, ethanol, n-propanol or z o-propanol, or mixtures of solvents.
  • reaction (XXI) -> (I-K) is preferably carried out in a temperature range from 0 ° C to + 40 ° C.
  • the compound of the formula (XXII) is known from the literature [cf. e.g. Winn M., J. Med. Chem. 1993, 36, 2676-7688; EP 634 413-A1; CN 1613849-A; EP 1626045-A1; WO 2009/018415] or can be prepared analogously to processes known from the literature.
  • the compound of the formula (XVII) can be prepared by methods known to those skilled in the art starting from compounds of the formula (V) (see also Examples 17A and 18A of the present experimental part).
  • the compounds of the invention act as potent stimulators of soluble guanylate cyclase, have valuable pharmacological properties, and are therefore suitable for the treatment and / or prophylaxis of diseases in humans and animals.
  • the compounds according to the invention have the same or improved physicochemical and / or therapeutic profile.
  • the compounds according to the invention have valuable pharmacological properties and can be used for the prevention and treatment of diseases in humans and animals.
  • the compounds according to the invention open up a further treatment alternative and thus represent an enrichment of pharmacy.
  • the compounds of the invention cause vasorelaxation and inhibition of platelet aggregation and lead to a reduction in blood pressure and to an increase in coronary blood flow. These effects are mediated by direct stimulation of soluble guanylate cyclase and intracellular cGMP increase.
  • the compounds of the invention potentiate the action of cGMP level enhancing substances such as endothelium-derived relaxing factor (EDRF), NO donors, protoporphyrin IX, arachidonic acid or phenylhydrazine derivatives.
  • the compounds according to the invention are suitable for the treatment and / or prophylaxis of cardiovascular, pulmonary, thromboembolic and fibrotic disorders.
  • the compounds according to the invention can therefore be used in medicaments for the treatment and / or prophylaxis of cardiovascular diseases such as hypertension, resistant hypertension, acute and chronic heart failure, coronary heart disease, stable and unstable angina pectoris, peripheral and cardiac vascular diseases, arrhythmias, atrial arrhythmias and ventricular dysfunctions such as atrial-ventricular blockades grade I-III (AB blockill), supraventricular tachyarrhythmia, atrial fibrillation, atrial flutter, ventricular fibrillation, ventricular tachyarrhythmia, torsade de pointes tachycardia, atrial and ventricular extrasystoles, AV -junctional extrasystoles, sick sinus syndrome, syncope, AV nodal reentry tachycardia, Wolff-Parkinson-White syndrome, acute coronary syndrome (ACS), autoimmune heart disease (pericarditis, endocarditis, valvolitis, aortitis, cardiomyopathy), shock
  • cardiac failure includes both acute and chronic manifestations of cardiac insufficiency, as well as more specific or related forms of disease such as acute decompensated heart failure, right heart failure, left heart failure, global insufficiency, ischemic cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, idiopathic cardiomyopathy, congenital heart defects.
  • heart failure heart valve defects mitral valve stenosis, mitral valve insufficiency, aortic valve stenosis, aortic regurgitation, tricuspid stenosis, tricuspid insufficiency, pulmonary valve stenosis, pulmonary valve, combined heart valve defects, heart muscle inflammation (myocarditis), chronic myocarditis, acute myocarditis, viral myocarditis, diabetic cardiac insufficiency, alcohol-toxic cardiomyopathy, cardiac storage diseases, diastolic cardiac insufficiency and systolic Heart failure and acute phases of Worsening of an existing chronic heart failure.
  • myocarditis myocarditis
  • chronic myocarditis chronic myocarditis
  • acute myocarditis viral myocarditis
  • diabetic cardiac insufficiency diabetic cardiac insufficiency
  • alcohol-toxic cardiomyopathy cardiac storage diseases
  • the compounds according to the invention may also be used for the treatment and / or prophylaxis of arteriosclerosis, lipid metabolism disorders, hypolipoproteinemias, dyslipidaemias, hypertriglyceridemias, hyperlipidemias, hypercholesterolemias, abetelipoproteinemia, sitosterolemia, xanthomatosis, Tangier's disease, obesity (obesity) and obesity combined hyperlipidaemias and the metabolic syndrome.
  • the compounds of the invention may be used for the treatment and / or prophylaxis of primary and secondary Raynaud's phenomenon, microcirculatory disorders, claudication, peripheral and autonomic neuropathies, diabetic microangiopathies, diabetic retinopathy, diabetic ulcers on the extremities, gangrenous, CREST syndrome, erythematosis, onychomycosis , rheumatic diseases and to promote wound healing.
  • the compounds according to the invention are suitable for the treatment of urological diseases such as benign prostatic syndrome (BPS), benign prostatic hyperplasia (BPH), benign prostate enlargement (BPE), bladder emptying disorder (BOO), lower urinary tract syndromes (LUTS, including Feiine's urological syndrome ( FUS)), diseases urogenital system including neurogenic overactive bladder (OAB) and (IC), incontinence (UI) such as mixed, urgency, stress, or overflow incontinence (MUI, UUI, SUI, OUI), pelvic pain, benign and malignant Diseases of the organs of the male and female urogenital system.
  • BPS benign prostatic syndrome
  • BPH benign prostatic hyperplasia
  • BPE benign prostate enlargement
  • BOO bladder emptying disorder
  • LUTS lower urinary tract syndromes
  • FUS Feiine's urological syndrome
  • UI incontinence
  • MUI UUI, SUI, OUI
  • pelvic pain benign and malignant Diseases of the organ
  • kidney diseases in particular of acute and chronic renal insufficiency, as well as of acute and chronic renal failure.
  • renal insufficiency includes both acute and chronic manifestations of renal insufficiency, as well as underlying or related renal diseases such as renal hypoperfusion, intradialytic hypotension, obstructive uropathy, glomerulopathies, glomerulonephritis, acute glomerulonephritis, glomerulosclerosis, tubulointerstitial disorders, nephropathic disorders such as primary and congenital kidney disease, nephritis, immunological kidney diseases such as renal transplant rejection, immune complex-induced kidney disease, nephropathy induced by toxic substances, contrast agent-induced nephropathy, diabetic and nondiabetic nephropathy, pyelonephritis, renal cysts, nephrosclerosis, hypertensive
  • the present invention also encompasses the use of the compounds of the invention for the treatment and / or prophylaxis of sequelae of renal insufficiency, such as pulmonary edema, heart failure, uremia, anemia, electrolyte imbalances (eg, hyperkalemia, hyponatremia) and disorders in bone and carbohydrate metabolism.
