SUBSTITUTED PYRAZOLO[1,5-A]PYRIDINES AND IMIDAZO[1,2-A]PYRAZINES AND THEIR USE

Abstract

The present application relates to novel substituted pyrazolo[1,5-a]pyridines and imidazo[1,2-a]pyrazines, to processes for preparation thereof, to the use thereof, alone or in combinations, for treatment and/or prophylaxis of diseases, and to the use thereof for production of medicaments for treatment and/or prophylaxis of diseases, especially for treatment and/or prophylaxis of cardiovascular disorders.

Claims

1. Compound of the formula (I-A) or (I-B) in which ##STR00108## A represents CH.sub.2, CD.sub.2 or CH(CH.sub.3), R.sup.1 represents (C.sub.4-C.sub.6)-alkyl, (C.sub.3-C.sub.7)-cycloalkyl, pyridyl or phenyl, where (C.sub.4-C.sub.6)-alkyl may be up to hexasubstituted by fluorine, where (C.sub.3-C.sub.7)-cycloalkyl may be substituted by 1 to 4 substituents independently of one another selected from the group consisting of fluorine, trifluoromethyl and (C.sub.1-C.sub.4)-alkyl, where pyridyl is substituted by 1 or 2 substituents independently of one another selected from the group consisting of halogen, cyano and (C.sub.1-C.sub.4)-alkyl, and where phenyl may be substituted by 1 to 4 substituents independently of one another selected from the group consisting of halogen, cyano, monofluoromethyl, difluoromethyl, trifluoromethyl, (C.sub.1-C.sub.4)-alkyl and (C.sub.1-C.sub.4)-alkoxy, R.sup.2 represents hydrogen, (C.sub.1-C.sub.4)-alkyl, (C.sub.1-C.sub.4)-alkoxymethyl, cyclopropyl, cyclobutyl, monofluoromethyl, difluoromethyl or trifluoromethyl, R.sup.3 represents phenyl or 5- to 10-membered heteroaryl, where phenyl may be substituted by 1 to 3 substituents independently of one another selected from the group of halogen, cyano, trifluoromethyl, difluoromethyl, (C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.4)-alkoxycarbonyl, (C.sub.1-C.sub.4)-alkylcarbonyl, hydroxycarbonyl, —(C═O)NR.sup.7R.sup.8, (C.sub.1-C.sub.4)-alkylsulphonyl, (C.sub.3-C.sub.6)-cycloalkylsulphonyl, (C.sub.1-C.sub.4)-alkylthio, (C.sub.1-C.sub.4)-alkoxy, trifluoromethoxy, difluoromethoxy, phenoxy, hydroxy, amino, morpholinyl, piperidinyl, pyrrolidinyl, piperazinyl, and (C.sub.3-C.sub.6)-cycloalkyl, in which amino may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of (C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.4)-alkylcarbonyl, (C.sub.3-C.sub.6)-cycloalkylsulphonyl, (C.sub.1-C.sub.4)-alkylsulphonyl and methoxy-(C.sub.1-C.sub.4)-alkyl, in which (C.sub.1-C.sub.6)-alkyl may be substituted by amine, in which (C.sub.1-C.sub.6)-alkyl may be substituted by 1 or 2 substituents selected from the group consisting of fluorine, trifluoromethoxy, —(C═O)NR.sup.7R.sup.8, (C.sub.1-C.sub.4)-alkoxy, (C.sub.3-C.sub.6)-cycloalkyl, morpholinyl, piperidinyl, pyrrolidinyl, piperazinyl, hydroxy and amino, in which amino may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of (C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.4)-alkylcarbonyl, (C.sub.1-C.sub.4)-alkoxycarbonyl, (C.sub.3-C.sub.6)-cycloalkylsulphonyl, (C.sub.1-C.sub.4)-alkylsulphonyl and methoxy-(C.sub.1-C.sub.4)-alkyl, and in which R.sup.7 and R.sup.8 each independently of one another represent hydrogen, (C.sub.1-C.sub.4)-alkyl or (C.sub.3-C.sub.7)-cycloalkyl, where 5- to 10-membered heteroaryl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of fluorine, chlorine, cyano, (C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.4)-alkoxy, amino, (C.sub.1-C.sub.4)-alkoxycarbonyl, hydroxycarbonyl, —(C═O)NR.sup.7R.sup.8, phenyl, pyridyl, pyrimidyl, 1,3-thiazol-5-yl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl and (C.sub.3-C.sub.7)-cycloalkyl, in which (C.sub.1-C.sub.6)-alkyl may be substituted by 1 to 3 substituents selected from the group consisting of fluorine, cyano, hydroxy, amino, trifluoromethyl, difluoromethyl, (C.sub.1-C.sub.4)-alkylsulphonyl, (C.sub.1-C.sub.4)-alkylcarbonyl, (C.sub.1-C.sub.4)-alkoxycarbonyl, hydroxycarbonyl, —(C═O)NR.sup.7R.sup.8 (C.sub.1-C.sub.4)-alkoxy, phenoxy, phenyl, pyridyl, pyrimidyl, 5-membered heteroaryl, (C.sub.3-C.sub.7)-cycloalkyl, morpholinyl, piperidinyl, pyrrolidinyl, piperazinyl, 1,1-dioxidothiomorpholin-4-yl and azetidine, in which 5-membered heteroaryl may be substituted by 1 to 3 substituents selected from the group consisting of halogen, (C.sub.1-C.sub.4)-alkyl and (C.sub.1-C.sub.4)-alkoxy, in which R.sup.7 and R.sup.8 each independently of one another represent hydrogen, (C.sub.1-C.sub.4)-alkyl or (C.sub.3-C.sub.7)-cycloalkyl, in which piperidinyl may be substituted by 1 to 4 fluorine substituents, in which phenyl may be substituted by 1 to 3 substituents selected from the group consisting of halogen, (C.sub.1-C.sub.4)-alkyl and (C.sub.1-C.sub.4)-alkoxy, in which azetidine may be substituted by hydroxy, in which amino may be substituted by 1 or 2 (C.sub.1-C.sub.4)-alkyl substituents, and in which piperazinyl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of (C.sub.1-C.sub.4)-alkyl, (C.sub.3-C.sub.7)-cycloalkyl and trifluoromethyl, in which (C.sub.3-C.sub.7)-alkyl may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of halogen, (C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.4)-alkoxycarbonyl and hydroxycarbonyl, in which (C.sub.1-C.sub.4)-alkoxy may be substituted by amino, in which amino may be substituted by 1 or 2 substituents independently of one another selected from (C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.4)-alkylcarbonyl, (C.sub.3-C.sub.6)-cycloalkylsulphonyl and (C.sub.1-C.sub.4)-alkylsulphonyl, in which (C.sub.1-C.sub.6)-alkyl may be substituted by amino, and in which (C.sub.1-C.sub.6)-alkyl may be substituted up to five times by fluorine, in which phenyl, pyridyl and pyrimidyl may be substituted by 1 or 2 substituents selected from the group consisting of methyl, ethyl and fluorine, in which R.sup.7 and R.sup.8 each independently of one another represent hydrogen, (C.sub.1-C.sub.4)-alkyl or (C.sub.3-C.sub.7)-cycloalkyl, or R.sup.3 represents a group of the formula ##STR00109## where * represents the point of attachment to the pyrazolopyridine or the imidazopyrazine, R.sup.9 represents hydrogen or (C.sub.1-C.sub.6)-alkyl, where (C.sub.1-C.sub.6)-alkyl may be substituted by amino, and in which (C.sub.1-C.sub.6)-alkyl may be substituted up to five times by fluorine, R.sup.10 represents hydrogen, methyl or ethyl, R.sup.11 represents hydrogen, methyl, ethyl, trifluoromethyl or cyclopropyl, or R.sup.10 and R.sup.11 together with the carbon atom to which they are attached form a 3- to 6-membered carbocycle, R.sup.4 represents hydrogen, R.sup.5 represents hydrogen, halogen, cyano, difluoromethyl, trifluoromethyl, (C.sub.1-C.sub.4)-alkyl, (C.sub.3-C.sub.7)-cycloalkyl, (C.sub.2-C.sub.4)-alkynyl, (C.sub.1-C.sub.4)-alkylamino, difluoromethoxy, trifluoromethoxy, (C.sub.1-C.sub.4)-alkoxy, amino, 4- to 7-membered heterocyclyl or 5- or 6-membered heteroaryl, R.sup.6 represents hydrogen, cyano or halogen, and the N-oxides, salts, solvates, salts of the N-oxides and solvates of the N-oxides and salts thereof.

2. A compound of the formula (I-A) or (I-B) as claimed in claim 1 in which A represents CH.sub.2 or CD.sub.2, R.sup.1 represents cyclohexyl, pyridyl or phenyl, where cyclohexyl may be substituted up to four times by fluorine, where pyridyl is substituted by 1 or 2 fluorine substituents, and where phenyl may be substituted by 1 to 4 substituents independently of one another selected from the group consisting of fluorine, chlorine, cyano, methyl and methoxy, R.sup.2 represents hydrogen, (C.sub.1-C.sub.4)-alkyl, cyclopropyl, difluoromethyl or trifluoromethyl, R.sup.3 represents phenyl or 5- or 6-membered heteroaryl, where phenyl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of fluorine, chlorine, cyano, trifluoromethyl, difluoromethyl, (C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.4)-alkoxycarbonyl, (C.sub.1-C.sub.4)-alkylcarbonyl, hydroxycarbonyl, —(C═O)NR.sup.7R.sup.8, (C.sub.1-C.sub.4)-alkylsulphonyl, (C.sub.3-C.sub.6)-cycloalkylsulphonyl, (C.sub.1-C.sub.4)-alkoxy, trifluoromethoxy, difluoromethoxy, hydroxy, amino, morpholinyl, piperidinyl, pyrrolidinyl, piperazinyl and cyclopropyl, in which amino may be substituted by 1 or 2 substituents independently of one another selected from (C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.4)-alkylcarbonyl and (C.sub.1-C.sub.4)-alkylsulphonyl, in which (C.sub.1-C.sub.6)-alkyl may be substituted by 1 or 2 substituents selected from the group consisting of fluorine, trifluoromethoxy, —(C═O)NR.sup.7R.sup.8, (C.sub.1-C.sub.4)-alkoxy, (C.sub.3-C.sub.6)-cycloalkyl, morpholinyl, piperidinyl, pyrrolidinyl, piperazinyl, hydroxy and amino, in which amino may be substituted by 1 or 2 substituents independently of one another selected from (C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.4)-alkylcarbonyl and (C.sub.1-C.sub.4)-alkylsulphonyl, and in which R.sup.7 and R.sup.8 each independently of one another represent hydrogen, (C.sub.1-C.sub.4)-alkyl or cyclopropyl, where 5- or 6-membered heteroaryl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of fluorine, chlorine, cyano, (C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.4)-alkoxy, amino, (C.sub.1-C.sub.4)-alkoxycarbonyl, hydroxycarbonyl, —(C═O)NR.sup.7R.sup.8, phenyl, pyridyl, pyrimidyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl and cyclopropyl, in which (C.sub.1-C.sub.6)-alkyl may be substituted by 1 to 3 substituents selected from the group consisting of fluorine, cyano, hydroxy, amino, trifluoromethyl, difluoromethyl, (C.sub.1-C.sub.4)-alkylsulphonyl, (C.sub.1-C.sub.4)-alkoxycarbonyl, hydroxycarbonyl, —(C═O)NR.sup.7R.sup.8, (C.sub.1-C.sub.4)-alkoxy, phenyl, pyridyl, pyrimidyl, 5-membered heteroaryl, (C.sub.3-C.sub.7)-cycloalkyl, morpholinyl, piperidinyl, pyrrolidinyl, piperazinyl, 1,1-dioxidothiomorpholin-4-yl and azetidine, in which 5-membered heteroaryl may be substituted by 1 to 3 substituents selected from the group consisting of fluorine, chlorine, methyl, ethyl and methoxy, in which R.sup.7 and R.sup.8 each independently of one another represent hydrogen, methyl, ethyl or cyclopropyl, in which piperidinyl may be substituted by 1 to 4 fluorine substituents, in which phenyl may be substituted by 1 to 3 substituents selected from the group consisting of fluorine, methyl, ethyl and methoxy, in which amino may be substituted by 1 or 2 substituents independently of one another selected from (C.sub.1-C.sub.6)-alkyl and (C.sub.1-C.sub.4)-alkylcarbonyl, in which (C.sub.1-C.sub.6)-alkyl may be substituted by amino, in which phenyl, pyridyl and pyrimidyl may be substituted by 1 or 2 substituents selected from the group consisting of methyl, ethyl and fluorine, and in which R.sup.7 and R.sup.8 each independently of one another represent hydrogen, methyl, ethyl or cyclopropyl, or R.sup.3 represents a group of the formula ##STR00110## where * represents the point of attachment to the pyrazolopyridine or the imidazopyrazine, R.sup.9 represents hydrogen or (C.sub.1-C.sub.6)-alkyl, where (C.sub.1-C.sub.6)-alkyl may be substituted by amino, R.sup.10 represents methyl or ethyl, R.sup.11 represents methyl, ethyl, trifluoromethyl or cyclopropyl, R.sup.4 represents hydrogen, R.sup.5 represents hydrogen, fluorine, chlorine, cyano, difluoromethyl, trifluoromethyl, (C.sub.1-C.sub.4)-alkyl or (C.sub.3-C.sub.5)-cycloalkyl, R.sup.6 represents hydrogen, and the N-oxides, salts, solvates, salts of the N-oxides and solvates of the N-oxides and salts thereof.

3. Compound of the formula (I-A) according to claim 1 in which A represents CH.sub.2 or CD.sub.2, R.sup.1 represents cyclohexyl, pyridyl or phenyl, where cyclohexyl may be substituted up to four times by fluorine, where pyridyl is substituted by 1 or 2 fluorine substituents, and where phenyl may be substituted by 1 to 4 substituents independently of one another selected from the group consisting of fluorine, chlorine, cyano, methyl and methoxy, R.sup.2 represents hydrogen, (C.sub.1-C.sub.4)-alkyl, cyclopropyl, difluoromethyl or trifluoromethyl, R.sup.3 represents phenyl or 5- or 6-membered heteroaryl, where phenyl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of fluorine, chlorine, cyano, trifluoromethyl, difluoromethyl, (C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.4)-alkoxycarbonyl, (C.sub.1-C.sub.4)-alkylcarbonyl, hydroxycarbonyl, —(C═O)NR.sup.7R.sup.8, (C.sub.1-C.sub.4)-alkylsulphonyl, (C.sub.3-C.sub.6)-cycloalkylsulphonyl, (C.sub.1-C.sub.4)-alkoxy, trifluoromethoxy, difluoromethoxy, hydroxy, amino, morpholinyl, piperidinyl, pyrrolidinyl, piperazinyl and cyclopropyl, in which amino may be substituted by 1 or 2 substituents independently of one another selected from (C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.4)-alkylcarbonyl and (C.sub.1-C.sub.4)-alkylsulphonyl, in which (C.sub.1-C.sub.6)-alkyl may be substituted by 1 or 2 substituents selected from the group consisting of fluorine, trifluoromethoxy, —(C═O)NR.sup.7R.sup.8, (C.sub.1-C.sub.4)-alkoxy, (C.sub.3-C.sub.6)-cycloalkyl, morpholinyl, piperidinyl, pyrrolidinyl, piperazinyl, hydroxy and amino, in which amino may be substituted by 1 or 2 substituents independently of one another selected from (C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.4)-alkylcarbonyl and (C.sub.1-C.sub.4)-alkylsulphonyl, and in which R.sup.7 and R.sup.8 each independently of one another represent hydrogen, (C.sub.1-C.sub.4)-alkyl or cyclopropyl, where 5- or 6-membered heteroaryl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of fluorine, chlorine, cyano, (C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.4)-alkoxy, amino, (C.sub.1-C.sub.4)-alkoxycarbonyl, hydroxycarbonyl, —(C═O)NR.sup.7R.sup.8, phenyl, pyridyl, pyrimidyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl and cyclopropyl, in which (C.sub.1-C.sub.6)-alkyl may be substituted by 1 to 3 substituents selected from the group consisting of fluorine, cyano, hydroxy, amino, trifluoromethyl, difluoromethyl, (C.sub.1-C.sub.4)-alkylsulphonyl, (C.sub.1-C.sub.4)-alkoxycarbonyl, hydroxycarbonyl, —(C═O)NR.sup.7R.sup.8, (C.sub.1-C.sub.4)-alkoxy, phenyl, pyridyl, pyrimidyl, 5-membered heteroaryl, (C.sub.3-C.sub.7)-cycloalkyl, morpholinyl, piperidinyl, pyrrolidinyl, piperazinyl, 1,1-dioxidothiomorpholin-4-yl and azetidine, in which 5-membered heteroaryl may be substituted by 1 to 3 substituents selected from the group consisting of fluorine, chlorine, methyl, ethyl and methoxy, in which R.sup.7 and R.sup.8 each independently of one another represent hydrogen, methyl, ethyl or cyclopropyl, in which piperidinyl may be substituted by 1 to 4 fluorine substituents, in which phenyl may be substituted by 1 to 3 substituents selected from the group consisting of fluorine, methyl, ethyl and methoxy, in which amino may be substituted by 1 or 2 substituents independently of one another selected from (C.sub.1-C.sub.6)-alkyl and (C.sub.1-C.sub.4)-alkylcarbonyl, in which (C.sub.1-C.sub.6)-alkyl may be substituted by amino, in which phenyl, pyridyl and pyrimidyl may be substituted by 1 or 2 substituents selected from the group consisting of methyl, ethyl and fluorine, and in which R.sup.7 and R.sup.8 each independently of one another represent hydrogen, methyl, ethyl or cyclopropyl, R.sup.4 represents hydrogen, R.sup.5 represents hydrogen, fluorine, chlorine, cyano, difluoromethyl, trifluoromethyl, (C.sub.1-C.sub.4)-alkyl or (C.sub.3-C.sub.5)-cycloalkyl, R.sup.6 represents hydrogen, and the N-oxides, salts, solvates, salts of the N-oxides and solvates of the N-oxides and salts thereof.

