MXPA06009160A

MXPA06009160A - Chemokine receptor antagonists

Info

Publication number: MXPA06009160A
Application number: MXPA/A/2006/009160A
Authority: MX
Inventors: Renehersperger; Janser Philipp; Pfenninger Emil; Juerg Wuethrich Hans; Miltz Wolfgang
Original assignee: Novartis Ag
Priority date: 2004-02-11
Filing date: 2006-08-11
Publication date: 2006-12-13

Abstract

A compound of formula (I) or a pharmaceutically acceptable salt or prodrug ester thereof, wherein the variants R, R9, Z, X, Q and Y are defined in the specification.

Description

ANTAGONISTS OF THE RECEIVER OF QUI 1QCINA The invention relates to bicyclic carbonyl amino derivatives, which are antagonists of the Chemokine Receptor 2 (CCR-2) and the Chemokine Receptor 5 (CCR-5), and their use in the treatment of diseases and disorders that involve the migration and activation of monocytes and T-cells, including inflammatory diseases. According to the above, the invention, in a first aspect, provides a compound of the formula (I), or a pharmaceutically acceptable salt or prodrug ester thereof: (I) where: Z is C RT RZ, O or S; R is selected from the group consisting of hydroxyl, an optionally substituted alkoxy of 1 to 7 carbon atoms, alkenoxyl of 2 to 7 carbon atoms, cycloalkyloxy, aryloxy, heteroaryloxy, arylalkoxy of 1 to 7 carbon atoms. carbon, or heteroaryl-alkoxy of 1 to 7 carbon atoms, an alkyl of 1 to 7 carbon atoms, or optionally substituted alkenyl of 2 to 7 carbon atoms, an optionally substituted aryl, heteroaryl, or an aryl-alkyl group of 1 to 7 carbon atoms optionally substituted; R 9 represents or not more ring substituents selected from the group consisting of H, hydroxyl, an alkoxy of 1 to 7 optionally substituted carbon atoms, alkanoxy of 2 to 7 carbon atoms, cycloalkylsiloxy , aryloxy, heteroaryloxy, aryl-alkoxy of 1 to carbon atoms or heteroaryl-alkoxy of 1 to 7 carbon atoms, an alkyl of 1 to 7 carbon atoms or alkenyl of 2 to 7 carbon atoms optionally substituted, an aryl optionally substituted, heteroaryl, or an aryl-alkyl group of 1 to 7 carbon atoms optionally substituted; Ri, R2, and R3 are independently selected from the group consisting of H and alkyl of 1 to 7 carbon atoms; X is cycloalkyl of 3 to 1 8, heterocycloalkyl, aryl, or heteroaryl, each of which may be optionally substituted; Q is a linker of between 1 and 3 atoms in length; Y is cycloalkyl of 3 to 18 carbon atoms, heterocycloalkyl, bridged cycloalkyl, bridged heterocycloalkyl, aryl, heteroaryl, aryl-heterocycloalkyl fused, all of which are optionally substituted one or more times independently. The substituent or optional substituents on R and R9 are independently selected from the group consisting of halogen, hydroxyl, alkyl of 1 to 7 carbon atoms, mono- or di-lower alkyl-amino, aminocarbonyl, mono- or di- lower alkyl aminocarbonyl, amino, carboxyl, alkoxy of 1 to 7 carbon atoms, cycloalkyl of 3 to 1 2 carbon atoms, heterocycloalkyl of 3 to 1 8 carbon atoms, alkyl of 1 to 7 atoms of carbon-carbonyl, alkoxy of 1 to 7 carbon atoms-carbonyl, nitrile, aryl; all of which, except halogen or, are optionally substituted independently by one or more substituents, selected from the group consisting of halogen, hydroxyl, alkyl of 1 to 7 carbon atoms, mono- or dialkyl of 1 to 7 carbon atoms-amino, aminocarbonyl, mono- or di-alkyl of 1 to 7 carbon atoms-aminocarbonyl, amino, carboxyl of 1 to 7 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, heterocycloalkyl of 3 to 1 8 carbon atoms, alkyl of 1 to 7 carbon atoms, carbonyl of 1 to 7 carbon atoms, nitrile, aryl. The substituent or optional substituents on X are independently selected from the group consisting of halogen, hydroxyl, alkyl of 1 to 7 carbon atoms, mono- or dialkyl of 1 to 7 carbon atoms-amino, aminocarbonyl, mono- or di-alkyl of 1 to 7 carbon atoms-aminocarbonyl, amino, carboxyl of 1 to 7 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, heterocycloalkyl of 3 to 18 carbon atoms, alkyl of 1 to 7 carbon atoms -carbonyl, alkoxy of 1 to 7 carbon atoms-carbonyl, nitrile, aryl; all of which, except halogen, are optionally substituted independently by one or more substituents selected from the group consisting of halogen, hydroxyl, alkoxy of 1 to 7 carbon atoms, m or o-d i -alk 1 to 7 carbon atoms-amine, aminecarbonyl, mono- or di-alkyl of 1 to 7 carbon atoms- aminocarbonyl, ammonium, carboxyl of 1 to 7 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, 3-heterocycloalkyl18 carbon atoms, alkyl of 1 to 7 carbon atoms-carbonyl, alkoxy of 1 to 7 carbon atoms-carbonyl, nitrile, aryl. The substituent or optional substituents on Y are independently selected from the group consisting of halogen, hydroxyl, alkyl of 1 to 7 carbon atoms, mono- or dialkyl of 1 to 7 carbon atoms-amino, aminocarbonyl, mono- or di-alkyl of 1 to 7 carbon atoms-aminocarbonyl, amino, carboxyl of 1 to 7 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, heterocycloalkyl of 3 to 1 8 carbon atoms, alkyl of 1 to 7 carbon atoms carbon-carbonyl, alkoxy of 1 to 7 carbon atoms-carbonyl, nitrile, aryl; all of which, except halogen, are optionally substituted independently by one or more substituents selected from the group consisting of halogen, hydroxyl, alkyl of 1 to 7 carbon atoms, mono- or di-alkyl of 1 to 7 carbon-amino, aminocarbonyl, mono- or di-alkyl atoms of 1 to 7 carbon atoms-aminocarbonyl, amino, carboxyl of 1 to 7 carbon atoms, cycloalkyl of 3 to 1 2 carbon atoms, heterocycloalkyl of 3 to 1 8 carbon atoms, alkyl of 1 to 7 carbon atoms, carbonyl of 1 to 7 carbon atoms, nitrile, aryl.

For the avoidance of doubt, it should be understood that the terms listed below have the following meanings throughout the present description and in the claims: The term "inferior", when referring to radicals or organic compounds, signifies a com or radical that can be branched or unbranched with up to and including 7 carbon atoms. A lower alkyl group can be branched, unbranched, or cyclic, and contains from 1 to 7 carbon atoms, preferably from 1 to 4 carbon atoms. Lower alkyl represents, for example: methyl, ethyl, propyl, butyl, isopropyl, isobutyl, tertiary butyl or 2,2-dimethylpropyl. A lower alkoxyl group may be branched or unbranched, and contains from 1 to 7 carbon atoms, preferably from 1 to 6 carbon atoms. Lower alkoxy represents, for example: methoxy, ethoxy, propoxy, butoxy, isopropoxy, isobutoxy, or tertiary butoxy. Lower alkoxy includes cycloalkyloxy and lower cycloalkyl-alkyloxy. A lower alkene, alkenyl, or alkenoxy group is branched or unbranched, and contains from 2 to 7 carbon atoms, preferably from 1 to 4 carbon atoms, and contains at least one carbon-carbon double bond. Lower alkene, lower alkenyl, or lower alkenyloxy represent, for example, vinyl, prop-1 -enyl, allyl, butenyl, isopropenyl, or isobutenyl, and their oxyl equivalents.

In the present application, oxygen-containing substituents, for example, alkoxy, alkenyloxy, alkynyloxy, carbonyl, etc., include their homologues containing sulfur, for example thioalkoxy, thioalkenyloxy, thioalkynyloxy, thiocarbonyl, sulfone, sulfoxide, and the like. Halo or halogen represents chlorine, fluorine, bromine or iodine. Aryl represents carbocyclic aryl, heterocyclic aryl, or biaryl.

Carbocyclic aryl is an aromatic cyclic hydrocarbon containing from 6 to 18 ring atoms. It can be monocyclic, bicyclic, or tricyclic, for example naphthyl, phenyl, phenyl mono-, di-, or tri-substituted by one, two or three substituents. Heterocyclic aryl is a monocyclic or bicyclic aromatic hydrocarbon containing from 5 to 18 ring atoms, one or more of which are heteroatoms selected from O, N, or S. Preferably, there are one or two heteroatoms. Heterocyclic aryl represents, for example: pyridyl, indolyl, quinoxalinyl, quinolinyl, isoquinolyl, benzothienyl, benzofuranyl, benzopyranyl, benzothiopyranyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, imidazolyl, thienyl. Heterocyclic aryl also includes these substituted radicals. Cycloalkyl represents a cyclic hydrocarbon containing 3 to 12 ring atoms, preferably 3 to 6 ring atoms.

Cycloalkyl represents, for example: cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. The cycloalkyl may be optionally substituted.

Heterocycloalkyl represents a mono-, di-, or tricyclic hydrocarbon, which may be saturated or unsaturated, and which contains one or more, preferably 1 to 3, heteroatoms selected from O, N, or S. It preferably contains between 3 and 1 8 ring atoms. The term "heterocycloalkyl" is also intended to include bridged cycloalkyl groups, such as 3-hydroxy-8-azabicyclo [3.2.1] oct-8-yl. The pharmaceutically acceptable prodrug esters are the ester derivatives which can be converted by solvolysis or under physiological conditions to the free carboxylic acid of the formula (I). These esters are, for example, lower alkyl-esters (such as methyl- or ethyl-ester), carboxy-lower alkyl-esters, such as carboxymethyl ester, nitro-oxy-lower alkyl-esters (such as 4- nitro-oxybutyl ester). Referring to formula (I), preferably Z is NH, NCH 3, CH 2, S or O. R is preferably hydroxyl, an optionally substituted lower alkoxyl, alkenoxyl, lower cycloalkyl-alkyloxy, aryloxy, heteroaryloxy, lower arylalkyloxy or lower heteroaryl-alkyloxy, an optionally substituted aryl, heteroaryl , or an optionally substituted aryl lower alkyl group. More preferably, R is an oxyl group, for example, alkoxy of 1 to 7 carbon atoms. Still more preferably, R is an alkoxy of 1 to 7 branched carbon atoms, or a substituted alkoxy of 1 to 7 carbon atoms. A preferred substituent for substituted alkoxy of 1 to 7 carbon atoms is a furyl or benzofuryl which is optionally substituted. R9 is preferably hydrogen. X is preferably selected from the group consisting of: In a more preferable way, X is: Q is preferably defined by -CR4R5 or -CR4R5-Q1-, where Q denotes -CReRy or -N R8-; R, R5, Re, R7 and Rs are independently selected from the group consisting of H, an optionally substituted lower alkyl, an optionally substituted lower alkenyl, an optionally substituted aryl, or an optionally substituted aryl lower alkyl group, for example methyl, (CH3) 2CH-CH2-, CH3-C (= CH2) -CH2-, (CH3) 3C-CH2-, benzyl; Q is more preferably selected from the group consisting of: -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH (CH3) -CH2-, -CH2-CH (CH3) -, -CH2-N H2-, -CH (CH3) -NH-, -CH2-N (CH3) -, -CH2-CH (CH2OH) -, or -CH (CH3) -NH (CH3) -; And it is preferably selected from the group consisting of: piperidinyl, azepanyl, azocanyl, phenyl, tetrahydropyranyl, 8-aza-bicyclo [3.2. 1] oct-8-yl, tetrahydropyridinyl, octahydroquinolizinyl, hexahydro-pyrroloxazinyl, octahydro-pyridoxazinyl, each of which is optionally substituted. Preferred optional substituents for Y are: hydroxyl, amino, halogen, alkyl of 1 to 7 carbon atoms. A second aspect of the invention provides a compound of the formula (I I), or a pharmaceutically acceptable salt, ester, or prodrug thereof: 00 wherein: Z 'is NH, N CH3, CH2, S or O. R' is hydroxyl, an optionally substituted alkoxy of 1 to 7 carbon atoms, cycloalkyl-alkyloxy of 1 to 7 carbon atoms, aryloxy, heteroaryloxy or aryl -alkyl oxyl of 1 to 7 carbon atoms, an optionally substituted aryl, heteroaryl, or an aryl-alkyl group of 1 to 7 carbon atoms optionally substituted; X 'is selected from the group consisting of: Q 'is selected from the group consisting of: -CH2-, CH2CH2-, -CH2CH2CH2-, -CH (CH3) -CH2-, -CH2-CH (CH3) -, -CH2-N H2-, CH (C H3) -N H-, -CH2-N (CH3) -, -CH2-CH (CH2OH) -, or -CH (CH3) -NH (CH3) -; Y 'is cycloalkyl of 3 to 1 8 carbon atoms, heterocycloalkyl, bridged cycloalkyl, bridged heterocycloalkyl, aryl, heteroaryl, fused aryl-heterocycloalkyl, all of which are optionally substituted in an independent manner once or more; the substituent or optional substituents on R 'are independently selected from the group consisting of halogen, hydroxyl, alkyl of 1 to 7 carbon atoms, mono- or dialkyl of 1 to 7 carbon-amino atoms, aminocarbonyl, mono- or di-alkyl of 1 to 7 carbon atoms-aminocarbonyl, amino, carboxyl of 1 to 7 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, heterocycloalkyl of 3 to 18 carbon atoms, alkyl of 1 to 7 carbon atoms carbon-carbonyl, alkoxy of 1 to 7 carbon atoms-carbonyl, nitrile, aryl; all of which, except halogen, are optionally substituted independently by one or more substituents selected from the group consisting of halogen, hydroxyl, alkyl of 1 to 7 carbon atoms, mono- or di-alkyl of 1 to 7 carbon-amino, aminocarbonyl, mono- or di-alkyl atoms of 1 to 7 carbon atoms-aminocarbonyl, amino, carboxyl of 1 to 7 carbon atoms, cycloalkyl of 3 to 1 2 carbon atoms, heterocycloalkyl of 3 to 1 8 carbon atoms, alkyl of 1 to 7 carbon atoms-carbonyl, alkoxy of 1 to 7 carbon atoms-carbonium, nitrile, aryl; the substituent or optional substituents on Y 'are independently selected from the group consisting of halogen, hydroxyl, alkyl of 1 to 7 carbon atoms, mono- or dialkyl of 1 to 7 carbon atoms; amino, aminocarbonyl, mono- or d i-alkyl of 1 to 7 carbon atoms-aminocarbonyl, amino, carboxyl of 1 to 7 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, heterocycloalkyl of 3 to 18 atoms carbon, alkyl of 1 to 7 carbon atoms-carbonyl, alkoxy of 1 to 7 carbon atoms-carbonyl, nitrile, aryl; all of which, except halogen, are optionally substituted independently by one or more substituents selected from the group consisting of halogen, hydroxyl, alkyl of 1 to 7 carbon atoms, mono- or di-alkyl of 1 to 7 carbon-amino, aminocarbonyl, mono- or di-alkyl atoms of 1 to 7 carbon atoms-aminocarbonyl, amino, carboxyl of 1 to 7 carbon atoms, cycloalkyl of 3 to 1 2 carbon atoms, heterocycloalkyl of 3 to 1 8 carbon atoms, alkyl of 1 to 7 carbon atoms, carbonyl of 1 to 7 carbon atoms, nitrile, aryl. Preferred compounds of the formula (I) are: [1- (2-azepan-1-yl-ethyl) -piperidin-4-yl] -amide of 4-methoxy-1 H-indole-2-carboxylic acid; 4-isopropoxy-1 H-indole-2-carboxylic acid [1 - (2-azepan-1-ethyl-ethyl) -piperidin-4-yl] -amide; . { 1 - [2- (4-hydroxy-piperidin-1-yl) -ethyl] -piperidin-4-yl} 4-isopropoxy-1 H-indole-2-carboxylic acid amide; [1- (2-azepan-1-yl-ethyl) -piperidin-4-yl] -amide of 4-cyclopropyl-methoxy-1H-l-2-carboxylic acid; . { 1- [2- (4-hydroxy-piperidin-1-yl) -ethyl] -piperidin-4-yl} -amide of 4-cyclopropylmethoxy-1 H -ind ol-2-carboxylic acid; . { 1 - [(S) -2- (4-hydroxy-piperidin-1-yl) -propyl] -piperidin-4-yl} 4-cyclopropylmethoxy-H-indole-2-carboxylic acid amide; . { 1 - [(S) -2- [3S, 4S) -4-hydroxy-piperidin-1-yl) -propl] -piperidin-4-yl} 4-cyclopropylmethoxy-1 H-indole-2-carboxylic acid amide; [1- (2-azepan-1-yl-ethyl) -piperidin-4-yl] -amide of 4-isobutoxy-1 H-indole-2-carboxylic acid; [1- (2-piperidin-1-yl-ethyl) -piperidin-4-yl] -amide of 4-isobutoxy-1H-indole-2-carboxylic acid; . { 1- [2- (RS) -2-methyl-piperidin-1-yl] -ethyl] -piperidin-4-yl} -amide of acid 4-isobutoxy-1H-indole-2-carboxylic acid; . { 1- [2- (4-methyl-piperidin-1-yl) -ethyl] -piperidin-4-yl} 4-isobutoxy-1H-indole-2-carboxylic acid amide; . { 1- [2 - ((2S, 6R) -2,6-dimethyl-piperidin-1-yl) -ethyl] -piperidin-4-yl} 4-isobutoxy-1 H-indole-2-carboxylic acid amide; . { 1- [2 - ((R) -3-hydroxy-piperidin-1-yl) -ethyl] -piperidin-4-yl} 4-isobutoxy-1 H-indole-2-carboxylic acid amide; . { 1- [2 - ((S) -3-hydroxy-piperidin-1-yl) -etl] -piperidin-4-yl} -amide of acid 4-isobutoxy-1 H-indole-2-carboxylic acid; . { 1- [2- (4-hydroxy-piperidin-1-yl) -ethyl] -piperidin-4-yl} 4-isobutoxy-1H-indole-2-carboxylic acid amide; . { 1- [2 - ((1R, 3S, 5S) -3-hydroxy-8-aza-bicyclo [32.1] oct-8-yl) -ethyl] -piperidin-4-yl} -amide of the acid or 4-isobutoxy-1 H-ind ol-2-carboxylic acid; . { 1 - [(S) -2- (4-Hydroxy-piperidin-1-yl) -propyl] -piperidin-4-yl} -amide of 4-isobutoxy-1 H-indole-2-carboxylic acid; [4- (2-azepan-1-ethyl-ethyl) -phenyl] -amide of the acid or 4-isobutoxy-1 H-indole-2-carboxylic acid; 4-Isobutoxy-1 H-indole-2-carboxylic acid (4- ({[methyl- (tetrahydro-pyran-4-yl) -amino] -methyl} -cyclohexyl) -amide; (4-. {[[Methyl- (tetrahydro-pyran-4-yl) -amino] -methyl] -phenyl] -amide of the acid 4-isobutoxy-1 H-indole-2-carboxylic acid; (4- ({R) -1 - [Methyl- (tetrahydro-pyran-4-yl) -amino] -ethyl} -phenyl) -amide of 4-isobutoxy-1 H-indole-2- carboxylic; 4-Cyclobutylmethoxy-1 H-indole-2-carboxylic acid [1 - (2-azepan-1-ethyl-ethyl) -piperidin-4-yl] -amide; . { 1 - [2- (3- (R) -hydroxy-piperidin-1-yl) -ethyl] -piperidin-4-yl} 4-cyclobutylmethoxy-1H-1-n-dol-2-carboxylic acid amide; . { 1 - [2- (4-Hydroxy-piperidin-1-yl) -ethyl] -piperidin-4-yl} 4-cyclobutylmethoxy-1 H-indole-2-carboxylic acid amide; . { 1 - [2 - ((3S, 4S) -4-hydroxy-3-methyl-piperidin-1-yl) -etl] -piperdin-4-yl} -a ida of 4-cyclobutylmethoxy-1 H-indole-2-carboxylic acid; . { 1 - [2 - ((1 R, 3S, 5S) -3-hydroxy-8-aza-bicyclo [3.2.1] oct-8-yl) -ethyl] -piperidin-4-yl} 4-cyclobutylmethoxy-1 H-indole-2-carboxylic acid amide; . { 1 - [8S) -2- (4-hydroxy-piperidin-1-yl) -propyl] -piperidin-4-yl} 4-cyclobutylmethoxy-1 H-indole-2-carboxylic acid amide; . { 1 - [(S) -2 - ((3S, 4S) -4-hydroxy-3-methyl-piperidin-1-yl) -propyl] -piperidin-4-yl} 4-cyclobutylmethoxy-1 H-indole-2-carboxylic acid amide; di clorhi while. { 1- [2- (4-hydroxy-piperidin-1-yl) -ethyl] -piperi in-4-yl} - 4- (3-methyl-butyloxy) -1H-indole-2-carboxylic acid amide; . { 1- [2- (4-hydroxy-piperidin-1-yl) -ethyl] -piperidin-4-yl} 4- pentylm ethoxy-1H-indole-2-carboxylic acid amide; 4- (1,2-Dimethyl-propoxy) -1H-indole-2-carboxylic acid [1- (2-azepan-1-yl-ethyl) -piperidin-4-yl] -amide; [1- (2-azepan-1-yl-eti!) -piperidin-4-yl] -amide of 4- (2,2-dimethyl-propoxy) -1H-indole-2-carboxylic acid; . { 1- [2- (4-hydroxy-piperidin-1-yl) -ethyl] -piperidin-4-yl} 4- (10-methyl-pentyloxy) -1H-indole-2-carboxylic acid amide; dihydrochloride. { 1- [2- (4-hydroxy-piperidin-1-yl) -ethyl] -piperidn-4-yl} - 4- (3,3-dimethyl-butoxy) -1H-indole-2-carboxylic acid amide; [1- (2-azepan-1-yl-ethyl-ethyl) -piperidin-4-yl] -amide of 4- (furan-2-ylmethoxy) -1 H-2-carboxylic acid; [4- (furan-3-ylmethoxy) -1H-2-carboxylic acid [1- (2-azepan-1-yl-ethyl) -piperidin-4-yl] -amide; . { 1- [2- (4-hydroxy-piperidin-1-yl) -ethyl] -piperidin-4-yl. { 4- (furan-3-ylmethoxy) -1H-indole-2-carboxylic acid amide; . { 1- [2 - ((3S, 4S) -4-hydroxy-3-methyl-piperidin-1-yl) -ethyl] -piperidin-4-yl} -20- (furan-3-ylmethoxy) -1H-indole-2-carboxylic acid amide; . { 1 - [(S) -2- (4-hydroxy-piperidin-1-yl) -propyl] -piperidin-4-yl} 4- (furan-3-ylmethoxy) -1H-indole-2-carboxylic acid amide; . { 1 - [(S) -2 - ((3S, 4S) -4-hydroxy-3-methyl-piperidin-1-yl) -propyl] -piperidin-4-yl} 4- (furan-3-ylmethoxy) -1H-indole-2-carboxylic acid amide; [4-Benzyloxy-1H-indole-2-carboxylic acid [1- (2-azepan-1-yl-ethyl) -piperidin-4-yl] -amide; dihydrochloride. { 1 - [(1S, 9aR) -1- (Octahydro-quinolizin-1-yl) methyl] -piperidin-4-yl} 4- (5-Choro-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid amide; [4- (5-Chlorobenzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid [1- (2-azepan-1-yl-ethyl) -piperidin-4-yl] -amide; . { 1- [2- (4-hydroxy-piperidin-1-yl) -ethyl] -piperidin-4-yl} 4- (5-Choro-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid amide; . { 1- [2 - ((3S, 4S) -4-hydroxy-3-methyl-piperidin-1-yl) -ethyl] -piperidn-4-yl} 4- (5-chloro-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid amide; dihydrochloride. { 1 - [(S) -2- (4-hydroxy-piperidin-1-yl) -propyl] -piperidin-4-yl} 4- (5-chloro-benzofuran-3-ylmethoxy) -1 H-indole-2-carboxylic acid amide; dihydrochloride. { 1 - [(S) -2 - ((3S, 4S) -4-hydroxy-3-methyl-piperidin-1-yl) -propyl] -piperidin-4-yl} 4- (5-chloro-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid amide; dihydrochloride. { 1 - [(1S, 9a) - (octahydro-quinolizin-1-yl) -methyl] -piperidin-4-yl} 4- (4-Fluoro-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid amide; dihydrochloride. { 1- [2- (4-hydroxy-piperidin-1-yl) -ethyl] -piperidin-4-yl} 4- (4-Fluoro-benzofuran-3-ylmethoxy) -1 H-indole-2-carboxylic acid amide; dihydrochloride. { 1 - [(1S, 9Ar) -1- (octahydro-quinolizin-1-yl) methyl] -piperidin-4-yl} 4- (benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid amide; . { 1- [2- (4-hydroxy-piperidin-1-yl) -ethyl] -piperidin-4-yl} 4- (benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid amide; . { 1- [2 - ((3S, 4S) -4-hydroxy-3-methyl-piperidin-1-yl) -etl] -piperidn-4-yl} - 4- (benzofuran-3-ylmethoxy) -1 H-indole-2-carboxylic acid amide; . { 1 - [(S) -2- (4-hydroxy-piperidin-1-yl) -propyl] -piperidin-4-yl} 4- (benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid amide; . { 1 - [(S) -2 - ((3S, 4S) -4-hydroxy-3-methyl-pipepdin-1-yl) -propyl] -p -peridin-4-yl} 4- (benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid amide; dihydrochloride. { 1 - [(1S, 9aR) -1- (octahydro-quinolizin-1-yl) -methyl] -piperidin-4-yl} - 4- (6-Fluoro-benzofuran-3-ylmethoxy) -1 H-indole-2-carboxylic acid amide hydrochloride. { 1- [2- (4-hydroxy-piperidin-1-yl) -ethyl] -piperidin-4-yl} 4- (6-Fluoro-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid amide; dihydrochloride. { 1- [2 - ((3S, 4S) -4-hydroxy-3-methyl-pipepdin-1-yl) -etii] -piperidin-4-yl} 4- (6-Fluoro-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid amide; dihydrochloride. { 1 - [(S) -2- (4-hydroxy-piperidin-1-yl) -propyl] -piperidin-4-yl} -amide of 4- (6-fluoro-benzofuran-3-ylmethoxy) -1 H -indole-2-carboxylic acid; . { 1 - [(S) -2 - ((3S, 4S) -4-hydroxy-3-methyl-piperidin-1-yl) -propyl] -piperidin-4-yl} 4- (6-Fluoro-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid amide; . { 1 - [(1S, 9a R) -1- (octahydro-quinolizin-1-yl) methyl] -piperidin-4-yl} 4- (5-Fluoro-benzofuran-3-yl-ethoxy) -1H-indole-2-carboxylic acid amide; dihydrochloride. { 1- [2- (4-hydroxy-piperidin-1-yl) -ethyl] -piperidin-4-yl} - 4- (5-Fluoro-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid amide; dihydrochloride. { 1- [2 - ((3R, 4R, 5S) -4-hydroxy-3,5-dimethyl-piperidin-1-yl) -ethyl] -piperidin-4-yl} 4- (5-Fluoro-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid amide; dihydrochloride. { 1 - [(S) -2- (4-hydroxy-piperidin-1-yl) -propyl] -piperidin-4-yl} 4- (5-Fluoro-benzofuran-3-i-methoxy) -1H-indole-2-carboxylic acid amide; . { 1 - [(S) -2 - ((3S, 4S) -4-hydroxy-3-methyl-piperidin-1-yl) -propii] -piperidin-4-yl} 4- (5-Fluoro-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid amide; dihydrochloride. { 1 - [(1S, 9aR) -1- (octahydro-quinolizin-1-yl) methyl] -piperidin-4-yl} 4- (7-fluoro-benzofuran-3-ylmethoxy) -1 H-indole-2-carboxylic acid amide; dihydrochloride. { 1 - [(1S, 9aR) -1- (octahydro-quinolizin-1-ylmethyl] -piperidin-4-yl} -amide of 4- (4,6-difluoro-benzofuran-3-ylmethoxy) - 1H-indole-2-carboxylic acid; 4- (4-hydroxy-piperidin-1-yl) -ethyl] -piperidin-4-yl} -amide of 4- (4, 6-difluoro-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid, di., 1- [2 - ((3S, 4S) -4-hydroxy-3-methyl-piperidin-1-yl) dihydrochloride. ) -ethyl] -piperidin-4-yl.} - 4- (4,6-difluoro-benzofuran-3-ylmethoxy) -1 H-indole-2-carboxylic acid amide; dihydrochloride. { 1 - [(S) -2- (4-hydroxy-piperidin-1-yl) -propyl] -piperidin-4-yl} 4- (4,6-difluoro-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid amide; dihydrochloride. { 1 - [(S) -2 - ((3S, 4S) -4-hydroxy-3-methyl-piperidin-1-yl) -propyl] -piperidin-4-yl} 4- (4,6-difluoro-benzofuran-3-i-methoxy) -1H-indole-2-carboxylic acid amide; dihydrochloride. { 1 - [(1S, 9aR) -1- (Octahydro-quinolizin-1-yl) methyl] -piperidin-4-yl. { 4- (7-chloro-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid amide; dihydrochloride. { 1 - [(1S, 9aR) -1- (Octahydro-quinolizin-1-yl) methyl] -piperidin-4-yl} 4- (6-chloro-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid amide; . { 1- [2- (4-hydroxy-piperidin-1-yl) -ethyl] -piperidin-4-yl} 4- (6-chloro-benzofuran-3-yl-methoxy) -1H-indole-2-carboxylic acid amide; . { 1- [2 - ((3SI4S) -4-hydroxy-3-methyl-piperidin-1-yl) -ethyl] -piperidin-4-yl} 4- (6-Choro-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid amide; dihydrochloride. { 1 - [(S) -2- (4-hydroxy-piperidin-1-yl) -propyl] -piperidin-4-yl} 4- (6-chloro-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid amide; dihydrochloride. { 1 - [(1S, 9aR) -1- (Octahydro-quinolizin-1-yl) methyl] -piperidin-4-yl} 4- (4-Choro-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid amide; dihydrochloride. { 1- [2- (4-Hydroxy-piperidin-1-ii) -ethyl] -piperidin-4-yl} 4- (4-chloro-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid amide; dihydrochloride. { 1- [2 - ((3R, 4R, 5S) -4-hydroxy-3,5-dimethyl-piperidin-1-yl) -ethyl] -piperidin-4-yl} 4- (4-chloro-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid amide; . { 1 - [(S) -1- (4-hydroxy-piperidin-1-yl) -propl] -piperidin-4-yl} 4- (4-chloro-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid amide; dihydrochloride. { 1 - [(1S, 9aR) -1- (Octahydro-quinolizin-1-yl) methyl] -piperidin-4-yl} 4- (7-methoxy-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid amide; [1- (2-piperidin-1-yl-methyl) -piperidin-4-yl] -amide of 4- (7-methoxy-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid; dihydrochloride. { 1- [2- (4-hydroxy-piperidin-1-yl) -etl] -piperidin-4-yl} 4- (7-methoxy-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid amide; dihydrochloride. { 1- [2 - ((3S, 4S) -4-hydroxy-3-methyl-p-perpent-1-yl) -ethyl] -piperidin-4-yl} 4- (7-methoxy-benzofuran-3-ylmethoxy) -1 H-indole-2-carboxylic acid amide; dihydrochloride. { 1 - [(S) -2- (4-hydroxy-piperidin-1-yl) -propl] -piperidin-4-yl} 4- (7-methoxy-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid amide; . { 1 - [(S) -2 - ((3S, 4S) -4-hydroxy-3-methyl-pipepdin-1-yl) -propyl] -piperidin-4-yl} 4- (7-methoxy-benzofuran-3-ylmethoxy) -1 H-indole-2-carboxylic acid amide; . { 1 - [(1S, 9aR) -1- (Octahydro-quinolizin-1-yl) methyl] -piperidin-4-yl} 4- (6-methoxy-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid amide; [1- (2-azepan-1-yl-ethyl) -piperidin-4-yl] -amide of 4- (6-methoxy-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid; . { 1- [2- (4-hydroxy-piperidin-1-yl) -ethyl] -piperidin-4-yl} -amide of 4- (6-methoxy-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid; dihydrochloride. { 1- [2 - ((3S, 4S) -4-hydroxy-3-methyl-piperidin-1-yl) -ethyl] -piperidin-4-yl} 4- (6-methoxy-benzofuran-3-ylmethoxy) -1 H-indole-2-carboxylic acid amide; . { 1 - [(S) -2- (4-hydroxy-piperidin-1-yl) -propyl] -piperidin-4-yl} 4- (6-methoxy-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid amide; . { 1 - [(S) -2 - ((3S, 4S) -4-hydroxy-3-methyl-piperidin-1-yl) -propyl] -piperidin-4-yl} 4- (6-methoxy-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid amide; [4- (5-methoxy-benzofuran-3-i-methoxy) -1H-indole-2-carboxylic acid [1- (2-azepan-1-yl-ethyl) -piperidin-4-yl] -amide; . { 1- [2- (4-hydroxy-piperidin-1-yl) -ethyl] -piperidin-4-yl} 4- (5-methoxy-benzofuran-3-i-methoxy) -1H-indole-2-carboxylic acid amide; . { 1 - [(1S, 9aR) -1- (octahydro-quinolizin-1-yl) methyl] -piperdin-4-yl} 4- (4-methoxy-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid amide; . { 1- [2- (4-hydroxy-piperidin-1-yl) -ethyl] -piperidin-4-yl} 4- (4-methoxy-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid amide; . { 1- [2 - ((3S, 4S) -4-hydroxy-3-methyl-piperidin-1-yl) -ethyl] -p -peridin-4-yl} 4- (4-methoxy-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid amide; . { 1 - [(S) -2- (4-hydroxy-piperidin-1-yl) -propyl] -piperidin-4-yl} 4- (4-methoxy-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid amide; . { 1 - [(S) -2 - ((3S, 4S) -4-hydroxy-3-methyl-piperidin-1-yl) -propyl] -piperidin-4-yl} 4- (4-methoxy-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid amide; dihydrochloride. { 1 - [(1S, 9aR) -1- (Octahydro-quinolizin-1-yl) ethyl] -piperidin-4-yl} 4- (4,6-dimethoxy-benzofuran-3-i-methoxy) -1H-indole-2-carboxylic acid amide; . { 1- [2- (4-hydroxy-piperidin-1-yl) -ethyl] -piperidin-4-yl} 4- (4,6-dimethoxy-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid amide; dihydrochloride. { 1- (4S, 4S) -4-hydroxy-3-methyl-piperidin-1-yl) -ethyl] -piperidin-4-yl] -amide of 4- (4,6-dimethoxy-benzofuran) -3-ylmethoxy) -1H-indole-2-carboxylic acid; . { 1 - [(S) -2- (4-hydroxy-piperidin-1-yl-propyl] -piperidin-4-yl} -amide of 4- (4,6-dimethoxy-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid; . { 1 - [(S) -2 - ((3S, 4S) -4-hydroxy-3-methyl-piperidin-1-yl) -propyl] -piperidin-4-yl} 4- (4,6-dimethoxy-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid amide; dihydrochloride. { 1 - [(1S, 9aR) -1- (octahydro-quinolizin-1-yl) methyl] -piperidin-4-yl} 4- (5,6-dimethyl-benzofuran-3-ylmethoxy) -1 H-indole-2-carboxylic acid amide; . { 1- [2- (4-hydroxy-piperidin-1-yl) -ethyl] -piperidin-4-yl} 4- (5,6-dimethyl-benzofuran-3-ylmethoxy) -1 H-indole-2-carboxylic acid amide; dihydrochloride. { 1- [2 - ((3S, 4S) -4-hydroxy-3-methyl-piperidin-1-yl) -ethyl] -piperidin-4-yl} 4- (5,6-dimethyl-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid amide; . { 1 - [(S) -2- (4-hydroxy-piperidin-1-yl) -propyl] -piperidin-4-yl} 4- (5,6-Di-ethyl-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid amide; dihydrochloride. { 1 - [(S) -2 - ((3S, 4S) -4-hydroxy-3-methyl-piperidin-1-yl) -propyl] -piperidin-4-yl} 4- (5,6-dimethyl-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid amide; . { 1 - [(S) -2- (4-hydroxy-piperidin-1-yl) -propyl] -piperidin-4-yl} 4- (4-ethoxy-phenyl) -1H-indole-2-carboxylic acid amide; . { 1 - [(S) -2- (4-hydroxy-piperidin-1-yl) -propyl] -piperidin-4-yl} 4- (4-methoxy-phenyl) -1H-indole-2-carboxylic acid amide; 4-Phenoxy-1H-indole-2-carboxylic acid [1- (2-azepan-1-yl-ethyl) -piperidin-4-yl] -amide; 4-M-Tolyloxy-1 H-indole-2-carboxylic acid [1- (2-azepan-1-yl-ethyl) -piperidin-4-yl] -amide; . { 1- [2- (3- (RS) -hydroxy-piperidin-1-yl) -ethyl] -piperidin-4-yl} 4-m-tolyloxy-1 H-indole-2-carboxylic acid amide; . { 1- [2- (4-hydroxy-piperidin-1-yl) -ethyl] -piperidin-4-yl} 4-m-tolyloxy-1H-indole-2-carboxylic acid amide; 4-p-Tolyloxy-1 H-indole-2-carboxylic acid [1- (2-azepan-1-yl-ethyl) -piperidin-4-yl] -amide; . { 1- [2- (3- (RS) -hydroxy-piperidin-1-yl) -ethyl] -piperidin-4-yl} 4-p-tolyloxy-1 H-indole-2-carboxylic acid amide; . { 1- [2- (4-hydroxy-piperidin-1-yl) -ethyl] -piperidin-4-yl} 4-p-tolyloxy-1H-indole-2-carboxylic acid amide; [1- (2-azepan-1-yl-ethyl) -piperidin-4-yl] -amide of 4- (3-fluoro-phenoxy) -1H-indole-2-carboxylic acid; . { 1- [2- (4-hydroxy-piperidin-1-yl) -ethyl] -piperidin-4-yl} 4- (3-fluoro-phenoxy) -1H-indole-2-carboxylic acid amide; [4- (4-Fluoro-phenoxy) -1H-indole-2-carboxylic acid [1- (2-azepan-1-yl-ethyl) -piperidin-4-yl] -amide; . { 1- [2- (4-hydroxy-piperidin-1-yl) -ethyl] -piperidin-4-yl} 4- (4-Fluoro-phenoxy) -1H-indole-2-carboxylic acid amide; [1- (2-azepan-1-yl-ethyl) -piperidin-4-yl] -amide of 4- (3,4-difluorophenoxy) -1H-indole-2-carboxylic acid; [1- (2-azepan-1-yl-ethyl) -piperidin-4-yl] -amide of 4- (3,5-difluorophenoxy) -1H-indole-2-carboxylic acid; . { 1- [2- (3-RS-hydroxy-piperidin-1-yl) -ethyl] -piperidin-4-yl} -amide of acid 4- (3,5-difluoro-phenoxy) -1 H -indole-2-carboxylic acid; . { 1- [2- (4-hydroxy-piperidin-1-yl) -ethyl] -piperidin-4-yl} 4- (3,5-difluoro-phenoxy) -1 H-indole-2-carboxylic acid amide; [1- (2-azepan-1-yl-ethyl) -piperidin-4-yl} 4- (6-chloro-pyridin-2-yloxy) -1H-indole-2-carboxylic acid amide; [1- (octahydro-quinolizin-1-ylmethyl) -piperidin-4-yl] -amide dihydrochloride of 4-isobutoxy-1H-indole-2-carboxylic acid; [1- (1-methyl-piperidin-3-ylmethyl) -piperidin-4-yl] -amide of 4-iobutoxy-1 H-indole-2-carboxylic acid; . { 1 - [(S, 9aR) -1- (Octahydro-quinolizin-1-yl) methyl] -piperidin-4-yl} -amide of 4-cyclobutylmethoxy-1 H-indole-2-carboxylic acid; . { 1 - [(S) -2 - ((3R, 4R) -4-hydroxy-3-methyl-piperidin-1-yl) -propyl] -piperidin-4-yl} -amide of 4-cyclobutylmethoxy-1 H-indole-2-carboxylic acid; . { 1 - [(S) -2 - ((3S, 4R, 5S) -34-dihydroxy-5-methyl-piperidin-1-yl) -propyl] -piperidin-4-yl} 4-cyclobutylmethoxy-1 H-indole-2-carboxylic acid amide; . { 1 - [(R) -3-hydroxy-2 - ((3S, 4S) -4-hydroxy-3-methyl-piperidin-1-yl) -propyl] -piperidin-4-yl} 4-cyclobutylmethoxy-1 H-indole-2-carboxylic acid amide; . { 1 - [(1S, 9aR) -1- (Octahydro-quinolizin-1-yl) methyl] -piperidin-4-yl} 4- (furan-3-ylmethoxy) -1H-indole-2-carboxylic acid amide; . { 1 - [(S) -2 - ((3R, 4R) -4-hydroxy-3-methyl-piperidin-1-yl) -propyl] -piperidin-4-yl} 4- (furan-3-ylmethoxy) -1H-indole-2-carboxylic acid amide; [4- (2-methyl-thiazol-4-ylmethoxy) -1H-indole-2-carboxylic acid [1- (octahydro-quinolizin-1-ylmethyl) -piperidin-4-yl] -amide; . { 1- [2- (3,4-Dihydroxy-5-methyl-piperidin-1-yl) -propyl] -piperidin-4-yl} -amide of 4- (benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid; . { 1 - [(S) -2 - ((3RS, 4SR) -3,4-dihydroxy-pperidin-1-yl) -propyl] -piperidin-4-yl} 4- (5-Fluoro-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid amide; . { 1 - [(S) -2- (3RS, 4SR) -3,4-dihydroxy-piperidin-1-yl) -propl] -piperidin-4-yl} 4- (5-chloro-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid amide; . { 1 - [(9S, 9aS) -1- (Octahydro-pyrido [2,1-c] [1,4] oxazin-9-yl) methyl] -piperidin-4-yl} 4- (5-chloro-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid amide; . { 1 - [(8S, 8aS) -1- (hexahydro-pyrrolo [2,1-c] [1,4] oxazin-8-yl) methyl] -piperidin-4-yl} 4- (5-chloro-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid amide; . { 1 - [(1S, 9aR) -1- (Octahydro-quinolizin-1-yl) methyl] -piperidin-4-yl} 4- (4-methoxy-phenyl) -1H-indole-2-carboxylic acid amide; . { 1 - [(1S, 9aR) -1- (Octahydro-quinolizin-1-yl) methyl] -piperidin-4-yl} -amide of 4- (4-ethoxy-phenyl) -1H-indole-2-carboxylic acid; . { 1 - [(S) -2 - ((3S, 4S) -4-hydroxy-3-methyl-piperidin-1-yl) -propyl] -piperidin-4-yl} 4- (6-methoxy-pyridin-3-yl) -1 H-indole-2-carboxylic acid amide; . { 1- [2 - ((3S, 4S) -4-hydroxy-3-methyl-piperidin-1-yl) -ethyl] -piperidin-4-yl} - 4- (6-methoxy-pyridin-3-yl) -1 H-indole-2-carboxylic acid amide; . { 1 - [(1S, 9aR) -1- (octahydro-quinolizin-1-yl) methyl] -piperidin-4-yl} 4-p-tolyloxy-1H-indole-2-carboxylic acid amide; [1- (2-azepan-1-yl-1S-methyl-ethyl) -piperidin-4-yl] -amide of 4-isobutoxy-1 H-indole-2-carboxylic acid; [1- (2-azepan-1-yl-1 R-methyl-ethyl) -piperidin-4-yl] -amide of 4-isobutoxy-1 H-indole-2-carboxylic acid; [1- (2S-azepan-1-yl-propyl) -piperidin-4-yl] -amide of 4- (furan-3-ylmethoxy) -1H-indole-2-carboxylic acid; [1- (2R-azepan-1-yl-propyl) -piperidin-4-yl] -amide of 4- (furan-3-ylmethoxy) -1H-indole-2-carboxylic acid; . { 1- [2- (3,6-Dihydro-2H-pyridin-1-yl) -ethyl] -piperidin-4-yl} 4-isobutoxy-1 H-indole-2-carboxylic acid amide; . { 1- [2- (4-hydroxy-azepan-1-yl) -ethyl] -piperidin-4-yl} -amide of 4-isobutoxy-1 H-indole-2-carboxylic acid; . { 1- [2- (3-amino-azepan-1-yl) -ethyl] -piperidin-4-yl} 4-isobutoxy-1 H-indole-2-carboxylic acid amide; . { 1- [2- (3-Fluoro-piperidin-1-yl) -ethyl] -piperidin-4-yl} 4-isobutoxy-1H-indole-2-carboxylic acid amide; [4- (5-Chloro-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid [4- (2-piperidin-1-yl-ethyl) -phenyl] -amide; . { 4- [2- (4-hydroxy-piperidin-1-yl) -ethyl] -phenyl} 4- (5-chloro-benzofu-ran-3-yl-ethoxy) -1H-indole-2-carboxylic acid amide; 4-Phenyl-1H-indole-2-carboxylic acid [1- (2-azepan-1-ethyl-ethyl) -piperidin-4-yl] -amide; 4- (4-Trifluoromethyl-phenyl) -1H-indole-2-carboxylic acid [1- (2-azepan-1-yl-ethyl) -piperidin-4-yl] -amide; 4-p-tolyl-1 H-indole-2-carboxylic acid [1- (2-azepan-1-yl-ethyl) -piperidin-4-yl] -amide; 4- (4-Dimethylamino-phenyl) -1 H -indole-2-carboxylic acid [1- (2-azepan-1-yl-ethyl) -piperidin-4-yl] -amide; 4-Benzo [12,5] oxadiazol-5-yl-1H-indole-2-carboxylic acid [1- (2-azepan-1-yl-ethyl) -piperidin-4-yl] -amide; [4- (4-methoxy-phenyl) -1H-indole-2-carboxylic acid [1- (2-azepan-1-yl-ethyl) -piperidin-4-yl] -amide; [1- (2-azepan-1-yl-ethyl) -piperidin-4-yl] -amide of 4- (3-cyano-phenyl) -1H-indole-2-carboxylic acid; [4- (4-Ethoxy-phenyl) -1H-indole-2-carboxylic acid [1- (2-azepan-1-yl-ethyl) -piperidin-4-yl] -amide; [4- (3- (3-methoxy-propoxy) -phenyl] -1H-indole-2-carboxylic acid [1- (2-azepan-1-yl-ethyl) -piperidin-4-yl] -amide; 4- (4-Trifluoromethoxy-phenyl) -1H-indole-2-carboxylic acid [1- (2-azepan-1-yl-ethyl) -piperidin-4-yl] -amide; [1- (2-azepan-1-yl-ethyl) -piperidin-4-yl] -amide of 4- (2,4-dimethoxy-phenyl) -1H-indole-2-carboxylic acid; [1- (2-azepan-1-yl-ethyl) -piperidin-4-yl] -amide of 4- (3,4-dimethoxy-p-n-1) -1-H-indole-2-carboxylic acid; 4-Benzo [1, 3] dioxol-5-yl-1H-indole-2-carboxylic acid [1- (2-azepan-1-yl-ethyl) -piperidin-4-yl] -amide; 4-Pyridin-4-yl-1H-indole-2-carboxylic acid [1- (2-azepan-1-yl-ethyl) -piperidin-4-yl] -amide; [1- (2-azepan-1-yl-ethyl) -piperidin-4-yl] -amide of 4- (6-methoxy-pyridin-3-yl) -1H-indole-2-carboxylic acid; [1- (2-piperidin-1-yl-ethyl) -piperidin-4-yl] -amide of 4- (4-ethoxy-phenyl) -1H-indole-2-carboxylic acid; . { 1- [2- (4-hydroxy-piperidin-1-yl) -ethyl] -piperidin-4-yl} 4- (4-methoxy-phenyl) -1H-indole-2-carboxylic acid amide; . { 1- [2- (4-hydroxy-piperidin-1-yl) -ethyl] -p -peridin-4-yl} 4- (4-ethoxy-phenyl) -1H-indole-2-carboxylic acid amide; . { 1- [2- (4-hydroxy-piperidin-1-yl) -ethyl] -piperidin-4-yl} 4- (6-methoxy-pyridin-3-yl) -1H-indole-2-carboxylic acid amide; . { 1- [2- (3-hydroxy-8-aza-bicyclo [3.2.1] oct-8-yl) -ethyl] -piperidin-4-yl} 4- (4-methoxy-phenyl) -1H-indole-2-carboxylic acid amide; . { 1- [2- (3-hydroxy-8-aza-bicyclo [3.2.1] oct-8-yl) -ethyl] -piperidin-4-yl} -amide of 4- (6-methoxy-pyridin-3-yl) -1H-indole-2-carboxylic acid; [1- (2-azepan-1-yl-ethyl) -piperidin-4-yl] -amide of 4-hydroxy-1H-indole-2-carboxylic acid; 4-methoxy-benzo [b] thiophene-2-carboxylic acid [1- (2-azepan-1-yl-ethyl) -piperidin-4-yl] -amide; 4-α-Butoxy-benzo [b] thiophene-2-carboxylic acid [1- (2-azepan-1-yl-ethyl) -piperidin-4-yl] -amide; [1- (2-piperidin-1-ethyl-ethyl) -piperidin-4-yl] -amide of 4-isobutoxy-benzo [b] thiophene-2-carboxylic acid; [1- (2-azepan-1-ethyl-ethyl) -piperidin-4-yl] -amide of 4-methoxy-benzofuran-2-carboxylic acid. According to a third aspect of the invention, a compound of the formula (I) is provided for use as a pharmaceutical product for the prevention, reduction or treatment of an autoimmune or inflammatory disease or condition. According to a fourth aspect of the invention, there is provided a process for the preparation of a compound of the formula (I), which comprises: (a) reacting a compound of the formula (11): 0") wherein R" is H or a lower alkyl group, with a compound of the formula N H2-XQY, defining the groups R, R9, Z, X, Q, and Y above, or (b) for the preparation of the compounds of the formula (I) wherein X is piperidin-4-yl and Q is -CH2-C H2-, and Y is a group having the formula -N R7R8, wherein R7 and R8 are linked to define collectively a hetero-cycloalkyl, bridged cycloalkyl, bridged heterocycloalkyl, heteroaryl, or aryl-heterocycloalkyl fused, reacting a compound of the formula (IV): (IV) with a compound of the formula N H R7R8, wherein R7 and R8 are as defined above, and R, R9, and Z are as defined above; or (c) for the preparation of compounds of the formula (I), wherein X is piperidin-4-yl and Q is CH2-, reacting a compound of the formula (V): (V) wherein R, R9 and Z are as defined above, with a compound of the formula HO-CH2-Y, wherein Y is as defined above; or (d) for the preparation of compounds of the formula (I), wherein R is an optionally substituted aryl group, appropriately use the group B r in a compound of the formula (VI) to replace this substituted aryl group : (SAW) wherein Z, R9, X, Q and Y are as defined above; and recovering the resulting compounds of formula (I) in free or salt form. The process of the invention is carried out in a conventional manner. The process variant (a) is a condensation reaction between acid or ester and amine. It is conveniently carried out by reacting the acid with the amine in the presence of coupling agents, for example TBTU / DI EA in a solvent such as dimethylformamide, or by reacting the ester with the amine in the presence of a coupling agent such as HOBT / EDC. The process variant (B) is a condensation reaction which is conveniently carried out using a reagent such as cyanomethyltriphenyl phosphonium iodide and H unig base. The process variant (c) is a condensation reaction which is also conveniently carried out using a reagent, such as cyanomethyltriphenyl phosphonium iodide and H unig base. The process variant (d) is a substitution reaction and is conveniently carried out using the appropriate aryl boronic acid and triphenylphosphine in the presence of lead acetate (I I). The compounds of the invention can be recovered from the reaction mixture, and can be purified in a conventional manner. The isomers, such as enantiomers, can be obtained in a conventional manner, for example by fractional crystallization or asymmetric synthesis from the corresponding asymmetrically substituted starting materials, for example optically active. The starting materials and the intermediates are known or can be prepared according to known methods or in a manner analogous to that described in the Examples. According to a fifth aspect of the invention, a compound that can be obtained by any of the aforementioned processes is provided. According to a sixth aspect of the invention, there is provided a pharmaceutical composition comprising a compound of the formula (I) in association with a pharmaceutically acceptable diluent or carrier. According to a seventh aspect of the invention, there is provided the use of a compound of the formula (I) in the manufacture of a medicament for use in the treatment of an autoimmune or inflammatory disease or condition. According to an eighth aspect of the invention, there is provided a method for inhibiting chemokine receptors or macrophage proteins, or for reducing inflammation in a subject in need of such treatment, the method of which comprises admiring this subject an effective amount of a compound of the formula (I). According to a ninth aspect of the invention, there is provided a method for the treatment of an inflammatory or autoimmune disease or condition, which comprises administering to this subject an effective amount of a compound of the formula (I). The agents of the invention can be prepared by the processes described below.