  • sequelae of renal insufficiency such as pulmonary edema, heart failure, uremia, anemia, electrolyte imbalances (eg, hyperkalemia, hyponatremia) and disorders in bone and carbohydrate metabolism.
  • the compounds according to the invention are also suitable for the treatment and / or prophylaxis of asthmatic diseases, pulmonary arterial hypertension (PAH) and other forms of pulmonary hypertension (PH), including left heart disease, HIV, sickle cell anemia, thromboembolism (CTEPH), sarcoidosis, COPD or Pulmonary fibrosis-associated pulmonary hypertension, chronic obstructive pulmonary disease (COPD), acute respiratory tract syndrome (ARDS), acute lung injury (ALI), alpha-1-antitrypsin deficiency (AATD), pulmonary fibrosis, pulmonary emphysema (eg, cigarette smoke-induced Pulmonary emphysema) and cystic fibrosis (CF).
  • PAH pulmonary arterial hypertension
  • PH pulmonary hypertension
  • COPD chronic obstructive pulmonary disease
  • ARDS acute respiratory tract syndrome
  • ALI acute lung injury
  • AATD alpha-1-antitrypsin deficiency
  • CF
  • the compounds described in the present invention are also agents for controlling diseases in the central nervous system, which are characterized by disorders of the NO / cGMP system.
  • they are suitable for improving the perception, concentration performance, learning performance or memory performance after cognitive disorders such as occur in situations / diseases / syndromes such as mild cognitive impairment, age-associated learning and memory disorders, age-associated memory loss, vascular dementia, cranial brain -Trauma, stroke, post-stroke dementia, post-traumatic traumatic brain injury, general attention deficit disorder, impaired concentration in children with learning and memory problems, Alzheimer's disease, dementia with Lewy Corpuscles, dementia with degeneration of the frontal lobes including Pick's syndrome, Parkinson's disease, progressive nuclear palsy, dementia with corticobasal degeneration, amyolateral sclerosis (ALS), Huntington's disease, demyelinization, multiple sclerosis, thalamic degeneration, Creutzfeld-Jacob's disease demen z, HIV dementia, schizophrenia with dementia or Korsakoff's psychosis
  • the compounds according to the invention are also suitable for regulating cerebral blood flow and are effective agents for combating migraine. They are also suitable for the prophylaxis and control of the consequences of cerebral infarct events (Apoplexia cerebri) such as stroke, cerebral ischaemias and craniocerebral trauma , Likewise, the compounds of the invention can be used to combat pain and tinnitus.
  • the compounds of the invention have anti-inflammatory action and can therefore be used as anti-inflammatory agents for the treatment and / or prophylaxis of sepsis (SIRS), multiple organ failure (MODS, MOF), inflammatory diseases of the kidney, chronic inflammatory bowel disease (IBD, Crohn's Disease, UC), pancreatitis , Peritonitis, rheumatoid diseases, inflammatory skin diseases as well as inflammatory eye diseases.
  • SIRS sepsis
  • MODS multiple organ failure
  • IBD chronic inflammatory bowel disease
  • UC chronic inflammatory bowel disease
  • pancreatitis atitis
  • Peritonitis rheumatoid diseases
  • inflammatory skin diseases as well as inflammatory eye diseases.
  • the compounds of the invention can also be used for the treatment and / or prophylaxis of autoimmune diseases.
  • fibrotic disorders encompasses in particular the following terms: liver fibrosis, cirrhosis of the liver, pulmonary fibrosis, endomyocardial fibrosis, nephropathy, glomerulonephritis, interstitial renal fibrosis, fibrotic damage as a result of diabetes, bone marrow fibrosis and similar fibrotic disorders, scleroderma, morphea, keloids, hypertrophic scarring (also after surgical procedures), nevi, diabetic retinopathy, proliferative vitroretinopathy and connective tissue disorders (eg sarcoidosis).
  • the compounds of the invention are useful for controlling postoperative scarring, e.g. as a result of glaucoma surgery.
  • the compounds according to the invention can likewise be used cosmetically for aging and keratinizing skin.
  • the compounds according to the invention are suitable for the treatment and / or prophylaxis of hepatitis, neoplasm, osteoporosis, glaucoma and gastroparesis.
  • Another object of the present invention is the use of the compounds of the invention for the treatment and / or prophylaxis of diseases, in particular the aforementioned diseases.
  • the present invention further relates to the use of the compounds according to the invention for the treatment and / or prophylaxis of cardiac insufficiency, angina pectoris, hypertension, pulmonary hypertension, ischaemias, vascular disorders, renal insufficiency, thromboembolic disorders, fibrotic disorders and atherosclerosis.
  • the present invention furthermore relates to the compounds according to the invention for use in a method for the treatment and / or prophylaxis of cardiac insufficiency, angina pectoris, hypertension, pulmonary hypertension, ischaemias, vascular disorders, renal insufficiency, thromboembolic disorders, fibrotic disorders and atherosclerosis.
  • Another object of the present invention is the use of the compounds of the invention for the manufacture of a medicament for the treatment and / or prophylaxis of diseases, in particular the aforementioned diseases.
  • Another object of the present invention is the use of the compounds of the invention for the manufacture of a medicament for the treatment and / or prophylaxis of heart failure, angina pectoris, hypertension, pulmonary hypertension, ischemia, vascular diseases, Renal insufficiency, thromboembolic disorders, fibrotic diseases and arteriosclerosis.
  • Another object of the present invention is a method for the treatment and / or prophylaxis of diseases, in particular the aforementioned diseases, using an effective amount of at least one of the compounds of the invention.
  • the present invention further provides a method for the treatment and / or prophylaxis of cardiac insufficiency, angina pectoris, hypertension, pulmonary hypertension, ischaemias, vascular diseases, renal insufficiency, thromboembolic disorders, fibrotic diseases and atherosclerosis, using an effective amount of at least one of the compounds according to the invention ,
  • the compounds of the invention may be used alone or as needed in combination with other agents.
  • Another object of the present invention are pharmaceutical compositions containing at least one of the compounds of the invention and one or more other active ingredients, in particular for the treatment and / or prophylaxis of the aforementioned diseases.