4. Compound of the formula (I-A) according to claim 1, in which A represents CH.sub.2, R.sup.1 represents phenyl, where phenyl is substituted up to three times by fluorine, R.sup.2 represents methyl, R.sup.3 represents phenyl, pyridyl, pyrimidyl or 4-pyrazolyl, where phenyl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of fluorine, (C.sub.1-C.sub.6)-alkyl, hydroxycarbonyl, —(C═O)NR.sup.7R.sup.8, methylsulphonyl, ethylsulphonyl, amino, morpholinyl, piperidinyl, pyrrolidinyl and piperazinyl, in which amino may be substituted by 1 or 2 substituents independently of one another selected from (C.sub.1-C.sub.6)-alkyl, methylcarbonyl, ethylcarbonyl, methylsulphonyl and ethylsulphonyl, in which (C.sub.1-C.sub.6)-alkyl may be substituted by 1 or 2 substituents selected from the group consisting of fluorine, morpholinyl, piperidinyl, pyrrolidinyl, piperazinyl and amino, in which amino may be substituted by 1 or 2 substituents independently of one another selected from (C.sub.1-C.sub.4)-alkyl, methylcarbonyl, ethylcarbonyl, methylsulphonyl and ethylsulphonyl, and in which R.sup.7 and R.sup.8 each independently of one another represent hydrogen or cyclopropyl, where pyridyl and 4-pyrazolyl may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of fluorine, chlorine, (C.sub.1-C.sub.6)-alkyl, methoxy, amino, hydroxycarbonyl, —(C═O)NR.sup.7R.sup.8, phenyl, pyridyl, pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl, in which (C.sub.1-C.sub.6)-alkyl may be substituted by 1 to 3 substituents selected from the group consisting of fluorine, hydroxy, amino, hydroxycarbonyl, —(C═O)NR.sup.7R.sup.8, methoxy, phenyl, pyridyl, pyrazolyl, (C.sub.3-C.sub.7)-cycloalkyl, morpholinyl, piperidinyl, pyrrolidinyl and piperazinyl, in which pyrazolyl may be substituted by 1 or 2 methyl substituents, and in which R.sup.7 and R.sup.8 each independently of one another represent hydrogen, methyl, ethyl or cyclopropyl, in which amino may be substituted by 1 or 2 (C.sub.1-C.sub.6)-alkyl substituents, in which (C.sub.1-C.sub.6)-alkyl may be substituted by amino, in which phenyl, pyridyl and pyrimidyl may be substituted by 1 or 2 substituents selected from the group consisting of methyl, ethyl and fluorine, and in which R.sup.7 and R.sup.8 each independently of one another represent hydrogen, methyl or cyclopropyl, R.sup.4 represents hydrogen, R.sup.5 represents hydrogen or methyl, R.sup.6 represents hydrogen, and the N-oxides, salts, solvates, salts of the N-oxides and solvates of the N-oxides and salts thereof.

5. Compound of the formula (I-A) according to claim 1, in which A represents CH.sub.2, R.sup.1 represents a phenyl group of the formula ##STR00111## where # represents the point of attachment to A, and R.sup.9 represents hydrogen or fluorine, R.sup.10 represents fluorine, R.sup.11 represents fluorine, R.sup.2 represents methyl, R.sup.3 represents phenyl, 3-pyridyl, 4-pyridyl or 4-pyrazolyl, where phenyl in the 3-position may be substituted by fluorine, (C.sub.1-C.sub.6)-alkyl, hydroxycarbonyl, —(C═O)NR.sup.7R.sup.8, methylsulphonyl, ethylsulphonyl, amino, morpholinyl, piperidinyl, pyrrolidinyl and piperazinyl, in which amino may be substituted by 1 or 2 substituents independently of one another selected from (C.sub.1-C.sub.6)-alkyl, methylcarbonyl, ethylcarbonyl, methylsulphonyl and ethylsulphonyl, in which (C.sub.1-C.sub.6)-alkyl may be substituted by 1 or 2 substituents selected from the group consisting of fluorine, morpholinyl, piperidinyl, pyrrolidinyl, piperazinyl and amino, in which amino may be substituted by 1 or 2 substituents independently of one another selected from (C.sub.1-C.sub.4)-alkyl, methylcarbonyl, ethylcarbonyl, methylsulphonyl and ethylsulphonyl, and in which R.sup.7 and R.sup.8 each independently of one another represent hydrogen or cyclopropyl, where 3-pyridyl and 4-pyridyl may each be substituted by 1 or 2 substituents independently of one another selected from the group consisting of fluorine, chlorine, (C.sub.1-C.sub.6)-alkyl, methoxy, amino, hydroxycarbonyl, —(C═O)NR.sup.7R.sup.8, phenyl, pyridyl, pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl, in which amino may be substituted by 1 or 2 (C.sub.1-C.sub.6)-alkyl substituents, in which (C.sub.1-C.sub.6)-alkyl may be substituted by amino, in which phenyl, pyridyl and pyrimidyl may be substituted by 1 or 2 substituents selected from the group consisting of methyl, ethyl and fluorine, and in which R.sup.7 and R.sup.8 each independently of one another represent hydrogen, methyl or cyclopropyl, where 4-pyrazolyl may be substituted at the 1-position by (C.sub.1-C.sub.6)-alkyl, phenyl or pyridyl, in which (C.sub.1-C.sub.6)-alkyl may be substituted by 1 to 3 substituents selected from the group consisting of fluorine, hydroxy, amino, methoxycarbonyl, ethoxycarbonyl, hydroxycarbonyl, —(C═O)NR.sup.7R.sup.8, methoxy, phenyl, pyridyl, pyrazolyl, (C.sub.3-C.sub.7)-cycloalkyl, morpholinyl, piperidinyl, pyrrolidinyl and piperazinyl, in which pyrazolyl may be substituted by 1 to 3 methyl substituents, in which R.sup.7 and R.sup.8 each independently of one another represent hydrogen, methyl, ethyl or cyclopropyl, in which phenyl and pyridyl may be substituted by 1 or 2 substituents selected from the group consisting of methyl, ethyl and fluorine, R.sup.4 represents hydrogen, R.sup.5 represents hydrogen or methyl, R.sup.6 represents hydrogen, and the N-oxides, salts, solvates, salts of the N-oxides and solvates of the N-oxides and salts thereof.

6. Compound of the formula (I-A) according to claim 1, in which A represents CH.sub.2, R.sup.1 represents a phenyl group of the formula ##STR00112## where # represents the point of attachment to A, and R.sup.9 represents hydrogen or fluorine, R.sup.10 represents fluorine, R.sup.11 represents fluorine, R.sup.2 represents methyl, R.sup.3 represents phenyl, 3-pyridyl, 4-pyridyl or 4-pyrazolyl, where phenyl in the 3-position may be substituted by (C.sub.1-C.sub.6)-alkyl, hydroxycarbonyl, —(C═O)NR.sup.7R.sup.8, methylsulphonyl, ethylsulphonyl, amino and pyrrolidinyl, in which amino may be substituted by 1 or 2 substituents independently of one another selected from (C.sub.1-C.sub.6)-alkyl, methylcarbonyl and methylsulphonyl, in which (C.sub.1-C.sub.6)-alkyl may be substituted by 1 or 2 substituents selected from the group consisting of fluorine, pyrrolidinyl and amino, in which amino may be substituted by 1 or 2 substituents independently of one another selected from (C.sub.1-C.sub.4)-alkyl, methylcarbonyl and methylsulphonyl, and in which R.sup.7 and R.sup.8 each independently of one another represent hydrogen or cyclopropyl, where 3-pyridyl and 4-pyridyl may each be substituted by 1 or 2 substituents independently of one another selected from the group consisting of fluorine, chlorine, (C.sub.1-C.sub.6)-alkyl, amino, hydroxycarbonyl, —(C═O)NR.sup.7R.sup.8, phenyl and piperazinyl, in which amino may be substituted by 1 or 2 (C.sub.1-C.sub.6)-alkyl substituents, in which (C.sub.1-C.sub.6)-alkyl may be substituted by amino, in which phenyl may be substituted by 1 or 2 substituents selected from the group consisting of methyl, ethyl and fluorine, and in which R.sup.7 and R.sup.8 each represent hydrogen, where 4-pyrazolyl may be substituted at the 1-position by (C.sub.1-C.sub.6)-alkyl or phenyl, in which (C.sub.1-C.sub.6)-alkyl may be substituted by 1 to 3 substituents selected from the group consisting of hydroxy, amino, methoxycarbonyl, hydroxycarbonyl, —(C═O)NR.sup.7R.sup.8, phenyl, pyrazolyl, (C.sub.3-C.sub.7)-cycloalkyl and morpholinyl, in which pyrazolyl may be substituted by 1 or 3 methyl substituents, in which R.sup.7 represents hydrogen, R.sup.8 represents cyclopropyl, in which phenyl and pyridyl may be substituted by 1 or 2 fluorine substituents, R.sup.4 represents hydrogen, R.sup.5 represents hydrogen or methyl, R.sup.6 represents hydrogen, and the N-oxides, salts, solvates, salts of the N-oxides and solvates of the N-oxides and salts thereof.

7. Compound of the formula (I-B) according to claim 1 in which A represents CH.sub.2 or CD.sub.2, R.sup.1 represents or phenyl, where phenyl is substituted by 1 to 3 fluorine substituents, R.sup.2 represents methyl, R.sup.3 represents 5- or 6-membered heteroaryl, where 5- or 6-membered heteroaryl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of (C.sub.1-C.sub.4)-alkyl and amino, in which (C.sub.1-C.sub.4)-alkyl may be substituted by 1 to 3 substituents selected from the group consisting of hydroxy, amino, (C.sub.1-C.sub.4)-alkoxycarbonyl, hydroxycarbonyl, phenyl, 5-membered heteroaryl, (C.sub.3-C.sub.7)-cycloalkyl, morpholinyl and 1,1-dioxidothiomorpholin-4-yl, in which amino may be substituted by (C.sub.1-C.sub.6)-alkyl, in which (C.sub.1-C.sub.6)-alkyl may be substituted by amino, or R.sup.3 represents a group of the formula ##STR00113## where * represents the point of attachment to the imidazopyrazine, R.sup.9 represents hydrogen or (C.sub.1-C.sub.6)-alkyl, where (C.sub.1-C.sub.6)-alkyl may be substituted by amino, R.sup.10 represents methyl or ethyl, R.sup.11 represents methyl, ethyl or trifluoromethyl, R.sup.4 represents hydrogen, R.sup.5 represents hydrogen or methyl, R.sup.6 represents hydrogen, and the N-oxides, salts, solvates, salts of the N-oxides and solvates of the N-oxides and salts thereof.

8. Process for preparing compounds of the formula (I-A) or (I-B) as defined in claim 1, comprising [A] reacting a compound of the formula (II) ##STR00114## in which A, R.sup.1, R.sup.2, R.sup.4, R.sup.5 and R.sup.6 each have the meanings given in claim 1 and T.sup.1 represents (C.sub.1-C.sub.4)-alkyl or benzyl, in an inert solvent in the presence of a suitable base or acid to give a carboxylic acid of the formula (III) ##STR00115## in which A, R.sup.1, R.sup.2, R.sup.4, R.sup.5 and R.sup.6 each have the meanings given above, converting the carboxylic acid of the formula (III) with a halogen equivalent in the presence of a suitable base into a compound of the formula (IV) ##STR00116## in which A, R.sup.1, R.sup.2, R.sup.4, R.sup.5 and R.sup.6 each have the meanings given above and X.sup.1 represents chlorine, bromine or iodine, and reacting the compound of the formula (IV) in an inert solvent, in the presence of a suitable transition metal catalyst, with a compound of the formula (V) ##STR00117## in which R.sup.3A has the meanings given above for R.sup.3 and T.sup.2 represents hydrogen or (C.sub.1-C.sub.4)-alkyl, or the two T.sup.2 radicals together form a —C(CH.sub.3).sub.2—C(CH.sub.3).sub.2— bridge, to give a compound of the formula (I-A1) ##STR00118## in which A, R.sup.1, R.sup.2, R.sup.4, R.sup.5 and R.sup.6 each have the meanings given above, and if R.sup.3A represents ##STR00119## reacting the compound of formula (I-A1) in an inert solvent in the presence of a suitable base with a compound of the formula (VII)
R.sup.12—X.sup.1  (VII), in which X.sup.1 represents a suitable leaving group, in particular chlorine, bromine, iodine, mesylate, triflate or tosylate, and R.sup.12 represents (C.sub.1-C.sub.6)-alkyl, in which (C.sub.1-C.sub.6)-alkyl may be substituted by 1 to 3 substituents selected from the group consisting of fluorine, cyano, hydroxy, amino, trifluoromethyl, difluoromethyl, (C.sub.1-C.sub.4)-alkylsulphonyl, (C.sub.1-C.sub.4)-alkylcarbonyl, (C.sub.1-C.sub.4)-alkoxycarbonyl, hydroxycarbonyl, —(C═O)NR.sup.7R.sup.8 (C.sub.1-C.sub.4)-alkoxy, phenoxy, phenyl, pyridyl, pyrimidyl, 5-membered heteroaryl, (C.sub.3-C.sub.7)-cycloalkyl, morpholinyl, piperidinyl, pyrrolidinyl, piperazinyl, 1,1-dioxidothiomorpholin-4-yl and azetidine, in which 5-membered heteroaryl may be substituted by 1 to 3 substituents selected from the group consisting of halogen, (C.sub.1-C.sub.4)-alkyl and (C.sub.1-C.sub.4)-alkoxy, in which R.sup.7 and R.sup.8 each independently of one another represent hydrogen, (C.sub.1-C.sub.4)-alkyl or (C.sub.3-C.sub.7)-cycloalkyl, in which piperidinyl may be substituted by 1 to 4 fluorine substituents, in which phenyl may be substituted by 1 to 3 substituents selected from the group consisting of halogen, (C.sub.1-C.sub.4)-alkyl and (C.sub.1-C.sub.4)-alkoxy, in which azetidine may be substituted by hydroxy, in which amino may be substituted by 1 or 2 (C.sub.1-C.sub.4)-alkyl substituents, and in which piperazinyl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of (C.sub.1-C.sub.4)-alkyl, (C.sub.3-C.sub.7)-cycloalkyl and trifluoromethyl, to give a compound of the formula (I-A2) ##STR00120## in which A, R.sup.1, R.sup.2, R.sup.4, R.sup.5, R.sup.6 and R.sup.12 each have the meanings given above, and detaching any protective groups present, and the resulting compounds of the formula (I-A) are optionally converted with the appropriate (i) solvents and/or (ii) acids or bases to the solvates, salts and/or solvates of the salts thereof. or [B] reacting a compound of the formula (VIII) ##STR00121## in which A, R.sup.1, R.sup.2, R.sup.4 and R.sup.5 each have the meanings given above and T.sup.1 represents (C.sub.1-C.sub.4)-alkyl or benzyl, in an inert solvent in the presence of a suitable base or acid to give a carboxylic acid of the formula (IX) ##STR00122## in which A, R.sup.1, R.sup.2, R.sup.4 and R.sup.5 each have the meanings given above, then converting the carboxylic acid of the formula IX with a halogen equivalent in the presence of a base into a compound of the formula (X) ##STR00123## in which A, R.sup.1, R.sup.2, R.sup.4 and R.sup.5 each have the meanings given above and X.sup.1 represents chlorine, bromine or iodine, and reacting the compound of the formula (X) in an inert solvent, in the presence of a suitable transition metal catalyst, with a compound of the formula (V) ##STR00124## in which R.sup.3A has the meanings given above for R.sup.3 and T.sup.2 represents hydrogen or (C.sub.1-C.sub.4)-alkyl, or the two T.sup.2 radicals together form a —C(CH.sub.3).sub.2—C(CH.sub.3).sub.2— bridge, then detaching any protective groups present, and optionally converting the resulting compounds of the formula (I-B) with the appropriate (i) solvents and/or (ii) acids or bases to the solvates, salts and/or solvates of the salts thereof.

9. (canceled)

10. (canceled)

11. Medicament comprising the compound of the formula (I-A) or (I-B) as defined in claim 1 in combination with an inert, non-toxic, pharmaceutically suitable excipient.

12. Medicament comprising the compound of the formula (I-A) or (I-B) as defined in claim 1 in combination with a further active compound selected from the group consisting of organic nitrates, NO donors, cGMP-PDE inhibitors, antithrombotic agents, hypotensive agents and lipid metabolism modifiers.

13. (canceled)

14. Method for the treatment and/or prophylaxis of heart failure, angina pectoris, hypertension, pulmonary hypertension, ischaemias, vascular disorders, renal insufficiency, thromboembolic disorders and arteriosclerosis in humans and animals comprising administering an effective amount of at least one compound of the formula (I-A) or (I-B) as defined in claim 1 to a human or animal in need thereof.

15. Method for the treatment and/or prophylaxis of heart failure, angina pectoris, hypertension, pulmonary hypertension, ischaemias, vascular disorders, renal insufficiency, thromboembolic disorders and arteriosclerosis in humans and animals comprising administering an effective amount of the medicament as defined in claim 11 to a human or animal in need thereof.

16. Method for the treatment and/or prophylaxis of heart failure, angina pectoris, hypertension, pulmonary hypertension, ischaemias, vascular disorders, renal insufficiency, thromboembolic disorders and arteriosclerosis in humans and animals comprising administering an effective amount of the medicament as defined in claim 12 to a human or animal in need thereof.

