SUBSTITUTED ANNULATED PYRIMIDINES AND USE THEREOF

Abstract

The present application relates to novel substituted fused pyrimidines, to processes for their preparation, to their use alone or in combinations for the treatment and/or prophylaxis of diseases, and to their use for producing medicaments for the treatment and/or prophylaxis of diseases, in particular for the treatment and/or prophylaxis of cardiovascular disorders.

Claims

1. A compound of the general formula (I) ##STR00240## in which the ring Q represents 5- or 6-membered monocyclic heteroaryl or 8- or 9-membered bicyclic heteroaryl, L represents a #.sup.1-CR.sup.5AR.sup.5B—(CR.sup.6AR.sup.6B).sub.m-#.sup.2 group, where #.sup.1 represents the point of attachment to the carbonyl group, #.sup.2 represents the attachment site to the pyrimidine ring, m represents a number 0, 1 or 2, R.sup.5A represents hydrogen, fluorine, (C.sub.1-C.sub.4)-alkyl, hydroxy or amino, in which (C.sub.1-C.sub.4)-alkyl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of fluorine, trifluoromethyl, hydroxy, hydroxycarbonyl, (C.sub.1-C.sub.4)-alkoxycarbonyl and amino, R.sup.5B represents hydrogen, fluorine, difluoromethyl, trifluoromethyl, (C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.4)-alkoxycarbonylamino, cyano, (C.sub.3-C.sub.7)-cycloalkyl, difluoromethoxy, trifluoromethoxy, phenyl or a group of the formula -M-R.sup.7, in which (C.sub.1-C.sub.6)-alkyl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of fluorine, cyano, trifluoromethyl, (C.sub.3-C.sub.7)-cycloalkyl, hydroxy, difluoromethoxy, trifluoromethoxy, (C.sub.1-C.sub.4)-alkoxy, hydroxycarbonyl, (C.sub.1-C.sub.4)-alkoxycarbonyl and amino, and in which M represents a bond or (C.sub.1-C.sub.4)-alkanediyl, R.sup.7 represents —(C═O).sub.rOR.sup.8, —(C═O).sub.rNR.sup.9R.sup.10, —C(═S)—NR.sup.9R.sup.10, —NR—(C═O)—R.sup.11, —NR.sup.8—(C═O)—NR.sup.9R.sup.10, —NR.sup.8—SO.sub.2—NR.sup.9R.sup.10, —NR.sup.8—SO.sub.2—R.sup.11, —S(O).sub.s—R.sup.11, —SO.sub.2—NR.sup.9R.sup.10, 4- to 7-membered heterocyclyl, phenyl or 5- or 6-membered heteroaryl, in which r represents the number 0 or 1, s represents the number 0, 1 or 2, R.sup.8, R.sup.9 and R.sup.10 independently of one another each represent hydrogen, (C.sub.1-C.sub.6)-alkyl, (C.sub.3-C.sub.8)-cycloalkyl, 4- to 7-membered heterocyclyl, phenyl or 5- or 6-membered heteroaryl, or R.sup.9 and R.sup.10 together with the atom(s) to which they are respectively attached form a 4- to 7-membered heterocycle, R.sup.11 represents (C.sub.1-C.sub.6)-alkyl or (C.sub.3-C.sub.7)-cycloalkyl, or R.sup.8 and R.sup.11 together with the atom(s) to which they are respectively attached form a 4- to 7-membered heterocycle, and in which the (C.sub.1-C.sub.6)-alkyl, (C.sub.3-C.sub.7)-cycloalkyl, (C.sub.3-C.sub.8)-cycloalkyl and 4- to 7-membered heterocyclyl groups mentioned above may each independently of one another additionally be substituted by 1 to 3 substituents independently of one another selected from the group consisting of fluorine, difluoromethyl, trifluoromethyl, (C.sub.1-C.sub.4)-alkyl, (C.sub.3-C.sub.7)-cycloalkyl, hydroxy, difluoromethoxy, trifluoromethoxy, (C.sub.1-C.sub.4)-alkoxy, hydroxycarbonyl, (C.sub.1-C.sub.4)-alkoxycarbonyl, amino, phenyl, 4- to 7-membered heterocyclyl and 5- or 6-membered heteroaryl, or R.sup.5A and R.sup.5B together with the carbon atom to which they are attached form a (C.sub.2-C.sub.4)-alkenyl group, an oxo group, a 3- to 6-membered carbocycle or a 4- to 7-membered heterocycle, in which the 3- to 6-membered carbocycle and the 4- to 7-membered heterocycle may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of fluorine, hydroxy, methoxy and (C.sub.1-C.sub.4)-alkyl, R.sup.6A represents hydrogen, fluorine, (C.sub.1-C.sub.4)-alkyl or hydroxy, R.sup.6B represents hydrogen, fluorine, (C.sub.1-C.sub.4)-alkyl or trifluoromethyl, R.sup.1 represents hydrogen, halogen, cyano, difluoromethyl, trifluoromethyl, (C.sub.1-C.sub.4)-alkyl, (C.sub.3-C.sub.7)-cycloalkyl, hydroxy, (C.sub.1-C.sub.4)-alkoxy, phenyl or 5- or 6-membered heterocyclyl, n represents a number 0, 1, 2 or 3, R.sup.2 represents trifluoromethyl, (C.sub.1-C.sub.6)-alkyl, (C.sub.3-C.sub.8)-cycloalkyl, phenyl or 5- or 6-membered heteroaryl, where (C.sub.1-C.sub.6)-alkyl is substituted by a substituent selected from the group consisting of difluoromethyl and trifluoromethyl and may furthermore be up to trisubstituted by fluorine, and where (C.sub.3-C.sub.8)-cycloalkyl may be substituted by 1 or 2 substituents selected independently of one another from the group consisting of fluorine, methyl and methoxy, and where phenyl may be substituted by 1 to 3 halogen substituents and furthermore by 1 or 2 substituents independently of one another selected from the group consisting of (C.sub.1-C.sub.4)-alkyl, (C.sub.1-C.sub.4)-alkoxy and cyano, and where 5- or 6-membered heteroaryl may be substituted by 1 or 2 substituents selected from the group consisting of trifluoromethyl and methyl and furthermore up to three times by fluorine, R.sup.3 represents hydrogen, (C.sub.1-C.sub.4)-alkyl or (C.sub.3-C.sub.8)-cycloalkyl, R.sup.4 represents hydrogen, (C.sub.1-C.sub.10)-alkyl, (C.sub.3-C.sub.8)-cycloalkyl, (C.sub.2-C.sub.6)-alkenyl, 4- to 7-membered heterocyclyl, phenyl, 5- or 6-membered heteroaryl, —NR.sup.12R.sup.13 or —OR.sup.14, where (C.sub.1-C.sub.10)-alkyl, (C.sub.3-C.sub.8)-cycloalkyl, (C.sub.2-C.sub.6)-alkenyl and 4- to 7-membered heterocyclyl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of fluorine, difluoromethyl, trifluoromethyl, methyl, ethyl, hydroxy, oxo, (C.sub.1-C.sub.6)-alkyl, (C.sub.3-C.sub.7)-cycloalkyl, difluoromethoxy, trifluoromethoxy, —OR.sup.15, —NR.sup.16—(C═O)—R.sup.17, —NR.sup.16—(C═O)—NR.sup.18R.sup.19, —NR.sup.18R.sup.19, —(C═O)—NR.sup.18R.sup.19, —S(O).sub.p—R.sup.20, —NR.sup.18—SO.sub.2—R.sup.19, —SO.sub.2—NR.sup.18R.sup.19, —(C═O)—OR.sup.21, —NR.sup.16—(C═O)—OR.sup.21, phenyl, 4- to 7-membered heterocyclyl and 5- or 6-membered heteroaryl, in which p represents the number 0, 1 or 2, R.sup.15 and R.sup.20 independently of one another each represent (C.sub.1-C.sub.6)-alkyl, phenyl or (C.sub.3-C.sub.8)-cycloalkyl, R.sup.16, R.sup.17, R.sup.18 and R.sup.19 independently of one another each represent hydrogen, (C.sub.1-C.sub.6)-alkyl or (C.sub.3-C.sub.8)-cycloalkyl, or R.sup.16 and R.sup.17 together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycle, or R.sup.18 and R.sup.19 together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycle, R.sup.21 represents hydrogen, (C.sub.1-C.sub.6)-alkyl or (C.sub.3-C.sub.8)-cycloalkyl, and where 5- or 6-membered heteroaryl and phenyl may each be substituted by 1 to 3 substituents independently of one another selected from the group consisting of halogen, difluoromethyl, trifluoromethyl, (C.sub.1-C.sub.4)-alkyl, (C.sub.1-C.sub.4)-alkoxy, difluoromethoxy, trifluoromethoxy, cyano, hydroxy and (C.sub.3-C.sub.7)-cycloalkyl, and where R.sup.12 and R.sup.13 independently of one another represent hydrogen or (C.sub.1-C.sub.4)-alkyl, in which (C.sub.1-C.sub.4)-alkyl may be substituted by 1 to 3 substituents selected from the group consisting of fluorine, hydroxy and (C.sub.1-C.sub.4)-alkoxy, or R.sup.12 and R.sup.13 together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycle, and where R.sup.14 represents (C.sub.1-C.sub.6)-alkyl, (C.sub.3-C.sub.7)-cycloalkyl or (C.sub.3-C.sub.6)-alkenyl, or R.sup.3 and R.sup.4 together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycle, where the 4- to 7-membered heterocycle may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of fluorine, difluoromethyl, trifluoromethyl, cyano, (C.sub.1-C.sub.4)-alkyl, (C.sub.3-C.sub.7)-cycloalkyl, hydroxy, oxo, (C.sub.1-C.sub.4)-alkoxy, difluoromethoxy, trifluoromethoxy and amino, and where the (C.sub.1-C.sub.4)-alkyl, (C.sub.1-C.sub.6)-alkyl, (C.sub.3-C.sub.8)-cycloalkyl, (C.sub.3-C.sub.7)-cycloalkyl, (C.sub.2-C.sub.6)-alkenyl, (C.sub.3-C.sub.6)-alkenyl and 4- to 7-membered heterocyclyl groups mentioned above, unless stated otherwise, may each independently of one another additionally be substituted by 1 to 3 substituents independently of one another selected from the group consisting of fluorine, difluoromethyl, trifluoromethyl, (C.sub.1-C.sub.4)-alkyl, (C.sub.3-C.sub.7)-cycloalkyl, hydroxy, difluoromethoxy, trifluoromethoxy, (C.sub.1-C.sub.4)-alkoxy, hydroxycarbonyl, (C.sub.1-C.sub.4)-alkoxycarbonyl, amino, phenyl, 4- to 7-membered heterocyclyl and 5- or 6-membered heteroaryl, and the N-oxides, salts, solvates, salts of the N-oxides and solvates of the N-oxides and salts thereof.

2. The compound of the formula (I) as claimed in claim 1 in which the ring Q represents a group of the formula ##STR00241## where * represents the point of attachment to —CH.sub.2—R.sup.2, ** represents the point of attachment to the pyrimidine ring, n represents a number 0, 1 or 2, A.sup.1, A.sup.2, A.sup.3 and A.sup.4 independently of one another each represent N, C—H or C—R.sup.1, with the proviso that not more than two of the A.sup.1, A.sup.2, A.sup.3 and A.sup.4 groups represent N, L represents a #.sup.1-CR.sup.5AR.sup.5B—(CR.sup.6AR.sup.6B).sub.m-#.sup.2 group, where #.sup.1 represents the point of attachment to the carbonyl group, #.sup.2 represents the attachment site to the pyrimidine ring, m represents a number 0 or 1, R.sup.5A represents hydrogen, fluorine, trifluoromethyl or (C.sub.1-C.sub.4)-alkyl, R.sup.5B represents hydrogen, fluorine, trifluoromethyl, (C.sub.1-C.sub.4)-alkyl, (C.sub.3-C.sub.7)-cycloalkyl or a group of the formula -M-R.sup.7, in which (C.sub.1-C.sub.4)-alkyl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of fluorine, cyano, trifluoromethyl, (C.sub.3-C.sub.7)-cycloalkyl, difluoromethoxy and trifluoromethoxy, M represents a bond or methylene, R.sup.7 represents —(C═O)—OR.sup.8 or —(C═O)—NR.sup.9R.sup.10, in which R.sup.8 represents hydrogen, (C.sub.1-C.sub.4)-alkyl, (C.sub.3-C.sub.6)-cycloalkyl or 4- or 7-membered heterocyclyl, R.sup.9 and R.sup.10 independently of one another each represent hydrogen, (C.sub.1-C.sub.4)-alkyl, (C.sub.3-C.sub.6)-cycloalkyl, 4- to 7-membered heterocyclyl, phenyl or 5- or 6-membered heteroaryl, or R.sup.9 and R.sup.10 together with the atom(s) to which they are respectively attached form a 4- to 7-membered heterocycle, or R.sup.5A and R.sup.5B together with the carbon atom to which they are attached form a (C.sub.2-C.sub.4)-alkenyl group, a 3- to 6-membered carbocycle or a 4- to 7-membered heterocycle, where the 3- to 6-membered carbocycle may be monosubstituted by hydroxy and up to disubstituted by fluorine, R.sup.6A represents hydrogen, fluorine, (C.sub.1-C.sub.4)-alkyl or hydroxy, R.sup.6B represents hydrogen, fluorine, (C.sub.1-C.sub.4)-alkyl or trifluoromethyl, R.sup.1 represents fluorine, chlorine, cyano, difluoromethyl, trifluoromethyl, (C.sub.1-C.sub.4)-alkyl, (C.sub.3-C.sub.5)-cycloalkyl or (C.sub.1-C.sub.4)-alkoxy, N represents a number 0, 1 or 2, R.sup.2 represents (C.sub.1-C.sub.6)-alkyl, phenyl or 5- or 6-membered heteroaryl, where (C.sub.1-C.sub.6)-alkyl is substituted by a substituent selected from the group consisting of difluoromethyl and trifluoromethyl and may furthermore be up to trisubstituted by fluorine, and where phenyl is substituted by 1 to 3 fluorine substituents and may furthermore be substituted by 1 or 2 substituents independently of one another selected from the group consisting of methyl and methoxy, and where 5- or 6-membered heteroaryl is up to disubstituted by fluorine, R.sup.3 represents hydrogen, (C.sub.1-C.sub.4)-alkyl or cyclopropyl, R.sup.4 represents hydrogen, (C.sub.1-C.sub.10)-alkyl, (C.sub.3-C.sub.7)-cycloalkyl, (C.sub.2-C.sub.6)-alkenyl, 4- to 7-membered heterocyclyl, phenyl, 5- or 6-membered heteroaryl, —NR.sup.12R.sup.13 or —OR.sup.14, where (C.sub.1-C.sub.10)-alkyl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of fluorine, difluoromethyl, trifluoromethyl, (C.sub.3-C.sub.7)-cycloalkyl, hydroxy, oxo, —OR.sup.15, —NR.sup.16—(C═O)—R.sup.17, —NR.sup.18R.sup.19, —(C═O)—NR.sup.18R.sup.19, —S(O).sub.p—R.sup.20, —NR.sup.18—S.sub.2—R.sup.19, phenyl, 4- to 7-membered heterocyclyl and 5- or 6-membered heteroaryl, in which (C.sub.3-C.sub.7)-cycloalkyl and 4- to 7-membered heterocyclyl independently of one another may each be substituted by a substituent selected from the group consisting of (C.sub.1-C.sub.4)-alkyl, oxo, hydroxy, amino and furthermore up to tetrasubstituted by fluorine, and in which phenyl and 5- or 6-membered heteroaryl independently of one another may each be substituted by (C.sub.1-C.sub.4)-alkyl and furthermore up to trisubstituted by fluorine, p represents the number 0, 1 or 2, R.sup.15 and R.sup.20 independently of one another represent (C.sub.1-C.sub.4)-alkyl which may be up to pentasubstituted by fluorine, represent phenyl or (C.sub.3-C.sub.7) cycloalkyl, R.sup.16 and R.sup.17 independently of one another each represent hydrogen, (C.sub.1-C.sub.4)-alkyl or (C.sub.3-C.sub.7)-cycloalkyl, R.sup.18 and R.sup.19 independently of one another represent hydrogen, (C.sub.1-C.sub.6)alkyl which may be up to pentasubstituted by fluorine, or represent (C.sub.3-C.sub.7)-cycloalkyl, or R.sup.18 and R.sup.19 together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycle, in which the 4- to 7-membered heterocycle may be up to tetrasubstituted by fluorine, where (C.sub.3-C.sub.7)-cycloalkyl may be substituted by a substituent selected from the group consisting of (C.sub.1-C.sub.4)-alkyl, hydroxy, amino, cyano and furthermore up to tetrasubstituted by fluorine, and where (C.sub.2-C.sub.6)-alkenyl may be substituted by (C.sub.1-C.sub.4)-alkyl and furthermore up to pentasubstituted by fluorine, and where 4- to 7-membered heterocyclyl may be substituted by 1 to 4 substituents independently of one another selected from the group consisting of fluorine, trifluoromethyl, oxo, (C.sub.1-C.sub.4)-alkyl, hydroxy and amino, and where 5- or 6-membered heteroaryl and phenyl may each be substituted by 1 to 3 substituents independently of one another selected from the group consisting of halogen, (C.sub.1-C.sub.4)-alkyl, (C.sub.1-C.sub.4)-alkoxy, cyano and (C.sub.3-C.sub.5)-cycloalkyl, and where R.sup.12 and R.sup.13 independently of one another represent hydrogen or (C.sub.1-C.sub.4)-alkyl, or R.sup.12 and R.sup.13 together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycle, and where R.sup.14 represents (C.sub.1-C.sub.6)-alkyl which may be up to pentasubstituted by fluorine, represents (C.sub.3-C.sub.7)-cycloalkyl or (C.sub.3-C.sub.6)-alkenyl, or R.sup.3 and R.sup.4 together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycle, where the 4- to 7-membered heterocycle may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of trifluoromethyl, (C.sub.1-C.sub.4)-alkyl, (C.sub.3-C.sub.7)-cycloalkyl, hydroxy, (C.sub.1-C.sub.4)-alkoxy, trifluoromethoxy and amino and furthermore up to tetrasubstituted by fluorine, and the salts, solvates and solvates of the salts thereof.

3. The compound of the formula (I) as claimed in claim 1 in which the ring Q represents a group of the formula ##STR00242## where * represents the point of attachment to —CH.sub.2—R.sup.2, ** represents the point of attachment to the pyrimidine ring, A.sup.1 represents N or C—H, R.sup.1a represents hydrogen or methyl if A.sup.1 represents nitrogen, or R.sup.1a represents hydrogen, fluorine or chlorine if A.sup.1 represents C—H, R.sup.1b represents hydrogen or fluorine, L represents a #.sup.1-CR.sup.5AR.sup.5B—(CR.sup.6AR.sup.6B).sub.m-#.sup.2 group, where #.sup.1 represents the point of attachment to the carbonyl group, #.sup.2 represents the attachment site to the pyrimidine ring, m represents a number 0, R.sup.5A represents hydrogen, methyl or ethyl, R.sup.5B represents hydrogen, fluorine, trifluoromethyl, methyl or ethyl, where methyl and ethyl may be up to trisubstituted by fluorine, or R.sup.5A and R.sup.5B together with the carbon atom to which they are attached form a cyclopropyl ring, R.sup.2 represents 2,2,2-trifluoroeth-1-yl, phenyl or pyridyl, where phenyl is substituted by 1 to 3 fluorine substituents, and where pyridyl is monosubstituted by fluorine, R.sup.3 represents hydrogen, (C.sub.1-C.sub.4)-alkyl or cyclopropyl, R.sup.4 represents hydrogen, (C.sub.1-C.sub.6)-alkyl, (C.sub.3-C.sub.6)-cycloalkyl, (C.sub.2-C.sub.6)-alkenyl, 5- or 6-membered heterocyclyl, phenyl, 5- or 6-membered heteroaryl or —OR.sup.14 where (C.sub.1-C.sub.6)-alkyl may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of difluoromethyl, trifluoromethyl, (C.sub.3-C.sub.6)cycloalkyl, hydroxy, oxo, —OR.sup.15, —NR.sup.16—(C═O)—R.sup.17, —NR.sup.18R.sup.19, —(C═O)—NR.sup.18R.sup.19, —S(O).sub.pR.sup.20, phenyl, 4- to 6-membered heterocyclyl and 5- or 6-membered heteroaryl and furthermore up to trisubstituted by fluorine, in which (C.sub.3-C.sub.6)-cycloalkyl and 4- to 6-membered heterocyclyl independently of one another may each be substituted by a substituent selected from the group consisting of (C.sub.1-C.sub.4)-alkyl, oxo, hydroxy, amino and furthermore up to tetrasubstituted by fluorine, and in which phenyl and 5- or 6-membered heteroaryl independently of one another may each be substituted by (C.sub.1-C.sub.4)-alkyl and furthermore up to trisubstituted by fluorine, p represents the number 0, 1 or 2, R.sup.15 and R.sup.20 each independently of one another represent (C.sub.1-C.sub.4)-alkyl, in which (C.sub.1-C.sub.4)-alkyl may be substituted up to five times by fluorine, R.sup.16 represents hydrogen or (C.sub.1-C.sub.4)-alkyl, R.sup.17 represents (C.sub.1-C.sub.4)-alkyl or (C.sub.3-C.sub.6)-cycloalkyl, R.sup.18 and R.sup.19 independently of one another represent hydrogen or (C.sub.1-C.sub.4)alkyl which may be up to pentasubstituted by fluorine, or R.sup.18 and R.sup.19 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocycle, where (C.sub.3-C.sub.6)-cycloalkyl may be substituted by a substituent selected from the group consisting of (C.sub.1-C.sub.4)-alkyl, hydroxy, amino, cyano and furthermore up to tetrasubstituted by fluorine, and where (C.sub.2-C.sub.6)-alkenyl may be up to trisubstituted by fluorine, and where 5- or 6-membered heterocyclyl may be substituted by a substituent selected from the group consisting of oxo, (C.sub.1-C.sub.4)-alkyl, hydroxy and amino and furthermore up to tetrasubstituted by fluorine, and where 5- or 6-membered heteroaryl and phenyl independently of one another may each be substituted by a substituent selected from the group consisting of halogen, (C.sub.1-C.sub.4)-alkyl, cyano and (C.sub.3-C.sub.5)-cycloalkyl, and where R.sup.14 represents (C.sub.1-C.sub.6)-alkyl which may be up to pentasubstituted by fluorine, or represents (C.sub.3-C.sub.6)-alkenyl, or R.sup.3 and R.sup.4 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocycle, where the 5- or 6-membered heterocycle may be substituted by a substituent selected from the group consisting of (C.sub.1-C.sub.4)-alkyl, oxo, hydroxy and furthermore up to tetrasubstituted by fluorine, and the salts, solvates and solvates of the salts thereof.