  • suitable combination active ingredients may be mentioned by way of example and preferably:
  • organic nitrates and NO donors such as sodium nitroprusside, nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, molsidomine or SIN-1, and inhaled NO; and or
  • cGMP cyclic guanosine monophosphate
  • PDE phosphodiesterases
  • sildenafil, vardenafil and tadalafil Compounds which inhibit the degradation of cyclic guanosine monophosphate (cGMP), such as inhibitors of phosphodiesterases (PDE) 1, 2 and / or 5, in particular PDE 5 inhibitors such as sildenafil, vardenafil and tadalafil; and or
  • Antithrombotic agents by way of example and preferably from the group of platelet aggregation inhibitors, anticoagulants or profibrinolytic substances; and or
  • Antihypertensive agents by way of example and preferably from the group of calcium antagonists, angiotensin AII antagonists, ACE inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor blockers, beta-receptor blockers, mineralocorticid Receptor antagonists, neutral endopeptidase (NEP) inhibitors and combinations of these groups and diuretics; and or
  • lipid metabolism-altering agents by way of example and preferably from the group of thyroid receptor agonists, cholesterol synthesis inhibitors, by way of example and by preference HMG-CoA reductase or squalene synthesis inhibitors, ACAT inhibitors, CETP inhibitors, MTP inhibitors, PPAR-alpha, PPAR-gamma and / or PPAR-delta agonists, cholesterol absorption inhibitors, lipase inhibitors , polymeric bile acid adsorber, bile acid reabsorption inhibitor and lipoprotein (a) antagonist; and / or antifibrotic agents, by way of example and preferably from the group of kinase inhibitors or TGF-beta or TNF-alpha modulators
  • Antithrombotic agents are preferably understood as meaning compounds from the group of platelet aggregation inhibitors, anticoagulants or profibrinolytic substances.
  • the compounds according to the invention are administered in combination with a platelet aggregation inhibitor, such as, by way of example and by way of preference, aspirin, clopidogrel, ticlopidine or dipyridamole.
  • the compounds according to the invention are administered in combination with a thrombin inhibitor, such as, by way of example and by way of preference, ximelagatran, dabigatran, melagatran, bivalirudin or Clexane.
  • a thrombin inhibitor such as, by way of example and by way of preference, ximelagatran, dabigatran, melagatran, bivalirudin or Clexane.
  • the compounds according to the invention are administered in combination with a GPIIb / IIIa antagonist, such as, by way of example and by way of preference, tirofiban or abciximab.
  • a GPIIb / IIIa antagonist such as, by way of example and by way of preference, tirofiban or abciximab.
  • the compounds according to the invention are administered in combination with a factor Xa inhibitor, such as by way of example and preferably rivaroxaban (BAY 59-7939), edoxaban (DU-176b), apixaban, otamixaban, fidexaban, razaxaban, Fondaparinux, Idraparinux, PMD-3112, YM-150, KFA-1982, EMD-503982, MCM-17, MLN-1021, DX 9065a, DPC 906, JTV 803, SSR-126512 or SSR-128428.
  • a factor Xa inhibitor such as by way of example and preferably rivaroxaban (BAY 59-7939), edoxaban (DU-176b), apixaban, otamixaban, fidexaban, razaxaban, Fondaparinux, Idraparinux, PMD-3112, YM-150, KFA-1982, EMD
  • the compounds according to the invention are administered in combination with heparin or a low molecular weight (LMW) heparin derivative.
  • LMW low molecular weight
  • the compounds according to the invention are administered in combination with a vitamin K antagonist, such as by way of example and preferably coumarin.
  • antihypertensive agents are preferably compounds from the group of calcium antagonists, angiotensin AII antagonists, ACE inhibitors, endothelin antagonists, Renin inhibitors, alpha-receptor B-relaxer, beta-receptor blockers, mineralocorticoid receptor antagonists, neutral endopeptidase (NEP) inhibitors and diuretics understood.
  • the compounds according to the invention are administered in combination with a calcium antagonist, such as by way of example and preferably nifedipine, amlodipine, verapamil or diltiazem.
  • a calcium antagonist such as by way of example and preferably nifedipine, amlodipine, verapamil or diltiazem.
  • the compounds according to the invention are administered in combination with an alpha-1-receptor blocker, such as by way of example and preferably prazosin.
  • the compounds according to the invention are used in combination with a beta-receptor blocker such as, by way of example and by way of preference, propranolol, atenolol, timolol, pindolol, alprenolol, oxprenolol, penbutolol, bupranolol, metipropanol, nadolol, mepindolol, Caroteneol, sotalol, metoprolol, betaxolol, celiprolol, bisoprolol, carteolol, esmolol, labetalol, carvedilol, adaprolol, landiolol, nebivolol, epanolol or bucinolol.
  • a beta-receptor blocker such as, by way of example and by way of preference, propranolol, atenolol,
  • the compounds according to the invention are used in combination with an angiotensin AII antagonist, such as by way of example and preferably losartan, candesartan, valsartan, telmisartan or embursatan or a dual angiotensin AII antagonist / NEP inhibitor, for example and preferably LCZ696 ( Valsartan / S acubitril).
  • angiotensin AII antagonist such as by way of example and preferably losartan, candesartan, valsartan, telmisartan or embursatan
  • a dual angiotensin AII antagonist / NEP inhibitor for example and preferably LCZ696 ( Valsartan / S acubitril).
  • the compounds according to the invention are administered in combination with an ACE inhibitor such as, by way of example and by way of preference, enalapril, captopril, lisinopril, ramipril, delapril, fosinopril, quinopril, perindopril or trandopril.
  • an ACE inhibitor such as, by way of example and by way of preference, enalapril, captopril, lisinopril, ramipril, delapril, fosinopril, quinopril, perindopril or trandopril.
  • the compounds according to the invention are administered in combination with an endothelin antagonist, such as, by way of example and by way of preference, bosentan, darusentan, ambrisentan or sitaxsentan.
  • an endothelin antagonist such as, by way of example and by way of preference, bosentan, darusentan, ambrisentan or sitaxsentan.
  • the compounds of the invention are administered in combination with a renin inhibitor, such as by way of example and preferably aliskiren, SPP-600 or SPP-800.
  • a renin inhibitor such as by way of example and preferably aliskiren, SPP-600 or SPP-800.