Description

A. EXAMPLES

Abbreviations and Acronyms:

[0517] abs. absolute (=dried) [0518] aq. aqueous solution [0519] calc. calculated [0520] Boc tert-butyloxycarbonyl [0521] br. broad signal (NMR coupling pattern) [0522] CAS No. Chemical Abstracts Service number [0523] Cbz benzyloxycarbonyl [0524] δ shift in the NMR spectrum (stated in ppm) [0525] d doublet (NMR coupling pattern) [0526] TLC thin-layer chromatography [0527] DCI direct chemical ionization (in MS) [0528] DMAP 4-N,N-dimethylaminopyridine [0529] DMF dimethylformamide [0530] DMSO dimethyl sulphoxide [0531] EDCI N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide [0532] ent enantiomerically pure [0533] eq. equivalent(s) [0534] ESI electrospray ionization (in MS) [0535] Et ethyl [0536] h hour(s) [0537] HATU N-[(dimethylamino)(3H-[1,2,3]triazolo[4,5-b]-pyridine-3-yloxy)methylene]-N-methylmethanaminium [0538] HOBT hexafluorophosphate 1H-benzotriazol-1-ol [0539] HPLC high-pressure, high-performance liquid chromatography [0540] HRMS high-resolution mass spectrometry [0541] ID internal diameter [0542] conc. concentrated [0543] LC-MS liquid chromatography-coupled mass spectrometry [0544] LiHMDS lithium hexamethyldisilazide [0545] m multiplet [0546] Me methyl [0547] min minute(s) [0548] MS mass spectrometry [0549] NMR nuclear magnetic resonance spectrometry [0550] PDA photodiode array detector [0551] Pd.sub.2dba.sub.3 tris(dibenzylideneacetone)dipalladium [0552] Ph phenyl [0553] q quartet (NMR coupling pattern) [0554] quint. quintet (NMR coupling pattern) [0555] rac racemic [0556] rel relative stereochemistry [0557] R.sub.F retention factor (in thin-layer chromatography) [0558] RT room temperature [0559] R.sub.t retention time (in HPLC) [0560] s singlet (NMR coupling pattern) [0561] t triplet (NMR coupling pattern) [0562] TFA Trifluoroacetic acid [0563] THF tetrahydrofuran [0564] TBTU (benzotriazol-1-yloxy)bisdimethylaminomethylium fluoroborate [0565] UPLC-MS ultra-pressure liquid chromatography-coupled mass spectrometry [0566] UV ultraviolet spectrometry [0567] v/v volume to volume ratio (of a solution) [0568] Xantphos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene [0569] XPHOS dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine

LC-MS and HPLC Methods:

Method 1 (LC-MS):

[0570] Instrument: Micromass Quattro Premier with Waters UPLC Acquity; column: Thermo Hypersil GOLD 1.9 50×1 mm; mobile phase A: 1 l of water+0.5 ml of 50% strength formic acid, mobile phase B: 1 l of acetonitrile+0.5 ml of 50% strength formic acid; gradient: 0.0 min 90% A.fwdarw.0.1 min 90% A.fwdarw.1.5 min 10% A.fwdarw.2.2 min 10% A; oven: 50° C.; flow rate: 0.33 ml/min; UV detection: 210 nm

Method 2 (LC-MS):

[0571] Instrument: Waters ACQUITY SQD UPLC system; column: Waters Acquity UPLC HSS T3 1.8μ 50×1 mm; mobile phase A: 1 l of water+0.25 ml of 99% strength formic acid, mobile phase B: 1 l of acetonitrile+0.25 ml of 99% strength formic acid; gradient: 0.0 min 90% A.fwdarw.1.2 min 5% A.fwdarw.2.0 min 5% A; oven: 50° C.; flow rate: 0.40 ml/min; UV detection: 210-400 nm.

Method 3 (LC-MS):

[0572] Instrument: Micromass Quattro Premier with Waters UPLC Acquity; column: Thermo Hypersil GOLD 1.9 50×1 mm; mobile phase A: 1 l of water+0.5 ml of 50% strength formic acid, mobile phase B: 1 l of acetonitrile+0.5 ml of 50% strength formic acid; gradient: 0.0 min 97% A.fwdarw.0.5 min 97% A.fwdarw.3.2 min 5% A.fwdarw.4.0 min 5% A; oven: 50° C.; flow rate: 0.3 ml/min; UV detection: 210 nm.

Method 4 (Preparative HPLC):

[0573] Chromatorex C18 10μ 250×20 mm gradient: A=water+0.5% HCOOH, B=CH.sub.3CN, 0 min=5% B, 3 min=5% B pre-rinse without substance, then injection, 5 min=5% B, 25 min=30% B, 38 min=30% B, 38.1 min=95% B, 43 min=95% B, 43.01 min=5% B, 48.0 min=5% B flow rate 20 ml/min, wavelength 210 nm.

Method 5 (Preparative HPLC):

[0574] Chromatorex C18 10μ 250×20 mm gradient: A=water+0.5% HCOOH, B=CH.sub.3CN, 0 min=5% B, 3 min=5% B pre-rinse without substance, then injection, 5 min=5% B, 25 min=50% B, 38.1 min=50% B, 38 min=95% B, 43 min=95% B, 43.01 min=5% B, 48.0 min=5% B flow rate 20 ml/min, wavelength 210 nm.

Method 6 (Preparative HPLC):

[0575] XBridge Prep. C18 5μ 50×19 mm gradient: A=water+0.5% NH.sub.4OH, B=CH.sub.3CN, 0 min=5% B, 3 min=5% B pre-rinse without substance, then injection, 5 min=5% B, 25 min=50% B, 38 min=50% B, 38.1 min=95% B, 43 min=95% B, 43.01 min=5% B, 48.0 min=5% B flow rate 15 ml/min, wavelength 210 nm.

Method 7 (LC-MS):

[0576] MS instrument: Waters (Micromass) QM; HPLC instrument: Agilent 1100 series; column: Agilent ZORBAX Extend-C18 3.0×50 mm 3.5 micron; mobile phase A: 1 l of water+0.01 mol of ammonium carbonate, mobile phase B: 1 l of acetonitrile; gradient: 0.0 min 98% A.fwdarw.0.2 min 98% A.fwdarw.3.0 min 5% A.fwdarw.4.5 min 5% A; oven: 40° C.; flow rate: 1.75 ml/min; UV detection: 210 nm.

Method 8 (LC-MS):

[0577] Instrument: Waters ACQUITY SQD UPLC system; column: Waters Acquity UPLC HSS T3 1.8μ 30×2 mm; mobile phase A: 1 l of water+0.25 ml of 99% strength formic acid, mobile phase B: 1 l of acetonitrile+0.25 ml of 99% strength formic acid; gradient: 0.0 min 90% A.fwdarw.1.2 min 5% A.fwdarw.2.0 min 5% A; oven: 50° C.; flow rate: 0.60 ml/min; UV detection: 208-400 nm.

Method 9 (Preparative HPLC):

[0578] MS instrument: Waters, HPLC instrument: Waters (column Waters X-Bridge C18, 18 mm×50 mm, 5 m, mobile phase A: water+0.05% triethylamine, mobile phase B: acetonitrile (ULC)+0.05% triethylamine, with gradient; flow rate: 40 ml/min; UV detection: DAD; 210-400 nm).

or:

[0579] MS instrument: Waters, HPLC instrument: Waters (column Phenomenex Luna 5μ C18(2) 100 A, AXIA Tech. 50×21.2 mm, mobile phase A: water+0.05% formic acids, mobile phase B: acetonitrile (ULC)+0.05% formic acid, with gradient; flow rate: 40 ml/min; UV detection: DAD; 210-400 nm).

Method 10 (LC-MS):

[0580] MS instrument: Waters SQD; HPLC instrument: Waters UPLC; column: Zorbax SB-Aq (Agilent), 50 mm×2.1 mm, 1.8 m; mobile phase A: water+0.025% formic acid, mobile phase B: acetonitrile (ULC)+0.025% formic acid; gradient: 0.0 min 98% A—0.9 min 25% A—1.0 min 5% A—1.4 min 5% A—1.41 min 98% A—1.5 min 98% A; oven: 40° C.; flow rate: 0.600 ml/min; UV detection: DAD; 210 nm.

Method 11 (MS):

[0581] Instrument: Waters ZQ 2000; electrospray ionization; mobile phase A: 1 l of water+0.25 ml of 99% strength formic acid, mobile phase B: 1 l of acetonitrile+0.25 ml of 99% strength formic acid; 25% A, 75% B; flow rate: 0.25 ml/min.

Method 12 (DCI-MS):

[0582] Instrument: Thermo Fisher-Scientific DSQ; chemical ionization; reactant gas NH.sub.3; source temperature: 200° C.; ionization energy 70 eV.

Method 13 (LC-MS):

[0583] MS instrument: Waters (Micromass) Quattro Micro; HPLC instrument: Agilent 1100 series; column: YMC-Triart C18 3μ 50×3 mm; mobile phase A: 1 l of water+0.01 mol of ammonium carbonate, mobile phase B: 1 l of acetonitrile; gradient: 0.0 min 100% A—2.75 min 5% A.fwdarw.4.5 min 5% A; oven: 40° C.; flow rate: 1.25 ml/min; UV detection: 210 nm.

Method 14 (GC-MS):

[0584] Instrument: Thermo Scientific DSQII, Thermo Scientific Trace GC Ultra; column: Restek RTX-35MS, 15 m×200 μm×0.33 μm; constant flow rate with helium: 1.20 ml/min; oven: 60° C.; inlet: 220° C.; gradient: 60° C., 30° C./min.fwdarw.300° C. (maintain for 3.33 min).

Method 15 (LC-MS, Analytical):

[0585] Instrument: Agilent MS Quad 6150; HPLC: Agilent 1290; column: Waters Acquity UPLC HSS T3 1.8μ 50×2.1 mm; mobile phase A: 1 l of water+0.25 ml of 99% strength formic acid, mobile phase B: 1 l of acetonitrile+0.25 ml of 99% strength formic acid; gradient: 0.0 min 90% A.fwdarw.0.3 min 90% A.fwdarw.1.7 min 5% A.fwdarw.3.0 min 5% A; oven: 50° C.; flow rate: 1.20 ml/min; UV detection: 205-305 nm.

Method 16 (LC-MS, Analytical):

[0586] MS instrument type: Thermo Scientific FT-MS; instrument type UHPLC+: Thermo Scientific UltiMate 3000; column: Waters, HSST3, 2.1×75 mm, C18 1.8 μm; mobile phase A: 1 l of water+0.01% formic acid; mobile phase B: 1 l of acetonitrile+0.01% formic acid; gradient: 0.0 min 10% B.fwdarw.2.5 min 95% B.fwdarw.3.5 min 95% B; oven: 50° C.; flow rate: 0.90 ml/min; UV detection: 210 nm/optimum integration path 210-300 nm.

[0587] Unless stated otherwise, the percentages in the tests and examples which follow are percentages by weight; parts are parts by weight. Solvent ratios, dilution ratios and concentration data for liquid/liquid solutions are based in each case on volume.

[0588] The multiplicities of proton signals in .sup.1H NMR spectra reported in the paragraphs which follow represent the signal form observed in each case and do not take account of any higher-order signal phenomena. In all .sup.1H NMR spectra data, the chemical shifts δ are stated in ppm.

[0589] Additionally, the starting materials, intermediates and working examples may be present as hydrates. There was no quantitative determination of the water content. In certain cases, the hydrates may affect the .sup.1H NMR spectrum and possibly shift and/or significantly broaden the water signal in the .sup.1H NMR.

[0590] In .sup.1H NMR spectra, the methyl group of the chemical system “2-methylpyrazolo[1,5-a]pyridine” appears as a singlet (frequently in DMSO-d.sub.6 and in the range of 2.40-2.60 ppm) and is clearly distinguishable as such, is superposed by the solvent signals or is completely under the signals of the solvents. In the .sup.1H NMR spectra, this signal can be assumed to be present.

[0591] When compounds of the invention are purified by preparative HPLC by the above-described methods in which the mobile phases contain additives, for example trifluoroacetic acid, formic acid or ammonia, the compounds of the invention may be obtained in salt form, for example as trifluoroacetate, formate or ammonium salt, if the compounds of the invention contain a sufficiently basic or acidic functionality. Such a salt can be converted to the corresponding free base or acid by various methods known to the person skilled in the art.

[0592] In the case of the synthesis intermediates and working examples of the invention described hereinafter, any compound specified in the form of a salt of the corresponding base or acid is generally a salt of unknown exact stoichiometric composition, as obtained by the respective preparation and/or purification process. Unless specified in more detail, additions to names and structural formulae, such as “hydrochloride”, “trifluoroacetate”, “sodium salt” or “x HCl”, “x CF.sub.3CO.sub.2H”, “x Na.sup.+” should not therefore be understood in a stoichiometric sense in the case of such salts, but have merely descriptive character with regard to the salt-forming components present therein.

[0593] This applies correspondingly if synthesis intermediates or working examples or salts thereof were obtained in the form of solvates, for example hydrates, of unknown stoichiometric composition (if they are of a defined type) by the preparation and/or purification processes described.

Starting Compounds and Intermediates:

Example 1A

2-[(2,6-Difluorobenzyl)oxy]-4-methylpyridine

[0594] ##STR00044##

[0595] A mixture of 5.00 g (24.2 mmol, 1.0 eq.) of 2,6-difluorobenzyl bromide [CAS No: 85118-00-9] and 3.16 g (29.0 mmol, 1.2 eq.) of 2-hydroxy-4-methylpyridine [CAS No: 13466-41-6] was dissolved in 50 ml of THF. 7.99 g (29.0 mmol, 1.2 eq.) of silver carbonate were added to the solution, and the mixture was heated at reflux with exclusion of light overnight. Subsequently, the reaction mixture was filtered through kieselguhr, eluting with ethyl acetate, and the filtrate was concentrated. The crude product was purified by means of Biotage Isolera (100 g silica gel cartridge, cyclohexane/ethyl acetate gradient, 0% to 10% ethyl acetate). This gave 3.51 g of the title compound (61% of theory).

[0596] TLC (silica gel, cyclohexane/ethyl acetate 10:1): R.sub.F=0.50

[0597] LC-MS (Method 2): R.sub.t=1.17 min

[0598] MS (ESpos): m/z=236 (M+H).sup.+

[0599] .sup.1H-NMR (400 Mhz, DMSO-d.sub.6): δ [ppm]=2.26 (s, 3H), 5.35 (s, 2H), 6.66 (s, 1H), 6.86 (d, 1H), 7.12-7.21 (m, 2H), 7.47-7.56 (m, 1H), 8.06 (d, 1H).

Example 2A

1-Amino-2-[(2,6-difluorobenzyl)oxy]-4-methylpyridinium 2,4,6-trimethylbenzenesulphonate

[0600] ##STR00045##

[0601] A mixture of 3.4 ml (43.9 mmol, 10 eq.) of trifluoroacetic acid and 0.33 ml water was cooled to −5° C. At this temperature, 1.88 g (6.59 mmol, 1.5 eq.) of ethyl (1E)-N-[(mesitylsulphonyl)oxy]ethanimidoate [CAS No: 38202-27-6] were added in portions. After 1.5 h, 30 ml of ice-water were added, the mixture was stirred briefly, and the precipitated O-(2-mesitylenesulphonyl)hydroxylamine (MSH) was filtered off using a precooled frit and washed with 30 ml of ice-water. The water-moist O-(2-mesitylenesulphonyl)hydroxylamine was dissolved in 12 ml of dichloromethane, dried with magnesium sulphate and filtered, and the filtrate was added dropwise directly to a solution of 1.03 g (4.39 mmol, 1.0 eq.) of 2-[(2,6-difluorobenzyl)oxy]-4-methylpyridine from Example 1A in 2 ml of dichloromethane. The mixture was stirred at RT overnight. Subsequently, diethyl ether was added dropwise, and the precipitate obtained was filtered off, washed with diethyl ether and dried. 1.3 g of the title compound were isolated (59% of theory, purity 90%).

[0602] .sup.1H-NMR (400 Mhz, DMSO-d.sub.6): δ [ppm]=2.17 (s, 3H), 2.46-2.57 (s, 3H and s, 6H superposed by the solvent signal), 5.64 (s, 2H), 6.74 (s, 2H), 7.23-7.48 (m, 4H), 7.60-7.70 (m, 1H), 7.86 (br s, 1H), 8.44 (d, 1H).

Example 3A

Ethyl 7-[(2,6-difluorobenzyl)oxy]-2,5-dimethylpyrazolo[1,5-a]pyridine-3-carboxylate

[0603] ##STR00046##

[0604] 1.62 g (3.60 mmol, 1.0 eq.) of 1-amino-2-[(2,6-difluorobenzyl)oxy]-4-methylpyridinium 2,4,6-trimethylbenzenesulphonate from Example 2A were dissolved in 36 ml of DMF, and 0.84 ml (7.19 mmol, 2.0 eq.) of ethyl but-2-ynoate [CAS No: 4341-76-8] were added. 0.994 g (7.19 mmol, 2.0 eq.) of potassium carbonate was added and the mixture was stirred at RT for 1.5 h. Subsequently, the mixture was poured onto 150 ml of water and stirred briefly, and the precipitated solids were filtered off, washed with water and dried. This gave 440 mg of the title compound (45% of theory, 87%).

[0605] LC-MS (Method 2): R.sub.t=1.22 min

[0606] MS (ESpos): m/z=361 (M+H).sup.+

Example 4A

7-[(2,6-Difluorobenzyl)oxy]-2,5-dimethylpyrazolo[1,5-a]pyridine-3-carboxylic acid

[0607] ##STR00047##

[0608] 4.9 ml (4.88 mmol, 4.0 eq.) of 1 N aqueous sodium hydroxide solution were added to a solution of 0.440 g (1.22 mmol, 1 eq.) of ethyl 7-[(2,6-difluorobenzyl)oxy]-2,5-dimethylpyrazolo[1,5-a]pyridine-3-carboxylate from Example 3A in 12.7 ml of dioxane, and the mixture was stirred at 90° C. for 36 h. Subsequently, the reaction mixture was concentrated and the precipitated solids were filtered off. The filtrate was acidified with 6 N aqueous hydrochloric acid and stirred briefly, and the precipitated solids were filtered off, washed with water and dried. This gave 248 mg of the title compound (61% of theory, purity 60%), which was converted further without further purification.

[0609] LC-MS (Method 2): R.sub.t=0.96 min

[0610] MS (ESpos): m/z=333 (M+H).sup.+

Example 5A

2-(Benzyloxy)-4-methylpyridine

[0611] ##STR00048##

[0612] A mixture of 13.6 ml (114 mmol, 1.0 eq.) of benzyl bromide and 15.0 g (137 mmol, 1.2 eq.) of 2-hydroxy-4-methylpyridine [CAS No: 13466-41-6] was dissolved in 470 ml of THF. 37.9 g (137 mmol, 1.2 eq.) of silver carbonate were added to the solution, and the mixture was heated at reflux with exclusion of light overnight. Subsequently, the reaction mixture was filtered through kieselguhr, eluting with ethyl acetate, and the filtrate was concentrated. The crude product was purified by silica gel chromatography (700 g of silica gel, cyclohexane/ethyl acetate 95:5). This gave 21.4 g of the title compound (94% of theory).

[0613] TLC (silica gel, cyclohexane/ethyl acetate 9:1): R.sub.F=0.41

[0614] LC-MS (Method 2): R.sub.t=1.12 min

[0615] MS (ESpos): m/z=200 (M+H).sup.+

[0616] .sup.1H-NMR (400 Mhz, DMSO-d.sub.6): δ [ppm]=2.27 (s, 3H), 5.33 (s, 2H), 6.70 (s, 1H), 6.83 (d, 1H), 7.27-7.45 (m, 5H), 8.02 (d, 1H).