4. The compound of the formula (I) as claimed in claim 1 in which the ring Q represents a group of the formula ##STR00243## where * represents the point of attachment to —CH.sub.2—R.sup.2, ** represents the point of attachment to the pyrimidine ring, in which L represents a #.sup.1-CR.sup.5AR.sup.5B—(CR.sup.6AR.sup.6B).sub.m-#.sup.2 group, where #.sup.1 represents the point of attachment to the carbonyl group, #.sup.2 represents the attachment site to the pyrimidine ring, m represents a number 0, R.sup.5A represents methyl, R.sup.5B represents methyl or trifluoromethyl, R.sup.2 represents a phenyl group of the formula ##STR00244## where # represents the point of attachment to the methylene group, R.sup.22 and R.sup.24 independently of one another each represent hydrogen or fluorine, R.sup.23 represents fluorine, or R.sup.2 represents 3-fluoropyrid-2-yl, R.sup.3 represents hydrogen or methyl, R.sup.4 represents hydrogen, (C.sub.1-C.sub.4)-alkyl or cyclopropyl, where (C.sub.1-C.sub.4)-alkyl may be substituted by a substituent selected from the group consisting of hydroxy, amino, methoxy, 2,2,2-trifluoroethoxy and cyclopropyl, and furthermore up to trisubstituted by fluorine, and where cyclopropyl may be substituted by cyano, and the salts, solvates and solvates of the salts thereof.

5. A process for preparing the compound of the formula (I) according to claim 1, comprising reacting a compound of the formula (II) ##STR00245## in which n, L, Q, R.sup.1 and R.sup.2 each have the meanings given above, in a first step in the presence of a suitable aqueous base or acid to give the carboxamide of the formula (I-A) ##STR00246## in which n, L, Q, R.sup.1 and R.sup.2 each have the meanings given above, and optionally converting the carboxamide (I-A) in a second step in an inert solvent in the presence of a suitable aqueous acid or base into a carboxylic acid of the formula (III) ##STR00247## in which n, L, Q, R.sup.1 and R.sup.2 each have the meanings given above, and subsequently reacting these in a third step, with activation of the carboxylic acid function, with an amine compound of the formula (IV) ##STR00248## in which R.sup.3 and R.sup.4 each have the meanings given above, to give the carboxamide of the formula (I-B) ##STR00249## in which n, L, Q, R.sup.1, R.sup.2, R.sup.3 and R.sup.4 each have the meanings given above, then detaching any protective groups present, and optionally converting the resulting compounds of the formulae (I-A) and (I-B), optionally with the appropriate (i) solvents and/or (ii) acids or bases, to the solvates, salts and/or solvates of the salts thereof.

6. (canceled)

7. (canceled)

8. A medicament comprising a compound as defined in claim 1 in combination with one or more inert, nontoxic, pharmaceutically suitable excipients.

9. A medicament comprising a compound as defined in claim 1 in combination with one or more further active compounds selected from the group consisting of organic nitrates, NO donors, cGMP-PDE inhibitors, antithrombotic agents, hypotensive agents and lipid metabolism modifiers.

10. (canceled)

11. A method for the treatment and/or prophylaxis of heart failure, angina pectoris, hypertension, pulmonary hypertension, ischemias, vascular disorders, renal insufficiency, thromboembolic disorders, fibrotic disorders, arteriosclerosis, dementia disorders and erectile dysfunction in humans and animals comprising administering an effective amount of at least one compound as defined in claim 1 to a human or animal in need thereof.

12. A method for the treatment and/or prophylaxis of heart failure, angina pectoris, hypertension, pulmonary hypertension, ischemias, vascular disorders, renal insufficiency, thromboembolic disorders, fibrotic disorders, arteriosclerosis, dementia disorders and erectile dysfunction in humans and animals comprising administering an effective amount of the medicament of claim 8 to a human or animal in need thereof.

13. A method for the treatment and/or prophylaxis of heart failure, angina pectoris, hypertension, pulmonary hypertension, ischemias, vascular disorders, renal insufficiency, thromboembolic disorders, fibrotic disorders, arteriosclerosis, dementia disorders and erectile dysfunction in humans and animals comprising administering an effective amount of the medicament of claim 9 to a human or animal in need thereof.

14. A method for the treatment and/or prophylaxis of heart failure, angina pectoris, hypertension, pulmonary hypertension, ischemias, vascular disorders, renal insufficiency, thromboembolic disorders, fibrotic disorders, arteriosclerosis, dementia disorders and erectile dysfunction in humans and animals comprising administering an effective amount of at least one compound as defined in claim 2 to a human or animal in need thereof.

15. A method for the treatment and/or prophylaxis of heart failure, angina pectoris, hypertension, pulmonary hypertension, ischemias, vascular disorders, renal insufficiency, thromboembolic disorders, fibrotic disorders, arteriosclerosis, dementia disorders and erectile dysfunction in humans and animals comprising administering an effective amount of at least one compound as defined in claim 3 to a human or animal in need thereof.

16. A method for the treatment and/or prophylaxis of heart failure, angina pectoris, hypertension, pulmonary hypertension, ischemias, vascular disorders, renal insufficiency, thromboembolic disorders, fibrotic disorders, arteriosclerosis, dementia disorders and erectile dysfunction in humans and animals comprising administering an effective amount of at least one compound as defined in claim 4 to a human or animal in need thereof.

Description

STARTING COMPOUNDS AND INTERMEDIATES

Example 1A

5-Fluoro-6-methyl-1H-pyrazolo[3,4-b]pyridine-3-amine

[0533] ##STR00032##

[0534] 58 g (340.03 mmol) of 2-chloro-5-fluoro-6-methylnicotinonitrile (preparation described in WO2007/041052, Example U-2, page 80) were initially charged in 1,2-ethanediol (580 ml), and hydrazine hydrate (24.81 ml) and 56.09 ml (340.03 mmol) of N,N-diisopropylethylamine were then added. The mixture was stirred at 80° C. for 16 h and then at 120° C. for 6 h. After cooling to RT, water (2.5 l) and ethyl acetate (2.5 l) were added and the resulting solid was filtered off with suction. The solid obtained was dried under reduced pressure. This gave 28.4 g (47% of theory) of the target compound.

[0535] LC-MS (Method 4): R.sub.t=1.77 min

[0536] MS (ESIpos): m/z=167 [M+H].sup.+

Example 2A

5-Fluoro-3-iodo-6-methyl-1H-pyrazolo[3,4-b]pyridine

[0537] ##STR00033##

[0538] 28 g (168.5 mmol) of 5-fluoro-6-methyl-1H-pyrazolo[3,4-b]pyridine-3-amine from Example 1A were initially charged in 1.32 l of THF, and the mixture was cooled to 0° C. 41.45 ml (337.03 mmol) of boron trifluoride diethyl ether complex were then added slowly. The reaction mixture was cooled to −10° C. A solution of 25.66 g (219.07 mmol) of isopentyl nitrite in 166 ml of THF was then added slowly, and the mixture was subsequently stirred for a further 30 min. The reaction solution was then concentrated to about a third of its volume. 988 ml of acetone were then added, and the solution was cooled to 0° C. A solution of 32.84 g (219.07 mmol) of sodium iodide in 412 ml of acetone was added dropwise to this solution, and the mixture was then stirred at RT for 2 h. The reaction mixture was poured into 5 l of ice-water and extracted three times with in each case 750 ml of ethyl acetate. The combined organic phases were washed with 750 ml of saturated aqueous sodium chloride solution, dried and then concentrated under reduced pressure. The crude product was purified using silica gel (silica gel, mobile phase: cyclohexane/ethyl acetate, gradient 9:1 to 1:1). This gave 14.90 g (32% of theory) of the title compound.

[0539] LC-MS (Method 1): R.sub.t=0.84 min

[0540] MS (ESIpos): m/z=278 [M+H].sup.+

Example 3A

1-(2,3-Difluorobenzyl)-5-fluoro-3-iodo-6-methyl-1H-pyrazolo[3,4-b]pyridine

[0541] ##STR00034##

[0542] 2.60 g (9.37 mmol) of 5-fluoro-3-iodo-6-methyl-1H-pyrazolo[3,4-b]pyridine from Example 2A were initially charged in 35 ml of DMF. A solution of 3.67 g (11.26 mmol) of cesium carbonate and 1.94 g (9.37 mmol) of 1-(bromomethyl)-2,3-difluorobenzene in 10 ml of DMF was then added, and the mixture was subsequently stirred at RT overnight. The reaction mixture was added to 200 ml of water and extracted twice with ethyl acetate. The collected organic phases were dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (silica gel, mobile phase: petroleum ether/ethyl acetate=10/1) and the product fractions were concentrated. Further purification was carried out by preparative HPLC (column: Sunfire C18, 5 μm, 250×20 mm; mobile phase: 12% water+85% methanol+3% 1% strength aqueous TFA solution; flow rate: 25 ml/min; temperature: 40° C.; wavelength: 210 nm). This gave 2.67 g (71% of theory) of the title compound.

[0543] LC-MS (Method 1): R.sub.t=1.29 min

[0544] MS (ESIpos): m/z=404 [M+H].sup.+

[0545] Analogously to Example 3A, the exemplary compounds shown in Table 1A were prepared by reacting 5-fluoro-3-iodo-6-methyl-1H-pyrazolo[3,4-b]pyridine from Example 2A with 1-(bromomethyl)-2-fluorobenzene, 2-(bromomethyl)-1,3,4-trifluorobenzene or 2-(chloromethyl)-3-fluoropyridine hydrochloride (1.1-1.5 equivalents) and cesium carbonate (1.2-2 equivalents) under the reaction conditions described (reaction time: 2-72 h; temperature: RT to 60° C.) in DMF.

[0546] Exemplary Work-Up of the Reaction Mixture:

[0547] Method A: The reaction mixture was added to water and then stirred at room temperature for about 1 h. The solid formed was filtered off, washed with water and dried under high vacuum.

[0548] Method B: Alternatively, the reaction mixture was added to water and extracted with ethyl acetate. The collected organic phases were dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (mobile phase: petroleum ether/ethyl acetate or dichloromethane/methanol).

[0549] Method C: Alternatively, the reaction mixture was diluted with acetonitrile and purified by preparative HPLC (RP18 column, mobile phase: acetonitrile/water gradient with addition of 0.1% TFA or 0.05% formic acid).

TABLE-US-00002 TABLE 1A Ex- IUPAC name/structure ample (Yield) Analytical data 4A [00035] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ = 2.60 (d, 3H), 5.68 (s, 2H), 7.13- 7.25 (m, 3H), 7.33-7.40 (m, 1H), 7.81 (d, 1H). LC-MS (Method 5): R.sub.t = 3.02 min MS (ESIpos): m/z = 386 [M + H].sup.+ 5A [00036] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ = 2.61 (d, 3H), 5.70 (s, 2H), 7.18 (ddt, 1H), 7.54 (ddt, 1H), 7.80 (d, 1H). LC-MS (Method 5): R.sub.t = 3.03 min MS (ESIpos): m/z = 422 [M + H].sup.+ 6A 5-fluoro-1-[(3-fluoropyridin-2-yl)methyl]-3-iodo-6- LC-MS (Method 1): R.sub.t = 1.10 min methyl-1H-pyrazolo[3,4-b]pyridine MS (ESIpos): m/z = 387 [M + H].sup.+ [00037] .sup.1) This starting material has already been described in WO2013/104703 (Example 50A).

Example 7A

1-(2,3-Difluorobenzyl)-5-fluoro-6-methyl-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile

[0550] ##STR00038##

[0551] A mixture of 2.47 g (6.13 mmol) of 1-(2,3-difluorobenzyl)-5-fluoro-3-iodo-6-methyl-1H-pyrazolo[3,4-b]pyridine from Example 3A and 0.576 g (6.43 mmol) of copper(I) cyanide was initially charged in 12.1 ml of abs. DMSO in a flask which had been dried by heating, and the mixture was stirred at 150° C. for 3 h. Ethyl acetate was added to the cooled reaction solution, and the mixture was washed three times with a mixture of semisaturated aqueous ammonium chloride solution and aqueous concentrated ammonia solution (3/1). The organic phase was dried over sodium sulfate, filtered and concentrated by evaporation. The crude product was purified by flash chromatography (silica gel, mobile phase: cyclohexane/ethyl acetate gradient: 15/1 to 10/1; then dichloromethane/methanol: 10/1). This gave 780 mg of the target compound (42% of theory).

[0552] LC-MS (Method 1): R.sub.t=1.19 min

[0553] MS (ESIpos): m/z=303 [M+H].sup.+

[0554] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=2.65 (d, 3H), 5.87 (s, 2H), 7.10-7.25 (m, 2H), 7.39-7.48 (m, 1H), 8.41 (d, 1H).

[0555] The exemplary compounds shown in Table 2A were prepared analogously to Example 7A by reacting the appropriate iodides with copper(I) cyanide (1.1-1.5 equivalents) under the reaction conditions described (reaction time: 1-5 h; temperature: 150° C.) in DMSO.

[0556] Exemplary Work-Up of the Reaction Mixture:

[0557] Method A: After cooling, ethyl acetate was added to the reaction mixture, and the mixture was washed three times with a mixture of semisaturated aqueous ammonium chloride solution and aqueous concentrated ammonia solution (3/1). The organic phase was dried over sodium sulfate and filtered and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (silica gel, mobile phase: cyclohexane/ethyl acetate gradient: or dichloromethane/methanol gradient).

[0558] Method B: Alternatively, the reaction mixture was diluted with acetonitrile and purified by preparative HPLC (RP18 column, mobile phase: acetonitrile/water gradient with addition of 0.1% TFA or 0.05% formic acid).

TABLE-US-00003 TABLE 2A Ex- IUPAC name/structure ample (Yield) Analytical data 8A [00039] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ = 2.65 (d, 3H), 5.82 (s, 2H), 7.18 (dt, 1H), 7.21-7.27 (m, 1H), 7.31 (dt, 1H), 7.37-7.44 (m, 1H), 8.38 (d, 1H). LC-MS (Method 1): R.sub.t = 1.15 min MS (ESIpos): m/z = 285 [M + H].sup.+ 9A [00040] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ = 2.65 (d, 3H), 5.85 (s, 2H), 7.21 (ddt, 1H), 7.58 (ddt, 1H), 8.37 (d, 1H). LC-MS (Method 1): R.sub.t = 1.15 min MS (ESIpos): m/z = 321 [M + H].sup.+ 10A  [00041] LC-MS (Method 5): R.sub.t = 2.44 min MS (ESIpos): m/z = 286 [M + H].sup.+ .sup.1) This starting material has already been described in WO2013/104703 (Example 51A).

Example 11A

1-(2,3-Difluorobenzyl)-5-fluoro-6-methyl-1H-pyrazolo[3,4-b]pyridine-3-carboximidamide

[0559] ##STR00042##

[0560] 960 mg (3.18 mmol) of 1-(2,3-difluorobenzyl)-5-fluoro-6-methyl-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile from Example 7A were initially charged in 9.47 ml of methanol. 0.69 ml (3.18 mmol) of sodium methoxide in methanol was added, and the mixture was subsequently stirred at RT for 1 h. Another 10 ml of methanol were then added, and the reaction mixture was subsequently stirred at 60° C. for 1 h. 204 mg (3.81 mmol) of ammonium chloride and 0.71 ml (12.39 mmol) of acetic acid were added and the reaction mixture was stirred under reflux for 7 h. The solvent was removed under reduced pressure and the residue was stirred with 38 ml of 1 N aqueous sodium hydroxide solution at room temperature for 1 h. The precipitate was then filtered off and washed with water. This gave 1.0 g of the target compound (90% of theory, purity 90%).

[0561] LC-MS (Method 1): R.sub.t=0.68 min

[0562] MS (ESIpos): m/z=320 [M+H].sup.+

[0563] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=2.60 (d, 3H), 5.77 (s, 2H), 6.62 (br. s, 3H), 6.91-6.98 (m, 1H), 7.11-7.20 (m, 1H), 7.34-7.44 (m, 1H), 8.29 (d, 1H).

[0564] The exemplary compounds shown in Table 3A were prepared analogously to Example 11A by reacting the appropriate nitriles with sodium methoxide (1.0-1.2 equivalents) in methanol and subsequently with ammonium chloride (1.2-1.5 equivalente) and acetic acid (3.5-5 equivalents) under the reaction conditions described (reaction time after addition of ammonium chloride and acetic acid: 5-24 h; temperature: reflux).

[0565] Exemplary Work-Up of the Reaction Mixture:

[0566] The solvent was evaporated and the residue was stirred with 1 N aqueous sodium hydroxide solution at room temperature for 0.5-2 h. The precipitate was then filtered off and washed with water and subsequently dried.

[0567] The target compounds obtained may, if appropriate partially, be present as acetate salt or acetate solvate.

TABLE-US-00004 TABLE 3A Ex- IUPAC name/structure ample (Yield) Analytical data 12A [00043] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ = 2.59 (d, 3H), 5.73 (s, 2H), 6.51 (br. s, 3H), 7.07-7.17 (m, 2H), 7.20- 7.27 (m, 1H), 7.32-7.39 (m, 1H), 8.29 (d, 1H). LC-MS (Method 7): R.sub.t = 0.83 min MS (ESIpos): m/z = 302 [M + H].sup.+ 13A [00044] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ = 2.60 (d, 3H), 5.75 (s, 2H), 6.36 (br. s, 3H), 7.17 (ddt, 1H), 7.53 (ddt, 1H), 8.25 (d, 2H). LC-MS (Method 5): R.sub.t = 2.14 min MS (ESIpos): m/z = 338 [M + H].sup.+ 14A 5-fluoro-1-[(3-fluoropyridin-2-yl)methyl]-6-methyl-1H- LC-MS (Method 1): R.sub.t = 0.55 min pyrazolo[3,4-b]pyridine-3-carboximidamide MS (ESIpos): m/z = 303 [M + H].sup.+ [00045] 1) This starting material has already been described as acetate salt in WO 2013/104703 (Example 52A).

Example 15A

5-Fluoro-1-[(3-fluoropyridin-2-yl)methyl]-1H-pyrazolo[3,4-b]pyridine-3-carboximidamide acetate

[0568] ##STR00046##

[0569] The preparation of the compound is described in WO 2013/004785, example 14A, pp. 69-70.

Example 16A

6-Chloro-1-(2-fluorobenzyl)-1H-indazole-3-carboximidamide acetate

[0570] ##STR00047##

[0571] The preparation of the compound is described in WO2013/104598, example 54A, pp. 97-98.

Example 17A

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

[0572] ##STR00048##

[0573] 2.34 g (6.67 mmol; purity 90%) of 1-(2,3-difluorobenzyl)-5-fluoro-6-methyl-1H-pyrazolo[3,4-b]pyridine-3-carboximidamide from Example 11A were initially charged in 50.5 ml of tert-butanol. 1.33 g (8.00 mmol) of methyl 3,3-dicyanopivalate were then added, and the mixture was subsequently stirred under reflux for 6 h. Another 8 ml of tert-butanol were added and the mixture was then heated under reflux overnight. After cooling to RT, water was added and the reaction mixture was stirred at room temperature for 30 min. The precipitate formed was filtered off and washed with water. The solid was dried under high vacuum. This gave 3.25 g (99% of theory; purity: 92%) of the title compound.

[0574] LC-MS (Method 1): R.sub.t=1.03 min

[0575] MS (ESIpos): m/z=454 [M+H].sup.+

[0576] The exemplary compounds shown in Table 4A were prepared analogously to Example 17A by reacting the appropriate carboximidamides (amidines) with methyl 3,3-dicyanopivalate (1.1-1.5 equivalents) in tert-butanol [0.2-1.4 equivalents of potassium tert-butoxide were added to amidines present as acetate salt or acetate solvate] under the reaction conditions described (reaction time: 4-24 h).

[0577] Exemplary Work-Up of the Reaction Mixture:

[0578] Water was added to the reaction mixture and the mixture was stirred at room temperature for 30 min. The precipitate formed was filtered off and washed with water.

TABLE-US-00005 TABLE 4A Ex- IUPAC name/structure ample (Yield) Analytical data 18A [00049] LC-MS (Method 1): R.sub.t = 1.01 min MS (ESIpos): m/z = 436 [M + H].sup.+ 19A 4-amino-2-[5-fluoro-6-methyl-1-(2,3,6-trifluorobenzyl)- LC-MS (Method 1): R.sub.t = 1.03 min 1H-pyrazolo[3,4-b]pyridin-3-yl]-5,5-dimethyl-5,7-dihydro- MS (ESIpos): m/z = 472 [M + H].sup.+ 6H-pyrrolo[2,3-d]pyrimidin-6-one [00050] 20A [00051] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ = 1.34 (s, 6H), 2.61 (d, 3H), 5.89 (s, 2H), 6.81 (br. s, 2H), 7.40-7.47 (m, 1H), 7.77 (t, 1H), 8.29 (d, 1H), 8.72 (d, 1H), 10.91 (br. s, 1H). LC-MS (Method 5): R.sub.t = 2.16 min MS (ESIpos): m/z = 437 [M + H].sup.+ 21A [00052] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ = 1.34 (s, 6H), 5.95 (s, 2H), 6.87 (br. s, 2H), 7.41-7.48 (m, 1H), 7.78 (t, 1H), 8.28 (d, 1H), 8.64-8.70 (m, 1H), 8.81-8.87 (m, 1H), 10.97 (br. s, 1H). LC-MS (Method 1): R.sub.t = 0.80 min MS (ESIpos): m/z = 423 [M + H].sup.+ 22A [00053] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ = ppm 1.34 (s, 6H), 5.79 (s, 2H), 6.79 (br. s, 2H), 7.06-7.32 (m, 4H), 7.32- 7.42 (m, 1H), 7.99 (s, 1H), 8.69 (d, 1H), 10.97 (br. s, 1H) LC-MS (Method 1): R.sub.t = 1.03 min MS (ESIpos): m/z = 437 [M + H].sup.+ .sup.1) This starting material has already been described in WO 2013/104703 (Example 55A).

Example 23A

Methyl 3,3-dicyano-2-(trifluoromethyl)acrylate

[0579] ##STR00054##

[0580] The synthesis of this compound is described in Journal of Fluorine Chemistry 1991, vol. 51, 3, pp. 323-334.

Example 24A

Methyl 2-(dicyanomethyl)-3,3,3-trifluoro-2-methylpropanoate

[0581] ##STR00055##

[0582] 3.00 g (14.70 mmol) of Example 23A were dissolved in tetrahydrofuran (30 ml) and the solution was cooled to 0° C. 7.35 ml (22.05 mmol) of methylmagnesium chloride (3 M in THF) were then added dropwise such that the temperature did not exceed 5° C. After the addition had ended, the mixture was stirred for another 10 min. 1 N aqueous hydrochloric acid was then added to the mixture, and the mixture was subsequently extracted with ethyl acetate. The phases were separated and the aqueous phase was extracted twice more with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The crude product was then purified by column chromatography (silica gel, mobile phase: cyclohexane, then cyclohexane:ethyl acetate 9:1 (v:v)). Concentration gave 3.24 g (63% of theory) of the title compound.