EXPERIMENTAL S ECTION Abbreviations; BOC: Terbutyloxycarbonyl B Boocc22OO :: Di-t-butyl dicarbonate DCC: Dicyclohexyl-carbodiimide DCE: Dichloroethane DCM: Dichloromethane DEAD: Diethyl azadicarboxylate D DII EEAA :: Ethyl-di-isopropyl-amine DMAP: Dimethyl-pyridine- 4-yl-amine DME: 1,2-dimethoxy-ethane DMF: N, N-dimethyl-formamide EDC: (3-Dimethylaminopropyl) -ethyl-carbodiimide hydrochloride Ether: Ethoxy-ethane EtOH: Ethanol EtOAc: Acetic acid ethyl ester HCl: Hydrochloric acid HOBT: Benzotriazole-1-ol LAH Lithium aluminum hydride LDA: Lithium di-isopropylamine MeOH: Methanol NaOH: Sodium hydroxide NMP: 1-methyl-pyrrolidin-2-one Pd / C : Palladium on carbon TBAF: Tetrabutylammonium fluoride TBME: t-butyl methyl ether TBDMS: t-butyl-dimethyl-silyl TBTU: O- (1H-benzotriazol-1-yl) -N, N, N 'tetrafluoroborate, N'- tetramethyluronium t-BuOH 2-methyl-propan-2-ol TFA: Trifluoroacetic acid THF: Tetrahydrofuran The 1 H-NMR spectra are recorded on a 400 MHz Varian Gemini NMR spectrometer. Significant peaks are tabulated in the order: multiplicity (s, singlet, d, doublet, t, triplet, q, quartet, m, multiplet; br, broad), and number of protons. The Electron Spray Ionization (ESI) mass spectra are recorded on a Hewlett Packard 5989A mass spectrometer. The results of mass spectrometry are reported as the ratio of mass to load. Purification HPLC purifications are carried out with columns XTerraTM RP18 of 19x150 millimeters, using acetonitrile / water or MeOH / water as eluent systems. All reagents, starting materials, and intermediates used in these examples are available from commercial sources, or are readily prepared by methods known to those skilled in the art.

Synthesis of the Amine Building Blocks The amines 1, 5, 7, 10, 12, 14, 17, 20, 21, 24, 27, 30, 35, 41, 50, 56, 60, 61, 63, 67, 70 and 72 are prepared according to the reaction schemes illustrated below: Reaction Scheme 1: (2) < 3. 4). (6) (D. (5) Reaction Scheme 2: (3) (ß) Í9), (11), < -t3), < 1S) < 7). (10), (12),. { 14) Reaction Scheme 3: (Zaragoza) (28), (26), (29) (21), (24), (27) Reaction Scheme 4: (33) (1 enantiomer) (34) (30) Reaction Scheme 5: Reaction Scheme 6: Reaction Scheme 7: Reaction Scheme 8: b Reaction Scheme 9: Reaction Scheme 10: Reaction Scheme 11 (73) (72) Synthesis of 1- (2-piperidin-1-yl-ethyl) -piperidin-4-ylamine tri-hydrochloride (1) (reaction scheme 1): (1) (1-Benzyl-piperidin-4-yl) -carbamic acid tertiary butyl ester 1-benzyl-piperidin-4-ylamine (50 grams, 262.76 mmol) is dissolved in a mixture of 200 milliliters of water, 145 milliliters of 2 molar aqueous sodium hydroxide, and 350 milliliters of t-BuOH at 0 ° C.

A solution of Boc2O (63.1 grams, 1.1 equivalents) in 150 milliliters of t-BuOH is added dropwise within 1 hour at 0 ° C. A white suspension is formed, which is left stirring overnight at room temperature. The reaction mixture is diluted with ether and washed with water. The organic layers are dried over anhydrous sodium sulfate and evaporated under reduced pressure. Yield: 71.5 grams of a pale yellow solid (93 percent). MS (ESI): 291 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 7.2-7.35 (m, 5H), 6.77 (br d, 1H), 3.44 (s, 2H), 3.22 (br m, 1H), 2.75 (m, 2H), 1.95 (dt, 2H), 1.68 (m, 2H), 1.38 (s, 9H), 1.36 (dt, 2H). (2) Piperidin-4-yl-carbamic acid terbutil ester (3) A solution of the above ester 2 (66 grams, 227.27 mmol) in 1 liter of ethanol is hydrogenated under normal pressure with 10 grams of Pd / C (10 per cent). cent) for 16 hours at room temperature. The mixture is filtered on Celite, and evaporated under reduced pressure. Recrystallization from ether gave 34.5 grams (76 percent) of white crystals. MS (ESI): 201 [M + H] +, 401 [2M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 6.7 (br d, NH), 3.22 (br m, 1H), 2.88 (dt, 2H), 2.39 (dt, 2H), 1.8 (brs, NH), 1.6 (dt, 2H), 1.35 (s, 9H), 118 (dt, 2H). (3) 1 - (2-Piperidin-1-yl-ethyl) -piperidin-4-yl] -carbamic acid terbutil ester Piperidin-4-yl-carbamic acid terbutil ester is dissolved (3) (4.8 grams, 23.72 millimoles), 1- (2-chloro-ethyl) -piperidine hydrochloride (53 grams, 26.09 millimoles) and DIEA (8.9 millimeters, 52.18 millimoles) in 150 milliliters of chloroform, and put on reflux for 18 hours. After the addition of more 1- (2-chloro-ethyl) -piperidine hydrochloride (2.65 grams, 13.05 mmol) and DIEA (4.4 milliliters, 26.09 mmol), the reaction mixture is refluxed for a further 4 hours. After cooling to room temperature, the mixture is diluted with DCM and washed with water and 5% aqueous sodium carbonate aqueous solution. Evaporation gave 7.3 grams of brown crystals, which are recrystallized from ether / hexane. Yield: 5.3 grams (72 percent) of beige crystals. MS (ESI): 312 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 6-75 (br d, NH), 3.18 (br m, 1 H), 2.8 (m, 2 H) , 2.23-2.4 (m, 8H), 1.92 (dt, 2H), 1.65 (m, 2H), 1.48 (m, 4H), 1.38 (s, 9H), 1.3-1.4 (m, 4H). (4) 1- (2-piperidin-1-yl-ethyl) -piperidin-4-ylamine trichlorohydrate (D Ester 4 above (5.2 grams, 16.7 millimoles) is suspended at 0 ° C in 60 milliliters of a 4M solution of HCl in dioxane, and stirred at room temperature for 3 hours. After evaporation under reduced pressure, the crude product is dried under a high vacuum. Yield: 5.3 grams (99 percent) of light beige crystals. MS (ESI): 212 [M + H] +, 1 H-NMR (D 2 O): d (ppm) 4.14 (m, 2H), 4.04 (br m, 5H), 3.8 (m, 4H), 3.65 (dt, 2H), 2.85 (d, 2H), 2.45 (m, 2H), 2.35 (m, 4H), 2.15 (m, 2H). Synthesis of 1- (2-azepan-1-yl-ethyl) -piperidin-4-ylamine trichlorohydrate (5) (reaction scheme 1): (1) [1- (2-azepan-1-yl-yl) -piperidin-4-yl] -carbamic acid terbutil ester (6) It is synthesized in an analogous manner to ester 4, starting from sodium chloride. - (hexamethyleneimino) ethyl (13.8 grams) and ester 3 (12.4 grams). Yield: 14 grams of a colorless solid (63 percent). MS (ESI): 326 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 6.75 (br d, NH), 3.18 (br m, 1 H), 2.8 (m, 2 H), 2.3 -2.6 (m, 8H), 1.95 (dt, 2H), 1.65 (m, 2H), 1.55 (m, 6H), 1.38 (s, 9H), 1.3-1.4 (m, 4H). (2) 1- (2-azepan-1-yl-ethyl) -piperidin-4-ylamine trichlorohydrate It is prepared in a manner analogous to 1, starting from ester 6 (14 grams). Yield: 13 grams (90 percent) of a colorless solid. MS (ESI): 226 [M + H] +, 1 H-NMR (120 ° C, DMSO-d 6): d (ppm) 8.5 (br, NH 3 +), 3.5 (m, 5H), 3.4 (m, 2H) , 3.3 (m, 4), 2.97 (m, 2H), 2.18 (m, 2H), 2.05 (m, 2H), 19 (m, 4H), 1. (m, 4H). Synthesis of 1-r2- (4-methyl-piperidin-1-yl) -etip-piperidin-4-ylamine trichlorohydrate (7) (reaction scheme 2) (1) [1- (2-Hydroxy-ethyl) -piperidin-4-yl] -carbamic acid terbutil ester (8) To a solution of piperidin-4-yl-carbamic acid terbutil-ester 3 (10-gram, 50 millimoles) in 100 milliliters of methanol, sodium carbonate (21.2 grams, 200 millimoles) and 2-bromoethanol (7.1 milliliters, 100 millimoles) are added. The mixture is stirred overnight. Then the solvents are evaporated, and the residue is triturated with DCM, filtered, and evaporated again. The crude product is purified by chromatography using EtOAc / MeOH (saturated with ammonia): 9/1. Yield: 8.07 (66 percent). MS (ESI): 245.2 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 6.75 (rd, 1H), 4.34 (t, 1H), 3.46 (q, 2H), 3.19 (br m, 1H), 2.8 (m, 2H), 23.5 (t, 2H), 1.95 (m, 2H), 1.66 (m, 2H), 1.39 (s, 9H), 1.35 (m, 2H). (2) Acid terbutilter. { 1- [2- (4-methyl-piperidin-1-yl-.}. -etl] -piperidin-4-yl}. -carbamic acid (9) To a mixture of ester 8 (3 grams, 12.28 millimoles), 4-methyl-piperidine (1.46 milliliters, 12.28 millimoles) and DIEA (2.7 milliliters, 15.96 millimoles) in 30 milliliters of propionitrile, is treated with solid cyanomethyl-trimethyl-phosphonium iodide (3.58 grams, 14.74 millimoles), and it is heated to reflux for 3 hours, after cooling to room temperature, a 2M K2CO3 solution is added until basic, and the mixture is extracted twice with DCM. The organic layers are washed with brine, dried over anhydrous sodium sulfate, and evaporated. The crude material is purified by chromatography using EtOH / MeOH (saturated with ammonia): 9/1. Yield: 2 grams (50 percent). MS (ESI): 326.3 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 6.74 (br d, 1 H), 3.16 (m, 1 H), 2.78 (m, 4 H), 2.33 ( br s, 4H), 1.86 (m, 4H), 1.64 (m, 2H), 1.53 (m, 2H), 1.36 (s, 9H), 1.32 (m, 3H), 1.08 (m, 2H), 0.86 ( d, 3H). (3) 1- [2- (4-Methyl-piperidin-1-yl) -ethyl-] - piperidin-4-ylamine trichlorohydrate (7) The terbutyl ester 9 (2 grams, 6.14 mmol) is suspended in 10 g. milliliters of dioxane. Then add DCM until the solid dissolves. To this mixture, 4M HCl in dioxane (123 milliliters, 49.2 mmol) is added. After stirring overnight, the solvents are evaporated to leave a white solid product.

Yield: 2.06 grams (100 percent). MS (ESI): 226.2 [M + H] +. Synthesis of 1-r2 - ((RS) -2-methyl-piperidin-1-yl) -etin-piperidin-4-ylamine trichlorohydrate (10) (reaction scheme 2): (1) Terbutil-acid ester. { 1- [2 - ((S) -2-methyl-piperidin-1-yl) -ethyl] -piperidin-4-yl} -carbamic (11) Prepared in a manner analogous to 9, starting from terbutil-ester 8 (2 grams, 8.19 mmol), (S) -2-methyl-piperidine (0.985 milliliters, 8.19 mmol), DIEA (1.8 milliliters, 10.65 millimoles) and cyanomethyl-trimethyl-phosphonium iodide (2.39 grams, 9.83 millimoles) Yield: 1.35 grams (51 percent). MS (ESI): 326.3 [M + H] +, 1 H-NMR (CDCl 3): d (ppm) 4.42 (br d, 1 H), 3.47 (m, 1 H), 2.84 (m, 4 H), 2.47 (m, 3 H), 2.15-2.35 (m, 2 H), 2.1 (m, 2H), 1.92 (m, 2H), 1.2-1.75 (m, 8H), 1.44 (s, 9H), 1.08 (d, 3H). (2) 1- [2 - ((RS) -2-methyl-piperidin-1-yl) -ethyl] -piperidin-4-ylamine trichlorohydrate (10) It is prepared by dissociation with BOC of the terbutyl ester ( 1.3 grams, 3.99 mmol) with 4M HCl in dioxane (8 milliliters, 32 millimoles), as described for amine 7. Yield: 1.3 grams (97 percent). MS (ESI): 226.2 [M + H] +.

Synthesis of trichlorohydrate of (R) -1-r2- (4-amino-piperidin-1-p-et pi-piperidin-3-ol (12) (reaction scheme 2): (1) Acid terbutiléster. { 1- [2 - ((R) -3-hydroxy-piperidin-1-M) -ethyl] -piperidin-4-yl} -carbamic (13) Prepared in a manner analogous to 9, started from terbutil-ester 8 (3.52 grams, 14.41 mmol), hydrochloride (R) -3-hydroxy-piperidine (2.18 grams, 15.85 mmol), DIEA (5.6 milliliters, 33.14 millimoles), and cyanomethyl-trimethyl-phosphonium iodide (4.2 grams, 17.29 millimoles). Yield: 3.53 grams (36 percent). MS (ESI): 328.2 [M + H] +, 1 H-NMR (CDCl 3): d (ppm) 4.61 (br d, 1 H), 3.89 (m, 3 H), 3.53 (m, 1 H), 3. 03 (m, 2H), 2.55-2.73 (m, 6H), 2.44 (m, 1H), 2.3 (m, 2H), 1.83-2.02 (m, 3H), 1.5-1.7 (m, 4H), 1.44 (s, 9H). (2) (R) -1- [2- (4-Amino-piperidin-1-yl) -ethyl] -piperidin-3-ol trichlorohydrate (12) It is prepared by dissociation with BOC of terbutyl ester 13 (1.7 grams, 5.19 mmol) with 4M HCl in dioxane (10.4 milliliters, 41.52 mmol), as described for amine 7. Yield: 1.69 grams (96 percent). MS (ESI): 228.3 [M + H] +. Synthesis of (3S, 4S) -1-r2- (4-amino-piperidin-1-yl) -etip-3-metii-piperidin-4-ol trichlorohydrate (14) (1) (3S, 4S) -1 - [2- (4-tert-butoxy-carbonylamino-piperidin-1-yl) -ethyl] -3-methyl-piperidin-4-yl) -ethyl] -3-methyl-piperidine -4-2,2-dimethyl-propionic acid ester (15) A solution of tert-butyl-8 (4.8 grams, 1 9.65 mmol) and triethylamine (4. 1 milliliters, 29.47 mmol) in 1 50 milliliters of DCM, is cooled at -78 ° C. Triflic anhydride (4.3 milliliters, 25.54 mmol) is slowly added, and stirring is continued for 1 hour. Then the mixture is allowed to warm to 0 ° C, and a solution of 3S-methyl-piperidin-4S-yl ester of 2,2-dimethyl-propionic acid 17 is added, for the preparation see below (3.72 grams, 1 8.66 millimoles ), in 20 milliliters of DCM at 0 ° C. Stirring is continued at room temperature for 1 hour. The mixture is washed twice with water, dried over sodium sulfate, filtered, and evaporated. Yield: 9.3 grams (> 1 00 percent, contained some triethylamine). MS (ESI): 426.3 [M + H] +. (2) Acid terbutilter. { 1 - [2 - ((3S, 4S) -4-hydroxy-3-methyl-piperidin-1-yl) -ethyl] -piperidin-4-yl} -carbámico (1 6) The crude 15 (8.2 grams, 192c.27 millimoles) is treated with NaOMe (0.5 in methanol, 77 milliliters, 38.5 millimoles), and heated under reflux for 24 hours. The solvent is then evaporated, the residue is taken up in DCM, and extracted with 1 N NaOH and brine.

Drying and evaporation gave a brown oil, which is purified by chromatography on silica gel using DCM (saturated with ammonia) and MeOH (from 1 percent to 5 percent).

Yield: 3.07 grams (46 percent). MS (ESI): 342.3 [M + H] +, 1 H-NMR (CDC): d (ppm) 4.51 (br d, 1H), 3.5 (br m, 1H), 3.17 (td, 1H), 2.85-3.08 (m, 4H), 2.63 (m, 4H), 2.1-2.35 (m, 3H), 1.48-2.04 (m, 9H), 1.42 (s, 9H), 0.99 (d, 3H). (3) (3S, 4S) -1- [2 ~ (4-amino-piperidin-1-yl) -etiI] -3-methyl-piperidin-4-ol trichlorohydrate (14) Prepared by dissociation with BOC of terbutil-ester 16 (3.07 grams, 8.98 mmol) with 4M HCl in dioxane (11.2 milliliters, 44.8 millimoles) as described for amine 7. Yield: 3.1 grams (98 percent). MS (ESI): 328.2 [M + H] +, 1 H-NMR (CDCl 3): d (ppm) 4.61 (br d, 1 H), 3.89 (m, 3 H), 3.53 (m, 1 H), 3.03 (m, 2 H), 2.55-2.73 (m, 6 H), 2.44 (m, 1H), 2.3 (m, 2H), 1.83-2.02 (m, 3H), 1.5-1.7 (m, 4H), 1.44 (s, 9H). Synthesis of (3S, 4S) -3-methyl-piperidin-4-yl-ester of 2,2-dithylene-propionic acid (17) (reaction scheme 2): (1) Step A: trans-2,2-dimethyl-propionic acid 1-benzyl-3-methyl-piperidin-4-yl ester (18). To a cis / trans mixture of 1-benzyl-3-methyl-piperidin-4-ol (50 grams, 243 mmol, prepared as described in Can. J. Chem. (1972) 50., 803) in tetrahydrofuran, add triethylamine (51 milliliters, 365 millimoles), followed by 2,2-dimethylpropionyl chloride (45 milliliters, 365 millimoles). The reaction is exothermic, and a precipitate forms. The mixture is heated under reflux for 18 hours, cooled, filtered, and washed with ether. The organic layers are washed with 1 N NaOH and brine, dried, and evaporated. The crude is purified by chromatography on silica gel using hexane and EtOAc (5 percent) to give the pure frans -omer as a colorless oil. Yield: 38 grams (54 percent). MS (ESI): 290.1 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 7.3 (m, 5H), 4.29 (td, 1H), 3.45 (d, 2H), 2.74 (d , 2H), 2.05 (td, 1H), 1.8 (m, 3H), 1.46 (m, 1H), 1.14 (s, 9H), 0.8 (d, 3H). (2) Step B: trans-2,2-dimethyl-propionic acid 3-methyl-piperidin-4-yl ester (19) The trans-ester 18 (104 grams, 359 mmol) is hydrogenated in methanol (1700 milliliters) ) with Pd / C in the presence of an equivalent of HCl (431 milliliters, 359 millimoles, 1.25M in MeOH). The mixture is filtered and evaporated. The residue is redissolved in ether, and extracted with 1N NaOH and brine. Evaporation gives a colorless oil. Yield: 62.7 grams (87 percent). MS (ESI): 200.2 [M + H] +, 1 H-NMR (CDCl 3): d (ppm) 4.46 (td, 1H), 3.06 (m, 2H), 2.68 (td, 1H), 2.35 (m, 1H ), 1.94 (m, 1H), 1.68 (m, 2H), 1.34-1.46 (m, 1H), 1.2 (s, 9 H), 0.96 (d, 3H). (3) Step C: (3S, 4S) -3-methyl-piperidin-4-yl-ester of 2,2-dimethyl-propionic acid (17). The racemic 19 (62.7 grams, 314.4 mmol) is dissolved in EtOAc (300 milliliters), and a solution of L - (-) - O, O'-dibenzoyl-tartaric acid (56.3 grams, 157.2 mmol) in EtOAc ( 450 milliliters). The solid formed is filtered, washed with cold EtOAc and dried. It is then recrystallized from hot methanol (400 milliliters). The crystals are harvested, and the free base is released by treatment with 1 N NaOH and extraction with ether Yield: 1 3 grams (21 percent). MS and 1 H-RM N are identical to racemic 1 9. [α] D = 65.1 (c = 1 in MeOH). Synthesis of (3R, 4R) -3-methyl-p -peridin-4-yl-ester of 2,2-dimethyl-propionic acid (20): The mother liquor of the previous one, is treated with 1 N NaOH, to obtain the free base, which is then crystallized with D - (+) - O, O'-dibenzoyl-tartaric acid as described above, for the antipode 20 Yield: 16 grams (25 percent). MS and 1 H-RM N are identical to racemic 1 9. [α] D = 64.7 (c = 1 in MeOH).

Synthesis of 1-r2- (4-amino-piperidin-1-yl) -eti-piperidin-4-ol trichlorohydrate (21) (reaction scheme 3): (1) 1- (2-hydroxy-ethyl) -piperidin-4-ol (22) Piperidin-4-ol (5 grams, 49.4 mmol) is dissolved in 200 milliliters of ethanol, and anhydrous sodium carbonate (21) is added. grams, 197.6 millimoles). 2-Bromo-ethanol (6.9 milliliters, 98.8 mmol) is added dropwise and the reaction mixture is refluxed for 16 hours. After evaporation under reduced pressure, the mixture is stirred with 200 milliliters of DCM, and it filters. The clear filtrate is evaporated under reduced pressure, and dried in a high vacuum. Yield: 4.3 grams (60 percent) of a colorless oil. MS (ESI): 146 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 4.52 (d, 1H), 4.32 (t, 1H), 3.48 (dt, 2H), 3.4 (m , 1H), 2.7 (m, 2H), 2.35 (t, 2H), 2.05 (m, 2H), 1.68 (m, 2H), 1.3-1.4 (m, 2H). (2) Acid terbutilter. { 1- [2- (4-hydroxy-piperidin-1-yl) -ethyl] -piperidin-4} -carbamic (23) The terbutil-ester of piperidin-4-yl-carbamic acid 3 (5 grams, 25 mmol), 1- (2-hydroxy-ethyl) -piperidin-4-ol 22 (4 grams, 27.5 mmol) and DIEA (5.6 milliliters, 32.5 millimoles) are suspended in 25 milliliters of propionitrile. Cyanomethyltrimethylphosphonium iodide (4 grams, 30 mmol) is added, and the reaction mixture is refluxed. Additional cyanomethyl-trimethyl-phosphonium (1.5 grams, 11.25 millimoles) is added after 90 minutes and after 3 hours. After cooling to room temperature, a solution of potassium carbonate (4 grams) in 250 milliliters of water is added, and the product is isolated by extraction with DCM. Evaporation under reduced pressure gave 6.9 grams of a red oil, which could be crystallized from ether. Yield: 2.2 grams (27 percent) of colorless crystals. MS (ESI): 328 [M + H] \ 1 H-NMR (DMSO-d 6): d (ppm) 6.72 (br d, 1H), 4. 5 (d, 1H), 3.42 (m, 1H), 3.2 (m, 1H), 2.8 (m, 2H), 2.7 (m, 2H), 2.35 (m, 4H), 2.0 (dt, 2H), 1.9 (dt, 2H), 1.68 (m, 4H), 1.4 (s, 9H), 1.35 (m, 4H. (3) 1- [2- (4-amino-piperidin-1-yl) -ethyl] trichlorohydrate] -piperidin-4-ol (21) Ester 23 (2.2 grams, 6.72 mmol) is dissolved in 4M HCl in dioxane at 0 ° C, and stirred at room temperature for 3 hours.After evaporation of the solvent, the product dried in a high vacuum Yield: 2.3 grams (100 percent) of a white solid MS (ESI): 228 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 5 (m , 1H), 3.4 (m, 4H), 2.7 (m, 4H), 24 (m, 2H), 1.85-2.0 (m, 4H), 1.65 (m, 4H), 1.35 (m, H), 1.2 ( m, 2H). Synthesis of 8-r2- (4-amino-piperidin-1-yl) -eti-8-aza-bicyclo3.2.noctan-3-ol trichlorohydrate (24) 3) reaction: (1) 8- (2-h idroxy-ethyl) -8-aza-bicyclo [3.2.1] octan-3-ol (25) 8-aza-bicyclo [3.2.1] octan-3-ol hydrochloride (5.1 grams, 31 .45 millimoles) and sodium carbonate (13.3 grams, 125.8 millimoles) are suspended in 50 milliliters of ethanol at room temperature. 2-Bromo-ethanol (4.4 milliliters, 62.9 millimoles) is added dropwise within 20 minutes, and the reaction mixture is refluxed for 15 hours. After cooling to room temperature, the reaction mixture is evaporated under reduced pressure. The mixture is stirred with 200 milliliters of DCM, and filtered. The clear filtrate is dried over anhydrous sodium sulfate, filtered, evaporated under reduced pressure, and dried in a high vacuum. Yield: 5.4 grams (1 00 percent) of a colorless oil. MS (ESI): 172 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 4.25 (d, 2 H), 3.78 (t, 1 H), 3.42 (t, 2 H), 3.06 (m, 2H), 2.36 (t, 2H), 2.03 (m, 2H), 1.85 (m, 2H), 1.75 (m, 2H), 1.55 (d, 2H). (2) Acid terbutilter. { 1 - [2- (3-Hydroxy-8-aza-bicyclo [3.2.1] oct-8-yl) -ethyl] -piperidin-4-yl} -carbamic (26) The terbutil-ester of picperidin-4-yl-carbamic acid 3 (1 gram, 5 millimoles), 8- (2-hydroxy-ethyl) -8-aza-bicyclo [3.2.1] octane-3 -ol 25 (1 gram, 5.5 millimoles), and DIEA (1.1 milliliters, 6.5 millimoles), are dissolved in 5 milliliters of propionitrile. Cyanomethyl-trimethyl-phosphonium iodide (792 milligrams, 6 mmol) is added with stirring, and the reaction mixture is refluxed, which is followed by thin layer chromatography. Additional cyanomethyl-trimethyl-phosphonium iodide (400 milligrams) is added after 2 hours, and the mixture is refluxed for another hour. After cooling to room temperature, DCM. The combined organic layers are washed with brine, dried over anhydrous, and a solution of potassium carbonate (4 grams) in 250 milliliters of water is added, and the product is isolated by extraction with sodium sulfate, filtered, and evaporates under reduced pressure. The crude product (1.9 grams) is crystallized from ether. Yield: 940 milligrams (53 percent) of light beige crystals. MS (ESI): 354 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 6.73 (br d, 1 H), 4.25 (d, OH), 3.8 (m, 1 H), 3.17 ( m, 1H), 3.08 (m, 2H), 2.8 (m, 2H), 2.35 (, 4H), 2.0 (m, 2H), 1.92 (m, 2H), 1.85 (dt, 2H), 1.78 (m, 2H), 1.65 (m, 2H), 1.53 (m, 2H), 1.38 (s, 9H), 1.33 (m, 2H). (3) 8- [2- (4-Amino-piperidin-1-yl) -ethyl] -8-aza-bicyclo [3.2.1] octan-3-ol trichlorohydrate (24) Ester 26 (4.5 grams, 12.73 mmol) is dissolved in 4M HCl in dioxane at 0 ° C, and stirred at room temperature for 3 hours. After evaporation of solvent, the product is dried in a high vacuum. Yield: 4.6 grams (100 percent) of a white solid. MS (ESI): 254 [M + H] +.

Synthesis of trichlorohydrate of 1-r2 - ((2S, 6R) 2,6-dimethyl-piperidin-1-yl) -etiH-p¡peridin-4-amlamine (27) (reaction scheme 3): (1) Terbutil-acid ester. { 1- [2- (2,6-dimethyl-piperidin-1-yl) -ethyl] -piperidin-4-yl} -carbamic (28) Compound 28 is prepared in a manner analogous to 25, starting from cis-2,6-dimethyl-piperidine (6.4 milliliters, 44.17 mmol) and bromoethanol (6.1 milliliters, 88.33 mmol). Yield: 3.9 grams (56 percent) of a yellow oil. MS (ESI): 158.1 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 4.48 (br, 1H), 3.4 (t, 2H), 2.6 (t, 2H), 24 (m, 2h), 1.1-1.6 (M, 6h) , 1.03 (D, 6h). (2) Acid terbutilter. { 1- [2- (2,6-dimethyl-piperidin-1-yl) -etl] -piperidin-4-yl} -carbamic (29) Compound 29 is prepared in a manner analogous to 26, starting from compound 28 (3.85 grams, 24.48 millimoles) and terbutil-ester of piperidin-4-yl-carbamic acid 3 (4.46 grams, 22.25 millimoles) ). Yield: 6.16 grams (82 percent) of a yellow oil. MS (ESI) 340.4 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 6.73 (br d, 1 H), 3.18 (m, 1 H), 2.75 (m, 2 H), 2.65 (m, 2H), 2.35 (m, 2H), 2.25 (m, 2H), 1.92 (m, 2H), 1.65 (m, 2H), 1.57 (m, 2H), 1.49 (m, 2H), 1.38 (s, 9H ), 1.35 (m, 2H), 1.12 (m, 2H), 1.03 (d, 6H). (3) 1- [2 - ((2S, 6R) -2,6-Dimethyl-piperidin-1-yl) -ethyl] -piperidin-4-ylalan-1-trichlorohydrate (27) Compound 27 is prepared from a analogous to 24, starting from the derivative protected with BOC 29 (6.1 6 grams, 1 8.14 millimoles). Yield: 6.3 grams (100 percent) of a white solid. MS 8ESI): 240.3 [M + H] +. Synthesis of (R) -1 - ((3a, 7a) -2,2-dimethyl-tetrahydro-ri, 31dioxolor4,5-clpiridin-5-yl) -propan-2-ol (30) (reaction scheme 4) : (1) 3,6-Dihydro-2H-pyridin-1-carboxylic acid benzyl ester (31) 1,2,3,6-tetrahydro-pyridine (3 grams, 36.1 mmol) is treated with carbonate of aqueous sodium at 1 0 percent (2.1 milliliters), and cooled to 0 ° C. Within 1 hour, benzyl chloroformate (Z-chloride, 5.1 milliliters, 36 mmol) is added dropwise within 1 hour. After further stirring for 2 hours, the mixture is treated with 30 milliliters of brine, and extracted four times with diethyl ether. The organic layers are dried over sodium sulphate and evaporated. The crude product, 7 grams of a colorless oil, is purified by chromatography by evaporation (silica gel, cyclohexane / ethyl acetate, 9: 1). Yield: 3.63 grams (46 percent) of a colorless oil. MS (ESI): 218 [M + H] +, 1 H-NMR (CDCl 3): d (ppm) 7.28-7.4 (m, 5H), 5.83 (m, 1H), 5.66 (m, 1H), 5.15 (s) , 2H), 3.95 (m 2H), 3.58 (t, 2H), 2.15 (m, 2H). (2) 3,4-Dihydroxy-piperidin-1-carboxylic acid benzyl ester (32) The 31 (3.63 grams, 16.7 mmol) is dissolved in 16 milliliters of a 1: 1 mixture of water and acetone. After the addition of N-methyl-morpholine N-oxide (2.9 grams, 24.8 millimoles), a 1 percent solution of osmium tetroxide in tert-butanol (7.23 milliliters, 0.28 millimoles) is added. The mixture is stirred at room temperature for 20 hours. Then add 70 milliliters of a saturated solution of sodium bisulfite. After 15 minutes of stirring at room temperature, the reaction mixture is extracted with ethyl acetate. The organic layers are dried over sodium sulphate and evaporated. The crude product, 4.7 grams of a yellow oil, is purified by evaporation chromatography (silica gel, ethyl acetate). Yield: 3.83 grams (91 percent). MS (ESI): 252 [M + H] +, 1 H-NMR (CDC 3): d (ppm) 7.27-7.4 (m, 5H), 5.13 (s, 2H), 3.88 (m, 1H), 3.79 (m , 2H), 3.66 (m, 2H), 3.5 (dd, 1H), 3.34 (m, 1H), 2.13 (m, 2H), 1. 82 (m, 1H), 1.7 (m, 1H). (3) 22-Dimethyl-tetrahydro- [1,3] dioxolo [4,5-c] pyridine-5-carboxylic acid benzyl ester (33) The previous 32 (3.72 grams, 14.8 mmol) is dissolved in 20 milliliters of dichloromethane. After the addition of 2,2-dimethoxypropane (3.6 milliliters, 30 millimoles) and p-toluenesulfonic acid (141 milligrams, 0.7 millimoles), the mixture is stirred at room temperature for 4 hours. The mixture is then diluted with 30 milliliters of dichloromethane, washed subsequently with 1N NaOH and brine, dried over sodium sulfate, and evaporated.