Example 6A

1-Amino-2-(benzyloxy)-4-methylpyridinium 2,4,6-trimethylbenzenesulphonate

[0617] ##STR00049##

[0618] A mixture of 18.0 ml of trifluoroacetic acid (233 mmol, 10 eq.) and 2.66 ml of water was cooled to −5° C. At this temperature, 9.99 g (35.0 mmol, 1.5 eq.) of ethyl (1E)-N-[(mesitylsulphonyl)oxy]ethanimidoate [CAS No: 38202-27-6] were added a little at a time. After 1.5 h, 150 ml of ice-water were added, and the mixture was stirred briefly and extracted with 100 ml of dichloromethane. The organic phase was dried with magnesium sulphate and filtered, and the resulting solution of O-(2-mesitylenesulphonyl)hydroxylamine (MSH) was added dropwise directly to a solution, cooled to 0° C., of 4.65 g (23.3 mmol, 1.0 eq.) of 2-(benzyloxy)-4-methylpyridine from Example 5A in 50 ml of dichloromethane. The mixture was stirred at RT for 2 h. Subsequently, 1 l of diethyl ether was added dropwise, and precipitated solids were filtered off, washed with 250 ml of diethyl ether and dried. 4.6 g of the title compound were isolated (48% of theory).

[0619] LC-MS (Method 2): R.sub.t=0.45 min;

[0620] MS (ESpos): m/z=215 (C.sub.13H.sub.15N.sub.2O) (M).sup.+; R.sub.t=0.57 min;

[0621] MS (ESneg): m/z=199 (C.sub.9H.sub.11O.sub.3S).sup.−;

Example 7A

Ethyl 7-(benzyloxy)-2,5-dimethylpyrazolo[1,5-a]pyridine-3-carboxylate

[0622] ##STR00050##

[0623] 11.7 g (28.2 mmol, 1.0 eq.) of 1-amino-2-(benzyloxy)-4-methylpyridinium 2,4,6-trimethylbenzenesulphonate from Example 6A were dissolved in 280 ml of DMF, and 6.6 ml (56 mmol, 2.0 eq.) of ethyl but-2-ynoate [CAS No: 4341-76-8] were added. 7.8 g (56 mmol, 2.0 eq.) of potassium carbonate was added and the mixture was stirred at RT for 1 h. Subsequently, 3.9 g (28 mmol, 1 eq.) of potassium carbonate was added and the mixture was stirred at RT for a further 16 h. Then the mixture was poured onto 540 ml of water and stirred briefly, and the precipitated solids were filtered off, washed with 220 ml of water and dried. This gave 3.1 g of the title compound (34% of theory, purity 87%).

[0624] LC-MS (Method 2): R.sub.t=1.20 min

[0625] MS (ESpos): m/z=325 (M+H).sup.+

[0626] .sup.1H-NMR (400 Mhz, DMSO-d.sub.6): δ [ppm]=1.34 (t, 3H), 2.43 (s, 3H), 4.27 (q, 2H), 5.43 (s, 2H), 6.60 (d, 1H), 7.37-7.49 (m, 4H), 7.52-7.59 (m, 2H), [s, 3H under solvent signal].

Example 8A

Ethyl 7-hydroxy-2,5-dimethylpyrazolo[1,5-a]pyridine-3-carboxylate

[0627] ##STR00051##

[0628] 2 g (5.98 mmol) of ethyl 7-(benzyloxy)-2,5-dimethylpyrazolo[1,5-a]pyridine-3-carboxylate from Example 7A were initially charged in 80 ml of ethanol under argon, and 636 mg (0.59 mmol, 10%) of palladium on activated carbon and 18 ml (179.42 mmol) of cyclohexene were added. The reaction mixture was stirred under reflux for 2.5 hours. Then the reaction mixture was filtered through kieselguhr and washed with ethanol, and the filtrate was concentrated. The residue was taken up in DMSO and acetonitrile and purified by preparative HPLC (RP18 column, mobile phase: acetonitrile/water gradient with addition of 0.1% TFA). The product fractions were combined, concentrated and lyophilized. This gave 1.2 g of the target compound (86% of theory).

[0629] LC-MS (Method 7): R.sub.t=1.60 min

[0630] MS (ESpos): m/z=235 (M+H).sup.+

[0631] .sup.1H-NMR (500 Mhz, DMSO-d.sub.6): δ=1.33 (t, 3H), 2.35 (s, 3H), 2.54 (s, 3H; obscurred under solvent peak), 4.26 (q, 2H), 6.17 (d, 1H), 7.26 (s, 1H).

Example 9A

Ethyl 2,5-dimethyl-7-[(2,3,6-trifluorobenzyl)oxy]pyrazolo[1,5-a]pyridine-3-carboxylate

[0632] ##STR00052##

[0633] 1.2 g (5.25 mmol) of ethyl 7-hydroxy-2,5-dimethylpyrazolo[1,5-a]pyridine-3-carboxylate from Example 8A were dissolved in 48 ml of THF. 1.7 g (10.50 mmol) of 2,3,6-trifluorobenzyl alcohol and 2.9 g (11.03 mmol) of triphenylphosphine were added. Subsequently, 2.2 ml (11.03 mmol) of diisopropyl (E)-diazene-1,2-dicarboxylate were added to the solution, which was stirred at RT for 1 h. 120 ml of tert-butyl methyl ether were added, then the mixture was stirred briefly, and the solids formed were filtered off and dried under high vacuum. This gave 1.2 g of the target compound (62% of theory).

[0634] LC-MS (Method 2): R.sub.t=1.22 min

[0635] MS (ESpos): m/z=379 (M+H).sup.+

[0636] .sup.1H-NMR (500 Mhz, DMSO-d.sub.6): δ=1.34 (t, 3H), 2.46 (s, 3H), 2.51 (s, 3H; obscurred under solvent peak), 4.28 (d, 2H), 5.51 (s, 2H), 6.70 (s, 1H), 7.29-7.37 (m, 1H), 7.48 (s, 1H), 7.66-7.76 (m, 1H).

Example 10A

2,5-Dimethyl-7-[(2,3,6-trifluorobenzyl)oxy]pyrazolo[1,5-a]pyridine-3-carboxylic acid

[0637] ##STR00053##

[0638] 700 mg (1.81 mmol) of ethyl 2,5-dimethyl-7-[(2,3,6-trifluorobenzyl)oxy]pyrazolo[1,5-a]pyridine-3-carboxylate from Example 9A were initially charged in 18 ml of dioxane and heated to 90° C. 4.5 ml of dioxane and 7.25 ml (14.50 mmol) of 2 N aqueous sodium hydroxide solution were added, and the reaction mixture was stirred at 90° C. for two days. Another 3.63 ml (7.26 mmol) of 2 N aqueous sodium hydroxide solution were added and the mixture was stirred at 90° C. for a further 2 hours. 15 ml of 1 N aqueous hydrochloric acid were added, and the reaction solution was stirred for 30 min. In the course of this, solids precipitated out. This suspension was filtered, and the solids filtered off were washed with a little water and dried under high vacuum. This gave 358 mg of the target compound (54% of theory).

[0639] LC-MS (Method 2): R.sub.t=0.97 min

[0640] MS (ESpos): m/z=351 (M+H).sup.+

Example 11A

Methyl 2-cyclopropyl-7-[(2,6-difluorobenzyl)oxy]-5-methylpyrazolo[1,5-a]pyridine-3-carboxylate

[0641] ##STR00054##

[0642] 1.0 g (2.22 mmol) of 1-amino-2-[(2,6-difluorobenzyl)oxy]-4-methylpyridinium 2,4,6-trimethylbenzenesulphonate from Example 2A were dissolved in 7.2 ml of DMF, and 496 mg (4.00 mmol) of methyl 3-cyclopropylprop-2-ynoate were added. 552 mg (4.00 mmol) of potassium carbonate was added and the mixture was stirred at RT for 3 h. Subsequently, the mixture was poured onto 50 ml of water and stirred briefly, and the precipitated solids were filtered off, washed with water and dried. This gave 384 mg of the title compound (46% of theory).

[0643] LC-MS (Method 2): R.sub.t=1.20 min

[0644] MS (ESpos): m/z=373 (M+H).sup.+

[0645] .sup.1H-NMR (500 Mhz, DMSO-d.sub.6): δ [ppm]=0.88-0.94 (m, 2H), 0.95-1.00 (m, 2H), 2.43 (s, 3H), 2.70-2.77 (m, 1H), 3.83 (s, 3H), 5.46 (s, 2H), 6.66 (s, 1H), 7.21-7.27 (m, 2H), 7.48 (s, 1H), 7.57-7.64 (m, 1H).

Example 12A

2-Cyclopropyl-7-[(2,6-difluorobenzyl)oxy]-5-methylpyrazolo[1,5-a]pyridine-3-carboxylic acid

[0646] ##STR00055##

[0647] 10.2 ml (10.2 mmol) of 1 N aqueous sodium hydroxide solution were added to a solution of 384 mg (1.02 mmol) of methyl 2-cyclopropyl-7-[(2,6-difluorobenzyl)oxy]-5-methylpyrazolo[1,5-a]pyridine-3-carboxylate from Example 99A in 10.6 ml of dioxane, and the mixture was stirred at 100° C. for 7 h. The reaction solution was cooled and adjusted to pH 2 with 1 N hydrochloric acid. The solids that precipitated out were filtered off and dried under high vacuum. More 1 N hydrochloric acid was added to the filtrate. The solids that precipitated out were filtered off and dried under high vacuum together with the previously isolated solids. A total of 361 mg of the title compound (74% by LC-MS, 73% of theory) were obtained and were converted without further purification.

[0648] LC-MS (Method 2): R.sub.t=1.00 min

[0649] MS (ESpos): m/z=359 (M+H).sup.+

[0650] .sup.1H-NMR (400 Mhz, DMSO-d.sub.6): δ [ppm]=0.87-0.99 (m, 4H), 2.42 (s, 3H), 2.73-2.82 (m, 1H), 5.45 (s, 2H), 6.61 (s, 1H), 7.20-7.28 (m, 2H), 7.48 (s, 1H), 7.55-7.65 (m, 1H), 12.29 (br. s, 1H).

Example 13A

3-[(2,6-Difluorobenzyl)oxy]-5-methylpyrazine-2-amine

[0651] ##STR00056##

[0652] 4.86 g of potassium tert-butoxide (43.3 mmol, 3.0 eq.) were added to a solution of 2.71 g of (2,6-difluorophenyl)methanol [CAS No.: 19064-18-7] (18.8 mmol, 1.3 eq.) in 120 ml of 1,2-dimethoxyethane, and the mixture was stirred at RT for 60 min. Subsequently, 2.60 g of 2-amino-3-chloro-5-methylpyrazine hydrochloride [CAS No.: 89182-14-9] (14.4 mmol, 1.0 eq.) were added and the mixture was stirred at 80° C. overnight. After cooling to room temperature, saturated aqueous sodium hydrogencarbonate solution was added and the aqueous phase was extracted three times with dichloromethane. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over magnesium sulphate, filtered and concentrated. The residue was purified by means of Biotage Isolera (340 g silica gel cartridge, cyclohexane/ethyl acetate gradient, 10%->72% ethyl acetate). This gave 1.77 g of the title compound (39% of theory, purity 85%).

[0653] LC-MS (Method 2): R.sub.t=0.94 min

[0654] MS (ESpos): m/z=252 (M+H).sup.+

[0655] .sup.1H-NMR (400 Mhz, DMSO-d.sub.6): δ [ppm]=2.20 (s, 3H), 5.35 (s, 2H), 5.88 (s, 2H), 7.09-7.23 (m, 2H), 7.37 (s, 1H), 7.46-7.57 (m, 1H).

Example 14A

Ethyl 8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyrazine-3-carboxylate

[0656] ##STR00057##

[0657] 4A molecular sieve and 11.1 g of ethyl 2-chloroacetoacetate [CAS No.: 609-15-4](70.5 mmol, 10 eq.) were added to a solution of 1.77 g of 3-[(2,6-difluorobenzyl)oxy]-5-methylpyrazine-2-amine (7.05 mmol, 1.0 eq.) from Example 13A in 50 ml of ethanol, and the mixture was heated at reflux overnight. Subsequently, 11.1 g of ethyl 2-chloroacetoacetate (70.5 mmol, 10.0 eq) were added and the mixture was heated to reflux overnight. Then the mixture was filtered, the filtrate was concentrated, the residue obtained was extracted by stirring with diethyl ether and filtered, and the filtrate was concentrated. The residue was purified twice by means of Biotage Isolera (120 g silica gel cartridge, cyclohexane/ethyl acetate gradient). 0.81 g of the title compound was isolated (16% of theory; 52% purity).

[0658] LC-MS (Method 2): R.sub.t=1.28 min

[0659] MS (ESpos): m/z=362 (M+H).sup.+

Example 15A

8-[(2,6-Difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyrazine-3-carboxylic acid

[0660] ##STR00058##

[0661] 5.8 ml of 1 N aqueous sodium hydroxide solution (5.8 mmol, 5 eq.) were added to a solution of 800 mg of ethyl 8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyrazine-3-carboxylate (52% purity, 1.15 mmol, 1.0 eq.) from Example 14A in 10 ml of dioxane, and the mixture was stirred at RT for 2 h. Subsequently, the mixture was concentrated, the residue was taken up in water and insoluble solid was filtered off. The filtrate was acidified with 1 N aqueous hydrochloric acid, and the solid formed was filtered off and dried. 354 mg of the title compound were isolated (83% of theory; 90% purity).

[0662] LC-MS (Method 2): R.sub.t=0.99 min

[0663] MS (ESpos): m/z=334 (M+H).sup.+

[0664] .sup.1H-NMR (400 Mhz, DMSO-d.sub.6): δ [ppm]=2.41 (s, 3H), 2.54 (s, 3H hidden under solvent peak), 5.55 (s, 2H), 7.12-7.28 (m, 2H), 7.49-7.64 (m, 1H), 8.64 (s, 1H), 13.20-13.66 (br s, 1H).

Example 16A

2-Methyl-2-nitropropyl trifluoromethanesulphonate

[0665] ##STR00059##

[0666] 1.0 g (8.40 mmol) of 2-methyl-2-nitropropan-1-ol was initially charged in 20 ml of dichloromethane, 1.0 ml (12.59 mmol) of pyridine was added, the mixture was cooled to 0° C. and 1.85 ml (10.91 mmol) of trifluoromethanesulphonic anhydride was added slowly. The mixture was then stirred at 0° C. for 1 h. The course of the reaction was monitored by TLC (cyclohexane/ethyl acetate 7/3, staining reagent: potassium permanganate stain). The reaction solution was washed in each case once with water and saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulphate and filtered and the filtrate was concentrated. This gave 2.18 g of the target compound (99% of theory). The target compound was stored at −18° C. and used without further purification.

[0667] MS (Method 12):

[0668] MS (ESpos): m/z=269 (M+NH.sub.4).sup.+

[0669] .sup.1H-NMR (400 Mhz, DMSO-d.sub.6) δ=1.64 (s, 6H), 5.13 (s, 2H).

Example 17A

3-Bromo-7-[(2,6-difluorobenzyl)oxy]-2,5-dimethylpyrazolo[1,5-a]pyridine

[0670] ##STR00060##

[0671] 3.79 g (45.14 mmol) of sodium bicarbonate were added to a solution of 5.0 g (15.1 mmol) of 7-[(2,6-difluorobenzyl)oxy]-2,5-dimethylpyrazolo[1,5-a]pyridine-3-carboxylic acid from Example 4A in 60 ml of DMF. At RT, a solution of 2.81 g (15.80 mmol) of N-bromosuccinimide in 40 ml of DMF was, very slowly [2.6 ml/h], added dropwise using a syringe pump. Subsequently, another 134 mg (0.75 mmol) of N-bromosuccinimide in 2 ml of DMF were, very slowly [2.6 ml/h], added dropwise at RT using a syringe pump. The reaction solution was diluted with dichloromethane and then washed twice with water. The combined aqueous phases were reextracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was stirred with water, and the solid obtained was filtered off and dried under high vacuum. 4.80 g of the title compound were isolated (84% of theory).

[0672] LC-MS (Method 2): R.sub.t=1.25 min

[0673] MS (ESpos): m/z=367 (M+H).sup.+

[0674] .sup.1H-NMR (400 Mhz, DMSO-d.sub.6): δ [ppm]=2.30 (s, 3H), 2.40 (s, 3H), 5.43 (s, 2H), 6.49 (s, 1H), 6.92 (s, 1H), 7.20-7.30 (m, 2H), 7.57-7.67 (m, 1H).

Example 18A

3-Bromo-2,5-dimethyl-7-[(2,3,6-trifluorobenzyl)oxy]pyrazolo[1,5-a]pyridine

[0675] ##STR00061##

[0676] 70 mg (0.84 mmol) of sodium bicarbonate were added to a solution of 103 mg (0.28 mmol) of 2,5-dimethyl-7-[(2,3,6-trifluorobenzyl)oxy]pyrazolo[1,5-a]pyridine-3-carboxylic acid from Example 10A in 1.1 ml of DMF. At RT, a solution of 52 mg (0.29 mmol) of N-bromosuccinimide in 0.75 ml of DMF was, very slowly [2.6 ml/h], added dropwise using a syringe pump. The reaction solution was diluted with dichloromethane and then washed twice with water. The combined aqueous phases were reextracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was stirred with water, and the solid obtained was filtered off and dried under high vacuum. 65 mg of the title compound were isolated (43% of theory; 71% purity).

[0677] LC-MS (Method 2): R.sub.t=1.29 min

[0678] MS (ESpos): m/z=385 (M+H).sup.+

Example 19A

3-Bromo-2-cyclopropyl-7-[(2,6-difluorobenzyl)oxy]-5-methylpyrazolo[1,5-a]pyridine

[0679] ##STR00062##

[0680] 1.79 g (21.35 mmol) of sodium bicarbonate were added to a solution of 3.0 g (6.2 mmol; purity 74%) of 2-cyclopropyl-7-[(2,6-difluorobenzyl)oxy]-5-methylpyrazolo[1,5-a]pyridine-3-carboxylic acid from Example 12A in 28.4 ml of DMF. At RT, a solution of 1.10 g (6.2 mmol) of N-bromosuccinimide in 19 ml of DMF was, very slowly [2.6 ml/h], added dropwise using a syringe pump. The reaction solution was diluted with dichloromethane and then washed twice with water. The combined aqueous phases were reextracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was stirred with water, and the solid obtained was filtered off and dried under high vacuum. 2.70 g of the title compound was isolated (98% of theory; 90% purity).