[0583] .sup.1H-NMR (400 MHz, CDCl.sub.3): δ [ppm]=1.81 (s, 3H), 3.95 (s, 3H), 4.48 (s, 1H).

Example 25A

rac-4-Amino-2-{5-fluoro-1-[(3-fluoropyridin-2-yl)methyl]-1H-pyrazolo[3,4-b]pyridin-3-yl}-5-methyl-5-(trifluoromethyl)-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one

[0584] ##STR00056##

[0585] 23.0 g (66.02 mmol) of 5-fluoro-1-[(3-fluoropyridin-2-yl)methyl]-1H-pyrazolo[3,4-b]pyridine-3-carboximidamide acetate from Example 15A were initially charged in tert-butanol (400 ml), and 13.43 g (119.68 mmol) of potassium tert-butoxide were added. Subsequently, 21.08 g (95.75 mmol) of methyl 2-(dicyanomethyl)-3,3,3-trifluoro-2-methylpropanoate from Example 24A in tert-butanol (100 ml) were added, and the mixture was heated under reflux overnight. After cooling to RT, water was added and the reaction mixture was stirred at room temperature for a further 30 min. The precipitate formed was filtered off and washed with water and a little diethyl ether. The solid was dried under high vacuum. This gave 16.1 g of the title compound (51% of theory).

[0586] LC-MS (Method 1): R.sub.t=0.95 min;

[0587] MS (ESIpos): m/z=477 [M+H].sup.+

[0588] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=1.72 (s, 3H), 5.96 (s, 2H), 7.10 (br. s, 2H), 7.42-7.48 (m, 1H), 7.75-7.80 (m, 1H), 8.27 (d, 1H), 8.68 (dd, 1H), 8.86 (dd, 1H), 11.60 (br. s, 1H).

[0589] The exemplary compounds shown in Table 5A were prepared analogously to Example 25A by reacting the appropriate carboximidamides (amidines) with methyl 2-(dicyanomethyl)-3,3,3-trifluoro-2-methylpropanoate (1.1-1.5 equivalents) in tert-butanol [0.2-1.4 equivalents of potassium tert-butoxide were added to amidines present as acetate salt or acetate solvate] under the reaction conditions described (reaction time: 0.5-24 h).

[0590] Alternatively, the reactions can be carried out in the microwave [0.5-10 h, 100° C.]

[0591] Exemplary Work-Up of the Reaction Mixture:

[0592] Water was added, and the reaction mixture was stirred at room temperature for 30 min. The precipitate formed was filtered off and washed with water.

TABLE-US-00006 TABLE 5A Ex- IUPAC name/structure ample (Yield) Analytical data 26A [00057] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ = 1.72 (s, 3H), 2.63 (d, 3H), 5.78 (s, 2H), 7.07 (br. m, 2H), 7.12-7.27 (m, 3H), 7.33-7.40 (m, 1H), 8.77 (d, 1H), 11.60 (s, 1H). LC-MS (Method 1): R.sub.t = 1.09 min MS (ESIpos): m/z = 490 [M + H].sup.+ 27A [00058] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ = 1.71 (s, 3H), 2.64 (d, 3H), 5.81 (s, 2H), 7.07 (br. s, 2H), 7.15-7.25 (m, 1H), 7.48-7.61 (m, 1H), 8.77 (d, 1H), 11.60 (s, 1H). LC-MS (Method 1): R.sub.t = 1.10 min MS (ESIpos): m/z = 526 [M + H].sup.+ 28A rac-4-amino-2-[1-(2,3-difluorobenzyl)-5-fluoro-6-methyl- LC-MS (Method 1): R.sub.t = 1.14 min 1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-5- MS (ESIpos): m/z = 508 [M + H].sup.+ (trifluoromethyl)-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin- 6-one [00059] 29A rac-4-amino-2-{5-fluoro-1-[(3-fluoropyridin-2-yl)methyl]- LC-MS (Method 1): R.sub.t = 0.99 min 6-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl}-5-methyl-5- MS (ESIpos): m/z = 491 [M + H].sup.+ (trifluoromethyl)-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin- 6-one [00060]

Example 30A

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

[0593] ##STR00061##

[0594] 3.25 g (6.61 mmol; purity 92%) of 4-amino-2-[1-(2,3-difluorobenzyl)-5-fluoro-6-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl]-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one from Example 17A were initially charged in 64 ml of dioxane, 4.42 ml (33.04 mmol) of isopentyl nitrite and 2.66 ml (33.04 mmol) of diiodomethane were added and the mixture was then heated at 85° C. for 3 h. After cooling, the mixture was concentrated under reduced pressure and the residue was chromatographed on silica gel (mobile phase: dichloromethane/methanol gradient). Removal of the solvent under reduced pressure gave 2.32 g (51% of theory, purity 82%) of the title compound.

[0595] LC-MS (Method 1): R.sub.t=1.34 min

[0596] MS (ESIpos): m/z=565 [M+H].sup.+

[0597] The exemplary compounds shown in Table 6A were prepared analogously to Example 30A by reacting the appropriate anilines with diiodomethane (3-18 equivalents) and isopentyl nitrite (3-10 equivalents) in dioxane under the reaction conditions described (temperature: 85° C.; reaction time: 2-10 h).

[0598] Exemplary Work-Up of the Reaction Mixture:

[0599] The reaction mixture was concentrated [if appropriate partitioned between water and an organic solvent and then concentrated] and the residue was chromatographed on silica gel (mobile phase: dichloromethane/methanol or cyclohexane/ethyl acetate gradient]. Optionally, further purification was carried out by preparative HPLC [column: Sunfire C18, 5 μM, 100×30 mm; mobile phase: water/acetonitrile+0.2% strength formic acid].

TABLE-US-00007 TABLE 6A Ex- IUPAC name/structure ample (Yield) Analytical data 31A [00062] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ = 1.42 (s, 6H), 2.64 (d, 3H), 5.82 (s, 2H), 7.12-7.20 (m, 2H), 7.20- 7.27 (m, 1H), 7.34-7.41 (m, 1H), 8.37 (d, 1H), 11.73 (s, 1H). LC-MS (Method 7): R.sub.t = 1.64 min MS (ESIpos): m/z = 547 [M + H].sup.+ 32A [00063] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ = 1.41 (s, 6H), 2.65 (d, 3H), 5.85 (s, 2H), 7.20 (ddt, 1H), 7.55 (ddt, 1H), 8.36 (d, 1H), 11.73 (s, 1H). LC-MS (Method 7): R.sub.t = 1.64 min MS (ESIpos): m/z = 583 [M + H].sup.+ 33A 2-{5-fluoro-1-[(3-fluoropyridin-2-yl)methyl]-6-methyl-1H- LC-MS (Method 1): R.sub.t = 1.15 min pyrazolo[3,4-b]pyridin-3-yl}-4-iodo-5,5-dimethyl-5,7- MS (ESIpos): m/z = 548 [M + H].sup.+ dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one [00064] 34A 2-{5-fluoro-1-[(3-fluoropyridin-2-yl)methyl]-1H- LC-MS (Method 7): R.sub.t = 1.36 min pyrazolo[3,4-b]pyridin-3-yl}-4-iodo-5,5-dimethyl-5,7- MS (ESIpos): m/z = 534 [M + H].sup.+ dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one [00065] 35A [00066] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ = 1.41 (s, 6H), 5.86 (s, 2H), 7.10- 7.29 (m, 3H), 7.31-7.44 (m, 2H), 8.06 (d, 1H), 8.47 (d, 1H), 11.75 (s, 1H). LC-MS (Method 1): R.sub.t = 1.32 min MS (ESIpos): m/z = 548 [M + H].sup.+ .sup.1) This starting material has already been described in WO 2013/104703 (Example 56A).

Example 36A

rac-2-{5-Fluoro-1-[(3-fluoropyridin-2-yl)methyl]-1H-pyrazolo[3,4-b]pyridin-3-yl}-4-iodo-5-methyl-5-(trifluoromethyl)-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one

[0600] ##STR00067##

[0601] 798 μl (5.93 mmol) of isopentyl nitrite and 286 μl (3.56 mmol) of diiodomethane were added to 565 mg (1.19 mmol) of rac-4-amino-2-{5-fluoro-1-[(3-fluoropyridin-2-yl)methyl]-1H-pyrazolo[3,4-b]pyridin-3-yl}-5-methyl-5-(trifluoromethyl)-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one from Example 25A in 15 ml of dioxane, and the mixture was heated to 85° C. for 4 h. After cooling, the mixture was concentrated under reduced pressure, the residue was taken up in dichloromethane, kieselguhr was added and the mixture was then concentrated under reduced pressure. The crude compound adsorbed on kieselguhr was then purified by column chromatography (silica gel, mobile phase: cyclohexane/ethyl acetate gradient). Concentration gave 297 mg (42% of theory) of the title compound.

[0602] LC-MS (Method 1): R.sub.t=1.19 min;

[0603] MS (ESIpos): m/z=588 [M+H].sup.+

[0604] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=1.81 (s, 3H), 6.04 (s, 2H), 7.43-7.47 (m, 1H), 7.77-7.82 (m, 1H), 8.26 (d, 1H), 8.47 (dd, 1H), 8.76 (dd, 1H), 12.41 (br. s, 1H).

[0605] The exemplary compounds shown in Table 7A were prepared analogously to Example 36A by reacting the appropriate anilines with diiodomethane (4-18 equivalents) and isopentyl nitrite (4-12 equivalents) in dioxane under the reaction conditions described (temperature: 85° C.; reaction time: 2-10 h).

[0606] Exemplary Work-Up of the Reaction Mixture:

[0607] The reaction mixture was concentrated and the residue was chromatographed on silica gel (mobile phase: dichloromethane/methanol gradient). Optionally, further purification was carried out by preparative HPLC [column: Kinetex C18, 5 μM, 100×300 mm; mobile phase: water/acetonitrile 35:65].

TABLE-US-00008 TABLE 7A Ex- IUPAC name/structure ample (Yield) Analytical data 37A [00068] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ = 1.81 (s, 3H), 2.64 (d, 3H), 5.84 (s, 2H), 7.13-7.27 (m, 3H), 7.34-7.41 (m, 1H), 8.37 (d, 1H), 12.39 (s, 1H). LC-MS (Method 7): R.sub.t = 1.64 min MS (ESIpos): m/z = 601 [M + H].sup.+ 38A [00069] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ = 1.80 (s, 3H), 2.65 (d, 3H), 5.87 (s, 2H), 7.21 (ddt, 1H), 7.56 (ddt, 1H), 8.36 (d, 1H), 12.39 (s, 1H). LC-MS (Method 2): R.sub.t = 4.45 min MS (ESIpos): m/z = 637 [M + H].sup.+ 39A rac-2-[1-(2,3-difluorobenzyl)-5-fluoro-6-methyl-1H- LC-MS (Method 1): R.sub.t = 1.35 min pyrazolo[3,4-b]pyridin-3-yl]-4-iodo-5-methyl-5- MS (ESIpos): m/z = 619 [M + H].sup.+ (trifluoromethyl)-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin- 6-one [00070] 40A rac-2-{5-fluoro-1-[(3-fluoropyridin-2-yl)methyl]-6- LC-MS (Method 1): R.sub.t = 1.26 min methyl-1H-pyrazolo[3,4-b]pyridin-3-yl}-4-iodo-5-methyl- MS (ESIpos): m/z = 602 [M + H].sup.+ 5-(trifluoromethyl)-5,7-dihydro-6H-pyrrolo[2,3- d]pyrimidin-6-one [00071]

Example 41A

2-[1-(2-Fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5,5-dimethyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-4-carbonitrile

[0608] ##STR00072##

[0609] This substance has already been described in WO 2013/104703.

[0610] Alternative Preparation Method:

[0611] 27 g (52.5 mmol) of 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4-iodo-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one [described in WO 2013/030288, Ex. 15A] and 5.17 g (57.75 mmol) copper(I) cyanide in 200 ml of DMSO were stirred at 150° C. for 2 h. After cooling to 40° C., the reaction mixture was poured into a mixture of water, aqueous conc. ammonia solution and ethyl acetate, stirred and filtered through kieselguhr. The phases were separated, the org. phase was washed twice with sat. sodium chloride solution, dried and concentrated and dried under high vacuum. The crude product was purified by column chromatography (silica gel, mobile phase: dichloromethane/methanol (2%)). Mixed fractions were subsequently purified by a second column chromatography (silica gel, dichloromethane/1-2% methanol). This gave a total of 12.0 g (55% of th.) of the title compound.

[0612] LC-MS (Method 7): R.sub.t=1.35 min

[0613] MS (ESIpos): m/z=414 [M+H].sup.+

[0614] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=1.48 (s, 6H), 5.89 (s, 2H), 7.09-7.29 (m, 3H), 7.32-7.41 (m, 1H), 7.44-7.56 (m, 1H), 8.71 (d, 1H), 8.82 (d, 1H), 12.17 (br. s, 1H).

Example 42A

2-[5-Fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5,5-dimethyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-4-carbonitrile

[0615] ##STR00073##

[0616] The substance has been described in WO 2013/104703 Example 81A, p. 163.

Example 43A

2-[1-(2,3-Difluorobenzyl)-5-fluoro-6-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl]-5,5-dimethyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-4-carbonitrile

[0617] ##STR00074##

[0618] In a flask which had been dried by heating, 150 mg (0.22 mmol; purity 82%) of 2-[1-(2,3-difluorobenzyl)-5-fluoro-6-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl]-4-iodo-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one from Example 30A were initially charged in 2 ml of abs. DMSO, 27 mg (0.30 mmol) of copper(I) cyanide were added and the mixture was heated at 150° C. for 2 h. The reaction solution was filtered through Celite, rinsed with about 14 ml of ethyl acetate and washed three times with a mixture of semiconcentrated aqueous ammonium chloride solution/concentrated aqueous ammonium chloride solution (3/1) and once with saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulfate, filtered and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (silica gel, mobile phase: dichloromethane to dichloromethane/methanol=100/1). The crude product obtained was then purified by a second column chromatography (silica gel, mobile phase: cyclohexane/ethyl acetate=5/1). Removal of the solvent under reduced pressure gave 104 mg (95% of theory; purity 93%) of the title compound.

[0619] LC-MS (Method 1): R.sub.t=1.20 min

[0620] MS (ESIpos): m/z=464 [M+H].sup.+

[0621] The exemplary compounds shown in Table 8A were prepared analogously to Example 43A by reacting the appropriate iodides with copper(I) cyanide (1.0-1.5 equivalents) in DMSO under the reaction conditions described (temperature: 150° C.; reaction time: 0.25-3 h).

[0622] Exemplary Work-Up of the Reaction Mixture:

[0623] Method A: The reaction solution was, if appropriate, filtered through Celite, rinsed with ethyl acetate and washed three times with a mixture of semiconcentrated aqueous ammonium chloride solution/concentrated aqueous ammonium chloride solution (3/1) and once with saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulfate, filtered and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (silica gel, mobile phase: dichloromethane/methanol or cyclohexane/ethyl acetate gradient) or preparative HPLC (RP18 column, mobile phase: acetonitrile/water gradient with addition of 0.1% TFA).

[0624] Method B: Alternatively or additionally, water/acetonitrile was added and the reaction mixture was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile/water gradient or methanol/water gradient with addition of 0.1% TFA).

TABLE-US-00009 TABLE 8A Ex- IUPAC name/structure ample (Yield) Analytical data 44A [00075] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ = 1.48 (s, 6H), 2.65 (d, 3H), 5.84 (s, 2H), 7.13-7.27 (m, 3H), 7.34-7.41 (m, 1H), 8.42 (d, 1H), 12.13 (s, 1H). LC-MS (Method 7): R.sub.t = 1.52 min MS (ESIpos): m/z = 446 [M + H].sup.+ 45A [00076] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ = 1.39 (s, 6H), 2.65 (d, 3H), 5.85 (s, 2H), 7.20 (t, 1H), 7.55 (ddt, 1H), 8.41 (d, 1H), 12.05 (s, 1H). LC-MS (Method 1): R.sub.t = 1.20 min MS (ESIpos): m/z = 482 [M + H].sup.+ 46A [00077] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ = 1.48 (s, 6H), 2.63 (d, 3H), 5.98 (s, 2H), 7.39-7.47 (m, 1H), 7.78 (t, 1H), 8.28 (d, 1H), 8.42 (d, 1H), 12.10 (s, 1H). LC-MS (Method 1): R.sub.t = 1.07 min MS (ESIpos): m/z = 447 [M + H].sup.+ 47A [00078] .sup.1H-NMR (500 MHz, DMSO-d.sub.6) δ = 1.48 (s, 6H), 6.03 (s, 2H), 7.40- 7.47 (m, 1H), 7.78 (t, 1H), 8.26 (d, 1H), 8.50-8.55 (m, 1H), 8.72-8.76 (m, 1H), 12.13 (s, 1H). LC-MS (Method 1): R.sub.t = 0.99 min MS (ESIpos): m/z = 433 [M + H].sup.+ 48A [00079] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ = 1.38-1.59 (m, 7H), 5.80-5.94 (m, 2H), 7.08-7.31 (m, 3H), 7.31-7.52 (m, 2H), 8.00-8.18 (m, 1H), 8.40- 8.57 (m, 1H), 12.01-12.26 (m, 1H). LC-MS (Method 1): R.sub.t = 1.23 min MS (ESIpos): m/z = 447

Example 49A

rac-2-{5-Fluoro-1-[(3-fluoropyridin-2-yl)methyl]-1H-pyrazolo[3,4-b]pyridin-3-yl}-5-methyl-6-oxo-5-(trifluoromethyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-4-carbonitrile

[0625] ##STR00080##

[0626] In a flask which had been dried by heating, 560 mg (0.84 mmol) of rac-2-{5-fluoro-1-[(3-fluoropyridin-2-yl)methyl]-1H-pyrazolo[3,4-b]pyridin-3-yl}-4-iodo-5-methyl-5-(trifluoromethyl)-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one from Example 36A were initially charged in 9 ml of abs. DMSO, 83 mg (0.92 mmol) of copper(I) cyanide were added and the mixture was then heated at 150° C. for 1.5 h. The reaction solution was cooled, water/acetonitrile were added and the mixture was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile/water gradient with addition of 0.1% TFA). Evaporation gave 80 mg (20% of theory) of the title compound.

[0627] LC-MS (Method 1): R.sub.t=1.07 min

[0628] MS (ESIpos): m/z=487 [M+H].sup.+

[0629] The exemplary compounds shown in Table 9A were prepared analogously to Example 49A by reacting the appropriate iodides with copper(I) cyanide (1.0-1.5 equivalents) in DMSO under the reaction conditions described (temperature: 150° C.; reaction time: 0.25-3 h).

[0630] Exemplary Work-Up of the Reaction Mixture:

[0631] The reaction solution was, if appropriate, filtered through Celite, rinsed with ethyl acetate and washed three times with a mixture of semiconcentrated aqueous ammonium chloride solution/concentrated aqueous ammonium chloride solution (3/1) and once with saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulfate, filtered and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (silica gel, mobile phase: dichloromethane/methanol gradient or cyclohexane/ethyl acetate gradient) preparative HPLC (RP18 column, mobile phase: acetonitrile/water gradient with addition of 0.1% TFA). Alternatively or additionally, water/acetonitrile was added and the reaction mixture was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile/water gradient with addition of 0.1% TFA).

TABLE-US-00010 TABLE 9A Ex- IUPAC name/structure ample (Yield) Analytical data 50A [00081] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ = 1.56 (s, 3H), 2.63 (d, 3H), 5.81 (s, 2H), 7.12-7.18 (m, 2H), 7.20-7.27 (m, 1H), 7.33-7.40 (m, 1H), 8.42 (d, 1H). LC-MS (Method 1): R.sub.t = 1.23 min MS (ESIpos): m/z = 500 [M + H].sup.+ 51A [00082] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ = 1.56 (s, 3H), 2.64 (d, 3H), 5.83 (s, 2H), 7.19 (ddt, 1H), 7.54 (ddt, 1H), 8.39 (d, 1H). LC-MS (Method 1): R.sub.t = 1.24 min MS (ESIpos): m/z = 536 [M + H].sup.+ 52A [00083] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ = 1.82 (s, 3H), 2.66 (d, 3H), 5.90 (s, 2H), 7.04-7.09 (m, 1H), 7.14-7.23 (m, 1H), 7.36-7.45 (m, 1H), 8.42 (d, 1H), 12.85 (br. s, 1H). LC-MS (Method 1): R.sub.t = 1.25 min MS (ESIpos): m/z = 518 [M + H].sup.+ 53A [00084] LC-MS (Method 1): R.sub.t = 1.13 min MS (ESIpos): m/z = 501 [M + H].sup.+

Example 54A

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

[0632] ##STR00085##

[0633] A suspension of 9.0 g (20.86 mmol) of 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5,5-dimethyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-4-carboxamide (Example 1) in 180 ml of conc. hydrochloric acid was stirred at 80° C. for 20 h. Water and ethyl acetate were then added, the pH was adjusted to 2-3 using 20% strength aqueous sodium hydroxide solution and the phases were separated. The aqueous phase was extracted with ethyl acetate and the combined organic phases were dried and concentrated under reduced pressure. The residue was dissolved in dichloromethane/methanol (9:1) and purified by column chromatography (silica gel, dichloromethane and dichloromethane/methanol (5-20%) as mobile phase). The crude product obtained was suspended in diethyl ether and the resulting solid was filtered off with suction and dried under high vacuum. 7.50 g (83% of theory) of the title compound were obtained.

[0634] LC-MS (Method 7): R.sub.t=1.13 min

[0635] MS (ESIpos): m/z=433 [M+H].sup.+

[0636] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=1.47 (s, 6H), 5.90 (s, 2H), 7.08-7.27 (m, 3H), 7.31-7.39 (m, 1H), 7.46 (dd, 1H), 8.68 (dd, 1H), 8.96 (dd, 1H), 11.80 (br. s, 1H), 14.10 (br. s, 1H).

Example 55A

2-[5-Fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5,5-dimethyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-4-carboxylic acid

[0637] ##STR00086##

[0638] A suspension of 2.02 g (4.5 mmol) of 2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5,5-dimethyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-4-carboxamide (Example 2) in 40 ml of conc. hydrochloric acid was stirred at 80° C. for 10 h. After cooling, the solid formed was filtered off with suction, washed with water and dried. 1.41 g (66% of theory) of the title compound were obtained.

[0639] LC-MS (Method 1): R.sub.t=0.95 min

[0640] MS (ESIpos): m/z=451 [M+H].sup.+

[0641] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=1.49 (s, 6H), 5.87 (s, 2H), 7.11-7.29 (m, 3H), 7.31-7.44 (m, 1H), 8.69 (dd, 1H), 8.76 (dd, 1H), 11.90 (s, 1H), 14.05 (br. s, 1H).

