Substituted 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-C]pyridines, their use as medicament, and pharmaceutical preparations comprising them

Abstract

The invention relates to substituted 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridines of formula (I), their use as medicament, and pharmaceutical preparations comprising them. The compounds of formula (I) act on the TASK-1 potassium channel. The compounds are particularly suitable for the treatment or prevention of atrial arrhythmias, for example atrial fibrillation (AF) or arterial flutter. ##STR00001##

Claims

1. A compound of the formula I ##STR00156## wherein A is a five- or six-membered heteroaryl comprising 1-3 heteroatoms selected from the group N, O and S, provided that the five- or six-membered heteroaryl is not pyrimidin-2-yl, the five- or six-membered heteroaryl being substituted with 1-3 groups selected independently from F, Cl, Br, CN, (C.sub.1-C.sub.6)-alkyl-, (C.sub.1-C.sub.6)-alkyl-O and (C.sub.1-C.sub.6)-alkyl-S, wherein one or more hydrogen atoms of the alkyl moieties are optionally replaced by fluorine; X is (C.sub.6-C.sub.10)-aryl or a five- or six-membered heteroaryl comprising 1-3 heteroatoms selected from the group N, O and S, wherein the aryl and heteroaryl are optionally substituted with 1-3 groups selected independently from F, Cl, Br, CN, (C.sub.1-C.sub.6)-alkyl-, (C.sub.1-C.sub.6)-alkyl-O, (C.sub.1-C.sub.6)-alkyl-S, (C.sub.1-C.sub.6)-alkyl-C(O) and (C.sub.1-C.sub.6)-alkyl-SO.sub.2, wherein one or more hydrogen atoms of the alkyl moieties are optionally replaced by fluorine; R1 is R5-C(O) or (C.sub.1-C.sub.6)-alkyl-SO.sub.2; R2 is H, (C.sub.1-C.sub.6)-alkyl- or (C.sub.3-C.sub.6)-cycloalkyl-; R3 is H or (C.sub.1-C.sub.4)-alkyl-; R4 is H or (C.sub.1-C.sub.4)-alkyl-; or R3 and R4 together form a (C.sub.2-C.sub.3)-alkylene bridge; R5 is H, (C.sub.1-C.sub.6)-alkyl-, (C.sub.3-C.sub.6)-cycloalkyl-, (C.sub.1-C.sub.6)-alkyl-O, (C.sub.1-C.sub.6)-alkyl-S, (C.sub.1 -C.sub.6)-alkyl-O(C.sub.1-C.sub.6)-alkyl-, HO(C.sub.1-C.sub.6)-alkyl-, (C.sub.3-C.sub.6)-cycloalkyl-(C.sub.1-C.sub.6)-alkyl-, (C.sub.6-C.sub.10)-aryl-, (C.sub.6-C.sub.10)-aryl-(C.sub.1-C.sub.6)-alkyl-, R7R6N, heteroaryl, heteroaryl-(C.sub.1-C.sub.6)-alkyl-or aliphatic heterocycle, wherein one or more hydrogen atoms of the alkyl moieties are optionally replaced by fluorine, and wherein the aliphatic heterocycle is selected from the group of morpholinyl, piperidinyl, pyrrolidinyl and four- to seven-membered aliphatic heterocycles comprising an oxygen atom, each optionally substituted with 1 to 3 substituents independently selected from F, OH, (C.sub.1-C.sub.6)-alkyl-O and (C.sub.1-C.sub.6)-alkyl-, and wherein the heteroaryl residues are five- or six-membered ring systems comprising 1-3 heteroatoms selected from the group N, O and S, and wherein the aryl and heteroaryl are optionally substituted with 1-3 groups selected independently from F, Cl, Br, CF.sub.3, (C.sub.1-C.sub.6)-alkyl-, (C.sub.1-C.sub.6)-alkyl-O, CN, (C.sub.1-C.sub.2)-alkyl-SO.sub.2; R6 is H, (C.sub.1-C.sub.6)-alkyl- or (C.sub.3-C.sub.6)-cycloalkyl-, wherein one hydrogen atom of the alkyl group is optionally replaced by hydroxy or (C.sub.1-C.sub.6)-alkyl-O, and wherein one or more hydrogen atoms of the alkyl group are optionally replaced by fluorine; and R7 is H or (C.sub.1-C.sub.6)-alkyl-, wherein one or more hydrogen atoms of the alkyl group are optionally replaced by fluorine; or a stereoisomer, stereoisomeric mixture or pharmaceutically acceptable salt thereof; with the proviso if R5 is methyl and R2, R3 and R4 are H and X is a phenyl residue, the residue A is not thiophen-2-yl.

2. The compound according to claim 1, wherein A is selected from the group consisting of thiophen-2-yl, thiophen-3-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrazin-2-yl, pyridazin-3-yl, pyridazin-4-yl, pyrazol-3-yl, pyrazol-4-yl, imidazol-2-yl, imidazol-4-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, pyrid-2-yl, pyrid-3-yl and pyrid-4-yl, each substituted with 1-3 groups selected independently from F, Cl, Br, CN, (C.sub.1-C.sub.6)-alkyl-, (C.sub.1-C.sub.6)-alkyl-O and (C.sub.1-C.sub.6)-alkyl-S, wherein one or more hydrogen atoms of the alkyl moieties are optionally replaced by fluorine.

3. The compound according to claim 1, wherein A is selected from the group consisting of thiophen-2-yl, thiophen-3-yl, pyrazol-3-yl, pyrazol-4-yl, imidazol-2-yl, imidazol-4-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, pyrid-2-yl, pyrid-3-yl and pyrid-4-yl, each substituted with 1-3 groups selected independently from F, Cl, Br, CN, (C.sub.1-C.sub.6)-alkyl-, (C.sub.1-C.sub.6)-alkyl-O and (C.sub.1-C.sub.6)-alkyl-S, wherein one or more hydrogen atoms of the alkyl moieties are optionally replaced by fluorine.

4. The compound according to claim 1, wherein A is selected from the group consisting of pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, thiophen-2-yl and thiophen-3-yl, each substituted with 1-3 groups selected independently from F, Cl, Br, CN, (C.sub.1-C.sub.6)-alkyl-, (C.sub.1-C.sub.6)-alkyl-O and (C.sub.1-C.sub.6)-alkyl-S, wherein one or more hydrogen atoms of the alkyl moieties are optionally replaced by fluorine; and X is a five- or six-membered heteroaryl comprising 1-3 heteroatoms selected from the group N, O and S, wherein the heteroaryl group is optionally substituted with 1-3 residues selected independently from F, Cl, Br, CN, (C.sub.1-C.sub.6)-alkyl-, (C.sub.1-C.sub.6)-alkyl-O, (C.sub.1-C.sub.6)-alkyl-S, (C.sub.1-C.sub.6)-alkyl-OC(O) and (C.sub.1-C.sub.6)-alkyl-SO.sub.2, wherein one or more hydrogen atoms of the alkyl moieties are optionally replaced by fluorine; or a stereoisomer, stereoisomeric mixture or pharmaceutically acceptable salt thereof.

5. A compound according to claim 1, wherein X is phenyl, thiophen-2-yl or thiophen-3-yl, each optionally substituted with 1-3 groups selected independently from F, Cl, Br, CN, (C.sub.1-C.sub.6)-alkyl-, (C.sub.1-C.sub.6)-alkyl-O, (C.sub.1-C.sub.6)-alkyl-S, (C.sub.1-C.sub.6)-alkyl-OC(O) and (C.sub.1-C.sub.6)-alkyl-SO.sub.2, wherein one or more hydrogen atoms of the alkyl moieties may be replaced by fluorine; or a stereoisomer, stereoisomeric mixture or pharmaceutically acceptable salt thereof.

6. A compound according to claim 5, wherein A is pyrid-2-yl, pyrid-3-yl or pyrid-4-yl, wherein the pyridyl residues are substituted with 1 or 2 residues selected independently from F, Cl, Br, CN, (C.sub.1-C.sub.4)-alkyl-, CF.sub.3, CF.sub.2H, CFH.sub.2, methoxy, ethoxy, OCF.sub.3, and (C.sub.1-C.sub.2)-alkyl-S; X is phenyl, thiophen-2-yl or thiophen-3-yl, wherein these residues are substituted with 1 or 2 residues selected independently from F, Cl, Br, CN, (C.sub.1-C.sub.4)-alkyl-, CF.sub.3, CF.sub.2H, CFH.sub.2, methoxy, ethoxy, OCF.sub.3, (C.sub.1-C.sub.2)-alkyl-S, (C.sub.1-C.sub.2)-alkyl-OC(O) and methyl-SO.sub.2; R1 is R5-C(O) or (C.sub.1-C.sub.2)-alkyl-SO.sub.2; R2 is H, methyl, ethyl, cyclopropyl; R3 and R4 is H; and R5 is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert.-butyl or R5 is cyclopropyl, cyclobutyl, cyclopentyl or (C.sub.3-C.sub.6)-cycloalkyl-(C.sub.1-C.sub.2)-alkyl-; or R5 is (C.sub.1-C.sub.2)-alkyl-O, (C.sub.1-C.sub.2)-alkyl-S, or OCF.sub.3, or R5 is (C.sub.1-C.sub.4)-alkyl-O-methyl-, HO(C.sub.1-C.sub.2)-alkyl-, or R5 is phenyl or phenylmethyl-, wherein the phenyl residues are optionally substituted with 1-3 groups selected independently from F, Cl, Br, CF.sub.3, (C.sub.1-C.sub.2)-alkyl-, (C.sub.1-C.sub.2)-alkyl-O, CN methyl-SO.sub.2; or R5 is R7R6N, wherein R6 is H, (C.sub.1-C.sub.4)-alkyl-, cyclopropyl, wherein one hydrogen atom of the alkyl group may be replaced by an OH, methoxy or ethoxy residue; and R7 is H, methyl-, ethyl; or R5 is heteroaryl, heteroaryl-(C.sub.1-C.sub.6)-alkyl-, wherein the heteroaryl residues are selected from the group consisting of pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, thiophen-2-yl, thiophen-3-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, pyrazol-3-yl, pyrazol-4-yl, imidazol-2-yl, imidazol-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyridazin-3-yl, pyridazin-4-yl, pyrazin-2-yl and payrazin-3-yl, and wherein the heteroaryl residues are optionally substituted with 1 or 2 groups selected independently from F, Cl, Br, CF.sub.3, (C.sub.1-C.sub.4)-alkyl-, (C.sub.1-C.sub.4)-alkyl-O, CN,(C.sub.1-C.sub.2)-alkyl-SO.sub.2; or R5 is morpholinyl, piperidinyl, pyrrolidinyl, oxetanyl and tetrahydrofuranyl, tetrahydropyranyl, each optionally substituted with 1 or 2 substituents independently selected from the group of F, OH, (C.sub.1-C.sub.2)-alkyl-O and (C.sub.1-C.sub.4)-alkyl-; or a stereoisomer, stereoisomeric mixture or pharmaceutically acceptable salt thereof.