The crude racemic product, 4.32 grams of a yellow oil, is separated into its enantiomers by chiral HPLC (Chiralcel, OJ, 20 microns, hexane / isopropanol, 9: 1). Yield: 810 milligrams peak 1, and 942 milligrams (peak 2) (40 percent). MS (ESI): 292.2 [M + H] +, 1 H-NMR (CDCl 3): d (ppm) 7.25-7.4 (m, 5H), 5.14 (s, 2H), 4.18-4.4 (m, 2H), 3.7 -3.82 (, 1H), 3.38-3.58 (m, 3H), 1.74-2.0 (m, 2H), 1.44 (s, 3H), 1.35 (s, 3H). (4) 2,2-dimethyI-hexahydro- [1,3] dioxolo [4,5-c] pyridine (34) (single enantiomer-c / s, absolute configuration unknown). The 33 (peak 1 of the previous) (450 milligrams, 1.54 millimoles) are dissolved in 10 milliliters of methanol. After the addition of 10 percent palladium on carbon (45 milligrams), the mixture is hydrogenated at room temperature for 20 hours. Then the mixture is filtered over Celite. Evaporation gave 240 milligrams (99 percent) of a colorless oil. MS (ESI): 158.2 [M + H] +, 1 H-NMR (CDCl 3): d (ppm) 4.25 (m, 1 H), 4.12 (m, 1 H), 2.9-3.1 (m, 3 H), 2.78 (m, 1 H), 1.85-2.40 (m, 3 H) , 1.52 (s, 3H), 1.38 (s, 3H). (5) 1- (2,2-dimethyl-tetrahydro- [1,3] dioxolo [4,5-c] pyridin-5-yl) -propan-2-ol (30) (sole enantiomer, absolute configuration of unknown dioxole) . 34 (90 milligrams, 0.57 millimoles), (R) (+) - propylene oxide (166 milligrams, 2.8 millimoles), and triethylamine (160 microliters, 1.1 millimoles) are dissolved in 2 milliliters of ethanol, and stirred at room temperature. environment for 4 hours. The reaction mixture is diluted with 20 milliliters of ethyl acetate, washed subsequently with 1N NaOH and brine, dried over sodium sulfate, and evaporated. The crude product, 100 milligrams of a yellow oil, is purified by evaporation chromatography (silica gel, dichloromethane / meta no I / ammonia, 95: 5: 0.5). Yield: 70 milligrams (70 percent). MS (ESI): 216.2 [M + H] +, 1 H-NMR (CDCl 3): d (ppm) 4.03-4.28 (m, 2H), 3.9 (m, 1H), 2.2-3.08 (m, 6H), 1.36 -2.13 (m, 3H), 1.51 (s, 3H), 1.38 (s, 3H), 1.12-1.22 (dd, 3H). Synthesis of (R) -1- (2,2,7-trimethyl-tetrahydro-ri, 31-dioxolor-4,5-clpyridin-5-yl) -propan-2-ol (35) (reaction scheme 5): (1) 1-benzyl-3- (R, S) -methyl-1J2,3,6-tetrahydro-pyridin-4-yl-trifluoromethanesulfonic acid ester (36) A solution of bis- (trimethylsilyl) 1M lithium amide in tetrahydrofuran (540 microliters, 0.54 mmol), diluted with 1 milliliter of tetrahydrofuran, and cooled to -78 ° C. A solution of 1-benzyl-3-methyl-4-piperidone (100 milligrams, 0.49 mmol) in 0.5 milliliters of tetrahydrofuran is added with a syringe within 5 minutes. After stirring for 2 hours at this temperature, a solution of N-phenyl-trifluoromethanesulfonimide (188 milligrams, 0.52 millimoles) in 1 milliliter of tetrahydrofuran is added within 10 minutes. The beige suspension is stirred for another 4 hours at 0 ° C. The yellow solution is quenched with 1 milliliter of a saturated solution of ammonium chloride, diluted with ice water, and extracted three times with ethyl acetate. The organic layers are washed with brine, dried over sodium sulfate, and evaporated. The crude product, 311 milligrams of a yellow oil, is purified by chromatography by evaporation (silica gel, cyclohexane / ethyl acetate, 4: 1). Yield: 127 milligrams (77 percent) of a colorless oil. MS (ESI): 336 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 7.22-7.36 (m, 5H), 5.89 (dd, 1H), 3.54-3.65 (m, 2H), 3.05 (br s, 2H), 2.75 (m, 1H), 2.59 (m, 1H), 2.32 (m, 1H), 1.06 ( d, 3H). (2) 1-benzyl-3- (R, S) -methyl-1,2,3,6-tetrahydro-pyridine (37) The previous 36 (100 milligrams, 0.3 mmol), palladium acetate (ll) (1.34) milligrams, 6 micromoles), triphenylphosphine (31 milligrams, 12 micromoles), and triethylamine (125 microliters, 0.9 millimoles), are dissolved in 1 milliliter of N, N-dimethylformamide. After the addition of formic acid (22.5 microliters, 0.6 mmol), the mixture is stirred for 1 hour at 60 ° C. The reaction mixture is diluted with ethyl acetate, washed subsequently with 1 N NaOH and brine, dried over sodium sulfate, and evaporated. The crude product, 78 milligrams of a yellow oil, is purified by evaporation chromatography (silica gel, cyclohexane / ethyl acetate, 3: 1). Yield: 42 milligrams (75 percent) of a yellow oil. MS (ESI): 188.2 [M + HJ +, 1 H-NMR (CDCl 3). d (ppm) 7.23-7.41 (m, 5H), 5.62 (s, 2H), 3.63 (br s, 2H), 3.12 (d, 1H), 2.83 (m, 2H), 2.48 (m, 1H), 2.02 (br s, 1H), 0.96 (d, 3H). (3) (3RSJ4SR, 5RS) -1-benzyl-5-methyl-piperidine-3,4-diol (racemic) (38) The 37 (570 milligrams, 3 mmol) is dissolved in 10 milliliters of a mixture of 1: 1 of water and acetone. After the addition of N-methyl-morpholine N-oxide (529 milligrams, 4.5 mmol), a 2.5 percent solution of osmium tetroxide in terbutanol (527 microliters, 52 micromoles) is added. The mixture is stirred at room temperature for 24 hours. Then add 10 milliliters of a saturated solution of sodium bisulfite. After 15 minutes of stirring at room temperature, the reaction mixture is extracted with ethyl acetate. The organic layers are subsequently washed with 1 N NaOH and brine, dried over sodium sulfate, and evaporated. The crude product, 460 milligrams of a dark brown oil, is purified by evaporation chromatography (silica gel, dichloromethane / methanol / ammonia, 95: 5: 0.5). Yield: 290 milligrams (43 percent) of the cis diol, after for the methyl group and 20 milligrams (3 percent) of the all-c / s derivative. MS (ESI): 222 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 7.17-7.32 (m, 5H), 4.21 (d, 1H), 4.04 (br d, 1H), 3.58 (m, 1H), 3.41 (dd, 2H), 3.02 (m, 1H), 2.62 (m, 1H), 2.56 (br d, 1H), 2.12 (br d, 1H), 1.69-1.88 (m, 2H), 0.86 (d, 3H). (4) (3aRS, 7RS, 7aSR) -5-benzyl-2,2,7-trimethyl-hexahydro- [1,3] dioxolo [4,5-c] pyridine (racemic) (39) The previous 38 (290 milligrams, 1.3 millimoles) is dissolved in 4 milliliters of dichloromethane. After the portionwise addition of 2,2-dimethoxypropane (1.6 milliliters, 13 millimoles) and p-toluenesulfonic acid (300 milligrams, 1.6 millimoles), the mixture is stirred at room temperature for 16 hours. Then the mixture is diluted with dichloromethane, washed subsequently with 1N NaOH and brine, dried over sodium sulfate and evaporated. The crude product, 333 milligrams of a yellow oil, is purified by evaporation chromatography (silica gel, cyclohexane / ethyl acetate, 3: 1). Yield: 303 milligrams (89 percent). MS (ESI): 262.2 [M + H] +, 1 H-NMR (CDCl 3): d (ppm) 7.20-7.40 (m, 5H), 4.19 (br s, 1H), 3.69 (br s, 1H), 3.43 -3.63 (m, 2H), 2.89 (m, 1H), 2.53 (m, 2H), 2.02 (m, 1H), 1.88 (m, 1H), 1.53 (s, 3H), 1.37 (s, 3H), 1.00 (d, 3H). (5) (3aRS, 7RS, 7aSR) -5-benzyl-2,2,7-trimethyl-hexahydro- [1,3] dioxolo [4,5-c] pyridine (racemic) (40). The previous 39 (250 milligrams, 0.96 millimoles) is dissolved in 5 milliliters of isopropanol. After the addition of 10 percent palladium on carbon (25 milligrams), the mixture is hydrogenated at room temperature for 16 hours. Then the mixture is filtered over Celite. Evaporation gave 170 milligrams (100 percent) of a colorless oil. MS (ESI): 172.2 [M + H] +, 1 H-NMR (CDCl 3): d (ppm) 4.05 (m, 1H), 3.67. (dd, 1H), 3.39 (d, 1H), 2.98 (m, 2H), 2.21 (t, 1H), 2.05 (m, 1H), 1.73 (m, 1H), 1.52 (s, 3H), 1.37 ( s, 3H), 0.98 (d, 3H). (6) 1- (2,2,7-Trimethyl-tetrahydro- [1,3] dioxolo [4,5-c] pyridin-5-yl) -propan-2-ol (35) (mixture of diastereomers). Dissolve 40 (175 milligrams, 1 millimole), and triethylamine (285 microliters, 2 mmol) in 3 milliliters of ethanol, and stirred at room temperature for 5 hours. After evaporation, the residue is dissolved in ethyl acetate, washed subsequently with 1N NaOH and brine, dried over sodium sulfate, and evaporated. The crude product, 214 milligrams of a yellow oil, is purified by evaporation chromatography (silica gel, dichloromethane / methanol / ammonia, 95: 5: 0.5). Yield: 140 milligrams (60 percent). MS (ESI): 172.2 [M + H] +, 1 H-NMR (CDCl 3): d (ppm) 4.05 (m, 1H), 3.67 (dd, 1H), 3.39 (d, 1H), 2.98 (m, 2H ), 2.21 (t, 1H), 2.05 (m, 1H), 1.73 (m, 1H), 1.53 (s, 3H), 1.37 (s, 3H), 0.98 (d, 3H).

Synthesis of (3R, 4R, 5S) -1-r2- (4-amino-piperidinyl) -eti-3,5-dimethyl-piperidin-4-ol trichlorohydrate (41) (reaction scheme 6) : (1) N '- [1-benzyl-3-methyl-piperidin- (4E) -ylidene] -N, N-dimethyl-hydrazine (42) N, N-dimethyl-hydrazine (3 milliliter, 39.3 mmol) and 1-benzyl-3-methyl-piperidin-4-one (4 grams, 19.7 mmol) are dissolved in 50 milliliters of ethanol, and refluxed for 18 hours. The reaction mixture is evaporated under reduced pressure and dried in a high vacuum. Yield: 4.8 grams of a pale oil (99 percent). MS (ESI): 246 [M + H] +, 1 H NMR (DMSO-d6): d (ppm) 7.29 (m, 4H), 7.23 (m, 1H), 3.48 (m, 2H), 2.8 (m, 1H ), 2.65 (m, 1H), 2.35-2.55 (m, 2H), 2.29 (s, 6H), 2.25 (m, 1H), 1.9-2.1 (m, 1H), 1.00 (d, 3H). (2) N '- (1-benzyl-35-dimethyl-p-peridin-4-ylidene) -N, N-dimethyl-hydrazine (43) Di-isopropyl-amine (3.3 milliliters, 23.5 mmol) is dissolved in 20 milliliters of tetrahydrofuran, and cooled to -5 ° C. A 1.6M solution of n-butyl lithium in tetrahydrofuran (14.7 milliliters, 23.5 millimoles) is added dropwise within 10 minutes. After a further 10 minutes at -5 ° C, a solution of 42 (4.8 grams, 19.6 millimoles) in 30 milliliters of tetrahydrofuran is added within 20 minutes (the color of the reaction mixture changed to red). Now the solution is cooled to -78 ° C. Methyl iodide (1.33 milliliters, 21.5 millimoles) is added dropwise within 15 minutes, and the mixture is allowed to warm to room temperature overnight. Dichloromethane is added, and the solution is washed with water. Evaporation gave 5 grams of a colorless oil, which is further purified by evaporation chromatography (silica gel, ethyl acetate / hexanes, 1: 1). Yield: 1.7 grams of a white solid (33 percent). MS (ESI): 260 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 7.33 (m, 4 H), 7.22 (m, 1 H), 3.48 (m, 2 H), 3.37 (m , 1H), 2.68 (m, 1H), 2.59 (m, 1H), 2.43 (m, 1H), 2.43 (m, 1H), 229 (s, 6H), 2.15 (m, 1H), 2.0 (m, 1H), 1.23 (d, 6H). (3) 1-benzyl-3,5-dimethyl-piperidin-4-one (44) The 43 (1.7 grams, 6.5 mmol) is dissolved in a 1.25M solution of HCl in methanol (20 milliliters, 25 mmol), and reflux for 1.5 hours. The reaction mixture is evaporated under reduced pressure, and dried in a high vacuum. The residue (1.7 grams of a colorless oil) is dissolved in ethyl acetate, and treated with 5M NaOH. The organic layers are evaporated under reduced pressure. Yield: 1.4 grams of a colorless oil (84 percent). MS (ESI): 218 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 7.3 (m, 4H), 7.25 (m, 1H), 3.58 (m, 2H), 3.07 (m, 2H), 2.68 (m, 2H), 1.97 (dd, 2H), 0.82 (d, 6H). (4) 1-benzyl-3,5-dimethyl-piperidin-4-ol (45) Sodium borohydride (121 milligrams, 3.2 mmol) is added to a solution of 44 (1.4 grams, 64 mmol) in 15 milliliters of methanol , and the mixture is stirred at room temperature for 30 minutes. The mixture is evaporated, and the residue is dissolved in ethyl acetate and washed with water. Yield: 1.4 grams of a colorless oil (99 percent). MS (ESI): 220 [M + H] +. (5) (3S, 4R, 5R) -1-benzyl-3,5-dimethyl-piperidin-4-yl-acetic acid ester (46) Add DMAP (40 milligrams, 0.3 mmol) to a solution of 45 ( 1.4 grams, 6.4 millimoles) in 10 milliliters of pyridine. After addition of acetic anhydride (0.9 milliliters, 9.5 mmol), the mixture is stirred at 110 ° C for 2 hours. The mixture is evaporated, and the residue is dissolved in dichloromethane, and washed with water. Evaporation gave 1.6 grams of a colorless oil, which is further purified by evaporation chromatography (silica gel, ethyl acetate / hexanes, 1: 9). Yield: 0.7 grams of a colorless oil (42 percent, fraction 1). MS (ESI) 262 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm 7.2-7.3 (m, 5H), 4.18 (dd, 1H), 3.42 (s, 2H), 2.8 (m , 2H), 2.05 (s, 3H), 1.7-1.8 (m, 4H), 0.72 (d, 6H). (6) (3R, 4R, 5S) -3,5-dimethyl-piperidin-4-yl- acetic acid ester (47) Palladium hydroxide on carbon (20 percent, 300 milligrams) is placed in a flask filled with argon, and carefully covered with 25 milliliters of methanol. A solution of 46 (0.7 grams, 2.7 mmol) in methanol is added, and the mixture is hydrogenated at room temperature for 15 hours. After filtration over Celite, the filtrate is evaporated and dried under a high vacuum. Yield: 0.41 grams of a colorless oil (89 percent). MS (ESI): 172 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 4.22 (dd, 1H), 2.8 (dd, 2H), 2.15 (dd, 2H), 2.05 (s, 3H), 1.5 (m, 2H), 0.7 (d, 6H). (7) (3S, 4R, 5R) -1- [2- (4-terbutoxy-carbonylamino-piperidin-1-yl) -ethyl] -3,5-dimethyl-piperidin-4-yl-ester of acetic acid ( 48). It is dissolved in 47 (2.3 grams, 13.4 millimoles) in 5 milliliters of propionitrile, and after the addition of 8 (33 grams, 13.4 millimoles), the mixture of cyanomethyl-trimethyl-phosphonium iodide (4.4 grams, 33.6 millimoles) and N-ethyldi-isopropyl-amine (11.5 milliliters, 67.1 mmol) is refluxed for 24 hours (control with thin layer chromatography). Then the mixture is evaporated under reduced pressure. The residue is diluted with ethyl acetate, washed with a 10 percent K2CO3 solution and NaCl, and dried over Na2SO4. Yield: 3.3 grams of a chestnut oil (62 percent). MS (ESI) 398 [M + H] +. (8) Terbutil-acid ester. { 1- [2 - ((3S, 4R, 5R) -4-hydroxy-3,5-dimethyl-piperidin-1-yl) -ethyl] -piperidin-4-yl} -carbamic (49) The 48 (3.3 grams, 8.3 millimoles) is dissolved in 100 milliliters of methanol, and after the addition of NaOMe powder (2.2 grams, 41.5 millimoles), the mixture is refluxed for 6 hours (control with thin layer chromatography). Then the mixture is evaporated under reduced pressure. The residue is diluted with ethyl acetate, washed with water, and dried over Na2SO. Evaporation gave 3.1 grams of a brown oil. The crude product is purified by recrystallization from ether. Yield: 800 milligrams of a colorless solid (27 percent).

MS (ESI): 356 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 6.7 (br d, 1 H), 4.4 (d, 1 H), 3.15 (br m, 1 H), 2.75 (, 4H), 2.4 (m, 1H), 2.3 (, 4H), 1.9 (m, 2H), 1.3-1.7 (m, 8H), 1.38 (s, 9H), 0.85 (d, 6H). (9) (3R, 4R, 5S) -1- [2- (4-Amino-pipepdin-1-yl) -ethyl] -3,5-dimethyl-piperidin-4-ol trichlorohydrate (41) The 49 Dissolve in a 4M solution of HCl in dioxane (20 milliliters), and stir for 4 hours (control with thin layer chromatography) at room temperature. Then the mixture is cooled to 0 ° C and filtered. The residue is washed with ether. Evaporation gave 510 milligrams (89 percent) of gray crystals. MS (ESI): 256 [M + H] +. Synthesis of 1-r (S) -2- (4-amino-piperidin-1-yl) -1-methyl-etiH-piperidin-4-ol trichlorohydrate (50) (reaction scheme 7): (1) 1-benzyl-piperidin-4-yl-ester of 2,2-dimethyl-propionic acid (51) A solution of 1-benzyl-piperidin-4-ol (25 grams, 130.7 mmol) and triethylamine (36.1 milliliters) , 261.4 millimoles) in 250 milliliters of tetrahydrofuran, treated with 2,2-dimethylpropionyl chloride (32.2 milliliters, 261.4 millimoles). The suspension is heated under reflux overnight. The solvent is evaporated, the residue is taken up in DCM, and washed with a saturated solution of sodium bicarbonate, and brine. Drying and evaporation gave an orange oil. Yield: 38.3 grams (100 percent crude). MS (ESI): 276 [M + H] +, 1 H-NMR (CDCl 3): d (ppm) 7.31 (m, 4 H), 7.25 (m, 1 H), 4.79 (m, 1 H), 3.5 (s, 2 H) ), 2.61 (m, 2H), 2.32 (m, 2H), 1.86 (m, 2H), 1.69 (m, 2H), 1.18 (s, 9H). (2) piperidin-4-yl-ester of 2,2-dimethyl-propionic acid (52) A solution of piperidine 51 (35.99 grams, 130.7 mmol) in methanol is hydrogenated with Pd / C in the presence of an equivalent of HCl (104.5 milliliters, 130.7 millimoles, 1.25M in MeOH). After filtration and evaporation, the crude is recovered in ether, and washed with 1N NaOH and brine. Drying, evaporation, and distillation (0.08 mbar, 75-90 ° C) gave a colorless oil. Yield: 17.98 grams (74 percent). MS (ESI): 186 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 9.22 (br s, 1H), 4. 89 (m, 1H), 3.08 (m, 4H), 1.99 (m, 2H), 1.78 (m, 2H), 1.15 (s, 9H). (3) 1 - ((R) -2-hydroxy-propyl) -piperidin-4-yl ester of 2,2-dimethyl-propionic acid (53) A solution of piperidine 52 (2 grams, 10.8 mmol) and (R) -2-Methyl-oxirane (3.78 milliliters, 54 mmol) in 2 milliliters of ethanol is stirred for 24 hours in a closed flask. The solvent is evaporated, and the solvent is distilled in a Kugeirohr apparatus (0.08 mbar, 75-90 ° C). Yield: 2.58 grams (98 percent). MS (ESI): 244.2 [M + H] +, 1 H-NMR (CDCl 3): d (ppm) 4.65 (m, 1H), 4.1 (br s, 1H), 3.72 (m, 1H), 2.55 (m, 2H), 2.31 (m, 2H), 2.23 (m, 1H), 2.14 (m, 1H), 1.75 (m, 2H), 1.55 (m, 2H), 1.14 (s, 9H), 1.03 (d, 3H), [a] D = 23.1 (c = 1 in MeOH). (4) 1 - [(S-2- (4-terbutoxy-carbonyl-amino-piperidin-1-yl) -1-methyl-ethyl] -piperidin-4-yl-ester (54) A solution of the alcohol 53 ( 1.26 grams, 5.16 millimoles) and triethylamine (1.43 milliliters, 10.32 millimoles) in 80 milliliters of DCM, cooled to -78 ° C. Triflic anhydride (0.85 milliliters, 5.16 millimoles) is slowly added, and stirring is continued for 1 hour Then the mixture is allowed to warm to 0 ° C, and cooled back to -78 ° C after 15 minutes. A solution of piperidin-4-yl-carbamic acid tert-butyl ester 3 (1.03 grams, 5.16 millimoles) in 40 milliliters of DCM at -78 ° C is slowly added. After the addition is complete, the cooling bath is removed, and the dark solution is allowed to warm to room temperature. The mixture is washed twice with water, dried over sodium sulfate, filtered, and evaporated. The crude is purified by chromatography on silica gel using DCM (saturated with ammonia) and MeOH (1 percent). Yield: 1.7 grams (77 percent). MS (ESI): 426.3 [M + H] +, 1 H-NMR (CDCl 3): d (ppm) 4.74 (m, 1H), 4.43 (m, 1H), 3.43 (br m, 1H), 2.89 (m, 1H), 1.97-2.82 (m, 11H), 1.87 (m, 4H), 1.64 (m, 2H), 1.43 (s, 9H), 1.38 (m, 1H), 1.19 (s, 9H), 1.0 (d , 3H). [a] D = 9.3 (c = 1 in MeOH). (5) Terbutil-acid ester. { 1 - [(S) -2-hydroxy-piperidin-1-yl) -propyl] -piperidin-4-M} -carbamic (55) The ester 54 above (1.7 grams, 3.52 mmol) is treated with NaOMe (0.5M in methanol, 21 milliliters, 10.5 mmol), and heated under reflux for 24 hours. The solvent is then evaporated, the residue is taken up in DCM, and extracted with 1N NaOH and brine. After drying and evaporation, the crude is purified by chromatography on silica gel using DCM (saturated with ammonia) and MeOH (1 to 3 percent) to give a white powder. Yield: 0.77 grams (56 percent). MS (ESI): 342.3 [M + H] +, 1 H-NMR (CDCl 3): d (ppm) 4.43 (, 1H), 3.64 (m, 1H), 3.43 (m, 1H), 2. 88 (m, 1H), 2.75 (m, 4H), 1.8-245 (m, 10H) 1.3-1.65 (m, 5H), 1.44 (s, 9H), 0.99 (d, 3H). [α] D = -15.3 (c = 1 in MeOH). (6) 1 - [(S) -2- (4-amino-piperidin-1-yl) -1-methyl-ethyl] -piperidin-4-ol trichlorohydrate (50) Prepared by BOC dissociation of the terbutil- ester 55 (0.666 grams, 1.95 millimoles) with 4M HCl in dioxane (2.93 milliliters, 11.72 millimoles), as described for amine 7. Yield: 0.64 (93 percent). MS (ES): 242.3 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 10.5-10.85 (br m, 2H), 8.3-88 (br m, 3H), 2.75-4.15 ( br m, 15H), 1.6-23 (br m, 7H), 1.39 (d, 3H). [a] D = +13.2 (c = 1 in MeOH). Synthesis of (3S.4S) -1-r (S) -2- (4-amino-piperidin-1-yl) -1-methyl-etip-3-methyl-piperidin-4-ol trichlorohydrate (56) ( reaction scheme 7): (1) (3S, 4S) -1 - ((R) -2-hydroxy-propyl) -3-methyl-piperidin-4-yl-ester of 2,2-dimethyl-propionic acid (57). A solution of the piperidine 17 (2 grams, 10.8 mmol) and (R) -2-methyl-oxirane (3.78 milliliters, 54 mmol) in 2 milliliters of ethanol is stirred for 24 hours in a closed flask. The solvent is evaporated, and the residue is distilled in a Kugeirohr apparatus (0.08 mbar, 75-90 ° C). Yield: 2.58 (98 percent). MS (ESI): 258.2 [M + H] +, 1 H-NMR (CD 3 OD): d (ppm) 4.39 (td, 1H), 3.82 (m, 1H), 2.95 (m, 1H), 2.76 (m, 1H ), 2.42 (td, 1H), 2.17-2.33 (m, 2), 1.96 (m, 1H), 1.75-1.9 (m, 2H), 1.62 (m, 1H), 12 (s, 9H), 1.13 ( d, 3H), 0.89 (d, 3H). [a] D = 23.1 (c = 1 in MeOH). (2) (3S, 4S) -1 - [(S) -2- (4-terbutoxy-carboniI-amino-piperidin-1-yl) -1-methyl-ethyl] -3-methyl-piperidin-4-yl 2,2-dimethyl-propionic acid ester (58) A solution of alcohol 57 (1.26 grams, 5.16 millimoles) and triethylamine (1.43 milliliters, 10.32 millimoles) in 80 milliliters of DCM is cooled to -78 ° C. Triflic anhydride (0.85 milliliters, 5.16 millimoles) is slowly added, and stirring is continued for 1 hour. Then the mixture is allowed to warm to 0 ° C, and cooled back to -78 ° C after 15 minutes. A solution of piperidin-4-yl-carbamic acid terbutilyester, 3, (1.03 grams, 5.16 millimoles) in 40 milliliters of DCM at -78 ° C is slowly added. After completing the addition, the cooling bath is removed, and the dark solution is allowed to warm to room temperature. The mixture is washed twice with water, dried over sodium sulfate, filtered, and evaporated. The crude is purified by chromatography on silica gel using DCM (saturated with ammonia) and MeOH (1 percent). Yield: 1.7 grams (77 percent). MS (ESI): 440.3 [M + H] +, 1 H-NMR (CD3OD): d (ppm) 4.3 (td, 1H), 3.34 (m, 1H), 3.01 (m, 1H), 2.78-2.91 (m , 4H), 2.52 (dd, 1H), 2.42 (td, 1H), 2.02-2.3 (m, 4H), 1.94 (m, 1H), 1.84 (m, 3H), 1.5 (m, 3H), 1.45 ( s, 9H), 1.21 (s, 9H), 1. 04 (d, 3H), 0.9 (d, 3H). [α] D = -9.3 (c = 1 in MeOH). (3) Acid terbutilter. { 1 - [(S) -2 - ((3S, 4S) -4-hydroxy-3-methyl-piperidin-1-yl) -propiI] -piperidin-4-yl} -carbamic (59) The ester 58 above (1.7 grams, 3.52 millimoles) is treated with NaOMe (0.5M in methanol, 21 milliliters, 10.5 millimoles), and heated under reflux for 24 hours. The solvent is then evaporated, the residue is taken up in DCM, and extracted with 1N NaOH and brine. After drying and evaporation, the crude is purified by chromatography on silica gel using DCM (saturated with ammonia) and MeOH (1 to 3 percent) to give a white powder. Yield: 0.77 grams (56 percent). MS (ESI): 356.3 [M + H] +, 1 H-NMR (CD 3 OD): d (ppm) 4.86 (s, 1 H), 3.32 (m, 1 H), 2.94-3.06 (m, 2H), 2.72-2.87 (m, 3H), 2.49 (dd, 1H), 2.34 (td, 1H), 2.14-2.28 (m, 2H), 1.97-2.1 (m, 2H), 1.75-1.93 (m, 3H), 1.53 (m, 4H), 1.44 (s, 9H), 1. 04 (d, 3H), 0.97 (d, 3H). [a] D = 15.3 (c = 1 in MeOH). (4) (3S, 4S) -1 - [(S) -2- (4-amino-piperidin-1-yl) -1-methyl-ethyl] -3-methyl-piperidin-4-ol trichlorohydrate (56) ) Prepared by BOC dissociation of terbutyl ester 59 (0.666 grams, 1.95 millimoles) with 4M-HCl in dioxane (2.93 milliliters, 11.72 millimoles), as described for amine 7. Yield: 0.64 grams (93 percent) . MS (ESI): 256.2 [M + H] +, 1 H-NMR (CD3OD): d (ppm) 4.25 (br m, 1H), 4.03 (br m, 3H), 3.05-3.9 (m, 9H), 1.95 -2.55 (m, 7H), 1.54 (d, 3H), 1.1 (d, 3H). [a] D = +13.2 (c = 1 in MeOH). Synthesis of (3S, 4S) -1 - ((S) -2-hydroxy-3-trityloxy-propyl) -3-methyl-piperidin-4-yl-ester of acid 2.2 -dimethyl propionic (60): Dissolve (S) -2-trithyloxymethyl-oxirane (636 milligrams, 2 mmol) and (3S, 4S) -3-methyl-piperidin-4-yl-ester of 2,2-dimethyl-propionic acid 17 (400 milligrams, 2 millimoles) in 7 milliliters of ethanoi, and stirred at room temperature for 23 hours. The white suspension is heated to 40 ° C, and stirred for an additional 2 hours. The reaction mixture is evaporated under reduced pressure, and the crude product is purified by chromatography by evaporation (silica gel, 20% ethyl acetate in cyclohexane). Yield: 681 milligrams (66 percent) of a white foam. MS (ESI): 516.4 [M + H] +, 1 H-NMR (CDCl 3): d (ppm) 7.4 (d, 6H), 7.31 (dd, 6H), 7.23 (dd, 3H), 4.62 (d, 1H ), 4.22 (m, 1H), 3.74 (m, 1H), 2.95 (d, 2H), 2.72 (m, 2H), 2.22-2.41 (m, 2H), 2.07 (m, 1H), 1.58-1.84 ( m, 3H), 1.14 (s, 9H), 0.76 (d, 3H). Synthesis of (1-r (1S, 9aR) -1- (octahydro-quinol-zin-1-yl) methylene-piperidin-4-ylamine trichlorohydrate (61) (reaction scheme 8): (1) Terbutil-acid ester. { 1 - [(1S, 9aR) -1- (Octahydro-quinolizin-1-yl) methyl] -piperidin-4-yl} -carbamic (62) Dissolve 3 (3 grams, 15 millimoles) in 150 milliliters of propionitrile. Ethyldi-isopropyl-amine (10.2 milliliters, 60 millimoles), (-) - lupinine (2.5 grams, 15 millimoles), and cyanomethyl-trimethyl-phosphonium iodide (Zaragoza reagent, 7.3 grams, 30 millimoles) are added. The reaction mixture is heated to 120 ° C, and stirred for 22 hours. Then the mixture is evaporated under reduced pressure. The residue is dissolved with ethyl acetate, washed with a 10 percent K2CO3 solution and NaCl, and dried over Na2SO4. Evaporation gave 57 grams of a brown oil. The crude product is purified by evaporation chromatography (ethyl acetate, then ethanol / ethyl acetate) (4: 6), silica gel). Yield: 4.3 grams (81.7 percent) of a chestnut oil. MS (ESI): 352 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 6.7 (br d, 1H), 3.2 (m, 1H), 2.7-2.75 (m, 4H), 2.4 (dd, 1H), 2.2 (dd, 1H), 1.38 (s, 9H), 1. 15-2.0 (m, 20H). (2) 1 - [(1S, 9aR) -1- (Octahydro-quinolin-1-yl) methyl] -piperidin-4-ylamine trichlorohydrate (61) The ester 62 (3.8 grams, 10.8 mmol) is dissolved in 15 g. milliliters of dioxane, and after the addition of 70 milliliters of a 4M solution of HCl in dioxane, the mixture is stirred for 4 hours at room temperature. The product is filtered and used in the next step without further purification. Yield: 3.9 grams (100 percent). MS (ESI): 252 [M + H] +. Synthesis of (9R, 9aS) -1- (octahydro-pyridon-2,1-cip, 41-oxazin-9-yl) -methanol (racemate) (63) (reaction scheme 9): (1) 4- (3-bromo-propyl) -morpholine-3,5-dione (64) A pale yellow suspension of morpholine-3,5-dione (1.2 grams, 10 mmol), 1,3-dibromopropane (3.4 milliliters, 3.3 millimoles), and potassium carbonate (2.7 grams, 19 millimoles) in 23 milliliters of 2-butanone, is refluxed under an argon atmosphere for 22 hours. After cooling, the suspension is concentrated on a rotary evaporator, poured into ice / water, and extracted twice with ethyl acetate. The combined organic phases are washed with water, dried over anhydrous sodium sulfate, and evaporated. The residual yellow oil (2.06 grams) is purified by chromatography (Biotage 40Mi, I = 15 centimeters, cyclohexane / ethyl acetate, 3: 1). Yield: 1.2 grams (52.5 percent) of a colorless oil. MS (El): 235 [M] +, 1 H-RM N (CDCl 3): d (ppm) 4.37 (s, 4H), 3.95 (t, 2H), 3.39 (t, 2H), 21 8 (m, 2H). (2) 4-Oxo-1, 3,4,6,7,8-hexahydro-pyrido [2,1-c] [1,4] oxazine-9-carboxylic acid ethyl ester To an icy suspension of hydride of sodium (1 50 milligrams, 60 percent in mineral oil, 3.75 millimoles) in 26 milliliters of anhydrous tetrahydrofuran under argon, is added a solution of triethyl phosphonoacetate (0.31 milliliters, 1.5 millimoles) in 6 milliliters of anhydrous tetrahydrofuran . The suspension is stirred at room temperature for 2 hours, then add 64 (354 milligrams, 1.5 millimoles) in 6 milliliters of tetrahydrofuran, and the resulting mixture is refluxed for 10 hours. After cooling, the suspension is concentrated on a rotary evaporator, poured onto ice / saturated aqueous solution of ammonium chloride, and extracted twice with ethyl acetate. The combined organic phases are washed with brine, dried over anhydrous sodium sulfate, and evaporated. The residual yellow oil (339 milligrams) is purified by chromatography (Biotage 12Mi, I = 15.5 centimeters, cyclohexane / ethyl acetate, 3: 1). Yield: 60.3 milligrams (17.8 percent) of a colorless oil. MS (ESI): 226 [M + H] +, 1 H-NMR (CDCl 3): d (ppm) 4.94 (s, 2H), 4.27 (s, 2H), 3.75 (dd, 2H), 2.45 (m, 2H), 1.88 (m, 2H), 1.30 (t, 3H). (3) (9RS, 9aSR) -4-oxo-octahydro-pyrido [2,1-c] [1,4] oxazine-9-carboxylic acid ethyl ester (racemate) (66) A solution of 65 (225 milligrams, 1.0 millimoles) in 5 milliliters of acetic acid, is hydrogenated on 225 milligrams of platinum dioxide at room temperature and at normal pressure during 18 hours. Another 225 milligrams of platinum dioxide is added, and the hydrogenation is continued for 24 hours. The black suspension is diluted with 10 milliliters of DCM, and filtered through a pad of Celite. The filtrate is evaporated to give 268 milligrams of a yellow oil, which is purified by chromatography (Biotage 12 Si, I = 7. 5 cm, ethyl acetate / ethanol, 9: 1). Yield: 144 milligrams (63.3 percent) of a yellow oil.

MS (ESI): 228 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm), 4.45 (m, 1 H), 4.00 (m, 2 H), 3.9-3.75 (m, 4 H), 3.60 (m, 1H), 2.65 (m, 1H), 2.55 (m, 1H), 1.90 (m, 2H), 1.75 (m, 1H), 1.45 (m, 1H), 116 (t, 3H). (4) (9RS, 9aSR) -1- (Octahydro-pyrido [2,1-c] [1,4] oxazin-9-yl) -methanol (racemate) (63) To a solution of 66 (114 milligrams, 0.5 millimoles) in 5 milliliters of anhydrous tetrahydrofuran, AH (40 milligrams, 1.0 mmol) is added, and the mixture is refluxed for 9 hours. The mixture is cooled to 0 ° C, and treated successively with 0.04 milliliters of water, 3N aqueous sodium hydroxide (0.04 milliliters, 0.12 millimoles), and 0.12 milliliters of water. The mixture is stirred for 15 minutes, and then extracted three times with DCM. The combined organic phases are dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residual pale yellow oil (75 milligrams) is purified by chromatography (Biotage, 12 Si, I = 7.5 cm, DCM / MeOH / Ammonia concentrate, 95: 4.5: 0.5). Yield: 35.1 (41.0'percent) of a pale yellow oil. MS (ESI): 172 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 4.30 (br s, 1 H), 3.65-3.55 (m, 4 H), 3.50-3.35 (m, 2 H) , 2.70 (br d, 1H), 2.55 (br d, 1H), 2.10-1.95 (m, 2H), 1.5-1.60 (m, 2H), 1.60-1.50 (m, 2H), 1.35-120 (m, 2H). Synthesis of (8R, 8aS) -1- (hexahydro-pyrroir-2,1-cU1,41-oxazin-8-yl) -methanol (racemate) (67) (reaction scheme 10): (1) 4-Oxo-3,4,6,7-tetrahydro-1H-pyrrolo [2,1-c] [1,4] oxazine-8-carboxylic acid ethyl ester (68) To a suspension of sodium hydride (480 milligrams, 60 percent in mineral oil, 12 millimoles) in 10 milliliters of anhydrous tetrahydrofuran, morpholine-3,5-dione (1.2 grams, 10 millimoles) is added in 20 milliliters of tetrahydrofuran under an argon atmosphere. After 10 minutes, 1-carbethoxy-cyclopropyl-triphenyl-phosphonium tetrafluoroborate (Fuchs reagent, 6.8 grams, 11 mmol) is added in 20 milliliters of tetrahydrofuran, and the mixture is refluxed for 21 hours. After cooling, the suspension is concentrated on a rotary evaporator, poured onto ice / saturated sodium bicarbonate solution, and extracted three times with ether. The combined organic phases are washed with brine, dried over anhydrous sodium sulfate, and evaporated. The residual yellow oil (3.04 grams) is purified by chromatography (silica gel 60, mesh 0.063-0.2, cyclohexane / ethyl acetate, 1: 1). Yield: 1.08 grams (51.2 percent) of a colorless solid. MS (El): 211 [M] +, 1 H-NMR (DMSO-d 6): d (ppm) 4.77 (s, 2 H), 4.1 (s, 2 H), 4.11 (q, 2 H), 3.82 (m, 2 H) ), 2.70 (m, 2H), 1.22 (t 3H). (2) (8RS, 8aSR) -4-oxo-hexahydro-pyrrolo [2,1-c] [1,4] oxazine-8-carboxylic acid ethyl ester (racemate) (69) A solution of 68 (1.056 grams , 5.0 millimoles) in 25 milliliters of acetic acid, is hydrogenated over 1056 grams of platinum dioxide at room temperature and at normal pressure for 18 hours. The black suspension is diluted with 20 milliliters of DCM, and filtered through a pad of Celite. The filtrate is evaporated to 1.09 grams of a yellow oil, which is purified by chromatography (silica gel 60, mesh 0.063-0.2, ethyl acetate / ethanol, 9: 1). Yield: 809 milligrams (75.7 percent) of a yellow oil.

MS (ESI): 214 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 4.15-3.80 (m, 6H), 3.70-3.05 (m, 4H), 2.70-1.90 (m, 2H), 1.18 (t, 3H). (3) (8RS, 8aSR) -1- (hexahydro-pyrrolo [2,1-c] [1,4] oxazin-8-yl) -methanol (racemate) (67) To a solution of 69 (1.1 grams, 5.0 millimoles) in 50 milliliters of anhydrous tetrahydrofuran, LAH (400 milligrams, 10 millimoles) is added, and the mixture is refluxed for 18 hours. The mixture is cooled to 0 ° C, and treated successively with 0.4 milliliters of water, 0.4 milliliters of 3N aqueous sodium hydroxide, and 1.2 milliliters of water. The mixture is stirred for 15 minutes, and then extracted three times with DCM. The combined organic phases are dried over anhydrous sodium sulfate and evaporated. The residual yellow oil (880 milligrams) is purified by chromatography (silica gel 60, mesh 0.063-0.2, DCM / MeOH / concentrated ammonia, 90: 9: 1). Yield: 552 milligrams (70.2 percent) of a pink oil. MS (ESI): 158 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 4.42 (br s, 1 H), 3.85 (m, 1 H), 3.65 (m, 1 H), 3.35 ( m, 2H), 3.15 (m, 1H), 2.95 (m, 1H), 2.85 (m, 1H), 2.15-1.90 (m, 5H), 1.75 (m, 1H), 1.20 (m, 1H). Synthesis of 4- (2-azepan-1-yl-ethyl) -phenylamine dihydrochloride (70): (1) 1- [2- (4-nitro-phenyl) -ethyl] -azepane (71) 1- (2-Bromo-ethyl) -4-nitro-benzene (10 grams, 43.47 millimoles) is added under argon, to a mixture of azepane (4.9 milliliters, 43.47 millimoles) and potassium carbonate (6 grams, 43.47 millimoles) in 100 milliliters of N, N-dimethylformamide. After stirring overnight at room temperature, the mixture is filtered and evaporated under a high vacuum. The residue is dissolved in ethyl acetate, washed with water and brine, and dried over sodium sulfate. Evaporation gave 9.1 grams (84 percent) of a yellow oil. MS (ESI): 247.2 [M + H] +, 1 H-NMR (CDCl 3): d (ppm) 8.15 (d, 2H), 7.55 (d, 2H), 2.87 (t, 2H), 2.73 (t, 2H ), 2.65 (t, 4H), 1.5-1.6 (m, 8H). (2) 4- (2-azepan-1-yl-ethyl) -phenylamine dihydrochloride (70) Compound 71 (9.1 grams, 36.65 mmol) is hydrogenated for 3 hours at room temperature with palladium on carbon in 150 milliliters of ethanol and 18.3 milliliters of 4M aqueous hydrochloric acid. The mixture is filtered over Celite, and evaporated. Yield: 10.7 grams (100 percent) of a beige solid. MS (ESI): 219 [M + H] +, 1 H-NMR (CDCl 3): d (ppm) 10.85 (br, 1H), 9.8 (br, 3H), 7.3 (m, 2H), 7.2 (m, 2H ), 3.42 (m, 2H), 3.25 (m, 2H), 3.18 (m, 2H), 3.08 (m, 2H), 1.85 (m, 4H), 1.68 (m, 2H), 1.58 (m, 2H) . Synthesis of di (1) - (4-amino-phenyl) -ethyl-1-methy1- (tetrahydro-pyran-4-yl) -amine dihydrochloride (72) (reaction scheme 11): (1) ethyl - [(R) -1- (4-nitro-phenyl) -ethyl] - (tetrahydro-pyran-4-yl) -amine (73) (R) -a-methyl-4-hydrochloride is dissolved -nitro-benzyl ammonium (Aldrich, 3 grams, 15 millimoles), tetrahydropyridone (1.5 grams, 15 millimoles), pyridine (1.2 millimeters, 15 millimoles) in 100 milliliters of DCE. Sodium triacetoxyborohydride (4 grams, 19 mmol, 95 percent) is added with stirring at room temperature; After 18 hours of reaction time, formaldehyde (2.4 milliliters, 30 percent in water) is added, followed by sodium triacetoxyborohydride (3 grams, 14 millimoles, 95 percent), and the mixture is stirred again for 18 hours at room temperature. After the addition of 2M HCl, the product is isolated by distribution between aqueous ammonia and EtOAc. The combined organic layers are washed with brine, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The crude product (3.2 grams, 82 percent) is used without further purification. MS (ESI): 265 [M + H] +, 1 H-NMR (CDCl 3): d (ppm) 8.20 (d, 2H), 7.55 (d, 2H), 4.0 (br m, 2H), 3.95 (br m , 1H), 3.3 (br m, 2H), 2.7 (br m, 1H), 2.20 (s, 3H), 1.7 (br m, 4H), 1.40 (d, 3H). (2) [(R) -1- (4-Amino-phenyl) -etiI] -methyl- (tetrahydro-pyran-4-yl) -amine dihydrochloride (72) Methyl - [(R) -1- ( 4-Nitro-phenyl) -ethyl] - (tetrahydro-pyran-4-yl) -amine 73 above (3.2 grams, 12 mmol) is stirred with RaNi (1 gram) in 100 milliliters of MeOH. Drip hydrazine monohydrate (3.2 milliliters) at room temperature, and the reaction mixture is stirred for an additional 3 hours. After filtration and evaporation under reduced pressure, the product is isolated by distribution between Et 2 O and brine, drying of the organic phase with sodium sulfate, filtration, and evaporation, as a yellow oil (2.6 grams, 92 percent). . MS (ESI): 235 [M + H] +, 1 H-NMR (CDCl 3): d (ppm) 7.15 (d, 2H), 6.65 (d, 2H), 4.0 (br m, 2H), 3.7 (br m , 1H), 3.6 (NH2), 3.3 (br m, 2H), 2.7 (rm, 1H), 2.20 (s, 3H), 1.7 (br m, 4H), 1.30 (d, 3H). Synthesis of the indole-2-carboxamides The indole-2-carboxamides are generally prepared by a TBTU-mediated coupling of the indole-2-carboxylic acids appropriately substituted with the corresponding amines in the presence of the Hunig base (Reaction Scheme 12) . Reaction Scheme 12: RNHj An illustrative example is given below. Example 1 4-methoxy-1H-indole-2-carboxylic acid [1- (2-azepan-1-yl-etiI) -piperidin-4-yl] -amide.