[0681] LC-MS (Method 15): R.sub.t=1.64 min

[0682] MS (ESpos): m/z=393 (M+H).sup.+

Example 20A

3-Bromo-8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyrazine

[0683] ##STR00063##

[0684] 91 mg (1.08 mmol) of sodium bicarbonate were added to a solution of 120 mg (0.32 mmol, purity 90%) of 8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyrazine-3-carboxylic acid from Example 15A in 1.4 ml of DMF. At RT, a solution of 57 mg (0.32 mmol) of N-bromosuccinimide in 1.0 ml of DMF was added dropwise over 40 min, and stirring of the mixture was continued at RT for 5 min. The reaction solution was diluted with dichloromethane and then washed twice with water. The combined aqueous phases were reextracted twice with dichloromethane. The combined organic phases were concentrated. The residue was stirred with water, and the solid obtained was filtered off and dried under high vacuum. 118 mg of the title compound were isolated (98% of theory).

[0685] LC-MS (Method 2): R.sub.t=1.21 min

[0686] MS (ESpos): m/z=368 (M+H).sup.+

[0687] .sup.1H-NMR (400 Mhz, DMSO-d.sub.6): δ [ppm]=2.30 (s, 3H), 2.39 (s, 3H), 5.55 (s, 2H), 7.17-7.24 (m, 2H), 7.52-7.62 (m, 1H), 7.84 (s, 1H).

Example 21A

7-[(2,6-Difluorobenzyl)oxy]-2,5-dimethyl-3-[1-(2-methyl-2-nitropropyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyridine

[0688] ##STR00064##

[0689] 40 mg (0.11 mmol) of 7-[(2,6-difluorobenzyl)oxy]-2,5-dimethyl-3-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine from Example 1 were initially charged in 0.65 ml of DMF, 41 mg (0.13 mmol) of caesium carbonate and 89 mg (0.32 mmol) of 2-methyl-2-nitropropyl trifluoromethanesulphonate Example 16A were added and the mixture was stirred at RT for 2 h. Another 89 mg (0.32 mmol) of 2-methyl-2-nitropropyl trifluoromethanesulphonate were then added and the mixture was stirred at RT for 1 h. Once more, 21 mg (0.06 mmol) of caesium carbonate and 89 mg (0.32 mmol) of 2-methyl-2-nitropropyl trifluoromethanesulphonate were added, and the mixture was stirred at RT overnight. Acetonitrile/water/TFA was added and the reaction mixture was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile/water gradient with addition of 0.1% TFA). This gave 28 mg of the target compound (58% of theory).

[0690] LC-MS (Method 2): R.sub.t=1.15 min

[0691] MS (ESpos): m/z=456 (M+H).sup.+

Example 22A

Ethyl 7-(cyclohexylmethoxy)-2,5-dimethylpyrazolo[1,5-a]pyridine-3-carboxylate

[0692] ##STR00065##

[0693] 0.5 g (2.13 mmol) of ethyl 7-hydroxy-2,5-dimethylpyrazolo[1,5-a]pyridine-3-carboxylate from Example 8A, 416 mg (2.35 mmol) of (bromomethyl)cyclohexane and 1.53 g (4.70 mmol) of caesium carbonate were initially charged in 31 ml of DMF, and the mixture was stirred at 100° C. overnight. The reaction mixture was poured into 260 ml of water. The precipitate was filtered off. This gave 196 mg of the target compound (28% of theory). The aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated. This gave another 425 mg of the target compound (55% of theory; purity 92%).

[0694] LC-MS (Method 2): R.sub.t=1.33 min

[0695] MS (ESpos): m/z=331 (M+H).sup.+

Example 23A

7-(Cyclohexylmethoxy)-2,5-dimethylpyrazolo[1,5-a]pyridine-3-carboxylic acid

[0696] ##STR00066##

[0697] 425 mg (1.18 mmol; purity 92%) of ethyl 7-(cyclohexylmethoxy)-2,5-dimethylpyrazolo[1,5-a]pyridine-3-carboxylate from Example 22A were initially charged in 12.3 ml of dioxane, and the mixture was heated to 90° C. 9.47 ml (9.47 mmol) of aqueous 1N sodium hydroxide solution were added and the reaction mixture was stirred at 90° C. for 8 h. The reaction solution was cooled and adjusted to pH 2 with 2N aqueous hydrochloric acid. The mixture was stirred at RT for 30 min. The suspension was filtered, and the solids filtered off were washed with a little water and dried under high vacuum. 10 ml of acetonitrile were added to the solid, the mixture was stirred and the solid was filtered off and dried under high vacuum. This gave 178 mg of the target compound (50% of theory).

[0698] LC-MS (Method 2): R.sub.t=1.08 min

[0699] MS (ESpos): m/z=303 (M+H).sup.+

Example 24A

3-Bromo-7-(cyclohexylmethoxy)-2,5-dimethylpyrazolo[1,5-a]pyridine

[0700] ##STR00067##

[0701] 148 mg (1.77 mmol) of sodium bicarbonate were added to a mixture of 178 mg (0.59 mmol) of 7-(cyclohexylmethoxy)-2,5-dimethylpyrazolo[1,5-a]pyridine-3-carboxylic acid from Example 23A in 2.34 ml of DMF. At RT, a solution of 105 mg (0.59 mmol) of N-bromosuccinimide in 1.56 ml of DMF was, very slowly [2.6 ml/h], added dropwise using a syringe pump. Subsequently, once more a solution of 5.3 mg (0.029 mmol) of N-bromosuccinimide in 77 μl of DMF was, very slowly, added to the reaction solution over 75 min. The mixture was stirred at RT for 30 min, diluted with dichloromethane and then washed twice with water. The combined aqueous phases were reextracted twice with dichloromethane. The combined organic phases were dried over sodium sulphate, filtered and concentrated by rotary evaporation. The residue was stirred with water, and the solid obtained was filtered off and dried under high vacuum. 179 mg of the title compound were isolated (78% of theory; 87% purity).

[0702] LC-MS (Method 2): R.sub.t=1.47 min

[0703] MS (ESpos): m/z=337 (M+H).sup.+

Example 25A

7-[(2,6-Difluorobenzyl)oxy]-2,5-dimethylpyrazolo[1,5-a]pyridine-3-carboxamide

[0704] ##STR00068##

[0705] Under argon, 0.80 g (2.19 mmol, purity 91%) of 7-[(2,6-difluorobenzyl)oxy]-2,5-dimethylpyrazolo[1,5-a]pyridine-3-carboxylic acid from Example 4A in 24 ml of DMF/dichloroethane (1/1) were initially charged, and 546 mg (2.85 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 436 mg (2.85 mmol) of 1-hydroxy-1H-benzotriazole hydrate (HOBT) were added successively at RT and the mixture was stirred at RT for 10 min. 586 mg (10.95 mmol) of ammonium chloride and 2.67 ml (15.34 mmol) of N,N-diisopropylethylamine were then added, and the mixture was stirred at RT for 10 min and at 40° C. for 10 min. Subsequently, another 126 mg (0.66 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 101 mg (0.66 mmol) of 1-hydroxy-1H-benzotriazole hydrate (HOBT) were added, and the mixture was stirred at 40° C. for 30 min. The mixture was concentrated, water was added to the residue and the mixture was stirred for 1 h. The solid formed was dried under reduced pressure. This gave 721 mg (84% of theory; purity 85%) of the title compound which was reacted further without purification.

[0706] LC-MS (Method 15): R.sub.t=1.05 min

[0707] MS (ESpos): m/z=332 (M+H).sup.+

Example 26A

7-[(2,6-Difluorobenzyl)oxy]-2,5-dimethylpyrazolo[1,5-a]pyridine-3-carbonitrile

[0708] ##STR00069##

[0709] 721 mg (1.85 mmol; purity 85%) of 7-[(2,6-difluorobenzyl)oxy]-2,5-dimethylpyrazolo[1,5-a]pyridine-3-carboxamide from Example 25A were initially charged in 8.6 ml of THF, and 0.39 ml (4.81 mmol) of pyridine was added. 0.68 ml (4.81 mmol) of trifluoroacetic anhydride were then added dropwise, and the mixture was stirred at RT for 5 h. The mixture was then added to water and stirred at RT for 30 min. The resulting solid was filtered off, washed with water and dried under reduced pressure. This gave 605 mg (87% of theory; purity 83%) of the title compound.

[0710] LC-MS (Method 2): R.sub.t=1.09 min

[0711] MS (ESpos): m/z=314 (M+H).sup.+

Example 27A

7-[(2,6-Difluorobenzyl)oxy]-N-hydroxy-2,5-dimethylpyrazolo[1,5-a]pyridine-3-carboximidamide

[0712] ##STR00070##

[0713] 250 mg (0.66 mmol; purity 83%) of 7-[(2,6-difluorobenzyl)oxy]-2,5-dimethylpyrazolo[1,5-a]pyridine-3-carbonitrile from Example 26A were suspended in 9.2 ml of ethanol, 368 mg (5.3 mmol) of hydroxylamine hydrochloride and 0.74 ml (5.3 mmol) of triethylamine were added and the mixture was stirred at 80° C. overnight. The mixture was then concentrated under reduced pressure, 8.9 of water and 0.45 ml of ethanol were added and the mixture was stirred for 1 h. The solid formed was filtered off, washed with 2.2 ml of water and dried under high vacuum. The residue was taken up in acetonitrile, water and trifluoroacetic acid were added and the mixture was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile/water gradient with addition of 0.1% TFA). 73 mg (31% of theory) of the title compound were obtained.

[0714] LC-MS (Method 2): R.sub.t=0.62 min

[0715] MS (ESpos): m/z=347 (M+H).sup.+

Example 28A

7-[(2,6-Difluorobenzyl)oxy]-2,5-dimethylpyrazolo[1,5-a]pyridine-3-carboximidamide acetate

[0716] ##STR00071##

[0717] 73 mg (0.21 mmol) of 7-[(2,6-difluorobenzyl)oxy]-N-hydroxy-2,5-dimethylpyrazolo[1,5-a]pyridine-3-carboximidamide from Example 27A were initially charged in 2.1 ml of acetic acid, and 23.4 μl (0.25 mmol) of acetic anhydride were added. 16 mg of palladium/carbon (10%, moist) were then added, and the mixture was hydrogenated at atmospheric pressure for 5 h. The mixture was filtered through a Millipore filter and washed with ethyl acetate. After concentration, twice in each case 2 ml of toluene were added to the residue, and the mixture was concentrated under reduced pressure. The residue was dried under high vacuum. This gave 65 mg (73% of theory; purity 91%) of the title compound.

[0718] LC-MS (Method 2): R.sub.t=0.62 min

[0719] MS (ESpos): m/z=331 (M-CH.sub.3CO.sub.2H+H).sup.+

Example 29A

2-{7-[(2,6-Difluorobenzyl)oxy]-2,5-dimethylpyrazolo[1,5-a]pyridin-3-yl}-4-iodo-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one

[0720] ##STR00072##

[0721] Under argon, 70 mg (0.12 mmol) of 4-amino-2-{7-[(2,6-difluorobenzyl)oxy]-2,5-dimethylpyrazolo[1,5-a]pyridin-3-yl}-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one trifluoroacetate from Example 34 were initially charged in 1.5 ml of abs. dioxane, at RT, 59 μl (0.74 mmol) of diiodomethane, 121 mg (1.03 mmol) of isopentyl nitrite and 200 mg of 4 A molecular sieve were added and the mixture was stirred at 85° C. overnight. The reaction mixture was subsequently filtered, the residue (molecular sieve) was rinsed with ethyl acetate and the solvent was evaporated. The residue was then diluted with acetonitrile/water, and a little TFA was added. The solution was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile/water gradient with addition of 0.1% TFA). The product fractions were concentrated, saturated sodium bicarbonate solution was added and the mixture was extracted three times with ethyl acetate. The solvent was removed on a rotary evaporator. 23 mg (31% of theory) of the title compound were obtained.

[0722] LC-MS (Method 16): R.sub.t=2.48 min

[0723] MS (ESpos): m/z=576 (M+H).sup.+

WORKING EXAMPLES

Example 1

7-[(2,6-Difluorobenzyl)oxy]-2,5-dimethyl-3-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine

[0724] ##STR00073##

[0725] 1.0 g (2.64 mmol) of 3-bromo-7-[(2,6-difluorobenzyl)oxy]-2,5-dimethylpyrazolo[1,5-a]pyridine from Example 17A and 1.17 g (3.96 mmol) of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate were initially charged in 32 ml of abs. acetonitrile and gassed with argon. 104 mg (0.13 mmol) of chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)palladium (II) [CAS: 1310584-14-5] were then added, followed by 15.9 ml (7.93 mmol) of aqueous 0.5 M potassium phosphate solution (oxygen-free). The reaction mixture was stirred vigorously at 60° C. for 12 h. Another 583 mg (1.98 mmol) of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate and 104 mg (0.13 mmol) of chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl) [2-(2′-amino-1,1′-biphenyl)palladium (II) [CAS: 1310584-14-5] were added. The reaction mixture was stirred vigorously at 60° C. for 5 h. The reaction solution was cooled, dichloromethane was added and the mixture was washed three times with water. The combined aqueous phases were reextracted twice with dichloromethane. The combined organic phases were dried over sodium sulphate, filtered and concentrated. The residue was purified in several portions by preparative HPLC (RP18 column, mobile phase: acetonitrile/water gradient with addition of 0.1% TFA). The product-containing fractions were concentrated, the residue was taken up in dichloromethane and a little methanol and washed twice with aqueous saturated sodium bicarbonate solution. The combined aqueous phases were reextracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. This gave 231 mg (19% of theory) of the title compound.

[0726] LC-MS (Method 2): R.sub.t=0.87 min

[0727] MS (ESpos): m/z=355 (M+H).sup.+

[0728] .sup.1H-NMR (500 Mhz, DMSO-d.sub.6): δ [ppm]=2.34-2.40 (m, 6H), 5.43 (s, 2H), 6.38 (s, 1H), 7.13 (s, 1H), 7.22-7.30 (m, 2H), 7.57-7.67 (m, 1H), 7.76 (br. s, 1H), 7.98 (br. s, 1H), 12.98 (br. s, 1H).

[0729] The example compounds shown in Table 1 were prepared analogously to Example 1 by reacting 3-bromo-7-[(2,6-difluorobenzyl)oxy]-2,5-dimethylpyrazolo[1,5-a]pyridine from Example 17A with the appropriate boronic acids or boronic esters, commercially available or known from the literature (1.5-2.5 equivalents), aqueous potassium phosphate solution (3 equivalents) and chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)palladium (II) [CAS: 1310584-14-5] (0.05-0.1 equivalents) under the reaction conditions described (solvent: acetonitrile; reaction time: 4-24 h; temperature: 60° C.).

[0730] In general, at the start of the reaction 0.05 equivalents of chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)palladium (II) [CAS: 1310584-14-5] and 1.5 equivalents of boronic acid or boronic ester were used. In the case of incomplete conversion, another 0.05 equivalents of chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)palladium (II) [CAS: 1310584-14-5] and 1.0 equivalents of boronic acid or boronic ester were added to the reaction mixture.

Exemplary Work-Up of the Reaction Mixture:

[0731] The reaction solution was cooled, water and dichloromethane (or ethyl acetate) was added and the mixture was washed three times with water. The combined aqueous phases were reextracted twice with dichloromethane (or ethyl acetate). The combined organic phases were dried over sodium sulphate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile/water gradient with addition of 0.1% TFA). The product-containing fractions were concentrated, the residue was taken up in dichloromethane and a little methanol and washed twice with aqueous saturated sodium bicarbonate solution. The combined aqueous phases were reextracted twice with dichloromethane. The combined organic phases were dried over sodium sulphate, filtered and concentrated.

[0732] The crude product was optionally purified again by thick-layer chromatography (solvent: dichloromethane/methanol=100/1 or 50/1 or 20/1 or dichloromethane/cyclohexane=10/1).