  • the compounds according to the invention are administered in combination with a mineralocorticoid receptor antagonist, such as by way of example and preferably spironolactone or eplerenone.
  • the compounds of the present invention are used in combination with a loop diuretic such as furosemide, torasemide, bumetanide and piretanide with potassium sparing diuretics such as amiloride and triamterene with aldosterone antagonists such as spironolactone, potassium canrenoate and eplerenone and thiazide diuretics such as Hydrochlorothiazide, chlorthalidone, xipamide, and indapamide.
  • a loop diuretic such as furosemide, torasemide, bumetanide and piretanide
  • potassium sparing diuretics such as amiloride and triamterene with aldosterone antagonists such as spironolactone, potassium canrenoate and eplerenone and thiazide diuretics
  • Hydrochlorothiazide chlorthalidone
  • xipamide xipamide
  • indapamide indapamide
  • lipid metabolizing agents are preferably compounds from the group of CETP inhibitors, thyroid receptor agonists, cholesterol synthesis inhibitors such as HMG-CoA reductase or squalene synthesis inhibitors, the ACAT inhibitors, MTP inhibitors, PPAR alpha- , PPAR gamma and / or PPAR delta agonists, cholesterol absorption inhibitors, polymeric bile acid adsorbers, bile acid reabsorption inhibitors, lipase inhibitors and lipoprotein (a) antagonists.
  • CETP inhibitors such as HMG-CoA reductase or squalene synthesis inhibitors
  • ACAT inhibitors such as HMG-CoA reductase or squalene synthesis inhibitors
  • MTP inhibitors MTP inhibitors
  • PPAR alpha- , PPAR gamma and / or PPAR delta agonists cholesterol absorption inhibitors
  • polymeric bile acid adsorbers bile acid reabsorption
  • the compounds of the invention are administered in combination with a CETP inhibitor such as, by way of example and by way of preference, dalcetrapib, BAY 60-5521, anacetrapib or CETP vaccine (CETi-1).
  • a CETP inhibitor such as, by way of example and by way of preference, dalcetrapib, BAY 60-5521, anacetrapib or CETP vaccine (CETi-1).
  • the compounds of the invention are administered in combination with a thyroid receptor agonist such as, by way of example and by way of preference, D-thyroxine, 3,5,3'-triiodothyronine (T3), CGS 23425 or axitirome (CGS 26214).
  • a thyroid receptor agonist such as, by way of example and by way of preference, D-thyroxine, 3,5,3'-triiodothyronine (T3), CGS 23425 or axitirome (CGS 26214).
  • the compounds according to the invention are administered in combination with an HMG-CoA reductase inhibitor from the class of statins, such as, for example and preferably, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin or pitavastatin.
  • statins such as, for example and preferably, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin or pitavastatin.
  • the compounds according to the invention are administered in combination with a squalene synthesis inhibitor, such as by way of example and preferably BMS-188494 or TAK-475.
  • a squalene synthesis inhibitor such as by way of example and preferably BMS-188494 or TAK-475.
  • the compounds according to the invention are administered in combination with an ACAT inhibitor, such as by way of example and preferably avasimibe, melinamide, pactimibe, eflucimibe or SMP-797.
  • an ACAT inhibitor such as by way of example and preferably avasimibe, melinamide, pactimibe, eflucimibe or SMP-797.
  • the compounds according to the invention are administered in combination with an MTP inhibitor such as, for example and preferably, implitapide, BMS-201038, R-103757 or JTT-130.
  • an MTP inhibitor such as, for example and preferably, implitapide, BMS-201038, R-103757 or JTT-130.
  • the compounds of the invention are administered in combination with a PPAR-gamma agonist such as, by way of example and by way of preference, pioglitazone or rosiglitazone.
  • the compounds according to the invention are administered in combination with a PPAR delta agonist, such as by way of example and preferably GW 501516 or BAY 68-5042.
  • the compounds according to the invention are administered in combination with a cholesterol absorption inhibitor, such as by way of example and preferably ezetimibe, tiqueside or pamaqueside.
  • a lipase inhibitor such as by way of example and preferably orlistat.
  • the compounds according to the invention are administered in combination with a polymeric bile acid adsorbent such as, by way of example and by way of preference, cholestyramine, colestipol, colesolvam, cholesta gel or colestimide.
  • a polymeric bile acid adsorbent such as, by way of example and by way of preference, cholestyramine, colestipol, colesolvam, cholesta gel or colestimide.
  • ASBT IBAT
  • the compounds of the invention are administered in combination with a lipoprotein (a) antagonist such as, by way of example and by way of preference, gemcabene calcium (CI-1027) or nicotinic acid.
  • the compounds according to the invention are administered in combination with a kinase inhibitor, such as by way of example and preferably nintedanib.
  • the compounds according to the invention are administered in combination with a TGF-beta or TNF-alpha modulator, such as by way of example and preferably pirfenidone.
  • a TGF-beta or TNF-alpha modulator such as by way of example and preferably pirfenidone.
  • the compounds according to the invention can act systemically and / or locally.
  • they may be applied in a suitable manner, e.g. oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival, otic or as an implant or stent.
  • the compounds according to the invention can be administered in suitable administration forms.
  • the inventive compounds rapidly and / or modified donating application forms containing the compounds of the invention in crystalline and / or amorphized and / or dissolved form, such.
  • Tablets uncoated or coated tablets, for example with enteric or delayed-release or insoluble coatings which control the release of the compound of the invention
  • Parenteral administration can be accomplished by bypassing a resorption step (e.g., intravenous, intraarterial, intracardiac, intraspinal, or intralumbar) or by resorting to absorption (e.g., intramuscular, subcutaneous, intracutaneous, percutaneous, or intraperitoneal).
  • a resorption step e.g., intravenous, intraarterial, intracardiac, intraspinal, or intralumbar
  • absorption e.g., intramuscular, subcutaneous, intracutaneous, percutaneous, or intraperitoneal.
  • parenteral administration are suitable as application forms u.a. Injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.
  • Inhalation medicaments including powder inhalers, nebulizers
  • nasal drops solutions or sprays
  • lingual, sublingual or buccal tablets films / wafers or capsules
  • suppositories ear or eye preparations
  • vaginal capsules aqueous suspensions (lotions, shake mixtures)
  • lipophilic suspensions ointments
  • creams transdermal therapeutic systems (eg plasters)
  • milk pastes, foams, powdered powders, implants or stents.