A solution of 4-methoxy-1H-indole-2-carboxylic acid (930 milligrams, 4.86 millimoles), amine 5 (1.63 grams, 4.86 millimoles), and DIEA (2.5 milliliters, 14.58 millimoles) in 20 milliliters of N, N ~ Dimethylformamide, treated with solid TBTU (1.56 grams, 4.86 millimoles). The mixture is stirred overnight, and then evaporated.

The crude residue is dissolved in EtOAc, and washed twice with sodium dicarbonate (10 percent). The aqueous layers are back extracted with DCM, the combined organic layers are washed with brine and dried with sodium sulfate. The crude product is then purified by chromatography on silica gel using DCM (saturated with ammonia) and MeOH (0 to 2 percent). Yield: 0.975 grams (50 percent) of a beige powder. MS (ESI) 399.3 [M + Hf, 1 H-NMR (DMSO-d 6): d (ppm) 11.65 (s, 1 H), 8.24 (d, 1 H), 7.28 (s, 1 H), 7.9 (t, 1 H) , 7.0 (d, 1H), 6.5 (d, 1H), 3.75- 3.9 (m, 4H), 2.92-3.25 (m, 8H), 2.73 (m, 2H), 2.2 (m, 2), 1.52-1.9 (m, 12H). The formation of the dihydrochlorides can be achieved by treating a solution of the free base in DCM or acetone with 2M HCl in ether at 0 ° C.

Example 2 4-isopropoxy-1 H-indole-2-carboxylic acid [1- (2-azepan-1-yl-ethyl) -piperidin-4-yl] -amide This compound is synthesized in a manner analogous to Example 1 from 4-isopropoxy-1H-indole-2-carboxylic acid 74 (for the preparation, see below) and the amine 5. MS (ESI): 427.3 [M + H] +, 1 H-NMR (DMSO-d6 ): d (ppm) 8.24 (d, 1H), 7.22 (d, 1H), 7.06 (t, 1H), 6.98 (d, 1H), 6.51 (d, 1H), 4.75 (m, 1H), 3. 75 (m, 1H), 2.99 (m, 2H), 253-2.64 (m, 6H), 2.39 (m, 2H), 2.02 (m, 2H), 1.77 (m, 2H), 1.49-163 (m, 10H), 1.35 (d, 6H). Synthesis of 4-isopropoxy-1H-indole-2-carboxylic acid (74): (1) Step A: 4-Hydroxy-1H-indole-2-carboxylic acid methyl ester (75) To an iced solution of 4-methylester of 4-methoester -methyloxy-1H-indole-2-carboxylic acid (1 gram, 4.87 mmol) in DCM (10 milliliters), BBr3 (1M in DCM, 4.9 milliliters, 4.9 mmol) is added. Stir for 1 hour, and add another equivalent (4.9 milliliters) of BBr3. After another hour, the mixture is poured onto ice, and the pH is adjusted to 7 with sodium bicarbonate. Extraction with DCM gave a yellow powder. Yield: 0.82 grams (88 percent), MS (ESI): 192.0 [M + H] +, 1 H-NMR (DMSO-de): d (ppm) 11.78 (br s, 1 H), 9.73 (s, 1 H) , 7.21 (d, 1H), 7.05 (dd, 1H), 6.89 (d, 1H), 6.4 (d, 1H), 3.86 (s, 3H). (2) Step B: 4-isopropoxy-1 H-indole-2-carboxylic acid methylester (76) Slowly add DEAD (0.227 milliliters, 1.47 millimoles) to a solution of 4-hydroxy-1H-indole methyl ester -2-carboxylic acid 75 (200 milligrams, 105 mmol), triphenylphosphine (384 milligrams, 1. 47 millimoles), and isopropanol (0.108 milliliters, 1.43 millimoles) in 2 milliliters of tetrahydrofuran. Stirring is continued for 20 minutes, and then the solvent is evaporated. The crude mixture is purified by chromatography on silica gel using cyclohexane / EtOAc (9/1). Yield: 89 milligrams (37 percent). MS (ESI): 234.0 [M + H] \ 1 H-NMR (DMSO-d 6): d (ppm) 11.89 (s, 1 H), 7.26 (t, 1 H), 7.70 (s, 1 H), 6.98 (d, 1H), 6.54 (d, 1H), 4.72 (m, 1H), 3.85 (s, 3H), 1.33 (d, 6H). (3) Step C: 4-isopropoxy-1H-indole-2-carboxylic acid (74) 4-isopropoxy-1H-indole-2-carboxylic acid methyl ester 76 (114 milligrams, 0.49 millimoles) is dissolved in 5 milliliters of tetrahydrofuran. A 2M solution of LiOH in water (2.5 milliliters, 5 mmol) is added, and the mixture is stirred for 48 hours. The solvent is then evaporated, and the residue is partitioned between water and EtOAc. The water layer is acidified with HCl, and extracted twice with EtOAc.

The combined organic layers are washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated to a yellow powder. Yield: 95 milligrams (89 percent). MS (ESI): 219.9 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 11.72 (br s, 1H), 7.14 (dd, 1H), 7.0 (m, 2H), 6.55 ( d, 1H), 4.72 (m, 1H), 1.33 (d, 6H). Example 36b. { 1- [2- (4-hydroxy-piperidin-1-yl) -ethyl] -piperidin-4-yl} 4-isopropoxy-1 H-indole-2-carboxylic acid amide This compound is synthesized in a manner analogous to Example 1, from 4-isopropoxy-1H-indole-2-carboxylic acid 74 (for the preparation, see Example 2), and the amine 21. MS (ESI): 429.3 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 11.42 (s, 1 H), 8.2 (d, 1 H), 7.19 (s, 1 H), 7.02 (t, 1 H), 6.94 (d, 1H), 6.48 (d, 1H), 4.72 (m, 1H), 45 (br s, 1H), 3.74 (m, 1H), 3.25-345 (m, 3H), 2.86 (m, 2H) , 2.71 (m, 2H), 2.37 (rs, 4H), 2.0 (m, 4H), 1.73 (m, 4H), 1.54 (m, 2H), 1.33 (d, 6H). Example 4 4-cyclopropylmethoxy-1 H-indole-2-carboxylic acid [1- (2-azepan-1-yl-ethyl) -piperidin-4-yl] -amide This compound is synthesized in a manner analogous to Example 1, starting from 4-cyclopropylmethoxy-1H-indole-2-carboxylic acid 77 (for the preparation, see below), and the amine 5. MS (ESI): 439.3 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 11.43 (s, 1H), 8.2 (d, 1H), 7.27 (s, 1H), 7.01 (t, 1H), 6.96 ( d, 1H), 6.42 (d, 1H), 3.9 (d, 2H), 3.72 (m, 1H), 2.87 (m, 2H), 2.52-2.62 (m, 6H), 2.37 (m, 2H), 2. 0 (m, 2H), 1.47-1.63 (m, 10H), 1.3 (m, 1H), 0.61 (m, 2H), 0.3 (m, 2H). Synthesis of 4-cyclopropylmethoxy-1 H-indole-2-carboxylic acid (77): (1) Step A: 4-Cyclopropylmethoxy-1H-indole-2-carboxylic acid (78) Slowly added DEAD (2.1 milliliters, 13.65 millimoles ) to a solution of 4-hydroxy-1H-indole-2-carboxylic acid ethyl ester 79 (2 grams, 9.75 mmol), triphenylphosphine (3.58 grams, 13.65 mmol), and cyclopropyl-methanol (1.05 milliliters, 12.26 mmol) in milliliters of tetrahydrofuran, in such a way that the temperature always remains below 30 ° C. Stirring is continued for 2 hours, and then the solvent is evaporated. The crude residue is purified by chromatography (cyclohexane: EtOAc / 95: 5) Yield: 1.17 grams (46 percent) MS (ESI): 260.1 [M + H] +, 1 H-NMR (CDCl 3): d (ppm) 8.85 (s, 1H), 7.4 (s, 1H), 7.19 (t, 1H), 6.99 (d, 1H), 6.45 (d, 1H), 4.4 (q, 2H), 3.95 (d, 2H), 1.41 (t, 3H), 1.34 (m, 1H), 0.66 (m, 2H), 0.4 (m, 2H). (2) Step B: 4-Cyclopropylmethoxy-1H-indole-2-carboxylic acid (77) Ethyl ester of the 4-cyclobutylmethoxy-1H-indole-2-carboxylic acid 78 obtained above, mixed with a 2M solution of KOH in EtOH (16.9 milliliters, 33.8 mmol), and stirred for 24 hours, then the solvent is evaporated, The water layer is acidified with HCl, and extracted twice with EtOAc, the combined organic layers are washed with brine, dried over anhydrous sodium sulfate, filtered, and evaporated. to yield a white powder Yield: 1.02 grams (99 percent) MS (ESI): 232.2 [M + H] +, 1H-NMR (CDCI3): d (ppm) 8.84 (s, 1H), 7.55 (s, 1H), 7.26 (t, 1H), 7.01 (d, 1H), 6.48 (d, 1H), 3.97 (d, 2H), 1.36 (m, 1H), 0.66 (m, 2H), 0.41 ( m, 2H). Example 5 { 1- [2- (4-hydroxy-piperidin-1-yl) -ethyl] -piperidin-4-yl} -amide of 4-cyclopropylmethoxy-1 H-indole-2-carboxylic acid This compound is synthesized in a manner analogous to Example 1, from 4-cyclopropylmethoxy-1H-indole-2-carboxylic acid 77 (for the preparation, see Example 4), and the amine 21. MS (ESI): 441.3 [M + H] +, 1H-NMR (DMSO-d6): d (ppm) 11.43 (s, 1H), 8.2 (d, 1H), 7.27 (s, 1H), 7.01 (t, 1H), 6.96 (d, 1H), 6.42 (d, 1H) ), 4.49 (d, 1H), 3.91 (d, 2H), 3.72 (m, 1H), 3.4 (m, 1H), 2.86 (br, 4H), 2.71 (m, 2H), 2.71 (m, 2H), 2.38 (br, 4H) ), 1.99 (m, 4H), 1.75 (m, 2H), 1.68 (m, 2H), 1.54 (m, 2H), 1.22-1.42 (m, 3H), 0.61 (m, 2H), 0.37 (m, 2H). Example 6 { 1 - [(S) -2- (4-hydroxy-piperidin-1-yl) -propyl] -piperidin-4-yl} -amide of 4-cyclopropylmethoxy-1H-indole-2-carboxylic acid This compound is synthesized in a manner analogous to Example 1, from 4-cyclopropylmethoxy-1H-indole-2-carboxylic acid 77 (see Example 4) and 50 amine. MS (ESI): 455.4 [M + H ] +, 1H-NMR (CD3OD): d (ppm) 7.14 (s, 1H), 6.98 (t, 1H), 6.89 (d, 1H), 6.33 (d, 1H), 3.83 (d, 2H), 3.75 (m, 1H), 3.45 (m, 1H), 2.93 (m, 1H), 2.77 (m, 1H), 2.68 (m, 3H), 2.39 (m, 1H), 2.26 (m, 2H), 211 ( m, 2H), 1.95 (m, 1H), 1.79 (m, 2H), 1.73 (m, 2H), 1.55 (m, 2H), 1.42 (m, 2H), 1.21 (m, 1H), 0.93 (d , 3H), 0.51 (m, 2H), 0.28 (m, 2H).

Example 7 { 1 - [(S) -2 - ((3S, 4S) -4-hydroxy-3-methyl-piperidin-1-yl) -propl] -piperidin-4-yl} -amide of 4-cyclopropylmethoxy-1 H-indole-2-carboxylic acid This compound is synthesized in a manner analogous to Example 1, from 4-cyclopropylmethoxy-1H-indole-2-carboxylic acid 77 (see Example 4), and amine 56. MS (ESI): 469.2 [M + H ] +, 1 H-NMR (DMSO-d 6): d (ppm) 11.44 (s, 1H), 8. 2 (d, 1H), 7.27 (s, 1H), 7.01 (t, 1H), 6.95 (d, 1H), 6.41 (d, 1H), 444 (d, 1H), 3.91 (d, 2H), 3.74 (m, 1H), 2.61-2.95 (m, 6H), 2.04-2.38 (m, 4H), 1.85-1.97 (m, 2H), 1.66-1.81 (m, 3H), 1.45-1.63 (m, 2H) , 1.2-1.43 (m, 3H), 0.91 (d, 3H), 0.87 (d, 3H), 0.61 (m, 2H), 0.37 (m, 2H). Example 8 4-Isobutoxy-1H-indole-2-carboxylic acid [1- (2-azepan-1-yl-ethyl) -piperidin-4-yl] -amide This compound is synthesized in a manner analogous to Example 1, starting from 4-isobutoxy-1 H-indole-2-carboxylic acid 80 (for the preparation, see below), and the amine 5.

MS (ESI): 441.3 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 11.45 (s, 1H), 8.21 (d, 1H), 7.23 (d, 1H), 7.03 (t , 1H), 6.97 (d, 1H), 6.46 (d, 1H), 3.84 (d, 2H), 3.75 (m, 1H), 2.99 (m, 1H), 2.53-267 (m, 6H), 2.41 ( m, 2H), 2.1 (m, 1H), 2.02 (m, 2H), 1.78 (m, 2H), 1.48-1.62 (m, 8H), 1.06 (d, 6H). Synthesis of 4-iobutoxy-1 H-indole-2-carboxylic acid (80): (1) Step A: 4-Hydroxy-1H-indole-2-carboxylic acid ethyl ester (79) To a solution of 4-benzyloxy acid -1 H-indole-2-carboxylic acid (29 grams, 98.2 mmol) in a mixture of MeOH (750 milliliters) and DCM (500 milliliters), 1 gram of Pd / C (10 percent) is added.

Hydrogenate under normal pressure for 24 hours. After filtration and evaporation, a white powder is obtained. Yield: 19.63 (97 percent). MS (ESI): 206.0 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 11.72 (br s, 1 H), 9.69 (s, 1 H), 7.2 (s, 1 H), 7.05. (t, 1H), 6.98 (d, 1H), 6.38 (d, 1H), 4.33 (q, 2H), 1.32 (t, 3H). (2) Step B: 4-Isobutoxy-1H-indole-2-carboxylic acid ethyl ester (81) Slowly add DEAD (10.2 milliliters, 65.28 millimoles) to a solution of 4-hydroxy-1H-indole-2-ethyl ester -carboxylic 79 (9.57 grams, 46.63 millimoles), triphenylphosphine (17.12 grams, 65.28 millimoles), and isobutanol (5.9 milliliters, 63.42 millimoles) in 100 milliliters of tetrahydrofuran, in such a way that the temperature always remains below 30 ° C. Stirring is continued for 3 hours, and then the solvent is evaporated. The crude mixture is purified by chromatography on silica gel, first using cyclohexane as eluent, and then increasing amounts of EtOAc (from 5 percent to 50 percent). Yield: 8 grams (65 percent). MS (ESI): 260.0 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 8.86 (s, 1H), 7. 36 (s, 1H), 7.22 (t, 1H), 6.99 (d, 1H), 6.48 (d, 1H), 4.4 (q, 2H), 3.86 (d, 2H), 2.2 (m, 1H), 1.42 (t, 3H), 1.09 (d, 6H). (3) Step C: 4-Isobutoxy-1 H-indole-2-carboxylic acid (80) The 4-isobutoxy-1H-indole-2-carboxylic acid ethyl ester 81 (5.2 grams, 19.9 mmol) is mixed with a solution 1M of KOH in EtOH (99.5 milliliters, 99.5 millimoles) and stirred for 24 hours. The solvent is then evaporated, and the residue is divided between water and ether. The water layer is acidified with HCl, and extracted twice with ether. The combined organic layers are washed with brine, dried over anhydrous sodium sulfate, filtered, and evaporated to give a beige powder. Yield: 4.32 grams (93 percent). MS (ESI): 2342 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 11.74 (br s, 1H), 7.13 (dd, 1H), 7.06 (s, 1H), 7.0 ( d, 1 H), 6.49 (d, 1 H), 3.85 (d, 2 H), 3.35 (br s, 1 H), 2.1 (m, 1 H), 1.03 (d, 6 H).

Example 9 [1- (2-piperidin-1-yl-ethyl) -piperidin-4-yl] -amide of 4-isobutoxy-1H-indole-2-carboxylic acid This compound is synthesized in a manner analogous to Example 1, from 4-isobutoxy-1 H-indole-2-carboxylic acid 80 (for the preparation, see Example 8), and the amine 1. MS (ESI): 427.3 [M + H] +, 1H- NMR (DMSO-d6): d (ppm) 11.45 (s, 1H), 8.21 (d, 1H), 7.23 (d, 1H), 7.03 (t, 1H), 6.96 (d, 1H), 3.84 (d, 2H), 3. 75 (m, 1H), 2.88 (m, 2H), 2.38 (m, 8H), 2.1 (m, 1H), 2.02 (m, 2H), 1. 78 (m, 2H), 1.32-1.63 (m, 9H), 1.07 (d, 6H). Example 10 { 1- [2- (RS) -2-methyl-piperidin-1-yl) -ethyl] -piperidin-4-yl} -amido of 4-isobutoxy-1 H-indole-2-carboxylic acid This compound is synthesized in a manner analogous to Example 1, from 4-isobutoxy-1H-indole-2-carboxylic acid 80 (for the preparation, see Example 8), and the amine 10. MS (ESI): 441.3 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 11.43 (s, 1 H), 8.19 (d, 1 H), 7.22 (d, 1 H), 7.03 (t, 1 H), 6.97 (d, 1H), 6.45 (d, 1H), 3.85 (d, 2H), 3.75 (m, 1H), 2.65-2.93 (m, 7H), 2.05-2.43 (, 5H), 2.01 (m, 2) , 1.78 (m, 2H), 1.1-1.62 (m, 6H), 1.06 (d, 6H), 1.01 (d, 3H). Example 11 { 1- [2- (4-methyl-piperidin-1-yl) -ethyl] -piperidin-4-yl} -amide of 4-isobutoxy-1 H-indole-2-carboxylic acid This compound is synthesized in a manner analogous to Example 1, from 4-isobutoxy-1H-indole-2-carboxylic acid 80 (for the preparation, see Example 8), and the amine 7. MS (ESI): 441.3 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 11.44 (s, 1 H), 8.2 (d, 1 H), 7.22 (d, 1 H), 7.02 (t, 1 H), 6.96 (d, 1H), 6.46 (d, 1H), 6.86 (d, 2H), 3.75 (m, 1H), 2.86 (m, 4H), 2.4 (br s, 4H), 2.11 (m, 1H), 2.02 (m, 2H), 1.9 (m, 2H), 1.79 (m, 2H), 1.55 (m, 4H), 1.3 (m, 1H), 1.11 (m, 2H), 1.06 (d, 6H), 0.88 ( d, 3H). Example 12 { 1- [2- (2,6-Dimethyl-piperidin-1-yl) -ethyl] -piperidin-4-yl} -amido of 4-iso b u toxi-1 H -indole-2-carboxylic acid This compound is synthesized in a manner analogous to Example 1, from 4-isobutoxy-1H-indole-2-carboxylic acid 80 (for the preparation, see Example 8), and the amine 27. MS (ESI): 455.3 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 8.2 (d, 1H), 7.2 (d, 1H), 7.04 (t, 1H), 6.96 (d, 1H), 6.45 ( d, 1H), 3.85 (d, 2H), 3.75 (m, 1H), 2.87 (m, 2H), 2.7 (m, 2H), 2.43 (m, 2H), 2.32 (m, 2H), 2.1 (m , 2H), 2.03 (m, 2H), 1.78 (m, 2H), 1.45-1.65 (m, 5H), 1.0-1.35 (m, 16H). Example 13 { 1- [2 - ((R) -3-hydroxy-piperidin-1-yl) -ethyl] -piperidin-4-yl} -amide of 4-isobutoxy-1 H-indole-2-carboxylic acid This compound is synthesized in a manner analogous to Example 1, starting from 4-isobutoxy-1H-indole-2-carboxylic acid 80 (for the preparation, see Example 8), and the amine 12. MS (ESI): 443.3 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 11.45 (s, 1 H), 8.21 (d, 1 H), 7.23 (s, 1 H), 7.04 (t, 1 H), 6.97 (d, 1H), 6.45 (d, 1H), 4.54 (d, 1H), 3.84 (d, 1H), 3.75 (m, 1H), 3.42 (m, 1H), 2.62-2.93 (m, 2H), 2.49 (br s, 4H), 2.1 (m, 1H), 2.0 (m, 2H), 1.3-1.9 (m, 11H), 1.06 (d, 6H). Example 14 { 1- [2 - ((S) -3-hydroxy-piperidin-1-yl) -ethyl] -piperidin-4-yl} -amido of 4-isobutoxy-1 H-indole-2-carboxylic acid This compound is obtained by separation of the preparation of the racemic material using a chiral HPLC stationary phase (CHIRALCEL OJ-H 1170). The absolute stereochemistry is assigned by a comparison with the enantiomerically defined (R) isomer of Example 13. Example 15. { 1- [2- (4-hydroxy-piperidin-1-yl) -ethyl] -piperidin-4-yl} -amido of 4-isobutoxy-1 H-indole-2-carboxylic acid This compound is synthesized in a manner analogous to Example 1, starting from 4-isobutoxy-1H-indole-2-carboxylic acid 80 (for the preparation, see Example 8), and the amine 21. MS (ESI): 443.3 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 11.45 (s, 1 H), 8.2 (d, 1 H), 7.23 (d, 1 H), 7.04 (t, 1 H), 6.97 (d, 1H), 6.45 (d, 1H), 4.5 (d, 1H), 3.85 (d, 2H), 3.74 (m, 1H), 3.41 (m, 1H), 2.88 (m, 2H), 2.71 ( m, 2H), 2.38 (m, 4H), 2.1 (m, 1H), 2.0 (m, 4H), 1.76 (m, 2H), 1.68 (m, 2H), 1.55 (m, 2H), 1.35 (m , 2H), 1.06 (d, 6H).

Example 16 { 1- [2- (3-hydroxy-8-aza-b-cyclo [3.2.1] oct-8-yl) -ethyl] -piperidin-4-yl} - 4-isobutoxy-1 H-indole-2-carboxylic acid amide This compound is synthesized in a manner analogous to Example 1, from 4-isobutoxy-1H-indole-2-carboxylic acid 80 (for the preparation, see Example 8), and the amine 24. MS (ESI): 469.3 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 8.23 (d, 1H), 7. 72 (s, 1H), 6.9-7.1 (m, 2H), 6.46 (d, 1H), 4.57 (br s, 1H), 3.85 (d, 2H), 3.77 (m, 1H), 3.2-3.7 (br m, 4H), 2.94 (m, 2H), 2.75 (m, 2H), 2.56 (m, 2H), 1.5-2.25 (m, 15H), 1.06 (d, 6H). Example 17 { 1 - [(S) -2- (4-hydroxy-piperidin-1-yl) -propyl] -piperidin-4-yl} -a ida of 4-isobutoxy-1 H-indole-2-carboxylic acid This compound is synthesized in a manner analogous to Example 1, from 4-isobutoxy-1 H-indole-2-carboxylic acid 80 (see Example 8), and 50 amine. MS (ESI): 457.2 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 11.43 (s, 1H), 8. 19 (d, 1H), 7.22 (d, 1H), 7.02 (t, 1H), 6.96 (d, 1H), 644 (d, 1H), 4. 47 (d, 1H), 3.84 (d, 2H), 3.73 (m, 1H), 3.37 (m, 1H), 2.6-2.95 (m, 5H), 2.05-2.38 (m, 6H), 1.92 (m, 1H), 1.76 (m, 2H), 1.69 (m, 2H), 1.2- 1.65 (m, 4H), 1.05 (d, 6H), 0.92 (d, 3H). Example 18 [4- (2-azepan-1-yl-ethyl) -phenyl] -amide of 4-isobutoxy-1H-indole-2-carboxylic acid This compound is synthesized in a manner analogous to Example 1, from 4-isobutoxy-1H-indole-2-carboxylic acid 80 (for the preparation, see Example 8), and the amine 70. MS (ESI): 434.3 [M + H] +, 1H- NMR (DMSO-d6): d (ppm) 11.65 (s, 1H), 10.07 (s, 1H), 7.67 (d, 2H), 7.48 (d, 1H), 7.18 (d, 2H), 7.08 (t, 1H), 7.01 (d, 1H), 6.49 (d, 1H), 3.88 (d, 2H), 257-2.62 (m, 8H), 2.13 (m, 2H), 1.48-1.63 (m, 8H), 1.08 (d, 6H).

Example 19 (4 - Isobutoxy-1H-indole-2-carboxylic acid methyl 4- (tetrahydro-pyran-4-yl) -amino] -methyl] -cyclohexyl) -amide This compound is synthesized in a manner analogous to Example 1, starting from 4-isobutoxy-1H-indole-2-carboxylic acid 80 (for the preparation, see Example 8), and trans-4-amino-cyclohexylmethyl) -methyl- (tetrahydro) -piran-4-yl) -amine (International Publication No.

WO2000 / 68203). MS (ESI): 442.3 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 11.43 (s, 1H), 8.18 (d, 1H), 7.23 (s, 1H), 7.03 (t , 1H), 6.96 (d, 1H), 6.45 (d, 1H), 3.82-3.93 (m, 4H), 3.74 (m, 1H, 3-22-3.31 (m, 2H), 2.7 (s, 3H) , 2.45 (m, 1H), 2.18 (m, 4H), 2.11 (m, 1H), 1.85 (m, 4H), 1.6 (m, 2H), 1.2-1.48 (m, 5H), 1.06 (d, 6H) Example 20 (4- {[Methyl- (tetrahydro-pyran-4-yl) -amino] -methyl} -amide of 4-isobutoxy-1H-indole-2-carboxylic acid This compound is synthesized in a manner analogous to Example 1, from 4-isobutoxy-1H-indole-2-carboxylic acid 80 (for the preparation, see Example 8), and (4-amino-benzyl) -methyl - (tetrahydropyran-4-yl) -amine (International Publication No. WO 99/32468). MS (ESI): 436.2 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 11.65 (s, 1 H), 10.12 (s, 1 H), 7.74 (d, 2 H), 7.5 (s) , 1H), 7.27 (d, 2H), 7.09 (t, 1H), 7.02 (d, 1H), 6.5 (d, 1H), 3.84-3.94 (m, 4H), 3.52 (s, 2H), 3.22- 3.32 (m, 2H), 2.6 (m, 1H), 2.08-2.2 (m, 4H), 1.72 (m, 2H), 1.53 (m, 2H), 1.07 (d, 6H). Example 21 (4- {(R) -1- [4-isobutoxy-1H-indole-2-methy1- (tetrahydro-pyran-4-yl) -amino] -ethyl} -phenyl) -arnide -carboxy This compound is synthesized in a manner analogous to Example 1, from 4-isobutoxy-1 H-indole-2-carboxylic acid 80 (for the preparation, see Example 8), and the amine 72. MS (ESI): 450.2 [M + H] +, 1H- NMR (DMSO-d6): d (ppm) 11.66 (s, 1H), 10.12 (s, 1H), 7.73 (d, 2H), 7.5 (d, 1H), 7.3 (d, 2H), 7.09 (t, 1H), 7.02 (d, 1H), 6.5 (d, 1H), 3.76-3.91 (m, 5H), 3.1-3.33 (m, 2H), 2.68 (m, 1H), 2.04-2.2 (m, 4H), 1.36-1.68 (m, 4H), 1.28 (d, 3H), '1.08 (d, 6H).

Example 22 [4-Cyclobutylmethoxy-1 H-indole-2-carboxylic acid 1- (2-azepan-1-yl-ethyl) -piperidin-4-yl] -amide This compound is synthesized in a manner analogous to Example 1 , from 4-cyclobutylmethoxy-1H-indole-2-carboxylic acid 82 (for the preparation, see below), and the amine 5. MS (ESI): 453.3 [M + H] +, 1H-NMR ( DMSO-d6): d (ppm) 11.43 (s, 1H), 8.21 (d, 1H), 7.19 (s, 1H), 7.03 (t, 1H), 6.96 (d, 1H), 6.47 (d, 1H) , 4.05 (d, 2H), 3.74 (m, 1H), 2.86 (m, 2H), 2.78 (m, 1H), 255-2.7 (m, 6H), 2.4 (m, 2H), 1.83-2.18 (m , 8H), 1.76 (m, 2H), 1.47-1.63 (m, 10H). Synthesis of 4-cyclobutylmethoxy-1H-indole-2-carboxylic acid (82): (1) Step A: 4-Cyclobutylmethoxy-1 H-indole-2-carboxylic acid (83) Slowly added DEAD (21 milliliters, 13.65 millimoles) to a solution of 4-hydroxy-1H-indole-2-carboxylic acid ethyl ester 79 (2 grams, 9.75 millimoles), triphenylphosphine (3.58 grams, 13.65 millimoles), and cyclobutylmethanol (1.25 milliliters, 12.26 millimoles) in 20 milliliters of tetrahydrofuran, so that the temperature always remains below 30 ° C. Stirring is continued for 2 hours, and then the solvent is evaporated. The crude residue is purified by chromatography (cyclohexane: EtOAc (95: 5) Yield: 1.86 grams (70 percent) MS (ESI): 274.2 [M + H] +, 1 H-NMR (CDCl 3): d (ppm ) 8.83 (, 1H), 7.35 (s, 1H), 7.21 (t, 1H), 6.98 (d, 1H), 6.49 (d, 1H), 4.4 (2, 2H), 4.07 (d, 2H), 2.85 (m, 1H), 217 (m, 2H), 1.95 (m, 4H), 1.42 (t, 3H). (2) Step B: 4-Cyclobutylmethoxy-1H-indoI-2-carboxylic acid (82) The ethyl ester of 4-cyclobutylmethoxy-1H-indole-2-carboxylic acid 83 obtained above is mixed with a 2M solution of KOH in EtOH (16.9 milliliters, 33.8 mmol), and stirred for 24 hours.

Then the solvent is evaporated, and the residue is divided between water and DCM. The water layer is acidified with HCl, and extracted twice with EtOAc. The combined organic layers are washed with brine, dried over anhydrous sodium sulfate, filtered, and evaporated, to give a white powder. Yield: 1.65 grams (99 percent). MS (ESI) 246.3 [M + H] +, 1 H-NMR (CDCl 3): d (ppm) 11.74 (br s, 1 H), 714 (t, 1 H), 7.03 (s, 1 H), 6. 99 (d, 1H), 6.51 (d, 1H), 4.05 (d, 2H), 28 (m, 1H), 2.11 (m, 2H), 1.93 (m, 4H). Example 23 { 1- [2- (3- (R) -hydroxy-piperidin-1-yl) -ethyl] -piperidin-4} -4-cyclobutylmethoxy-1H-indoI-2-carboxylic acid amide This compound is synthesized in a manner analogous to Example 1, from 4-cyclobutylmethoxy-1H-indole-2-carboxylic acid 82 (for the preparation, see Example 22), and amine 12. MS (ESI): 455.4 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 11.43 (s, 1H), 8.22 (d, 1H), 7.19 (s, 1H), 7.03 (t, 1H), 6.97 ( d, 1H), 6.47 (d, 1H), 4.56 (br s, 1H), 4.05 (d, 2H), 3.75 (m, 1H), 3.43 (m, 1H), 2.88 (m, 3H), 2.78 ( m, 1H), 2.68 (m, 1H), 2.42 (br s, 1H), 1.83-2.2 (m, 8H), 177 (m, 4H), 1.56 (m, 4H), 1.38 (m, 2H). Example 24 { 1- [2- (4-hydroxy-piperidin-1-yl) -ethyl] -piperidin-4-yl} 4-cyclobutylmethoxy-1H-indole-2-carboxylic acid amide This compound is synthesized in a manner analogous to Example 1, from 4-cyclobutylmethoxy-1H-indole-2-carboxylic acid 82 (for the preparation, see Example 22), and the amine 21. MS (ESI): 455.4 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 11.43 (s, 1H), 8.21 (d, 1H), 7.19 (s, 1H), 7.03 (t, 1H), 6.96 ( d, 1H), 6.47 (d, 1H), 4.49 (s, 1H), 4.05 (d, 2H), 3.73 (m, 1H), 3.41 (m, 1H), 2.87 (m, 2H), 2.78 (m , 1H), 2.7 (m, 2H), 2.38 (m, 4H), 2.14 (m, 2H), 1.83-2.07 (m, 8H), 1.76 (m, 2H), 1.68 (m, 2H), 1.54 ( m, 2H), 1.35 (m, 2H).

Example 25 { 1- [2 - ((3S, 4S) -4-hydroxy-3-methyl-p-perpent-1-yl) -ethyl] -piperidin-4-yl} 4-cyclobutylmethoxy-1H-indole-2-carboxylic acid amide This compound is synthesized in a manner analogous to Example 1, starting from 4-cyclobutylmethoxy-1H-indole-2-carboxylic acid 82 (see Example 22) ), and the amine 14. MS (ESI): 469.2 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 11.44 (s, 1H), 8.21 (d, 1H), 7.19 (s) , 1H), 7.03 (t, 1H), 6.96 (d, 1H), 4.48 (d, 1H), 4.04 (d, 2H), 3.73 (br m, 1H), 2.64-2.97 (m, 6H), 2.37 (m, 4H), 2.05-2.2 (m, 2H), 1.81-2.05 (m, 7H), 1.65-1.81 (m, 3H), 1.46-165 (m, 3H), 127-1.46 (m, 2H) , 0.86 (d, 3H). Example 26 { 1- [2- (3- (R) -hydroxy-p -peridin-1-yl) -etl] -piperidin-4-yl} -a ida of 4-cyclobutylmethoxy-1H-indole-2-carboxylic acid This compound is synthesized in a manner analogous to Example 1, from 4-cyclobutylmethoxy-1H-indole-2-carboxylic acid 82 (for the preparation, see Example 22), and the amine 24. MS (ESI): 481.3 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 11.44 (s, 1 H), 8.21 (d, 1 H), 7.19 (s, 1 H), 7.03 (t, 1 H), 6.96 (d, 1H), 6.47 (d, 1H), 4.31 (br s, 1H), 4.04 (d, 2), 3.8 (br s, 1H), 3.74 (m, 1H), 2.89 (m, 2H), 2.78 (m, 1H), 2.42 (rm, 6H), 1.7-2.2 (m, 16H), 1.56 (m, 4H). Example 27 { 1 - [(S) -2- (4-hydroxy-piperidin-1-yl) -propyl} -piperidin-4-il} -a ida of 4-cyclobutylmethoxy-1H-indole-2-carboxylic acid This compound is synthesized in a manner analogous to Example 1, from 4-cyclobutylmethoxy-1H-indole-2-carboxylic acid 82 (see Example 22), and 50 amine. MS (ESI): 469.2 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 11.45 (s, 1 H), 8.21 (d, 1 H), 7.18 (s, 1 H), 7.03 (t, 1 H), 6.96 (d, 1 H) ), 6.46 (d, 1H), 4.46 (d, 1H), 4.05 (d, 2H), 3.74 (m, 1H), 3.36 (m, 1H), 2.6-2.95 (m, 6H), 2.04-2.4 ( m, 7H), 1.83-2.0 (m, 4H), 1.64-1.81 (m, 4H), 1.45-1.63 (m, 2H), 1.23-1.42 (m, 2H), 0.92 (d, 3H). Example 28 { 1 - [(S) -2 - ((3S, 4S) -4-hydroxy-3-methyl-piperidin-1-yl) -propiI] -piperidin-4-yl} 4-cyclobutylmethoxy-1 H-indole-2-carboxylic acid amideOH This compound is synthesized in a manner analogous to Example 1, from 4-cyclobutylmethoxy-1H-indole-2-carboxylic acid 82 (see Example 22), and amine 56. MS (ESI): 483.2 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 11.46 (s, 1H), 8.22 (d, 1H), 7.19 (s, 1H), 7.03 (t, 1H), 6.96 (d, 1H), 6.46 (d, 1H), 4.44 (d, 1H), 4.04 (d, 2H), 3.74 (m, 1H), 2.6-2.95 (m, 7H), 2.33 (m, 1H), 2.24 (m , 1H), 2.02-2.19 (m, 4H), 1.82-2.01 (m, 6H), 1.66-1.81 (m, 3H), 1.45-1.64 (m, 2H), 1.2-1.43 (m, 2H), 0.91 (d, 3H), 0.87 (d, 3H). Example 29 Dihydrochloride of. { 1- [2- (4-hydroxy-piperidin-1-yl) -ethyl] -piperidin-4-yl} 4- (3-Methyl-butyloxy) -1H-indole-2-carboxylic acid amide.

This compound is synthesized in a manner analogous to Example 1, from 4- (3-methyl-butyloxy) -1H-indole-2-carboxylic acid (84) (for the preparation, see below), and the amine 21. Yield: 110 milligrams (43 percent). MS (ESI): 457 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 11.4 (s, 1H), 10.5-10.8 (br, 2H), 8.58 (d, 1H), 7.22. (s, 1H), 7.05 (dd, 1H), 6.95 (d, 1H), 6.48 (d, 1H), 4.1 (t, 2H), 3.4-3.75 (m, 9H), 2.9-3.2 (m, 4H) ), 1.65-2.1 (m, 11H), 0.95 (d, 6H).

Synthesis of 4- (3-methyl-butyloxy) -1H-indole-2-carboxylic acid (84): This compound is synthesized in a manner analogous to Example (85), starting from 3-methyl-butan-1-ol . Yield: 0.54 grams (100 percent). MS (ESI): 246 [MH] ". Example 30 { 1- [2- (4-hydroxy-piperidin-1-yl) -ethyl] -piperidin-4-yl}. cyt pen ti Im ethoxy -1 H-indole-2-carboxylic acid This compound is synthesized in a manner analogous to Example 1, from 4-cyclopentylmethoxy-1H-indole-2-carboxylic acid 86 (for the preparation, see below), and the amine 21. MS (ESI): 469.3 [ M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 11.42 (s, 1H), 8.19 (d, 1H), 7.18 (s, 1H), 7.01 (t, 1H), 6.95 (d , 1H), 6.45 (d, 1H), 4.48 (br. S, 1H), 3.93 (d, 2H), 3.72 (br.s, 1H) 2.86 (m, 1H), 3.4 (m, 1H), 3.15 (br. (m, 2H), 2.7 (m, 2H), 2.37 (m, 4H), 1.99 (m, 4H), 1.25-1.88 (m, 16H). Synthesis of 4-cyclopentylmethoxy-1 H-indole-2-carboxylic acid (86) (1) Step A: 4-Cyclopentylmethoxy-1H-indole-2-carboxylic acid ethyl ester (87) Slowly add DEAD (5.3 milliliters, 34.1 millimoles) to a solution of 4-hydroxy-1H-indole-2-carboxylic acid ethyl ester 79 (2 grams, 24.36 mmol), triphenylphosphine (8.95 grams, 34.1 mmol) and cyclopentyl-methanol (3.58 milliliters, 33.13 mmol) in 30 milliliters of tetrahydrofuran, in such a way that the temperature always remains below 30 ° C. Stirring is continued for 2 hours, and then the solvent is evaporated. The crude residue is purified by chromatography (cyclohexane: EtOAc / 90: 10). Yield: 3.88 grams (55 percent). MS (ESI): 28.3 [M + H] +, 1 H-NMR (CDCl 3): d (ppm) 8.86 (br. S, 1H), 7.35 (s, 1H), 7.21 (t, 1H), 6.98 (d , 1H), 648 (d, 1), 4.4 (q, 2H), 3.98 (d, 2H), 2.47 (m, 1H), 1.89 (m, 2H), 1.65 (m, 4H), 1.42 (t, 3H and overlapping m, 2H). (2) Step B: 4-Cyclopentylmethoxy-1H-indole-2-carboxylic acid (86) The ethyl ester of 4-cyclopentylmethoxy-1H-indole-2-carboxylic acid 87 obtained above is mixed with a 2M solution of KaOH in EtOH (33.8 milliliters, 67.6 mmol) and stirred for 24 hours. The solvent is then evaporated, and the residue is divided between water and ether. The water layer is acidified with HCl, and extracted twice with EtOAc. The combined organic layers are washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated to give a white powder. Yield: 2.55 grams (73 percent). MS (ESI): 260.1 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 11.73 (br. S, 1H), 7.12 (t, 1H), 7.02 (s, 1H), 6.98 (d, 1H), 6.5 (d, 1H), 3.96 (d, 2H), 2.39 (m, 1H), 1.82 (m, 2H), 1.6 (m, 4H), 14 (m, 2H). Example: 1- (1- (2-azepan-1-yl-ethyl) -piperidin-4-yl] -amide of 4- (1,2-dimethyl-propoxy) -1H-indole-2-carboxylic acid This compound is synthesized in a manner analogous to Example 1, from 4- (1,2-dimethyl-propoxy) -1H-indole-2-carboxylic acid 88 (for the preparation, see below), and the amine 5. MS (ESI): 455.2 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 11.4 (s, 1H), 8.2 (d, 1H) , 7.18 (d, 1H), 7.02 (dd, 1H), 6.93 (d, 1H), 6.47 (d, 1H), 4.37 (m, 1H), 3.74 (m, 1H), 2.88 (m, 2H), 2.52-2.62 (m, 6H), 2.37 (m, 2H), 1.89-2.06 (m, 3H), 1.75 (m, 2H), 1.46-1.62 (m, 10H), 1.24 (d, 3H), 1.0 ( m, 6H). Synthesis of 4- (1,2-dimethyl-propoxy) -1H-indole-2-carboxylic acid (88): (1) Step A: 4- (1,2-dimethyl-propoxy) -1H-indole -2-carboxylic acid (89). Slowly add DEAD (5.3 milliliters, 34.1 millimoles) to a solution of 4-hydroxy-1H-indole-2-carboxylic acid ethyl ester 79 (5 grams, 24.36 millimoles), triphenylphosphine (8.95 grams, 34.1 millimoles), and 3 -methyl-butan-2-ol (3.58 milliliters, 33.13 millimoles) in 50 milliliters of tetrahydrofuran, in such a way that the temperature always remains below 30 ° C. Stirring is continued for 3 days, and then the solvent is evaporated. The crude mixture is purified by chromatography on silica gel, first using cyclohexane as eluent, and then increasing amounts of EtOAc (from 5 percent to 50 percent). Yield: 2.4 grams (36 percent). MS (ESI): 276.3 [M + H] +, 1 H-NMR (CDCl 3): d (ppm) 8.9 (br s, 1H), 7.35 (s, 1H), 7.2 (dd, 1H), 6.96 (d, 1H), 6.5 (d, 1H), 4.4 (q, 2H), 4.34 (t, 1H), 2.03 (m, 1H), 1.42 (t, 3H), 1.31 (d, 3H), 1.04 (m, 6H). (2) Step B: 4- (1,2-Dimethyl-propoxy) -1H-indole-2-carboxylic acid (88). The 4- (1,2-dimethyl-propoxy) -1H-indole-2-carboxylic acid 89 ester (2.4 grams, 8.72 mmol) is mixed with a 1M solution of KOH in EtOH (43.6 milliliters, 87.2 mmol), and it is stirred for 48 hours. The solvent is then evaporated, and the residue is divided between water and ether. The water layer is acidified with HCl, and extracted twice with ether. The combined organic layers are washed with brine, dried over anhydrous sodium sulfate, filtered, and evaporated, to give a beige powder. Yield: 2.14 grams (99 percent). MS (ESI): 248.1 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 8.92 (br s, 1 H), 7.52 (s, 1 H), 7.27 (m, 1 H), 6.99 ( d, 1H), 6.51 (d, 1H), 4.34 (m, 1H), 2.02 (m, 1H), 1.33 (d, 3H), 1.04 (m, 6H).