Example 56A

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

[0642] ##STR00087##

[0643] A mixture of 386 mg (0.80 mmol) of 2-[1-(2,3-difluorobenzyl)-5-fluoro-6-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl]-5,5-dimethyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-4-carboxamide from Example 4 in 19 ml of conc. hydrochloric acid and 19 ml of conc. acetic acid was stirred at 95° C. for 24 h. After cooling to RT, water was added to the mixture and the suspension formed was then stirred at RT for 30 min. The resulting solid was then filtered off, washed with water and dried under reduced pressure. This gave 416 mg (crude product; purity about 93%) of the title compound.

[0644] LC-MS (Method 11): R.sub.t=12.19 min

[0645] MS (ESIpos): m/z=483 [M+H].sup.+

[0646] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=1.48 (s, 6H), 2.65 (d, 3H), 5.87 (s, 2H), 6.99-7.05 (m, 1H), 7.13-7.21 (m, 1H), 7.35-7.42 (m, 1H), 8.59 (d, 1H), 11.88 (s, 1H), 14.02 (br. s, 1H).

Example 57A

2-{5-Fluoro-1-[(3-fluoropyridin-2-yl)methyl]-1H-pyrazolo[3,4-b]pyridin-3-yl}-5,5-dimethyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-4-carboxylic acid

[0647] ##STR00088##

[0648] A suspension of 245 mg (0.54 mmol) of 2-{5-fluoro-1-[(3-fluoropyridin-2-yl)methyl]-1H-pyrazolo[3,4-b]pyridin-3-yl}-5,5-dimethyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-4-carboxamide from Example 8 in 6.4 ml of conc. hydrochloric acid was stirred at 80° C. for 11 h. After cooling to RT, the solvent was removed under reduced pressure. The residue was taken up in water and a little acetonitrile and the mixture was stirred at 50° C. for 30 min. The resulting solid was filtered off, washed with water and dried. This gave 269 mg (96% of theory; purity 86%) of the title compound.

[0649] LC-MS (Method 11): R.sub.t=9.89 min

[0650] MS (ESIpos): m/z=452 [M+H].sup.+

[0651] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=1.48 (s, 6H), 6.02 (s, 2H), 7.39-7.47 (m, 1H), 7.74-7.81 (m, 1H), 8.23-8.30 (m, 1H), 8.66-8.78 (m, 2H), 11.88 (s, 1H), 14.02 (br. s, 1H).

Example 58A

2-[6-Chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5,5-dimethyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-4-carboxylic acid

[0652] ##STR00089##

[0653] 1.83 g (3.94 mmol) of 2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5,5-dimethyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-4-carboxamide (Example 3) were stirred in 20 ml of concentrated hydrochloric acid and 20 ml of conc. acetic acid at 95° C. for 18 h. With stirring, the warm reaction mixture was then carefully introduced into 250 ml of warm water at 70° C. After cool-cooling of the mixture, the solid formed was filtered off with suction, washed with water and dried. 1.57 g (86% of theory) of the title compound were obtained.

[0654] LC-MS (Method 2): R.sub.t=3.19 min

[0655] MS (ESIpos): m/z=466 [M+H].sup.+

[0656] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=1.47 (s, 6H), 5.86 (s, 2H), 7.12-7.28 (m, 3H), 7.32-7.44 (m, 2H), 8.06 (d, 1H), 8.65 (d, 1H), 11.87 (s, 1H), 14.0 (br. s, 1H).

Example 59A

rac-2-[(Diphenylmethylene)amino]-4,4-difluorobutanonitrile

[0657] ##STR00090##

[0658] 18 g (81.72 mmol) of [(diphenylmethylene)amino]acetonitrile were initially charged in 500 ml of abs. THF, and 39.22 ml (98.06 mmol) of n-butyllithium (2.5 N in hexane) were added at −78° C. under argon, and the mixture was then stirred at −78° C. for 15 min. Subsequently, the reaction solution was brought to 0° C. 17.25 g (89.89 mmol) of 1,1-difluoro-2-iodoethane were added dropwise, and the mixture was then stirred at 0° C. for 15 min. At 0° C., first water and then ethyl acetate were then added to the reaction solution, and the mixture was washed three times with semisaturated aqueous sodium chloride solution. The combined aqueous phases were furthermore extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was purified by means of column chromatography (silica gel, mobile phase: dichloromethane/cyclohexane=1/1). This gave 13.57 g of the target compound (49% of theory, purity 84%).

[0659] LC-MS (Method 3): Rt=2.48 min

[0660] MS (ESIpos): m/z=285 [M+H]+

[0661] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=2.53-2.61 (m, 2H; partially superposed by solvent peak), 4.50 (t, 1H), 6.08-6.41 (m, 1H), 7.23-7.33 (m, 2H), 7.38-7.47 (m, 2H), 7.49-7.67 (m, 6H).

Example 60A

rac-2-[(Diphenylmethylene)amino]-4,4-difluoro-2-methylbutanenitrile

[0662] ##STR00091##

[0663] To an initial charge of 13.07 g (38.62 mmol) of rac-2-[(diphenylmethylene)amino]-4,4-difluorobutanonitrile from Example 59A in 255 ml of abs. THF were added 15.6 ml (39.0 mmol) of n-butyllithium (2.5 N in hexane) at −78° C. under argon, and the mixture was then stirred at −78° C. for 10 min. Subsequently, 22.6 g (154.46 mmol) of iodomethane were added to the reaction solution at −78° C. The reaction mixture was gradually brought to 0° C. over 3.5 h. At 0° C., first water and then ethyl acetate were then added, and the mixture was washed twice with saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulfate, filtered and concentrated. The residue was purified by means of column chromatography (silica gel, mobile phase: cyclohexane/ethyl acetate=15/1). This gave 11.4 g of the target compound (91% of theory, purity 92%).

[0664] LC-MS (Method 3): R.sub.t=2.52 min

[0665] MS (ESIpos): m/z=299 [M+H].sup.+

[0666] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=1.67 (s, 3H), 2.55-2.77 (m, 2H), 6.14-6.48 (m, 1H), 7.28-7.34 (m, 2H), 7.36-7.44 (m, 2H), 7.44-7.54 (m, 6H).

Example 61A

rac-2-Amino-4,4-difluoro-2-methylbutanonitrile hydrochloride

[0667] ##STR00092##

[0668] 10.84 g (33.43 mmol; 92% purity) of rac-2-[(diphenylmethylene)amino]-4,4-difluoro-2-methylbutanonitrile from Example 60A were dissolved in 156 ml of tetrahydrofuran and 6 ml of water, 73.5 ml (36.77 mmol) of hydrogen chloride solution (0.5 N in diethyl ether) were added and the mixture was stirred at room temperature overnight. 16.71 ml (33.43 mmol) of hydrogen chloride solution (2 N in diethyl ether) were then added to the reaction solution, and the mixture was concentrated. The isolated crude product was reacted further directly without further purification.

[0669] LC-MS (Method 3): R.sub.t=0.32 min

[0670] MS (ESIpos): m/z=135 (M−HCl+H).sup.+

Example 62A

rac-Benzyl (2-cyano-4,4-difluorobutan-2-yl)carbamate

[0671] ##STR00093##

[0672] The crude product rac-2-amino-4,4-difluoro-2-methylbutanonitrile hydrochloride from Example 61A was initially charged in 109 ml of tetrahydrofuran/water (1:1), and 18.94 g (137.06 mmol) of potassium carbonate and 6.27 g (36.77 mmol) of benzyl chloroformate were added. The reaction mixture was stirred at room temperature overnight. Another 1.14 g (6.69 mmol) of benzyl chloroformate were added to the reaction and the mixture was stirred at room temperature for a further 2 h. The phases were then separated and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed once with saturated aqueous sodium chloride solution, and then dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (mobile phase: cyclohexane/ethyl acetate gradient 20/1 to 5/1). This gave 7.68 g of the target compound (61% of theory over two steps, purity 71%).

[0673] LC-MS (Method 3): R.sub.t=2.04 min

[0674] MS (ESIpos): m/z=269 [M+H].sup.+

[0675] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=1.65 (s, 3H), 2.51-2.65 (m, 2H), 5.10 (s, 2H), 6.08-6.41 (m, 1H), 7.27-7.44 (m, 5H), 8.24 (br. s, 1H).

Example 63A

ent-Benzyl (2-cyano-4,4-difluorobutan-2-yl)carbamate (enantiomer A)

[0676] ##STR00094##

[0677] 7.68 g (20.33 mmol, purity 71%) of rac-benzyl (2-cyano-4,4-difluorobutan-2-yl)carbamate from Example 62A were separated into the enantiomers by preparative separation on the chiral phase [column: Daicel Chiralpak AY-H, 5 μm, 250×20 mm, mobile phase: 80% isohexane, 20% isopropanol; flow rate: 25 ml/min; temperature: 22° C., detection: 210 nm].

[0678] Enantiomer A: yield: 2.64 g (>99% ee)

[0679] R.sub.t=6.67 min [Chiralpak AY-H, 5 μm, 250×4.6 mm; mobile phase: 80% isohexane, 20% isopropanol; flow rate: 3 ml/min; detection: 220 nm].

Example 64A

ent-Benzyl (2-cyano-4,4-difluorobutan-2-yl)carbamate (enantiomer B)

[0680] ##STR00095##

[0681] 7.68 g (20.33 mmol, purity 71%) of rac-benzyl (2-cyano-4,4-difluorobutan-2-yl)carbamate from Example 62A were separated into the enantiomers by preparative separation on the chiral phase [column: Daicel Chiralpak AY-H, 5 μm, 250×20 mm, mobile phase: 80% isohexane, 20% isopropanol; flow rate: 25 ml/min; temperature: 22° C., detection: 210 nm].

[0682] Enantiomer B: yield: 2.76 g (93% ee)

[0683] R.sub.t=7.66 min [Chiralpak AY-H, 5 μm, 250×4.6 mm; mobile phase: 80% isohexane, 20% isopropanol; flow rate: 3 ml/min; detection: 220 nm].

Example 65A

ent-Benzyl (1-amino-4,4-difluoro-2-methylbutan-2-yl)carbamate (enantiomer A)

[0684] ##STR00096##

[0685] 2.3 g (8.57 mmol) of ent-benzyl (2-cyano-4,4-difluorobutan-2-yl)carbamate (enantiomer A) from Example 63A were dissolved in 75 ml of methanolic ammonia solution (7 N in methanol), and 2.66 g of Raney nickel (50% aqueous slurry) were added under argon. The reaction mixture was hydrogenated in an autoclave at 20-30 bar for 1.5 h. The reaction mixture was filtered through Celite, rinsed with methanol and methanolic ammonia solution (2 N in methanol) and concentrated. This gave 2.23 g of the target compound (94% of theory).

[0686] LC-MS (Method 3): R.sub.t=1.48 min

[0687] MS (ESIpos): m/z=273 [M+H].sup.+

[0688] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=1.19 (s, 3H), 1.48 (br. s, 2H), 2.08-2.40 (m, 2H), 2.53 2.72 (m, 2H; partially superposed by solvent peak), 5.00 (s, 2H), 5.90-6.23 (m, 1H), 6.95 (br. s, 1H), 7.25-7.41 (m, 5H).

Example 66A

ent-Benzyl (1-amino-4,4-difluoro-2-methylbutan-2-yl)carbamate (enantiomer B)

[0689] ##STR00097##

[0690] 2.76 g (10.29 mmol) of ent-benzyl (2-cyano-4,4-difluorobutan-2-yl)carbamate (enantiomer B) from Example 64A were dissolved in 90 ml of methanolic ammonia solution (7 N in methanol), and 3.19 g of Raney nickel (50% aqueous slurry) were added under argon. The reaction mixture was hydrogenated in an autoclave at 20-30 bar of hydrogen for 1.5 h. The reaction mixture was filtered through Celite and rinsed with methanol and methanolic ammonia solution (2 N in methanol), and the mixture was concentrated. This gave 2.64 g of the target compound (88% of theory, purity 93%).

[0691] LC-MS (Method 3): R.sub.t=1.49 min

[0692] MS (ESIpos): m/z=273 [M+H].sup.+

[0693] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=1.19 (s, 3H), 1.48 (br. s, 2H), 2.08-2.40 (m, 2H), 2.53 2.73 (m, 2H; partially superposed by solvent peak), 5.00 (s, 2H), 5.90-6.24 (m, 1H), 6.95 (br. s, 1H), 7.25-7.41 (m, 5H).

Example 67A

ent-Benzyl (4,4-difluoro-1-{[(2-{5-fluoro-1-[(3-fluoropyridin-2-yl)methyl]-1H-pyrazolo[3,4-b]pyridin-3-yl}-5,5-dimethyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)carbonyl]amino}-2-methylbutan-2-yl)carbamate (enantiomer A)

[0694] ##STR00098##

[0695] 25 mg (0.05 mmol) of 2-{5-fluoro-1-[(3-fluoropyridin-2-yl)methyl]-1H-pyrazolo[3,4-b]pyridin-3-yl}-5,5-dimethyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-4-carboxylic acid from Example 57A, 39 mg (0.14 mmol) of ent-benzyl (1-amino-4,4-difluoro-2-methylbutan-2-yl)carbamate (enantiomer A) from Example 65A and 40 μl (0.29 mmol) of triethylamine were dissolved in 0.3 ml of DMF, 43 μl (0.07 mmol) of 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (T3P, 50% solution in ethyl acetate) were added and the mixture was stirred at RT for 3 h. Another 39 mg (0.14 mmol) ent-benzyl (1-amino-4,4-difluoro-2-methylbutan-2-yl)carbamate (enantiomer A), 20 μl (0.14 mmol) of triethylamine and 23 μl (0.04 mmol) of 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (T3P, 50% solution in ethyl acetate) were added and the reaction mixture was stirred at RT overnight. Acetonitrile/water and TFA were then 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 26 mg of the target compound (63% of theory, purity 80%).

[0696] LC-MS (Method 1): R.sub.t=1.19 min

[0697] MS (ESIpos): m/z=706.5 [M+H].sup.+

[0698] The exemplary compounds listed in Table 10A were prepared analogously to the procedure from Example 67A from the acids of the starting materials 56A, 57A and the appropriate amines (Examples 65A and 66A). If appropriate, further amine (1-3 equivalents), 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (50% in ethyl acetate) (0.5-1.0 equivalent) and triethylamine (2-4 equivalents) were added to the reaction mixtures and stirring was continued until the reaction had gone to completion (1-24 h). Purifications were carried out by preparative HPLC (RP18 column, mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid or 0.1% TFA).

TABLE-US-00011 TABLE 10 A Ex- IUPAC name/structure Workup, ample (Yield) Analytical data 68A ent-Benzyl (4,4-difluoro-1-{[(2-{5-fluoro-1-[(3- LC-MS (Method 1): R.sub.t = 1.19 min fluoropyridin-2-yl)methyl]-1H-pyrazolo[3,4-b]pyridin-3- MS (ESIpos): m/z = 706.5 [M + H].sup.+ yl}-5,5-dimethyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3- d]pyrimidin-4-yl)carbonyl]amino}-2-methylbutan-2- yl)carbamate (enantiomer B) .sup.1) [00099] 69A ent-Benzyl {1-[({2-[1-(2,3-difluorobenzyl)-5-fluoro-6- LC-MS (Method 1): R.sub.t = 1.28 min methyl-1H-pyrazolo[3,4-b]pyridin-3-yl]-5,5-dimethyl-6- MS (ESIpos): m/z = 737 [M + H].sup.+ oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4- yl}carbonyl)amino]-4,4-difluoro-2-methylbutan-2- yl}carbamate (enantiomer A) .sup.2) [00100] 70A ent-Benzyl {1-[({2-[1-(2,3-difluorobenzyl)-5-fluoro-6- LC-MS (Method 1): R.sub.t = 1.28 min methyl-1H-pyrazolo[3,4-b]pyridin-3-yl]-5,5-dimethyl-6- MS (ESIpos): m/z = 737 [M + H].sup.+ oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4- yl}carbonyl)amino]-4,4-difluoro-2-methylbutan-2- yl}carbamate (enantiomer B) .sup.1) [00101] .sup.1) ent-Benzyl (1-amino-4,4-difluoro-2-methylbutan-2-yl)carbamate (enantiomer B) from Example 66A was employed. .sup.2) ent-Benzyl (1-amino-4,4-difluoro-2-methylbutan-2-yl)carbamate (enantiomer A) from Example 65A was employed.

WORKING EXAMPLES

Example 1

2-[1-(2-Fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5,5-dimethyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-4-carboxamide

[0699] ##STR00102##

[0700] 11.5 g (27.8 mmol) of 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5,5-dimethyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-4-carbonitrile (Ex. 41A) in 100 ml of dioxane and 35 ml of 2 M aqueous sodium hydroxide solution were stirred at 80° C. overnight. The reaction mixture was poured into a mixture of 10% aqueous sodium chloride solution and ethyl acetate and, with stirring, adjusted to pH 3 using semiconcentrated hydrochloric acid. The resulting precipitate was filtered off, washed with ethyl acetate and dried. This gave 9.0 g (75% of theory) of the title compound. The phases of the fitrate were separated, the aqueous phase was re-extracted once with ethyl acetate, the combined organic phases were dried and the solvent was removed under reduced pressure, giving a further 3.1 g of crude product (15% of theory, purity 59%).

[0701] LC-MS (Method 7): R.sub.t=1.12 min

[0702] MS (ESIpos): m/z=432 [M+H].sup.+

[0703] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ [ppm]=1.50 (s, 6H), 5.88 (s, 2H), 7.10-7.27 (m, 3H), 7.32-7.41 (m, 1H), 7.46 (dd, 1H), 8.05 (br. s, 1H), 8.10 (br. s, 1H), 8.69 (dd, 1H), 8.93 (dd, 1H), 11.86 (s, 1H)

Example 2

2-[5-Fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5,5-dimethyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-4-carboxamide

[0704] ##STR00103##

[0705] 2.11 g (purity 75%, 3.67 mmol) of 2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5,5-dimethyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-4-carbonitrile (described in WO 2013/104703, Ex. 81A) in 70 ml of dioxane and 24 ml of 2 M aqueous sodium hydroxide solution were stirred at 80° C. for 6 h. The reaction mixture was then adjusted to pH 5 using formic acid and concentrated under reduced pressure, and the residue was subsequently diluted with 100 ml of water. The precipitate formed was then filtered off with suction and dried. The resulting solid was suspended in 50 ml of petroleum ether and 2 ml of dichloromethane and then filtered off with suction and dried. This gave 2.23 g of crude product which was reacted further to give the compound from Example 55A. Pure material was obtained by preparative HPLC (RP18, gradient of water+0.1% formic acid/acetonitrile (5-95%)).

[0706] LC-MS (Method 1): R.sub.t=0.94 min

[0707] MS (ESIpos): m/z=450 [M+H].sup.+

[0708] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=1.50 (s, 6H), 5.88 (s, 2H), 7.11-7.29 (m, 3H), 7.32-7.42 (m, 1H), 8.01 (br. s, 1H), 8.20 (br. s, 1H), 8.69 (dd, 1H), 8.75 (dd, 1H), 11.84 (s, 1H).

Example 3

2-[6-Chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5,5-dimethyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-4-carboxamide

[0709] ##STR00104##

[0710] 1.69 g (3.77 mmol) of 2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5,5-dimethyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-4-carbonitrile (Ex. 48A) were stirred in 12 ml of dioxane and 4 ml of 2 M aqueous sodium hydroxide solution at 80° C. for 5 h. The reaction mixture was then adjusted to pH 5 using formic acid, the reaction mixture was concentrated under reduced pressure, water was then added to the residue and the resulting suspension was stirred at 50° C. After cooling to RT, the precipitate formed was filtered off with suction and dried. This gave 1.83 g of crude product which was reacted further to give the compound from Example 58A. Pure material was obtained by preparative HPLC (RP18, gradient of water+0.1% formic acid/acetonitrile (5-95%)).

[0711] LC-MS (Method 1): R.sub.t=1.05 min

[0712] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=1.49 (s, 6H), 5.86 (s, 2H), 7.12-7.27 (m, 3H), 7.33-7.42 (m, 2H), 8.01-8.08 (m, 1H), 8.54 (d, 1H), 11.83 (s, 1H).

Example 4

2-[1-(2,3-Difluorobenzyl)-5-fluoro-6-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl]-5,5-dimethyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-4-carboxamide

[0713] ##STR00105##

[0714] 424 mg (0.86 mmol; purity 93%) of 2-[1-(2,3-difluorobenzyl)-5-fluoro-6-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl]-5,5-dimethyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-4-carbonitrile from Example 43A were initially charged in 13 ml of abs. dioxane, 3.23 ml (6.46 mmol) of 2 N aqueous sodium hydroxide solution were added and the mixture was stirred at 90° C. for 10 h. The reaction solution was cooled to RT and diluted with 1 ml of 1 M aqueous sodium hydroxide solution. A further 1.08 ml (2.16 mmol) of 2 N sodium hydroxide solution were added and the mixture was then stirred at 90° C. for a further 8 h. The mixture was adjusted to pH 3 using 1 N hydrochloric acid. The suspension was freed from the dioxane on a rotary evaporator. The solid obtained was then filtered off. This gave 413 mg (95% of theory, purity 95%) of the title compound.

[0715] LC-MS (Method 1): R.sub.t=0.97 min

[0716] MS (ESIpos): m/z=482 [M+H].sup.+

[0717] .sup.1H-NMR (500 MHz, DMSO-d.sub.6): δ [ppm]=1.49 (s, 6H), 2.64 (d, 3H), 5.88 (s, 2H), 6.99-7.05 (m, 1H), 7.13-7.20 (m, 1H), 7.37-7.42 (m, 1H), 8.01 (br. s, 1H), 8.19 (br. s, 1H), 8.59 (d, 1H), 11.82 (br. s, 1H).

Example 5

2-[5-Fluoro-1-(2-fluorobenzyl)-6-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl]-5,5-dimethyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-4-carboxamide

[0718] ##STR00106##

[0719] 39 mg (0.09 mmol) of 2-[5-fluoro-1-(2-fluorobenzyl)-6-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl]-5,5-dimethyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-4-carbonitrile from Example 44A were initially charged in 1.7 ml of abs. dioxane, 0.70 ml (1.40 mmol) of 2 N aqueous sodium hydroxide solution were added and the mixture was stirred at 80° C. for 6 h. The reaction solution was cooled and diluted with 5 ml of 1 N aqueous sodium hydroxide solution. The mixture was subsequently adjusted to pH 5 using saturated aqueous ammonium chloride solution. The solid obtained was filtered off, washed with water and dried under high vacuum. This gave 36 mg (85% of theory; purity 96%) of the title compound.

[0720] LC-MS (Method 7): R.sub.t=1.29 min

[0721] MS (ESIpos): m/z=464 [M+H].sup.+

[0722] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=1.46 (s, 6H), 2.64 (d, 3H), 5.83 (s, 2H), 7.12-7.20 (m, 2H), 7.20-7.28 (m, 1H), 7.33-7.40 (m, 1H), 7.95 (br. s, 1H), 8.15 (br. s, 1H), 8.58 (d, 1H), 10.83 (br. s, 1H).