  • the compounds according to the invention can be converted into the stated administration forms. This can be done in a conventional manner by mixing with inert, non-toxic, pharmaceutically suitable excipients.
  • excipients include carriers (For example, microcrystalline cellulose, lactose, mannitol), solvents (eg, liquid polyethylene glycols), emulsifiers and dispersing or wetting agents (for example, sodium dodecyl sulfate, Polyoxysorbitanoleat), binders (for example, polyvinylpyrrolidone), synthetic and natural polymers (for example, albumin), stabilizers (For example, antioxidants such as ascorbic acid), dyes (eg, inorganic pigments such as iron oxides) and flavor and / or odoriferous.
  • carriers For example, microcrystalline cellulose, lactose, mannitol
  • solvents eg, liquid polyethylene glycols
  • emulsifiers and dispersing or wetting agents for example, sodium dode
  • the dosage is about 0.01 to 100 mg / kg, preferably about 0.01 to 20 mg / kg and most preferably 0.1 to 10 mg / kg of body weight.
  • Instrament Waters ACQUITY SQD UPLC System; Column: Waters Acquity UPLC HSS T3 1,8 ⁇ 50 x 1mm; Eluent A: 1 l of water + 0.25 ml of 99% formic acid, eluent B: 1 l of acetonitrile + 0.25 ml of 99% formic acid; Gradient: 0.0 min 90% A -> 1.2 min 5% A -> 2.0 min 5% A; Oven: 50 ° C; Flow: 0.40 ml / min; UV detection: 210 - 400 nm.
  • Instrument MS Waters
  • instrument HPLC Waters (column Waters X-Bridge C18, 18 mm x 50 mm, 5 ⁇
  • eluent A water + 0.05% triethylamine
  • eluent B acetonitrile (ULC) + 0.05% triethylamine
  • UV detection DAD, 210 - 400 nm).
  • Example 5A (2-fluorobenzyl) -3-iodo-1H-pyrazolo [3,4-b] pyridine
  • Example 5A 10.00 g (28.317 mmol) of Example 5A, 5.563 g (56.635 mmol) of trimethylsilylacetylene, 808 mg (4.248 mmol) of copper (I) iodide and 1.988 g (2.832 mmol) of bis (triphenylphosphine) palladium (II) chloride were added in Tetrahydrofuran / triethylamine (25 mL, 1: 1 (v / v)) and heated to reflux overnight. Subsequently, the reaction mixture was concentrated. The residue was taken up in dichloromethane and purified by chromatography on silica gel (mobile phase: dichloromethane-cyclohexane, gradient). There was obtained 12.49 g of the title compound in 70% purity (95% of theory).
  • Example 6A 12.49 g (about 28,317 mmol) of Example 6A and 391 mg (2,832 mmol) of potassium carbonate were stirred in methanol (150 ml) for 30 minutes at room temperature. It was then filtered from a precipitate, washed with methanol, concentrated and dried under high vacuum. 7.18 g of the target compound (100% of theory) were obtained.
  • Example 1A 5.00 g (16.705 mmol) of Example 1A were initially charged in methanol (25 ml) and tetrahydrofuran (12.5 ml) and admixed with 16.254 ml (334.105 mmol) of hydrazine hydrate and then heated to 65 ° C. for 2.5 hours. It was then concentrated and dried under high vacuum. 4.83 g of the target compound (100% of theory) were obtained.
  • Example IIA Ethyl 3- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] -1,4,4-oxadiazole-5-carboxylate
  • Example 9A 3.05 g (7,934 mmol) of Example 9A were heated to 200 ° C. in the pointed flask under argon for 1.5 hours. The raw material was used without further purification in the next step. 2.49 g of the target compound were obtained (42.5% of theory, about 50% purity).
  • Example 12A 200 mg (about 0.273 mmol) of Example 12A and 45 mg (0.328 mmol) of potassium carbonate were initially charged in dimethylformamide (3 ml) and combined with 17 .mu.l (0.273 mmol) of iodomethane. It was then stirred for 1.5 hours at room temperature.
  • the crude batch was prepared by preparative HPLC purified (acetonitrile: water (+0.05% formic acid) gradient). 80 mg of the target compound were obtained (77% of theory).
  • the diazonium salt thus prepared was added in portions to a 0 ° C cold solution of 12.81 g (85.45 mmol) of sodium iodide in acetone (329 ml) and the mixture stirred for 30 min at RT.
  • the reaction mixture was added to ice water (1.8 L) and extracted twice with ethyl acetate (487 mL each).
  • the collected organic phases were washed with saturated aqueous sodium chloride solution (244 ml), dried, filtered and concentrated. This gave 12.1 g (86% purity, 60% of theory) of the desired compound as a brown solid.
  • the crude product was reacted without further purification.
  • the aqueous phase was separated and extracted twice more with ethyl acetate (200 ml each time).
  • the combined organic phases were washed twice with 10% aqueous sodium chloride solution (100 ml each), dried and concentrated in vacuo.
  • the crude product was reacted without further purification.
  • Example 2A 500 mg (1.843 mmol) of Example 2A, 201.6 mg (2.212 mmol) of hydrazolecarbothioamide and 1.06 g (5.530 mmol) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride were taken up in dimethylformamide (7 ml) and stirred at room temperature overnight , Thereafter, 84 mg (0.922 mmol) of hydrazine carbothioamide was added and heated to 50 ° C overnight. It was then added to water and cooled. The resulting precipitate was filtered off, washed with water and then dried under high vacuum. 259 mg of the target compound were obtained (45% of theory).
  • Example 2 207 mg (0.669 mmol) of Example 2 were initially charged in pyridine / dichloromethane (6 ml, 1: 1 v: v), mixed with 54 .mu.l (0.702 mmol) of methyl chloroformate and stirred overnight at room temperature. Thereafter, the reaction mixture was concentrated and slurried in a mixture of acetonitrile, dimethylformamide and water. After filtering off a precipitate, the filtrate was purified by preparative HPLC (acetonitrile-water (+0.05% formic acid) gradient).
  • Example 3A 724 mg (2.460 mmol) of Example 3A were initially charged in n-pentanol (7 ml) and treated with 183 ⁇ (3.444 mmol) of methylhydrazine and heated to reflux overnight. It was then poured into ice-water and filtered with suction, a precipitate which was washed with water and ethyl acetate. The precipitate was discarded and the phases of the filtrate were separated. The aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried with sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (acetonitrile-water (+0.05% formic acid) gradient).