Example 32 4- (2,2-dimethyl-propoxy) -1H-indole-2-carboxylic acid 1- (2-azepan-1-yl-ethyl) -piperidin-4-yl] -amide This compound is synthesized in a manner analogous to Example 1, from 4- (2,2-dimethyl-propoxy) -1H-indole-2-carboxylic acid 85 (for the preparation, see below), and the amine 5. MS ( ESI): 455.3 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 11.47 (s, 1H), 8.25 (d, 1H), 7.25 (d, 1H), 7.06 (t, 1H ), 6.99 (d, 1H), 6.48 (d, 1H), 3. 72-3.84 (m, 3H), 2.92 (m, 1H), 2.54-2.63 (m, 6H), 2.41 (m, 2H), 2.04 (m, 2H), 1.79 (m, 2H), 1.5-1.65 (m, m, 1H), 1.1 (s, 9H). Synthesis of 4- (2,2-dimethyl-propoxy) -1H-indole-2-carboxylic acid (85): (1) Step A: Methyl ester of 4- (2,2-dimethyl-propoxy) -1H- ndol-2-carboxylic acid (90) Slowly add DEAD (0.414 milliliters, 2.66 mmol) to a solution of 4-hydroxy-1 H-indole-2-carboxylic acid methyl ester 75 (363 milligrams, 1.9 mmol), triphenylphosphine (698 milligrams, 2.66 millimoles), and 2,2-dimethyl-propan-1-ol (228 milligrams, 1.58 millimoles) in 8 milliliters of tetrahydrofuran. Stirring is continued for 20 hours, and then the solvent is evaporated. The crude mixture is purified by chromatography on silica gel using cyclohexane / EtOAc (9/1). Yield: 271 milligrams (55 percent). MS (ESI): 261.9 [M + H] +, 1 H-NMR (CDCl 3): d (ppm) 8.9 (br s, 1H), 7.39 (s, 1H), 7.23 (dd, 1H), 7.0 (d, 1H), 6.47 (d, 1H), 3.95 (s, 3H), 3.74 (s, 2H), 1.0 (s, 9H). (2) Step B: 4- (2,2-Dimethyl-propoxy) -1H-indole-2-carboxylic acid (85). The 4- (2,2-dimethyl-propoxy) -1H-indole-2-carboxylic acid 90 methyl ester (270 milligrams, 1.03 mmol) is dissolved in 20 milliliters of tetrahydrofuran. A 2M solution of LiOH in water (5.2 milliliters, 11 mmol) is added, and the mixture is stirred for 48 hours. The solvent is then evaporated, and the residue is divided between water and ether. The water layer is acidified with HCl, and extracted twice with EtOAc. The combined organic layers are washed with brine, dried over anhydrous sodium sulfate, filtered, and evaporated to a yellow powder. Yield: 230 milligrams 90 percent). MS (ESI): 248.0 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 11.75 (br s, 1H), 7.13 (dd, 1H), 7.08 (s, 1H), 70 (d, 1H), 6.49 (d, 1H), 4.74 (s, 2H), 1.07 (s, 9H). Example 33 Dichlorohydrate of. { 1- [2- (4-hydroxy-piperidin-1-yl) -ethyl] -piperidin-4-yl} 4- (4-methyl-pentyloxy) -1 H-indole-2-carboxylic acid amide This compound is synthesized in a manner analogous to Example 1, from 4- (4-methyl-pentyloxy) -1H-indole-2-carboxylic acid (91) (for the preparation, see below), and the amine 21. Yield: 145 milligrams (70 percent). MS (ESI): 471 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 11.5 (s, 1H), 10.4-10.7 (br, 2H), 8.58 (d, 1H), 7.25 (s, 1H), 7.05 (dd, 1H), 6.95 (d, 1H), 6.45 (d, 1H), 3.95-4.2 (m, 4H), 2.95-3.8 (m, 12), 1.7-2.1 (, 10H), 1.6 (m, 2H), 1.35 (m, 2H), 0.9 (d, 6H). Synthesis of 4- (4-methyl-pentyloxy) -1H-indole-2-carboxylic acid This compound is synthesized in a manner analogous to (85), from 4-methyl-pentan-1-ol. Yield: 0.61 grams (94 percent). MS (ESI): 260 [MH] ", 1 H-NMR (DMSO-d 6): d (ppm) 12.8 (s, 1 H), 11.65 (s, 1 H), 7.1 (dd, 1 H), 7.0 (s, 1 H) ), 6.98 (d, 1H), 6.48 (d, 1H), 4.05 (t, 2H), 1.77 (t, 2H), 1.63 (m, 1H), 1.35 (m, 2H), 0.9 (d, 6H) Example 34 4- (3,3-Dimethyl-butoxy) 4- {2- (4-hydroxy-piperidin-1-yl) -ethyl] -piperidin-4-yl} -amide. ) -1 H-Indole-2-carboxylic acid This compound is synthesized in a manner analogous to Example 1, from 4- (3,3-dimethyl-butoxy) -1H-indole-2-carboxylic acid (92) (for the preparation, see below), and the amine 21. Yield: 60 milligrams (24 percent). MS (ESI): 471 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 11.4 (s, 1 H), 10.5 (br 1 H) 8.58 (d, 1 H), 7.17 (s, 1 H) ), 7.0-7.1 (m, 2H), 65 (d, 1H), 4.2 (m, 2H), 4.15 (m, 1H), 3.85 (m, 1H), 3.65 (m, 4H), 31-3.5 ( m, 8H), 2.0-2.2 (m, 6H), 1.75- 1.85 (m, 4H), 1.03 (s, 9H). Synthesis of 4- (3,3-dimethyl-butoxy) -1H-indole-2-carboxylic acid (92): This compound is synthesized in a manner analogous to (85), from 3,3-dimethyl-butan- 1-ol. Yield: 1.1 grams (100 percent). MS (ESI): 260 [MH] ", 1 H-NMR (DMSO-d 6): d (ppm) 12.8 (s, 1 H), 11.65 (s, 1 H), 7.12 (dd, 1 H), 6.98 (s, 1 H) ), 6.95 (d, 1H), 6.52 (d, 1H), 4.13 (t, 2H), 1.75 (t, 2H), 1.0 (s, 9H), Example 35 [1- (2-azepan-1-yl 4- (furan-2-ylmethoxy) -1H-indoI-2-carboxylic acid (ethyl) -piperidin-4-yl] -amide.

This compound is synthesized in a manner analogous to Example 1, from 4- (furan-2-ylmethoxy) -1H-indole-2-carboxylic acid 93 (for the preparation, see below), and amine 5.

MS (ESI): 465.3 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 11.48 (s, 1 H), 8.13 (d, 1 H), 7.71 (s, 1 H), 7.23 (s) , 1H), 7.06 (t, 1H), 7.0 (d, 1H), 6.63 (m, 2H), 6.48 (s, 1H), 5.13 (s, 2H), 3.72 (m, 1H), 2.88 (m, 2H), 2.5-6.6 (m, 6H), 2.36 (m, 2H), 2.0 (m, 2H), 1.74 (m, 2H), 1.45-1.6 (m, 10H). Synthesis of 4- (furan-2-ylmethoxy) -1H-indole-2-carboxylic acid (93): (1) Step A: 4- (furan-2-ylmethoxy) -1H-indole-2- acid ethyl ester carboxylic (94). Slowly add DEAD (2.1 milliliters, 13.65 millimoles) to a solution of 4-hydroxy-1H-indole-2-carboxylic acid ethyl ester 79 (2 grams, 9.75 millimoles), triphenylphosphine (3.58 grams, 13.65 millimoles), and furan- 2-yl-methanol (1.18 milliliters, 12.26 millimoles) in 10 milliliters of tetrahydrofuran, such that the temperature always remains below 30 ° C. Stirring is continued for 2 hours, and then the solvent is evaporated. The crude residue is purified by chromatography (cyclohexane: EtOAc / 95: 5). Yield: 0.76 grams (27 percent). (2) Step B: 4- (furan-2-ylmethoxy) -1 H -indole-2-carboxylic acid (93). Ethyl ester of 4- (furan-2-ylmethoxy) -1 H-indole-2-carboxylic acid 94 obtained above, is mixed with a 1M solution of KOH in EtOH (13.3 milliliters, 13.3 mmol), and stirred for 24 hours.

The solvent is then evaporated, and the residue is divided between water and ether. The water layer is acidified with HCl, and extracted twice with EtOAc. The combined organic layers are washed with brine, dried over anhydrous sodium sulfate, filtered, and evaporated to a white powder. Yield: 0.329 milligrams (48 percent). 1 H-NMR (DMSO-d 6): d (ppm) 12.79 (br s, 1 H), 11.73 (s, 1 H), 7.69 (s, 1 H), 7.14 (t, 1 H), 7. 02 (d, 1H), 6.98 (s, 1H), 6.61 (s, 1H), 6.47 (s, 1H), 5.16 (s, 2H). Example 36 4- (furan-3-ylmethoxy) -1H-indole-2-carboxylic acid 1- (2-azepan-1-yl-ethyl) -piperidin-4-yl] -amide This compound is synthesized in a manner analogous to Example 1, from 4- (furan-3-ylmethoxy) -1H-indole-2-carboxylic acid 95 (for the preparation, see below), and the amine 5. MS (ESI): 465.3 [M + Hf, 1 H-NMR (DMSO-d 6): d (ppm) 11.46 (s, 1 H), 8.14 (d, 1 H), 7.82 (s, 1 H), 7.68 (s, 1 H) , 7.22 (s, 1H), 7.06 (t, 1H), 6.99 (d, 1H), 6.62 (s, 1H), 6.6 (d, 1H), 5.03 (s, 2H), 3.72 (m, 1H), 2.87 (m, 2H), 2.52-2.62 (m, 6H), 2.37 (m, 2H), 2.0 (m, 2H), 1.75 (m, 2H), 1.45-1.62 (m, 10H). Synthesis of 4- (furan-3-ylmethoxy) -1 H-indole-2-carboxylic acid (9511 (1) Step A: 4- (furan-3-ylmethoxy) -1H-indole-2-carboxylic acid ethyl ester (96) Slowly add DEAD (2.1 milliliters, 1.65 millimoles) to a solution of 4-hydroxy-1H-indole-2-carboxylic acid ethyl ester 79 (2 grams, 9.75 millimole), triphenylphosphine (3.58 grams, 132.65). millimoles), and furan-3-yl-methanol (1.018 milliliters, 12.26 mmol) in 1 0 milliliters of tetrahydrofuran, in such a way that the temperature always remains below 30 ° C. Stirring is continued for 2 hours, and then the solvent is evaporated. The crude residue is triturated with ether, and the white precipitate is filtered. It contains mainly the product. The mother liquor is purified by chromatography (cyclohexane: EtOAc / 95: 5), and combined with the first precipitate. Yield: 3 grams (> 1 00 percent). (2) Step B: 4- (furan-3-ylmethoxy) -1 H-indole-2-carboxylic acid (95). Ethyl ester of 4- (furan-3-ylmethoxy) -1H-indole-2-carboxylic acid 96 obtained above, is mixed with a 1 M solution of KOH in EtOH (35 milliliters, 35 mmol), and stirred for 24 hours. The solvent is then evaporated, and the residue is divided between water and ether. The water layer is acidified with HCl, and extracted twice with EtOAc. The combined organic layers are washed with brine, dried over anhydrous sodium sulfate, filtered, and evaporated to a white powder. Yield: 1.63 grams (65 percent). MS (ES I): 258.0 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 12.79 (br s, 1 H), 1 1 .71 (s, 1 H), 7.81 (s) , 1 H), 7.67 (s, 1 H), 7.1 3 (m, 1 H), 7.01 (m, 2 H), 6.62 (m, 2 H), 5.07 (s, 2 H). Example 37 { 1- [2- (4-hydroxy-piperidin-1-yl) -ethyl] -piperidin-4-yl} -amide of 4- (furan-3-ylmethoxy) -1H-indole-2-carboxylic acid This compound is synthesized in a manner analogous to Example 1, from 4- (furan-3-ylmethoxy) -1H-indole-2-carboxylic acid 95 (see Example 36), and the amine 21. MS (ESI): 467 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 11.48 (s, 1H), 8. 13 (d, 1H), 7.81 (s, 1H), 768 (t, 1H), 7.22 (d, 1H), 7.06 (t, 1H), 6.98 (d, 1H), 6.62 (s, 1H), 6.6 (d, 1H), 5.03 (s, 2H), 4.48 (d, 1H), 3.73 (m, 1H), 3.4 (m, 1H), 2.86 (m, 2H), 2.7 (m, 2H), 2.36 (br s, 4H), 2.0 (m, 4H), 1.72 (m, 4H), 1.52 (m, 2H), 1.35 (m, 2H). Example 38 { 1- [2 - ((3S, 4S) -4-hydroxy-3-methyl-piperidin-1-yl) -ethyl] -piperidin-4-yl} -amide of 4- (furan-3-ylmethoxy) -1H-indole-2-carboxylic acid This compound is synthesized in a manner analogous to Example 1, from 4- (furan-3-methoxy) -1H-indole-2-carboxylic acid 95 (for the preparation, see Example 36), and the amine 14. MS (ESI): 481.2 [M + H] +, 1 H-NMR (CD 3 -OD): d (ppm) 7.63 (s, 1 H), 7.51 (s, 1 H), 7.23 (s, 1 H), 7.13 (t, 1H), 7.04 (d, 1H), 6.6 (d, 1H), 6.57 (s, 1H), 5.08 (s, 2H), 3.9 (m, 1H), 2.83-3.12 (m, 5H), 2.55 (m, 4H), 2.21 (m, 2H), 2.11 (m, 1H), 1.84-2.0 (m, 3H), 151-1.83 (m, 5H), 0.99 (d, 3H). Example 39 { 1 - [(S) -2- (4-hydroxy-piperidin-1-yl) -propyl] -piperidin-4-yl} -amide of 4- (furan-3-ylmethoxy) -1H-indole-2-carboxylic acid This compound is synthesized in a manner analogous to Example 1, from 4- (furan-3-ylmethoxy) -1H-indole-2-carboxylic acid 95 (see Example 36), and amine 50. MS (ESI) ): 481.2 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 11.47 (s, 1 H), 8.14 (d, 1 H), 7.82 (s, 1 H), 7.68 (s, 1 H) , 7.22 (s, 1H), 7.05 (t, 1H), 6.99 (d, 1H), 6.62 (s, 1H), 6.60 (d, 1H), 5.03 (d, 2H), 4.45 (d, 1H), 3.73 (m, 1H), 3.37 (m, 1H), 2.9 (m, 1H), 2.8 (m, 1H), 2.6-2.75 (m, 3H), 2.05-2.37 (m, 5H), 1.9 (m, 1H), 1.65-1.8 (m, 4H), 1.42-1.62 (m, 2H), 1.2-1.4 (m, 2H), 0.92 (d, 3H).

Example 40 { 1 - [(S) -2 - ((3S, 4S) -4-hydroxy-3-methyl-piperidn-1-yl) -propyl] -piperidin-4-yl} -amide of 4- (furan-3-ylmethoxy) -1 H-indole-2-carboxylic acid This compound is synthesized in a manner analogous to Example 1, from 4- (furan-3-ylmethoxy) -1H-indole-2-carboxylic acid 95 (see Example 36), and amine 56. MS (ESI): 495.2 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 11.46 (s, 1H), 8.14 (d, 1H), 7.82 (s, 1H), 7.68 (s, 1H), 7.23 (s, 1H), 7.05 ( t 1H), 6.99 (d, 1H), 6.62 (s, 1H), 6.6 (d, 1H), 5.03 (s, 2H), 4.43 (d, 1H), 3.72 (m, 1H), 2.58-2.94 (m, 5H), 2.32 (m, 1H), 2.24 (m, 1H), 2.03-2.19 (m, 2H), 1.84-1.96 (m, 2H), 1.66-1.79 (m, 3H), 1.42-1.62 (m, 2H), 1.2-1.41 (m, 3H), 0.91 (d, 3H), 0.86 (d, 3H). Example 41 4-benzyloxy-1H-indole-2-carboxylic acid 1- (2-azepan-1-yl-ethyl) -piperidin-4-yl] -amide This compound is synthesized in a manner analogous to Example 1, from 4-benzyloxy-1H-indole-2-carboxylic acid and amine 5. MS (ESI): 475.3 [M + H] +, 1 H-NMR (DMSO -d6): d (ppm) 11.5 (s, 1H), 8.16 (d, 1H), 7.3-7.54 (m, 5H), 7.26 (d, 1H), 7.06 (t, 1H), 7.0 (d, 1H) ), 6.6 (d, 1H), 5.18 (s, 2H), 3.74 (m, 1H), 2.86 (m, 2H), 2.47-2.62 (m, 6H), 2.37 (m, 2H), 2.0 (m, 2H), 1.75 (m, 2H), 1.45-1.64 (m, 10H). Example 42 Dichlorohydrate of. { 1 - [(1S, 9aR) -1- (octahydro-quinolizin-1-yl) methyI] -piperidin-4-yl} -amide of 4- (5-chloro-benzofuran-3-ylmethoxy) -1 H-indole-2-carboxylic acid This compound is synthesized from 4- (5-chloro-benzofuran-3-ylmethoxy) -1H-indole carboxylic acid (97) (for the preparation, see below), and the amine 61, in a manner analogous to method described in Example 1. Yield: 200 milligrams (59 percent). MS (ESI): 575 [M + H] +, 1 H-NMR (DMSO-de): d (ppm) 11.5 m (s, 1 H), 10.1-10.7 (, 2 H), 8.5 (t, 1 H), 8.24 (s, 1H), 7.75 (d, 1H), 7.68 (d, 1H), 7.37 (dd, 1H), 7.25 (m, 1H), 7.1 (m, 1H), 7.05 (d, 1H), 6.7 ( d, 1H), 5.35 (s, 2H), 4.0 (m, 1H), 2.8-3.6 (m, 14H), 1.3-2.1 (m, 12H).

Reaction Scheme 13: Synthesis of 4-hydroxyindole-1,2-dicarboxylic acid 1-tert-butyl ester (102): (1) Step A: 4-benzyloxy-indole-2-ethyl ester of 4-benzyloxy-indole -1,2-dicarboxylic acid (103) The 4-benzyloxy-1 H-indole-2-carboxylic acid ethyl ester (50 milligrams, 169.3 mmol) is dissolved in 500 milliliters of ethyl acetate, and DMAP (141 milligrams, 3.4 millimoles). The mixture is then cooled to 0 ° C, and BOC2O (36.9 grams, 1 69.3 mmol), dissolved in 20 milliliters of ethyl acetate, is added dropwise. After the addition is complete, the reaction mixture is allowed to stir overnight at room temperature. The mixture is washed with 1 M tartaric acid and brine. The organic layers are dried over sodium sulfate, and evaporated. Yield: 72 grams of a colorless oil, which is used in the next step without further purification.

MS (ESI): 396 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 7.51 (m, 1 H), 7.47 (m, 2 H), 7.40 (m, 1 H), 7.38 (m , 2H), 7.31 (m, 1H), 7.21 (s, 1H), 6.92 (d, 1H), 5.26 (s, 2H), 4.28 (q, 2H), 1.56 (s, 9H), 1.31 (t, 3H). (2) Step B: 4-hydroxyindole-1,2-dicarboxylic acid 1-terbutil ester 2-ethyl ester (102) 103 (46.2 grams, 116.8 mmol) is dissolved in ethanol (300 milliliters), and after addition of ammonium formate (8.3 grams, 128.5 mmol) and 10 percent Pd-C (5 grams), the mixture is stirred at room temperature for 1 hour. Then the mixture is filtered. Evaporation under reduced pressure gave 6.89 grams of a white solid, which is further purified by recrystallization from ether / hexanes. Yield: 27.75 grams (78 percent). MS (ESI): 304 [MH] ", 1 H-NMR (DMSO-d 6): d (ppm) 10.1 (s, 1H), 7.38 (d, 1H), 7.25 (s, 1H), 7.23 (dd, 1H) ), 6.65 (d, 1H), 4.3 (q, 2H), 1.55 (s, 9H), 1.3 (t, 3H) Synthesis of 4- (5-chloro-benzofuran-3-ylmethoxy) -1H-indole -2- carboxylic acid (97): (1) Step A: 2- (benzotriazol-1-ylmethoxy) -5-chloro-benzaldehyde (98), 5-chloro-2-hydroxy-benzaldehyde is dissolved (8.45 grams, 54 millimoles ) in NN-dimethylformamide (100 milliliters), and after the addition of 1- (chloromethyl) -1H-benzotriazole (9.96 grams, 59.4 millimoles) and K2CO3 (9.7 grams, 70.2 millimoles), the mixture is stirred at 45 °. C for 1 hour (control with thin layer chromatography) .Then the mixture is evaporated under a high vacuum.The residue is diluted with ethyl acetate, washed with brine, and dried over Na2SO4, evaporation gave 3.9 grams of a colorless solid The product is used in the next step without further purification Yield: 17 grams (100 percent) of a white solid MS (ESI): 288 [M + H] +, 1H-RM N (DMSO-d6): d (ppm) 10.01 (s, 1H), 8.08 (d, 1H), 7.97 (d, 1H), 7.78 (dd, 1H), 7.68 (d, 1H), 7.62 (dd, 1H), 7.55 (d, 1H), 7.43 (dd, 1H), 6.95 (d, s, 2H). (2) Step B: 1- (4-chloro-2-oxiranyl-phenoxymethyl) -1 H-benzotriazole (99). The 98 (15.5 grams, 54 millimoles) is dissolved in 150 milliliters of DCM and 150 milliliters of an aqueous solution of sodium hydroxide at 40 percent. After the addition of trimethylsulfonium iodide (14.3 grams, 70.2 mmol) and tetrabutylammonium iodide (1.4 grams, 3.8 mmol), the mixture is refluxed for 18 hours. The reaction mixture is diluted with DCM, washed with water, and the organic layers are dried over Na2SO4. Evaporation gave 18.7 grams of a yellow oil, which is further purified by evaporation chromatography (silica gel, ethyl acetate / hexanes, 3: 7). Yield: 11.7 grams (72 percent) of a colorless oil. MS (ESI): 302 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 8.08 (d, 1H), 7.92 (d, 1H), 7.62 (dd, 1H), 7.5 (dd, 1H), 7.45 (dd, 1H), 7.4 (dd, 1H), 6.92 (d, 1H), 6.83 (dd, 1H), 3.8 (m, 1H), 2.8 (dd, 2H), 2.48 (dd, 1H) ). (3) Step C: (5-chloro-benzofuran-3-yl) -methanol (100). The 99 (25.7 grams, 85.1 millimoles) is dissolved in 300 milliliters of tetrahydrofuran and cooled to -78 ° C. A 2M solution of LDA in tetrahydrofuran (93.7 milliliters, 187.4 millimoles) is added dropwise within 45 minutes. The reaction mixture is allowed to warm to room temperature within 17 hours. Then the reaction mixture is quenched with a saturated aqueous solution of ammonium chloride, and evaporated under reduced pressure. The residue is diluted with ethyl acetate, washed with water and brine, and dried over sodium sulfate. Evaporation gave 17.2 grams of a brown resin, which is further purified by evaporation chromatography (silica gel, ethyl acetate / hexanes, 2: 8). Yield: 10.4 milligrams of a white solid (67 percent). MS (ESI): 181 [MH] ", 1 H-NMR (DMSO-d 6): d (ppm) 7.91 (d, 1H), 7.72 (d, 1H), 7.56 (d, 1H), 7.32 (dd, 1H ), 5.18 (t, 1H), 4.58 (d, 2H). (4) Step D: 4- (5-Chloro-benzofuran-3-ylmethoxy) -indol-1-1-tert-butyl ester , 2-dicarboxylic (101) Dissolve 100 (4 grams, 21.9 millimoles), 102 (6.7 grams, 21.9 millimoles), triphenylphosphine (17.3 grams, 65.8 millimoles), and a 40 percent solution of diethyl azadicarboxylate. (31.8 milliliters, 65.8 millimoles) in tetrahydrofuran, and cooled to 0 ° C. A solution of N-ethyldi-isopropylamine (11.2 milliliters, 65.8 millimoles) in tetrahydrofuran is then added dropwise. The mixture is stirred at room temperature for 2 hours, then the mixture is evaporated under reduced pressure.The residue is diluted with ethyl acetate, washed with a saturated solution of NaHCO 3, and dried over Na 2 SO 4 The crude product is purified by chromatography by evaporation (e acetate lime / hexanes (3: 7), silica gel). Yield: 7.7 grams (75 percent) of a lightly colored oil. MS (ESI): 469 [Mf, 1 H-NMR (DMSO-d 6): d (ppm) 8.27 (s, 1H), 7.79 (d, 1H), 7.63 (d, 1H), 7.53 (d, 1H), 7.40 (d, 1H), 7.36 (dd, 1H), 7.21 (s, 1H), 7.04 (d, 1H) ), 5.42 (s, 2H), 4.29 (q, 2H), 1.55 (s, 9H), 1.29 (t, 3H). (5) Step E: 4- (5-Chloro-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid (97). 101 (7.7 grams, 16.3 millimoles) is dissolved in 15 milliliters of a 1: 1: 1 mixture of tetrahydrofuran / water / ethanol, and after the addition of KOH beads (5.4 grams, 81.9 millimoles), the mixture is mixed. stir for 2 hours at 85 ° C. Then the organic phase is evaporated under reduced pressure. The residue is dissolved in ethyl acetate, acidified with 2N HCl, and filtered. The crude product is purified by crystallization from ethyl acetate. Yield: 4.4 grams (79 percent) of white crystals. MS (ESI): 340 [MH] ", 1 H-NMR (DMSO-d 6): d (ppm) 12.8 (s, 1H), 11.7 (s, 1H), 8.25 (s, 1H), 7.79 (d, 1H ), 7.62 (d, 1H), 7.35 (dd, 1H), 7.15 (dd, 1H), 7.0-7.05 (m, 2H), 6.71 (d, 1H), 5.39 (s, 2H).

Example 43 4- (5-chloro-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid 1- (2-azepan-1-yl-ethyl) -piperidin-4-yl] -amide is synthesized from 4- (5-chlorobenzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid 97 (see Example 42), and amine 5, in a manner analogous to the method described in Example 1. Yield: 52 milligrams (16 percent). MS (ESI): 549 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 10.98 (br s, 1 H), 8.12 (s, 1 H), 7.68 (d, 1 H), 7.53 (d, 1 H), 7.0-7.2 (m, 5 H) , 6.65 (d, 1H), 5.43 (s, 2H), 3.75 (m, 1H), 2.35-2.65 (m, 12H), 2.1 (m, 2H), 1.8 (m, H), 1.5-1.6 (m , 8H). Example 44 { 1- [2- (4-hydroxy-piperidin-1-yl) -ethyl] -piperidin-4-M} -amide of 4- (5-chloro-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid This compound is synthesized from 4- (5-chloro-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid 97 (see Example 42), and amine 21, in a manner analogous to the method described in Example 1. Yield: 50 milligrams (24 percent). MS (ESI): 551 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 11.45 (s, 1H), 8.22 (s, 1H), 8.12 (d, 1H), 7.78 (s, 1H), 7.67 (d, 1H), 7.37 (d, 1H), 7.18 (s, 1H), 7.08 (dd, 1H), 7.02 (d, 1H), 6.67 (m, 1H), 5.33 (s, 2H), 4.49 (b, 1H), 3.7 (m, 1H), 3.4 (m, 1H), 2.85 (m, 2H), 2.7 (m, 2H), 2.5 (m, 2H), 2.35 (m, 2H), 1.95 (m, 4H), 1.25-1.8 (m, 8H). Example 45 { 1- [2 - ((3S, 4S) -4-hydroxy-3-methyl-piperidin-1-yl) -ethyl] -piperidin-4-yl} -amide of 4- (5-chloro-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid This compound is synthesized from 4- (5-chloro-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid 97 (see Example 42), and amine 14, in a manner analogous to the method described in Example 1. Yield: 85 milligrams (45 percent). MS (ESI): 565 [M + H] +, 1 H-NMR (DMSO-de): d (ppm) 11.29 (br s, 1H), 8.2 (d, 1H), 8.1 (s, 1H), 7.74 ( s, 1H), 7.57 (d, 1H), 7.34 (d, 1H), 7.22 (s, 1H), 7.09 (m, 1H), 6.72 (d, 1H), 5.39 (s, 2H), 2.6-4.1 (m, 15H), 1.75-2.2 (m, 8H), 1.00 (d, 3H).

EXAMPLE 46 Dichlorohydrate of. { 1 - [(S) -2- (4-hydroxy-piperidin-1-yl) -propl] -piperidin-4-yl} 4- (5-chloro-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid amide This compound is synthesized from 4- (5-chloro-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid 97 (see Example 42), and amine 50, in a manner analogous to the method described in Example 1. Yield: 125 milligrams (71 percent): MS (ESI): 565 [M + H] +, 1 H-NMR (DMSO-de): d (ppm) 11.5 (s, 1H), 10.3-10.7 (br, 2H), 8.52 (d, 1H), 8.24 (s, 1H), 7.75 (d, 1H), 7.68 (s, 1H), 7.35 (dd, 1H), 7.23 (s, 1H), 7.1 ( dd, 1H), 7.03 (d, 1H), 6.7 (d, 1H), 5.35 (s, 2H), 5.1 (br, 1H), 4.05 (m, 1H), 2.7-3.7 (m, 12H), 1.7 -2.1 (m, 8H), 1.35 / 1.3 (d, 3H) (rotamers).

Example 47 Dichlorohydrate of. { 1 - [(S) -2 - ((3S, 4S) -4-hydroxy-3-methyl-piperidin-1-yl) -propyl] -piperidin-4-yl} 4- (5-Chloro-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid amide.

This compound is synthesized from 4- (5-chloro-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid 97 (see Example 42), and amine 56, in a manner analogous to the method described in Example 1. Yield: 123 milligrams (64 percent). MS (ESI): 579 [M + H] +, 1 H-NMR (DMSO-de): d (ppm) 11.5 (s, 1H), 10.4-10.6 (br 2H), 8.52 (d, 1H), 8.26 ( s, 1H), 7.77 (d, 1H), 7.68 (d, 1H), 7.38 (dd, 1H), 7.23 (s, 1H), 7.12 (dd, 1H), 7.03 (d, 1H), 6.7 (d , 1H), 5.35 (s, 2H), 5.1 (br 1H), 4.05 (m, 1H), 2.8-3.9 (, 13H), 1.9-2.1 (m, 6H), 1.31 (d, 3H), 0.94 ( d, 3H). Example 48 Dichlorohydrate of. { 1 - [(1S, 9aR) -1- (Octahydro-quinolizin-1-yl) methyl] -piperidin-4-yl} 4- (4-Fluoro-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid amide This compound is synthesized from 4- (4-fluoro-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid (104) (for the preparation, see below), and amine 61, from a analogous to the method described in Example 1. Yield: 49 milligrams (22.5 percent). MS (ESI): 559.3 [M + H] +, 1 H-NMR (DMSO-de): d (ppm) 11.5 (s, 1H), 10.5 (br d, 1H), 10.2 (br d, 1H), 8.45 (m, 1H), 8.25 (s, 1H), 7.5 (d, 1H), 7.38 (m, 1H), 7.25 (m, 1H), 7.1 (m, 2H), 7.03 (d, 1H), 6.7 (d, 1H), 5.3 (s, 2H), 4.0 (m, 1H), 2.8-3.6 (m, 14H), 1.3-2.1 (m, 12H). Synthesis of 4- (4-fluoro-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid (104): This compound is synthesized from 2-fluoro-6-hydroxy-benzaldehyde, in a manner analogous to method described for 97 (see Example 42). Yield: 220 milligrams (49 percent) of white crystals. MS (ESI): 324.3 [MH]. "Example 49 {1,4- [2- (4-Hydroxy-piperidin-1-yl) -ethyl] -piperidin-4-yl} -amide of 4 - (4-fluoro-benzofuran-3-ylmethoxy) -1H-indoI-2-carboxylic acid This compound is synthesized from 4- (4-fluorobenzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid (104) (see Example 48), and the amine 21, in a manner analogous to the method described in Example 1. Yield: 100 milligrams (61 percent). MS (ESI): 535 [M + H] +, 1 H-NMR (DMSO-de): d (ppm) 11.45 (s, 1H), 10.5 (br, 1H), 10.35 (br, 1H), 8.48 (d , 1H), 8.23 (m, 2H), 7.5 (d, 1H), 7.35 (m, 1H), 7.2 (s, 1H), 7.1 (m, 1H), 7.03 (d, 1H), 6.7 (d, 1H), 5.3 (s, 2H), 5.05 (br, 1H), 4.05 (m, 1H), 2.9-3.75 (m, 13H), 1.65-2.1 (m, 8H). Example 50 Dihydrochloride. { 1 - [(1S, 9aR) -1- (Octahydro-quinolizin-1-yl) methyl] -piperidin-4-yl} -amide of 4- (benzofuran-3-ylmethoxy) -1 H-indole-2-carboxylic acid This compound is synthesized from 4- (benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid (105) (for the preparation, see below), and the amine 61, in a manner analogous to the method described in Example 1. Yield: 68 milligrams (34 percent). MS (ESI): 541 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 11.56 (s, 1 H), 10.5 (br d, 1 H), 10.2 (br d, 1 H), 8.5 (t, 1H), 8.18 (s, 1H), 7.72 (d, 1H), 7.6 (d, 1H), 7.25-7.35 (m, 3H), 7.12 (d, 1H), 7.03 (d, 1H), 6.75 (d, 1H), 5.57 (s, 2H), 4.01 (m, 1H), 2.8-3.6 (m, 14H), 1.3-2.1 (m, 12H). Synthesis of 4- (benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid (105): This compound is synthesized from 2-hydroxy-benzaldehyde, in a manner analogous to the method described for 97 (see Example 42). MS (ESI): 306 [MH] ", 1 H-NMR (DMSO-d 6): d (ppm) 12.8 (br s, 1 H), 11.7 (s, 1 H), 8.15 (s, 1 H), 7.73 (d, 1H), 7.58 (d, 1H), '7.33 (dd, 1H), 7.29 (dd, 1H), 7.15 (dd, 1H), 7.05 (s, 1H), 7.02 (d, 1H), 6.73 (d, 1H), 5.38 (s, 2H), Example 51 { 1- [2- (4-Hydroxy-piperidin-1-yl) -ethyl] -piperidin-4-yl} -amide of 4- ( benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid This compound is synthesized in a manner analogous to the Example, from 4- (benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid 05 (see Example 50), and amine 21. S (ESI): 517.2 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 11.48 (s, 1 H), 8.17 (s, 1 H), 8.1 (d, 1 H), 7.72 (d, 1 H), 7.61 (d, 1H), 7.35 (t, 1H), 7.28 (d, 1H), 7.18 (s, 1H), 7.09 (t, 1H), 7.01 (d, 1H), 6.71 (d, 1H), 5.35 ( s, 2H), 4.48 (d, 1H), 3.71 (m, 1H), 3.39 (m, 1H), 2.84 (m, 2H), 2.69 (m, 2H), 2.35 (m, 4H), 1.98 (m , 4H), 1.69 (m, 4H), 148 (m, 2H), 1.34 (m, 2H). Example 52 { 1- [2 - ((3S, 4S) -4-hydroxy-3-methyl-piperidin-1-yl) -ethyl] -piperidin-4-yl} - 4- (Benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid amide This compound is synthesized in a manner analogous to Example 1, from 4- (benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid 105 (see Example 50), and amine 14. MS (ESI) ): 531.2 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 11.48 (s, 1 H), 8.17 (s, 1 H), 8.11 (d, 1 H), 7.72 (d, 1 H) , 7.61 (d, 1H), 7.35 (t, 1H), 7.29 (t, 1H), 7.19 (s, 1H), 7.09 (t, 1H), 7.01 (d, 1H), 6.71 (d, 1H), 5.35 (d, 2H), 4.47 (d, 1H), 3.7 (m, 1H), 3.3 (m, 1H), 2.65-2.91 (m, 5H), 2.34 (m, 4H), 1.83-2.04 (, 3H) ), 165-1.77 (m, 3H), 1.27-1.63 (m, 5H), 0.85 (d, 3H). Example 53 { 1 - [(S) -2- (4-hydroxy-piperidin-1-yl) -propyl] -piperidin-4-yl} -amide of 4- (benzofuran-3-ylmethoxy) -1 H-indole-2-carboxylic acid This compound is synthesized in a manner analogous to Example 1, from 4- (benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid (ico 105 (see Example 50), and amine 50. MS ( ESI): 531.3 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 11.48 (s, 1H), 8. 17 (s, 1H), 8.11 (d, 1H), 7.72 (d, 1H), 7.61 (d, 1H), 7.35 (t, 1H), 7.29 (t, 1H), 7.19 (d, 1H), 7.09 (t, 1H), 7.01 (d, 1H), 6.71 (d, 1H), 5.35 (s, 2H), 4.44 (d, 1H), 3.7 (br m, 1H), 3.35 (m, 1H), 2.97 (m, 1H), 2.6-2.9 (m, 4H), 2.0-2.35 (m, 4H), 1.89 (m, 1H), 1.63-1.77 (m, 3H), • 1.4-1.6 (m, 3H), 1.2-1.38 (m, 3H), 0.90 (d, 3H). Example 54 { 1 - [(S) -2 - ((3S, 4S) -4-hydroxy-3-methyl-piperidin-1-yl) -propyl] -piperidin-4-yl} -amide of 4- (benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid This compound is synthesized in a manner analogous to Example 1, from 4- (benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid 105 (see Example 50), and amine 56. MS (ESI) ): 545.2 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 11.48 (s, 1 H), 8.17 (s, 1 H), 8.11 (d, 1 H), 7.72 (d, 1 H) , 7.61 (d, 1H), 7.35 (t, 1H), 7.29 (t, 1H), 7.19 (s, 1H), 7.09 (t, 1H), 7.01 (d, 1H), 6.71 (d, 1H), 5.35 (s, 2H), 4.43 (d, 1H), 3.71 (m, 1H), 2.59-2.92 (m, 6H), 2.31 (m, 1H), 2.22 (m, 1H), 2.01-2.17 (m, 2H), 1.88 (m, 2H), 1.66-1.76 (m, 3H), 1.2-1.58 (m, 4H), 0.89 (d, 3H), 0.86 (d, 3H). Example 55 Di hydrochloride. { 1 - [(1S, 9aR) -1- (Octahydro-quinolizin-1-yl) methyl] -piperidin-4-yl} -amide of 4- (6-fluoro-benzofuran-3-ylmethoxy) -1 H -indole-2-carboxylic acid This compound is synthesized from 4- (6-fluoro-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid (106) (for the preparation, see below), and amine 61, in a manner analogous to the method described in Example 1. Yield: 80 milligrams (41.2 percent). MS (ESI): 559 [M + H] +, 1 H-NMR (DMSO-de): d (ppm) 11.55 (s, 1H), 10.63 (br d, 1H), 10.35 (br d, 1H), 8.5 (m, 1H), 8.2 (s, 1H), 7.72 (dd, 1H), 7.58 (dd, 1H), 7.25 (m, 1H), 7.2 (m, 1H), 7.1 (d, 1H), 7.03 ( d, 1H), 6.7 (d, 1H), 5.35 (s, 2H), 4.0 (m, 1H), 2.6-3.6 (m, 14H), 1.3-2.1 (m, 12H). Reaction Scheme 14: Synthesis of 4- (6-fluoro-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid (106): (1) Step A: Ethyl ester of (3-fluoro-phenoxy) -acetic acid (107). 3-Fluoro-phenol (100 grams, 892 mmol) is dissolved in acetone (250 milliliters), and after the addition of chloroacetic acid ethyl ester (114 milliliters, 1.07 mol) and K2C03 (249 grams, 1.78 mol), the mixture it is refluxed for 24 hours. After cooling to 0 ° C, the mixture is filtered, and the filtrate is evaporated under reduced pressure. Yield: 198 grams (100 percent) of a red oil. (2) Step B: 2- (3-Fluoro-phenoxy) -3-oxo-succinic acid diethyl ester (108) NaH 60 percent in mineral oil (19.5 grams, 488.4 millimoles) is covered with 600 milliliters of dry diethyl ether. Ethanol (28.1 milliliters, 444 millimoles) is added dropwise within 25 minutes. Then diethyl ester of oxalic acid (66 ml, 488 m unlimited) was added dropwise within 20 minutes. After 10 minutes of stirring at room temperature, the mixture is heated to reflux. A solution of 1 07 (88 grams, 444 μm) is added dropwise in 80 μl of dry diethyl ether within 30 minutes, and the mixture is refluxed for 1 hour. After cooling to room temperature, the reaction mixture is poured into 2M HCl (400 milliliters) / ice (400 grams), and extracted with diethyl ether. The organic layers are dried over sodium sulfate, filtered, and evaporated. The crude product is purified by filtration on silica gel (ethyl acetate / hexane, 1: 1). Evaporation gave 140 grams of a red oil. The mineral oil could be removed using a separating funnel. Yield: 132 grams (100 percent). (3) Step C: 6-Fluoro-benzofuran-2,3-dicarboxylic acid diethyl ester (109) Dissolve 1 08 (66 grams, 221.3 millimoles) in 245 milliliters of concentrated and cooled sulfuric acid (- 15 ° C), and stirred for 3 hours, while slowly heating the reaction mixture to room temperature. The mixture is then poured onto 1 kilogram of ice, and extracted with diethyl ether. The organic layers are washed with brine, dried over sodium sulfate, filtered and evaporated. The crude product is used in the next step without further purification. Yield: 1 9.7 grams (32 percent) of a yellow oil. MS (ESI): 281 [M + H] +. 1 H-NMR (DMS0-d 6): d (ppm) 7.88 (dd, 1H), 7.82 (dd, 1H), 7.35 (ddd, 1H), 4.38 (m, 4H), 1.33 (t, 3H), 1.32 ( t, 6H). Cyclization gave only the 6-substituted benzofuran. (4) Step D: 6-Fluoro-benzofuran-3-carboxylic acid ethyl ester (110) The 109 (40 grams, 142.7 mmol) is dissolved in 300 milliliters of dimethyl sulfoxide, and after the addition of sodium (16.7 grams, 285.4 millimoles) and water (5.1 milliliters), the mixture is stirred for 4 hours at 160 ° C (temperature of the reaction mixture). The mixture is then allowed to cool and evaporated in a high vacuum. The residue is dissolved in ethyl acetate, washed with water and brine, and dried over sodium sulfate. Evaporation gave 14.8 grams of a red oil, which is further purified by filtration on silica gel (ethyl acetate / hexanes, 2: 8). Yield: 7.8 grams (26 percent) of a yellow solid. MS (ESI): 208 [M] +, 1 H-NMR (DMSO-d 6): d (ppm) 8.77 (s, 1 H), 7.92 (dd, 1 H), 7.68 (dd, 1 H), 7.29 (ddd, 1 H) , 4.35 (q, 2H), 1.32 (t, 3H). (5) Step E: (6-fluoro-benzofuran-3-yl) -methanol (111) A solution of LYAH4 in tetrahydrofuran (75.9 milliliters, 75.9 millimoles) is diluted with 100 milliliters of tetrahydrofuran, and cooled to 0 ° C. . Dissolve 110 (7.9 grams, 37.9 millimoles) in 100 milliliters of tetrahydrofuran, and add by drip within 30 minutes. After the addition is complete, the mixture is allowed to stir at room temperature for 2 hours. Then the reaction mixture is cooled to -15 ° C, and 10 milliliters of a 1M NaOH solution are added very slowly. The mixture is filtered on Celite, and evaporation under reduced pressure gave 5.3 grams of a yellow oil. (6) Step F: 4- (6-Fluorobenzofuran-3-ylmethoxy) -indol-1,2-dicarboxylic acid 1-tert-butyl ester (112) 111 (2 grams) is dissolved , 12 millimoles), 102 (3.7 grams, 12 millimoles), triphenylphosphine (9.4 grams, 36.1 millimoles) of DIPEA (62 milliliters, 36.1 millimoles) in 50 milliliters of tetrahydrofuran, and cooled to 0 ° C. Then a solution of 40 percent ethyl azodicarboxylate in tetrahydrofuran (15.7 milliliters, 36.1 millimoles) is added dropwise. After the addition is complete, the mixture is stirred for 16 hours (control with thin layer chromatography) at room temperature. Then the mixture is evaporated under reduced pressure. The residue is diluted with ethyl acetate, washed with a saturated solution of NaHCO 3 and NaCl, and dried over Na2S0. The crude product is purified by evaporation chromatography (ethyl acetate / hexanes, 1: 9), silica gel). Yield: 1.2 grams (22 percent) of a red oil. MS (ESI): 454 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 8.22 (s, 1H), 7.73 (dd, 1H), 7. 58 (dd, 1H), 7.53 (d, 1H), 7.38-7.40 (m, 2H), 7.15-77.25 (m, 1H), 7.05 (d, 1H), 5.43 (s, 2H), 4.05 (q, 2H), 155 (s, 9H), 1.29 (t, 3H). (7) Step G: 4- (6-Fluoro-benzofuran-3-ylmethoxy) -1H-indoI-2-carboxylic acid Dissolve 112 (1.2 grams, 2.6 mmol) in 30 milliliters of a 1: 1 mixture: 1 of tetrahydrofuran, ethanol, and water. After the addition of KOH beads (742 milligrams, 13.2 mmol), the mixture is stirred for 2 hours (control with thin layer chromatography) at 85 ° C. Then the organic solvent is removed under reduced pressure. The residue is cooled to 0 ° C, and treated with 2M HCl. The crude product is filtered and dried under a high vacuum. The crude product (800 milligrams) is recrystallized from ethyl acetate. Yield: 520 milligrams (60 percent) of colorless crystals. MS (ESI): 324 [MH] ", 1 H-NMR (DMSO-d 6): d (ppm) 12.8 (br s, 1 H), 11.7 (s, 1 H), 8.18 (s, 1 H), 7.73 (dd, 1H), 7.57 (dd, 1H), 7.18 (dd, 1H), 7.15 (d, 1H), 7.05 (s, 1H), 7.02 (d, 1H), 6.72 (d, 1H), 5.38 (s, 2H) Example 56. 4- (6-Fluoro-benzofuran-) 4- {2- (4-hydroxy-piperidin-1-yl) -ethyl] -piperidin-4-yl} -amide. 3-ylmethoxy) -1H-indole-2-carboxylic acid This compound is synthesized from 4- (6-fluoro-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid 106 (see Example 55) and amine 21, in a manner analogous to the method described in Example 1.