Example 6

2-[5-Fluoro-6-methyl-1-(2,3,6-trifluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5,5-dimethyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-4-carboxamide

[0723] ##STR00107##

[0724] 180 mg (0.37 mmol) of 2-[5-fluoro-6-methyl-1-(2,3,6-trifluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5,5-dimethyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-4-carbonitrile from Example 45A were initially charged in 7 ml of abs. dioxane, 3.0 ml (6.00 mmol) of 2 N aqueous sodium hydroxide solution were added and the mixture was stirred at RT overnight and at 80° C. for 5 h. The reaction solution was cooled and diluted with 5 ml of 1 N aqueous sodium hydroxide solution. The mixture was subsequently adjusted to pH 5 using saturated aqueous ammonium chloride solution. The suspension was freed from the dioxane on a rotary evaporator. The solid obtained was then filtered off. This solid was washed with water and dried under high vacuum. This gave 149 mg (73% of theory; purity 92%) of the title compound.

[0725] LC-MS (Method 1): R.sub.t=1.02 min

[0726] MS (ESIpos): m/z=500 [M+H].sup.+

[0727] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=1.48 (s, 6H), 2.65 (d, 3H), 5.86 (s, 2H), 7.16-7.24 (m, 1H), 7.55 (ddt, 1H), 8.00 (br. s, 1H), 8.17 (br. s, 1H), 8.56 (d, 1H), 11.82 (br. s, 1H).

Example 7

2-{5-Fluoro-1-[(3-fluoropyridin-2-yl)methyl]-6-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl}-5,5-dimethyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-4-carboxamide

[0728] ##STR00108##

[0729] 55 mg (0.12 mmol) of 2-{5-fluoro-1-[(3-fluoropyridin-2-yl)methyl]-6-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl}-5,5-dimethyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-4-carbonitrile from Example 46A were initially charged in 2.4 ml of abs. dioxane, 0.305 ml (0.61 mmol) of 2 N aqueous sodium hydroxide solution were added and the mixture was stirred at 90° C. for 13 h. A further 0.061 ml (0.122 mmol) of 2 N sodium hydroxide solution were added and the mixture was then stirred at 90° C. for 5 h. A further 0.091 ml (0.182 mmol) of 2 N aqueous sodium hydroxide solution was added and the mixture was then stirred at 90° C. for 4 h. The reaction solution was concentrated by evaporation, water/acetonitrile was added and the mixture was purified by preparative HPLC (column: RP18, mobile phase: acetonitrile/water gradient with addition of 0.1% TFA). 43 mg (75% of theory) of the title compound were obtained.

[0730] LC-MS (Method 1): R.sub.t=0.86 min

[0731] MS (ESIpos): m/z=465 [M+H].sup.+

[0732] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=1.49 (s, 6H), 2.60 (d, 3H), 5.97 (s, 2H), 7.39-7.46 (m, 1H), 7.72-7.82 (m, 1H), 7.99 (br. s, 1H), 8.19 (br. s, 1H), 8.28 (d, 1H), 8.59 (d, 1H), 11.80 (br. s, 1H).

Example 8

[0733] ##STR00109##

[0734] 319 mg (0.74 mmol) of 2-{5-fluoro-1-[(3-fluoropyridin-2-yl)methyl]-1H-pyrazolo[3,4-b]pyridin-3-yl}-5,5-dimethyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-4-carbonitrile from Example 47A were initially charged in 10.5 ml of abs. dioxane, 1.85 ml (3.70 mmol) of 2 N aqueous sodium hydroxide solution were added and the mixture was stirred at 90° C. for 13 h. The reaction solution was cooled and the organic solvent was evaporated. Ethyl acetate was then added and the mixture was adjusted to pH 3 using 1 N hydrochloric acid. The solid obtained was filtered off and washed with water. This gave 258 mg (77% of theory) of the title compound.

[0735] LC-MS (Method 1): R.sub.t=0.80 min

[0736] MS (ESIpos): m/z=451 [M+H].sup.+

[0737] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=1.50 (s, 6H), 6.02 (s, 2H), 7.41-7.47 (m, 1H), 7.74-7.81 (m, 1H), 8.01 (br. s, 1H), 8.20 (br. s, 1H), 8.24-8.29 (m, 1H), 8.66-8.73 (m, 2H), 11.82 (br. s, 1H).

Example 9

rac-2-[1-(2,3-difluorobenzyl)-5-fluoro-6-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-5-(trifluoromethyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-4-carboxamide

[0738] ##STR00110##

[0739] 340 mg (0.66 mmol) of rac-2-[1-(2,3-difluorobenzyl)-5-fluoro-6-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-5-(trifluoromethyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-4-carbonitrile from Example 52A were initially charged in 10 ml of abs. dioxane, 1.64 ml (3.28 mmol) of 2 N aqueous sodium hydroxide solution were added and the mixture was stirred at 90° C. for 5.5 h. A further 0.82 ml (0.164 mmol) of 2 N sodium hydroxide solution were added and the mixture was then stirred at 90° C. for 4 h. The volatile constituents were removed under reduced pressure, and water/acetonitrile/TFA and a little methanol were then added to the residue. The precipitate formed was filtered off and dried. This gave 333 mg (93% of theory) of the title compound.

[0740] LC-MS (Method 1): R.sub.t=1.06 min

[0741] MS (ESIpos): m/z=536 [M+H].sup.+

[0742] .sup.1H-NMR (500 MHz, DMSO-d.sub.6): δ [ppm]=1.90 (s, 3H), 2.63 (d, 3H), 5.89 (s, 2H), 7.02-7.08 (m, 1H), 7.14-7.21 (m, 1H), 7.37-7.43 (m, 1H), 7.98 (br. s, 1H), 8.29 (br. s, 1H), 8.55 (d, 1H), 12.48 (br. s, 1H).

Example 10

ent-2-[1-(2,3-Difluorobenzyl)-5-fluoro-6-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-5-(trifluoromethyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-4-carboxamide (enantiomer A)

[0743] ##STR00111##

[0744] 300 mg of rac-2-[1-(2,3-difluorobenzyl)-5-fluoro-6-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-5-(trifluoromethyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-4-carboxamide (Example 9) were separated on a chiral phase into the enantiomers [SFC column: Daicel Chiralpak IB, 5 μm, 250×20 mm, mobile phase: 82% CO.sub.2, 18% ethanol, flow rate 50 ml/min; 40° C., detection: 210 nm].

[0745] Enantiomer A: 107 mg (>99% ee)

[0746] R.sub.t=2.07 min [SFC: Daicel Chiralpak IB, 5 μm, 250×4.6 mm; mobile phase: 5.fwdarw.60% ethanol; flow rate 3.0 ml/min; detection: 220 nm].

Example 11

ent-2-[1-(2,3-Difluorobenzyl)-5-fluoro-6-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-5-(trifluoromethyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-4-carboxamide (enantiomer B)

[0747] ##STR00112##

[0748] 300 mg of rac-2-[1-(2,3-difluorobenzyl)-5-fluoro-6-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-5-(trifluoromethyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-4-carboxamide (Example 9) were separated on a chiral phase into the enantiomers [SFC column: Daicel Chiralpak IB, 5 μm, 250×20 mm, mobile phase: 82% CO.sub.2, 18% ethanol, flow rate 50 ml/min; 40° C., detection: 210 nm].

[0749] Enantiomer B: 105 mg (96% ee)

[0750] R.sub.t=2.16 min [SFC: Daicel Chiralpak IB, 5 μm, 250×4.6 mm; mobile phase: 5.fwdarw.60% ethanol; flow rate 3.0 ml/min; detection: 220 nm].

Example 12

rac-2-[5-fluoro-1-(2-fluorobenzyl)-6-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-5-(trifluoromethyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-4-carboxamide

[0751] ##STR00113##

[0752] 138 mg (0.26 mmol; purity 94%) of rac-2-[5-fluoro-1-(2-fluorobenzyl)-6-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-5-(trifluoromethyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-4-carbonitrile from Example 50A were initially charged in 4 ml of abs. dioxane, 1.5 ml (3.00 mmol) of 2 N aqueous sodium hydroxide solution were added and the mixture was stirred at RT overnight and at 80° C. for 5 h. The reaction solution was cooled to RT and diluted with 5 ml of 1 N aqueous sodium hydroxide solution. The mixture was subsequently adjusted to pH 5 using saturated aqueous ammonium chloride solution. The suspension was freed from the dioxane on a rotary evaporator. The solid obtained was then filtered off. This solid was washed with water and dried under high vacuum. This gave 116 mg (83% of theory, purity 96%) of the title compound.

[0753] LC-MS (Method 1): R.sub.t=1.03 min

[0754] MS (ESIpos): m/z=518 [M+H].sup.+

[0755] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=1.91 (s, 3H), 2.65 (d, 3H), 5.84 (s, 2H), 7.13-7.27 (m, 3H), 7.34-7.41 (m, 1H), 7.99 (s, 1H), 8.29 (s, 1H), 8.54 (d, 1H), 12.46 (br. s, 1H).

Example 13

ent-2-[5-fluoro-1-(2-fluorobenzyl)-6-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-5-(trifluoromethyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-4-carboxamide (enantiomer A)

[0756] ##STR00114##

[0757] 102 mg of rac-2-[5-fluoro-1-(2-fluorobenzyl)-6-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-5-(trifluoromethyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-4-carboxamide (Example 12) were separated on a chiral phase into the enantiomers [SFC column: Daicel Chiralcel OJ-H, 5 μm, SFC 250×20 mm, mobile phase 85% CO.sub.2, 15% isopropanol, flow rate 100 ml/min; 40° C., detection: 210 nm].

[0758] Enantiomer A: 37 mg (purity >99%, >99% ee)

[0759] R.sub.t=2.09 min [SFC: Daicel Chiralcel OJ-H, 5 μm, 250×4.6 mm; mobile phase: 5.fwdarw.50% isopropanol gradient; flow rate 3.0 ml/min; detection: 220 nm].

Example 14

ent-2-[5-fluoro-1-(2-fluorobenzyl)-6-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-5-(trifluoromethyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-4-carboxamide (enantiomer B)

[0760] ##STR00115##

[0761] 102 mg of rac-2-[5-fluoro-1-(2-fluorobenzyl)-6-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-5-(trifluoromethyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-4-carboxamide (Example 12) were separated on a chiral phase into the enantiomers [SFC column: Daicel Chiralcel OJ-H, 5 μm, SFC 250×20 mm, mobile phase 85% CO.sub.2, 15% isopropanol, flow rate 100 ml/min; 40° C., detection: 210 nm].

[0762] Enantiomer B: 38 mg (purity >99%, >99% ee)

[0763] R.sub.t=2.54 min [SFC: Daicel Chiralcel OJ-H, 5 μm, 250×4.6 mm; mobile phase: 5.fwdarw.50% isopropanol gradient; flow rate 3.0 ml/min; detection: 220 nm].

Example 15

rac-2-[5-fluoro-6-methyl-1-(2,3,6-trifluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-5-(trifluoromethyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-4-carboxamide

[0764] ##STR00116##

[0765] 121 mg (0.20 mmol; purity 90%) of rac-2-[5-fluoro-6-methyl-1-(2,3,6-trifluorobenzyl)-1H-pyrazol-3,4-b]pyridin-3-yl-5-methyl-6-oxo-5-(trifluoromethyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-4-carbonitrile from Example 51A were initially charged in 4 ml of abs. dioxane, 1.5 ml (3.00 mmol) of 2 N aqueous sodium hydroxide solution were added and the mixture was stirred at RT overnight and then at 80° C. for 5 h. The reaction solution was then cooled to RT and diluted with 5 ml of 1 N aqueous sodium hydroxide solution. The mixture was subsequently adjusted to pH 5 using saturated aqueous ammonium chloride solution. The suspension was freed from the dioxane on a rotary evaporator. The solid obtained was then filtered off. This solid was washed with water and dried under high vacuum. This gave 116 mg (83% of theory, purity 96%) of the title compound.

[0766] LC-MS (Method 1): R.sub.t=1.04 min

[0767] MS (ESIpos): m/z=554 [M+H].sup.+

[0768] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=1.90 (s, 3H), 2.66 (d, 3H), 5.87 (s, 2H), 7.20 (ddt, 1H), 7.55 (ddt, 1H), 7.99 (s, 1H), 8.29 (s, 1H), 8.54 (d, 1H), 12.45 (br. s, 1H).

Example 16

ent-2-[5-Fluoro-6-methyl-1-(2,3,6-trifluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-5-(trifluoromethyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-4-carboxamide (enantiomer A)

[0769] ##STR00117##

[0770] 85 mg of rac-2-[5-fluoro-6-methyl-1-(2,3,6-trifluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-5-(trifluoromethyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-4-carboxamide (Example 15) were separated on a chiral phase into the enantiomers [SFC column: Daicel Chiralcel OJ-H, 5 μm, 250×20 mm, mobile phase: 85% CO.sub.2, 15% isopropanol, flow rate 80 ml/min; 40° C., detection: 210 nm].

[0771] Enantiomer A: 36 mg (purity >99%, >99% ee)

[0772] R.sub.t=2.04 min [SFC: Daicel Chiralcel OJ-H, 5 μm, 250×4.6 mm; mobile phase: 5.fwdarw.60% isopropanol; flow rate 3.0 ml/min; detection: 220 nm].

Example 17

ent-2-[5-Fluoro-6-methyl-1-(2,3,6-trifluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-5-(trifluoromethyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-4-carboxamide (enantiomer B)

[0773] ##STR00118##

[0774] 85 mg of rac-2-[5-fluoro-6-methyl-1-(2,3,6-trifluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-5-(trifluoromethyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-4-carboxamide (Example 15) were separated on a chiral phase into the enantiomers [SFC column: Daicel Chiralcel OJ-H, 5 μm, 250×20 mm, mobile phase: 85% CO.sub.2, 15% isopropanol, flow rate 80 ml/min; 40° C., detection: 210 nm].

[0775] Enantiomer B: 36 mg (purity >99%, >99% ee)

[0776] R.sub.t=2.57 min [SFC: Daicel Chiralcel OJ-H, 5 μm, 250×4.6 mm; mobile phase: 5-60% isopropanol; flow rate 3.0 ml/min; detection: 220 nm].

Example 18

rac-2-{5-Fluoro-1-[(3-fluoropyridin-2-yl)methyl]-6-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl}-5-methyl-6-oxo-5-(trifluoromethyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-4-carboxamide

[0777] ##STR00119##

[0778] 100 mg (0.20 mmol) of rac-2-{5-fluoro-1-[(3-fluoropyridin-2-yl)methyl]-6-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl}-5-methyl-6-oxo-5-(trifluoromethyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-4-carbonitrile from Example 53A were initially charged in 3.0 ml of abs. dioxane, 0.50 ml (1.00 mmol) of 2 N aqueous sodium hydroxide solution were added and the mixture was stirred at 90° C. for 7 h. The reaction solution was cooled to RT and 1.20 ml (1.2 mmol) of 1 M hydrochloric acid were added. Water/acetonitrile were then added and the mixture was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile/water gradient with addition of 0.1% TFA). 67 mg (63% of theory) of the title compound were obtained.

[0779] LC-MS (Method 1): R.sub.t=0.92 min

[0780] MS (ESIpos): m/z=519 [M+H].sup.+

[0781] .sup.1H-NMR (500 MHz, DMSO-d.sub.6): δ [ppm]=1.89 (s, 3H), 2.63 (d, 3H), 5.98 (s, 2H), 7.39-7.44 (m, 1H), 7.75-7.81 (m, 1H), 7.98 (br. s, 1H) 8.24-8.33 (m, 2H), 8.55 (d, 1H), 12.43 (br. s, 1H).

Example 19

ent-2-{5-Fluoro-1-[(3-fluoropyridin-2-yl)methyl]-6-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl}-5-methyl-6-oxo-5-(trifluoromethyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-4-carboxamide (enantiomer A)

[0782] ##STR00120##

[0783] 67 mg of rac-2-{5-fluoro-1-[(3-fluoropyridin-2-yl)methyl]-6-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl}-5-methyl-6-oxo-5-(trifluoromethyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-4-carboxamide (Example 18) were separated on a chiral phase into the enantiomers [SFC column: Daicel Chiralpak OJ-H, 5 μm, 250×20 mm, mobile phase: 80% CO.sub.2, 20% methanol, flow rate 100 ml/min; 30° C., detection: 210 nm].

[0784] Enantiomer A: 26 mg (purity 98%, >99% ee)

[0785] R.sub.t=1.99 min [SFC: Daicel Chiralpak OJ-H, 5 μm, 250×4.6 mm, mobile phase: 5.fwdarw.50% methanol; flow rate 3.0 ml/min; detection: 220 nm].

Example 20

ent-2-{5-Fluoro-1-[(3-fluoropyridin-2-yl)methyl]-6-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl}-5-methyl-6-oxo-5-(trifluoromethyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-4-carboxamide (enantiomer B)

[0786] ##STR00121##

[0787] 67 mg of rac-2-{5-fluoro-1-[(3-fluoropyridin-2-yl)methyl]-6-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl}-5-methyl-6-oxo-5-(trifluoromethyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-4-carboxamide (Example 18) were separated on a chiral phase into the enantiomers [SFC column: Daicel Chiralpak OJ-H, 5 μm, 250×20 mm, mobile phase: 80% CO.sub.2, 20% methanol, flow rate 100 ml/min; 30° C., dedetection: 210 nm].

[0788] Enantiomer B: 29 mg (purity 98%, 99% ee)

[0789] R.sub.t=2.59 min [SFC: Daicel Chiralpak OJ-H, 5 μm, 250×4.6 mm, mobile phase: 5.fwdarw.50% methanol; flow rate 3.0 ml/min; detection: 220 nm].

Example 21

rac-2-{5-Fluoro-1-[(3-fluoropyridin-2-yl)methyl]-1H-pyrazolo[3,4-b]pyridin-3-yl}-5-methyl-6-oxo-5-(trifluoromethyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-4-carboxamide

[0790] ##STR00122##

[0791] 80 mg (0.16 mmol) of 2-{5-fluoro-1-[(3-fluoropyridin-2-yl)methyl]-1H-pyrazolo[3,4-b]pyridin-3-yl}-5-methyl-6-oxo-5-(trifluoromethyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-4-carbonitrile from Example 49A were initially charged in 2.5 ml of abs. dioxane, 0.41 ml (0.82 mmol) of 2 N aqueous sodium hydroxide solution were added and the mixture was stirred at 90° C. for 7 h. The reaction solution was cooled to RT and diluted with 1.00 ml (1.00 mmol) of 1 M hydrochloric acid. Water/acetonitrile were then added and the mixture was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile/water gradient with addition of 0.1% TFA). This gave 54 mg (63% of theory; purity 97%) of the title compound.

[0792] LC-MS (Method 1): R.sub.t=0.86 min

[0793] MS (ESIpos): m/z=505 [M+H].sup.+

[0794] .sup.1H-NMR (500 MHz, DMSO-d.sub.6): δ [ppm]=1.92 (s, 3H), 6.04 (s, 2H), 7.41-7.47 (m, 1H), 7.74-7.81 (m, 1H), 7.98 (br. s, 1H) 8.24-8.28 (m, 1H), 8.31 (s, 1H), 8.63-8.68 (m, 1H), 8.72-8.75 (m, 1H), 12.46 (br. s, 1H).

Example 22

ent-2-{5-Fluoro-1-[(3-fluoropyridin-2-yl)methyl]-1H-pyrazolo[3,4-b]pyridin-3-yl}-5-methyl-6-oxo-5-(trifluoromethyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-4-carboxamide (enantiomer A)

[0795] ##STR00123##

[0796] 48 mg of rac-2-{5-fluoro-1-[(3-fluoropyridin-2-yl)methyl]-1H-pyrazolo[3,4-b]pyridin-3-yl}-5-methyl-6-oxo-5-(trifluoromethyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-4-carboxamide (Example 21) were separated on a chiral phase into the enantiomers [SFC column: Daicel Chiralpak IB, 5 μm, 250×30 mm, mobile phase: 80% CO.sub.2, 20% ethanol, flow rate 80 ml/min; 40° C., detection: 210 nm].

[0797] Enantiomer A: 16 mg (purity 97%, >99% ee)

[0798] R.sub.t=3.26 min [SFC: Daicel Chiralpak IB, 5 μm, 250×4.6 mm; mobile phase: 5.fwdarw.50% ethanol; flow rate 3.0 ml/min; detection: 220 nm].

Example 23

ent-2-{5-Fluoro-1-[(3-fluoropyridin-2-yl)methyl]-1H-pyrazolo[3,4-b]pyridin-3-yl}-5-methyl-6-oxo-5-(trifluoromethyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-4-carboxamide (enantiomer B)

[0799] ##STR00124##

[0800] 48 mg of rac-2-{5-fluoro-1-[(3-fluoropyridin-2-yl)methyl]-1H-pyrazolo[3,4-b]pyridin-3-yl}-5-methyl-6-oxo-5-(trifluoromethyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-4-carboxamide (Example 21) were separated on a chiral phase into the enantiomers [SFC column: Daicel Chiralpak IB, 5 μm, 250×30 mm, mobile phase: 80% CO.sub.2, 20% ethanol, flow rate 80 ml/min; 40° C., detection: 210 nm].

[0801] Enantiomer B: 18 mg (purity 97%, 93% ee)

[0802] R.sub.t=3.84 min [SFC: Daicel Chiralpak IB, 5 μm, 250×4.6 mm; mobile phase: 5.fwdarw.50% ethanol; flow rate 3.0 ml/min; detection: 220 nm].

Example 24

N-Cyclopropyl-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5,5-dimethyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-4-carboxamide

[0803] ##STR00125##

[0804] 38 mg (0.09 mmol) of the compound from Example 54A, 10 mg (0.18 mmol) of cyclopropylamine and 46 μl (34 mg, 0.26 mmol) of diisopropylethylamine were dissolved in 0.8 ml of DMF, 78.5 μl (0.13 mmol) of 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (T3P, 50% solution in ethyl acetate) were added and the mixture was stirred at RT for 10 h. A further 5 mg (0.09 mmol) of cyclopropylamine and 42 μl (0.07 mmol) of 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (T3P, 50% solution in ethyl acetate) were added and the mixture was stirred at 50° C. for 5 h. The reaction mixture was concentrated under reduced pressure, dissolved in DMSO and acetonitrile, acidified slightly with 5 M formic acid and purified by preparative HPLC (RP18, mobile phase: 0.1% aqueous formic acid—acetonitrile, 5-95%). The residue was purified on silica gel (mobile phase: gradient of cyclohexane/ethyl acetate 5-65%). This gave 19 mg (46% of theory) of the title compound.