7. The compound according to claim 1, wherein R5 is heteroaryl or heteroaryl-(C.sub.1-C.sub.6)-alkyl-, wherein the heteroaryl residues are five- or six-membered ring systems, comprising 1-3 heteroatoms selected from the group N, O and S, optionally substituted with 1-3 residues selected independently from F, Cl, Br, CF.sub.3, (C.sub.1-C.sub.6)-alkyl-, (C.sub.1-C.sub.6)-alkyl-O, CN and (C.sub.1-C.sub.2)-alkyl-SO.sub.2, wherein one or more hydrogen atoms of the alkyl moieties are optionally replaced by fluorine, or R5 is methyl, with the proviso if R2, R3 and R4 are hydrogen and X is a 2,4-difluorophenyl residue A is not pyridin-3-yl, and with the proviso if R2, R3 and R4 are hydrogen and X is phenyl A is not thiophen-2-yl, and or R5 is H, (C.sub.2-C.sub.6)-alkyl, CF.sub.3, CF.sub.2H or CFH.sub.2, wherein one or more hydrogen atoms of the alkyl residue are optionally replaced by fluorine; or R5 is (C.sub.3-C.sub.6)-cycloalkyl or (C.sub.3-C.sub.6)-cycloalkyl-(C.sub.1-C.sub.4)-alkyl-, or R5 is (C.sub.1-C.sub.4)-alkyl-O, or (C.sub.1-C.sub.4)-alkyl-S, wherein one or more hydrogen atoms of the alkyl moieties are optionally replaced by fluorine; or R5 is (C.sub.1-C.sub.4)-alkyl-O(C.sub.1-C.sub.2)-alkyl- or HO(C.sub.1-C.sub.4)-alkyl-; or R5 is phenyl or phenyl-(C.sub.1-C.sub.4)-alkyl-, wherein the phenyl residue is optionally substituted with 1-3 residues selected independently from F, Cl, Br, CF.sub.3, (C.sub.1-C.sub.6)-alkyl-, (C.sub.1-C.sub.6)-alkyl-O, CN and (C.sub.1-C.sub.2)-alkyl-SO.sub.2, and wherein one or more hydrogen atoms of the alkyl moieties are optionally replaced by fluorine, or R5 is R7R6N, wherein R6 is H, (C.sub.1-C.sub.4)-alkyl- or cyclopropyl-, wherein one hydrogen atom of the alkyl group is optionally replaced by hydroxy, methoxy or ethoxy, and R7 is H or (C.sub.1-C.sub.2)-alkyl-; or R5 is selected from the group of oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, piperidinyl, pyrrolidinyl, each optionally substituted with 1 or 2 substituents selected from the group of F, OH, (C.sub.1-C.sub.4)-alkyl-O and (C.sub.1-C.sub.4)-alkyl-, and wherein one or more hydrogen atoms of the alkyl groups are optionally replaced by fluorine, or a stereoisomer, stereoisomeric mixture or pharmaceutically acceptable salt thereof.

8. The compound according to claim 7, wherein A is pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, thiophen-2-yl or thiophen-3-yl, substituted with 1 or 2 residues selected independently from F, Cl, Br, CN, (C.sub.1-C.sub.4)-alkyl-, CF.sub.3, CF.sub.2H, CFH.sub.2, methoxy, ethoxy, OCF.sub.3 and (C.sub.1-C.sub.2)-alkyl-S; X is phenyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, thiophen-2-yl, thiophen-3-yl, thiazol2-yl, thiazol-4-yl or thiazol-5-yl, each optionally substituted with 1 or 2 residues selected independently from F, Cl, Br, CN, (C.sub.1-C.sub.4)-alkyl-, CF.sub.3, CF.sub.2H, CFH.sub.2, methoxy, ethoxy, OCF.sub.3, (C.sub.1-C.sub.2)-alkyl-S, (C.sub.1-C.sub.2)-alkyl-OC(O) and methyl-SO.sub.2; R1 is R5-C(O) or (C.sub.1-C.sub.2)-alkyl-SO.sub.2; R2 is H, (C.sub.1-C.sub.2)-alkyl- or cyclopropyl-; R3 is H or (C.sub.1-C.sub.2)-alkyl-; R4 is H or (C.sub.1-C.sub.2)-alkyl-; or R3 and R4 together form an ethylene bridge; R5 is heteroaryl or heteroaryl-(C.sub.1-C.sub.6)-alkyl-, wherein the heteroaryl residues are selected from the group consisting of pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, thiophen-2-yl, thiophen-3-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, pyrazol-3-yl, pyrazol-4-yl, imidazol-2-yl, imidazol-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyridazin-3-yl, pyridazin-4-yl, pyrazin-2-yl and payrazin-3-yl, each optionally substituted with 1 or 2 residues selected independently from F, Cl, Br, CF.sub.3, methyl, ethyl, methoxy, ethoxy, CN and methyl-SO.sub.2, or R5 is methyl, with the proviso if in compounds of formula I R2, R3 and R4 are hydrogen and X is a 2,4-difluorophenyl residue A is not pyridin-3-yl, and with the proviso if in compounds of formula I R2, R3 and R4 are hydrogen and X is phenyl A is not thiophen-2-yl, and or R5 is H or (C.sub.2-C.sub.4)-alkyl, CF.sub.3; or R5 to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or (C.sub.3-C.sub.6)-cycloalkyl-(C.sub.1-C.sub.2)-alkyl-, or R5 is (C.sub.1-C.sub.2)-alkyl-O or (C.sub.1-C.sub.2)-alkyl-S, wherein one or more hydrogen atoms of the alkyl moieties are optionally replaced by fluorine; or R5 is (C.sub.1-C.sub.4)-alkyl-O-methyl- or HO(C.sub.1-C.sub.2)-alkyl-, wherein one or more hydrogen atoms of the alkyl moieties are optionally replaced by fluorine; or R5 is phenyl or phenyl-(C.sub.1-C.sub.2)-alkyl-, wherein the phenyl residues are optionally substituted with 1-3 residues selected independently from F, Cl, Br, CF.sub.3, (C.sub.1-C.sub.2)-alkyl-, (C.sub.1-C.sub.2)-alkyl-, CN and methyl-SO.sub.2, and wherein one or more hydrogen atoms of the alkyl moieties are optionally replaced by fluorine, or R5 is R7R6N, wherein R6 is H, (C.sub.1-C.sub.4)-alkyl-, cyclopropyl-, wherein one hydrogen atom of the alkyl group is optionally replaced by hydroxy, methoxy or ethoxy, and R7 is H, methyl- or ethyl-; or R5 is selected from the group of oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, piperidinyl, pyrrolidinyl, each optionally substituted with 1 or 2 substituents selected from the group of F, OH, (C.sub.1-C.sub.2)-alkyl-O and (C.sub.1-C.sub.4)-alkyl-, wherein one or more hydrogen atoms of the alkyl groups are optionally replaced by fluorine; or a stereoisomer, stereoisomeric mixture or pharmaceutically acceptable salt thereof.

9. The compound according to claim 1 selected from the group consisting of: 2-[5-Acetyl-1-(2,4-difluoro-benzyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-isonicotinonitrile; 6-[5-Acetyl-1-(2,4-difluoro-benzyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-pyridine-2-carbonitrile; 1-[1-(2,4-Difluoro-benzyl)-3-(3-methyl-pyridin-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone; 1-[1-(2,4-Difluoro-benzyl)-3-(4-methoxy-pyridin-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone; 1-[3-(5-Chloro-thiophen-2-yl)-1-(2,4-difluoro-benzyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone; 1-[1-(4-Fluoro-benzyl)-3-(6-trifluoromethyl-pyridin-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone; 1-[1-(2,4-Difluoro-benzyl)-3-(4-trifluoromethyl-pyridin-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone; 1-[1-(2,4-Difluoro-benzyl)-3-(6-trifluoromethyl-pyridin-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone; 1-[3-(4-Bromo-pyridin-2-yl)-1-(2,4-difluoro-benzyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone; 1-[3-(2-Bromo-pyridin-4-yl)-1-(2,4-difluoro-benzyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone; 1-[3-(5-Bromo-pyridin-3-yl)-1-(2,4-difluoro-benzyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone; 1-[1-[1-(4-Fluoro-phenyl)-ethyl]-3-(6-trifluoromethyl-pyridin-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone; 1-[1-(2,4-Difluoro-benzyl)-3-(6-methyl-pyridin-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone; 1-[3-(6-Bromo-pyridin-2-yl)-1-(2,4-difluoro-benzyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone; 1-[1-(2,4-Difluoro-benzyl)-3-(4-methyl-pyridin-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone; 1-[1-(2,4-Difluoro-benzyl)-3-(6-methoxy-pyridin-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone; 1-[3-(6-Chloro-5-methoxy-pyridin-2-yl)-1-(2,4- difluoro-benzyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone; or a stereoisomer, stereoisomeric mixture or pharmaceutically acceptable salt thereof.

10. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof.

11. A pharmaceutical composition comprising a compound of claim 7 or a pharmaceutically acceptable salt thereof.

Description

EXAMPLES

(1) The following examples illustrate the various embodiments of the present invention and are part of the present invention.

1-(4-Morpholin-4-yl-3,6-dihydro-2H-pyridin-1-yl)-ethanone (1)

(2) ##STR00015##

(3) According to Scheme 1, step 1: a mixture of morpholine (67.85 g, 0.779 mol). 1-acetyl-4-piperidone (99:95 g, 0.708 mol) and para-toluenesulfonic acid (0.366 g, 2.1 mmol) in toluene (300 ml) was heated in a Dean-Stark trap apparatus for 16 h at reflux. Solvents were evaporated in vacuo to give 149 g of 1-(4-Morpholin-4-yl-3,6-dihydro-2H-pyridin-1-yl)-ethanone (1) which was used in the next step without any further purification.

3-(5-Acetyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-benzonitrile (3a)

(4) ##STR00016##

(5) According to Scheme 1, method A: steps 2-3: to a solution of 1-(4-Morpholin-4-yl-3,6-dihydro-2H-pyridine-1-yl)-ethanone (1) (6.35 g, 30.2 mmol) in dry dichloromethane (30 ml) at 0 C. was added triethylamine (3.056 g, 30.2 mmol) and after stirring the solution at 0 C. for 10 min, 3-cyanobenzoyl chloride (5 g, 30.2 mmol) was added. The mixture was stirred for 45 min at 0 C. then the mixture was allowed to warm to room temperature and stirred overnight 5% aqueous HCl was added and the mixture was stirred for 2 h. The mixture was extracted with dichloromethane and the organic layer was washed with water, filtered over a short pad of silica gel and evaporated to dryness to give 8 g of 3-(1-Acetyl-4-oxo-piperidine-3-carbonyl)-benzonitrile (2a) which was used immediately in the next step without purification.