Yield: 70 milligrams (38 percent). MS (ESI): 535 [M + H] +, 1 H-NMR (DMSO-de): d (ppm) 11.5 (s, 1H), 10.55 (br, 1H), 10.45 (br, 1H), 8.5 (br d, 1H), 8.2 (s, 1H), 7.7 (dd, 1H), 7.6 (dd, 2H), 7.15-7.25 (m, 2H), 7.1 (dd, 1H), 7.03 (d, 1H), 5.35 (s, 2H), 5.0 (br 1H), 4.05 (m, 1H), 2.9-3.7 (m, 13H), 1.7-2.1 (m, 8H).

Example 57 Dichlorohydrate of. { 1- [2 - ((3S, 4S) -4-hydroxy-3-methyl-piperidin-1-yl) -ethyl] -piperidin-4-yl} ~ 4- (6-Fluoro-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid amide.

This compound is synthesized from 4- (6-fluoro-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid 106 (see Example 55) and amine 14, in a manner analogous to the method described in Example 1. Yield: 135 milligrams (71 percent). MS (ESI): 549 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 11.5 (s, 1H), 10.65 (br, 2H), 8.52 (d, 1H), 8.2 (s, 1H), 7.72 ( dd, 1H), 7.58 (dd, 1H), 7.24 (s, 1H), 7.2 (m, 1H), 7.1 (dd, 1H), 7.04 (d, 1H), 6.72 d, 1H), 5.35 (s, 2H), 2.6-2.2 (m, 14H), 1.75-2.2 (m, 8H), 0.93 (d, 3H). Example 58 Dichlorohydrate. { 1 - [(S) -2- (4-hydroxy-piperidin-1-yl) -propyl] -piperidin-4-yl} -amide of 4- (6-fluoro-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid This compound is synthesized from 4- (6-fluoro-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid 106 (see Example 55) and amine 50, in a manner analogous to the method described in Example 1. Yield: 75 milligrams (39 percent). MS (ESI): 549 [M + H] +, 1 H-NMR (DMSO-de): d (ppm) 11.55 (s, 1H), 10.3-10.7 (br, 2H), 8.53 (d, 1H), 8.2 (s, 1H), 7.72 (dd, 1H), 7.58 (dd, 1H), 7.24 (s, 1H), 7.2 (m, 1H), 7.1 (dd, 1H), 7.03 (d, 1H), 6.71 (d, 1H), 5.33 (s, 2H), 5.1 (br, 1H), 2.8-41 (m, 13H), 1.7-2.2 (m, 8H), 1.35 / 13 (d, 3H) (rotamers). Example 59 { 1 - [(S) -2 - ((3S, 4S) -h, droxy-3-rnetiI-piperidin-1-yl) -propl] -piperidin-4-yl} 4- (6-Fluoro-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid amide This compound is synthesized in a manner analogous to Example 1, from 4- (6-fluoro-benzofuran- 3-ylmethoxy) -1H-indole-2-carboxylic acid 106 (see Example 55) and amine 56. MS (ESI): 463.2 [M + H] +, 1 H-NMR (DMSO-d6): d (ppm ) 11.48 (s, 1H), 8.19 (s, 1H), 8.11 (d, 1H), 7.71 (dd, 1H), 7.58 (dd, 1H), 719 (m, 2H), 7.09 (t, 1H), 7.01 (d, 1H), 6.7 (d, 1H), 5.34 (s, 2H), 4.43 (d, 1H), 3.71 (m, 1H), 2.58-2.92 (m, 6H), 2.31 (m, 1H) , 2.22 (m, 1H), 2.02-2.18 (m, 2H), 1.89 (m, 2H), 1.64-1.78 (m, 3H), 1.42-1.59 (m, 2H), 1.2-1.4 (m, 2H) , .9 (d, 3H), 0.86 (d, 3H). Example 60 { 1 - [(1S, 9aR) -1- (octahydro-quinolizln-1-yl) methyI] -piperidin-4-yl} -amide of 4- (5-fluoro-benzofuran-3-ylmethoxy) -1H-indoI-2-carboxylic acid This compound is synthesized from 4- (6-fluorobenzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid 113 (for the preparation, see below) and the amine 61, in a manner analogous to the method described in Example 1. Yield: 840 milligrams (72.5 percent). MS (ESI): 559 [M + H] \ 1 H-NMR (DMSO-de): d (ppm) 11.45 (s, 1H), 8.23 (s, 1H), 8.1 (d, 1H), 7.64 (dd, 1H), 7.48 (dd, 1H), 7.17 (m, 2H), 7.08 (dd, 1H), 7.0 (d, 1H), 6.68 (d, 1H), 5.35 (s, 2H), 3.75 (m, 1H) ), 2.65-2.85 (m, 4H), 2.47 (m, 1H), 2.25 (dd, 1H), 1.2-2.05 (m, 20H). Synthesis of 4- (5-fluoro-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid (113): This compound is synthesized from 4-fluoro-phenol, in a manner analogous to the method described for 106 (see Example 55). MS (ESI): 324.2 [MH] ", 1 H-NMR (DMSO-d 6): d (ppm) 12.81 (br s, 1 H), 11.7 (s, 1 H), 8.24 (s, 1 H), 7.64 (dd, 1H), 7.51 (dd, 1H), 7.15 (m, 2H), 7.05 (m, 2H), 6.7 (d, 1H), 5.37 (s, 2H). Example 61 [1- [2- (4-Dihydrochloride 4- (5-fIuoro-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid-hydroxy-piperidin-1-yl) -ethyl] -piperidin-4-yl} -amide.

This compound is synthesized from 4- (5-fluorobenzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid 113 (see Example 60) and amine 21, in a manner analogous to the method described in Example 1. Yield: 160 milligrams (57 percent). MS (ESI): 535 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 11.5 (s, 1H), 10.65 (br, 1H), 10.55 (br, 1H), 8.51 (br d, 1H), 8.25 (s, 1H), 7.65 (m, 1H), 7.45 (dd, 2H), 72 (s, 1H), 7.05 - 7.15 (m, 3H), 6.7 (d, 1H), 5.35 (s, 2H), 4.12 (m, 1H), 3.84 (m, 1H), 2.9-3.7 (m, 13H), 1.75-2.2 (m, 8H). Example 62 Dichlorohydrate of. { 1- [2 - ((3R, 4R, 5S) -4-hydroxy-3,5-dimethyl-piperidin-1-yl) -etiI] -piperidin-4-yl} -amide of 4- (5-fIuoro-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid This compound is synthesized from 4- (5-fluoro-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid 113 (see Example 60) and amine 41, in a manner analogous to the method described in Example 1. Yield: 110 milligrams (56 percent). MS (ESI): 563 [M + H] +, 1 H-NMR (DMSO-de): d (ppm) 11.5 (s, 1H), 10.5-10.7 (br 2H), 8.5 (d, 1H), 8.22 (s, 1H), 7.61 (dd, 1H), 7.49 (dd, 1H), 7.2 (m, 2H), 7. 1 (d, 1H), 7.02 (d, 1H), 67 (d, 1H), 5.32 (s, 2H), 5.05 (br, 1H), 4.05 (m, 1H), 2.6-3.8 (m, 13H), 1.8-2.1 (m, 6H), 0.93 (d, 6H). Example 63 Dichlorohydrate of. { 1 - [(S) -2- (4-hydroxy-p? Peridin-1-yl) -propyl] -piperidin-4-yl} 4- (5-Fluoro-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid amide This compound is synthesized from 4- (5-fluoro-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid 113 (see Example 60) and amine 50, in a manner analogous to the method described in Example 1. Yield: 85 milligrams (45 percent). MS (ESI): 549 [M + H] +, 1 H-NMR (DMSO-de): d (ppm) 11.55 (s, 1H), 10.2-10.6 (br, 2H), 8.5 (d, 1H), 8.24 (s, 1H), 7.65 (dd, 1H), 75 (m, 1H), 7.15-73 (m, 2H), 7.1 (dd, 1H), 7.03 (dd, 1H), 6.71 (d, 1H), 5.33 (s, 2H), 5.04 (br, 1H), 2.8-4.1 (m, 13H), 1.7-2.2 (m, 8H), 1.35 / 13 (d, 3H) (rotamers). Example 64 { 1 - [(S) -2 - ((3S, 4S) -4-hydroxy-3-methyl-piperidin-1-yl) -propyl] -p? Peridin-4-yl} -amide of 4- (5-fluoro-benzofuran-3-ylmethoxy) - 1H-indole-2-carboxylic acid This compound is synthesized analogously to Example 1, from 4- (5-fluoro-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid 113 (see Example 60) and amine 56. MS ( ESI): 563.1 [M + H] +, 1 H-NMR (CD 3 OD): d (ppm) 7.95 (s, 1 H), 7.48 (dd, 1 H), 7.43 (dd, 1 H), 7.21 (s, 1 H), 7.15 (t, 1H), 7.02-7.12 (m, 2H), 6.69 (d, 1H), 5.34 (s, 2H), 3.86 (m, 1H), 2.72-3.12 (m, 6H), 2.51 (m, 1H), 2.17-2.41 (m, 3H), 1.97-2.15 (m, 2H), 1.81-1.96 (m, 3H), 1.45-1.76 (m, 4H), 1.05 (d, 3H), 0.98 (d, 3H). Example 65 Dihydrochloride of. { 1 - ((1S, 9aR) -1- (Octahydro-quinolizin-1-yl) methyl] -piperidin-4-yl}. -amide of 4- (7-fluoro-benzofuran-3-ylmethoxy) - 1H -indole-2-carboxylic This compound is synthesized from 4- (7-fluorobenzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid (114) (for the preparation, see below), and the amine 61, in a manner analogous to the method described in Example 1. Yield: 194 milligrams (40 percent). MS (ESI): 559 [M + H] +, 1 H-NMR (DMSO-de): d (ppm) 11.5 (s, 1H), 10.2-10.7 (br, 2H), 8.45 (dd, 1H), 8.28 (s, 1H), 7.58 (dd, 1H), 7.2-7.3 (m, 3H), 7.1 (m, 1H), 7.05 (d, 1H), 6.72 (d, 1H), 5.38 (s, 2H), 4.0 (m, 1H) , 2.65-2.85 (m, 6H), 1.2-2.05 (m, 20H).

Synthesis of 4- (7-fluoro-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid (114): This compound is synthesized from 2-fluoro-phenol, in a manner analogous to the method described for the 106 (see Example 55). MS (ESI): 324.2 [M-H] ~, 1 H-NMR (DMSO-d 6): d (ppm) 12.85 (br s, 1H), 11.75 (s, 1H), 8.25 (s, 1H), 7.58 (dd, 1H), 7.2-7.3 (m, 2H), 7.15 (dd, 1H), 7.05 (s, 1H), 7.02 (d , 1H), 6.72 (d, 1H), 5.4 (s, 2H).

Example 66 Dihydrochloride of. { 1 - [(1S, 9aR) -1- (octahydro-quinolizin-1-yl) methyI] -piperidin-4-yl} 4- (4,6-difluoro-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid amide.

This compound is synthesized from 4- (4,6-difluoro-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid (115) (for the preparation, see below), and amine 61, from a manner analogous to the method described in Example 1. Yield: 155 milligrams (82 percent). MS (ESI): 577 [M + H] +, 1 H-NMR (DMSO-de): d (ppm) 11.5 (s, 1H), 10.5 (br d, 1H), 10.2 (br d, 1H), 8.45 (br d, 1H), 8.25 (s, 1H), 7.55 (d, 1H), 7.2-7.25 (m, 2H), 7.1 (m, 1H), 7.05 (d, 1H), 6.7 (d, 1H) , 5.3 (s, 2H), 4.0 (m, 1H), 2.8-3.6 (m, 14H), 1.3-2.1 (m, 12H). Synthesis of 4- (4,6-difluoro-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid (115): This compound is synthesized from 3,5-difluoro-phenol in a manner analogous to the method described for 106 (see the Example 55). MS (ESI): 342 [MH] ", 1 H-NMR (DMSO-d 6): d (ppm) 12.8 (br s, 1 H), 11.6 (s, 1 H), 8.24 (s, 1 H), 7.51 (dd, 1H), 7.2 (dd, 1H), 7.15 (dd, 1H), 7.04 (d, 1H), 7.02 (s, 1H), 6.7 (d, 1H), 5.32 (s, 2H).

Example 67 Dichlorohydrate of. { 1- [2- (4-hydroxy-piperidin-1-yl) -eti] -piperidin-4-yl} -amide of 4- (4,6-difluoro-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid This compound is synthesized from 4- (4,6-difluoro-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid 115 (see Example 66), and amine 21, in a manner analogous to described in Example 1. Yield: 90 milligrams (49 percent). MS (ESI): 553 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 11.5 (s, 1H), 10.5 (br, 1H), 10.35 (br, 1H), 8.48 (br d, 1H), 8.25 (s, 1H), 7.54 (d, 1H), 7.2 (m, 2H), 7.12 (d, 1H), 7.03 (d, 1H), 6.7 (d, 1H), 5.3 (s) , 2H), 5.05 (br, 1H), 4.07 (m, 1H), 2.9-3.75 (m, 13H), 1.65-2.1 (m, 8H).

Example 68 Dichlorohydrate of. { 1-'2 - ((3S, 4S) -4-hydroxy-3-methyl-piperidin-1-yl) -ethyl] -piperidin-1-yl} -amide of 4- (4,6-difiuoro-benzofuran-3-i Imethoxy) -1H -indole-2-carboxylic acid This compound is synthesized from 4- (4,6-difluoro-benzofuran- 3-ylmethoxy) -1H-indole-2-carboxylic acid (115) (see example) 66), and the amine 14, in a manner analogous to the method described in Example 1. Yield: 125 milligrams (67 percent). MS (ESI): 567 [M + H] +, 1 H-NMR (DMSO-de): d (ppm) 11.5 (s, 1H), 10.65 (br, 2H), 8.5 (d, 1H), 8.25 (s, 1H), 7.53 (dd, 1H), 7.2-7.3 (m, 2H), 7.1 (dd, 1H), 7.02 (d, 1H), 6.7 (d, 1H), 5.3 (s, 2H), 2.6-4.1 (m, 14H), 1.75-2.2 (m, 8H), 0. 93 (d, 3H). Example 69 Dichlorohydrate of. { 1 - [(S) -2- (4-hydroxy-piperidin-1-yl) -propiI] -piperidin-4-yl} 4- (4,6-difluoro-benzofuran-3-ylmethoxy) -1 H-indole-2-carboxylic acid amide This compound is synthesized from 4- (4,6-difluorobenzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid 115 (see Example 66), and amine 50, in a manner analogous to the method described in Example 1. Yield: 105 milligrams (56 percent). MS (ESI): 567 [M + H] +, 1 H NMR (120 ° C, DMSO-d 6): d (ppm) 11.5 (s, 1H), 10.3-10.7 (br, 2H), 8. 52 (d, 1H), 8.26 (s, 1H), 7.53 (d, 1H), 7.2 (m, 2H), 7.1 (dd, 1H), 7. 02 (d, 1H), 6.7 (d, 1H), 5.3 (s, 2H), 5.05 (br, 1H), 4.05 (m, 1H), 2.9- 3.9 (m, 12H), 1.7-2.2 (m, 8H), 1.34 (d, 3H). Example 70 Dihydrochloride. { 1 - [(S) -2 - ((3S, 4S) -4-hydroxy-3-methyl-piperidin-1-M) -propyl] -piperidin-4-yl} -amide of 4- (4,6-difluoro-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid This compound is synthesized from 4- (4,6-difluoro-benzofuran-3-yloxy) -1H-indole-2-carboxylic acid 115 (see Example 66), and amine 56, in a manner analogous to od described in Example 1. Yield: 130 milligrams (68 percent). MS (ESI): 581 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 11.5 (s, 1H), 10.4-10.6 (br, 2H), 8.5 (d, 1H), 8.27 (, 1H), 7.55 (d, 1H), 7.2 (m, 2H), 7.1 (dd, 1H), 7.03 (d, 1H), 6. 7 (d, 1H), 5.3 (s, 2H), 5.1 (br, 1H), 4.05 (m, 1H), 2.8-3.9 (m, 13H), 1. 9-2.1 (m, 6H), 1.3 (d, 3H), 0.93 (d, 3H). Example 71 Dihydrochloride of. { 1 - [(1S, 9aR) -1- (octahydro-quinolizin-1-yl) yl] -piperidin-4-yl} 4- (7-Chloro-benzofuran-3-yloxy) - 1H-indole-2-carboxylic acid amide This compound is synthesized from 4- (7-chloro-benzofuran-3-yloxy) -1H-indole-2-carboxylic acid (116) (for the preparation, see below), and the amine 61, in a manner analogous to the od described in Example 1. Yield: 55 milligrams (29 percent). MS (ESI): 575 [M + H] +, 1 H-NMR (DMSO-de): d (ppm) 11.5 (s, 1H), 10.1-10.6 (br, 2H), 8.5 (dd, 1H), 8.3 (s, 1H), 7.7 (d, 1H), 7.48 (d, 1H), 7.32 (dd, 1H), 7.25 (m, 1H), 7.1 (m, 1H), 7.05 (d, 1H), 6.7 ( d, 1H), 5.38 (s, 2H), 2.65 (s, 2H), 4.0 (m, 1H), 2.65-2.85 (m, 6H), 1.2-2.05 (m, 20H). Synthesis of 4- (7-chloro-benzofuran-3-yloxy) -1H-indole-2-carboxylic acid (116): This compound is synthesized from 2-chloro-phenol, in a manner analogous to the od described for 106 (see Example 55). MS (ESI): 340 [MH] ", 1 H-NMR (DMS0-d 6): d (ppm) 10.86 (s, 1 H), 8.25 (s, 1 H), 7.71 (d, 1 H), 7.42 (d, 1 H ), 7.30 (dd, 1H), 6.93 (m, 2H), 6.58 (d, 1H), 6.34 (s, 1H), 5.36 (s, 2H) (potassium salt), Example 72 Di hydrochloride of. 1 - [(1S, 9aR) -1- (Octahydro-quinolizin-1-yl) yl] - piperidin-4-yl.} - amide of 4- (6-chloro-benzofuran-3-yloxy) - 1H-i dol-2-carboxylic acid This compound is synthesized from 4- (6-chloro-benzofuran-3-yloxy) -1H-indole-2-carboxylic acid (117) (for the preparation, see below), and the amine 61, in a manner analogous to the od described in Example 1. Yield: 85 milligrams (49.8 percent). MS (ESI): 575 [M + H] +, 1 H-NMR (DMSO-de): d (ppm) 11.5 (s, 1H), 10.6 (br d, 1H), 10.3 (br d, 1H), 8.49 (br dd, 1H), 8.22 (s, 1H), 7.8 (d, 1H), 7.72 (d, 1H), 7.38 (d, 1H), 7.25 (m, 1H), 7.1 (m, 1H), 7.03 (d, 1H), 6.7 (d, 1H), 5.35 (s, 2H), 4.0 (m, 1H), 2.8-38 (m, 14H), 1.3-2.1 (m, 12H).

Synthesis of 4- (6-chloro-benzofuran-3-yloxy) -1H-indole-2-carboxylic acid (117): This compound is synthesized from 3-chloro-phenol, in a manner analogous to the od described for the 106 (see Example 55). Cyclization with concentrated sulfuric acid (Step C) yielded a 1: 1 mixture of the 4- and 6-substituted benzofurans, which could be separated in step D. MS (ESI): 340 [M-H]. Example 73 { 1- [2- (4-hydroxy-piperidin-1-yl) -ethyl] -piperidin-4-yl} 4 ~ (6-Chloro-benzofuran-3-yloxy) -1H-indole-2-carboxylic acid amide This compound is synthesized from 4- (6-chloro-benzofuran-3-yloxy) -1H-indol-2-carboxylic acid 117 (see Example 72), and the amine 21, in a manner analogous to the od described in Example 1. Yield: 63 milligrams (34 percent). MS (ESI): 551 [M + H] +, 1 H-NMR (DMSO-de): d (ppm) 11.5 (s, 1H), 8.22 (s, 1H), 8.15 (br d, 1H), 7.81 ( s, 1H), 7.75 (d, 1H), 7.35 (dd, 1H), 7.18 (s, 1H), 7.1 (dd, 1H), 7.02 (d, 1H), 6.7 (d, 1H), 5.35 (s) , 2H), 4.75 (b, 1H), 2.1-3.9 (m, 14H), 1.4-1.8 (m, 8H).

Example 74 { 1- [2 - ((3S, 4S) -4-hydroxy-3-yl-piperidin-1-yl) -ethyl] -piperidin-4-yl} - 4- (6-chloro-benzofuran-3-yloxy) -1H-indole-2-carboxylic acid amide This compound is synthesized from 4- (6-chloro-benzofuran-3-yloxy) -1H-indole-2-carboxylic acid 117 (see Example 72), and amine 14, in a manner analogous to the od described in Example 1. Yield: 55 milligrams (32 percent). MS (ESI): 565 [M + H] +, 1 H-NMR (DMSO-de): d (ppm) 11.55 (s, 1H), 10.5 (br, 2H), 8.48 (d, 1H), 8.22 (s) , 1H), 7.80 (s, 1H), 7.70 (d, 1H), 7.37 (d, 1H), 7.22 (s, 1H), 7.1 (dd, 1H), 7.02 (d, 1H), 6.71 (d, 1H), 5.34 (s, 2H), 2.6-42 (m, 14H), 1.75-2.2 (m, 8H), 0.93 (d, 3H).

Example 75 Dihydrochloride. { 1 - [(S) -2- (4-hydroxy-piperidin-1-yl) -propyl] -piperidin-4-yl} 4- (6-chloro-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid amide This compound is synthesized from 4- (6-chloro-benzofuran-3-ylmethoxy) -1H- indole-2-carboxylic acid 117 (see Example 72), and amine 50, in a manner analogous to the method described in Example 1. Yield: 85 milligrams (46 percent). MS (ESI): 565 [M + H] +, 1 H-NMR (DMSO-de): d (ppm) 11.5 (s, 1H), 10.2-10.6 (br, 2H), 8.5 (d, 1H), 8.21 (s, 1H), 7.8 (d, 1H), 7.7 (s, 1H), 7.35 (dd, 1H), 7.24 (s, 1H), 7.1 (dd, 1H), 7.03 (d, 1H), 6.7 ( d, 1H), 5.35 (s, 2H), 5.0 (br, 1H), 2.85-4.2 (m, 13H), 1.7-22 (m, 8H), 1.35 / 1.3 (d, 3H) (rotamers). Example 76 Dichlorohydrate of. { 1 - [(1S, 9aR) -1- (Octahydro-quinoizin-1-yl) methyl] -piperidin-4-yl} 4- (4-Chloro-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid amide This compound is synthesized from 4- (4-chlorobenzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid (118) (for the preparation, see below), and the amine 61, in a manner analogous to the method described in Example 1. Yield: 230 milligrams (58.8 percent). MS (ESI): 575 [M + H] +, 1 H-NMR (DMSO-de): d (ppm) 11.5 (s, 1H), 10.6 (br d, 1H), 10.3 (br d, 1H), 8.45 (br dd, 1H), 8.3 (s, 1H), 7.65 (dd, 1H), 7.3-7.4 (m, 2H), 7.25 (m, 1H), 7.1 (m, 1H), 7.03 (d, 1H) , 6.7 (d, 1H), 5.35 (s, 2H), 4.0 (m, 1H), 2.8-3.8 (m, 14H), 1.3-2.1 (m, 12H).

Synthesis of 4- (4-chloro-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid (118): This compound is synthesized from 3-chloro-phenoxy, in a manner analogous to the method described for 106 ( see Example 55). Cyclization with concentrated sulfuric acid (Step C) yielded a 1: 1 mixture of the 4- and 6-substituted benzofurans, which could be separated in Step D. MS (ESI): 340 [MH] ", 1H- NMR (DMSO-d6): d (ppm) 12.75 (br s, 1H), 11.7 (s, 1H), 8.31 (s, 1H), 7.6 (dd, 1H), 7.35 (m, 2H), 7.15 (dd) , 1H), 7.02 (m, 2H), 6.75 (d, 1H), 5.42 (s, 2H).

Example 77 Dichlorohydrate of. { 1- [2- (4-hydroxy-piperidin-1-yl) -etiI] -piperidin-4-yl} -amide of 4- (4-chloro-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid This compound is synthesized from 4- (4-chloro-benzofuran-3-ylmethoxy) -1H- indole-2-carboxylic acid 118 (see Example 76), and amine 21, in a manner analogous to the method described in Example 1. Yield: 160 milligrams (99 percent). MS (ESI): 551 [M + H] +, 1 H-NMR (DMSO-de): d (ppm) 11.52 (s, 1H), 10.35 (br, 1H), 10.2 (br, 1H), 8.5 (br , 1H), 8.31 (s, 1H), 7.63 (d, 1H), 7.36 (m, 2H), 7.22 (s, 1H), 7.11 (dd, 1H), 7.03 (d, 1H), 6.71 (d, 1H), 5.37 (s, 2H), 5.02 (br, 1H), 4.05 (m, 1H), 2.9-3.75 (m, 13H), 1.65-2.1 (m, 8H). Example 78 Dihydrochloride of. { 1- [2 - ((3R, 4R, 5S) -4-hydroxy-355-d-methyl-p-penny-1-yl) -ethyl] -piperidin-4-yl} -amide of 4- (4-chloro-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid This compound is synthesized from 4- (4-chlorobenzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid 118 (see Example 76), and amine 41, in a manner analogous to the method described in Example 1. Yield: 45 milligrams (39 percent). MS (ESI): 577 [MH] ", 1 H-NMR (DMSO-de): d (ppm) 11.5 (s, 1H), 10.45-10.7 (br, 2H), 8.47 (d, 1H), 8.32 (s) , 1H), 7.65 (d, 1H), 7.35 (m, 2H), 7.21 (s, 1H), 7.1 (dd, 1H), 7.02 (d, 1H), 6.71 (d, 1H), 5.35 (s, 2H), 5.0 (br, 1H), 4.05 (m, 1H), 2.6-3.8 (m, 13H), 1.8-2.1 (m, 6H), 0.93 (d, 6H), Example 79. (S) -2- (4-hydroxy-piperidin-1-yl) -propyl] -piperidin-4-yl}. -amide of 4- (4-chloro-benzofuran-3-ylmethoxy) -1H-indole -2-carboxylic This compound is synthesized from 4- (4-chloro-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid 118 (see Example 76), and amine 50, in a manner analogous to the method described in Example 1. Yield: 20 milligrams (13 percent). MS (ESI): 565 [M + H] +, 1 H-NMR (DMSO-de): d (ppm) 11.5 (s, 1H), 8.3 (s, 1H), 8.1 (d, 1H), 7.62 (d, 1H), 7.35 (m, 2H), 7.2 ( s, 1H), 7.1 (dd, 1H), 7.0 (d, 1H), 6.7 (d, 1H), 5.4 (s, 2H), 45 (br, 1H), 4.05 (m, 1H), 3.7 (m , 1H), 2.6-2.9 (m, 4H), 1.1-2.4 (m, 15H), 0.9 (d, 3H). Example 80 Dichlorohydrate. { 1 - [(1S, 9aR) -1- (Octahydro-quinolizin-1-yl) methyl] -piperidin-4-yl} -amide of 4- (7-methoxy-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid This compound is synthesized from 4- (7-methoxy-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid 119 (for the preparation, see below), and amine 61, in a manner analogous to method described in Example 1. Yield: 130 milligrams (68.1 percent). MS (ESI): 571 [M + Hf, 1 H-NMR (DMSO-de): d (ppm) 11.55 (s, 1H), 10.5 (br d, 1H), 10.2 (rd, 1H), 8.47 (dd, 1H), 8.13 (s, 1H), 7.25 (m, 2H), 7.2 (dd, 1H), 7.09 (d, 1H), 7.02 (d, 1H), 6.95 (d, 1H), 6.72 (d, 1H) ), 5.32 (s, 2H), 4.0 (m, 1H), 3.83 (s, 3H), 2.8-3.8 (m, 14H), 1.3-2.1 (m, 12H). Synthesis of 4- (7-methoxy-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid (119): This compound is synthesized from 2-methoxy-phenol, in a manner analogous to the method described for 106 (see Example 55). MS (ESI): 336 [MH] ', 1 H-NMR (DMSO-d 6): d (ppm) 12.8 (br s, 1 H), 11.54 (br s, 1 H), 8.11 (s, 1 H), 7.28 (d , 1H), 7.18 (dd, 1H), 7.09 (m, 1H), 7.0 (d, 1H), 6.95 (d, 1H), 6.92 (m, 1H), 6.70 (d, 1H), 5.35 (s, 2H), 3.92 (s, 3H). Example 81 [1- (2-piperidin-1-yl-ethyl) -piperidin-4-yl] -amide of 4- (7-methoxy-benzofu-n -3-i -methoxy) -1H- I ndol-2-carboxy I ico This compound is synthesized from 4- (7-methoxy-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid 119 (see Example 80), and amine 1, in a manner analogous to the method described in Example 1. Yield: 162 milligrams (48 percent). MS (ESi): 531 [M + H] +, 1 H-NMR (DMSO-de): d (ppm) 11.53 (s, 1H), 10.55 (br, 1H), 10.31 (br, 1H), 8.49 (d , 1H), 8.12 (s, 1H), 7.25 (dd, 1H), 7.22 (br s, 1H), 7.19 (dd, 1H), 71 (dd, 1H), 7.02 (d, 1H), 7.95 (d , 1H), 6.7 (d, 1H), 5.31 (s, 2H), 4.05 (m, 1H), 3.93 (s, 3H), 3.5-3.8 (m, 8H), 3.1 (m, 2H), 1.7- 2.1 (m, 8H), 1.4 (m, 2H).

Example 82 Dihydrochloride of. { 1- [2- (4-hydroxy-piperidin-1-yl) -ethyl] -piperidin-4-yl} -amide of 4- (7-methoxy-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid This compound is synthesized from 4- (7-methoxy-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid 119 (see Example 80), and amine 21, in a manner analogous to the method described in Example 1. Yield: 135 milligrams (73 percent). MS (ESI): 547 [M + H] +, 1 H-NMR (DMSO-de): d (ppm) 11.45 (s, 1H), 10.5 (br, 1H), 10.4 (br, 1H), 8.5 (br , 1H), 8.14 (s, 1H), 7.2-7.3 (m, 3H), 7.1 (dd, 1H), 7.0 (d, 1H), 6.95 (d, 1H), 6.7 (d, 1H) 5.32 (s) , 2H), 5.05 (br, 1H), 4.05 (m, 1H), 3.93 (s, 3H), 2.7-37 (m, 13H), 1.6-2.1 (m, 8H).

Example 83 Dichlorohydrate of. { 1- [2 - ((3S, 4S) -4-hydroxy-3-methyl-piperidin-1-yl) -ethyl] -piperidin-4-yl} -amide of 4- (7-methoxy-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid This compound is synthesized from 4- (7-methoxy-benzofuran-3-ylmethoxy) -1H-indole -2-carboxylic acid 119 (see Example 80), and amine 14, in a manner analogous to the method described in Example 1. Yield: 100 milligrams (53 percent). MS (ESI): 561 [M + H] +, 1 H-NMR (DMSO-de): d (ppm) 11.5 (s, 1H), 10.6 (br, 2H), 8.5 (d, 1H), 8.13 (s) , 1H), 7.18 7.3 (m, 3H), 7.1 (dd, 1H), 7.03 (d, 1H), 6.96 (d, 1H), 6.71 (d, 1H), 5.33 (s, 2H), 3.95 (s) , 3H), 2.6-4.2 (m, 14H), 1.75-2.2 (m, 8H), 0.93 (d, 3H). Example 84 { 1 - [(S) -2- (4-hydroxy-piperidin-1-yl) -propyl] -piperidin-4-yl} -amide of 4- (7-methoxy-benzofuran-3-ylmethoxy) -1H-indo! -2-carboxylic acid This compound is synthesized from 4- (7-methoxy-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid 119 (see Example 80), and the amine 50, in a manner analogous to the method described in Example 1. Yield: 166 milligrams (94 percent). MS (ESI): 561 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 11.5 (s, 1H), 10.2-10.6 (br, 2H), 8.5 (d, 1H), 8.14 (s, 1H), 7.28 (d, 1H), 7.23 (s, 1H), 7.22 (dd, 1H), 7.1 (dd, 1H), 7.03 (d, 1H), 6.95 (d, 1H), 6.7 ( d, 1H), 5.33 (s, 2H), 5.05 (br, 1H), 3.93 (s, 3H), 2.9-4.1 (m, 13H), 1.7-2.2 (m, 8H), 1.35 / 1.3 (d, 3H) (rotamers). Example 85 { 1 - [(S) -2 - ((3S, 4S) -4-hydroxy-3-methyl-piperidin-1-yl) -propyl] -piperidin-4-yl} -amide of 4- (7-methoxy-benzofuran-3-ylmethoxy) -1 H-indole-2-carboxylic acid This compound is synthesized in a manner analogous to Example 1, from 4- (7-methoxy-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid 119 (see Example 80), and amine 56. MS (ESI): 575.1 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 11.49 (s, 1 H), 8.15 (s, 1 H), 8.13 (d, 1 H), 7.26 (d , 1H), 7.22 (t, 1H), 7.2 (s, 1H), 7.1 (t, 1H), 7.02 (d, 1H), 6.97 (d, 1H), 6.71 (d, 1H), 5.34 (s, 2H), 4.43 (d, 1H), 3.95 (s, 3H), 3.72 (m, 1H), 2.6-2.93 (m, 6H), 2.31 (m, 1H), 2.23 (m, 1H), 2.03-2.17 (m, 2H), 1.89 (m, 2H), 1.66-1.77 (m, 3H), 1.42- 1.58 (m, 2H), 1.2-1.4 (m, 2H), 0.89 (d, 3H), 0.85 (d , 3H). Example 86 { 1 - [(1s, 9aR) -1- (octahydro-quinolizin-1-yl) methyl] -pipep "din-4-yl] -amide of 4- (6-methoxy) -amide benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid This compound is synthesized from 4- (6-methoxy-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid (120) (for the preparation, see below), and the amine 61, in a manner analogous to the method described in Example 1. Yield: 108 milligrams (63.8 percent). MS (ESI): 571 [M + H] +, 1 H-NMR (DMSO-de): d (ppm) 11.45 (s, 1H), 8.1 (d, 1H), 8.03 (s, 1H), 7.55 (d , 1H), 7.2 (m, 2H), 7.08 (dd, 1H), 7.0 (d, 1H), 6.93 (dd, 1H), 6.7 (d, 1H), 53 (s, 2H), 3.78 (s, 3H), 3.73 (m, 1H), 2.65-2.85 (m, 4H), 2.47 (m, 1H), 2.25 (dd, 1H), 1.2-2.05 (m, 20H).

Synthesis of 4- (6-methoxy-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid (120): This compound is synthesized from 3-methoxy-phenol, in a manner analogous to the method described for the 106 (see Example 55). Cyclization with concentrated sulfuric acid (Step C) gave only the 6-substituted benzofuran. MS (ESI): 336 [MH] ", 1 H-NMR (DMSO-de): d (ppm) 12.81 (br s, 1H), 11.71 (s, 1H), 8.02 (s, 1H), 7.56 (d, 1H), 7.18 (s, 1H), 7.13 (dd, 1H), 7.01 (s, 1H), 6.99 (m, 1H), 6.9 (dd, 1H), 6.71 (d, 1H), 5.33 (s, 2H) ), 3.78 (s, 3H). Example 87 4- (6-methoxy-benzofuran-3-ylmethoxy) - 1- (2-azepan-1-yl-ethyl) -piperidin-4-yl] -amide of 4- (6-methoxy-benzofuran-3-ylmethoxy) - 1H-indole-2-carboxylic acid This compound is synthesized from 4- (6-methoxy-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid 120 (see Example 86), and amine 5, in a manner analogous to the method described in Example 1. Yield: 121 milligrams (50 percent). MS (ESI): 545 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 11.5 (s, 1H), 8.12 (d, 1H), 8.05 (s, 1H), 7.55 (d , 1H), 7.2 (m, 2H), 7.08 (dd, 1H), 7.0 (d, 1H), 6.91 (dd, 1H), 6.7 (d, 1H), 5.3 (s, 2H), 3.8 (s, 3H), 3.7 (, 1H), 2.85 (m, 2H), 2.5-6.6 (m, 8H), 2.35 (dd, 2H), 2.0 (m, 2H), 1.72 (m, 2H), 1.45-1.6 ( m, 8H). Example 88 4- (6-methoxy-benzofuran-3-ylmethoxy) -1H-indole- (1- (2-r2- (4-hydroxy-piperidin-1-yl) -etin-piperidin-4-yl) -alkyl) -ai 2-carboxylic This compound is synthesized from 4- (6-methoxy-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid 120 (see Example 86), and amine 21, in a manner analogous to the method described in Example 1. Yield: 65 milligrams (27 percent). MS (ESI): 547 [M + H] +, 1 H-NMR (DMSO-de): d (ppm) 11.45 (s, 1H), 8.1 (br d, 1H), 8.03 (s, 1H), 7.55 (d, 1H), 7.18 (m, 2H), 7.08 (dd, 1H), 7.0 (d, 1H), 6.9 (dd 1H), 6.68 (d, 1H), 5.3 (s, 2H) , 45 (br, 1H), 3.78 (s, 3H), 3.72 (m, 1H), 3.4 (m, 1H), 2.9 (m, 2H), 27 (m, 2H), 2.4 (m, 4H), 2.0 (m, 4H), 1.7 (m, 4H), 1.5 (m, 2H), 1.35 (, 2H).

EXAMPLE 89 f1-r2 - ((3S, 4S) -4-hydroxy-3-methyl-piperidin-1-yl) - etn-pyperidin-4-yl) -amide hydrochloride 4- 4- 6- methoxy-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid This compound is synthesized from 4- (6-methoxy-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid 120 (see Example 86), and amine 14, in a manner analogous to the method described in Example 1. Yield: 188 milligrams (89 percent). MS (ESI): 561 [M + H] +, 1 H-NMR (DMSO-de): d (ppm) 11.55 (s, 1H), 10.6 (br, 2H), 8.5 (d, 1H), 8.04 (s) , 1H), 7.55 (d, 1H), 7.1-7.3 (m, 3H), 7.0 (d, 1H), 6.9 (dd, 1H), 6.71 (d, 1H), 5.34 (s, 2H), 2.6- 4.2 (m, 14H), 1.75-2.2 (m, 8H), 0.93 (d, 3H).