TABLE-US-00001 TABLE 1 Ex- am- ple IUPAC name Analytical No. (Yield) data  2 1-(3-{7-[(2,6-Difluorobenzyl)oxy]-2,5- dimethylpyrazolo[1,5-a]pyridin-3- yl}phenyl)ethanone   [00074]   The boronic acid was used. (62% of theory) LC-MS (Method 2): R.sub.t = 1.16 min MS (ESpos): m/z = 407 (M + H).sup.+  3 1-(3-{7-[(2,6-Difluorobenzyl)oxy]-2,5- dimethylpyrazolo[1,5-a]pyridin-3- yl}phenyl)acetamide   [00075]   The boronic acid was used. (30% of theory) LC-MS (Method 2): R.sub.t = 1.02 min MS (ESpos): m/z = 422 (M + H).sup.+  4 7-[(2,6-Difluorobenzyl)oxy]-2,5-dimethyl-3-[5- (morpholin-4-ylmethyl)-3-thienyl]pyrazolo[1,5- a]pyridine   [00076]   The boronic acid pinacol ester was used. (58% of theory) LC-MS (Method 2): R.sub.t = 0.80 min MS (ESpos): m/z = 470 (M + H).sup.+ .sup.1H-NMR (400 Mhz, DMSO- d.sub.6) δ = 2.36- 2.48 (m, 10H), 3.57-3.65 (m, 4H), 3.73 (s, 2H), 5.43 (s, 2H), 6.42 (s, 1H), 7.13 (s, 1H), 7.20 (s, 1H), 7.22- 7.30 (m, 2H), 7.40 (s, 1H), 7.58-7.67 (m, 1H).  5 7-[(2,6-Difluorobenzyl)oxy]-2,5-dimethyl-3-{1- [2-(morpholin-4-yl)ethyl]-1H-pyrazol-4- yl}pyrazolo[1,5-a]pyridine   [00077]   The boronic acid pinacol ester was used. (38% of theory) LC-MS (Method 2): R.sub.t = 0.71min MS (ESpos): m/z = 468 (M + H).sup.+ .sup.1H-NMR (400 Mhz, DMSO- d.sub.6) δ = 2.36- 2.48 (m, 10H), 2.70-2.82 (m, 2H), 3.53-3.65 (m, 4H), 4.24- 4.34 (m, 2H), 5.43 (s, 2H), 6.38 (s, 1H), 7.13 (s, 1H), 7.22-7.30 (m, 2H), 7.58-7.67 (m, 1H), 7.70 (s, 1H), 8.02 (s, 1H).  6 3-(1-Benzyl-1H-pyrazol-4-yl)-7-[(2,6- difluorobenzyl)oxy]-2,5-dimethylpyrazolo[1,5- a]pyridine   [00078]   The boronic acid pinacol ester was used. (68% of theory) LC-MS (Method 2): R.sub.t = 1.21 min MS (ESpos): m/z = 445 (M + H).sup.+  7 7-[(2,6-Difluorobenzyl)oxy]-3-[3- (ethylsulphonyl)phenyl]-2,5- dimethylpyrazolo[1,5-a]pyridine   [00079]   The boronic acid was used. (65% of theory) LC-MS (Method 2): R.sub.t = 1.14 min MS (ESpos): m/z = 457 (M + H).sup.+  8 7-[(2,6-Difluorobenzyl)oxy]-3-[1-(4- fluorophenyl)-1H-pyrazol-4-yl]-2,5- dimethylpyrazolo[1,5-a]pyridine   [00080]   The boronic acid was used. (18% of theory) LC-MS (Method 2): R.sub.t = 1.27 min MS (ESpos): m/z = 449 (M + H).sup.+  9 3-(6-Chloro-5-methylpyridin-3-yl)-7-[(2,6- difluorobenzyl)oxy]-2,5-dimethylpyrazolo[1,5- a]pyridine   [00081]   The boronic acid was used. (4% of theory) LC-MS (Method 2): R.sub.t = 1.30 min MS (ESpos): m/z = 414 (M + H).sup.+ 10 N-(3-{7-[(2,6-Difluorobenzyl)oxy]-2,5- dimethylpyrazolo[1,5-a]pyridin-3-yl}benzyl)-N- methylethanamine   [00082]   The boronic acid was used. (36% of theory) LC-MS (Method 2): R.sub.t = 0.81 min MS (ESpos): m/z = 436 (M + H).sup.+ 11 7-[(2,6-Difluorobenzyl)oxy]-2,5-dimethyl-3-[3- (pyrrolidin-1-ylmethyl)phenyl]pyrazolo[1,5- a]pyridine   [00083]   The boronic acid was used. (34% of theory) LC-MS (Method 2): R.sub.t = 0.81 min MS (ESpos): m/z = 448 (M + H).sup.+ 12 3-{7-[(2,6-Difluorobenzyl)oxy]-2,5- dimethylpyrazolo[1,5-a]pyridin-3-yl}benzamide   [00084]   The boronic acid pinacol ester was used. (49% of theory) LC-MS (Method 2): R.sub.t = 0.95 min MS (ESpos): m/z = 408 (M + H).sup.+ 13 N-(3-{7-[(2,6-Difluorobenzyl)oxy]-2,5- dimethylpyrazolo[1,5-a]pyridin-3- yl}phenyl)methansulphonamide   [00085]   The boronic acid pinacol ester was used. (24% of theory) LC-MS (Method 2): R.sub.t = 1.10 min MS (ESpos): m/z = 458 (M + H).sup.+ 14 7-[(2,6-Difluorobenzyl)oxy]-2,5-dimethyl-3-[3- (pyrrolidin-1-yl)phenyl]pyrazolo[1,5-a]pyridine   [00086]   The boronic acid was used. (48% of theory) LC-MS (Method 2): R.sub.t = 1.51 min MS (ESpos): m/z = 434 (M + H).sup.+ .sup.1H-NMR (500 Mhz, DMSO- d.sub.6) δ = 1.94- 2.02 (m, 4H), 2.35-2.42 (m, 6H), 3.23-3.33 (m, 4H, superposed by solvent peak), 5.43 (s, 2H), 6.38 (s, 1H), 6.49 (d, 1H), 6.53 (s, 1H), 6.65 (d, 1H), 7.08 (s, 1H), 7.20-7.30 (m, 3H), 7.58- 7.67 (m, 1H). 15 7-[(2,6-Difluorobenzyl)oxy]-2,5-dimethyl-3-[2- (piperazin-1-yl)pyridin-4-yl]pyrazolo[1,5- a]pyridine   [00087]   The boronic acid pinacol ester was used. (33% of theory) LC-MS (Method 2): R.sub.t = 0.72 min MS (ESpos): m/z = 450 (M + H).sup.+

Example 16

1-(4-{7-[(2,6-Difluorobenzyl)oxy]-2,5-dimethylpyrazolo[1,5-a]pyridin-3-yl}-1H-pyrazol-1-yl)-2-methylpropane-2-amine

[0733] ##STR00088##

[0734] About 102 mg of Raney nickel (50% aqueous suspension) were added to 35 mg (0.08 mmol) of 7-[(2,6-difluorobenzyl)oxy]-2,5-dimethyl-3-[1-(2-methyl-2-nitropropyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyridine from Example 21A in 1 ml of ethanol, and the mixture was hydrogenated under atmospheric pressure at room temperature overnight. The reaction mixture was filtered through Celite and the filter cake was washed with dichloromethane and 2 N ammonia solution in methanol. The filtrate was concentrated and the residue was purified by thick-layer chromatography (mobile phase: dichloromethane/2 N ammonia in methanol (45/1)). This gave 20 mg of the target compound (60% of theory).

[0735] LC-MS (Method 2): R.sub.t=0.72 min

[0736] MS (ESpos): m/z=426 (M+H).sup.+

[0737] .sup.1H-NMR (500 Mhz, DMSO-d.sub.6) δ=1.02 (s, 6H), 1.69 (br. s, 2H), 2.36-2.41 (m, 6H), 4.02 (s, 2H), 5.42 (s, 2H), 6.38 (s, 1H), 7.12-7.15 (m, 1H), 7.23-7.30 (m, 2H), 7.59-7.66 (m, 1H), 7.73 (s, 1H), 7.97 (s, 1H).

Example 17

7-[(2,6-Difluorobenzyl)oxy]-3-(2,5-difluoropyridin-4-yl)-2,5-dimethylpyrazolo[1,5-a]pyridine

[0738] ##STR00089##

[0739] Under argon, 79 mg (0.50 mmol) of (2,5-difluoropyridin-4-yl)boric acid, 126 mg (0.59 mmol) of potassium phosphate and 10 mg (0.02 mmol) of bis(tri-tert-butylphosphine)palladium(0) were added in succession to 75 mg (0.20 mmol) of 3-bromo-7-[(2,6-difluorobenzyl)oxy]-2,5-dimethylpyrazolo[1,5-a]pyridine (Example 17A) in a mixture of 1.44 ml of ethanol, 0.72 ml of water and 0.72 ml of toluene. The suspension was degassed with argon and then stirred at 120° C. for 30 min. After the reaction had ended, the reaction mixture was concentrated and the residue was taken up in ethyl acetate/water and extracted. The aqueous phase was extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulphate, filtered, concentrated and dried under high vacuum. The residue was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile/water gradient with addition of 0.1% TFA). The product-containing fractions were concentrated, the residue was taken up in dichloromethane and washed twice with aqueous saturated sodium bicarbonate solution. The combined aqueous phases were reextracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. This gave 75 mg of the target compound (91% of theory).

[0740] LC-MS (Method 2): R.sub.t=1.19 min

[0741] MS (ESpos): m/z=402 (M+H).sup.+

Example 18

Ethyl 5-{7-[(2,6-difluorobenzyl)oxy]-2,5-dimethylpyrazolo[1,5-a]pyridin-3-yl}nicotinate

[0742] ##STR00090##

[0743] Under argon, 60 mg (0.22 mmol) of ethyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinate, 92 mg (0.43 mmol) of potassium phosphate and 7 mg (0,014 mmol) of bis(tri-tert-butylphosphine)palladium(0) were added in succession to 53 mg (0.14 mmol) of 3-bromo-7-[(2,6-difluorobenzyl)oxy]-2,5-dimethylpyrazolo[1,5-a]pyridine (Example 17A) in a mixture of 0.26 ml of ethanol, 0.53 ml of water and 0.53 ml of toluene. The suspension was degassed with argon and then stirred at 120° C. for 30 min. After the reaction had ended, the reaction mixture was concentrated and the residue was taken up in ethyl acetate/water and extracted. The aqueous phase was extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulphate, filtered, concentrated and dried under high vacuum. The residue was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile/water gradient with addition of 0.1% TFA). The product-containing fractions were concentrated and purified once more by thick-layer chromatography (mobile phase: dichloromethane/methanol=100/1). This gave 34 mg of the target compound (52% of theory).

[0744] LC-MS (Method 2): R.sub.t=1.18 min

[0745] MS (ESpos): m/z=438 (M+H).sup.+

Example 19

8-[(2,6-Difluorobenzyl)oxy]-2,6-dimethyl-3-(1H-pyrazol-4-yl)imidazo[1,2-a]pyrazine trifluoroacetate

[0746] ##STR00091##

mg (0.11 mmol) of 3-bromo-8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyrazine from Example 20A and 48 mg (0.16 mmol) of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate were initially charged in 1.3 ml of abs. acetonitrile and gassed with argon. 4.3 mg (0.01 mmol) of chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)palladium (II) [CAS: 1310584-14-5] were then added, followed by 0.65 ml (0.33 mmol) of aqueous 0.5 M potassium phosphate solution (oxygen-free). The reaction mixture was stirred at 60° C. overnight. The reaction solution was cooled, TFA was added and the product was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile/water gradient with addition of 0.1% TFA). 2.4 mg (4% of theory, purity 90%) of the title compound were isolated.

[0747] LC-MS (Method 2): R.sub.t=0.79 min

[0748] MS (ESpos): m/z=356 (M-TFA+H).sup.+

[0749] .sup.1H-NMR (400 Mhz, DMSO-d.sub.6): δ [ppm]=2.34-2.40 (m, 6H), 5.57 (s, 2H), 7.17-7.24 (m, 2H), 7.52-7.62 (m, 1H), 7.86 (s, 1H), 7.95-8.15 (m, 2H).

Example 20

6-{8-[(2,6-Difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyrazin-3-yl}-1,3,5-triazine-2,4-diamine trifluoroacetate

[0750] ##STR00092##

[0751] Under argon, 40 mg (0.29 mmol) of imidodicarbonimidediamide hydrochloride [biguanide hydrochloride] were initially charged in 0.87 ml abs. methanol, 138 mg (0.15 ml, 0.64 mmol) of sodium methoxide (25% in methanol) were added and the mixture was stirred at 50° C. for 30 min. Subsequently, 70 mg (0.19 mmol) of ethyl 8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyrazine-3-carboxylate from Example 14A were added and the mixture was stirred under reflux overnight. After cooling, water and TFA were added and the mixture was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile/water gradient with addition of 0.1% TFA). The product-containing fractions were concentrated, dissolved in dichloromethane and washed with saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted twice with dichloromethane with addition of a little methanol. The combined organic phases were dried over sodium sulphate and filtered, the filtrate was concentrated and the residue was stirred with water. The precipitate was filtered off with suction and dried under high vacuum. This gave 3.7 mg of the target compound (3.7% of theory).

[0752] LC-MS (Method 2): R.sub.t=0.85 min

[0753] MS (ESpos): m/z=399 (M-TFA+H).sup.+

Example 21

Methyl 3-(4-{7-[(2,6-difluorobenzyl)oxy]-2,5-dimethylpyrazolo[1,5-a]pyridin-3-yl}-1H-pyrazol-1-yl)propanoate trifluoroacetate

[0754] ##STR00093##

[0755] 202 mg (0.62 mmol) of caesium carbonate, 4 mg (0.02 mmol) of potassium iodide and 52 mg (0.31 mmol) of methyl 3-bromopropanoate were added to 90 mg (0.24 mmol) of 7-[(2,6-difluorobenzyl)oxy]-2,5-dimethyl-3-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine from Example 1 in 1.5 ml of DMF, and the mixture was stirred at 60° C. for 2 h. After cooling, the mixture was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile/water gradient with addition of 0.1% TFA). This gave 71 mg of the target compound (53% of theory).

[0756] LC-MS (Method 2): R.sub.t=1.04 min

[0757] MS (ESpos): m/z=441 (M-TFA+H).sup.+

[0758] .sup.1H-NMR (400 Mhz, DMSO-d.sub.6) δ=2.35-2.43 (m, 6H), 2.94 (t, 2H), 3.62 (s, 3H), 4.41 (t, 2H), 5.42 (s, 2H), 6.38 (s, 1H), 7.14 (s, 1H), 7.26 (t, 2H), 7.57-7.67 (m, 1H), 7.72 (s, 1H), 8.00 (s, 1H).

Example 22

3-(4-{7-[(2,6-Difluorobenzyl)oxy]-2,5-dimethylpyrazolo[1,5-a]pyridin-3-yl}-1H-pyrazol-1-yl)propanoic acid trifluoroacetate

[0759] ##STR00094##

[0760] 0.32 ml (0.32 mmol) of 1 N aqueous lithium hydroxide solution was added to 60 mg (0.11 mmol) of methyl 3-(4-{7-[(2,6-difluorobenzyl)oxy]-2,5-dimethylpyrazolo[1,5-a]pyridin-3-yl}-1H-pyrazol-1-yl)propanoate trifluoroacetate from Example 21 in 2.30 ml of THF/methanol (5/1), and the mixture was stirred at room temperature for 2 h. 0.34 ml of 1 N aqueous hydrochloric acid was added and the reaction solution was then purified by preparative HPLC (RP18 column, mobile phase: acetonitrile/water gradient with addition of 0.1% TFA). This gave 52 mg of the target compound (87% of theory).

[0761] LC-MS (Method 2): R.sub.t=0.92 min

[0762] MS (ESpos): m/z=427 (M-TFA+H).sup.+

[0763] .sup.1H-NMR (400 Mhz, DMSO-d.sub.6) δ=2.33-2.42 (m, 6H), 2.86 (t, 2H), 4.37 (t, 2H), 5.41 (s, 2H), 6.38 (s, 1H), 7.14 (s, 1H), 7.27 (t, 2H), 7.57-7.67 (m, 1H), 7.72 (s, 1H), 8.00 (s, 1H), 12.39 (br. s, 1H).

Example 23

N-Cyclopropyl-3-(4-{7-[(2,6-difluorobenzyl)oxy]-2,5-dimethylpyrazolo[1,5-a]pyridin-3-yl}-1H-pyrazol-1-yl)propanamide

[0764] ##STR00095##

[0765] 25 mg (0.05 mmol) of 3-(4-{7-[(2,6-difluorobenzyl)oxy]-2,5-dimethylpyrazolo[1,5-a]pyridin-3-yl}-1H-pyrazol-1-yl)propanoic acid trifluoroacetate from Example 22, 23 mg (0.06 mmol) of HATU and 0.04 ml (0.23 mmol) of N,N-diisopropylethylamine in 0.16 ml of DMF were stirred at RT for 20 min, 6 μl (0.09 mmol) of cyclopropylamine were added and the mixture was stirred at RT for 1.5 h. Acetonitrile, water and TFA were added and the reaction solution was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile/water gradient with addition of 0.1% TFA). The product-containing fractions were concentrated, dissolved in dichloromethane and washed twice with saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted twice with dichloromethane. The combined organic phases were dried over sodium sulphate and filtered, and the filtrate was concentrated. This gave 20 mg of the target compound (91% of theory).

[0766] LC-MS (Method 2): R.sub.t=0.93 min

[0767] MS (ESpos): m/z=466 (M+H).sup.+

[0768] .sup.1H-NMR (500 Mhz, DMSO-d.sub.6) δ=0.30-0.36 (m, 2H), 0.57-0.61 (m, 2H), 2.34-2.40 (m, 6H), 2.58-2.67 (m, 3H), 4.38 (t, 2H), 5.42 (s, 2H), 6.38 (s, 1H), 7.12 (s, 1H), 7.25 (t, 2H), 7.58-7.66 (m, 1H), 7.70 (s, 1H), 7.90 (s, 1H), 8.01 (s, 1H).

Example 24

2-(4-{7-[(2,6-Difluorobenzyl)oxy]-2,5-dimethylpyrazolo[1,5-a]pyridin-3-yl}-1H-pyrazol-1-yl)ethanol trifluoroacetate

[0769] ##STR00096##

[0770] 98 mg (0.30 mmol) of caesium carbonate, 2 mg (0.01 mmol) of potassium iodide and 0.012 ml (0.15 mmol) of iodoethanol were added to 45 mg (0.12 mmol) of 7-[(2,6-difluorobenzyl)oxy]-2,5-dimethyl-3-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine from Example 1 in 0.63 of DMF, and the mixture was stirred at 70° C. for 1.5 h. Subsequently, another 0.018 ml (0.23 mmol) of iodoethanol were added and the mixture was stirred at 70° C. for 4.5 h. After cooling, water was added and the mixture was extracted three times with ethyl acetate. The combined organic phases were washed with water once. The combined aqueous phases were extracted three times with dichloromethane. The collected organic phases were dried over sodium sulphate, filtered and concentrated. The residue was purified by thick-layer chromatography (solvent: dichloromethane/ethanol=30/1). The product fractions were concentrated and the residue was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile/water gradient with addition of 0.1% TFA). This gave 5 mg of the target compound (8% of theory).

[0771] LC-MS (Method 2): R.sub.t=0.89 min

[0772] MS (ESpos): m/z=399 (M-TFA+H).sup.+

Example 25

7-[(2,6-Difluorobenzyl)oxy]-3-{1-[2-(3,5-dimethyl-1H-pyrazol-4-yl)ethyl]-1H-pyrazol-4-yl}-2,5-dimethylpyrazolo[1,5-a]pyridine

[0773] ##STR00097##

[0774] 0.08 ml (0.08 mmol) of potassium tert-butoxide solution (1 N in THF) was added to 23 mg (0.06 mmol) of 7-[(2,6-difluorobenzyl)oxy]-2,5-dimethyl-3-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine from Example 1 in 0.3 ml of DMF, the mixture was stirred at room temperature for 5 min, 18 mg (0.09 mmol) of 4-(2-bromoethyl)-3,5-dimethyl-1H-pyrazole and 1 mg (0.01 mmol) of potassium iodide were then added and the mixture was stirred at 70° C. overnight. The reaction mixture was concentrated and the residue was purified by thick-layer chromatography (solvent: dichloromethane/ethanol=20/1).