(6) To a mixture of 3-(1-Acetyl-4-oxo-piperidine-3-carbonyl)-benzonitrile (2a) (8 g, 29.6 mmol) in ethanol (26 ml) at 10 C. hydrazine hydrate (4.44 g, 88.8 mmol) was added slowly within 5 min. The mixture was stirred 3 h and allowed to warm to room temperature overnight. The mixture was concentrated to of its volume until a precipitate formed. The suspension was stirred for 2 h, cooled down and filtrated. The solid was washed with a small amount of ethanol. A second portion of product precipitated overnight from the filtrate and was pooled with the first portion of solid to give 4.02 g of 3-(5-Acetyl-4,5,6,7--tetrahydro-1H-pyrazolo[4,3-c]-pyridin-3-yl)-benzonitrile (3a) as a solid. R.sub.t=1.20 mm (LC-method 7). Detected mess: 267.15 [M+H.sup.+]

1-[3-(4-Trifluoromethylpyridin-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone (3m)

(7) ##STR00017##

(8) According to Scheme 1, method B: to a solution of 4-(trifluoromethyl)-2-pyridinecarboxylic acid (0.42 g, 1.54 mmol) in dry tetrahydrofuran was added N-methylmorpholine (163 mgt 1.62 mmol) and isobutylchloroformate (221 mg, 1.62 mmol) and the mixture was stirred for 30 min at room temperature and the solid was filtered off. The filtrate was used in the subsequent reaction. To a solution of 1-acetyl-4-piperidone (0.207 g, 1.466 mmol) in tetrahydrofuran at 0 C. was added dropwise 1M lithium bis(trimethyldisilazide) in tetrahydrofuran (1.54 mmol, 1.54 ml) and the mixture was stirred for 15 min at 0 C., then the mixture was cooled down to 78 C. The mixed anhydride solution generated above was added to this mixture at 78 C., the mixture was allowed to warm to room temperature and stirred for 90 min. To this mixture at 10 C. was added ethanol (5 ml) and hydrazine hydrate (0.603 g, 7.72 mmol) and the mixture was stirred 16 h at room temperature. The mixture was concentrated and after addition of CH.sub.2Cl.sub.2 and aqueous NaHCO.sub.3 the mixture was extracted 3 times with CH.sub.2Cl.sub.2, the combined organic layers were washed with brine, dried over NaCl, filtrated and the filtrate was evaporated to dryness to give 323 mg of 1-[3-(4-Trifluoromethyl-pyridin-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone (3m). The product was used crude in the next reaction steps without further purification. R.sub.t=1.61 min (LC-method 1), Detected mass: 311.18 [M+H.sup.+]

(9) The examples in the following table were obtained according to Scheme 1, Method A or Method B as specified, from the specified starting compound (SC) (by following a similar procedure as used for the synthesis of (3a); in part the compounds were purified by reverse phase HPLC (CH.sub.3CN/water gradient with 0.1% trifluoroacetic acid).

(10) TABLE-US-00001 Comp. R.sub.t/[min] No. Starting (LC-Meth.) (Meth.) Comp. Product Chemical Name [M + H.sup.+] 3b (A) 4-fluoro-benzoyl chloride 1-[3-(4-Fluoro- phenyl)-1,4,6,7- tetrahydro- pyrazolo[4,3- c]pyridin-5-yl]- ethanone 2.32 (8) 260.12 3c (A) 6-(trifluoro- methyl)- pyridine-2- carbonyl chloride 1-[3-(6-Trifluoro- methyl-pyridin-2- yl)-1,4,6,7- tetrahydro- pyrazolo[4,3- c]pyridin-5-yl]- ethanone 1.10 (4) 311.2 3d (A) 3- Trifluoromethyl- benzoyl chloride 0 1-[3-(3-Trifluoro- methyl-phenyl)- 1,4,6,7- tetrahydro- pyrazolo[4,3- c]pyridin-5-yl]- ethanone 1.12 (4) 310.11 3e (A) 3- Trifluoromethxy- benzoyl chloride 1-[3-(3- Trifluoromethoxy- phenyl)-1,4,6,7- tetrahydro- pyrazolo[4,3- c]pyridin-5-yl]- ethanone 3.60 (2) 326.16 3f (A) 3-chloro-benzoyl chloride 1-[3-(3-Chloro- phenyl)-1,4,6,7- tetrahydro- pyrazolo[4,3- c]pyridin-5-yl]- ethanone 0.94 (4) 275.08 3g (A) 2-Fluoro-5- methoxy-benzoyl chloride 1-[3-(2-Fluoro-5- methoxy-phenyl)- 1,4,6,7- tetrahydro- pyrazolo[4,3- c]pyridin-5-yl]- ethanone 2.97 (2) 290.15 3h (A) 3-methoxy- benzoyl chloride 1-[3-(3-Methoxy- phenyl)-1,4,6,7- tetrahydro- pyrazolo[4,3- c]pyridin-5-yl]- ethanone 0.99 (4) 272.5 3i (A) 4-Fluoro-3- methoxy-benzoyl chloride 1-[3-(4-Fluoro-3- methoxy-phenyl)- 1,4,6,7- tetrahydro- pyrazolo[4,3- c]pyridin-5-yl]- ethanone 1.02 (4) 290.2 3j (A) 4-Fluoro-3- cyano-benzoyl chloride 5-(5-Acetyl- 4,5,6,7- tetrahydro-1H- pyrazolo[4,3- c]pyridin-3-yl)- 2-fluoro- benzonitrile 1.01 (4) 285.1 3k (A) 3-Fluoro-benzoyl chloride 1-[3-(3-Fluoro- phenyl)-1,4,6,7- tetrahydro- pyrazolo[4,3- c]pyridin-5-yl]- ethanone 1.47 (9) 260.16 3l (A) 4- Trifluoromethyl- benzoyl chloride 1-[3-(4- Trifluoromethyl- phenyl)-1,4,6,7- tetrahydro- pyrazolo[4,3- c]pyridin-5-yl]- ethanone 1.00 (4) 309.9 3n (B) 4-Bromo- pyridine-2- carbonyl chloride 1-[3-(4-Bromo- pyridin-2-yl)- 1,4,6,7- tetrahydro- pyrazolo[4,3- c]pyridin-5-yl]- ethanone 0.91 (1) 321.09 3o (B) 2-Bromo-iso- nicotinoyl chloride 0 1-[3-(2-Bromo- pyridin-4-yl)- 1,4,6,7- tetrahydro- pyrazolo[4,3- c]pyridin-5-yl]- ethanone 0.81 (1) 321.06 3p (B) 5-Bromo- nicotinoyl chloride 1-[3-(5-Bromo- pyridin-3-yl)- 1,4,6,7- tetrahydro- pyrazolo[4,3- c]pyridin-5-yl]- ethanone 0.96 (4) 321.12 3q (A) 3-Methyl- benzoyl chloride 1-(3-m-Tolyl- 1,4,6,7- tetrahydro- pyrazolo[4,3- c]pyridin-5-yl)- ethanone 0.92 (1) 256.18 3r (B) 6-Methyl- pyridine-2- carbonyl chloride 1-[3-(6-Methyl- pyridin-2-yl)- 1,4,6,7- tetrahydro- pyrazolo[4,3- c]pyridin-5-yl]- ethanone 0.74 (1) 257.11 3s (A) 6-Bromo- pyridine-2- carbonyl chloride 1-[3-(6-Bromo- pyridin-2-yl)- 1,4,6,7- tetrahydro- pyrazolo[4,3- c]pyridin-5-yl]- ethanone 1.06 (4) 321.1 3t (B) 4-Methyl- pyridine-2- carbonyl chloride 1-[3-(4-Methyl- pyridin-2-yl)- 1,4,6,7- tetrahydro- pyrazolo[4,3- c]pyridin-5-yl]- ethanone nd (nd) nd 3u (A) 6-Methoxy- pyridine-2- carbonyl chloride 1-[3-(6-Methoxy- pyridin-2-yl)- 1,4,6,7- tetrahydro- pyrazolo[4,3- c]pyridin-5-yl]- ethanone 0.9 (1) 273.15 3v (A) 6-Chloro-5- methoxy- pyridine-2- carbonyl chloride 1-[3-(6-Chloro-5- methoxy-pyridin- 2-yl)-1,4,6,7- tetrahydro- pyrazolo[4,3- c]pyridin-5-yl]- ethanone 1.02 (4) 307.1 3w (B) 3-Methyl- pyridine-2- carbonyl chloride 1-[3-(3-Methyl- pyridin-2-yl)- 1,4,6,7- tetrahydro- pyrazolo[4,3- c]pyridin-5-yl]- ethanone nd (nd) nd 3x (A) 4-Methoxy- pyridine-2- carbonyl chloride 1-[3-(4-Methoxy- pyridin-2-yl)- 1,4,6,7- tetrahydro- pyrazolo[4,3- c]pyridin-5- yl]- ethanone 0.55 (1) 273.16 3y (A) Thiophene-2- carbonyl chloride 0 1-(3-Thiophen-2- yl-1,4,6,7- tetrahydro- pyrazolo[4,3- c]pyridin-5-yl)- ethanone 0.94 (4) 248.08 3z (A) 5-Chloro- thiophene-2- carbonyl chloride 1-[3-(5-Chloro- thiophen-2-yl)- 1,4,6,7- tetrahydro- pyrazolo[4,3- c]pyridin-5-yl]- ethanone 1.07 (4) 282.02 3aa (A) Thiophene-3- carbonyl chloride 1-(3-Thiophen-3- yl-1,4,6,7- tetrahydro- pyrazolo[4,3- c]pyridin-5-yl)- ethanone 0.93 (4) 248.05

8-Acetyl-8-aza-bicyclo[3.2.1]octan-3-one (4a)

(11) ##STR00043##

(12) According to Scheme 2, Step 1:

(13) A suspension of nortropinone hydrochloride (1 g, 6.187 mmol) in acetic anhydride was stirred at 70 C. for 3 h. Water was added, the mixture was boiled for 30 min and cooled down to room temperature. CH.sub.2Cl.sub.2 and 1N aqueous NaOH was added until pH 9 was reached. The mixture was extracted 2 times with CH.sub.2Cl.sub.2, the combined organic layers were dried over Na.sub.2SO.sub.4, filtrated and the solution was evaporated to dryness to give 0.7 g of 8-Acetyl-8-aza-bicyolo[3.2.1]octan-3-one (4a). R.sub.t=1.76 min (LC-method 2). Defected mass: 168.24 [M+H.sup.+]

1-(3-Phenyl-4,5,11-triaza-tricyclo[6.2.1.1.0*2,6*]undeca-2(6),3-dien-11-yl)-ethanone (5a)

(14) ##STR00044##

(15) According to Scheme 2, Steps 2+3:

(16) To a mixture of 8-Acetyl-8-aza-bicyclo[3.2.1]octan-3-one (4a) (350 mg, 2.1 mmol) in dry tetrahydrofuran at 0 C. was added 1N lithium hexamethyldisilazide (2.2 ml, 2.2 mmol) and after 5 min the mixture was cooled to 78 C.