Example 90 { 1-R (S) -2- (4-hydroxy-piperidinyl-1-yl) -propin-piperidin-4-yl) -a ida of 4- (6-methoxy-benzofuran-3-ylmethoxy) - 1H-Indole-2-carboxylic acid This compound is synthesized from 4- (6-methoxy-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid 120 (see Example 86), and amine 50, in a manner analogous to the method described in Example 1. Yield: 63 milligrams (38 percent). MS (ESI): 561 [M + H] +, 1 H-NMR (DMSO-de): d (ppm) 11.5 (s, 1H), 8.18 (d, 1H), 8.04 (s, 1H), 7.55 (d , 1H), 7.2 (m, 2H), 7.08 (dd, 1H), 7.0 (d, 1H), 6.9 (dd, 1H), 6.7 (d, 1H), 5.3 (s, 2H), 4.75 (br, 1H), 2.6-4.1 (m, 7H), 0.9-2.4 (m, 20H). Example 91 { 1-r (S) -2 - ((3S, 4S) -4-hydroxy-3-methyl-piperidin-1-yl) -propyl-piperidin-4-yl) -amide of 4- (6-) acid methoxy-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid This compound is synthesized in a manner analogous to Example 1, from 4- (6-methoxy-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid 120 (see Example 86), and amine 56. MS (ESI): 575.1 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 11.47 (s, 1 H), 8.03 (s, 1 H), 7.56 (d, 1 H), 7.21 (d , 1H), 7.19 (s, 1H), 7.08 (t, 1H), 7.01 (d, 1H), 6.92 (d, 1H), 6.69 (d, 1H), 5.3 (s, 2H), 3.8 (s, 3H), 3.65-3.8 (m, 1H), 3.31 (m, 2H), 2.59-2.92 (m, 6H), 2.01-2.4 (m, 4H), 1.89 (m, 2H), 1.65-1.78 (m, 3H), 1.19-1.59 (m, 4H), 0.89 (d, 3H), 0.86 (d, 3H). Example 92 4- (5-methoxy-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid 4- (5-methoxy-benzofuran-3-ylmethoxy) -1- (2-azepan-1-yl-ethyl) -piperidin-4-ylamide This compound is synthesized from 4- (5-methoxy-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid (121) (for the preparation, see below), and amine 5, from a analogous to the method described in Example 1. Yield: 77 milligrams (48 percent). MS (ESI): 545 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 11.48 (s, 1 H), 8.13 (m, 2 H), 7.48 (d, 1 H), 7.23 (s, 1 H), 7.2 (d, 1 H), 7.08 ( dd, 1H), 7.02 (d, 1H), 6.92 (dd, 1H), 6.71 (d, 1H), 5.32 (s, 2H), 3.74 (s, 3H), 3.68 (m, 1H), 2.83 (m , 2H), 2.5-2.6 (m, 8H), 2.35 (dd, 2H), 1.98 (dd, 2H), 1.70 (m, 2H), 1.45-16 (m, 8H). Synthesis of 4- (5-methoxy-benzofuran-3-ylmethoxy) -1 H-indole-2-carboxylic acid (121): This compound is synthesized from 4-methoxy-phenol, in a manner analogous to the method described for 106 (see Example 55). 460 milligrams (86 percent). MS (ESI): 336 [MH] ", 1 H-NMR (DMSO-de): d (ppm) 12.79 (br s, 1 H), 11.73 (s, 1 H), 8.1 (s, 1 H), 7.46 (d, 1H), 7.22 (d, 1H), 7.15 (dd, 1H), 7.06 (d, 1H), 7.02 (d, 1H), 6.91 (dd, 1H), 6.73 (d, 1H), 5.37 (s, 2H) ), 3.75 (s, 3H).

Example 93 { 4- (5-methoxy-benzofuran-3-ylmethoxy) -1H-indole-1-r2- (4-hydroxy-piperidin-1-yl) -etin-piperidin-4-yl) -amide -2-carboxylic This compound is synthesized from 4- (5-methoxy-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid 121 (see Example 92), and amine 21, in a manner analogous to the method described in Example 1. Yield: 105 milligrams (65 percent). MS (ESI): 547 [M + H] +, 1 H-NMR (DMSO-dβ): d (ppm) 11.5 (s, 1H), 8.15 (d, 1H), 8.11 (s, 1H), 7.49 (d , 1H), 7.24 (s, 1H), 7.20 (d, 1H), 7.09 (dd, 1H), 7.02 (d, 1H), 6.93 (dd, 1H), 6.71 (d, 1H), 5.33 (s, 2H), 4.51 (br, 1H), 3.75 (s, 3H), 3.7 (m, 1H), 3.41 (m, 1H), 2.85 (m, 2H), 2.7 (m, 2H), 2.39 (m, 4H) ), 2.0 (m, 4H), 1.71 (m, 4H), 1.52 (m, 2H), 1.35 (m, 2H). Example 94 f1-r 1S.9aR) -1- (octahydro-quinolizin-1-yl) metin-piperidin-4-yl > -amide of 4- (4-methoxy-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid This compound is synthesized in a manner analogous to Example 1, from 4- (4-methoxy-benzofuran-3-methoxy) -1H-indole-2-carboxylic acid (122) (for the preparation, see below) , and 1 - [(1S, 9aR) -1- (octahydro-quinolizin-1-yl) methyl] -piperidin-4-ylamino, 61. MS (ESI): 571.2 [M + H] +, 1 H-NMR ( CD3OD): d (ppm) 7.75 (s, 1H), 7.27 (s, 2H), 7.25 (t, 1H), 7.18 (t, 1H), 7.10 (d, 1H), 7.07 (d, 1H), 6.75 (d, 1H), 6.67 (d, 1H), 5.43 (s, 2H), 4.15 (br s, 1H), 3.4-3.8 (br m, 7H), 3.83 (s, 3H), 2.9-3.25 (m , 4H), 2.53 (br m, 1H), 1.5-2.3 (m, 14H). Synthesis of 4- (4-methoxy-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid (122) (1) 4-methoxy-benzofuran-3-carbaldehyde, 123. To a solution of 4-methoxy- 3-methyl-benzofuran (J. Chem. Res. Synopses (1 996), 132) (4 grams, 24.66 millimoles), in 40 milliliters of dioxane, selenium dioxide (3.39 grams, 29. 59 mmol), and the mixture is heated under reflux for 24 hours. Then it cools and filters. The solvent evaporates, and the crude red solid is used as such in the next step. Yield: 4.86 grams (> 100 percent). MS (ES I): 1 77.0 [M + H] +. (2) (4-methoxy-benzofuran-3-yl) -methanol, 124. The above aldehyde 1 23 (4.34 grams, 24.63 mmol) is dissolved in 10 milliliters of methanol, and cooled in an ice bath. Solid sodium borohydride (4.9 grams, 123.2 mmol) is added in portions, and the mixture is stirred for 2 hours. It is then poured onto ice cold HCl, extracted three times with DCM, dried, and evaporated. The crude material is purified by chromatography on silica gel using hexane and EtOAc (from 20 percent to 50 percent). Yield: 1.82 grams (41 percent). MS (ESI): 1 96. 1 [M + N H 4] +. (3) 4- (4-Methoxy-benzofuran-3-ylmethoxy) -indol-1,2-dicarboxylic acid, 1-tert-butyl ester ester, 125-indole ester is prepared from alcohol 1 24 and 102, under Mitsunobu conditions (as described in Example 50 for 1 05). MS (ES I): 41 0.2 [(M-CMe3) + H] +. (4) 4- (4-Methoxy-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid, 122. The title compound is prepared from the ester 125, by dissociation with KOH / EtOH / THF (as described in Example 50 for 105). MS (ESI): 338.2 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 11.76 (s, 1 H), 8.07 (s, 1 H), 7.29 (t, 1 H), 7.21 (s) , 1H), 7.19 (t, 1H), 7.1 (s, 1H), 7.04 (d, 1H), 6.83 (d, 1H), 6.69 (d, 1H), 5.39 (s, 2H), 3.84 (s, 3H). Example 95 { 1- [2- (4-hydroxy-piperidin-1-yl) -ethyl] -piperidin-4-yl} -amide of 4- (4-methoxy-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid This compound is synthesized in a manner analogous to Example 1, from 4- (4-methoxy-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid 122 (see Example 94), and amine 21. MS (ESI): 547.2 [M + H] +, 1 H-NMR (CD3OD): d (ppm) 7.63 (s, 1H), 7.13 (s, 1H), 7.12 (t, 1H), 7.04 (t, 1H ), 6.98 (d, 1H), 6.94 (d, 1H), 6.62 (d, 1H), 6.53 (d, 1H), 5.3 (s, 2H), 3.76 (m, 1H), 3.71 (s, 3H) , 3.54 (m, 1H), 2.85 (m, 2H), 2.73 (m, 2H), 2.42 (m, 4H), 2.07 (m, 4H), 1.81 (m, 2H), 1.74 (m, 2H), 1.53 (m, 2H), 1.45 (m, 2H).

Example 96 { 1- [2 - ((3S, 4S) -4-hydroxy-3-methy1-piperidin-1-yl) -ethyl] -piperidin-4-yl} -amide of 4- (4-methoxy-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid This compound is synthesized in a manner analogous to Example 1, from 4- (4-methoxy-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid 122 (see Example 94), and amine 14. MS (ESI): 561.3 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 11.47 (s, 1H), 8.09 (d, 1H), 8.01 (s, 1H), 7.27 (t , 1H), 7.23 (s, 1H), 7.2 (t, 1H), 7.09 (t, 1H), 7.01 (d, 1H), 6.81 (d, 1H), 6.65 (d, 1H), 5.34 (s, 2H), 4.47 (d, 1H), 3.79 (s, 3H), 3.7 (m, 1H), 2.64-2.93 (m, 4H), 235 (m, 4H), 1.82-2.05 (m, 3H), 1.63 -1.8 (m, 3H), 1.26-1.63 (m, 6H), 0.85 (d, 3H). Example 97 { 4- (4-methoxy-benzofuran-3-yl-ethoxy) 1- (f) -2- (4-hydroxy-piperidin-1-yl) -propyl-pyridin-4-yl) -amide) - 1H -i ndol-2 -carboxylic This compound is synthesized in a manner analogous to Example 1, from 4- (4-methoxy-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid, 122 (see Example 94), and the amine 50. MS (ESI): 561.2 [M + H] +, 1 H-NMR (CD 3 OD): d (ppm) 7.62 (s, 1 H), 7.13 (s, 1 H), 7.12 (t, 1 H), 7.04 (t , 1H), 6.97 (d, 1H), 6.94 (d, 1H), 6. 62 (d, 1H), 6.52 (d, 1H), 5.3 (s, 2H), 3.74 (m, 1H), 3.71 (s, 3H), 3.46 (br m, 1H), 2.93 (m, 1H), 2.7 (m, 1H), 2.65-2.75 (m, 3H), 2.4 (m, 1H), 2.28 (m, 2H), 2.12 (m, 2H), 197 (m, 1H), 1.75 (m, 4H) , 1.35-1.65 (m, 5H), 0.93 (d, 3H).

Example 98 { 1 - [(S) -2 - ((3S, 4S) -4-hydroxy-3-methyl-piperidin-1-yl) -propyl] -piperidin-4-yl} -amide of 4- (4-methoxy-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid This compound is synthesized in a manner analogous to Example 1, from 4- (4-methoxy-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid, 122 (see Example 94), and amine 56 MS (ESI): 575.1 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 11.45 (s, 1 H), 8.08 (m, 1 H), 8.0 (s, 1 H), 7.27 ( t, 1H), 7.22 (s, 1H), 7.2 (t, 1H), 7.09 (t, 1H), 7.01 (d, 1H), 6.81 (d, 1H), 6.65 (d, 1H), 5.34 (s) , 2H), 4.42 (m, 1H), 3.79 (s, 3H), 3.73 (m, 1H), 2.58-2.92 (m, 6H), 2.31 (m, 1H), 2.22 (m, 1H), 2.02-2.17 (m, 2H), 1.89 (m, 2H), 1.66-1.78 (m, 3H), 1.2-1.6 (m, 4H), 0.9 (d, 3H), 0.86 (d, 3H). Example 99 Di hydrochloride. { 1 - [(1S, 9aR) -1- (Octahydro-quinolizin-1-yl) methyl] -piperidin-4-yl} -amide of 4- (4,6-dimethoxy-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid This compound is synthesized from 4- (4,6-dimethoxy-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid, 126 (for the preparation, see below), and amine 61, from a analogous to the method described in Example 1. Yield: 146 milligrams (76.3 percent). MS (ESI): 601 [M + H] +, 1 H-NMR (DMSO-de): d (ppm) 11.5 (s, 1H), 10.1-10.7 (br, 2H), 8.1-8.5 (br, 1H) , 7.89 (s, 1H), 7.3 (br s, 1H), 7.1 (dd, 1H), 7.0 (d, 1H), 6.8 (s, 1H), 6.62 (d, 1H), 6.42 (s, 1H) , 5.28 (s, 2H), 4.0 (m, 1H), 3.8 (s, 3H), 3.75 (s, 3H), 2.8-3.8 (m, 14H), 1.3-2.1 (m, 12H). Synthesis of 4- (4,6-dimethoxy-benzofuran-3-ylmethoxy) -1H-n-dol-2-carboxylic acid (126): This compound is synthesized from 3,5-dimethoxyphenol, in a manner analogous to the method described for 106 (see Example 55). MS (ESI): 366 [MH] ", 1 H-NMR (DMSO-ds): d (ppm) 12.78 (br s, 1H), 11.7 (s, 1H), 7.89 (s, 1H), 7.14 (dd, 1H), 7.08 (d, 1H), 7.02 (d, 1H), 6.78 (d, 1H), 6.65 (d, 1H), 6.41 (d, 1H), 5.31 (s, 2H), 3.79 (s, 3H) ), 3.31 (s, 3H) .Example 100 { 1- [2- (4-hydroxy-piperidin-1-yl) -ethyl] -piperidin-4-yl} -amide of 4- (4J6) acid. -dimethoxy-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid This compound is synthesized in a manner analogous to Example 1, from 4- (4,6-dimethoxy-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid 126 (see Example 99), and the amine 21. MS (ESI): 577.2 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 11.46 (s, 1 H), 8.1 (d, 1 H), 7.87 (s, 1 H), 7.22 (s, 1H), 7.08 (t 1H), 7.0 (d, 1H), 6.81 (s, 1H), 6.63 (d, 1H), 6.42 (s, 1H), 5.28 (s, 2H), 4.49 (m , 1H), 3.8 (s, 3H), 3.76 (s, 3H), 3.73 (m, 1H), 3.16 (m, 1H), 2.85 (m, 2H), 2.69 (m, 2H), 2.36 (m, 4H), 1.99 (m, 4H), 1.7 (m, 4H), 1.5 (m, 2H), 1.34 (m, 2H).

Example 101 Dihydrochloride of. { 1- [2 - ((3S, 4S) -4-hydroxy-3-methyl-piperidin-1-yl) -ethyl] -piperidin-4-yl} -amide of 4- (4,6-dimethoxy-benzofuran-3-ylmethoxy) -1H-indoI-2-carboxylic acid This compound is synthesized from 4- (4,6-dimethoxy-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid, 126 (see Example 99), and amine 12, in a manner analogous to method described in Example 1. Yield: 85 milligrams (47 percent). MS (ESI): 591 [M + H] +, 1 H-NMR (DMSO-de): d (ppm) 11.5 (s, 1H), 10.6 (br, 2H), 8.5 (d, 1H), 7.87 (s) , 1H), 7.25 (s, 1H), 7.1 (dd, 1H), 7.02 (d, 1H), 6.8 (d, 1H), 6.64 (d, 1H), 6.4 (d, 1H), 5.26 (s, 2H), 5.1 (br, 1H), 4.05 (m, 1H), 3.8 (s, 3H), 3.77 (s, 3H), 2.6-3.8 (m, 12H), 1.75-2.2 (m, 8H), 0.93 (d, 3H). Example 102 { 1 - [(S) -2- (4-hydroxy-piperidin-1-yl) -propyl] -piperidin-4-yl} 4- (4,6-Dimethoxy-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid amide This compound is synthesized in a manner analogous to Example 1, from 4- (4-dimethoxy) benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid, 126 (see Example 99), and 50 amine. MS (ESI): 591.3 [M + H] +, 1 H-NMR (CD3OD): d (ppm) 7.63 (s, 1H), 7.23 (s, 1H), 7.14 (t, 1H), 7.04 (d, 1H), 6.67 (s, 1H), 6.62 (d, 1H), 6.37 (s, 1H) ), 5.35 (d, 2H), 3.85 (m, 1H), 3.82 (s, 3H), 3.78 (s, 3H), 3.57 (m, 1H), 3.05 (m, 1H), 2.89 (m, 1H) , 2.75-2.87 (m, 3H), 2.35-2.55 (m, 3H), 2.24 (m, 2H), 2.08 (m, 1H), 1.8-1.95 (m, 4H), 1.45-1.75 (m, 4H) , 1.04 (d, 3H). Example 103 { 1 - [(S) -2 - ((3S, 4S) -4-hydroxy-3-methyl-piperidin-1-yl) -propl] -piperidin-4-yl} -amide of 4- (4,6-dimethoxy-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid This compound is synthesized in a manner analogous to Example 1, from 4- (4,6-dimethoxy-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid, 126 (see Example 99), and the Amine 56. MS (ESI): 605.1 [M + H] +, 1 H-NMR (CD 3 OD): d (ppm) 7.64 (s, 1 H), 7.23 (s, 1 H), 7.15 (t, 1 H), 7.05 ( d, 1H), 6.69 (s, 1H), 6.64 (d, 1H), 6.38 (s, 1H), 4.85 (s, 2H), 3.88 (m, 1H), 3.84 (s, 3H), 3.8 (s) , 3H), 2.78-3.17 (m, 6H), 2.57 (m, 1H), 2.23-2.47 (m, 3H), 2.03-2.21 (m, 2H), 1.87-1.98 (m, 3H), 1.45-1.8 (m, 4H), 1.08 (d, 3H), 0.99 (d, 3H). Example 104 Dihydrochloride of. { 1 - [(1S, 9aR) -1- (octahydro-quinolizin-1-yl) methyI] -piperidin-4-yl} -amide of 4- (5,6-dimethyl-benzofuran-3-ylmethoxy) -1 H-indole-2-carboxylic acid This compound is synthesized from 4- (5,6-dimethyl-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid 127 (for the preparation, see below), and the amine 61, in a manner analogous to the method described in Example 1. Yield: 146 milligrams (76.3 percent). MS (ESI): 569 [M + H] +, 1 H-NMR (DMSO-de): d (ppm) 11.45 (s, 1H), 10.4-10.4 (br, 2H), 8.5 (br, 1H), 8.02 (s, 1H), 7.45 (s, 1H), 7.38 (s, 1H), 7.27 (br s, 1H), 7.1 (dd, 1H), 7.02 (d, 1H), 6.7 (d, 1H), 5.3 (s, 2H), 4.0 (m, 1H), 2.8-3.8 (m, 14H), 2.32 (s, 3H), 2.28 (s, 3H), 1.3-2.1 (m, 12H). Synthesis of 4- (5,6-dimethyl-benzofuran-3-ylmethoxy) -1 H-indole-2-carboxylic acid (127): This compound is synthesized from 3,4-dimethylphenol in a manner analogous to the method described for 106 (see Example 55). MS (ESI): 334 [MH] ", 1 H-NMR (DMSO-d 6): d (ppm) 12.9 (br s, 1 H), 11.55 (s, 1 H), 8.02 (s, 1 H), 7.47 (s, 1H), 7.38 (s, 1H), 7.15 (dd, 1H), 7.0 (m, 2H), 6.7 (d, 1H), 5.3 (s, 2H), 2.35 (s, 3H), 2.3 (s, 3H) ).Example 105 { 1- [2- (4-hydroxy-piperidin-1-yl) -ethyl] -piperidin-4-yl} -amide of 4- (5,6-dimethyl-benzofuran-3-ylmethoxy) -1H-1-dol-2-carboxylic acid This compound is synthesized from 4- (5,6-dimethyl-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid, 127 (see Example 104), and amine 21, in a manner analogous to method described in Example 1. Yield: 96 milligrams (51 percent). MS (ESI): 545.5 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 11.5 (s, 1H), 8.09 (d, 1H), 8.05 (s, 1H), 7.22 (s) , 1H), 7.18 (s, 1H), 7.10 (dd, 1H), 7.0 (d, 1H), 6.88 (s, 1H), 6.7 (d, 1H), 5.28 (s, 2H), 4.45 (d, 1H), 3.7 (m, 1H), 3.38 (m, 1H), 2.84 (m, 2H), 2.7 (m, 2H), 2.5 (s, 3H), 2.38 (s, 3H), 2.35 (m, 4H) ), 1.95 (m, 4H), 1.7 (m, 4H), 1.45 (m, 2H), 1.3 (m, 2H).

Example 106 Dichlorohydrate of. { 1- [2 - ((3S, 4S) -4-hydroxy-3-methyl-piperidin-1-yl) -ethyl] -piperidin-4-yl} -amide of 4- (5,6-dimethyl-benzofuran-3-N-methoxy) -1H-indole-2-carboxylic acid This compound is synthesized from 4- (5,6-dimethyl-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid, 127 (see Example 104), and amine 14, in an analogous manner to the method described in Example 1. Yield: 105 milligrams (56 percent). MS (ESI): 559 [M + H] +, 1 H-NMR (DMSO-de): d (ppm) 11.5 (s, 1H), 10.6 (br, 2H), 8.5 (d, 1H), 8.02 (s) , 1H), 7.45 (s, 1H), 7.4 (s, 1H), 7.25 (d, 1H), 7.1 (dd, 1H), 7.02 (d, 1H), 6.7 (d, 1H), 5.29 (s, 2H), 4.05 (m, 1H), 2.6-3.8 (m, 13H), 2.33 (s, 3H), 2.3 (s, 3H), 1.75-2.2 (m, 8H), 0.93 (d, 3H).

Example 107 Dichlorohydrate of. { 1 - [(S) -2- (4-hydroxy-piperidin-1-yl) -propyl] -4-yl} - 4- (5,6-dimethyl-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid amide This compound is synthesized from 4- (5,6-dimethyl-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid, 127 (see Example 104), and amine 50, in a manner analogous to method described in Example 1. Yield: 112 milligrams (56.8 percent). MS (ESI): 1559 [M + H] +, 1 H-NMR (DMSO-de): d (ppm) 11.5 (s, 1H), 10.3-10.6 (br, 2H), 8.5 (d, 1H), 8.12 (s, 1H), 7.45 (s, 1H), 7.38 (s, 1H), 7.25 (s, 1H), 7.1 (dd, 1H) 7.03 (d, 1H), 6.7 (d, 1H), 5.3 (s) , 2H), 5.05 (br, 1H), 2.9-4.1 (m, 13H), 2.35 (s, 3H), 2.28 (s, 3H), 1.7-2.2 (m, 8H), 1.35 / 1.3 (d, 3H) ) (isomers).

Example 108 Dichlorohydrate of. { 1 - [(S) -2 - ((3S, 4S) -4-hydroxy-3-methyl-piperidin-1-yl) -propyl] -piperidin-4-yl} -amide of 4- (5,6-dimethyl-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid This compound is synthesized from 4- (5,6-dimethyl-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid, 127 (see Example 104), and amine 56, in a manner analogous to method described in Example 1. Yield: 130 milligrams (68 percent). MS (ESI): 573 [M + H] +, 1 H-NMR (DMSO-ds): d (ppm) 11.5 (s, 1H), 10.4-10.6 (br, 2H), 8.52 (d, 1H), 8.02 (s, 1H), 7.45 (s, 1H), 7.4 (s, 1H), 7.25 (s, 1H), 7.12 (d, 1H), 7.03 (d, 1H), 6.7 (d, 1H), 5.3 ( s, 2H), 5.1 (br, 1H), 4.05 (m, 1H), 2. 8-3.9 (m, 13H), 2.32 (s, 3H), 2.29 (s, 3H), 1.9-21 (m, 6H), 1.32 (d, 3H), 0.93 (d, 3H). Example 109 { 1 - [(S) -2- (4-hydroxy-piperidin-1-yl) -propyl] -piperidin-4-yl} 4- (4-ethoxy-phenyl) -1H-indole-2-carboxylic acid amide This compound is synthesized in a manner analogous to Example 1, from 4- (4-ethoxy-phenyl) -1H-indole -2-carboxylic acid (preparation in a manner analogous to 128, see Example 141), and amine 50. MS (ESI): 505.2 [M + H] +, 1 H-NMR (DMSO-d6): d (ppm) 11.6 (s, 1H), 8.25 (d, 1H), 7.56 (d, 2H), 7.36 (d, 1H), 7.31 (s, 1H), 7.2 (t, 1H), 7.05 (d, 2H), 7.02 (d, 1H), 4.48 (m, 1H), 4.09 (q, 2H), 3.76 (m, 1H), 3.37 (m, 1H), 2.58-2.96 (m, 5H), 1.85-2.43 (m, 6H) ), 1.42-1.83 (m, 6H), 1.37 (t, 3H), 1.33 (m, 2H), 0.93 (d, 3H). Example 110 { 1 - [(S) -2- (4-hydroxy-piperidin-1-yl) -propyl] -piperidin-4-yl] -amide of 4- (4-methoxy-phenyl) -1H-indole-2- carboxylic This compound is synthesized in a manner analogous to Example 1, from 4- (4-ethoxy-phenyl) -1H-indole-2-carboxylic acid 128 (see Example 141), and amine 50. MS (ESI) ): 491 [M + H] +, 1 H-NMR (DMSO-de): d (ppm) 11.59 (s, 1H), 8.23 (d, 1H), 7.56 (d, 2H), 7.34 (d, 1H) , 7.31 (s, 1H), 7.2 (t, 1H), 7.06 (d, 2H), 7.01 (d, 1H), 4.44 (d, 1H), 3.81 (s, 3H), 3.75 (m, 1H), 2.96 (m, 1H), 2.6-2.95 (m, 5H), 2.04-2.4 (m, 5H), 1.92 (m, 1H), 1.2-1.85 (m, 8H), 0.91 (d, 3H).

The 4-aryloxy-indole-2-carboxamides are prepared in general by coupling the 4-hydroxy-indole-2-carboxamides with the corresponding 1-fluoro-2-nitro-benzenes (Reaction Esquema 15). Reaction Scheme 15: Example 111: 4-phenoxy-1H-n-dol-2-carboxylic acid 1- (2-azepan-1-yl-ethyl) -piperidin-4-yl] -amide This compound is synthesized in a manner analogous to Example 1, from 4-phenoxy-1H-indole-2-carboxylic acid 129 (for the preparation, see below), and amine 5. Yield: 105 milligrams (41 percent) of a beige solid. MS (ESI): 459.4 [MH] \ 1H-NMR (DMSO-d6): d (ppm) 11.7 (s, 1H), 8.22 (d, 1H), 7.34 (dd, 2H), 7.24 (d, 1H) , 7.04-7.15 (m, 3H), 6.95 (d, 2H), 6.55 (d, 1H), 3.72 (m, 1H), 2.85 (m, 2H), 2.52-2.6 (m, 6H), 2.38 (m , 2H), 2.0 (t, 4H), 1.72 (m, 2H), 1.48 (m, 8H).

Synthesis of 4-phenoxy-1H-indole-2-carboxylic acid (129): (1) Step A: 4- (2-Nitro-phenoxy) -1H-indole-2-carboxylic acid ethyl ester (130). 4-Hydroxy-1H-indole-2-carboxylic acid ethyl ester (0: 5 grams, 2436 mmol), and 2-fluoro-nitro-benzene are dissolved. (0.257 milliliters, 2.436 millimoles) in 10 milliliters of dimethylformamide. After the addition of potassium carbonate (0.67 grams, 4.87 mmol), the mixture is stirred overnight at room temperature. Then the reaction mixture is evaporated under reduced pressure, dissolved with ethyl acetate, and washed with water. The organic layers are dried over sodium sulphate and evaporated. The crude product is used in the next step without further purification. Yield: 0.72 grams (91 percent) of a beige solid. MS (ESI): 325.2 [M-H] ", 1 H-NMR (DMSO-de): d (ppm) 12.15 (s, 1H), 8.1 (d, 1H), 7.6 (dd, 1H), 7.32 (m, 2H), 7.25 (dd, 1H), 7.03 (m, 1H), 6.85 (m, 1H), 6.7 (d, 1H), 4.3 ( q, 2H), 1.3 (t, 3H). (2) Step B: 4- (2-Amino-phenoxy) -1H-indoI-2-carboxylic acid ethyl ester (131). The 130 (0.5 grams, 1532 millimoles) is dissolved in 100 milliliters of ethanol, and after the addition of Pd-C (100 milligrams), the mixture is hydrogenated at room temperature for 3 hours. The mixture is filtered over Celite, to remove the catalyst, and evaporated. Yield: 390 milligrams (86 percent) of a gray solid. MS (ESI): 297 [MH] ", 1 H-NMR (DMSO-de): d (ppm) 11.95 (s, 1H), 7.13 (m, 2H), 7.0 (s, 1H), 6.88 (m, 1H ), 6.8 (dd, 1H), 6.75 (dd, 1H), 6.5 (m, 1H), 6.38 (m, 1H), 4.9 (br, 2H), 4.3 (q, 2H), 1.3 (t, 3H) (3) Step C: 4-phenoxy-1H-indole-2-carboxylic acid ethyl ester (132): Tertbutyl nitrite (0.2 milliliters, 1,687 millimoles) is dissolved in 5 milliliters of dimethylformamide, and heated to 65 C. A solution of 131 (0.5 grams, 1687 millimoles) in 5 milliliters of dimethylformamide is added dropwise, and the mixture is stirred for an additional 10 minutes.The chestnut solution is cooled to room temperature, and diluted with diethyl ether, and washed with 2N HCl and brine The organic layers are dried over sodium sulfate and evaporated The crude product (370 milligrams of a brown oil) is further purified by evaporation chromatography (hexane / ethyl acetate, 9: 1) Yield: 163 milligrams (34 percent) of a yellow solid MS (ESI): 280.2 [MH ] ", 1H-NMR (DMSO-d6): d (ppm) 12.05 (s, 1H), 7.37 (d, 1H), 7.35 (d, 1H), 7.23 (m, 2H), 7.1 (dd, 1H) , 7.0 (d, 2H), 6.82 (s, 1H), 6.6 (d, 1H), 4.3 (q, 2H), 1.3 (t, 3H). (4) Step D: 4-phenoxy-1 H-indole-2-carboxylic acid (129). The 132 is dissolved (160 milligrams, 0.569 millimoles) in 5 milliliters of methanol, and treated with a solution of LiOH (27.2 milligrams, 1138 millimoles) in 3 milliliters of water. The mixture is stirred at room temperature overnight. Because the reaction is not complete, thin layer chromatography), additional LiOH (30 milligrams, 1.25 millimoles) is added, and stirring is continued for an additional 18 hours. After evaporation, the crude product is acidified at 0 ° C with 2M HCl, and extracted with ethyl acetate. The organic layers are dried over sodium sulphate and evaporated. Yield: 146 milligrams (100 percent) of a yellow solid; MS (ESI): 253 [M] +, 1 H-NMR (DMSO-d 6): d (ppm) 12.9 (s, 1 H), 11.9 (s, 1H), 7.38 (d, 1H), 7.34 (d, 1H), 7.2 (m, 2H), 7.12 (m, 1H), 7.0 (d, 2H), 6.75 (s, 1H), 6.58 (d, 1H). Example 112 [1- (2-azepan-1-yl-ethyl-ethyl) -piperidin-4-yl] -amide of 4-m-tolyloxy-1H-indole-2-carboxylic acid This compound is synthesized in a manner analogous to Example 1, from 4-m-tolyloxy-1H-indole-2-carboxylic acid 133 (for the preparation, see below), and amine 5. Yield: 12 milligrams (11.3 percent) of a white solid; MS (ESI): 473.3 [MH] ", 1 H-NMR (DMSO-d 6): d (ppm) 11.65 (s, 1H), 8.2 (d, 1H), 7.2 (m, 2H), 7.1 (m, 2H ), 6.88 (d, 1H), 6.78 (m, 1H), 6.7 (m, 1H), 6.54 (d, 1H), 3.72 (m, 1H), 2.85 (m, 2H), 2.48-2.58 (m, 8H), 2.35 (m, 2H), 2.25 (s, 3H), 1.98 (m, 2H), 1.75 (m, 2H), 1.48-1.55 (m, 8H). Synthesis of 4-m-tolyloxy-1H acid -indole-2-carboxylic acid (133): (1) Step A: 4- (5-Methyl-2-nitro-phenoxy) -1H-indole-2-carboxylic acid ethyl ester (134). -hydroxy-1H-indole-2-carboxylic acid (1 gram, 4.87 mmol) and 2-fluoro-4-methyl-1-nitro-benzene (756 milligrams, 4.87 mmol) in 20 milliliters of dimethylformamide. After the addition of potassium carbonate (1.3 grams, 9.74 millimoles), the mixture is stirred overnight at room temperature. Then the reaction mixture is evaporated under reduced pressure, dissolved with ethyl acetate, and washed with water. The organic layers are dried over sodium sulphate and evaporated. The crude product is used in the next step without further purification. Yield: 1.59 grams (96 percent) of a beige solid. MS (ESI): 341 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 12.15 (s, 1H), 7.98 (d, 1H), 7.3 (d, 1H), 7.25 (dd, 1H), 7.15 (d, 1H), 6.88 (d, 1H), 6.63 (d, 1H), 43 (q, 2H), 2.28 ( s, 3H), 13 (t, 3H). (2) Step B: 4- (2-Amino-5-methyl-phenoxy) -1H-indole-2-carboxylic acid ethyl ester (135). 134 (1.3 grams, 3.82 mmol) is dissolved in 250 milliliters of ethyl acetate, and, after the addition of Pd-C (200 milligrams), the mixture is hydrogenated at room temperature for 2 hours. The mixture is filtered over Celite, to remove the catalyst, and evaporated. Yield: 1.12 grams (95 percent) of a gray solid. MS (ESI): 311 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 11.95 (br, 1H), 7.13 (m, 2H), 7.03 (s, 1H), 6.72 (s) , 2H), 6.58 (s, 1H), 6.37 (m, 1H), 4.68 (br, 2H), 4.3 (q, 2H), 2.08 (s, 3H), 1.3 (t, 3H). (3) Step C: 4-M-Tolyloxy-1H-indole-2-carboxylic acid ethyl ester (136) Tertbutyl nitrite (0.428 milliliters, 3,609 millimoles) is dissolved in 5 milliliters of dimethylformamide, and heated to 65 ° C . A solution of 135 (1.1 grams, 3,609 millimoles) in 5 milliliters of dimethylformamide is added dropwise, and the mixture is stirred for an additional 10 minutes. The brown solution is cooled to room temperature, diluted with diethyl ether, and washed with 2N HCl and brine. The organic layers are dried over sodium sulfate, and evaporated. The crude product (930 grams of a brown oil) is further purified by evaporation chromatography (hexane / ethyl acetate, 7: 3). Yield: 520 milligrams (49 percent) of a yellow solid; MS (ESI): 294.2 [MH] ", 1 H-NMR (DMSO-d 6): d (ppm) 12.0 (s, 1H), 7.18 - 7.24 (m, 3H), 6.92 (m, 1H), 6.82 (m , 2H), 6.78 (dd, 1H), 6.58 (dd, 1H), 4.28 (q, 2H), 2.27 (s, 3H), 1.3 (t, 3H). (4) Step D: 4-m- Acid tolyloxy-1 H-indole-2-carboxylic acid (133). Dissolve in 136 (520 milligrams, 1761 millimoles) in 10 milliliters of methanol, and treat with a solution of LiOH (84.3 milligrams, 3.52 millimoles) in 5 milliliters of methanol. The mixture is stirred at room temperature for 18 hours.After evaporation, the crude product is acidified at 0 ° C with 2M HCl, and extracted with ethyl acetate.The organic layers are dried over sodium sulfate and evaporate Yield: 460 milligrams (98 percent) of a beige solid, MS (ESI): 266.1 [MH] ", 1 H-NMR (DMSO-d6: d (ppm) 12.9 (s, 1H), 11.9 (s, 1H), 7.15-2.25 (m, 3H), 6.9 (m, 1H), 6.84 (m, 1H), 6.78 (m, 2H), 6.57 (m, 1H), 2.27 (s, 3H).

Example 113 { 1- [2- (3- (RS) -hydroxy-piperidin-1-yl) -ethyl] -piperidin-4-yl} 4-m-tolyloxy-1H-indole-2-carboxylic acid amide.

This compound is synthesized in a manner analogous to Example 1 from 4-m-tolyloxy-1H-indole-2-carboxylic acid 133 (see Example 112) and racemic amine 12. Yield: 34 milligrams (21 percent) ) of a yellow solid; MS (ESI): 477.3 [M + H] +, 1 H-NMR (80 ° C, DMSO-d 6): d (ppm) 11.2 (s, 1 H), 7.77 (d, 1 H), 7.24 (dd, 1 H) , 7.2 (dd, 1H), 7.1 (ss, 1H), 7.04 (s, 1H), 6.88 (d, 1H), 6.8 (m, 1H), 6.75 (m, 1H), 6.54 (d, 1H), 3.75 (m, 1H), 3.5 (m, 1H), 2.7-2.9 (m, 4H), 2.6 (m, 1H), 2.44 (m, 4H), 2.3 (s, 3H), 2.13 (m, 2H) , 2.05 (m, 1H), 1.95 (m, 1H), 1.7-1.85 (m, 3H), 1.55-1.65 (m, 3H), 1.4 (m, 1H), 1.15 (m, 1H).

Example 114 { 1- [2- (4-hydroxy-piperidin-1-yl) -ethyl] -piperidin-4-yl} 4-m-tolyloxy-1H-indoI-2-carboxylic acid amide.

This compound is synthesized in a manner analogous to Example 1, from 4-m-tolyloxy-1H-indole-2-carboxylic acid 133 (see Example 112), and amine 21. Yield: 45 milligrams (28 ppm) cent) of a white solid; MS (ESI): 477 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 11.7 (s, 1 H), 8.2 (d, 1 H), 7.2 (m, 2 H), 7.1 (m , 2H), 6.88 (d, 1H), 6.78 (m, 1H), 6.7 (m, 1H), 6.54 (d, 1H), 4.47 (m, 1H), 3.72 (m, 1H), 3.38 (m, 1H), 2.85 (m, 2H), 2.7 (m, 2H), 2.38 (m, 4H), 2.28 (s, 3H), 1.98 (m, 4H), 1.63 - 1.75 (m, 4H), 1.5 (m , 2H), 1.35 (m, 2H). Example 4-p-Toy-Ioxo-1H-indole-2-carboxylic acid [1- (2-azepan-1-yl-ethyl-ethyl) -piperidin-4-yl] -amide.