  • Example 4 124 mg (0.385 mmol) of Example 4 were initially charged in pyridine (3 ml) and treated with 29 .mu.l (0.385 mmol) of methyl chloroformate and stirred overnight at room temperature. Subsequently, another 9 .mu.l (0.115 mmol) of methyl chloroformate were added and after 4 hours a further 9 .mu.l (0.115 mmol) of methyl chloroformate. It was stirred for another night at room temperature. The mixture was then treated with water and dichloromethane. The phases were separated and the aqueous phase was extracted twice with dichloromethane. The combined organic phases were dried with sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (acetonitrile-water (+0.05% formic acid) gradient).
  • Example 1 420 mg (1.358 mmol) of Example 1 and 225 mg (1.629 mmol) of potassium carbonate were initially charged in dimethylformamide (5 ml) and admixed with 148 ⁇ l (1.358 mmol) of methyl 3-bromopropionate. It was then stirred overnight at room temperature. The crude batch was purified by preparative HPLC (acetonitrile: water (+0.05% formic acid) gradient). 406 mg of the target compound were obtained (75% of theory).
  • Example 5 40 mg (0.105 mmol) of Example 5 were initially charged in tetrahydrofuran (3 ml) and admixed at 0 ° C. with 116 ⁇ l (0.116 mmol) of an IM solution of bis (trimethylsilyl) sodium amide in tetrahydrofuran and stirred at 0 ° C. for 30 min. Subsequently, 13 .mu.l (0.210 mmol) of iodomethane was added and stirred at room temperature for 3 days.
  • Example 4A 400 mg (1.485 mmol) of Example 4A were initially charged in dimethylformamide (3 ml) and treated with 101 ⁇ (1.485 mmol) of methyl isothiocyanate and 284 ⁇ (1.634 mmol) of ⁇ , ⁇ -diisopropylethylamine and stirred overnight at room temperature. Subsequently, 101 ⁇ (1.485 mmol) of methyl isothiocyanate was added again and stirred overnight at room temperature. Finally, 101 ⁇ (1.485 mmol) of methyl isothiocyanate were again added and stirred at room temperature for 3 h.
  • Example 1 200 mg (0.647 mmol) of Example 1 and 107 mg (0.647 mmol) of potassium carbonate were initially charged in dimethylformamide (5 ml) and admixed with 120 mg (0.647 mmol) of 2-bromoethylmethylsulfone. After 1.5 hours at room temperature, the reaction mixture was heated to 60 ° C. After 12 hours at 60 ° C, the reaction mixture was purified by preparative HPLC (acetonitrile-water (+0.05% formic acid) gradient). 122 mg of the target compound were obtained (41% of theory).
  • Example 1 200 mg (0.647 mmol) of Example 1 and 107 mg (0.647 mmol) of potassium carbonate were initially charged in dimethylformamide (5 ml), and 60 ⁇ l (0.647 mmol) of 2-bromoethylmethyl ether were added. After 1.5 hours at room temperature, the reaction mixture was heated to 60 ° C. After 12 hours at 60 ° C, the reaction mixture was purified by preparative HPLC (acetonitrile-water (+0.05% formic acid) gradient). 24 mg of the target compound were obtained (10% of t.l.).
  • Example 1 200 mg (0.647 mmol) of Example 1 and 107 mg (0.647 mmol) of potassium carbonate were initially charged in dimethylformamide (5 ml) and admixed with 122 mg (0.647 mmol) of 2-fluorobenzyl bromide. After 1.5 hours at room temperature, the reaction mixture was heated to 60 ° C. After 12 hours at 60 ° C, the reaction mixture was purified by preparative HPLC (acetonitrile-water (+0.05% formic acid) gradient). 65 mg of the target compound were obtained (24% of t.l.).
  • Example 1 200 mg (0.647 mmol) of Example 1 and 107 mg (0.647 mmol) of potassium carbonate were initially charged in dimethylformamide (5 ml) and treated with 122 mg (0.647 mmol) of 3-fluorobenzyl bromide. After 1.5 hours at room temperature, the reaction mixture was heated to 60 ° C. After 12 hours at 60 ° C, the reaction mixture was purified by preparative HPLC (acetonitrile-water (+0.05% formic acid) gradient). 43 mg of the target compound were obtained (16% of theory).
  • Example 1 200 mg (0.647 mmol) of Example 1 and 107 mg (0.647 mmol) of potassium carbonate were initially charged in dimethylformamide (5 ml) and 122 mg (0.647 mmol) of 4-fluorobenzyl bromide were added. After 1.5 hours at room temperature, the reaction mixture was heated to 60 ° C. After 12 hours at 60 ° C, the reaction mixture was purified by preparative HPLC (acetonitrile-water (+0.05% formic acid) gradient). 9 mg of the target compound were obtained (3% of t.l.).
  • Example 7A 100 mg (0.398 mmol) of Example 7A, 61.3 mg (0.398 mmol) of 2-piperidineethyl azide, 7.8 mg (0.04 mmol) of sodium ascorbate and 0.9 mg (0.004 mmol) of copper (II) sulfate pentahydrate were dissolved in water (2 ml ) and ethanol (1ml) and heated to 50 ° C overnight with stirring.
  • the reaction mixture was purified by preparative HPLC (acetonitrile-water (+0.05% formic acid) gradient). 149 mg of the target compound were obtained (92% of theory).
  • Example 7A 1.00 g (3.980 mmol) of Example 7A, 523 ⁇ (3.980 mmol) of azidotrimethylsilane, 157 mg (0.796 mmol) of sodium ascorbate and 69 mg (0.279 mmol) of copper (II) sulfate pentahydrate were dissolved in water (20 ml) and ethanol ( 10ml) and heated to 50 ° C overnight with stirring. The next day, 157 mg (0.796 mmol) of sodium ascorbate and 69 mg (0.279 mmol) of copper (II) sulfate pentahydrate were added again and the mixture was refluxed overnight (bath temperature 85 ° C.).