(17) To a solution of 3-cyanobenzoic acid (323 mg, 2.2 mmol) and N-methyl-morpholine (232 mg, 2.3 mmol) in tetrahydrofuran was added isobutylchloroformate (300 mg, 2.2 mmol). The mixture was stirred for 5 min at 25 C., filtrated and washed with dry tetrahydrofuran. This solution was added dropwise to the 78 C. mixture above and the mixture was then allowed to warm to 25 C. for 1 h. Solvents were evaporated, CH.sub.2Cl.sub.2 and water were added, the organic layer was dried over Na.sub.2SO.sub.4, filtrated and the solution was evaporated to dryness, redissolved in ethanol (10 ml). Hydrazine hydrate (245 mg, 3.14 mmol) was added and the solution was stirred for 30 min. Solvents were evaporated and the crude product was purified by silica gel chromatography (dichloromethane/methanol 100/0 to 70/30) to give 45 mg of 1-(3-Phenyl-4,5,11-triaza-tricyclo[6.2.1.0*2,6*]undeca-2(6),3-dien-11-yl)-ethanone (5a). R.sub.t=1.01 min (LC-method 4). Detected mass: 293.18 [M+H.sup.+]

1-[3-(4-Fluoro-phenyl)-4,5,11-triaza-tricyclo[6.2.1.0*2,6*]undeca-2(6),3-dien-11-yl]-ethanone (5b)

(18) ##STR00045## 1-[3-(4-Fluoro-phenyl)-4,5,11-triaza-tricyclo[6.2.1.0*2,6*]undeca-2(6),3-dien-11-yl]-ethanone (5b) was obtained by following a similar reaction as used for synthesis of (5a). R.sub.t=1.06 min (LC-method 4). Detected mass: 286.18 [M+M.sup.+]

3-[5-Acetyl-1-(2,4-difluoro-benzyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile (6a)

(19) ##STR00046##

(20) According to Scheme 3:

(21) A mixture of 3-(6-Acetyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-benzonitrile (3a) (0.48 g, 1.8 mmol), 2,4-difluorobenzyl bromide (0.41 g, 1.99 mmol) and K.sub.2CO.sub.3 (498 mg, 3.6 mmol) in 14 ml CH.sub.3CN was stirred at 80 C. for 16 h. A second portion of 2,4-difluorobenzyl bromide (0.41 g, 1.99 mmol) was added and the mixture was stirred for additional 7 h. Wafer was added, the mixture was extracted 3 times with ethyl acetate, the combined organic layers were dried over MgSO.sub.4, filtrated and the solution was evaporated to dryness. The crude product was crystallized from 10 ml 2-propanol and dried in vacuole give 0.364 g of 3-[5-Acetyl-1-(2,4-difluoro-benzyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile (6a). R.sub.t=1.62 min (LC method 7). Detected mass: 393.15 [M+H.sup.+].

(22) The examples in the following table were obtained according to Scheme 4 by following a similar reaction as used for synthesis of (6a). The corresponding halogenides used (Hal-CH.sub.2X; particularly the corresponding bromides or chlorides) are obvious to the man skilled in the art and were commercially available. Reaction conditions varied slightly by reaction time (1-3 days), temperature (50-80 C.). Products were routinely purified by reverse phase HPLC (CH.sub.3CN/water gradient with 0.1% trifluoroacetic acid).