[0805] LC-MS (Method 1): R.sub.t=1.02 min

[0806] MS (ESIpos): m/z=472 [M+H].sup.+

[0807] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=0.63-0.72 (m, 2H), 0.75-0.85 (m, 2H), 1.49 (s, 6H), 2.87-2.98 (m, 1H), 5.88 (s, 2H), 7.10-7.29 (m, 3H), 7.32-7.41 (m, 1H), 7.48 (dd, 1H), 8.65-8.76 (m, 2H), 8.84 (dd, 1H), 11.86 (br. s, 1H).

[0808] The exemplary compounds listed in Table 1 were prepared analogously to the procedure from Example 24 from the acid of Example 58A and the appropriate amines.

TABLE-US-00012 TABLE 1 Ex- IUPAC name/structure ample (Yield) Analytical data 25 [00126] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.20 (s, 6H), 1.52 (s, 6H), 4.92 (br. s, 1H), 5.89 (s, 2H), 7.10- 7.28 (m, 3H), 7.32-7.41 (m, 1H), 7.44 (dd, 1H), 8.63-8.75 (m, 2H), 8.94 (d, 1H), 11.93 (s, 1H). LC-MS (Method 1): R.sub.t = 0.98 min MS (ESIpos): m/z = 504 [M + H].sup.+ 26 [00127] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.28-1.43 (m, 6H), 1.72- 2.06 (m, 2H), 3.15-3.24 (m, 1H), 3.16-3.70 (m, 4H) superposed by water signal, 4.19-4.41 (m, 1H), 4.88-5.16 (m, 1H), 5.88 (s, 2H), 7.10-7.28 (m, 3H), 7.32-7.41 (m, 1H), 7.42-7.49 (m, 1H), 8.68 (dd, 1H), 8.78-8.86 (m, 1H), 11.81 (s, 1H). LC-MS (Method 1): R.sub.t = 0.84 min MS (ESIpos): m/z = 502 [M + H].sup.+

Example 27

2-[5-Fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-N-[(1-hydroxycyclopropyl)methyl]-5,5-dimethyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-4-carboxamide

[0809] ##STR00128##

[0810] 50 mg (0.11 mmol) of the compound from Example 55A, 19 mg (0.22 mmol) of 1-(aminomethyl)cyclopropanol and 93 μl (0.67 mmol) of triethylamine were dissolved in 0.7 ml of DMF, 99 μl (0.17 mmol) of 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (T3P, 50% solution in ethyl acetate) were added and the mixture was stirred at RT for 9 h. The reaction mixture was concentrated under reduced pressure, dissolved in DMSO and acetonitrile, acidified slightly with formic acid and purified by preparative HPLC (RP 18, mobile phase: 0.1% aqueous formic acid-acetonitrile, 5-95%). 33 mg (55% of theory) of the title compound were obtained.

[0811] LC-MS (Method 1): R.sub.t=1.01 min

[0812] MS (ESIpos): m/z=520 [M+H].sup.+

[0813] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=0.60-0.70 (m, 4H), 1.50 (s, 6H), 3.51 (d, 2H), 5.89 (s, 2H), 7.12-7.30 (m, 3H), 7.33-7.42 (m, 1H), 8.64 (d, 1H), 8.70-8.80 (m, 2H), 11.89 (s, 1H).

[0814] The exemplary compounds listed in Table 2 were prepared analogously to the procedure from Example 27 from the acids of the starting materials 55A, 56A and 57A and the appropriate amines. If appropriate, further amine (1-3 equivalents), 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (50% in ethyl acetate) (0.5-1.0 equivalent) and triethylamine (2-4 equivalents) were added to the reaction mixtures and stirring was continued until the reaction had gone to completion (1-24 h). Purifications were carried out by preparative HPLC (RP18 column, mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid or 0.1% TFA).

TABLE-US-00013 TABLE 2 Ex- IUPAC name/structure Workup, ample (Yield) analytical data 28 [00129] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 0.63-0.70 (m, 2H), 0.76- 0.84 (m, 2H), 1.49 (s, 6H), 2.94 (m, 1H), 5.88 (s, 2H), 7.12-7.27 (m, 3H), 7.33-7.41 (m, 1H), 8.59 (dd, 1H), 8.72-8.79 (m, 2H), 11.84 (s, 1H). LC-MS (Method 1): R.sub.t = 1.11 min MS (ESIpos): m/z = 490 [M + H].sup.+ 29 [00130] Additional purification by stirring with water/methanol/sat. potassium carbonate solution .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.19 (s, 6H), 1.50 (s, 6H), 3.35 (d, 2H), 4.77 (s, 1H), 5.88 (s, 2H), 7.12-7.29 (m, 3H), 7.33-7.41 (m, 1H), 8.59-8.67 (m, 2H), 8.76 (s, 1H), 11.90 (br. s, 1H). LC-MS (Method 5): R.sub.t = 2.42 min MS (ESIpos): m/z = 522 [M + H].sup.+ 30 [00131] .sup.1H-NMR (400 MHz, DMSO- d.sub.6/D.sub.2O): δ [ppm] = 1.15 (s, 6H), 1.51 (s, 6H), 3.28 (s, 2H), 5.88 (s, 2H), 7.12-7.31 (m, 3H), 7.34-7.42 (m, 1H), 8.74-8.78 (m, 1H), 8.81 (dd, 1H). LC-MS (Method 1): R.sub.t = 0.75 min MS (ESIpos): m/z = 521 [M + H]+ 31 [00132] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.32-1.41 (m, 2H), 1.49 (s, 6H), 1.63-1.71 (m, 2H), 5.88 (s, 2H), 7.11-7.27 (m, 3H), 7.33-7.42 (m, 1H), 8.65 (dd, 1H), 8.77 (dd, 1H), 9.66 (s, 1H), 11.92 (s, 1H). LC-MS (Method 5): R.sub.t = 1.07 min MS (ESIpos): m/z = 515 [M + H].sup.+ 32 [00133] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 0.65-0.70 (m, 2H), 0.76- 0.83 (m, 2H), 1.50 (s, 6H), 2.89- 2.98 (m, 1H), 6.02 (s, 2H), 7.40- 7.47 (m, 1H), 7.74-7.81 (m, 1H), 8.24 (d, 1H), 8.57-8.62 (m, 1H), 8.68-8.78 (m, 2H), 11.81 (s, 1H). LC-MS (Method 1): R.sub.t = 0.95 min MS (ESIpos): m/z = 491 [M + H].sup.+ 33 [00134] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 0.10-0.17 (m, 1H), 0.30- 0.40 (m, 2H), 0.53-0.60 (m, 1H), 0.95-1.08 and 1.12-1.22 (2 m, together 1H), 1.31 (s, 3H), 1.36 (s, 3H), 2.92 and 3.13 (2 s, together 3H), 3.06 and 3.44 (2 d, together 2H), 5.98-6.05 (m, 2H), 7.40-7.47 (m, 1H), 7.74-7.81 (m, 1H), 8.25- 8.28 (m, 1H), 8.58-8.63 (m, 1H), 8.69-8.74 (m, 1H), 11.73-11.79 (m, 1H). (~1:1 mixture of amide rotational isomers). LC-MS (Method 1): R.sub.t = 0.93 min MS (ESIpos): m/z = 519 [M + H].sup.+ 34 [00135] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 0.34-0.48 (m, 6H), 0.53- 0.62 (m, 2H), 1.13-1.24 (m, 2H), 1.49 (s, 6H), 3.08-3.14 (m, 1H), 6.02 (s, 2H), 7.40-7.47 (m, 1H), 7.74-7.81 (m, 1H), 8.26 (d, 1H), 8.60-8.66 (m, 1H), 8.68-8.78 (m, 2H), 11.81 (s, 1H). LC-MS (Method 1): R.sub.t = 1.11 min MS (ESIpos): m/z = 545 [M + H].sup.+ 35 [00136] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.35/1.36 (2 s, together 6H), 2.91/3.12 (2 s, together 3H), 3.48-3.56 (m, 1H), 3.59-3.65 (m, 1H), 3.67-3.72 (m, 1H), 4.62 and 4.82 (2 br. s, together 1H), 6.02 (s, 2H), 7.40-7.47 (m, 1H), 7.74-7.81 (m, 1H), 8.28 (d, 1H), 8.48-8.58 (m, 1H), 8.69-8.73 (m, 1H), 11.74 (s, 1H) [further signal under solvent peak]). (~1:1 mixture of amide rotational isomers). LC-MS (Method 1): R.sub.t = 0.70 min MS (ESIpos): m/z = 509 [M + H].sup.+ 36 [00137] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.50 (s, 6H), 3.35 (s, 3H; superposed by solvent peak), 3.52- 3.60 (m, 4H), 6.02 (s, 2H), 7.40- 7.47 (m, 1H), 7.74-7.81 (m, 1H), 8.27 (d, 1H), 8.57-8.62 (m, 1H), 8.70-8.78 (m, 2H), 11.85 (s, 1H). LC-MS (Method 1): R.sub.t = 0.88 min MS (ESIpos): m/z = 509 [M + H].sup.+ 37 [00138] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 0.64-0.69 (m, 2H), 0.78- 0.83 (m, 2H), 1.49 (s, 6H), 2.67 (d, 3H), 2.89-2.98 (m, 1H), 5.88 (s, 2H), 6.98-7.05 (m, 1H), 7.13-7.21 (m, 1H), 7.36-7.45 (m, 1H), 8.48 (d, 1H), 8.73 (d, 1H), 11.80 (br. s, 1H). LC-MS (Method 1): R.sub.t = 1.19 min MS (ESIpos): m/z = 522 [M + H].sup.+ 38 [00139] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 0.12-0.17 (m, 1H), 0.30- 0.40 (m, 2H), 0.53-0.60 (m, 1H), 0.98-1.10 and 1.12-1.22 (2 m, together 1H), 1.31 (s, 3H), 1.36 (s, 3H), 2.62-2.66 (m, 3H), 2.91 and 3.13 (2 s, together 3H), 3.05 and 3.46 (2 d, together 2H), 5.84-5.88 (m, 2H), 6.99-7.10 (m, 1H), 7.12- 7.20 (m, 1H), 7.35-7.44 (m, 1H), 8.40 (d, 1H), 11.71-11.78 (m, 1H). (~1:1 mixture of amide rotational isomers). LC-MS (Method 1): R.sub.t = 1.13 min MS (ESIpos): m/z = 550 [M + H].sup.+ 39 [00140] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 0.33-0.48 (m, 6H), 0.52- 0.61 (m, 2H), 1.13-1.23 (m, 2H), 1.48 (s, 6H), 2.67 (d, 3H), 3.08- 3.16 (m, 1H), 5.88 (s, 2H), 7.02- 7.08 (m, 1H), 7.13-7.22 (m, 1H), 7.36-7.45 (m, 1H), 8.52 (d, 1H), 8.69 (d, 1H), 11.82 (s, 1H). LC-MS (Method 1): R.sub.t = 1.34 min MS (ESIpos): m/z = 576 [M + H].sup.+ 40 [00141] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.35/1.36 (2 s, together 6H), 2.65 d, 3H), 2.92/3.12 (2 s, together 3H), 3.48-3.56 (m, 1H), 3.59-3.65 (m, 1H), 3.67-3.72 (m, 1H), 4.70 (br. s, 1H), 5.88 (s, 2H), 6.98-7.08 (m, 1H), 7.12-7.22 (m, 1H), 7.35-7.45 (m, 1H), 8.38-8.48 (m, 1H), 11.75 (s, 1H). [further signal under solvent peak]). (~1:1 1:1 mixture of amide rotational isomers) LC-MS (Method 1): R.sub.t = 0.91 min MS (ESIpos): m/z = 540 [M + H].sup.+ 41 [00142] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.50 (s, 6H), 2.67 (d, 3H), 3.35 (s, 3H), 3.53-3.61 (m, 4H), 5.88 (s, 2H), 6.98-7.05 (m, 1H), 7.13-7.21 (m, 1H), 7.36-7.45 (m, 1H), 8.49 (d, 1H), 8.69-8.76 (m, 1H), 11.86 (s, 1H). LC-MS (Method 1): R.sub.t = 1.10 min MS (ESIpos): m/z = 540 [M + H].sup.+

Example 42

2-[6-Chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-N-(cyclopropylmethyl)-5,5-dimethyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-4-carboxamide

[0815] ##STR00143##

[0816] 70 mg (0.15 mmol) of the compound from Example 58A, 21 mg (0.3 mmol) of 1-cyclopropylmethanamine and 61 mg (0.6 mmol) of triethylamine in 1 ml of THF were heated to 60° C., 0.18 ml (0.3 mmol) of 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (T3P, 50% solution in ethyl acetate) were then added and the mixture was stirred at this temperature for 30 min. The reaction mixture was partitioned between water and ethyl acetate (extraction), and the organic phase was washed with sat. sodium chloride solution, dried and concentrated. The residue was purified by means of column chromatography (silica gel, mobile phase: gradient of cyclohexane/ethyl acetate 5-65%). This gave 59 mg (76% of theory) of the title compound.

[0817] LC-MS (Method 1): R.sub.t=1.23 min

[0818] MS (ESIpos): m/z=519 [M+H].sup.+

[0819] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=0.29-0.36 (m, 1H), 0.48-0.54 (m, 1H), 1.07-1.17 (m, 1H), 1.50 (s, 6H), 3.26 (t, 2H), 5.87 (s, 2H), 7.14-7.28 (m, 3H), 7.33-7.42 (m, 2H), 8.09 (s, 1H), 8.53 (d, 1H), 8.70 (t, 1H), 11.85 (s, 1H).

[0820] The exemplary compounds listed in Table 3 were prepared analogously to the procedure from Example 42 from the acids of Example 58A and Example 55A, respectively, and the appropriate amines. If the amine was employed as a salt, 2 equivalents of triethylamine were additionally employed. If appropriate, further amine, 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (50% solution in ethyl acetate) and triethylamine were added and stirring was continued until the reaction had gone to completion.

[0821] Work-Up:

[0822] Method a): extraction and column chromatography on silica gel as described in Example 42.

[0823] Method b): water, acetonitrile and formic acid are added to the reaction mixture (pH 3-4), and the precipitate formed is filtered off and washed with water/acetonitrile.

[0824] Method c): the reaction mixture is concentrated, the residue is dissolved in DMSO/acetonitrile/aq. formic acid and purified by preparative HPLC (column: RP 18, gradient of water+0.1% formic acid/acetonitrile (5-95%)).

TABLE-US-00014 TABLE 3 Ex- IUPAC name/structure Workup, ample (Yield) analytical data 43 [00144] work-up Method a) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 0.63-0.69 (m, 2H), 0.76- 0.83 (m, 2H), 1.48 (s, 6H), 2.88- 2.97 (m, 1H), 5.86 (s, 2H), 7.12- 7.28 (m, 3H), 7.33-7.43 (m, 2H), 8.06 (s, 1H), 8.46 (d, 1H), 8.64 (d, 1H), 11.83 (s, 1H). LC-MS (Method 1): R.sub.t = 1.16 min MS (ESIpos): m/z = 505 [M + H].sup.+ 44 [00145] work-up Method b) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.47 (s, 6H), 4.14-4.27 (m, 2H), 5.87 (s, 2H), 7.10-7.28 (m, 3H), 7.31-7.43 (m, 2H), 8.08 (s, 1H), 8.53 (d, 1H), 9.19 (t, 1H), 11.90 (s, 1H). LC-MS (Method 1): R.sub.t = 1.17 min MS (ESIpos): m/z = 547 [M + H].sup.+ 45 [00146] work-up Method a) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.50 (s, 6H), 2.56-2.72 (m, 2H), 3.64 (q, 2H), 5.87 (s, 2H), 7.10- 7.28 (m, 3H), 7.31-7.42 (m, 2H), 8.07 (s, 1H), 8.53 (d, 1H), 8.87 (t, 1H), 11.87 (s, 1H). LC-MS (Method 1): R.sub.t = 1.22 min MS (ESIpos): m/z = 561 [M + H].sup.+ 46 [00147] work-up Method c) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 0.41-0.58 (m, 3H), 0.74- 0.89 (m, 1H), 1.31 (s, 1.5H), 1.35 (s, 4.5H), 2.77 (s, 0.75H), 2.85-2.93 (m, 0.75H), 2.96-3.03 (m, 0.25H), 3.07 (s, 2.25H), 5.84 (s, 2H), 7.14- 7.28 (m, 3H), 7.34-7.42 (m, 2H), 8.06 (s, 1H), 8.45 (d, 0.25H), 8.50 (d, 0.75H), 11.77 (s, 1H). (~3:1 mixture of amide rotational isomers LC-MS (Method 3): R.sub.t = 2.55 min MS (ESIpos): m/z = 519 [M + H].sup.+ 47 [00148] work-up Method c) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 0.09-0.16 (m, 1H), 0.30- 0.40 (m, 2H), 0.52-0.60 (m, 1H), 0.97-1.08 (m, 1H), 1.11-1.21 (m, 1H), 1.31 (s, 3H), 1.36 (s, 3H), 2.92 (s, 1.5H), 3.05 (d, 1H), 3.13 (s, 1.5H), 3.43 (d, 1H), 5.84 (s, 1H), 5.86 (s, 1H), 7.13-7.27 (m, 3H), 7.33-7.41 (m, 2H), 8.06 (br. s., 1H), 8.43-8.52 (m, 1H), 11.77 (br. s., 1H). (~1:1 mixture of amide rotational isomers). LC-MS (Method 1): R.sub.t = 1.17 min MS (ESIpos): m/z = 533 [M + H].sup.+ 48 [00149] work-up Method a) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.76-1.86 (m, 2H), 1.86- 1.95 (m, 2H), 3.27-3.37 (m, superposed by water signal), 3.56 (t, 2H), 5.85 (s, 2H), 7.13-7.27 (m, 3H), 7.33-7.42 (m, 2H), 8.06 (s, 1H), 8.47 (d, 1H), 11.76 (s, 1H). LC-MS (Method 1): R.sub.t = 1.11 min MS (ESIpos): m/z = 519 [M + H].sup.+ 49 [00150] work-up Method c) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 0.29-0.40 (m, 2H), 0.45- 0.56 (m, 2H), 1.08-1.19 (m, 1H), 1.50 (s, 6H), 3.27 (t, 2H), 5.88 (s, 2H), 7.11-7.29 (m, 3H), 7.32-7.42 (m, 1H), 8.66 (dd, 1H), 8.74-8.86 (m, 2H), 11.83 (br. s, 1H). LC-MS (Method 1): R.sub.t = 1.19 min MS (ESIpos): m/z = 504 [M + H].sup.+ 50 [00151] work-up Method c) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.48 (s, 6H), 4.15-4.28 (m, 2H), 5.89 (s, 2H), 7.12-7.28 (m, 3H), 7.33-7.42 (m, 1H), 8.65 (dd, 1H), 8.77 (dd, 1H), 9.31 (t, 1H), 11.83-12.02 (m, 1H). LC-MS (Method 1): R.sub.t = 1.17 min MS (ESIpos): m/z = 532 [M + H].sup.+ 51 [00152] work-up Method c) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.50 (s, 6H), 2.57-2.73 (m, 2H), 3.65 (q, 2H), 5.88 (s, 2H), 7.11- 7.28 (m, 3H), 7.33-7.42 (m, 1H), 8.65 (dd, 1H), 8.73-8.79 (m, 1H), 8.97 (t, 1H), 11.89 (s, 1H). LC-MS (Method 1): R.sub.t = 1.18 min MS (ESIpos): m/z = 546 [M + H].sup.+ 52 [00153] work-up Method c) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 0.42-0.58 (m, 3H), 0.74- 0.91 (m, 1H), 1.31 (s, 1.5H), 1.35 (s, 4.5H), 2.77 (s, 1H), 2.85-2.92 (m, 0.75H), 2.96-3.03 (m, 0.25 H), 3.07 (s, 2H), 5.87 (s, 2H), 7.12-7.30 (m, 3H), 7.33-7.41 (m, 1H), 8.48 (dd, 0.25H), 8.54 (dd, 0.75H), 8.71-8.79 (m, 1H), 11.79 (br. s, 1H). (~3:1 mixture of amide rotational isomers). LC-MS (Method 1): R.sub.t = 1.07 min MS (ESIpos): m/z = 504 [M + H].sup.+ 53 [00154] work-up Method c) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 0.10-0.17 (m, 1H), 0.30- 0.40 (m, 2H), 0.52-0.59 (m, 1H), 0.98-1.08 (m, 0.5H), 1.10-1.22 (m, 0.5H), 1.32 (s, 3H), 1.36 (s, 3H), 2.92 (s, 1.5H), 3.06 (d, 1H), 3.14 (s, 1.5H), 3.44 (d, 1H), 5.84-5.90 (m, 2H), 7.12-7.31 (m, 3H), 7.33-7.41 (m, 1H), 8.47-8.53 (m, 1H), 8.74- 8.78 (m, 1H), 11.78 (br. s, 1H). (~1:1 mixture of amide rotational isomers). LC-MS (Method 1): R.sub.t = 1.12 min MS (ESIpos): m/z = 518 [M + H].sup.+ 54 [00155] work-up Method c) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.36 (s, 6H), 1.75-1.96 (m, 4H), 3.32 signal superposed by water peak 3.56 (t, 2H), 5.87 (s, 2H), 7.17 (t, 1H), 7.19-7.28 (m, 2H), 7.33-7.42 (m, 1H), 8.51 (dd, 1H), 8.73-8.78 (m, 1H), 11.77 (s, 1H). LC-MS (Method 1): R.sub.t = 1.04 min MS (ESIpos): m/z = 504 [M + H].sup.+

Example 55

ent-N-(2-Amino-4,4-difluoro-2-methylbutyl)-2-{5-fluoro-1-[(3-fluoropyridin-2-yl)methyl]-1H-pyrazolo[3,4-b]pyridin-3-yl}-5,5-dimethyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-4-carboxamide (enantiomer A)

[0825] ##STR00156##

[0826] 26 mg (0.03 mmol) of ent-benzyl (4,4-difluoro-1-{[(2-{5-fluoro-1-[(3-fluoropyridin-2-yl)methyl]-1H-pyrazolo[3,4-b]pyridin-3-yl}-5,5-dimethyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)carbonyl]amino}-2-methylbutan-2-yl)carbamate (enantiomer A) from Example 67A were dissolved in 0.8 ml of ethanol, 11 μl (0.15 mmol) of trifluoroacetic acid and 1 mg of palladium on activated carbon (10%) were added and the mixture was hydrogenated at atmospheric pressure and RT for 2 h. The reaction solution was subsequently filtered through a Millipore filter and the filtrate was concentrated under reduced pressure. The residue was taken up in dichloromethane/methanolic ammonia solution (2 N in methanol) and then purified by preparative thick-layer chromatography (mobile phase: dichloromethane/methanol=10/1). The product fractions were combined and concentrated. This gave 12 mg of the target compound (72% of theory).