  • Example 18 30 mg (0.102 mmol) of Example 18 and 16.9 mg (0.122 mmol) of potassium carbonate were initially charged in dimethylformamide (2 ml) and admixed with 16.7 ⁇ l (0.102 mmol) of 2,2,2-trifluoroethyltrichloromethanesulfonate. After 24 hours at room temperature, the mixture was purified by preparative HPLC (acetonitrile-water (+0.05% formic acid)). Gradient).
  • Example 17 The title compound was obtained in the synthesis of Example 19 as another isomer. There were obtained 16 mg of the target compound (39% of Th) and 13 mg (34% of theory) of 1- (2-fluorobenzyl) -3- [1- (2,2,2-trifluoroethyl) -H -l, 2,3-triazol-4-yl] -1H-pyrazolo [3,4-b] pyridine (Example 17).
  • Example I IA 100 mg (0.272 mmol) of Example I IA were presented in 5 ml of ammonia (2.0 M in ethanol) and then treated for 20 minutes at 70 ° C in the microwave. After cooling, a precipitate was filtered off, washed with ethanol and dried under high vacuum. 92 mg of the target compound were obtained (79% of theory).
  • Example 7A 1.00 g (3.980 mmol) of Example 7A, 4.78 ml (7.960 mmol) of ethyl azidoacetate (25% in ethanol), 157 mg (0.796 mmol) of sodium ascorbate and 69 mg (0.279 mmol) of copper (II) sulfate pentahydrate were dissolved in water ( 20 ml) and ethanol (10 ml) and stirred overnight at room temperature. Thereafter, the ethanol was removed by means of a rotary evaporator and the precipitate formed was filtered off with suction and washed with ethanol. 1.24 g of the target compound were obtained (81% of theory).
  • Example 10A 100 mg (0.396 mmol) of Example 10A, 41 mg (0.436 mmol) of 2-aminopyridine, 72 mg (0.396 mmol) of copper (II) acetate, 4.6 mg (0.020 mmol) of 3,4,7,8-tetramethyl-1 , 10-phenanthroline and 12.6 mg (0.040 mmol) of zinc iodide were taken up in 1,2-dichlorobenzene (3 ml) and stirred at 130 ° C overnight. The reaction mixture was filtered and purified by preparative HPLC (acetonitrile-water (+0.05% formic acid) gradient). There were obtained 65 mg of the target compound (48% of t.l.).
  • Example 12A 100 mg (0.253 mmol) of Example 12A and 45 ⁇ (0.303 mmol) of l, 8-diazabicyclo [5.4.0] undec-7-ene were taken up in DMSO (3 ml) and stirred for 2 hours at 100 ° C. Then the reaction mixture was purified by preparative HPLC (acetonitrile: water (+0.05% formic acid) gradient). 82 mg of the target compound were obtained (89% of theory).
  • Example 4A 100 mg (0.327 mmol) of Example 4A, 1.00 ml (12.45 mmol) of cyanocyclobutane, 213 mg (0.654 mmol) of cesium carbonate and 2.3 mg (0.016 mmol) of copper (I) bromide were dissolved in DMSO (3 ml). taken up and stirred overnight at 120 ° C. It was then filtered and purified by preparative HPLC (acetonitrile: water (+0.05% formic acid) gradient). 75 mg of the target compound were obtained (66% of theory).
  • Example 13A 69 mg (0.181 mmol) of Example 13A were initially charged in 2.5 ml of ammonia (2.0 M in ethanol) and then treated in the microwave at 70 ° C. for 20 minutes. Subsequently, another 1 ml of ammonia (2.0 M in ethanol) was added and heated for 20 minutes at 70 ° C in the microwave. Subsequently, 1 ml of ammonia (2.0 M in ethanol) was added again and heated to 70 ° C for 1 hour under microwave irradiation. After cooling, a precipitate was filtered off, washed with ethanol and dried under high vacuum. 18 mg of the target compound were obtained (29% of theory).
  • Example 4A 100 mg (0.327 mmol) of Example 4A, 1.00 ml (24.602 mmol) of acetonitrile, 213 mg (0.654 mmol) of cesium carbonate and 2.3 mg (0.016 mmol) of copper (I) bromide were taken up in DMSO (3 ml) and overnight Stirred at 120 ° C. It was then filtered and purified by preparative HPLC (acetonitrile: water (+0.05% formic acid) gradient). 29 mg of the target compound were obtained (29% of theory).
  • Example 10A 100 mg (0.396 mmol) of Example 10A, 41 mg (0.436 mmol) of 2-aminopyrimidine, 72 mg (0.396 mmol) of copper (II) acetate, 4.6 mg (0.020 mmol) of 3,4,7,8-tetramethyl-1 , 10-phenanthroline and 12.6 mg (0.040 mmol) of zinc iodide were taken up in 1,2-dichlorobenzene (3 ml) and at 130 ° C for 5 days touched. It was then filtered and purified by preparative HPLC (acetonitrile: water (+0.05% formic acid) gradient). 8 mg of the target compound were obtained (6% of theory).
  • Instrument MS Waters
  • Instrument HPLC Waters (column Phenomenex Luna 5 ⁇ C18 (2) 100A, AXIA Tech 50 x 21.2 mm
  • eluent A water + 0.05% formic acid
  • eluent B acetonitrile (ULC) + 0.05% formic acid
  • gradient 0.0 min 95% A - 0.15 min 95% A - 8.0 min 5% A - 9.0 min 5% A
  • flow 40 ml / min
  • UV detection DAD, 210 - 400 nm).
  • the product-containing fractions were concentrated by means of a centrifugal dryer in vacuo.
  • the residue of the individual fractions was dissolved in 0.6 ml of DMSO and combined. Subsequently, the solvent was completely evaporated in a centrifugal dryer. 7.4 mg (20% of theory) of target product were obtained.
  • Example 27A 38 mg (0.407 mmol) 2-aminopyridine, 67 mg (0.370 mmol) copper (II) acetate, 4.3 mg (0.019 mmol) 3,4,7,8-tetramethyl-1 , 10-phenanthroline and 11.8 mg (0.037 mmol) of zinc iodide were taken up in 1,2-dichlorobenzene (2.8 ml) and stirred at 130 ° C overnight. The reaction mixture was filtered and purified by preparative HPLC (acetonitrile-water (+0.05% formic acid) gradient). There was obtained 40 mg of the target compound in 91% purity (30% of theory).
  • the force of contraction is detected with Statham UC2 cells, amplified and digitized via A / D converters (DAS-1802 HC, Keithley Instruments Munich) and registered in parallel on chart recorders.