(23) TABLE-US-00002 R.sub.t/[min] Comp. (LC-Method) No. SC Product Chemical Name [M + H.sup.+] 6b 3d 1-[1-(6-Chloro-pyridin-3- ylmethyl)-3-(3- trifluoromethyl-phenyl)- 1,4,6,7-tetrahydro- pyrazolo[4,3-c]pyridin-5- yl]-ethanone 1.26 (4) 435.09 6c 3d 1-[1-(4-Chloro-pyridin-3- ylmethyl)-3-(3- trifluoromethyl-phenyl)- 1,4,6,7-tetrahydro- pyrazolo[4,3-c]pyridin-5- yl]-ethanone 1.22 (4) 435.09 6d 3d 1-[1-(3-Methyl-pyridin-2- ylmethyl)-3-(3- trifluoromethyl-phenyl)- 1,4,6,7-tetrahydro- pyrazolo[4,3-c]pyridin-5- yl]-ethanone 3.97 (2) 415.28 6e 3b 0 1-[1-Benzyl-3-(4-fluoro- phenyl)-1,4,6,7-tetrahydro- pyrazolo[4,3-c]pyridin-5- yl]-ethanone 2.29 (15) 350.16 6f 3b 1-[1-(2,4-Difluoro-benzyl)- 3-(4-fluoro-phenyl)- 1,4,6,7-tetrahydro- pyrazolo[4,3-c]pyridin-5- yl]-ethanone 2.35 (12) 386.02 6g 3c 1-[1-(4-Fluoro-benzyl)-3- (6-trifluoromethyl-pyridin- 2-yl)-1,4,6,7-tetrahydro- pyrazolo[4,3-c]pyridin-5- yl]-ethanone 1.31 (4) 419.17 6h 3m 1-[1-(2,4-Difluoro-benzyl)- 3-(4-trifluoromethyl- pyridin-2-yl)-1,4,6,7- tetrahydro-pyrazolo[4,3- c]pyridin-5-yl]-ethanone 2.02 (9) 437.23 6i 3c 1-[1-(2,4-Difluoro-benzyl)- 3-(6-trifluoromethyl- pyridin-2-yl)-1,4,6,7- tetrahydro-pyrazolo[4,3- c]pyridin-5-yl]-ethanone 1.3 (4) 437.15 6j 3n 1-[3-(4-Bromo-pyridin-2- yl)-1-(2,4-difluoro-benzyl)- 1,4,6,7-tetrahydro- pyrazolo[4,3-c]pyridin-5- yl]-ethanone 1.2 (1) 447.1 6k 3o 1-[3-(2-Bromo-pyridin-4- yl)-1-(2,4-difluoro-benzyl)- 1,4,6,7-tetrahydro- pyrazolo[4,3-c]pyridin-5- yl]-ethanone 1.12 (1) 447.14 6m 3p 1-[3-(5-Bromo-pyridin-3- yl)-1-(2,4-difluoro-benzyl)- 1,4,6,7-tetrahydro- pyrazolo[4,3-c]pyridin-5- yl]-ethanone 1.24 (4) 447.2 6n 5a 3-[11-Acetyl-5-(2,4- difluoro-benzyl)-4,5,11- triaza- tricyclo[6.2.1.02,6]undeca- 2(6),3-dien-3-yl]- benzonitrile 1.25 (4) 419.21 6o 5b 1-[5-(2,4-Difluoro-benzyl)- 3-(4-fluoro-phenyl)-4,5,11- triaza- tricyclo[6.2.1.02,6]undeca- 2(6),3-dien-11-yl]-ethanone 1.26 (4) 412.17 6p 3q 0 1-[1-(6-Chloro-pyridin-3- ylmethyl)-3-m-tolyl- 1,4,6,7-tetrahydro- pyrazolo[4,3-c]pyridin-5- yl]-ethanone 1.2 (4) 381.12 6q 3d 1-[1-(4-Methoxy-pyridin-2- ylmethyl)-3-(3- trifluoromethyl-phenyl)- 1,4,6,7-tetrahydro- pyrazolo[4,3-c]pyridin-5- yl]-ethanone 3.25 (2) 431.3 6r 3q 1-[1-(4-Chloro-pyridin-3- ylmethyl)-3-m-tolyl- 1,4,6,7-tetrahydro- pyrazolo[4,3-c]pyridin-5- yl]-ethanone 1.16 (4) 381.11 6s 3d 1-[1-(3-Methoxy-pyridin-2- ylmethyl)-3-(3- trifluoromethyl-phenyl)- 1,4,6,7-tetrahydro- pyrazolo[4,3-c]pyridin-5- yl]-ethanone 4.04 (2) 431.3 6t 3f 1-[3-(3-Chloro-phenyl)-1- (3-methyl-pyridin-2- ylmethyl)-1,4,6,7- tetrahydro-pyrazolo[4,3- c]pyridin-5-yl]-ethanone 1.1 (1) 381.12 6u 3c 1-[1-[1-(4-Fluoro-phenyl)- ethyl]-3-(6-trifluoromethyl- pyridin-2-yl)-1,4,6,7- tetrahydro-pyrazolo[4,3- c]pyridin-5-yl]-ethanone 1.35 (4) 433.14 6v 3r 1-[1-(2,4-Difluoro-benzyl)- 3-(6-methyl-pyridin-2-yl)- 1,4,6,7-tetrahydro- pyrazolo[4,3-c]pyridin-5- yl]-ethanone 3.15 (2) 383.23 6w 3s 1-[3-(6-Bromo-pyridin-2- yl)-1-(2,4-difluoro-benzyl)- 1,4,6,7-tetrahydro- pyrazolo[4,3-c]pyridin-5- yl]-ethanone 3.3 (4) 447.17 6x 3t 1-[1-(2,4-Difluoro-benzyl)- 3-(4-methyl-pyridin-2-yl)- 1,4,6,7-tetrahydro- pyrazolo[4,3-c]pyridin-5- yl]-ethanone 0.97 (1) 383.2 6y 3u 1-[1-(2,4-Difluoro-benzyl)- 3-(6-methoxy-pyridin-2- yl)-1,4,6,7-tetrahydro- pyrazolo[4,3-c]pyridin-5- yl]-ethanone 1.15 (1) 399.19 6z 3v 0 1-[3-(6-Chloro-5-methoxy- pyridin-2-yl)-1-(2,4- difluoro-benzyl)-1,4,6,7- tetrahydro-pyrazolo[4,3- c]pyridin-5-yl]-ethanone 1.25 (4) 433.11 6ab 3w 1-[1-(2,4-Difluoro-benzyl)- 3-(3-methyl-pyridin-2-yl)- 1,4,6,7-tetrahydro- pyrazolo[4,3-c]pyridin-5- yl]-ethanone 1.14 (4) 383.1 6ac 3x 1-[1-(2,4-Difluoro-benzyl)- 3-(4-methoxy-pyridin-2- yl)-1,4,6,7-tetrahydro- pyrazolo[4,3-c]pyridin-5- yl]-ethanone 2.75 (2) 399.26 6ad 3d 1-[1-(2-Methyl-thiazol-4- ylmethyl)-3-(3- trifluoromethyl-phenyl)- 1,4,6,7-tetrahydro- pyrazolo[4,3-c]pyridin-5- yl]-ethanone 1.23 (4) 421.12 6ae 3d 1-[1-Thiazol-2-ylmethyl-3- (3-trifluoromethyl-phenyl)- 1,4,6,7-tetrahydro- pyrazolo[4,3-c]pyridin-5- yl]-ethanone 1.2 (4) 407.07 6af 3y 1-[1-(2,4-Difluoro-benzyl)- 3-thiophen-2-yl-1,4,6,7- tetrahydro-pyrazolo[4,3- c]pyridin-5-yl]-ethanone 1.22 (4) 374.07 6ag 3q 1-[1-(5-Chloro-thiophen-2- ylmethyl)-3-m-tolyl- 1,4,6,7-tetrahydro- pyrazolo[4,3-c]pyridin-5- yl]-ethanone 1.3 (4) 386.08 6ah 3d 1-[1-(5-Chloro-thiophen-2- ylmethyl)-3-(3- trifluoromethyl-phenyl)- 1,4,6,7-tetrahydro- pyrazolo[4,3-c]pyridin-5- yl]-ethanone 1.35 (4) 440.07 6ai 3a 3-[5-Acetyl-1-(5-chloro- thiophen-2-ylmethyl)- 4,5,6,7-tetrahydro-1H- pyrazolo[4,3-c]pyridin-3- yl]-benzonitrile 1.17 (1) 397.03 6aj 3f 1-[3-(3-Chloro-phenyl)-1- (5-chloro-thiophen-2- ylmethyl)-1,4,6,7- tetrahydro-pyrazolo[4,3- c]pyridin-5-yl]-ethanone 1.25 (1) 406.02 6ak 3z 0 1-[3-(5-Chloro-thiophen-2- yl)-1-(2,4-difluoro-benzyl)- 1,4,6,7-tetrahydro- pyrazolo[4,3-c]pyridin-5- yl]-ethanone 1.31 (4) 408.01 6al 3aa 1-[1-(2,4-Difluoro-benzyl)- 3-thiophen-3-yl-1,4,6,7- tetrahydro-pyrazolo[4,3- c]pyridin-5-yl]-ethanone 1.21 (4) 374.06 6am 3d 4-[5-Acetyl-3-(3- trifluoromethyl-phenyl)- 4,5,6,7-tetrahydro- pyrazolo[4,3-c]pyridin-1- ylmethyl]-benzonitrile 4.52 (2) 425.29 6an 3a 3-{5-Acetyl-1-[1-(4-fluoro- phenyl)-ethyl]-4,5,6,7- tetrahydro-1H- pyrazolo[4,3-c]pyridin-3- yl}-benzonitrile 1.29 (4) 389.2 6ao 3b 1-[1-[Cyclopropyl-(4- fluoro-phenyl)-methyl]-3- (4-fluoro-phenyl)-1,4,6,7- tetrahydro-pyrazolo[4,3- c]pyridin-5-yl]-ethanone 4.55 (2) 408.34 6ap 3e 1-[1-(2,4-Difluoro-benzyl)- 3-(3-trifluoromethoxy- phenyl)-1,4,6,7-tetrahydro- pyrazolo[4,3-c]pyridin-5- yl]-ethanone 1.23 (4) 452.13 6aq 3b 1-[1-(2,6-Difluoro-benzyl)- 3-(4-fluoro-phenyl)- 1,4,6,7-tetrahydro- pyrazolo[4,3-c]pyridin-5- yl]-ethanone 2.31 (12) 386.03 6ar 3b 1-[3-(4-Fluoro-phenyl)-1- [1-(4-fluoro-phenyl)ethyl]- 1,4,6,7-tetrahydro- pyrazolo[4,3-c]pyridin-5- yl]-ethanone 3.65 (8) 382.25 6as 3b 1-[3-(4-Fluoro-phenyl)-1- (4-trifluoromethyl-benzyl)- 1,4,6,7-tetrahydro- pyrazolo[4,3-c]pyridin-5- yl]-ethanone 2.5 (12) 418.11 6at 3h 1-[1-(2,4-Difluoro-benzyl)- 3-(3-methoxy-phenyl)- 1,4,6,7-tetrahydro- pyrazolo[4,3-c]pyridin-5- yl]-ethanone 1.61 (7) 398.13 6av 3b 0 1-[3-(4-Fluoro-phenyl)-1- (3-trifluoromethyl-benzyl)- 1,4,6,7-tetrahydro- pyrazolo[4,3-c]pyridin-5- yl]-ethanone 2.49 (12) 418.02 6aw 3e 1-[1-[1-(4-Fluoro-phenyl)- ethyl]-3-(3- trifluoromethoxy-phenyl)- 1,4,6,7-tetrahydro- pyrazolo[4,3-c]pyridin-5- yl]-ethanone 1.25 (4) 447.74 6ax 3i 1-[1-(2,4-Difluoro-benzyl)- 3-(4-fluoro-3-methoxy- phenyl)-1,4,6,7-tetrahydro- pyrazolo[4,3-c]pyridin-5- yl]-ethanone 1.26 (4) 416.22 6ay 3a 3-[5-Acetyl-1-(2,5- difluoro-benzyl)-4,5,6,7- tetrahydro-1H- pyrazolo[4,3-c]pyridin-3- yl]-benzonitrile 1.13 (1) 393.13 6az 3q 1-[1-(2,4-Difluoro-benzyl)- 3-m-tolyl-1,4,6,7- tetrahydro-pyrazolo[4,3- c]pyridin-5-yl]-ethanone 1.16 (1) 382.3 6ba 3f 1-[3-(3-Chloro-phenyl)-1- (4-fluoro-2-methyl- benzyl)-1,4,6,7-tetrahydro- pyrazolo[4,3-c]pyridin-5- yl]-ethanone 1.24 (1) 398.12 6bb 3q 1-[1-(2-Fluoro-benzyl)-3- m-tolyl-1,4,6,7-tetrahydro- pyrazolo[4,3-c]pyridin-5- yl]-ethanone 1.26 (4) 364.18 6bc 3d 1-[1-(2-Methoxy-benzyl)- 3-(3-trifluoromethyl- phenyl)-1,4,6,7-tetrahydro- pyrazolo[4,3-c]pyridin-5- yl]-ethanone 4.73 (2) 430.32 6bd 3f 1-[3-(3-Chloro-phenyl)-1- (3-methoxy-benzyl)- 1,4,6,7-tetrahydro- pyrazolo[4,3-c]pyridin-5- yl]-ethanone 1.19 (1) 396.08 6be 3b (+)-1-{3-(4-Fluoro- phenyl)-1-[1-(4-fluoro- phenyl)-ethyl]-1,4,6,7- tetrahydro-pyrazolo[4,3- c]pyridin-5-yl}-ethanone 4.79 (11) 382.23 6bf 3b 00 ()-1-{3-(4-Fluoro- phenyl)-1-[1-(4-fluoro- phenyl)-ethyl]-1,4,6,7- tetrahydro-pyrazolo[4,3- c]pyridin-5-yl}-ethanone 4.79 (11) 382.23 6bg 3b 01 1-[1-(4-Chloro-3-fluoro- benzyl)-3-(4-fluoro- phenyl)-1,4,6,7-tetrahydro- pyrazolo[4,3-c]pyridin-5- yl]-ethanone 2.47 (12) 402.00 6bh 3g 02 1-[1-(2,4-Difluoro-benzyl)- 3-(2-fluoro-5-methoxy- phenyl)-1,4,6,7-tetrahydro- pyrazolo[4,3-c]pyridin-5- yl]-ethanone 1.13 (4) 416.12 6bi 3j 03 5-[5-Acetyl-1-(2,4- difluoro-benzyl)-4,5,6,7- tetrahydro-1H- pyrazolo[4,3-c]pyridin-3- yl]-2-fluoro-benzonitrile 1.26 (4) 411.19 6bj 3k 04 1-[1-(2,4-Difluoro-benzyl)- 3-(3-fluoro-phenyl)- 1,4,6,7-tetrahydro- pyrazolo[4,3-c]pyridin-5- yl]-ethanone 3.45 (13) 386.18 6bk 3l 05 1-[1-(2,4-Difluoro-benzyl)- 3-(4-trifluoromethyl- phenyl)-1,4,6,7-tetrahydro- pyrazolo[4,3-c]pyridin-5- yl]-ethanone 1.2 (1) 435.88 6bl 3b 06 1-[1-[1-(4-Chloro-phenyl)- propyl]-3-(4-fluoro- phenyl)-1,4,6,7-tetrahydro- pyrazolo[4,3-c]pyridin-5- yl]-ethanone, enantiomer 1 3.81 (8) 412.14 6bm 3b 07 1-[1-[1-(4-Chloro-phenyl)- propyl]-3-(4-fluoro- phenyl)-1,4,6,7-tetrahydro- pyrazolo[4,3-c]pyridin-5- yl]-ethanone, enantiomer 2 3.81 (8) 412.14 6bn 3d 08 1-[1-(2-Fluoro-4-methyl- benzyl)-3-(3- trifluoromethyl-phenyl)- 1,4,6,7-tetrahydro- pyrazolo[4,3-c]pyridin-5- yl]-ethanone 1.35 (4) 432.13

1-(2,4-Difluoro-benzyl)-3-(4-fluoro-phenyl)-6-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine, trifluoroacetate salt (7a)

(24) ##STR00109##

(25) According to Scheme 4:

(26) To a solution of 1 N lithium hexamethyldisilazide in dry tetrahydrofuran (4.69 ml, 4.69 mmol) at 78 C. was added a solution of N-tert-butoxycarbonyl-4-piperidone (1.0 g, 4.69 mmol) in dry diethyl ether (9 ml) dropwise and the mixture was stirred at 78 C. for 30 min. A solution of 4-fluorobenzoyl chloride (743 mg, 4.69 mmol) in dry diethyl ether was added. The mixture was allowed to warm to 25 C. overnight. Water was added, the solution was extracted 3 times with CH.sub.2Cl.sub.2, the combined organic layers were washed once with brine, dried over Na.sub.2SO.sub.2, filtrated and the solution was evaporated to dryness, redissolved in ethanol (25 ml) and tetrahydrofuran (11 ml), (2,4-Difluoro-benzyl)-hydrazine (731 mg, 4.62 mmol) was added and the mixture was stirred for 10 min at 25 C. The mixture was poured on 1N aqueous NaOH, extracted 3 times with ethyl acetate, the combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4, filtrated and the solution was evaporated to dryness. The residue was dissolved in 4H HCl/dioxane (3 ml, 12 mmol) and stirred for 2 days. Solvents were evaporated and the crude product was purified by reverse phase HPLC (CH.sub.3CN/water gradient with 0.1 % trifluoroacetic acid) to give 257 mg of 1-(2,4-Difluoro-benzyl)-3-(4-fluoro-phenyl)-6-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine, trifluoroacetate salt (7a). R.sub.t=1.05 min (LC-method 4). Detected mass: 358.24 [M+H.sup.+]

1-benzyl-3-(4-fluoro-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine; hydrochloride (7b)

(27) ##STR00110##

(28) According to Scheme 5:

(29) A mixture of 1-[1-Benzyl-3-(4-fluoro-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone (6e) (6.9 g, 20 mmol), ethanol (73 ml) and 10N aqueous HCl (137 ml) was stirred at 80 C. for 2 h and then overnight at room temperature. The mixture was concentrated in vacuo and the product was filtrated off and washed with a small amount of cold water to give 4.87 g of 1-Benzyl-3-(4-fluoro-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine; hydrochloride (7b). R.sub.t=1.80 min (LC-method 12). Detected mass: 308.17 [M+H.sup.+]

(30) The examples in the following table were obtained according to Scheme 5 by following a similar reaction as used for synthesis of (7b). Reaction conditions varied slightly by reaction time (2 h-3 days), concentration of the aqueous HCl (2-10M) and work-up procedure (sometimes after evaporation of solvents the residue was purified by reverse phase HPLC (CH.sub.3CN/water gradient with 0.1% trifluoroacetic acid). The free amine was easily obtained by adding aqueous NaHCO3 and extracting with 3 times CH.sub.2Cl.sub.2, combining organic layers, drying over Na.sub.2SO.sub.4, filtrating off and evaporating solvents of the filtrate to dryness.