[0775] This gave 10 mg of the target compound (34% of theory).

[0776] LC-MS (Method 2): R.sub.t=0.88 min

[0777] MS (ESpos): m/z=477 (M+H).sup.+

Example 26

N.SUP.1.-(4-{7-[(2,6-Difluorobenzyl)oxy]-2,5-dimethylpyrazolo[1,5-a]pyridin-3-yl}-5-fluoropyridin-2-yl)-2-methylpropane-1,2-diamine trifluoroacetate

[0778] ##STR00098##

[0779] 35 mg (0.085 mmol) of 7-[(2,6-difluorobenzyl)oxy]-3-(2,5-difluoropyridin-4-yl)-2,5-dimethylpyrazolo[1,5-a]pyridine from Example 17 were initially charged in 0.20 ml of NMP. At room temperature, 89 mg (1.02 mmol) of 2-methylpropane-1,2-diamine were added and the mixture was stirred at 150° C. in a closed vessel in the microwave for 2 h. The reaction solution was diluted with acetonitrile/water, TFA was added and the mixture was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile/water gradient with addition of 0.1% TFA). This gave 2 mg of the target compound (1% of theory).

[0780] LC-MS (Method 2): R.sub.t=0.61 min

[0781] MS (ESpos): m/z=470 (M-TFA+H).sup.+

Example 27

5-{7-[(2,6-Difluorobenzyl)oxy]-2,5-dimethylpyrazolo[1,5-a]pyridin-3-yl}nicotinic acid

[0782] ##STR00099##

[0783] 0.35 ml (0.35 mmol) of 1N aqueous lithium hydroxide solution were added to 31 mg (0.07 mmol) ethyl 5-{7-[(2,6-difluorobenzyl)oxy]-2,5-dimethylpyrazolo[1,5-a]pyridin-3-yl}nicotinate from Example 18 in 1.5 ml of THF/ethanol (5/1), and the mixture was stirred at room temperature for 4 h. Another 0.35 ml (0.35 mmol) of 1N aqueous lithium hydroxide solution and 0.36 ml of THF/Ethanol (5/1) were added and the mixture was stirred at room temperature overnight. 0.48 ml of THF/Ethanol (5/1) was added and the mixture was stirred at room temperature for another 3 h. With ice cooling, the mixture was adjusted to pH=4 using 1 N aqueous hydrochloric acid solution, and the organic solvent was then removed on a rotary evaporator. The suspension was filtered off, washed with water and dried. 26 mg (87% of theory) of the title compound were obtained.

[0784] LC-MS (Method 2): R.sub.t=0.90 min

[0785] MS (ESpos): m/z=410 (M+H).sup.+

Example 28

5-{7-[(2,6-Difluorobenzyl)oxy]-2,5-dimethylpyrazolo[1,5-a]pyridin-3-yl}nicotinamide

[0786] ##STR00100##

[0787] 15 mg (0.08 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 12 mg (0.08 mmol) of 1-hydroxy-1H-benzotriazole hydrate were added to 22 mg (0.05 mmol) of 5-{7-[(2,6-difluorobenzyl)oxy]-2,5-dimethylpyrazolo[1,5-a]pyridin-3-yl}nicotinic acid from Example 27 in 1.0 ml of dichloromethane, and the mixture was stirred at room temperature for 10 min. Subsequently, 14 mg (0.26 mmol) of ammonium chloride and 46 mg (0.36 mmol) of N,N-diisopropylethylamine were added and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated and the residue was purified by thick-layer chromatography (mobile phase: dichloromethane/2 N ammonia in methanol=20/1). 15 mg (70% of theory) of the title compound were obtained.

[0788] LC-MS (Method 2): R.sub.t=0.82 min

[0789] MS (ESpos): m/z=409 (M+H).sup.+

[0790] .sup.1H-NMR (500 Mhz, DMSO-d.sub.6) δ=2.40 (s, 3H), 2.42 (s, 3H), 5.47 (s, 2H), 6.52 (s, 1H), 7.15 (s, 1H), 7.28 (t, 2H), 7.59-7.69 (m, 2H), 8.23 (br. s, 2H), 8.78 (s, 1H), 8.95 (s, 1H).

Example 29

7-[(2,6-Difluorobenzyl)oxy]-2,5-dimethyl-3-(pyrimidin-5-yl)pyrazolo[1,5-a]pyridine

[0791] ##STR00101##

[0792] 60 mg (0.16 mmol) of 3-bromo-7-[(2,6-difluorobenzyl)oxy]-2,5-dimethylpyrazolo[1,5-a]pyridine from Example 17A and 30 mg (0.24 mmol) of pyrimidin-5-ylboric acid were initially charged in 2 ml of abs. acetonitrile and gassed with argon. 6 mg (0.008 mmol) of chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)palladium (II) [CAS: 1310584-14-5] were then added, followed by 0.98 ml (0.49 mmol) of aqueous 0.5 M potassium phosphate solution (oxygen-free). The reaction mixture was stirred vigorously at 60° C. for 5 h. The reaction solution was cooled, water was added and the mixture was extracted three times with ethyl acetate. The combined organic phases were washed with water once, dried over sodium sulphate, filtered and concentrated. The residue was dissolved in acetonitrile, water and TFA and purified by preparative HPLC (RP18 column, mobile phase: acetonitrile/water gradient with addition of 0.1% TFA). The product-containing fractions were concentrated, the residue was taken up in dichloromethane and a little methanol and washed twice with aqueous saturated sodium bicarbonate solution. The combined aqueous phases were reextracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. This gave 6 mg (10% of theory) of the title compound.

[0793] LC-MS (Method 2): R.sub.t=0.98 min

[0794] MS (ESpos): m/z=367 (M+H).sup.+

Example 30

2-Cyclopropyl-7-[(2,6-difluorobenzyl)oxy]-5-methyl-3-{1-[2-(morpholin-4-yl)ethyl]-1H-pyrazol-4-yl}pyrazolo[1,5-a]pyridine

[0795] ##STR00102##

[0796] 60 mg (0.14 mmol, purity 90%) of 3-bromo-2-cyclopropyl-7-[(2,6-difluorobenzyl)oxy]-5-methylpyrazolo[1,5-a]pyridine from Example 19A and 63 mg (0.21 mmol) of 4-{2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]ethyl}morpholine were initially charged in 1.7 ml of abs. acetonitrile and gassed with argon. 5.4 mg (0.007 mmol) of chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl) [2-(2′-amino-1,1′-biphenyl)palladium (II) [CAS: 1310584-14-5] were then added, followed by 0.82 ml (0.41 mmol) of aqueous 0.5 M potassium phosphate solution (oxygen-free). The reaction mixture was stirred vigorously at 100° C. for 5 min. The reaction solution was cooled, dissolved in acetonitrile, water and TFA and purified by preparative HPLC (RP18 column, mobile phase: acetonitrile/water gradient with addition of 0.1% TFA). The product-containing fractions were concentrated, the residue was taken up in dichloromethane and a little methanol and washed twice with aqueous saturated sodium bicarbonate solution. The combined aqueous phases were reextracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. This gave 45 mg (65% of theory) of the title compound.

[0797] LC-MS (Method 2): R.sub.t=0.82 min

[0798] MS (ESpos): m/z=494 (M+H).sup.+

Example 31

2-Cyclopropyl-7-[(2,6-difluorobenzyl)oxy]-5-methyl-3-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine

[0799] ##STR00103##

[0800] 60 mg (0.14 mmol, purity 90%) of 3-bromo-2-cyclopropyl-7-[(2,6-difluorobenzyl)oxy]-5-methylpyrazolo[1,5-a]pyridine from Example 19A and 61 mg (0.21 mmol) of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-carboxylate were initially charged in 0.8 ml of abs. acetonitrile and gassed with argon. 5.4 mg (0.007 mmol) of chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl) [2-(2′-amino-1,1′-biphenyl)palladium (II) [CAS: 1310584-14-5] were then added, followed by 0.82 ml (0.41 mmol) of aqueous 0.5 M potassium phosphate solution (oxygen-free). The reaction mixture was stirred vigorously at 100° C. for 10 min. The reaction solution was cooled and purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% TFA). The product-containing fractions were concentrated, the residue was taken up in dichloromethane and washed twice with aqueous saturated sodium bicarbonate solution. The combined aqueous phases were reextracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. This gave 9 mg of the title compound.

[0801] The product-relevant fractions [i.e. the target compound still protected with Boc] from the preparative HPLC were concentrated. 0.1 ml of diethyl ether and 0.2 ml of hydrogen chloride solution (2 N in diethyl ether) were added to the residue, and the mixture was stirred at RT overnight. 1 ml of hydrogen chloride solution (2 N in diethyl ether) was then added, and the mixture was once more stirred at RT overnight. The reaction mixture was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile/water gradient with addition of 0.1% TFA). The product-containing fractions were concentrated, the residue was taken up in dichloromethane and washed twice with aqueous saturated sodium bicarbonate solution. The combined aqueous phases were reextracted twice with dichloromethane. The combined organic phases were dried over sodium sulphate, filtered and concentrated together with the fraction obtained above. This gave 14 mg (26% of theory) of the title compound in total.

[0802] LC-MS (Method 2): R.sub.t=1.01 min

[0803] MS (ESpos): m/z=381 (M+H).sup.+

Example 32

2,5-Dimethyl-3-{1-[2-(morpholin-4-yl)ethyl]-1H-pyrazol-4-yl}-7-[(2,3,6-trifluorobenzyl)oxy]pyrazolo[1,5-a]pyridine trifluoroacetate

[0804] ##STR00104##

[0805] 25 mg (0.05 mmol, purity 71%) of 3-bromo-2,5-dimethyl-7-[(2,3,6-trifluorobenzyl)oxy]pyrazolo[1,5-a]pyridine from Example 18A and 21 mg (0.07 mmol) of 4-{2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]ethyl}morpholine were initially charged in 0.6 ml of abs. acetonitrile and gassed with argon. 2 mg (0.002 mmol) of chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl) [2-(2′-amino-1,1′-biphenyl)palladium (II) [CAS: 1310584-14-5] were then added, followed by 0.28 ml (0.14 mmol) of aqueous 0.5 M potassium phosphate solution (oxygen-free). The reaction mixture was stirred vigorously at 60° C. for 7.5 h. Another 2 mg (0.002 mmol) of chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl) [2-(2′-amino-1,1′-biphenyl)palladium (II) [CAS: 1310584-14-5] and 14 mg (0.05 mmol) of 4-{2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]ethyl}morpholine were added, and the mixture was stirred at 100° C. for 20 min. The reaction mixture was cooled, water was added and the mixture was extracted three times with ethyl acetate. The combined organic phases were washed with water once, dried over sodium sulphate, filtered and concentrated. The residue was dissolved in acetonitrile, water and TFA and purified by preparative HPLC (RP18 column, mobile phase: acetonitrile/water gradient with addition of 0.1% TFA). This gave 3.5 mg (13% of theory) of the title compound.

[0806] LC-MS (Method 2): R.sub.t=0.76 min

[0807] MS (ESpos): m/z=486 (M-TFA+H).sup.+

Example 33

7-(Cyclohexylmethoxy)-2,5-dimethyl-3-{1-[2-(morpholin-4-yl)ethyl]-1H-pyrazol-4-yl}pyrazolo[1,5-a]pyridine

[0808] ##STR00105##

[0809] 35 mg (0.09 mmol, purity 87%) of 3-bromo-7-(cyclohexylmethoxy)-2,5-dimethylpyrazolo[1,5-a]pyridine from Example 24A and 42 mg (0.14 mmol) of 4-{2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]ethyl}morpholine were initially charged in 1.1 ml of abs. acetonitrile and gassed with argon. 3.5 mg (0.005 mmol) of chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)palladium (II) [CAS: 1310584-14-5] were then added, followed by 0.54 ml (0.27 mmol) of aqueous 0.5 M potassium phosphate solution (oxygen-free). The reaction mixture was stirred vigorously at 60° C. overnight. Another 3.5 mg (0.005 mmol) of chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)palladium (II) [CAS: 1310584-14-5] and 10 mg (0.03 mmol) of 4-{2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]ethyl}morpholine were then added, and the mixture was stirred vigorously at 100° C. for 25 min. The reaction solution was cooled, water was added and the mixture was extracted three times with ethyl acetate. The combined organic phases were washed with water once, dried over sodium sulphate, filtered and concentrated. The residue was dissolved in acetonitrile, water and TFA and purified by preparative HPLC (RP18 column, mobile phase: acetonitrile/water gradient with addition of 0.1% TFA). The product-containing fractions were concentrated, the residue was taken up in dichloromethane and a little methanol and washed twice with aqueous saturated sodium bicarbonate solution. The combined aqueous phases were extracted twice with dichloromethane. The combined organic phases were dried over sodium sulphate, filtered and concentrated. This gave 22 mg (55% of theory) of the title compound.

[0810] LC-MS (Method 2): R.sub.t=0.82 min

[0811] MS (ESpos): m/z=438 (M+H).sup.+

Example 34

4-Amino-2-{7-[(2,6-difluorobenzyl)oxy]-2,5-dimethylpyrazolo[1,5-a]pyridin-3-yl}-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one trifluoroacetate

[0812] ##STR00106##

[0813] Under argon, 65 mg (0.15 mmol; purity 91%) of 7-[(2,6-difluorobenzyl)oxy]-2,5-dimethylpyrazolo[1,5-a]pyridine-3-carboximidamide acetate from Example 28A were initially charged in 1.7 ml of tert-butanol, 26 mg (0.23 mmol) of potassium tert-butoxide and 38 mg (0.23 mmol) of methyl 3,3-dicyano-2,2-dimethylpropanoate were added in succession at RT and the mixture was heated at reflux overnight. The mixture was then cooled and concentrated. The residue was taken up in acetonitrile, water and trifluoroacetic acid were added and the mixture was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile/water gradient with addition of 0.1% TFA). This gave 19 mg (21% of theory) of the title compound.

[0814] LC-MS (Method 2): R.sub.t=0.97 min

[0815] MS (ESpos): m/z=465 (M-TFA+H).sup.+

[0816] .sup.1H-NMR (400 Mhz, DMSO-d.sub.6) δ=1.32 (s, 6H), 2.44 (s, 3H), 2.68 (s, 3H), 5.43 (s, 2H), 6.38-6.60 (m, 3H), 7.27 (t, 2H), 7.58-7.68 (m, 2H), 8.12 (s, 1H), 10.75 (br. s, 1H).

Example 35

4-[(2-Amino-2-methylpropyl)amino]-2-{7-[(2,6-difluorobenzyl)oxy]-2,5-dimethylpyrazolo[1,5-a]pyridin-3-yl}-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one

[0817] ##STR00107##

[0818] Under argon, 20 mg (0.035 mmol) of 2-{7-[(2,6-difluorobenzyl)oxy]-2,5-dimethylpyrazolo[1,5-a]pyridin-3-yl}-4-iodo-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one from Example 29A were initially charged in 0.15 ml of 1-methyl-2-pyrrolidone (NMP), 23 mg (0.26 mmol) of 2-methylpropane-1,2-diamine were added and the mixture was stirred at 120° C. for 135 min. The mixture was then cooled and purified by preparative HPLC (RP18 column, mobile phase: acetonitrile/water gradient with addition of 0.1% TFA). The product fractions were concentrated and the residue was taken up in dichloromethane. The solution was extracted twice with 2 ml of saturated aqueous sodium bicarbonate solution. The organic phase was dried over sodium sulfate, filtered, concentrated and lyophilized. 5.3 mg (28% of theory) of the title compound were obtained.

[0819] LC-MS (Method 2): R.sub.t=0.81 min

[0820] MS (ESpos): m/z=536 (M+H).sup.+

B. ASSESSMENT OF PHARMACOLOGICAL EFFICACY

[0821] The following abbreviations are used:

TABLE-US-00002 ATP adenosine triphosphate Brij35 polyoxyethylene(23) lauryl ether BSA bovine serum albumin DTT dithiothreitol TEA triethanolamine

[0822] The pharmacological action of the compounds of the invention can be demonstrated in the following assays:

B-1. Measurement of sGC Enzyme Activity by Means of PPi Detection

[0823] Soluble guanylyl cyclase (sGC) converts GTP to cGMP and pyrophosphate (PPi) when stimulated. PPi is detected with the aid of the method described in WO 2008/061626. The signal that arises in the assay increases as the reaction progresses and serves as a measure of the sGC enzyme activity. With the aid of a PPi reference curve, the enzyme can be characterized in a known manner, for example in terms of conversion rate, stimulability or Michaelis constant.

Conduct of the Test

[0824] To conduct the test, 29 μl of enzyme solution (0-10 nM soluble guanylyl cyclase (prepared according to Hinicka et al., Journal of Molecular Medicine 77 (1999) 14-23), in 50 mM TEA, 2 mM magnesium chloride, 0.1% BSA (fraction V), 0.005% Brij 35, pH 7.5) were initially charged in the microplate, and 1 μl of the stimulator solution (0-10 μM 3-morpholinosydnonimine, SIN-1, Merck in DMSO) was added. The microplate was incubated at RT for 10 min. Then 20 μl of detection mix (1.2 nM Firefly Luciferase (Photinus pyralis luciferase, Promega), 29 μM dehydroluciferin (prepared according to Bitler & McElroy, Arch. Biochem. Biophys. 72 (1957) 358), 122 μM luciferin (Promega), 153 μM ATP (Sigma) and 0.4 mM DTT (Sigma) in 50 mM TEA, 2 mM magnesium chloride, 0.1% BSA (fraction V), 0.005% Brij 35, pH 7.5) were added. The enzyme reaction was started by adding 20 μl of substrate solution (1.25 mM guanosine 5′-triphosphate (Sigma) in 50 mM TEA, 2 mM magnesium chloride, 0.1% BSA (fraction V), 0.005% Brij 35, pH 7.5) and analysed continuously in a luminometer.

B-2. Effect on a Recombinant Guanylate Cyclase Reporter Cell Line

[0825] The cellular activity of the compounds according to the invention is determined using a recombinant guanylate cyclase reporter cell line, as described in F. Wunder et al., Anal. Biochem. 339, 104-112 (2005).