  • DAS-1802 HC A / D converters
  • phenylephrine is added cumulatively to the bath in increasing concentration.
  • the substance to be examined is added in each subsequent course in increasing dosages and the height of the contraction is compared with the height of the contraction achieved in the last predistortion. This is used to calculate the concentration required to reduce the level of the control value by 50% (IC50 value).
  • the standard application volume is 5 ⁇ , the DMSO content in the bath solution corresponds to 0.1%.
  • the cellular activity of the compounds of this invention is measured on a recombinant guanylate cyclase reporter cell line as described in F. Wunder et al., Anal. Biochem. 339. 104-112 (2005).
  • a commercially available telemetry system from DATA SCIENCES INTERNATIONAL DSI, USA is used for the blood pressure measurement on awake rats described below.
  • the system consists of 3 main components: Implantable Transmitters (Physiotel® Telemetry Transmitter)
  • Data acquisition computer are connected.
  • the telemetry system allows a continuous recording of blood pressure heart rate and body movement on awake animals in their habitual habitat.
  • the experimental animals are kept individually in macroion cages type 3 after transmitter implantation. You have free access to standard food and water.
  • the day - night rhythm in the experimental laboratory is changed by room lighting at 6:00 in the morning and at 19:00 in the evening.
  • the TAH PA - C40 telemetry transmitters are surgically implanted into the experimental animals under aseptic conditions at least 14 days before the first trial.
  • the animals so instrumented are repeatedly used after healing of the wound and ingrowth of the implant.
  • the fasting animals are anesthetized with pentobabital (Nembutal, Sanofi: 50 mg / kg i.p.) and shaved and disinfected on the ventral side.
  • pentobabital Nembutal, Sanofi: 50 mg / kg i.p.
  • tissue adhesive VetBonD TM, 3M.
  • the transmitter housing is fixed intraperitoneally to the abdominal wall musculature and the wound is closed in layers.
  • an antibiotic is administered for infection prevention (Tardomyocel COMP Bayer 1ml / kg s.c.)
  • the existing telemetry measuring device is configured for 24 animals. Each trial is registered under a trial number (VYear month day).
  • the instrumented rats living in the plant each have their own receiving antenna (1010 receivers, DSI).
  • the implanted transmitters can be activated externally via a built-in magnetic switch. They will be put on the air during the trial run.
  • the emitted signals can be recorded online by a data acquisition system (Dataquest TM A.R.T. for Windows, DSI) and processed accordingly. The storage of the data takes place in each case in a folder opened for this purpose which carries the test number.
  • SBP Systolic blood pressure
  • DBP Diastolic blood pressure
  • MAP Mean arterial pressure
  • the measured value acquisition is repeated computer-controlled in 5-minute intervals.
  • the absolute value of the source data is corrected in the diagram with the currently measured barometric pressure (Ambient Pressure Reference Monitor, APR-1) and stored in individual data. Further technical details can be found in the extensive documentation of the manufacturer (DSI).
  • test substances will take place at 9 o'clock on the day of the experiment. Following the application, the parameters described above are measured for 24 hours.
  • the collected individual data are sorted with the analysis software (DATAQUEST TM ART TM ANALYSIS).
  • the blank will be here 2 hours before application assuming that the selected record comprises the period from 7:00 on the trial day to 9:00 on the following day.
  • the data is smoothed over a presettable time by averaging (15 minutes average) and transferred as a text file to a disk.
  • the presorted and compressed measured values are transferred to Excel templates and displayed in tabular form.
  • the filing of the collected data takes place per experiment day in a separate folder that bears the test number. Results and test reports are sorted in folders and sorted by paper.
  • the compounds according to the invention can be converted into pharmaceutical preparations as follows:
  • composition
  • the mixture of compound of the invention, lactose and starch is granulated with a 5% solution (m / m) of the PVP in water.
  • the granules are mixed after drying with the magnesium stearate for 5 minutes.
  • This mixture is compressed with a conventional tablet press (for the tablet format see above).
  • a pressing force of 15 kN is used as a guideline for the compression.
  • the rhodigel is suspended in ethanol, the compound according to the invention is added to the suspension. While stirring, the addition of water. Until the completion of the swelling of Rhodigels is stirred for about 6 h.
  • the compound of the invention is suspended in the mixture of polyethylene glycol and polysorbate with stirring. The stirring is continued until complete dissolution of the compound according to the invention.
  • iv Solution The compound of the present invention is dissolved in a concentration below the saturation solubility in a physiologically acceptable solvent (e.g., isotonic saline, glucose solution 5% and / or PEG 400 solution 30%). The solution is sterile filtered and filled into sterile and pyrogen-free injection containers.
  • a physiologically acceptable solvent e.g., isotonic saline, glucose solution 5% and / or PEG 400 solution 30%.

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Abstract

La présente invention concerne des composés de formule (I) dans laquelle Q représente un groupe de formule (A) ou (B), R1 représente eau ou fluor, et R2 représente alkyle (C1-C6) ou benzyle (alkyle C1-C6) étant substitué par un substituant trifluorométhyle et pouvant être substitué par 1 à 3 substituants fluor, et benzyle étant substitué par 1 à 3 substituants fluor), et leur utilisation pour la fabrication de médicaments destinés au traitement et/ou à la prophylaxie de maladies, en particulier pour le traitement et/ou la prophylaxie de maladies cardio-vasculaires.
PCT/EP2017/050326 2016-01-15 2017-01-09 Dérivés de 1h-pyrazolo[3,4-b]pyridine 1,3-disubstitués et leur utilisation en tant que stimulateurs de la guanylacte cyclase soluble WO2017121700A1 (fr)

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US11180493B2 (en) 2016-11-08 2021-11-23 Cyclerion Therapeutics, Inc. SGC stimulators
US11242335B2 (en) 2017-04-11 2022-02-08 Sunshine Lake Pharma Co., Ltd. Fluorine-substituted indazole compounds and uses thereof
US11690828B2 (en) 2016-11-08 2023-07-04 Cyclerion Therapeutics, Inc. Treatment of CNS diseases with sGC stimulators

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WO2012152629A1 (fr) 2011-05-06 2012-11-15 Bayer Intellectual Property Gmbh Imidazopyridazines substituées et imidazopyridazines, et leur utilisation
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