(31) TABLE-US-00003 R.sub.t/[min] (LC- Comp. Method) No. SC Product Chemical Name [M + H.sup.+] 7c 6a 3-[1-(2,4-Difluoro- benzyl)-4,5,6,7- tetrahydro-1H- pyrazolo[4,3- c]pyridin-3-yl]- benzonitrile 0.96 (4) 351.33 7d 6f 1-(2,4-Difluoro- benzyl)-3-(4-fluoro- phenyl)-4,5,6,7- tetrahydro-1H- pyrazolo[4,3- c]pyridine 1.07 (4) 344.19 7e 6be 3-(4-Fluoro- phenyl)-1-[1-(4- fluoro-phenyl)- ethyl]-4,5,6,7- tetrahydro-1H- pyrazolo[4,3- c]pyridine (enantiomer 1) 2.01 (3) 340.1 7f 6bf 3-(4-Fluoro- phenyl)-1-[1-(4- fluoro-phenyl)- ethyl]-4,5,6,7- tetrahydro-1H- pyrazolo[4,3- c]pyridine (enantiomer 2) 2.01 (3) 340.11

3-[1-(2,4-Difluoro-benzyl)-5-(3-methyl-oxetane-3-carbonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile (8a)

(32) ##STR00115##

(33) According to Scheme 6, method A:

(34) To a 10 C. cold solution of 3-[1-(2,4-Difluoro-benzyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile, trifluoroacetate (7c) (0.055 g, 0.118 mmol) in N,N-dimethylformamide (2 ml) was added triethylamine (18 l, 0.13 mmol), 1-hydroxybenzotriazole (17 mg, 0.124 mmol). 3-methyl-3-oxetane carboxylic acid (13.8 mg) and finally 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (24 mg, 0.124 mmol). The mixture was allowed to warm to 25 C. and stirred for 16 h and purified by reverse phase HPLC (CH3CN/water gradient with 0.1 % trifluoroacetic acid) to give 38 mg of 3-[1-(2,4-Difluoro-benzyl)-5-(3-methyl-oxetane-3-carbonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile (8a). R.sub.t=1.23 min (LC-method 4). Detected mass: 449.27 [M+H.sup.+]

3-[1-(2,4-Difluoro-benzyl)-5-isobutyryl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile (8b)

(35) ##STR00116##

(36) According to Scheme 6, method B:

(37) A mixture of 3-[1-(2,4-Difluoro-benzyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile (7c) (0.057 g, 0.163 mmol), K.sub.2CO.sub.3 (45 mg, 0.327 mmol) and isobutyryl chloride (21 mg, 0.196 mmol) in dry CH.sub.3CN (1.5 ml) was stirred at 60 C. for 1 h. Water was added, the solution was extracted 3 times with CH.sub.2Cl.sub.2, the combined organic layers were washed once with brine, dried over Na.sub.2SO.sub.4, filtrated and the residue was purified by reverse phase HPLC (CH.sub.3CN/wafer gradient with 0.1% trifluoroacetic acid) to give 48 mg of 3-[1-(2,4-Difluoro-benzyl)-5-isobutyryl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile (8b). R.sub.t=1.18 min (LC-method 1). Detected mass: 421.29 [M+H.sup.+].

3-[5-Cyclopropanecarbonyl-1-(2,4-difluoro-benzyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile (8c)

(38) ##STR00117##

(39) According to Scheme 6, method C.

(40) To a 0 C. cold mixture of 3-[1-(2,4-Difluoro-benzyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile, hydrochloride salt (7c), (0.050 g, 0.129 mmol), NaHCO.sub.3 (44 mg, 0.517 mmol), water (2 ml) and ethyl acetate (2 ml) was added cyclopropanecarbonyl chloride (13.5 mg, 0.129 mmol) and the mixture was stirred at 25 C. for 16 h. Water was added, the solution was extracted 2 times with ethyl acetate, the combined organic layers were washed once with brine, dried over MgSO4, filtrated and purified by reverse phase HPLC (CH.sub.3CN/water gradient with 0.1% trifluoroacetic acid) to give 21 mg of 3-[5-Cyclopropanecarbonyl-1-(2,4-difluoro-benzyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile (8c). R.sub.t=4.14 min (LC-method 13). Detected mass: 419.18 [M+H.sup.+]

3-[5-(2-tert-butoxy-acetyl)-1-(2,4-difluoro-benzyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile (8d)

(41) ##STR00118##

(42) According to Scheme 6, method D:

(43) To a 0 C. cold mixture of 3-[1-(2,4-Difluoro-benzyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile (7c) (0.4 g, 1.142 mmol) and 2-tert-butoxyacetic acid (196 mg, 1.485 mmol) was added N,N-diisopropylethylamine (0.59 g, 4.57 mmol) and TOTU (O-(Cyano(ethoxycarbonyl)methylenamino)-1,1,3,3-tetramethyluronium tetrafluoroborate, 562 mg, 1.71 mmol) and the mixture was stirred at 25 C. for 1 h. The crude product was purified by reverse phase HPLC (CH.sub.3CN/water gradient with 0.1% trifluoroacetic acid) to give 120 mg of 3-[5-(2-tert-Butoxy-acetyl)-1-(2,4-difluoro-benzyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile (8d). R.sub.t=1.34 min (LC-method 4). Defected mass: 465.3 [M+H.sup.+]

3-[1-(2,4-Difluoro-benzyl)-5-(3-methyl-3H-imidazole-4-carbonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile (8w)

(44) ##STR00119##

(45) According to Scheme 6, method E:

(46) A mixture of 3-[1-(2,4-Difluoro-benzyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile (7c) (0.04 g, 0.114 mmol), 3-methyl-3H-imidazole-4-carbonyl chloride (0.083 g, 0.457 mmol) and triethylamine (138 mg, 1.37 mmol) in CH.sub.2Cl.sub.2 was stirred at 25 C. for 16 h. The crude product was purified by reverse phase HPLC (CH3CN/water gradient with 0.1 % trifluoroacetic acid) to give 43 mg of 3-[1-(2,4-Difluoro-benzyl)-5-(3-methyl-3H-imidazole-4-carbonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile (8w). R.sub.t=3.53 min (LC-method 2). Detected mass: 459.24 [M+H.sup.+]

1-[1-(2,4-Difluoro-benzyl)-3-(4-fluoro-phenyl)-6-methyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone (8z)

(47) ##STR00120##

(48) According to Scheme 6, method F:

(49) A mixture of 1-(2,4-Difluoro-benzyl)-3-(4-fluoro-phenyl)-6-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine (7a) (0.53 g, 1.35 mmol), acetic anhydride (5.5 ml) and pyridine (5.5 ml) was stirred at 25 C. for 16 h. The mixture was poured on 50 ml water, extracted with 150 ml ethyl acetate, the combined organic layers were washed with 3 times 0.5 N NaOH (50 ml) and once with brine, dried over MgSO.sub.4, filtrated and evaporated to dryness. The crude product was silica gel chromatography (eluting with heptane/ethyl acetate) to give 156 mg of 1-[1-(2,4-Difluoro-benzyl)-3-(4-fluoro-phenyl)-6-methyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone (8z).

(50) R.sub.t=1.3 min (LC-method 4). Detected mass: 400.22 [M+H.sup.+]

(51) The examples in the following table were obtained according to Scheme 6 by following one of the methods described for the synthesis of 8a-8c (Method (A) according to 8a, Method (B) and Method (C) according to 8c), The acylating reagents are obvious to the man skilled in the art and therefore not mentioned.