[0826] Representative MEC values (MEC=minimum effective concentration) for the compounds of the invention are shown in the table below (in some cases as mean values from individual determinations):

TABLE-US-00003 TABLE A MEC Example [μM] 1 0.03 2 0.53 3 0.065 4 0.07 5 0.07 6 0.1 7 0.065 8 1.0 9 3.0 10 0.065 11 0.03 12 0.055 13 0.1 14 2.0 15 0.3 16 0.1 17 2.0 18 10.0 19 0.3 20 2.0 21 0.03 22 0.10 23 0.03 24 0.065 25 0.065 27 2.0 28 0.03 29 0.30 30 0.01 31 0.03 32 0.10 33 0.10 34 1.0 35 3.0

B-3. Vasorelaxant Effect In Vitro

[0827] Rabbits are stunned by a blow to the neck and exsanguinated. The aorta is removed, freed from adhering tissue and divided into rings of width 1.5 mm, which are placed individually under prestress into 5 ml organ baths with carbogen-sparged Krebs-Henseleit solution at 37° C. having the following composition (each in mM): sodium chloride: 119; potassium chloride: 4.8; calcium chloride dihydrate: 1; magnesium sulfate heptahydrate: 1.4; potassium dihydrogenphosphate: 1.2; sodium bicarbonate: 25; glucose: 10. The contractile force is determined with Statham UC2 cells, amplified and digitalized using A/D transducers (DAS-1802 HC, Keithley Instruments Munich), and recorded in parallel on linear recorders. To generate a contraction, phenylephrine is added to the bath cumulatively in increasing concentration. After several control cycles, the substance to be studied is added in increasing dosage each time in every further run, and the magnitude of the contraction is compared with the magnitude of the contraction attained in the last preceding run. This is used to calculate the concentration needed to reduce the magnitude of the control value by 50% (IC.sub.50 value). The standard administration volume is 5 μl; the DMSO content in the bath solution corresponds to 0.1%.

B-4. Blood Pressure Measurement on Anaesthetized Rats

[0828] Male Wistar rats having a body weight of 300-350 g are anaesthetized with thiopental (100 mg/kg i.p.). After tracheotomy, a catheter is introduced into the femoral artery to measure the blood pressure. The substances to be tested are administered as solutions, either orally by means of a gavage or intravenously via the femoral vein (Stasch et al. Br. J. Pharmacol. 2002; 135: 344-355).

B-5. Radiotelemetry Measurement of Blood Pressure in Conscious, Spontaneously Hypertensive Rats

[0829] A commercially available telemetry system from DATA SCIENCES INTERNATIONAL DSI, USA, is employed for the blood pressure measurement on conscious rats described below.

[0830] The system consists of 3 main components:

implantable transmitters (Physiotel® telemetry transmitter)
receivers (Physiotel® receiver) which are linked via a multiplexer (DSI Data Exchange Matrix) to a
data acquisition computer.

[0831] The telemetry system makes it possible to continuously record blood pressure, heart rate and body motion of conscious animals in their usual habitat.

Animal Material

[0832] The studies are conducted on adult female spontaneously hypertensive rats (SHR Okamoto) with a body weight of >200 g. SHR/NCrl from the Okamoto Kyoto School of Medicine, 1963, were a cross of male Wistar Kyoto rats having greatly elevated blood pressure and female rats having slightly elevated blood pressure, and were handed over at F13 to the U.S. National Institutes of Health.

[0833] After transmitter implantation, the experimental animals are housed singly in type 3 Makrolon cages. They have free access to standard feed and water.

[0834] The day/night rhythm in the experimental laboratory is changed by the room lighting at 6:00 am and at 7:00 pm.

Transmitter Implantation

[0835] The TA11 PA-C40 telemetry transmitters used are surgically implanted under aseptic conditions in the experimental animals at least 14 days before the first experimental use.

[0836] The animals instrumented in this way can be used repeatedly after the wound has healed and the implant has settled.

[0837] For the implantation, the fasted animals are anaesthetized with pentobarbital (Nembutal, Sanofi: 50 mg/kg i.p.) and shaved and disinfected over a large area of their abdomens. After the abdominal cavity has been opened along the linea alba, the liquid-filled measuring catheter of the system is inserted into the descending aorta in the cranial direction above the bifurcation and fixed with tissue glue (VetBonD™, 3M). The transmitter housing is fixed intraperitoneally to the abdominal wall muscle, and the wound is closed layer by layer.

[0838] An antibiotic (Tardomyocel COMP, Bayer, 1 ml/kg s.c.) is administered postoperatively for prophylaxis of infection.

Substances and Solutions

[0839] Unless stated otherwise, the substances to be studied are administered orally by gavage to a group of animals in each case (n=6). In accordance with an administration volume of 5 ml/kg of body weight, the test substances are dissolved in suitable solvent mixtures or suspended in 0.5% tylose.

[0840] A solvent-treated group of animals is used as control.

Experimental Procedure

[0841] The telemetry measuring unit present is configured for 24 animals. Each experiment is recorded under an experiment number (Vyear month day).

[0842] Each of the instrumented rats living in the system is assigned a separate receiving antenna (1010 Receiver, DSI).

[0843] The implanted transmitters can be activated externally by means of an incorporated magnetic switch. They are switched to transmission in the run-up to the experiment. The signals emitted can be detected online by a data acquisition system (Dataquest™ A.R.T. for WINDOWS, DSI) and processed accordingly. The data are stored in each case in a file created for this purpose and bearing the experiment number.

[0844] In the standard procedure, the following are measured for 10-second periods in each case:

systolic blood pressure (SBP)
diastolic blood pressure (DBP)
mean arterial pressure (MAP)
heart rate (HR)
activity (ACT).

[0845] The acquisition of measurements is repeated under computer control at 5-minute intervals.

[0846] The source data obtained as absolute values are corrected in the diagram with the currently measured barometric pressure (Ambient Pressure Reference Monitor; APR-1) and stored as individual data. Further technical details are given in the extensive documentation from the manufacturer company (DSI).

[0847] Unless indicated otherwise, the test substances are administered at 9:00 am on the day of the experiment. Following the administration, the parameters described above are measured over 24 hours.

Evaluation

[0848] After the end of the experiment, the acquired individual data are sorted using the analysis software (DATAQUEST™ A.R.T.™ ANALYSIS). The blank value is assumed here to be the time 2 hours before administration, and so the selected data set encompasses the period from 7:00 am on the day of the experiment to 9:00 am on the following day.

[0849] The data are smoothed over a predefinable period by determination of the average (15-minute average) and transferred as a text file to a storage medium. The measured values presorted and compressed in this way are transferred to Excel templates and tabulated. For each day of the experiment, the data obtained are stored in a dedicated file bearing the number of the experiment. Results and test protocols are stored in files in paper form sorted by numbers.

LITERATURE

[0850] Klaus Witte, Kai Hu, Johanna Swiatek, Claudia Müssig, Georg Ertl and Björn Lemmer: Experimental heart failure in rats: effects on cardiovascular circadian rhythms and on myocardial β-adrenergic signaling. Cardiovasc Res 47 (2): 203-405, 2000; Kozo Okamoto: Spontaneous hypertension in rats. Int Rev Exp Pathol 7: 227-270, 1969; Maarten van den Buuse: Circadian Rhythms of Blood Pressure, Heart Rate, and Locomotor Activity in Spontaneously Hypertensive Rats as Measured With Radio-Telemetry. Physiology & Behavior 55(4): 783-787, 1994.

B-6. Determination of Pharmacokinetic Parameters Following Intravenous and Oral Administration

[0851] The pharmacokinetic parameters of the compounds according to the invention are determined in male CD-1 mice, male Wistar rats and female beagles. Intravenous administration in the case of mice and rats is carried out by means of a species-specific plasma/DMSO formulation, and in the case of dogs by means of a water/PEG400/ethanol formulation. In all species, oral administration of the dissolved substance is performed via gavage, based on a water/PEG400/ethanol formulation. The removal of blood from rats is simplified by inserting a silicone catheter into the right Vena jugularis externa prior to substance administration. The operation is carried out at least one day prior to the experiment with isofluran anaesthesia and administration of an analgesic (atropine/rimadyl (3/1) 0.1 ml s.c.). The blood is taken (generally more than 10 time points) within a time window including terminal time points of at least 24 to a maximum of 72 hours after substance administration. The blood is removed into heparinized tubes. The blood plasma is then obtained by centrifugation; if required, it is stored at −20° C. until further processing.

[0852] An internal standard (which may also be a chemically unrelated substance) is added to the samples of the compounds of the invention, calibration samples and qualifiers, and there follows protein precipitation by means of acetonitrile in excess. Addition of a buffer solution matched to the LC conditions, and subsequent vortexing, is followed by centrifugation at 1000 g. The supernatant is analysed by LC-MS/MS using C18 reversed-phase columns and variable mobile phase mixtures. The substances are quantified via the peak heights or areas from extracted ion chromatograms of specific selected ion monitoring experiments.

[0853] The plasma concentration/time plots determined are used to calculate the pharmacokinetic parameters such as AUC, C.sub.max, t.sub.1/2 (terminal half-life), F (bioavailability), MRT (mean residence time) and CL (clearance), by means of a validated pharmacokinetic calculation program.

[0854] Since the substance quantification is performed in plasma, it is necessary to determine the blood/plasma distribution of the substance in order to be able to adjust the pharmacokinetic parameters correspondingly. For this purpose, a defined amount of substance is incubated in heparinized whole blood of the species in question in a rocking roller mixer for 20 min. After centrifugation at 1000 g, the plasma concentration is measured (by means of LC-MS/MS; see above) and determined by calculating the ratio of the C.sub.blood/C.sub.plasma value.

B-7. Metabolic Study

[0855] To determine the metabolic profile of the inventive compounds, they are incubated with recombinant human cytochrome P450 (CYP) enzymes, liver microsomes or primary fresh hepatocytes from various animal species (e.g. rats, dogs), and also of human origin, in order to obtain and to compare information about a very substantially complete hepatic phase I and phase II metabolism, and about the enzymes involved in the metabolism.

[0856] The compounds of the invention were incubated with a concentration of about 0.1-10 μM. To this end, stock solutions of the compounds of the invention having a concentration of 0.01-1 mM in acetonitrile were prepared, and then pipetted with a 1:100 dilution into the incubation mixture. The liver microsomes and recombinant enzymes were incubated at 37° C. in 50 mM potassium phosphate buffer pH 7.4 with and without NADPH-generating system consisting of 1 mM NADP.sup.+, 10 mM glucose-6-phosphate and 1 unit glucose-6-phosphate dehydrogenase. Primary hepatocytes were incubated in suspension in Williams E medium, likewise at 37° C. After an incubation time of 0-4 h, the incubation mixtures were stopped with acetonitrile (final concentration about 30%) and the protein was centrifuged off at about 15 000×g. The samples thus stopped were either analyzed directly or stored at −20° C. until analysis.

[0857] The analysis is carried out by high-performance liquid chromatography with ultraviolet and mass spectrometry detection (HPLC-UV-MS/MS). To this end, the supernatants of the incubation samples are chromatographed with suitable C18 reversed-phase columns and variable mobile phase mixtures of acetonitrile and 10 mM aqueous ammonium formate solution or 0.05% formic acid. The UV chromatograms in conjunction with mass spectrometry data serve for identification, structural elucidation and quantitative estimation of the metabolites, and for quantitative metabolic reduction of the compound of the invention in the incubation mixtures.

B-8. Caco-2 Permeability Test

[0858] The permeability of a test substance was determined with the aid of the Caco-2 cell line, an established in vitro model for permeability prediction at the gastrointestinal barrier (Artursson, P. and Karlsson, J. (1991). Correlation between oral drug absorption in humans and apparent drug permeability coefficients in human intestinal epithelial (Caco-2) cells. Biochem. Biophys. 175 (3), 880-885). The Caco-2 cells (ACC No. 169, DSMZ, Deutsche Sammlung von Mikroorganismen und Zellkulturen, Braunschweig, Germany) were sown in 24-well plates having an insert and cultivated for 14 to 16 days. For the permeability studies, the test substance was dissolved in DMSO and diluted to the final test concentration with transport buffer (Hanks Buffered Salt Solution, Gibco/Invitrogen, with 19.9 mM glucose and 9.8 mM HEPES). In order to determine the apical to basolateral permeability (P.sub.appA-B) of the test substance, the solution comprising the test substance was applied to the apical side of the Caco-2 cell monolayer, and transport buffer to the basolateral side. In order to determine the basolateral to apical permeability (P.sub.appB-A) of the test substance, the solution comprising the test substance was applied to the basolateral side of the Caco-2 cell monolayer, and transport buffer to the apical side. At the start of the experiment, samples were taken from the respective donor compartment in order to ensure the mass balance. After an incubation time of two hours at 37° C., samples were taken from the two compartments. The samples were analyzed by means of LC-MS/MS and the apparent permeability coefficients (P.sub.app) were calculated. For each cell monolayer, the permeability of Lucifer Yellow was determined to ensure cell layer integrity. In each test run, the permeability of atenolol (marker for low permeability) and sulfasalazine (marker for active excretion) was also determined as quality control.

B-9. hERG Potassium Current Assay

[0859] The hERG (human ether-a-go-go related gene) potassium current makes a significant contribution to the repolarization of the human cardiac action potential (Scheel et al., 2011). Inhibition of this current by pharmaceuticals can in rare cases cause potentially lethal cardiac arrhythmias, and is therefore studied at an early stage during drug development.

[0860] The functional hERG assay used here is based on a recombinant HEK293 cell line which stably expresses the KCNH2(HERG) gene (Zhou et al., 1998). These cells are studied by means of the “whole-cell voltage-clamp” technique (Hamill et al., 1981) in an automated system (Patchliner™; Nanion, Munich, Germany), which controls the membrane voltage and measures the hERG potassium current at room temperature. The PatchControlHT™ software (Nanion) controls the Patchliner system, data capture and data analysis. The voltage is controlled by 2 EPC-10 quadro amplifiers controlled by the PatchMasterPro™ software (both: HEKA Elektronik, Lambrecht, Germany). NPC-16 chips with moderate resistance (˜2 MΩ; Nanion) serve as the planar substrate for the voltage clamp experiments.

[0861] NPC-16 chips are filled with intra- and extracellular solution (cf. Himmel, 2007) and with cell suspension. After forming a gigaohm seal and establishing whole-cell mode (including several automated quality control steps), the cell membrane is clamped at the −80 mV holding potential. The subsequent voltage clamp protocol changes the command voltage to +20 mV (for 1000 ms), −120 mV (for 500 ms), and back to the −80 mV holding potential; this is repeated every 12 s. After an initial stabilization phase (about 5-6 minutes), test substance solution is introduced by pipette in rising concentrations (e.g. 0.1, 1, and 10 μmol/1) (exposure about 5-6 minutes per concentration), followed by several washing steps.

[0862] The amplitude of the inward “tail” current which is generated by a change in potential from +20 mV to −120 mV serves to quantify the hERG potassium current, and is described as a function of time (IgorPro™ Software). Die Stromamplitude am Ende verschiedener Zeitabschnitte (z.B. Stabilisierungsphase vor Testsubstanz, erste/zweite/dritte Konzentration Testsubstanz) dient zur Erstellung einer Konzentrations-Wirkungs-Kurve, aus der die halbmaximale Hemmkonzentration IC.sub.50 der Testsubstanz errechnet wird. [0863] Hamill O P, Marty A, Neher E, Sakmann B, Sigworth F J. Improved patch-clamp techniques for high-resolution current recording from cells and cell-free membrane patches. Pfluegers Arch 1981; 391:85-100. [0864] Himmel H M. Suitability of commonly used excipients for electrophysiological in-vitro safety pharmacology assessment of effects on hERG potassium current and on rabbit Purkinje fiber action potential. J Pharmacol Toxicol Methods 2007; 56:145-158. [0865] Scheel O, Himmel H, Rascher-Eggstein G, Knott T. Introduction of a modular automated voltage-clamp platform and its correlation with manual human ether-a-go-go related gene voltage-clamp data. Assay Drug Dev Technol 2011; 9:600-607. [0866] Zhou Z F, Gong Q, Ye B, Fan Z, Makielski J C, Robertson G A, January C T. Properties of hERG channels stably expressed in HEK293 cells studied at physiological temperature. Biophys J 1998; 74:230-241.

C. WORKING EXAMPLES OF PHARMACEUTICAL COMPOSITIONS

[0867] The compounds of the invention can be converted to pharmaceutical preparations as follows:

Tablet:

Composition:

[0868] 100 mg of the compound of the invention, 50 mg of lactose (monohydrate), 50 mg of corn starch (native), 10 mg of polyvinylpyrrolidone (PVP 25) (BASF, Ludwigshafen, Germany) and 2 mg of magnesium stearate.

[0869] Tablet weight 212 mg. Diameter 8 mm, radius of curvature 12 mm.

Production:

[0870] The mixture of compound of the invention, lactose and starch is granulated with a 5% solution (w/w) of the PVP in water. The granules are dried and then mixed with the magnesium stearate for 5 minutes. This mixture is compressed using a conventional tableting press (see above for format of the tablet). The guide value used for the pressing is a pressing force of 15 kN.

Suspension for Oral Administration:

Composition:

[0871] 1000 mg of the compound of the invention, 1000 mg of ethanol (96%), 400 mg of Rhodigel® (xanthan gum from FMC, Pennsylvania, USA) and 99 g of water. 10 ml of oral suspension correspond to a single dose of 100 mg of the compound of the invention.

Production:

[0872] The Rhodigel is suspended in ethanol; the compound of the invention is added to the suspension. The water is added while stirring. The mixture is stirred for about 6 h until the swelling of the Rhodigel is complete.

Solution for Oral Administration:

Composition:

[0873] 500 mg of the compound of the invention, 2.5 g of polysorbate and 97 g of polyethylene glycol 400. 20 g of oral solution correspond to a single dose of 100 mg of the compound of the invention.

Production:

[0874] The compound of the invention is suspended in the mixture of polyethylene glycol and polysorbate with stirring. The stirring operation is continued until dissolution of the compound of the invention is complete.

I.V. Solution:

[0875] The compound of the invention is dissolved in a concentration below the saturation solubility in a physiologically acceptable solvent (e.g. isotonic saline solution, glucose solution 5% and/or PEG 400 solution 30%). The resulting solution is subjected to sterile filtration and dispensed into sterile and pyrogen-free injection vessels.