[0827] LC-MS (Method 1): R.sub.t=0.71 min

[0828] MS (ESIpos): m/z=572.5 [M+H].sup.+

[0829] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=1.13 (s, 3H), 1.51 (d, 6H), 1.93-2.07 (m, 2H), 3.25-3.42 (m, 2H; superposed by solvent peak), 6.02 (s, 2H), 6.13-6.46 (m, 1H), 7.41-7.47 (m, 1H), 7.74-7.81 (m, 1H), 8.24-8.28 (m, 1H), 8.71-8.74 (m, 1H), 8.75-8.79 (m, 1H), 8.84 (t, 1H).

[0830] The exemplary compounds listed in Table 4 were prepared analogously to the procedure from Example 55 from the appropriate starting materials. In each case, the reaction times were 0.5-3 h. Purifications were carried out by preparative thick-layer chromatography (mobile phase: dichloromethane/methanol=10/1 or 20/1).

TABLE-US-00015 TABLE 4 Ex- IUPAC name/structure ample (Yield) Work-up, analytical data 56 [00157] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.13 (s, 3H), 1.51 (d, 6H), 1.93-2.07 (m, 2H), 3.25-3.42 (m, 2H; superposed by solvent peak), 6.02 (s, 2H), 6.13-6.46 (m, 1H), 7.41-7.47 (m, 1H), 7.74-7.81 (m, 1H), 8.24-8.28 (m, 1H), 8.71-8.74 (m, 1H), 8.75-8.79 (m, 1H), 8.84 (t, 1H). LC-MS (Method 1): R.sub.t = 0.71 min MS (ESIpos): m/z = 572.5 [M + H].sup.+ 57 [00158] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.13 (s, 3H), 1.50 (d, 6H), 1.94-2.07 (m, 2H), 2.65 (d, 3H), 3.25-3.42 (m, 2H; superposed by solvent peak), 5.88 (s, 2H), 6.13- 6.46 (m, 1H), 7.01-7.08 (m, 1H), 7.13-7.21 (m, 1H), 7.36-7.45 (m, 1H), 8.67 (d, 1H), 8.83 (t, 1H). LC-MS (Method 1): R.sub.t = 0.85 min MS (ESIpos): m/z = 603.5 [M + H].sup.+ 58 [00159] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 1.13 (s, 3H), 1.50 (d, 6H), 1.94-2.08 (m, 2H), 2.65 (d, 3H), 3.25-3.42 (m, 2H; superposed by solvent peak), 5.88 (s, 2H), 6.13- 6.46 (m, 1H), 7.01-7.08 (m, 1H), 7.13-7.21 (m, 1H), 7.35-7.44 (m, 1H), 8.67 (d, 1H), 8.83 (t, 1H). LC-MS (Method 1): R.sub.t = 0.84 min MS (ESIpos): m/z = 603.5 [M + H].sup.+ .sup.1) ent-Benzyl (4,4-difluoro-1-{[(2-{5-fluoro-1-[(3-fluoropyridin-2-yl)methyl]-1H-pyrazolo[3,4-b]pyridin-3-yl}-5,5-dimethyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)carbonyl]amino}-2-methylbutan-2-yl)carbamate (enantiomer B) from Example 68A was employed. .sup.2) ent-Benzyl {1-[({2-[1-(2,3-difluorobenzyl)-5-fluoro-6-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl]-5,5-dimethyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl}carbonyl)amino]-4,4-difluoro-2-methylbutan-2-yl}carbamate (enantiomer A) from Example 69A was employed. .sup.3) ent-Benzyl {1-[({2-[1-(2,3-difluorobenzyl)-5-fluoro-6-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl]-5,5-dimethyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl}carbonyl)amino]-4,4-difluoro-2-methylbutan-2-yl}carbamate (enantiomer B) from Example 70A was employed.

Example 59

N-(2-Ethylbutyl)-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5,5-dimethyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-4-carboxamide

[0831] ##STR00160##

Step 1: 2-[1-(2-Fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5,5-dimethyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-4-carbonyl chloride

[0832] At 0 C, 40.77 g (342.73 mmol) of thionyl chloride were added to 14.82 g (34.27 mmol) of 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5,5-dimethyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-carboxylic acid (Example 54A), and the mixture was stirred at RT for 3 h. The reaction solution was subsequently concentrated completely. 50 ml of toluene were then added to the residue and the solvent was subsequently removed under reduced pressure. This procedure was repeated twice.

Step 2: N-(2-Ethylbutyl)-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5,5-dimethyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-4-carboxamide

[0833] 10.12 mg (0.10 mmol) of 2-ethylbutane-1-amine were initially charged in a multititer plate (96 deep wells), and a solution of 45.09 mg (0.10 mmol) of 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5,5-dimethyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-4-carbonyl chloride (from step 1) in 0.6 ml of 1,2-dichloroethane was added. 64.62 mg (0.5 mol) of N,N-diisopropylethylamine were then added and the mixture was shaken at RT overnight. The solvent was then removed completely using a centrifugal drier, and 0.6 ml of DMF were then added to the residue. The reaction mixture was then filtered and the target compound was isolated from the filtrate by preparative LC-MS (Method 10). The product-containing fractions were concentrated under reduced pressure using a centrifugal dryer. The resulting residue of each product fraction was dissolved in 0.6 ml of DMSO. These fractions were then combined and finally freed of the solvent in a centrifugal dryer. 10.8 mg (21% of theory) of the title compound were obtained.

[0834] LC-MS (Method 9): R.sub.t=1.26 min

[0835] MS (ESIpos): m/z=516 [M+H].sup.+

[0836] The exemplary compounds shown in Table 5 were prepared analogously to Example 59 using the appropriate amines:

TABLE-US-00016 TABLE 5 Ex- IUPAC name/structure ample (Yield) Analytical data 60 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-N- LC-MS (Method 9): R.sub.t = 1.12 min [(1-hydroxycyclopropyl)methyl]-5,5-dimethyl-6-oxo-6,7- MS (ESIpos): m/z = 506 [M + H].sup.+ dihydro-5H-pyrrolo[2,3-d]pyrimidine-4-carboxamide [00161] 61 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5,5- LC-MS (Method 9): R.sub.t = 1.16 min dimethyl-N-[3-(methylsulfanyl)propyl]-6-oxo-6,7-dihydro- MS (ESIpos): m/z = 520 [M + H].sup.+ 5H-pyrrolo[2,3-d]pyrimidine-4-carboxamide [00162] 62 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5,5- LC-MS (Method 9): R.sub.t = 1.17 min dimethyl-6-oxo-N-(prop-2-en-1-yloxy)-6,7-dihydro-5H- MS (ESIpos): m/z = 488 [M + H].sup.+ pyrrolo[2,3-d]pyrimidine-4-carboxamide [00163] 63 rac-N-(butan-2-yl)-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4- LC-MS (Method 9): R.sub.t = 1.17 min b]pyridin-3-yl]-5,5-dimethyl-6-oxo-6,7-dihydro-5H- MS (ESIpos): m/z = 488 [M + H].sup.+ pyrrolo[2,3-d]pyrimidine-4-carboxamide [00164] 64 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5,5- LC-MS (Method 9): R.sub.t = 0.96 min dimethyl-N-[2-(methylsulfinyl)ethyl]-6-oxo-6,7-dihydro- MS (ESIpos): m/z = 522 [M + H].sup.+ 5H-pyrrolo[2,3-d]pyrimidine-4-carboxamide [00165] 65 rac-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3- LC-MS (Method 9): R.sub.t = 1.07 min yl]-5,5-dimethyl-6-oxo-N-(tetrahydrofuran-3-yl)-6,7- MS (ESIpos): m/z = 502 [M + H].sup.+ dihydro-5H-pyrrolo[2,3-d]pyrimidine-4-carboxamide [00166] 66 rac-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3- LC-MS (Method 9): R.sub.t = 1.15 min yl]-5,5-dimethyl-6-oxo-N-(3-oxopentan-2-yl)-6,7-dihydro- MS (ESIpos): m/z = 516 [M + H].sup.+ 5H-pyrrolo[2,3-d]pyrimidine-4-carboxamide [00167] 67 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5,5- LC-MS (Method 9): R.sub.t = 1.10 min dimethyl-N-(1-methyl-1H-pyrazol-5-yl)-6-oxo-6,7- MS (ESIpos): m/z = 512 [M + H].sup.+ dihydro-5H-pyrrolo[2,3-d]pyrimidine-4-carboxamide [00168] 68 rac-N-(1-cyclopropylpropan-2-yl)-2-[1-(2-fluorobenzyl)- LC-MS (Method 9): R.sub.t = 1.21 min 1H-pyrazolo[3,4-b]pyridin-3-yl]-5,5-dimethyl-6-oxo-6,7- MS (ESIpos): m/z = 514 [M + H].sup.+ dihydro-5H-pyrrolo[2,3-d]pyrimidine-4-carboxamide [00169] 69 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-N- LC-MS (Method 9): R.sub.t = 1.14 min (furan-2-ylmethyl)-5,5-dimethyl-6-oxo-6,7-dihydro-5H- MS (ESIpos): m/z = 512 [M + H].sup.+ pyrrolo[2,3-d]pyrimidine-4-carboxamide [00170] 70 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5,5- LC-MS (Method 9): R.sub.t = 1.10 min dimethyl-N-(1-methyl-1H-pyrazol-3-yl)-6-oxo-6,7- MS (ESIpos): m/z = 5 12 [M + H].sup.+ dihydro-5H-pyrrolo[2,3-d]pyrimidine-4-carboxamide [00171] 71 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5,5- LC-MS (Method 9): R.sub.t = 1.03 min dimethyl-N-(5-methyl-1,3,4-oxadiazol-2-yl)-6-oxo-6,7- MS (ESIpos): m/z = 5 14 [M + H].sup.+ dihydro-5H-pyrrolo[2,3-d]pyrimidine-4-carboxamide [00172] 72 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5,5- LC-MS (Method 9): R.sub.t = 1.17 min dimethyl-6-oxo-N-(1,3-thiazol-2-yl)-6,7-dihydro-5H- MS (ESIpos): m/z = 515 [M + H].sup.+ pyrrolo[2,3-d]pyrimidine-4-carboxamide [00173] 73 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5,5- LC-MS (Method 9): R.sub.t = 1.20 min dimethyl-6-oxo-N-{2-[(trifluoromethyl)sulfanyl]ethyl}- MS (ESIpos): m/z = 560 [M + H].sup.+ 6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-4-carboxamide [00174] 74 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5,5- LC-MS (Method 9): R.sub.t = 1.16 min dimethyl-6-oxo-N-(3,3,3-trifluoropropyl)-6,7-dihydro-5H- MS (ESIpos): m/z = 528 [M + H].sup.+ pyrrolo[2,3-d]pyrimidine-4-carboxamide [00175] 75 N-(2-amino-2-oxoethyl)-2-[1-(2-fluorobenzyl)-1H- LC-MS (Method 9): R.sub.t = 0.94 min pyrazolo[3,4-b]pyridin-3-yl]-5,5-dimethyl-6-oxo-6,7- MS (ESIpos): m/z = 489 [M + H].sup.+ dihydro-5H-pyrrolo[2,3-d]pyrimidine-4-carboxamide [00176] 76 N-(3,5-difluorophenyl)-2-[1-(2-fluorobenzyl)-1H- LC-MS (Method 9): R.sub.t = 1.30 min pyrazolo[3,4-b]pyridin-3-yl]-5,5-dimethyl-6-oxo-6,7- MS (ESIpos): m/z = 544 [M + H].sup.+ dihydro-5H-pyrrolo[2,3-d]pyrimidine-4-carboxamide [00177] 77 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5,5- LC-MS (Method 9): R.sub.t = 1.32 min dimethyl-6-oxo-N-(3,4,5-trifluorophenyl)-6,7-dihydro-5H- MS (ESIpos): m/z = 562 [M + H].sup.+ pyrrolo[2,3-d]pyrimidine-4-carboxamide [00178] 78 rac-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3- LC-MS (Method 9): R.sub.t = 1.04 min yl]-5,5-dimethyl-6-oxo-N-(2-oxotetrahydrofuran-3-yl)-6,7- MS (ESIpos): m/z = 516 [M + H].sup.+ dihydro-5H-pyrrolo[2,3-d]pyrimidine-4-carboxamide [00179] 79 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-N- LC-MS (Method 9): R.sub.t = 1.03 min methoxy-5,5-dimethyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3- MS (ESIpos): m/z = 462 [M + H].sup.+ d]pyrimidine-4-carboxamide [00180] 80 N-[(2S)-1-amino-1-oxopropan-2-yl]-2-[1-(2-fluorobenzyl)- LC-MS (Method 9): R.sub.t = 0.97 min 1H-pyrazolo[3,4-b]pyridin-3-yl]-5,5-dimethyl-6-oxo-6,7- MS (ESIpos): m/z = 503 [M + H].sup.+ dihydro-5H-pyrrolo[2,3-d]pyrimidine-4-carboxamide [00181] 81 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5,5- LC-MS (Method 9): R.sub.t = 1.14 min dimethyl-6-oxo-N-propyl-6,7-dihydro-5H-pyrrolo[2,3- MS (ESIpos): m/z = 474 [M + H].sup.+ d]pyrimidine-4-carboxamide [00182] 82 N-[1,1′-bi(cyclopropyl)-1-yl]-2-[1-(2-fluorobenzyl)-1H- LC-MS (Method 9): R.sub.t = 1.17 min pyrazolo[3,4-b]pyridin-3-yl]-5,5-dimethyl-6-oxo-6,7- MS (ESIpos): m/z = 512 [M + H].sup.+ dihydro-5H-pyrrolo[2,3-d]pyrimidine-4-carboxamide [00183] 83 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-N- LC-MS (Method 9): R.sub.t = 1.08 min (2-fluoroethyl)-5,5-dimethyl-6-oxo-6,7-dihydro-5H- MS (ESIpos): m/z = 478 [M + H].sup.+ pyrrolo[2,3-d]pyrimidine-4-carboxamide [00184] 84 N-(cyclopropylmethyl)-2-[1-(2-fluorobenzyl)-1H- LC-MS (Method 9): R.sub.t = 1.15 min pyrazolo[3,4-b]pyridin-3-yl]-5,5-dimethyl-6-oxo-6,7- MS (ESIpos): m/z = 486 [M + H].sup.+ dihydro-5H-pyrrolo[2,3-d]pyrimidine-4-carboxamide [00185] 85 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5,5- LC-MS (Method 9): R.sub.t = 1.20 min dimethyl-N-(3-methylbut-2-en-1-yl)-6-oxo-6,7-dihydro- MS (ESIpos): m/z = 500 [M + H].sup.+ 5H-pyrrolo[2,3-d]pyrimidine-4-carboxamide [00186] 86 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]- LC-MS (Method 9): R.sub.t = 1.04 min N,5,5-trimethyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3- MS (ESIpos): m/z = 446 [M + H].sup.+ d]pyrimidine-4-carboxamide [00187] 87 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5,5- LC-MS (Method 9): R.sub.t = 1.04 min dimethyl-6-oxo-N-(1H-pyrazol-3-yl)-6,7-dihydro-5H- MS (ESIpos): m/z = 498 [M + H].sup.+ pyrrolo[2,3-d]pyrimidine-4-carboxamide [00188] 88 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5,5- LC-MS (Method 9): R.sub.t = 0.99 min dimethyl-6-oxo-N-(1H-pyrazol-3-yl)-6,7-dihydro-5H- MS (ESIpos): m/z = 517 [M + H].sup.+ pyrrolo[2,3-d]pyrimidine-4-carboxamide [00189] 89 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5,5- LC-MS (Method 9): R.sub.t = 1.07 min dimethyl-6-oxo-N-(pyridin-3-yl)-6,7-dihydro-5H- MS (ESIpos): m/z = 509 [M + H].sup.+ pyrrolo[2,3-d]pyrimidine-4-carboxamide [00190] 90 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-N- LC-MS (Method 9): R.sub.t = 1.10 min (3-methoxypropyl)-5,5-dimethyl-6-oxo-6,7-dihydro-5H- MS (ESIpos): m/z = 504 [M + H].sup.+ pyrrolo[2,3-d]pyrimidine-4-carboxamide [00191] 91 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5,5- LC-MS (Method 9): R.sub.t = 0.97 min dimethyl-N-(6-methylpyridin-3-yl)-6-oxo-6,7-dihydro-5H- MS (ESIpos): m/z = 523 [M + H].sup.+ pyrrolo[2,3-d]pyrimidine-4-carboxamide [00192] 92 N-(cyclopentylmethyl)-2-[1-(2-fluorobenzyl)-1H- LC-MS (Method 9): R.sub.t = 1.24 min pyrazolo[3,4-b]pyridin-3-yl]-5,5-dimethyl-6-oxo-6,7- MS (ESIpos): m/z = 514 [M + H].sup.+ dihydro-5H-pyrrolo[2,3-d]pyrimidine-4-carboxamide [00193] 93 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5,5- LC-MS (Method 9): R.sub.t = 1.11 min dimethyl-6-oxo-N-(1,3,4-thiadiazol-2-yl)-6,7-dihydro-5H- MS (ESIpos): m/z = 516 [M + H].sup.+ pyrrolo[2,3-d]pyrimidine-4-carboxamide [00194] 94 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5,5- LC-MS (Method 9): R.sub.t = 0.99 min dimethyl-6-oxo-N-(4H-1,2,4-triazol-3-yl)-6,7-dihydro-5H- MS (ESIpos): m/z = 499 [M + H].sup.+ pyrrolo[2,3-d]pyrimidine-4-carboxamide [00195] 95 N-(3-amino-3-oxopropyl)-2-[1-(2-fluorobenzyl)-1H- LC-MS (Method 9): R.sub.t = 0.95 min pyrazolo[3,4-b]pyridin-3-yl]-5,5-dimethyl-6-oxo-6,7- MS (ESIpos): m/z = 503 [M + H].sup.+ dihydro-5H-pyrrolo[2,3-d]pyrimidine-4-carboxamide [00196] 96 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5,5- LC-MS (Method 9): R.sub.t = 1.15 min dimethyl-6-oxo-N-[2-(2,2,2-trifluoroethoxy)ethyl]-6,7- MS (ESIpos): m/z = 558 [M + H].sup.+ dihydro-5H-pyrrolo[2,3-d]pyrimidine-4-carboxamide [00197] 97 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5,5- LC-MS (Method 9): R.sub.t = 1.20 min dimethyl-N-(1-methylcyclobutyl)-6-oxo-6,7-dihydro-5H- MS (ESIpos): m/z = 500 [M + H].sup.+ pyrrolo[2,3-d]pyrimidine-4-carboxamide [00198] 98 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5,5- LC-MS (Method 9): R.sub.t = 1.08 min dimethyl-6-oxo-N-(tetrahydro-2H-pyran-4-yl)-6,7- MS (ESIpos): m/z = 516 [M + H].sup.+ dihydro-5H-pyrrolo[2,3-d]pyrimidine-4-carboxamide [00199] 99 rac-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3- LC-MS (Method 9): R.sub.t = 1.08 min yl]-5,5-dimethyl-6-oxo-N-(tetrahydrofuran-3-ylmethyl)- MS (ESIpos): m/z = 516 [M + H].sup.+ 6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-4-carboxamide [00200] 100 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5,5- LC-MS (Method 9): R.sub.t = 1.03 min dimethyl-6-oxo-N-(1H-pyrazol-4-yl)-6,7-dihydro-5H- MS (ESIpos): m/z = 498 [M + H].sup.+ pyrrolo[2,3-d]pyrimidine-4-carboxamide [00201] 101 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5,5- LC-MS (Method 9): R.sub.t = 0.92 min dimethyl-N-(3-methylpyridin-4-yl)-6-oxo-6,7-dihydro-5H- MS (ESIpos): m/z = 523 [M + H].sup.+ pyrrolo[2,3-d]pyrimidine-4-carboxamide [00202] 102 N-(2,2-dimethylpropyl)-2-[1-(2-fluorobenzyl)-1H- LC-MS (Method 9): R.sub.t = 1.22 min pyrazolo[3,4-b]pyridin-3-yl]-5,5-dimethyl-6-oxo-6,7- MS (ESIpos): m/z = 502 [M + H].sup.+ dihydro-5H-pyrrolo[2,3-d]pyrimidine-4-carboxamide [00203] 103 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5,5- LC-MS (Method 9): R.sub.t = 1.09 min dimethyl-N-[(3-methyloxetan-3-yl)methyl]-6-oxo-6,7- MS (ESIpos): m/z = 516 [M + H].sup.+ dihydro-5H-pyrrolo[2,3-d]pyrimidine-4-carboxamide [00204] 104 rac-N-(1-cyclopropylethyl)-2-[1-(2-fluorobenzyl)-1H- LC-MS (Method 9): R.sub.t = 1.18 min pyrazolo[3,4-b]pyridin-3-yl]-5,5-dimethyl-6-oxo-6,7- MS (ESIpos): m/z = 500 [M + H].sup.+ dihydro-5H-pyrrolo[2,3-d]pyrimidine-4-carboxamide [00205] 105 rac-N-[2-(dimethylamino)propyl]-2-[1-(2-fluorobenzyl)- LC-MS (Method 9): R.sub.t = 0.78 min 1H-pyrazolo[3,4-b]pyridin-3-yl]-5,5-dimethyl-6-oxo-6,7- MS (ESIpos): m/z = 517 [M + H].sup.+ dihydro-5H-pyrrolo[2,3-d]pyrimidine-4-carboxamide [00206] 106 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5,5- LC-MS (Method 9): R.sub.t = 0.86 min dimethyl-N-(2-methylpyridin-4-yl)-6-oxo-6,7-dihydro-5H- MS (ESIpos): m/z = 523 [M + H].sup.+ pyrrolo[2,3-d]pyrimidine-4-carboxamide [00207] 107 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-N- LC-MS (Method 9): R.sub.t = 1.19 min (5-fluoropyridin-3-yl)-5,5-dimethyl-6-oxo-6,7-dihydro-5H- MS (ESIpos): m/z = 527 [M + H].sup.+ pyrrolo[2,3-d]pyrimidine-4-carboxamide [00208] 108 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5,5- LC-MS (Method 9): R.sub.t = 1.19 min dimethyl-6-oxo-N-(pyrazin-2-yl)-6,7-dihydro-5H- MS (ESIpos): m/z = 510 [M + H].sup.+ pyrrolo[2,3-d]pyrimidine-4-carboxamide [00209] 109 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5,5- LC-MS (Method 9): R.sub.t = 1.03 min dimethyl-N-(1-methyl-1H-1,2,4-triazol-3-yl)-6-oxo-6,7- MS (ESIpos): m/z = 513 [M + H].sup.+ dihydro-5H-pyrrolo[2,3-d]pyrimidine-4-carboxamide [00210] 110 N-(3-amino-3-oxopropyl)-2-[1-(2-fluorobenzyl)-1H- LC-MS (Method 9): R.sub.t = 0.91 min pyrazolo[3,4-b]pyridin-3-yl]-N,5,5-trimethyl-6-oxo-6,7- MS (ESIpos): m/z = 517 [M + H].sup.+ dihydro-5H-pyrrolo[2,3-d]pyrimidine-4-carboxamide [00211] 111 N-(cyclopropylmethyl)-2-[1-(2-fluorobenzyl)-1H- LC-MS (Method 9): R.sub.t = 1.11 min pyrazolo[3,4-b]pyridin-3-yl]-N,5,5-trimethyl-6-oxo-6,7- MS (ESIpos): m/z = 500 [M + H].sup.+ dihydro-5H-pyrrolo[2,3-d]pyrimidine-4-carboxamide [00212] 112 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]- LC-MS (Method 9): R.sub.t = 1.10 min N,5,5-trimethyl-6-oxo-N-(propan-2-yl)-6,7-dihydro-5H- MS (ESIpos): m/z = 488 [M + H].sup.+ pyrrolo[2,3-d]pyrimidine-4-carboxamide [00213] 113 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5,5- LC-MS (Method 9): R.sub.t = 1.09 min dimethyl-N-(3-methylpyridin-2-yl)-6-oxo-6,7-dihydro-5H- MS (ESIpos): m/z = 523 [M + H].sup.+ pyrrolo[2,3-d]pyrimidine-4-carboxamide [00214] 114 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-N- LC-MS (Method 9): R.sub.t = 0.98 min (2-hydroxyethyl)-5,5-dimethyl-6-oxo-6,7-dihydro-5H- MS (ESIpos): m/z = 476 [M + H].sup.+ pyrrolo[2,3-d]pyrimidine-4-carboxamide [00215] 115 N-benzyl-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4- LC-MS (Method 9): R.sub.t = 1.18 min b]pyridin-3-yl]-5,5-dimethyl-6-oxo-6,7-dihydro-5H- MS (ESIpos): m/z = 522 [M + H].sup.+ pyrrolo[2,3-d]pyrimidine-4-carboxamide [00216] 116 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5,5- LC-MS (Method 9): R.sub.t = 0.88 min dimethyl-6-oxo-N-(pyridin-4-yl)-6,7-dihydro-5H- MS (ESIpos): m/z = 509 [M + H].sup.+ pyrrolo[2,3-d]pyrimidine-4-carboxamide [00217] 117 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5,5- LC-MS (Method 9): R.sub.t = 1.05 min dimethyl-6-oxo-N-(pyridin-2-ylmethyl)-6,7-dihydro-5H- MS (ESIpos): m/z = 523 [M + H].sup.+ pyrrolo[2,3-d]pyrimidine-4-carboxamide [00218] 118 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5,5- LC-MS (Method 9): R.sub.t = 0.91 min dimethyl-6-oxo-N-(pyridin-4-ylmethyl)-6,7-dihydro-5H- MS (ESIpos): m/z = 523 [M + H].sup.+ pyrrolo[2,3-d]pyrimidine-4-carboxamide [00219] 119 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5,5- LC-MS (Method 9): R.sub.t = 0.99 min dimethyl-N-(4-methylpyridin-3-yl)-6-oxo-6,7-dihydro-5H- MS (ESIpos): m/z = 523 [M + H].sup.+ pyrrolo[2,3-d]pyrimidine-4-carboxamide [00220] 120 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-N- LC-MS (Method 9): R.sub.t = 0.94 min (2-hydroxyethyl)-N,5,5-trimethyl-6-oxo-6,7-dihydro-5H- MS (ESIpos): m/z = 490 [M + H].sup.+ pyrrolo[2,3-d]pyrimidine-4-carboxamide [00221] 121 N-butyl-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin- LC-MS (Method 9): R.sub.t = 1.19 min 3-yl]-5,5-dimethyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3- MS (ESIpos): m/z = 488 [M + H].sup.+ d]pyrimidine-4-carboxamide [00222] 122 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5,5- LC-MS (Method 9): R.sub.t = 1.19 min dimethyl-N-(2-methylpropyl)-6-oxo-6,7-dihydro-5H- MS (ESIpos): m/z = 488 [M + H].sup.+ pyrrolo[2,3-d]pyrimidine-4-carboxamide [00223] 123 N-(3-ethoxypropyl)-2-[1-(2-fluorobenzyl)-1H- LC-MS (Method 9): R.sub.t = 1.13 min pyrazolo[3,4-b]pyridin-3-yl]-5,5-dimethyl-6-oxo-6,7- MS (ESIpos): m/z = 518 [M + H].sup.+ dihydro-5H-pyrrolo[2,3-d]pyrimidine-4-carboxamide [00224] 124 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-N- LC-MS (Method 9): R.sub.t = 1.23 min hexyl-5,5-dimethyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3- MS (ESIpos): m/z = 516 [M + H].sup.+ d]pyrimidine-4-carboxamide [00225] 125 rac-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3- LC-MS (Method 9): R.sub.t = 1.23 min yl]-5,5-dimethyl-N-(2-methylbutyl)-6-oxo-6,7-dihydro- MS (ESIpos): m/z = 502 [M + H].sup.+ 5H-pyrrolo[2,3-d]pyrimidine-4-carboxamide [00226] 126 N-cyclopentyl-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4- LC-MS (Method 9): R.sub.t = 1.20 min b]pyridin-3-yl]-5,5-dimethyl-6-oxo-6,7-dihydro-5H- MS (ESIpos): m/z = 500 [M + H].sup.+ pyrrolo[2,3-d]pyrimidine-4-carboxamide [00227] 127 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-N- LC-MS (Method 9): R.sub.t = 1.09 min (2-methoxyethyl)-5,5-dimethyl-6-oxo-6,7-dihydro-5H- MS (ESIpos): m/z = 490 [M + H].sup.+ pyrrolo[2,3-d]pyrimidine-4-carboxamide [00228] 128 N-[2-(dimethylamino)ethyl]-2-[1-(2-fluorobenzyl)-1H- LC-MS (Method 9): R.sub.t = 0.79 min pyrazolo[3,4-b]pyridin-3-yl]-5,5-dimethyl-6-oxo-6,7- MS (ESIpos): m/z = 503 [M + H].sup.+ dihydro-5H-pyrrolo[2,3-d]pyrimidine-4-carboxamide [00229] 129 N-ethyl-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin- LC-MS (Method 9): R.sub.t = 1.10 min 3-yl]-5,5-dimethyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3- MS (ESIpos): m/z = 460 [M + H].sup.+ d]pyrimidine-4-carboxamide [00230] 130 rac-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3- LC-MS (Method 9): R.sub.t = 1.13 min yl]-5,5-dimethyl-6-oxo-N-(tetrahydrofuran-2-ylmethyl)- MS (ESIpos): m/z = 516 [M + H].sup.+ 6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-4-carboxamide [00231] 131 2-[1-(2-Fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]- LC-MS (Method 9): R.sub.t = 1.23 min 5,5-dimethyl-6-oxo-N-pentyl-6,7-dihydro-5H-pyrrolo[2,3- MS (ESIpos): m/z = 502 [M + H].sup.+ d]pyrimidine-4-carboxamide [00232] 132 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5,5- LC-MS (Method 9): R.sub.t = 1.22 min dimethyl-N-(3-methylbutyl)-6-oxo-6,7-dihydro-5H- MS (ESIpos): m/z = 502 [M + H].sup.+ pyrrolo[2,3-d]pyrimidine-4-carboxamide [00233] 133 rac-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3- LC-MS (Method 9): R.sub.t = 1.22 min yl]-5,5-dimethyl-N-(3-methylbutan-2-yl)-6-oxo-6,7- MS (ESIpos): m/z = 502 [M + H].sup.+ dihydro-5H-pyrrolo[2,3-d]pyrimidine-4-carboxamide [00234] 134 N-[(2S)-butan-2-yl]-2-[1-(2-fluorobenzyl)-1H- LC-MS (Method 9): R.sub.t = 1.18 min pyrazolo[3,4-b]pyridin-3-yl]-5,5-dimethyl-6-oxo-6,7- MS (ESIpos): m/z = 488 [M + H].sup.+ dihydro-5H-pyrrolo[2,3-d]pyrimidine-4-carboxamide [00235] 135 N-(3,3-dimethylbutyl)-2-[1-(2-fluorobenzyl)-1H- LC-MS (Method 9): R.sub.t = 1.23 min pyrazolo[3,4-b]pyridin-3-yl]-5,5-dimethyl-6-oxo-6,7- MS (ESIpos): m/z = 516 [M + H].sup.+ dihydro-5H-pyrrolo[2,3-d]pyrimidine-4-carboxamide [00236] 136 rac-N-(2-amino-4,4,4-trifluorobutyl)-2-[1-(2- LC-MS (Method 9): R.sub.t = 0.84 min fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5,5- MS (ESIpos): m/z = 557 [M + H].sup.+ dimethyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine- 4-carboxamide [00237] 137 rac-N-(2-amino-4,4,4-trifluorobutyl)-2-[1-(2- LC-MS (Method 9): R.sub.t = 1.01 min fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5,5- MS (ESIpos): m/z = 557 [M + H].sup.+ dimethyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine- 4-carboxamide [00238] 138 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-N- LC-MS (Method 9): R.sub.t = 1.03 min [(1-hydroxycyclopropyl)methyl]-5,5-dimethyl-6-oxo-6,7- MS (ESIpos): m/z = 502 [M + H].sup.+ dihydro-5H-pyrrolo[2,3-d]pyrimidine-4-carboxamide [00239]