(52) TABLE-US-00004 R.sub.t/[min] (LC- Comp. SC Method) No. (M) Product Chemical Name [M + H.sup.+] 8e 7c (A) 3-[1-(2,4-Difluoro- benzyl)-5-(3- methanesulfonyl- benzoyl)-4,5,6,7- tetrahydro-1H- pyrazolo[4,3- c]pyridin-3-yl]- benzonitrile 3.93 (13) 533.16 8f 7b (C) [1-Benzyl-3-(4- fluoro-phenyl)- 1,4,6,7- tetrahydro- pyrazolo[4,3- c]pyridin-5-yl]-(4- fluoro-phenyl)- methanone 3.49 (8) 430.1 8g 7b (C) [1-Benzyl-3-(4- fluoro-phenyl)- 1,4,6,7- tetrahydro- pyrazolo[4,3- c]pyridin-5-yl]-(4- methoxy-phenyl)- methanone 3.44 (8) 442.13 8h 7b (C) [1-Benzyl-3-(4- fluoro-phenyl)- 1,4,6,7- tetrahydro- pyrazolo[4,3- c]pyridin-5-yl]- phenyl- methanone 3.45 (8) 412.1 8i 7c (B) 3-[5-Cyclobutane- carbonyl-1-(2,4- difluoro-benzyl)- 4,5,6,7- tetrahydro-1H- pyrazolo[4,3- c]pyridin-3-yl]- benzonitrile 1.2 (1) 433.28 8j 7c (B) 3-[5- Cyclopentane- carbonyl-1-(2,4- difluoro-benzyl)- 4,5,6,7- tetrahydro-1H- pyrazolo[4,3- c]pyridin-3-yl]- benzonitrile 1.23 (1) 447.23 8k 7c (A) 3-[1-(2,4-Difluoro- benzyl)-5-(4- methanesulfonyl- benzoyl)-4,5,6,7- tetrahydro-1H- pyrazolo[4,3- c]pyridin-3-yl]- benzonitrile 3.97 (13) 533.15 8l 7c (C) 3-[1-(2,4-Difluoro- benzyl)-5-(tetra- hydro-pyran-4- carbonyl)-4,5,6,7- tetrahydro-1H- pyrazolo[4,3- c]pyridin-3-yl]- benzonitrile 1.23 (4) 463.29 8m 7c (C) 3-[1-(2,4-Difluoro- benzyl)-5- (tetrahydro-furan- 3-carbonyl)- 4,5,6,7- tetrahydro-1H- pyrazolo[4,3- c]pyridin-3-yl]- benzonitrile 1.23 (4) 449.25 8n 7c (B) 0 3-[1-(2,4-Difluoro- benzyl)-5-(2- methoxy-acetyl)- 4,5,6,7- tetrahydro-1H- pyrazolo[4,3- c]pyridin-3-yl]- benzonitrile 1.24 (4) 423.18 8o 7c (B) 3-[1-(2,4-Difluoro- benzyl)-5-(2,2- dimethyl- propionyl)- 4,5,6,7- tetrahydro-1H- pyrazolo[4,3- c]pyridin-3-yl]- benzonitrile 1.36 (4) 435.31 8p 7c (B) 3-[1-(2,4-Difluoro- benzyl)-5- propionyl-4,5,6,7- tetrahydro-1H- pyrazolo[4,3- c]pyridin-3-yl]- benzonitrile 1.28 (4) 407.27 8q 7c (A) 3-[1-(2,4-Difluoro- benzyl)-5-((S)-2- hydroxy- propionyl)- 4,5,6,7- tetrahydro-1H- pyrazolo[4,3- c]pyridin-3-yl]- benzonitrile 1.18 (4) 423.25 8r 7b (C) [1-Benzyl-3-(4- fluoro-phenyl)- 1,4,6,7- tetrahydro- pyrazolo[4,3- c]pyridin-5-yl]-2- phenyl-ethanone 3.47 (8) 426.12 8s 7c (C) 3-[5-Butyryl-1- (2,4-difluoro- benzyl)-4,5,6,7- tetrahydro-1H- pyrazolo[4,3- c]pyridin-3-yl]- benzonitrile 1.18 (1) 421.28 8t 7c (C) 3-[1-(2,4-Difluoro- benzyl)-5- (pyridine-2- carbonyl)-4,5,6,7- tetrahydro-1H- pyrazolo[4,3- c]pyridin-3-yl]- benzonitrile 4.07 (13) 456.17 8u 7c (A) 3-[1-(2,4-Difluoro- benzyl)-5-(3- fluoro-pyridine-4- carbonyl)-4,5,6,7- tetrahydro-1H- pyrazolo[4,3- c]pyridin-3-yl]- benzonitrile 4.49 (2) 474.19 8v 7c (A) 3-[1-(2,4-Difluoro- benzyl)-5- (pyrimidine-4- carbonyl)-4,5,6,7- tetrahydro-1H- pyrazolo[4,3- c]pyridin-3-yl]- benzonitrile 1.19 (4) 457.31 8x 7c (E) 3-[1-(2,4-Difluoro- benzyl)-5-(1- methyl-1H- pyrazole-3- carbonyl)-4,5,6,7- tetrahydro-1H- pyrazolo[4,3- c]pyridin-3-yl]- benzonitrile 4.49 (2) 459.24 8y 7c (B) 0 3-(3-Cyano- phenyl)-1-(2,4- difluoro-benzyl)- 4,5,6,7- tetrahydro- pyrazolo[4,3- c]pyridine-5- carboxylic acid ethyl ester 1.35 (4) 423.2

3-(4-Fluoro-phenyl)-1-[(R)-1-(4-fluoro-phenyl)-ethyl]-5-methanesulfonyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine, enantiomer 1 (9a)

(53) ##STR00141##

(54) According to Scheme 7:

(55) To a mixture of 3-(4-Fluoro-phenyl)-1-[1-(4-fluoro-phenyl)-ethyl]-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine (enantiomer 1) (7e) (0.120 g, 0.353 mmol) and triethylamine (0.135 ml, 1.06 mmol) in CH.sub.2Cl.sub.2 at 0 C. was added methanesulfonyl chloride (49 mg, 0.424 mmol) and the mixture was stirred at 25 C. for 16 h. The crude product was purified by reverse phase HPLC (CH.sub.3CN/wafer gradient with 0.1% trifluoroacetic acid) to give 96 mg of 3-(4-Fluoro-phenyl)-1-[(R)-1-(4-fluoro-phenyl)-ethyl]-5-methanesulfonyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine (9a). R.sub.t=3.58 min (LC-method 8). Detected mass: 418.09 [M+H.sup.+]

3-(4-Fluoro-phenyl)-1-[(R)-1-(4-fluoro-phenyl)-ethyl]-5-methanesulfonyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine, enantiomer 2 (9b)

(56) ##STR00142##

(57) 3-(4-Fluoro-phenyl)-1-[(R)-1-(4-fluoro-phenyl)-ethyl]-5-methanesulfonyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine, enantiomer 2 (9b) was obtained starting from 3-(4-Fluoro-phenyl)-1-[1-(4-fluoro-phenyl)-ethyl]-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine (enantiomer 2) (7f) by following a similar reaction as used for synthesis of (9a). R.sub.t=3.58 min (LC-method 8). Detected mass: 418.09 [M+H.sup.+]

3-(3-Cyano-phenyl)-1-(2,4-difluoro-benzyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid isopropylamide (11a)

(58) ##STR00143##

(59) According to Scheme 8:

(60) To a mixture of 3-[1-(2,4-Difluoro-benzyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile (7c) (0.060 g, 0.171 mmol) and triethylamine (138 mg, 1.37 mmol) at 0 C. was added isopropylisocyanate (17.5 mg, 0.21 mmol) and the mixture was stirred at room temperature for 16 h. The crude product was purified by reverse phase HPLC (CH.sub.3CN/water gradient with 0.1 % trifluoroacetic) to give 19 mg of 3-(3-Cyano-phenyl)-1-(2,4-difluoro-benzyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid isopropylamide (11a). R.sub.t=1.16 min (LC-method 1). Detected mass: 436.25 [M+H.sup.+].

(61) The examples in the following table were obtained according to Scheme 9 by following a similar reaction as used for synthesis of (11a).

(62) TABLE-US-00005 R.sub.t/[min] (LC- Comp. Method) No. SC Product Chemical Name [M + H.sup.+] 11b 7e 3-(4-Fluoro- phenyl)-1-[1-(4- fluoro-phenyl)- ethyl]-1,4,6,7- tetrahydro- pyrazolo[4,3- c]pyridine-5- carboxylic acid ethylamide, enantiomer 1 3.45 (8) 411.17 11c 7f 3-(4-Fluoro- phenyl)-1-[1-(4- fluoro-phenyl)- ethyl]-1,4,6,7- tetrahydro- pyrazolo[4,3- c]pyridine-5- carboxylic acid ethylamide, enantiomer 2 3.45 (8) 411.16 11f 7e 3-(4-Fluoro- phenyl)-1-[1-(4- fluoro-phenyl)- ethyl]-1,4,6,7- tetrahydro- pyrazolo[4,3- c]pyridine-5- carboxylic acid tert-butylamide, enantiomer 1 4.15 (13) 439.15 11h 7c 3-(3-Cyano- phenyl)-1-(2,4- difluoro-benzyl)- 1,4,6,7- tetrahydro- pyrazolo[4,3- c]pyridine-5- carboxylic acid ethylamide 1.14 (1) 422.21

3-(3-Cyano-phenyl)-1-(2,4-difluoro-benzyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid methylamide (12a)

(63) ##STR00148##

(64) According to Scheme 9:

(65) To a mixture of 3-[1-(2,4-Difluoro-benzyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile (7c) (0.060 g, 0.171 mmol) and triethylamine (60 mg, 0.60 mmol) in CH.sub.2Cl.sub.2 at 0 C. was added para-nitrophenylchloroformate (38 mg, 0.188 mmol) and the mixture was stirred at 0 C. for 45 min. 2 M methylamine in tetrahydrofuran (2 ml, 4 mmol) was added and the mixture was stirred for 3 days at room temperature. The crude product was purified by reverse phase HPLC (CH.sub.3CN/water gradient with 0.1 % trifluoroacetic) to give 3.4 mg of 3-(3-Cyano-phenyl)-1-(2,4-difluoro-benzyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid methylamide (12a). R.sub.t=1.11 min (LC-method 1). Detected mass: 408.15 [M+H.sup.+]

(66) The examples in the following table were obtained according to Scheme 10 by following a similar reaction as used for synthesis of (12a), but at a reaction temperature of 80 C.

(67) TABLE-US-00006 R.sub.t/[min] Comp. (Method) No. SC Product Chemical Name [M + H.sup.+] 12b 7e {3-(4-Fluoro- phenyl)-1-[1-(4- fluoro-phenyl)- ethyl]-1,4,6,7- tetrahydro-py- razolo[4,3-c]pyridin- 5-yl}-morpholin-4- yl-methanone, enantiomer 1 3.74 (13) 453.11 12c 7e 0 {3-(4-Fluoro- phenyl)-1-[1-(4- fluoro-phenyl)- ethyl]-1,4,6,7- tetrahydro- pyrazolo[4,3- c]pyridin-5-yl}-((S)- 3-hydroxy- pyrrolidin-1-yl)- methanone, enantiomer 1 3.37 (13) 453.11 12d 7c 3-(3-Cyano- phenyl)-1-(2,4- difluoro-benzyl)- 1,4,6,7-tetrahydro- pyrazolo[4,3- c]pyridine-5- carboxylic acid dimethylamide 1.16 (1) 422.2 12e 7c 3-(3-Cyano- phenyl)-1-(2,4- difluoro-benzyl)- 1,4,6,7-tetrahydro- pyrazolo[4,3- c]pyridine-5- carboxylic acid (2- hydroxy-ethyl)- methyl-amide 1.34 (14) 452.1

2-[5-Acetyl-1-(2,4-difluoro-benzyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-isonicotinonitrile (13a)

(68) ##STR00153##

(69) According to Scheme 10:

(70) To a solution of Zn(CN).sub.2 (39 mg, 0.335 mmol) and tetrakis(triphenylphosphine)palladium(0) (19 mg, 0.016 mmol) in dry N,N-dimethylformamide (0.6 ml) at 150 C. was slowly added a solution of 1-[3-(4-Bromo-pyridin-2-yl)-1-(2,4-difluoro-benzyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone (6j) (0.15 g, 0.335 mmol) in dry N,N-dimethylformamide (1 ml). The mixture was stirred at 150 C. for 3 h and then at 25 C. for 16 h. The mixture was diluted with methyl-tert-butylether, filtrated over Celite, washed with water, dried over Na.sub.2SO.sub.4, filtrated and evaporated to dryness. The residue was suspended in methanol, and the solid was filtrated off to give 67 mg of 2-[5-Acetyl-1-(2,4-difluoro-benzyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-isonicotinonitrile (13a). R.sub.t=1.11 min (LC-method 1). Detected mass: 394.22 [M+H.sup.+]

(71) The examples in the following table were obtained according to Scheme 11 by following a similar reaction as described for the synthesis of 13a. Sometimes the products were purified by reverse phase HPLC (CH.sub.3CN/water gradient with 0.1% trifluoroacetic acid).

(72) TABLE-US-00007 R.sub.t/[min] (LC- Comp Method) No. SC Product Chemical Name [M + H.sup.+] 13b 6w 6-[5-Acetyl-1-(2,4- difluoro-benzyl)- 4,5,6,7- tetrahydro-1H- pyrazolo[4,3- c]pyridin-3-yl]- pyridine-2- carbonitrile 1.11 (1) 394.22

3-[1-(2,4-Difluoro-benzyl)-5-(2-hydroxy-acetyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile (14a)

(73) ##STR00155##

(74) A solution of 3-[5-(2-tert-Butoxy-acetyl)-1-(2,4-difluoro-benzyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile (8d) (90 mg, 0.193 mmol) and trifluoroacetic acid (221 mg, 1.94 mmol) in CH.sub.2Cl.sub.2 was stirred at 25 C. for 1 day. Solvents were evaporated and the residue purified by reverse phase HPLC (CH.sub.3CN/water gradient with 0.1% trifluoroacetic acid) to give 48 mg of 3-[1-(2,4-Difluoro-benzyl)-5-(2-hydroxy-acetyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile (14a). R.sub.t=1.19 min (method 4). Detected mass: 409.21 [M+H.sup.+]

(75) The following LC methods were used to analyze the exemplary embodiments:

(76) Following abbreviations are used: FA: formic acid TFA: trifluoroacetic acid ACN: acetonitrile LC method 1: Stationary phase: Waters UPLC BEH C18 2.1*50 mm; 1.7 Gradient: H.sub.2O+0.05% FA:ACN+0.035% FA 95:5 (0 min) to 5:95 (1.1 min) to 5:95 (1.7 min) to 95:5 (1.9 min) to 95:5 (2 min) Flow: 0.9 mL/mm, 55 C. LC method 2: Stationary phase: Waters XBridge C18 4.6*50 mm; 2.5 Gradient: H.sub.2O+0.1 % FA:AcN+0.1% FA 97:3 (0 min) to 40:60 (3.5 min) to 2:98 (4 min) to 2:98 (5 min) to 97:3 (5.2 min) to 97.3 (6.5 min); Flow: 1.3 mL/min LC method 3: Stationary phase: WatersXBridgeC18, 4.6*50; 2.5 Gradient: H.sub.2O+0.05% TFA:ACN+0.05% TFA 95:5 (0 min) to 95:5 (0.2 min) to 5:95 (2.4 min) to 5:93 (3.2 min) to 95:5 (3.3 min) to 95:5 (4.0 min) Flow: 1:7 mL/min, 40 C. LC method 4: Stationary phase: Waters UPLC BEH C18 2.1*50 mm; 1.7 Gradient: H.sub.2O+0.1% FA:ACN+0.08% FA 95:5 (0 min) to 5:95 (1.1 min) to 5:95 (1.7 min) to 95:5 (1.8 min) to 95:5 (2 min) Flow: 0.9 ml/min, 55 C. LC method 5: Stationary phase: WatersXBridgeC18, 4.8*50, 2.5 Gradient: H.sub.2O+0.05% TFA:ACN+0.05% TFA 95:5 (0 min) to 95:5 (0.2 min) to 5:95 (2.4 min) to 5:95 (3.5 min) to 95:5 (3.6 min) to 95:5 (4.5 min) Flow: 1.7 mL/min, 50 C. LC method 6: Stationary phase: WatersXBridgeC18.4, 4.6*50, 2.5 Gradient: H.sub.2O+0.05% TFA:ACN+0.05% TFA 95:5 (0 min) to 5:95 (2.6 min) to 5:95 (3.0 min) to 95:5 (3.1 min), to 95:5 (4.0 min) Flow: 1.7 mL/min, 40 C. LC method 7: Stationary phase: Merck Chromolith FastGrad, RP-18e, 502 mm Gradient: H.sub.2O+0.05% TFA:ACN+0.05% TFA 98:2 (0 min) to 98:2 (0.2 min) to 2:98 (2.4 min) to 2:98 (3.2 min) to 98:2 (3.3 min) to 98:2 (4 min) Flow: 2 mL/min, 50 C. LC method 8: Stationary phase: WatersXBridgeC18, 4.6*50, 2.5 Gradient: H.sub.2O+0.05% TFA:ACN+0.05% TFA 95:5 (0 min) to 95:5 (0.3 min) to 5:95 (3.5 min) to 5:95 (4 min) Flow: 1.3 ml/min, 40 C. LC method 9: Stationary phase: Waters UPLC BEH C18 2.1*50 mm; 1.7 Gradient: H2O+0.05% FA:ACN+0.035% FA 98:2 (0 min) to 5:95 (2 min) to 5:95 (2.6 min) to 95:5 (2.7 min) to 95:5 (3 min) Flow: 0.9 ml/min 55 LC method 10: Stationary phase: 0.2l 102.0 LunaC18, 3 Gradient: 0 min 93% H.sub.2O (0.05% TFA)1.0 min95% ACN, 95% ACN to 1.45 min; 7% ACN 1.50 min Flow: 1 ml/min 55 C. LC method 11: Stationary phase: Waters XBridge C18 4.6*50 mm; 2.5 Gradient: H.sub.2O+0.1 % FA:ACN+0.08% FA 97:3 (0 min) to 40:60 (3.5 min) to 2:98 (4 min) to 2:98 (5 min) to 97:3 (5.2 min) to 97:3 (6.5 min) Flow: 1.3 ml, 45 C. LC method 12: Stationary phase: YMC JSphere33*2, 4 Gradient H.sub.2O+0.05% FA:ACN+0.05% FA 95:5 (0 min) to 95:5 (0.5 min) to 5:95 (3.5 min) to 5:95 (4 min) Flow: 1.3 ml/min, r.t. LC method 13: Stationary phase: YMC-Pack JSphere H80 33*2. Gradient: H.sub.2O+0.05% TFA:CH.sub.3OH+0.05% TFA 98:2 (1 min) to 5:95 (5.0 min) to 5:95 (6.25 min) Flow: 1.0 ml/min, r.t. LC method 14: Stationary phase: YMC-JSphere-ODS-H80 (202 1 4) Gradient: 0 min 96% H.sub.2O (0.05% TFA) to 95% CH.sub.3CN (2.4 min) to 4% CH.sub.3CN (2.45 min) Flow: 1.0 ml/min, 30 C. LC method 15: Stationary phase: YMC JSphere33*2.4. Gradient: (AcN+0.05% TFA): H2O+0.05% TFA; 5:95 (0 min) to 5:95 (0.5 min) to 95:5 (3.5 min) to 95:5 (4 min) Flow: 1.3 ml/min

(77) Determination of the Activity of the TASK-1 Channel in Xenopus oocytes

(78) Human TASK-1 channels were expressed in Xenopus oocytes. For this purpose, oocytes were isolated from Xenopus laevis and defoliated. Subsequently, TASK-1-encoding RNA synthesized in vitro was injected into oocytes. After two days of TASK-1 protein expression, TASK-1 currents were measured by two-microelectrode voltage clamp. Data were acquired and analyzed using a TEC-10cx amplifier (NPI Electronic, Tamm, Germany) connected to an ITC-16 Interface (Instrutech Corp., Long Island, USA) and Pulse software (HEKA Elektronik, Lambrecht, Germany). Oocytes were clamped to 90 mV and TASK-1 mediated currents were measured during 500 ms voltage pulses to 40 mV. Oocytes were continuously superfused with ND96 buffer containing: NaCl 96 mM, KCl 2 mM, CaCl.sub.2 1.8 mM, MgCl.sub.2 1 mM, HEPES 5 mM (pH adjusted to 7.4 with NaOH). All experiments were performed at room temperature.

(79) Test substances were consecutively added, to the bath solution at rising concentrations. Compound effects were calculated as the percentage inhibition of TASK-1 control current before compound application. IC.sub.50 values were obtained by fitting the data to the general dose-response equation.

(80) The following products/compounds were tested in said assay by using the respective form (salt or free base) obtained as in the examples described above and the following activities were measured (IC50 values or inhibition (in %) at 5 M).

(81) TABLE-US-00008 Example Inhibition (%) No. IC50 (M) at 5 M 6a 0.095 6ab 76% 6ac 80% 6ad 86% 6ae 84% 6af 72% 6ag 75% 6ah 53% 6ai 79% 6aj 76% 6ak 0.27 6al 75% 6am 0.114 6an 0.187 6ao 0.258 6ap 0.285 6aq 0.359 6ar 0.552 6as 0.659 6at 0.72 6av 0.911 6aw 0.947 6ax 0.975 6ay 86% 6az 89% 6b 0.172 6ba 81% 6bb 82% 6bc 70% 6bd <10 6be 0.5 6bf 0.5 6bg 0.398 6bh <10 6bi 1.645 6bj 1.16 6bk 1.15 6bl 0.966 6bm 0.251 6bn 81% 6c 0.215 6d 0.422 6f 0.598 6g 0.0995 6h 0.19 6i 0.216 6j <10 6k 78% 6m 2.441 6n 0.091 6o <10 6p 88% 6q 70% 6r 79% 6s 83% 6t 62% 6u 89% 6v 73% 6w <10 6x 82% 6y 86% 6z 75% 8a 0.276 8b 0.019 8c 0.047 8d 75% 8e 1.625 8f 1.28 8g 3.264 8h 2.399 8i 0.064 8j 0.722 8k 0.906 8l 0.585 8m 0.89 8n 80% 8o 0.131 8p 0.53 8q 0.756 8r 1.138 8s <10 8t 0.246 8u 0.416 8v 0.864 8w 1.149 8x 1.878 8y 77% 8z 0.511 9a 0.54 9b 0.611 11a 76% 11b 1.52 11c 1.167 11f 58% 11h 91% 12a 0.38 12b 0.511 12c 0.734 12d 74% 12e 65% 13a 0.422 13b 0.462 14a <10

(82) Investigation of the Refractory Period and the Left-Atrial Vulnerability in the Pig

(83) The compounds were tested for prolongation of the refractory period and antiarrhythmic activity on the atrium of the anesthetized pig as described in the literature (Knobloch at al. 2002. Naunyn-Schmiedberg's Arch. Pharmacol. 366; 482-487). Here the anti-arrhythmic action relates to the inhibition of the occurrence of episodes of arrhythmias which are induced by a prematurely placed extra-stimulus (S2) in the left atrium (=left-atrial vulnerability). The refractory period values are stated in percent of the basal values 15 minutes after injection. Mean values for the refractory periods are shown from three rates (150, 200 and 250/min). The inhibitory values for the inhibition of episodes of arrhythmias refer to 3 measurements (3 timepoints) before administration vs. 3 measurements during the first hour after administration of the compounds.

(84) The action of 3-[5-Acetyl-1-(2,4-difluoro-benzyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile (6a) on the refractory period of the left atrium and antiarrhythmic activity in the anesthetized pig after a bolus administration of 1 mg/kg shown in table 1. From the results shown in table 1, it is seen that it was possible to prevent 61% of the induced arrhythmias.

(85) TABLE-US-00009 TABLE 1 Mean value % increase in the refractory period 14% % inhibition of the arrhythmias 61% Number of animals n = 3