B. Assessment of Pharmacological Efficacy

[0837] The pharmacological activity of the compounds of the invention can be demonstrated by in vitro and in vivo studies as known to the person skilled in the art. The application examples which follow describe the biological action of the compounds of the invention, without restricting the invention to these examples.

Abbreviations and Acronyms

[0838] The following abbreviations are used: [0839] AUC area under the curve [0840] BSA bovine serum albumin [0841] C.sub.max peak plasma concentration [0842] Caco-2 epithelial cell line [0843] DMSO dimethyl sulfoxide [0844] EDTA ethylenediaminetetraacetic acid [0845] F bioavailability [0846] Hepes 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid [0847] IC inhibition concentration [0848] MEC minimum effective concentration [0849] NADH nicotinamide adenine dinucleotide phosphate [0850] PDE 5 phosphodiesterase 5 [0851] PEG polyethylene glycol [0852] Tris tris(hydroxymethyl)aminomethane

B-1. Vasorelaxant Effect In Vitro

[0853] The determination of the relaxant activity of the compounds of the invention on isolated vessels was carried out as described in JP Stasch et al., Br J Pharmacol. 2002; 135, 333-343. 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.

[0854] 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-2. Effect on a Recombinant Guanylate Cyclase Reporter Cell Line

[0855] The cellular activity of the compounds of the invention is determined using a recombinant guanylate cyclase reporter cell line, as described in F. Wunder et al., Anal. Biochem. 2005, 339, 104-112. Representative values (MEC=minimum effective concentration) for the compounds of the invention are shown in the table below (Table 1B; in some cases as means of individual determinations):

TABLE-US-00017 TABLE 1B Example no. MEC [μM] 1 0.065 2 0.03 3 0.03 4 0.2 5 0.3 6 0.2 7 3 8 2 9 0.3 10 0.3 11 0.1 12 0.065 13 0.1 14 0.03 15 0.2 16 0.17 17 0.03 18 0.3 19 10 20 1 21 3 22 2 23 6.5 24 0.1 25 0.3 26 0.3 27 0.1 28 0.03 29 0.3 30 1 31 0.1 32 1 33 0.1 34 1 35 10 36 3 37 0.1 38 0.01 39 0.3 40 0.03 41 0.065 42 0.3 43 0.3 44 0.3 45 0.3 46 0.03 47 0.03 48 0.1 49 0.1 50 0.1 51 0.1 52 0.01 53 0.01 54 0.03 55 3 56 3 57 1 58 1 59 1 60 0.3 61 0.1 62 0.1 63 0.1 64 1 65 1 66 0.3 67 0.3 68 0.1 69 0.1 70 0.3 71 0.3 72 1 73 0.3 74 0.1 75 0.3 76 1 77 1 78 0.3 79 0.1 80 1 81 0.1 82 0.1 83 0.1 84 0.1 85 0.1 86 0.1 87 0.3 88 0.3 89 0.3 90 0.1 91 0.3 92 0.3 93 0.1 94 0.3 95 1 96 0.03 97 0.3 98 1 99 0.3 100 0.3 101 0.3 102 0.3 103 0.3 104 0.1 105 1 106 0.3 107 0.3 108 0.3 109 0.3 110 1 111 0.01 112 0.03 113 0.1 114 0.3 115 0.1 116 1 117 0.1 118 0.1 119 0.3 120 0.1 121 0.3 122 0.1 123 0.1 124 1 125 0.3 126 0.3 127 0.1 128 1 129 0.1 130 0.3 131 0.3 132 0.3 133 1 134 0.3 135 1 136 1 137 0.3 138 1

B-3. Inhibition of Human Phosphodiesterase 5 (PDE 5)

[0856] PDE 5 preparations are obtained from human platelets by disruption (Microfluidizer®, 800 bar, 3 passes), followed by centrifugation (75 000 g, 60 min, 4° C.) and ion exchange chromatography of the supernatant on a Mono Q 10/10 column (linear sodium chloride gradient, elution with a 0.2-0.3M solution of sodium chloride in buffer (20 mM Hepes pH 7.2, 2 mM magnesium chloride). Fractions having PDE 5 activity are combined (PDE 5 preparation) and stored at −80° C.

[0857] To determine their in vitro action on human PDE 5, the test substances are dissolved in 100% DMSO and serially diluted. Typically, dilution series (1:3) from 200 μM to 0.091 μM are prepared (resulting final concentrations in the test: 4 μM to 0.0018 μM). In each case 2 μl of the diluted substance solutions are placed into the wells of microtitre plates (Isoplate-96/200W; Perkin Elmer). Subsequently, 50 μl of a dilution of the above-described PDE 5 preparation are added. The dilution of the PDE 5 preparation is chosen such that during the later incubation less than 70% of the substrate are converted (typical dilution: 1:100; dilution buffer: 50 mM tris/hydrochloric acid pH 7.5, 8.3 mM magnesium chloride, 1.7 mM EDTA, 0.2% BSA). The substrate, [8-.sup.3H] cyclic guanosine-3′,5′-monophosphate (1 μCi/μl; Perkin Elmer), is diluted 1:2000 with assay buffer (50 mM tris/hydrochloric acid pH 7.5, 8.3 mM magnesium chloride, 1.7 mM EDTA) to a concentration of 0.0005 μCi/μl. By addition of 50 μl (0.025 μCi) of the diluted substrate, the enzyme reaction is finally started. The test mixtures are incubated at room temperature for 60 min and the reaction is stopped by adding 25 μl of a suspension of 18 mg/ml yttrium scintillation proximity beads in water (phosphodiesterase beads for SPA assays, RPNQ 0150, Perkin Elmer). The microtitre plates are sealed with a film and left to stand at room temperature for 60 min. Subsequently, the plates are analysed for 30 s per well in a Microbeta scintillation counter (Perkin Elmer). IC.sub.50 values are determined using the graphic plot of the substance concentration against percentage PDE 5 inhibition. Representative IC.sub.50 values for the compounds of the invention are shown in the table below (Table 2B; in some cases as means of individual determinations):

TABLE-US-00018 TABLE 2B Example no. IC50 [nM] 1 20 2 13 3 100 4 110 5 86 6 140 7 130 8 81 9 58 10 110 11 91 12 130 13 600 14 130 15 1200 16 170 17 280 18 570 19 220 20 190 21 230 22 170 23 1300 24 3.5 25 2.0 26 930 27 51 28 5.2 29 12 30 310 31 10 32 12 33 110 34 77 35 1300 36 73 37 4 38 770 39 34 40 240 41 88 42 74 43 14 44 110 45 130 46 1000 47 730 48 1100 49 33 50 19 51 87 52 150 53 110 54 1200 55 190 56 120 57 100 58 86 59 91 60 15 61 16 62 18 63 11 64 74 65 6.8 66 87 67 2.6 68 13 69 10 70 24 71 170 72 46 73 52 74 26 76 60 77 87 78 9.3 79 30 80 23 81 15 82 8.6 83 13 84 23 85 38 86 44 87 24 88 46 89 9.0 90 14 91 68 92 35 93 55 94 16 95 48 96 62 97 8.2 98 33 99 31 100 4.3 103 10 104 11 105 620 107 73 108 25 109 39 111 710 112 93 113 44 114 15 115 41 117 25 118 21 119 10 120 220 121 27 122 20 123 26 125 30 126 6 127 16 128 330 129 10 130 28 131 38 132 33 133 30 134 13 136 42 137 42 138 21

B-4. Radiotelemetry Measurement of Blood Pressure in Conscious, Spontaneously Hypertensive Rats

[0858] A commercially available telemetry system from DATA SCIENCES INTERNATIONAL DSI, USA, is employed for the blood pressure measurement on conscious rats described below.

[0859] The system consists of 3 main components: [0860] implantable transmitters (Physiotel® telemetry transmitter) [0861] receivers (Physiotel® receiver) which are linked via a multiplexer (DSI Data Exchange Matrix) to a [0862] data acquisition computer.

[0863] 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

[0864] 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.

[0865] After transmitter implantation, the experimental animals are housed singly in type 3 μMakrolon cages. They have free access to standard feed and water.

[0866] 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

[0867] 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. The animals instrumented in this way can be used repeatedly after the wound has healed and the implant has settled.

[0868] For the implantation, the fasted animals are anesthetized 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 TM, 3M). The transmitter housing is fixed intraperitoneally to the abdominal wall muscle, and the wound is closed layer by layer.

[0869] An antibiotic (Tardomyocel COMP, Bayer, 1 ml/kg s.c.) is administered postoperatively for prophylaxis of infection.

Substances and Solutions

[0870] 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.

[0871] A solvent-treated group of animals is used as control.

Experimental Procedure

[0872] The telemetry measuring unit present is configured for 24 animals. Each experiment is recorded under an experiment number (Vyear month day).

[0873] Each of the instrumented rats living in the system is assigned a separate receiving antenna (1010 Receiver, DSI).

[0874] 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 TM 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.

[0875] In the standard procedure, the following are measured for 10-second periods in each case: [0876] systolic blood pressure (SBP) [0877] diastolic blood pressure (DBP) [0878] mean arterial pressure (MAP) [0879] heart rate (HR) [0880] activity (ACT).

[0881] The acquisition of measurements is repeated under computer control at 5-minute intervals. 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).

[0882] 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

[0883] After the end of the experiment, the acquired individual data are sorted using the analysis software (DATAQUEST TM A.R.T. TM 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.

[0884] 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.

REFERENCES

[0885] Klaus Witte, Kai Hu, Johanna Swiatek, Claudia Mtissig, Georg Ertl and Bjorn 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-5. Determination of Organ-Protective Effects in a Long-Term Experiment on Rats

[0886] The organ-protective effects of the compounds of the invention are shown in a therapeutically relevant “low nitric oxide (NO)/high renin” hypertension model in rats. The study was carried out analogously to the recently published article (Sharkovska Y, et al. J Hypertension 2010; 28: 1666-1675). This involves treating renin-transgenic rats (TGR(mRen2)27) to which the NO synthase inhibitor L-NAME had been administered via drinking water simultaneously with the compound according to the invention or vehicle over several weeks. Hemodynamic and renal parameters are determined during the treatment period. At the end of the long-term study, organ protection (kidney, lung, heart, aorta) is shown by histopathological studies, biomarkers, expression analyses and cardiovascular plasma parameters.

B-6. Measurements of the Pulmonary Artery Pressure (PAP) in Conscious Dogs Under Hypoxia Conditions

[0887] A telemetry system from DATA SCIENCES INTERNATIONAL DSI, USA, for example, is employed for the blood pressure measurement on conscious dogs described below. The system consists of implantable pressure transmitters, receiver and a data acquisition computer. The telemetry system makes it possible to continuously monitor blood pressures and heart rate of conscious animals. The telemetry transmitters used are surgically implanted under aseptic conditions in the experimental animals before the first experimental use. The animals instrumented in this way can be used repeatedly after the wound has healed and the implant has settled. The tests are carried out using adult male beagles. Technical details can be found in the documentation from the manufacturing company (DSI).

Substances and Solutions

[0888] The substances to be tested are each administered to a group of dogs (n=3-6), orally via a gelatine capsule or intravenously in suitable solvent mixtures. A vehicle-treated group of animals is employed as control.

Experimental Procedure

[0889] For the measurements under hypoxia conditions, the animals are transferred to a chamber with a hypoxic atmosphere (oxygen content about 10%). This is established using commercially available hypoxia generators (from Hoehenbalance, Cologne, Germany). In a standard experiment, for example, one hour and five hours after substance administration the dogs are transferred to the hypoxia chamber for 30 min. About 10 min before and after entering the hypoxia chamber, as well as during the stay in the hypoxia chamber, pressures and heart rate are measured by telemetry.

Evaluation

[0890] In healthy dogs, under hypoxia there is a rapid increase in PAP. By substance administration, this increase can be reduced. To quantify the PAP increase and the differences in heart rate and systemic blood pressure, the data before and during the hypoxia period, smoothed by determination of means, are compared. The courses of the measured parameters are presented graphically using the Prism software (GraphPad, USA).

B-7. Determination of Pharmacokinetic Parameters Following Intravenous and Oral Administration

[0891] The pharmacokinetic parameters of the compounds of the invention are determined in male CD-1 mice, male Wistar rats, female beagles and female cynomolgus monkeys. Intravenous administration in the case of mice and rats is effected by means of a species-specific plasma/DMSO formulation, and in the case of dogs and monkeys 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 experiexperiment 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.

[0892] 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 LCMS(/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 or high-resolution LC-MS experiments.

[0893] The plasma concentration/time plots determined are used to calculate the pharmacokinetic parameters such as AUC, C.sub.max, F (bioavailability), t.sub.1/2 (terminal half life), MRT (mean residence time) and CL (clearance), using a validated pharmacokinetic calculation program.

[0894] 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.

[0895] 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. Plasma is obtained by centrifugation at 1000 g. After measurement of the concentrations in plasma and blood (by LC-MS(/MS); see above), the C.sub.blood/C.sub.plasmama value is determined by quotient formation.

B-8. Metabolic Study

[0896] To determine the metabolic profile of the compounds of the invention, 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.

[0897] 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.

[0898] 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-9. Caco-2 Permeability Test

[0899] 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. “Correlation between oral drug absorption in humans and apparent drug permeability coefficients in human intestinal epithelial (Caco-2) cells” Biochem. Biophys. 1991, 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 15 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.appBA) 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.

C. Working Examples of Pharmaceutical Compositions

[0900] The compounds of the invention can be converted to pharmaceutical preparations as follows:

Tablet:

Composition:

[0901] 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.

[0902] Tablet weight 212 mg. Diameter 8 mm, radius of curvature 12 mm.

Production:

[0903] 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:

[0904] 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.

[0905] 10 ml of oral suspension correspond to a single dose of 100 mg of the compound of the invention.

Production:

[0906] 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:

[0907] 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:

[0908] 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:

[0909] 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 solution is subjected to sterile filtration and dispensed into sterile and pyrogen-free injection vessels.