This compound is synthesized in a manner analogous to Example 1, from 4-p-tolyloxy-1H-indole-2-carboxylic acid 137 (for the preparation, see below), and the amine 5. Yield: 12 milligrams ( 11.3 percent) of a white solid; MS (ESI): 473.3 [M-H] ", 1 H-NMR (DMSO-d 6): d (ppm) 11.65 (s, 1H), 8. 18 (d, 1H), 7.05 - 7.2 (m, 5H), 6.85 (d, 2H), 6.47 (m, 1H), 3.7 (m, 1H), 2.85 (m, 2H), 2.47 - 2.58 (m, 6H), 2.35 (m, 2H), 2.25 (s, 3H), 1.98 (m, 2H), 1.75 (m, 2H), 1.48 - 1.55 (m, 10H). Synthesis of 4-p-tolyloxy-1H-indole-2-carboxylic acid (137): (1) Step A: 4- (3,5-difiuoro-2-nitro-phenoxy) -1H-indole ethyl ester -2-carboxylic (138). 4-Hydroxy-1H-indole-2-carboxylic acid ethyl ester (1 gram, 4.87 mmol) and 1-fluoro-4-methyl-2-nitro-benzene (0.6 milliliter, 4.87 mmol) are dissolved in 10 milliliters of dimethyl formamide. After the addition of potassium carbonate (1.3 grams, 9.74 millimoles), the mixture is stirred overnight at room temperature. Then the reaction mixture is evaporated under reduced pressure, dissolved with ethyl acetate, and washed with water. The organic layers are dried over sodium sulfate, and evaporated. The crude product (1.51 grams of a brown oil) is further purified by evaporation chromatography (hexane / ethyl acetate, 9: 1). Yield: 570 milligrams (34 percent) of a white solid. MS (ESI): 341 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 12.1 (s, 1H), 7.88 (d, 1H), 7.45 (dd, 1H), 7.27 (d , 1H), 7.22 (dd, 1H), 6.98 (d, 1H), 6.87 (s, 1H), 6.6 (d, 1H), 4.3 (q, 2H), 2.35 (s, 3H), 1.3 (t, 3H). (2) Step B: 4- (2-Amino-4-methyl-phenoxy) -1H-indole-2-carboxylic acid ethyl ester (139). 138 (570 milligrams, 1675 millimoles) is dissolved in 150 milliliters of ethanol, and, after the addition of Pd-C (200 milligrams), the mixture is hydrogenated at room temperature during 2 hours. The mixture is filtered over Celite to remove the catalyst, and evaporated. Yield: 3.08 grams (100 percent) of a chestnut oil. MS (ESI): 311 [M + H] +. (3) Step C: 4-p-Tolyloxy-1H-indole-2-carboxylic acid ethyl ester (140). Tertbutyl nitrite (0.176 milliliters, 1.48 millimoles) is dissolved in 5 milliliters of dimethylformamide, and heated to 65 ° C. A solution of 139 (460 milligrams, 1.48 millimoles) in 5 milliliters of dimethyl formamide is added dropwise, and the mixture is stirred for an additional 10 minutes. The brown solution is cooled to room temperature, diluted with diethyl ether, and washed with 2N HCl and brine. The organic layers are dried over sodium sulphate and evaporated. The crude product (420 milligrams of a brown oil) is further purified by evaporation chromatography (hexane / ethyl acetate, 9: 1). Yield: 70 milligrams (16 percent) of a yellow solid; MS (ESI) 294.2 [MH] ", 1 H-NMR (DMSO-ds): d (ppm) 12.0 (s, 1H), 7.15-7.24 (m, 4H), 7.4 (m, 2H), 6.85 (d, 1H), 6.52 (dd, 1H), 4.3 (q, 2H), 2.28 (s, 3H), 1.3 (t, 3H). (4) Step D: 4-p-toyloxy-1H-indole-2- acid carboxylic (137) Dissolve the 140 (70 milligrams, 0.237 millimoles) in 5 milliliters of methanol and treat with a solution of LiOH (11.4 m iligrams, 0.474 millimoles) in 3 milliliters of water The mixture is stirred at room temperature for 18 hours.After evaporation, the crude product is acidified at 0 ° C with 2M HCl, and extracted with ethyl acetate.The organic layers are dried over sodium sulfate and evaporated Yield: 60 milligrams (100%) one hundred) of a beige solid, MS (ESI) 266.2 [MH] -, 1 H-NMR (DMSO-d 6): d (ppm) 12.9 (s, 1 H), 11.8 (s, 1 H), 7.13-7.2 (m, 4H), 6.9 (m, 2H), 6.77 (d, 1H), 6.52 (dd, 1H), 2. 29 (s, 3H). Example 116 { 1- [2- (3- (RS) -hydroxy-piperiin-1-yl) -ethyl-piperidin-4-yl} 4-p-tolyloxy-1H-indole-2-carboxylic acid amide This compound is synthesized in a manner analogous to Example 1, from 4-p-tolyloxy-1H-indole-2-carboxylic acid 137 (see Example 115) and racemic amine 12. Yield: 87 milligrams (49 percent) of a beige solid; MS (ESI) 475.3 [MH] -, 1 H-NMR (DMSO-d 6): d (ppm) 11.65 (s, 1 H), 8.2 (d, 1 H), 7.08-7.2 (m, 5 H), 6.87 (s, 2H), 6.47 (d, 1H), 4.53 (d, 1H), 3.72 (m, 1H), 3.4 (m, 1H), 2.85 (m, 3H), 2.65 (m, 1H), 2.37 (m, 4H) ), 2.28 (s, 3H), 1.98 (t, 2H), 1.7-1.85 (m, 5H), 1.55 (m, 3H), 1.35 (m, 1H), 1.05 (m, 1H). Example 117:. { 1- [2- (4-hydroxy-piperidin-1-yl) -ethyl] -piperidin-4-yl} 4-p-tolyloxy-1H-indole-2-carboxylic acid amide This compound is synthesized in a manner analogous to Example 1 from 4-p-tolyloxy-1H-indole-2-carboxylic acid 137 (see, Example 115) and amine 21. Yield: 80 milligrams (45 percent) of a solid beige; MS (ESI) 475.3 [MH] -, 1 H-NMR (DMSO-d 6): d (ppm) 11.65 (s, 1H), 8.2 (d, 1H), 7.07-7.2 (m, 5H), 6.85 (d, 2H), 6.47 (d, 1H), 4.48 (br, 1H), 3.72 (m, 1H), 3.4 (m, 1H), 2.85 (m, 2H), 2.7 (m, 2H), 2.35 (m, 4H) ), 2.27 (s, 3H), 195-2.05 (m, 4H), 1.65-1.75 (m, 4H), 1.5 (m, 2H), 1.35 (m, 2H). Example: 4- (3-Fluoro-phenoxy) -1H-indole-2-carboxylic acid 1- (2-azepan-1-yl-ethyl) -piperidin-4-yl] -amide. This compound is synthesized in a analogous to Example 1, starting with 4- (3-fluoro-phenoxy) -1H-indole-2-carboxylic acid 141 (for the preparation, see below) and the amine 5. Yield: 50 milligrams (28.3 percent) of a white solid; MS (ESI) 479.3 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 11.75 (s, 1H), 8. 2 (d, 1H), 7.35 (dd, 1H), 7.28 (d, 1H), 7.18 (dd, 1H), 7.05 (s, 1H), 6.9 (dd, 1H), 6.73-6.8 (m, 2H) , 6.68 (d, 1H), 3.72 (m, 1H), 2.85 (m, 2H), 2.5-2.58 (m, 6H), 2.35 (m, 2H), 1.98 (m, 2H), 1.72 (m, 2H) ), 1.48-1.55 (m, 10H). Synthesis of 4-p-tolyloxy-1H-indole-2-carboxylic acid (141): (1) Step A: 4- (3,5-Difluoro-2-nitro-phenoxy) -1H-indole-2-carboxylic acid ethyl ester (142) The 4-hydroxyethyl-ethyl ester is dissolved 1H-indole-2-carboxylic acid (1 gram, 4.87 mmol) and 2,4-difluoro-1-nitro-benzene (0.534 milliliters, 4.87 mmol) in 20 milliliters of dimethylformamide. After the addition of potassium carbonate (1.3 grams, 9.74 millimoles), the mixture is stirred overnight at room temperature. Then the reaction mixture is evaporated under reduced pressure, is added with ethyl acetate and washed with water. The organic layers are dried over sodium sulphate and evaporated. The crude product is used in the next step without further processing. Yield: 1.63 g ram (97 percent) of a gray resin; MS (ES I): 343.1 [MH] ". (2) Step B: 4,4- (2-amino-5-fIuoro-phenoxy) -1H-indole-2-carboxylic acid ethyl ester (143) ) The 142 (1.6 grams, 4734 millimoles) is dissolved in 250 milliliters of ethyl acetate and, after the addition of Pd-C (200 milligrams), the mixture is hydrogenated at room temperature during 2 hours. The mixture is filtered over Celite to remove the catalyst and evaporated. Yield: 1.41 grams (95 percent) of a gray foam. MS (ESI): 315.2 [M + H] +. (3) Step C: 4- (3-fIuoro-phenoxy) -1H-indoI-2-carboxylic acid ethyl ester (144) Tert-butyl nitrite (0.46 milliliters, 4.45 millimoles) is dissolved in 5 milliliters of dimethylformamide and heated to 65 ° C. A solution of 143 (1.4 grams, 4.45 mmol) in 5 milliliters of dimethylformamide is added dropwise and the mixture is stirred for an additional 10 minutes. The brown solution is cooled to room temperature, diluted with diethyl ether and washed with 2N HCl and brine. The organic layers are dried over sodium sulphate and evaporated. The crude product (1.0 grams of a brown oil) is further purified by evaporation chromatography (hexane / ethyl acetate 7: 3). Yield: 440 milligrams (33 percent) of a yellow solid; MS (ESI) 298.2 [MH] ", 1 H-NMR (DMSO-d 6): d (ppm) 12.1 (s, 1H), 7.35 (dd, 1H), 7.3 (d, 1H), 7.25 (dd, 1H) , 6.92 (dd, 1H), 6.77-6.87 (m, 3H), 6.7 (d, 1H), 4.3 (q, 2H), 1.3 (t, 3H). (4) Step D: Acid 4- (3- fluoro-phenoxy) -1 H-indole-2-carboxylic acid (141) The 144 (440 milligrams, 1.47 mmol) is dissolved in 10 milliliters of methanol and treated with a solution of LiOH (70 milligrams, 1.47 millimoles) in 5 milliliters The mixture is stirred at room temperature for 18 hours.After evaporation, the crude product is acidified at 0 ° C with 2M HCl and extracted with ethyl acetate.The organic layers are dried over sodium sulfate and evaporate Yield: 420 milligrams (100 percent) of a yellow solid, MS (ESI): 270.1 [MH] ", 1 H-NMR (DMSO-d6): d (ppm) 12.95 (s, 1H), 11.9 (s) , 1H), 7.35 (dd, 1H), 7.28 (dd, 1H), 6.9 (dd, 1H), 6.77-6.85 (m, 2H), 5.75 (s, 1H), 6.7 (d, 1H). Example 119 { 1- [2- (4-hydroxy-piperidin-1-yl) -ethyl] -piperidin-4-yl} -amide of 4- (3-f luoro-f in oxy) -1H-indole-2-carboxylic acid This compound is synthesized in a manner analogous to Example 1, from 4- (3-fluoro-phenoxy) -1H-indole-2-carboxylic acid 141 (see example 118) and amine 21. Yield: 35 milligrams (20 ppm) cent) of a white solid; MS (ESI): 479 [M-H] ", 1 H-NMR (DMSO-d 6): d (ppm) 11.75 (s, 1 H), 8.21 (d, 1H), 7.35 (dd, 1H), 7.29 (d, 1H), 7.18 (dd, 1H), 7.05 (s, 1H), 6.9 (dd, 1H), 6.73-6.8 (m, 2H), 6.68 (d, 1H), 4.49 (d, 1H), 3.72 (m, 1H), 3. 4 (m, 1H), 2.85 (m, 2H), 2.7 (m, 2H), 2.37 (m, 4H), 1.95 (m, 4H), 1. 63-1.77 (m, 4H), 1.5 (m, 2H), 1.35 (m, 2H). Example: 4- (Fluoro-phenoxy) -1 H-indole-2-carboxylic acid 1- (2-azepan-1-yl-ethyl) -piperidin-4-yl] -amide This compound is synthesized analogously to Example 1, from 4- (4-fluoro-phenoxy) -1H-indole-2-carboxylic acid 145 (for the preparation, see below) and the amine 5. Yield: 86 milligrams (49 percent) of a white solid; MS (ESI): 477.3 [MH] ", 1 H-NMR (DMSO-d 6): d (ppm) 1.75 (s, 1 H), 8.2 (d, 1 H), 7.14-7.24 (m, 5 H), 7.0 (m , 2H), 6.5 (d, 1H), 3.72 (m, 1H), 2.85 (m, 2H), 2.5-2.6 (m, 6H), 2.36 (, 2H), 1.98 (m, 2H), 1.72 (m , 2H), 1.48-1.57 (m, 10H) Synthesis of 4-p-tolyloxy-1H-indole-2-carboxylic acid (145): (1) Step A: Ethyl 4- (4-fluoro) ester -2-nitro-phenoxy?) - 1H-indole-2-carboxylic acid (146) 4-Hydroxy-1H-indole-2-carboxylic acid ethyl ester (0.92 grams, 4.483 mmol) and 1, 4- are dissolved difluoro-2-nitrobenzene (0.486 milliliters, 4.483 millimoles) in 10 milliliters of dimethylformamide After the addition of potassium carbonate (1.2 grams, 8.96 millimoles), the mixture is stirred overnight at room temperature. The reaction mixture is evaporated under reduced pressure, dissolved with ethyl acetate and washed with water, the organic layers are dried over sodium sulfate and evaporated, the crude product is used in the next step without further purification. Yield: 1.45 grams (94 percent) of a gray resin; MS (ESI): 343.1 [MH] "] -, 1 H-NMR (DMSO-d 6): d (ppm) 12.15 (s, 1H), 8.08 (m, 1H), 7.55 (m, 1H), 7.3 (d , 1H), 7.24 (dd, 1H), 7.15 (dd, 1H), 6.9 (s, 1H), 6.62 (d, 1H), 4.3 (q, 2H) 1.32 (t, 3H). (2) Step B : 4- (2-Amino-4-fluoro-phenoxy) -1H-indole-2-carboxylic acid ethyl ester (147) The 146 (1.5 grams, 4.21 mmol) is dissolved in 200 milliliters of ethyl acetate and, After the addition of Pd-C (200 milligrams), the mixture is hydrogenated at room temperature for 2 hours.The mixture is filtered over Celite to remove the catalyst and evaporated Yield: 1.31 grams (99 percent) of a solid beige; MS (ESI): 313.2 [MH] -, 1 H-NMR (DMSO-d 6): d (ppm) 11.95 (s, 1 H), 7.12 (m, 2 H), 7.05 (m, 1 H), 6.75 (dd) , 1H), 6.58 (dd, 1H), 6.34 (m, 1H), 6.28 (dt, 1 H), 5.25 (br, 2H), 4.3 (q, 2H), 1.32 (t, 3H). 3) Step C: 4- (4-Fluoro-phenoxy) -H-indole-2-carboxylic acid ethyl ester (148) Tert-butyl nitrite (0.46 milliliter, 4.45 mmol) is dissolved in 5 milliliters of dimethylformamide and heated to 65 ° C. A solution of 147 (1.4 grams) is added dropwise, 4.45 millimoles) in 5 milliliters of dimethylformamide and the mixture is stirred an additional 10 minutes. The brown solution is cooled to room temperature, diluted with diethyl ether and washed with HCl 2N and brine. The organic layers are dried over sodium sulphate and evaporated. The crude product (1.0 grams of a brown oil) is further purified by evaporation chromatography (hexane / ethyl acetate 7: 3). Yield: 440 milligrams (33 percent) of a yellow solid; MS (ESI): 298.2 [M-H] ", 1 H-RM N (DMSO-d 6): d (ppm) 12.05 (s, 1 H), 7. 2 (m, 4H), 7.05 (m, 2H), 6.85 (m, 1 H), 6.54 (d, 1 H), 4.3 (q, 2H), 1 .3 (t, 3H). (4) Step D: 4- (4-Fluoro-phenoxy) -1H-indole-2-carboxylic acid (145) The 148 (510 milligrams, 1.7 millimoles) is dissolved in 10 milliliters of methanol and treated with a solution of LiOH (82 milligrams, 3.4 millimoles) in 5 milliliters of water. The mixture is stirred at room temperature for 18 hours. After evaporation, the crude product is acidified at 0 ° C with 2M HCl and extracted with ethyl acetate. The organic layers are dried over sodium sulphate and evaporated. Yield: 460 milligrams (100 percent) of a yellow solid; MS (ESI): 270.1 [MH] ", 1 H-NMR (DMSO-d 6): d (ppm) 13.0 (s, 1H), 11.9 (s, H), 7.15-7.22 (m, 4H), 7.05 (m , 2H), 6.78 (m, 1H), 6.55 (d, 1H), Example 121 { 1- [2 - (- 4-hydroxy-piperidin-1-yl) -ethyl] -piperidin-4-yl} - 4- (4-Fluoro-phenoxy) -1H-indole-2-carboxylic acid amide This compound is synthesized analogously to Example 1, from 4- (4-fluoro-phenoxy) -1H-indole-2-carboxylic acid 145 (see example 120) and amine 21. Yield: 66 milligrams (37 ppm) cent) of a white solid; MS (ESI): 479 [MH] ", 1 H-NMR (DMSO-d 6): d (ppm) 11.7 (s, 1 H), 8.2 (d, 1 H), 7.1-7.24 (m, 5 H), 7.0 (m , 2H), 6.5 (d, 1H), 4.46 (br, 1H), 3.72 (, 1H), 3.42 (m, 1H), 2.85 (m, 2H), 2.7 (m, 2H), 2.38 (m, 4H) ), 2.0 (m, 4H), 1.64-1.77 (m, 4H), 1.53 (m, 2H), 1.35 (m, 2H).

Example 1-4- (3,4-Dichloro-phenoxy) -1H-indole-2-carboxylic acid 1- (2-azepan-1-yl-ethyl) -pipericin-4-yl] -amide This compound is synthesizes analogously to Example 1, from 4- (3,4-difluoro-phenoxy) -1H-indole-2-carboxylic acid 149 (for the preparation, see below) and amine 5. Yield: 62 milligrams (36 percent) of a white solid; MS (ESI): 495.3 [MH] ", 1 H-NMR (DMSO-d 6): d (ppm) 11.75 (s, 1 H), 8.23 (d, 1 H), 7.44 (m, 1 H), 7.26 (d, 1 H) ), 7.14 (m, 1H), 7.0 (m, 1H), 6.80 (m, 1H), 6.56 (d, 2H), 3.72 (m, 1H), 2.87 (m, 2H), 2.5-2.6 (m, 6H), 2.38 (m, 2H), 2.0 (m, 2H), 1.75 (m, 2H), 1.47-1.55 (m, 10H). Synthesis of 4- (3,5-difluoro-phenoxy) -1H- Ndol-2-carboxylic acid (149): (1) Step A: 4- (3,5-difluoro-2-nitro-phenoxy) -1H-indole-2-carboxylic acid ethyl ester (150) Dissolve the ethyl ester of 4-hydroxy-1 H-indole-2-carboxylic acid (1 gram, 4.87 mmol) and 1,2,4-trifluoro-5-nitro-benzene (0.559 milliliters, 4.87 mmol in 10 milliliters of dimethylformamide) After adding potassium carbonate (1.3 grams, 9.74 millimoles) the mixture is stirred overnight at room temperature, then the reaction mixture is evaporated under reduced pressure, dissolved with ethyl acetate and washed with water. The organic layers are dried over sodium sulphate and evaporated, yield: 1.79 grams. (1 00 percent) of a yellow foam; M S (ES I): 361. 1 [MH]. "(2) Step B: 4- (2-Amino-4,5-difluoro-phenoxy) - 1 H-indole-2-carboxylic acid ethyl ester (151) 150 (1. 8 grams, 4.87 mmol) is dissolved in 1 50 milliliters of ethyl acetate and, after the addition of Pd-C (500 milligrams), the mixture is hydrogenated at room temperature during 2 hours. The mixture is filtered over Celite to remove the catalyst and evaporated. Yield: 1.61 grams (99 percent) of a brown foam; MS (ESI): 333.2 [M + H] +. (3) Step C: 4- (3,4-difluoro-phenoxy) -1H-indole-2-carboxylic acid ethyl ester (152) Tert-buryl nitrite (0.575 milliliters, 4.85 millimoles) is dissolved in 5 milliliters of dimethylformamide and heated to 65 ° C. A solution of 151 (1.6 grams, 4.85 mmol) in 5 milliliters of dimethylformamide is added dropwise and the mixture is stirred for an additional 10 minutes. The brown solution is cooled to room temperature, diluted with diethyl ether and washed with 2N HCl and brine. The organic layers are dried over sodium sulphate and evaporated. The crude product (1.78 grams of a brown oil) is further purified by evaporation chromatography (hexane / ethyl acetate 9: 1). Yield: 380 milligrams (25 percent) of a slightly yellow solid; MS (ESI): 316.2 [M-H] ", 1 H-NMR (DMSO-d 6): d (ppm) 12.1 (s, 1H), 7.45 (m, 1H), 7.27 (d, 1H), 7.2 (dd, 1H), 7.05 (m, 1H), 6.98 (m, 1H), 6.95 (m, 1H), 6.55 (d, 1H), 4.3 (q, 2H), 1.34 (t, 3H). (4) Step D: 4- (3,4-difluoro-phenoxy) -1 H-indole-2-carboxylic acid (149) The 152 (380 milligrams, 1.2 mmol) is dissolved in 10 milliliters of methanol and treated with a solution of LiOH (57 milligrams, 2.4 millimoles) in 5 milliliters of water. The mixture is stirred at room temperature for 18 hours. After evaporation, the crude product is acidified at 0 ° C with 2M HCl and extracted with ethyl acetate. The organic layers are dried over sodium sulphate and evaporated. Yield: 310 milligrams (90 percent) of a yellow solid; MS (ESI): 288.1 [MH] ", 1 H-NMR (DMSO-d 6): d (ppm) 13.0 (s, 1H), 12.0 (s, 1H), 7.45 (m, 1H), 7.25 (d, 1H ), 7.18 (dd, 1H), 7.05 (m, 1H), 6. 98 (m, 1H), 6.87 (s, 1H), 6.55 (d, 1H). Example of 4- (3,5-difluoro-phenoxy) -1H-indole-2-carboxylic acid 1- (2-azepan-1-yl-ethyl) -piperidin-4-yl] -amine This compound is synthesized analogously to Example 1, from 4- (3,5-difluoro-phenoxy) -1H-indole-2-carboxylic acid 153 (for the preparation, see below) and the amine 5. Performance : 180 milligrams (33.2 percent) of a yellow solid; MS (ESI): 495.3 [MH] ", 1 H-NMR (DMSO-d 6): d (ppm) 11.8 (s, 1H), 8.21 (d, 1H), 7.33 (d, 1H), 7.2 (dd, 1H ), 7.04 (d, 1H), 6.94 (m, 1H), 6. 75 (d, 1H), 6.62 (m, 2H), 3.7 (m, 1H), 2.85 (m, 2H), 2.47-2.58 (m, 6H), 2.36 (m, 2H), 1.98 (m, 2H) , 1.75 (m, 2H), 1.47-1.55 (m, 10H). Synthesis of 4- (3,5-difluoro-phenoxy) -1H-indole-2-carboxylic acid (153): (1) Step A: Ethyl ester of 4- (3,5-difluoro-phenoxy) -1H acid -indole-2-carboxylic acid (154) The ethyl ester of 4-hydroxy-1H-indole-2-carboxylic acid (1 gram, 4.87 mmol) and 1,3,5-trifluoro-2-nitro-benzene are dissolved ( 0.57 milliliters, 4.87 millimoles) in 10 milliliters of dimethylformamide. After the addition of potassium carbonate (1.3 grams, 9.74 mmol), the mixture is stirred overnight at room temperature. Then the reaction mixture is evaporated under reduced pressure, dissolved with ethyl acetate and washed with water. The organic layers are dried over sodium sulphate and evaporated. Yield: 1.8 grams (100 percent) of a yellow foam; MS (ESI): 361.2 [MH] ". (2) Step B: 4- (2-Amino-3,5-difluoro-phenoxy) -1H-indole-2-carboxylic acid ethyl ester (155) The 154 ( 1.8 grams, 4.87 mmol) is dissolved in ethyl acetate and, after addition of Pd-C (500 milligrams), the mixture is hydrogenated at room temperature for 2 hours.The mixture is filtered over Celite to remove the catalyst and evaporate Yield: 1.53 grams (94 percent) of a brown foam MS (ESI): 333.2 [M + H] +. (3) Step C: 4- (3,5-difluoro-phenoxy) ethyl ester ) -1H-Indole-2-carboxylic acid (156) Tert-butyl nitrite (0.547 milliliters, 4.6 mmol) is dissolved in 5 milliliters of dimethylformamide and heated to 65 ° C. A solution of 155 (1.5 grams) is added dropwise. 4.6 mmol) in dimethylformamide and the mixture is stirred for an additional 10 minutes.The brown solution is cooled to room temperature, diluted with diethyl ether and washed with 2N HCl and brine.The organic layers are dried over sodium sulfate. gave and evaporate. The crude product (1.5 grams of a brown oil) is further purified by evaporation chromatography (hexane / ethyl acetate 9: 1). Yield: 260 milligrams (17.8 percent) of a yellow solid; MS (ESI): 316.2 [MH] ", 1 H-NMR (DMSO-d 6): d (ppm) 12.2 (s, 1H), 7.35 (d, 1H), 7.28 (dd, 1H), 6.95 (m, 1H ), 6.82 (d, 1H), 6.79 (d, 1H), 6.68 (dd, 1H), 4.3 (q, 2H), 1.3 (t, 3H). (4) Step D: Acid 4- (3.5 -difluoro-phenoxy) -1H-indole-2-carboxylic acid (153) The 156 (260 milligrams, 0.82 millimole) is dissolved in 10 milliliters of methanol and treated with a solution of LiOH (40 milligrams, 1.6 millimoles) in 5 milliliters The mixture is stirred at room temperature for 18 hours.After evaporation, the crude product is acidified at 0 ° C with 2M HCl and extracted with ethyl acetate.The organic layers are dried over sodium sulfate and evaporate Yield: 2410 milligrams (100 percent) of a yellow solid; Example 124 { 1- [2- [3-RS-hydroxy-piperidin-1-yl) -ethyl] -piperidin-4-yl.} -amide of 4- (3,5-difluoro-phenoxy) -1H-indole-2-carboxylic acid This compound is synthesized in a manner analogous to Example 1, from 4- (3,5-difluoro-phenoxy) -1H-indole-2-carboxylic acid 153 (see Example 123) and racemic amine 12. Yield: 38 grams (32 percent) of a white solid; MS (ESI): 499 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 11.8 (s, 1 H), 8.25 (d, 1 H), 7.33 (d, 1 H), 7.2 (dd) , 1H), 7.04 (s, 1H), 6.92 (dd, 1H), 6.76 (d, 1H), 6.63 (d, 2H), 4.02 (d, 1H), 3.72 (m, 1H), 3.4 (, 1H) ), 2.8-2.9 (m, 3H), 2.67 (m, 2H), 2.38 (m, 4H), 1.99 (m, 2H), 1.68-1.88 (m, 5H), 1.47-1.6 (m, 3H), 1.371 (m, 1H), 1.05 (m, 1H). Example 125 { 1- [2- (4-hydroxy-piperidin-1-yl) -ethyl] -piper-dine-4-yl} -amine of 4- (3,5-difluoro-phenoxy) -1H-indole-2-carboxylic acid This compound is synthesized in a manner analogous to Example 1, starting with 4- (3,5-difluoro-phenoxy) -1H-indole-2-carboxylic acid 153 (see Example 123) and amine 21. Yield: 23 milligrams ( 13 percent) of a white solid; MS (ESI): 497.2 [MH] ", 1 H-NMR (DMSO-d 6): d (ppm) 11.79 (s, 1 H), 8.22 (br, 1 H), 7.32 (d, 1 H), 7.2 (dd, 1 H) , 7.04 (s, 1H), 6.9 (dd, 1H), 6.75 (d, 1H), 6.6 (d, 2H), 4.46 (s, 1H), 3.72 (m, 1H), 3.39 (m, 1H), 2.83 (m, 2H), 2.67 (m, 2H), 2.35 (m, 4H), 1.98 (m, 4H), 1.75 (m, 2H), 1.65 (m, 2H), 1.51 (m, 2H), 1.35 (m, 2H) Alternatively, the 4-alkoxy-indole-2-carboxamides are prepared as shown in reaction scheme Reaction Scheme 1116: Example 126 4- (6-chloro-pyridin-2-yloxy) -1H-indole-2-carboxylic acid [1- (2-azepan-1-yl-ethyl) -piperidin-4-yl] -amide.

This compound is synthesized in a manner analogous to Example 1, from 4- (6-chloro-pyridin-2-yloxy) -1H-indole-2-carboxylic acid 157 (for the preparation, see below) and the amine. Yield: 85 milligrams (54 percent) of a yellow crystal; MS (ESI): 494.3 [MH] ", 1 H-NMR (DMSO-ds): d (ppm) 11.8 (s, 1 H), 8.2 (d, 1 H), 7.85 (dd, 1 H), 7.3 (d, 1 H) , 7.2 (m, 2H), 6.95 (s, 1H), 6.9 (d, 1H), 6.8 (d, 1H), 3.7 (m, 1H), 2.85 (m, 2H), 2.5-2.6 (m, 6H) ), 2.35 (m, 2H), 2.0 (t, 2H), 1.75 (m, 2H), 1.5 (m, 10H) Synthesis of 4- (6-chloro-pyridin-2-yloxy) -1H-indole -2- carboxylic (157) (1) 2-ethyl-ester of 4-benzyloxy-indo-1,2-dicarboxylic acid-1-tert-butyl ester (158) The ethyl ester of 4-benzyloxy-1H is dissolved -indole-2-carboxylic acid (10 grams, 34 millimoles) and DMPA (80 milligrams) in 80 milliliters of ethyl acetate BOC20 (8.9 grams, 41 millimoles) dissolved in a small amount of ethyl acetate is added at room temperature. The mixture is stirred overnight at room temperature, then the reaction mixture is washed with 1M aqueous tartaric acid, water and brine, the organic layers are dried over sodium sulfate and evaporated, the crude product is used in the following step without further purification Yield: 13.8 grams (100 percent) of a yellow oil; 1 H NMR (CDCl 3): d (ppm) 7.7 (d, 1H), 7.3-7.5 (m, 7H), 6.75 (d, 1H), 5.2 (s, 2H), 4.4 (q, 2H), 1.7 ( s, 9H), 1.4 (t, 3H). (2) Step B: 4-hydroxyindole-1,2-dicarboxylic acid 1-tert-butyl ester (159) 158 (8 grams, 20 mmol) is dissolved in 80 milliliters of ethyl acetate. ethyl and, after the addition of 5 percent Pd-C (700 milligrams), the mixture is hydrogenated at room temperature for 7 hours. The mixture is filtered over Celite to remove the catalyst and evaporated. The solid is suspended in ether / hexane and filtered. Yield: 4.6 grams (74 percent). 1 H-NMR (CDCl 3): d (ppm) 7.7 (d, 1H), 7.3 (m, 2H), 6.7 (d, 1H), 5.5 (s, 1H), 4.4 (q, 2H), 1.7 (s, 9H), 1.4 (t, 3H). (3) Step C: 4- (6-Chloro-pyridin-2-yloxy) -1H-indole-2-carboxylic acid ethyl ester (160) Dissolve 159 (500 milligrams, 1.6 mmol), 2.6 .dichloro-pyridine (360 milligrams, 24 millimoles) in 15 milliliters of dimethylformamide. After the addition of potassium carbonate (340 milligrams, 24 millimoles) and a catalytic amount of Cu powder, the mixture is heated at 160 ° C for 3 hours. The reaction mixture is cooled to room temperature, diluted with ethyl acetate and washed with water. The organic layers are dried over sodium sulphate and evaporated. The crude product is dissolved in dichloromethane and, after evaporation, crystallized with cyclohexane. Yield: 300 milligrams (58 percent) of a beige solid; MS (ESI): 317.2 [M + H] +, 1 H-NMR (CDCl 3): d (ppm) 9.2 (br, 1H), 7.7 (dd, 1H), 7.3 (m, 2H), 7.1 (m, 2H), 6.95 (dd, 1H), 6.75 (d, 1H), 4.4 (q, 2H), 1.4 (t, 3H). (4) Step D: 4- (6-Chloro-pyrridin-2-yloxy) -1H-indole-2-carboxylic acid (157) The 160 (100 milligrams, 0.315 mmol) is dissolved in 4 milliliters of methanol, and treat with a solution of NaOH (1 milliliter, 2N). The mixture is stirred 1 hour at room temperature. The reaction mixture is acidified with HCl (1 milliliter, 2N) and evaporated. The crude mixture is used in the next step without further purification. Alternatively, the 4-alkoxy-indole-2-carboxamides are prepared as shown in reaction scheme 17. Reaction Scheme 17: EXAMPLE 127 4-Isobutoxy-1H-indole-2-carboxylic acid [1- (octahydro-quinolizin-1-ylmethyl) -piperidin-4-yl] -amide hydrochloride 161 (for preparation, see below) (2.5 grams, 7.1 mmol), octahydro-2H-quinolizin-1-ylmethanol (Lupinine) (1.2 grams, 7.1 mmol) and ethyldi-isopropylamine (12.2 milliliters, 71 mmol) are dissolved. in 10 milliliters of propionitrile After the addition of cyanomethyl-trimethyl-phosphonium iodide (4.1 grams, 17 mmol) the mixture is refluxed for 3 hours.After cooling to room temperature, the mixture is diluted with ethyl acetate and washed with a potassium carbonate solution The crude product (3.9 grams of a brown oil) is crystallized from methanol, Yield: 2 grams (52 percent) of a white solid, MS (ESI): 467 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 11.42 (s, NH), 8.16 (d, NH), 7.22 (d, 1H), 7.02 (dd, 1H), 6.96 (d, 1H), 6.45 (d, 1H), 3.83 (d, 2H), 3.75 (m, 1H), 3.49 (s, 2H), 2.81 (m, 2H), 2.70 (m, 2H), 2.29 ( m, 1H), 2.15-2.00 (m, 2H), 1.95-1.73 (m, 7H), 1.72-1.27 (m, 9H), 1.26-1.10 (m, 2H), 1.05 (d, 6H). Synthesis of 4-isobutoxy-1H-indole-2-carboxylic acid (1-benzyl-piperidin-4-yl) -amine (1) Step A: 4-isobutoxy-1H-indole-2-carboxylic acid (1-benzyl-piperidin-4-yl) -amide - sobutoxy-1H-indole-2-carboxylic acid (161) 4-Isobutoxy-1H-indole-2-carboxylic acid 80 (4.7 grams, 20.1 mmol, for the preparation, see Example 8) and 1- benzyl are dissolved -piperidin-4-ylamine (4.2 milliliters, 20.1 millimoles) in N, N-dimethylformamide and after the addition of TBTU (7.3 grams, 22.1 millimoles) and ethyldi-isopropylamine (13.8 millimoles, 80.4 millimoles), the mixture was Stir at room temperature for 2 hours. Then, the solvent is evaporated to high vacuum. The residue is dissolved in ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and brine. The organic layers are dried over sodium sulphate and evaporated under reduced pressure. Yield: 8.96 grams of a beige solid; MS (ESI): 406.5 [M + H] +. (2) Step B: 4-Isobutoxy-1H-indole-2-carboxylic acid piperidin-4-ylamide hydrochloride (161) 161 (8.1 grams, 20 mmol) is dissolved in 200 milliliters of ethanol and, after addition of Pd-C (200 milligrams) and 10 milliliters of 4M HCl, the mixture is hydrogenated at room temperature for 3 hours. The mixture is filtered over Celite to remove the catalyst and evaporated. Yield: 7.13 grams (100 percent) of a white solid; MS (ESI): 316 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 11.5 (s, 1H), 8.42 (d, 1H), 7.25 (s, 2H), 7.04 (dd, 1H), 6.95 (d, 1H), 6.45 (d, 1H), 4.0 (m, 1H), 3.83 (d, 2H), 3.22 (m, 2H) ), 2.88 (m, 2H), 2.1 (m, 1H), 1.9 (m, 2H), 1.7 (m, 2H), 1.05 (d, 6H). Example: 4- [1- (1-meth yl-piperidin-3-ylmethyl) -piperidin-4-yl] -amide of 4-isobutoxy-1H-indole-2-carboxylic acid This compound is synthesized from compound 161 (see Example 127) and (1-methyl-piperidin-3-yl) -methanol analogously to the method described in Example 127. Yield: 60 milligrams (50 percent); MS (ESI): 427 [M + H] +, 1 H-NMR (DMSO-de): d (ppm) 11.45 (s, NH), 8.18 (d, NH), 7.21 (s, 1H), 7.02 (dd) , 1H), 6.95 (d, 1H), 6.45 (d, 1H), 3.85 (d, 2H), 3.75 (m, 1H), 2.88 (m, 1H), 2.78 (m, 2H), 2.62 (m, 1H), 2.12 (s, 3H), 2.13-2.05 (m, 3H), 2.00-1.84 (m, 2H), 1.84-1.40 (m, 10H), 1.05 (d, 6H), 0.82 (m, 1H) . Example 129 { 1 - [(1S, 9aR) -1- (octahydro-quinolizin-1-yl) methyI] -piperidin-4-yl} 4-chlorobutylmethoxy-1 H-indole-2-carboxylic acid amide This compound is synthesized from 4-cyclobutylmethoxy-1H-indole-2-carboxylic acid piperidin-4-ylamide, 162 (for the preparation, see below) and (1R, 9aR) -1- (octahydro-quinozin) -1-) 1-methanol in a manner analogous to the method described in Example 127. MS (ESI): 479.1 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 11.44 (s, 1H ), 8.2 (d, 1H), 7.2 (d, 1H), 7.03 (t, 1H), 6.96 (d, 1H), 6.47 (d, 1H), 4.04 (d, 2H), 3.76 (m, 1H) , 2.6-2.9 (m, 5H), 2.22-2.54 (m, 2H), 1.08-2.17 (m, 26H). Synthesis of 4-cyclobutylmethoxy-1H-indole-2-carboxylic acid piperidin-4-ylamide, 162 (1) Step A: 4 - [(4-Cyclobutylmethoxy-1H-indole-2-carbonyl tert-butyl ester ) -amino] -piperidine-1-carboxylic acid Tert-butyl ester of 4-amino-piperidine-1-carboxylic acid (1.98 grams, 9.87 millimoles), HOBT (1.37 grams, 8.97 millimoles), triethylamine (2.5 milliliters, 17.94 mmol) and EDC (1.72 grams, 8.97 mmol) to a solution of 4-cyclobutylmethoxy-1H-indole-2-carboxylic acid (82) from Example 34 (2.2 grams, 8.97 mmol) in 20 milliliters of DCM. The mixture is stirred at room temperature overnight. Then, it is washed with 2N NaOH and brine, dried over anhydrous sodium sulfate and evaporated to give a yellow powder. The crude material is purified by chromatography on silica gel using hexane and EtOAc (from 0 percent to 20 percent). Yield: 3.02 grams (79 percent); MS (ESI): 426.3 [MH] ", 1 H-NMR (CDCl 3): d (ppm) 9.33 (s, 1H), 7.17 (t, 1H), 7.03 (d, 1H), 6.97 (s, 1H), 6.5 (d, 1H), 6.12 (d, 1H), 4.13 (m, 4H), 4.07 (d, 2H), 2.78-2.97 (m, 4H), 1.88-2.25 (m, 8H), 1.46 (s, 9H). (2) Step B: 4-cyclobutylmethoxy-1H-indole-2-carboxylic acid piperidin-4-ylamide, 162 Tert-butyl-ester (163) above (3.02 grams, 7.05 mmol) is dissolved in 20 ml. milliliters of dioxane, a 4M solution of HCl in dioxane (14.1 milliliters, 56.4 mmol) and the mixture is stirred for 24 hours. Evaporation gave the hydrochloride as a white powder. Yield: 2.93 grams (> 100 percent, not completely dry). MS (ESI): 427 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 11.59 (s, 1H), 8. 75 (br m, 2H), 8.51 (d, 1H), 7.25 (s, 1H), 7.07 (t, 1H), 6.99 (d, 1H), 6. 5 (d, 1H), 4.1 (m, 1H), 4.05 (d, 2H), 3.25-3.45 (m, 2H), 3.02 (m, 2H), 2.78 (m, 1H), 2.14 (m, 2H), 1.85-2.04 (m, 5H), 1.76 (m, 2H). Example 130 { 1 - [(S) -2 - ((3R, 4R) -hydroxy-3-methyl-piperidin-1-yl) -propyl] -piperidin-4-yl} 4-cyclobutylmethoxy-1H-indole-2-carboxylic acid amide This compound is synthesized from 4-cyclobutyl-methoxy-1H-indole-2-carboxylic acid piperidin-4-yl-amide 162 (see Example 129) and (3R, 4R) -1 - ((R) - 2-hydroxy-propyl) -3-methyl-piperidin-4-yl-ester of 2,2-dimethyl-propionic acid 164 (for the preparation, see below), in a manner analogous to the method described in Example 127, followed by dissociation of pivaloyl, as described for amine 55. MS (ESI): 483.2 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 11.43 (s, 1H), 8. 2 (br s, 1H), 7.19 (s, 1H), 7.03 (t, 1H), 6.96 (d, 1H), 6.47 (d, 1H), 4.44 (m, 1H), 4.04 (d, 2H), 3.73 (m, 1H), 2.58 - 2.96 (m, 7H), 2.04 - 2.41 (m, 6H), 1.83 - 2.02 (m, 6H), 1.66 - 1.82 (m, 3H), 1.45 - 1.65 (m, 2H), 1.2-1.44 (m, 2H), 0.91 (d, 3H), 0.86 (d, 3H). (1) (3R, 4R) -1 - ((R) -2-hydroxy-propyl) -3-methyl-piperidin-4-yl-ester of 2,2-dimethyl-propionic acid (164). A solution of piperidine 20 (3 grams, 15.05 millimoles) and (R) -2-Methyl-oxirane (15.05 milliliters, 150.5 mmol) in 10 milliliters of ethanol is stirred for 24 hours in a closed flask. The solvent is evaporated and the residue is distilled in a Kugeirohr apparatus. (0.08 mbar, 80-90 ° C). Yield: 3.82 grams (99 percent). MS (ESI): 258.2 [M + H] +, 1 H-NMR (DMSO-de): d (ppm) 4.34 (br s, 1 H), 4.24 (td, 1 H), 3.70 (sextet, 1H), 2.79 (m, 2H), 2.03 - 2.28 (m, 3H), 1.65 - 1.9 (m, 3H), 1. 45 (qd, 1H), 1.14 (s, 9H), 1.02 (d, 3H), 0.81 (d, 3H), [a] D = -66.1 (c = 1.5 in MeOH).

Example 131 { 1 - [(S) -2 - ((3S, 4R, 5S) -3,4-dihydroxy-5-methyl-piperidin-1-yl) -propiI] -piperidin-4-yl} -amide of 4-cyclobutyl-methoxy-1H-indoI-2-carboxylic acid.

This compound is synthesized from the 4-cyclobutyl-methoxy-1H-indo! -2-carboxylic acid piperidin-4-yl-amide 162 (see Example 129) and the amine 35, in a manner analogous to the method described at 54, followed by dissociation of the protecting group. MS (ESI): 499.4 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 11.47 (s, 1H), 8. 28 (br s, 1H), 7.23 (s, 1H), 7.04 (t, 1H), 6.99 (d, 1H), 6.49 (d, 1H), 4.07 (m, 1H), 4.06 (d, 2H), 4.02 (m, 1H), 3.76 (m, 1H), 3.55 (m, 1H), 2.58-2.96 (m, 6H), 2.25-2.4 (m, 3H), 1.83-2.15 (m, 11H), 1.66 - 1.82 (m, 2H), 1.45-1.65 (m, 2H), 0.91 (d, 3H), 0.86 (d, 3H). Example 132 { 1 - [(R) -3-hydroxy-2 - ((3S) 4S) -4-hydroxy-3-methyl-piperidin-1-yl) -propyl] -piperidin-4-yl} 4-cyclo-butyl-methoxy-1H-indoI-2-carboxylic acid amide.

This compound is synthesized from the 4-cyclo-butyl-methoxy-1H-indole-2-carboxylic acid piperidin-4-yl-amide 162 (see Example 129) and (3S, 4S) -1- ((S) -2-hydroxy-3-trityloxy-propyl) -3-methyl-piperidin-4-yl-ester of 2,2-dimethyl-propionic acid (60), in a manner analogous to the method described in 56, followed by the subsequent removal of the protection groups with sodium methylate and 80 percent acetic acid. MS (ESI): 499.5 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 11.44 (s, 1H), 8.22 (d, 1H), 7.2 (d, 1H), 7.03 (t , 1H), 6.96 (d, 1H), 6.47 (d, 1H), 4.45 (d, 1H), 4.28-4.45 (m, 1H), 4.04 (d, 2H), 3.7-3.8 (m, 1H), 3.42 (d, 2H), 2.6-2.98 (m, 7H), 1.15-2.18 (m, 16H), 0.86 (d, 3H). Example 133. { 1 - [(1S, 9aR) -1- (octahydro-quinolizin-1-yl) -methyl] -piperidin-4-yl} 4- (furan-3-yl-methoxy) -1H-indole-2-carboxylic acid amide.

This compound is synthesized from 4- (furan-3-yl-methoxy) -1H-indole-2-carboxylic acid piperidin-4-yl-amide 165 (for the preparation, see below), and ( 1R, 9aR) -1- (octahydro-quinolizin-1-yl) -methanol, in a manner analogous to the method described in Example 127. MS (ESI): 491.1 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 11.45 (s, 1 H), 8.13 (d, 1 H), 7.82 (s, 1 H), 7.68 (t , 1H), 7.22 (d, 1H), 7.05 (t, 1H), 6.98 (d, 1H), 6.62 (s, 1H), 6.59 (d, 1H), 5.03 (s, 2H), 3.74 (m, 1H), 2.8 (m, 2H), 2.69 (m, 2H), 2.43-2.53 (m, 1H), 2.27 (m, 1H), 2.02 (m, 1H), 1.07-1.95 (m, 19H). Synthesis of 4- (furan-3-yl-methoxy-1H-indole-2-carboxylic acid piperidin-4-yl-amide (165) (1) Step A: Terbutil-4-acid ester. - (furan-3-yl-methoxy) -1H-indole-2-carbonyl] -amino} -piperidine-1-carboxylic acid (166) To a solution of 4- (furan-3-yl-methoxy) acid -1H-indole-2-carboxylic acid (95) from Example 33 (5 grams, 19.44 mmol) in 10 milliliters of DCM, 4-amino-piperidine-1-carboxylic acid terbutyl ester (3.89 grams, 19.44 mmol) is added ), HOBT (2.98 grams, 19.44 millimoles), triethylamine (5.4 milliliters, 38.88 millimoles), and EDC (3.73 grams, 19.44 millimoles) The mixture is stirred at room temperature overnight, then washed with 2N NaOH and Brine, dry over anhydrous sodium sulfate, and evaporate to give a yellow powder The crude material is purified by chromatography on silica gel using DCM and EtOAc (from 0 percent to 10 percent) Yield: 7.51 grams (88 percent) MS (ESI): 438.3 [MH] ", 1 H-NMR (CDCl 3): d (ppm) 9.42 (s, 1H), 7.57 (s, 1H), 7.46 (s, 1H), 7.21 (t, 1H), 7.05 (d, 1H), 6.96 (s, 1H), 6.6 (d, 1H), 6.55 (s, 1H), 6.08 (d, 1H), 5.07 (d, 2H), 4.04 - 4.2 (overlapped m, 3H), 2.91 (m, 2H), 2.01 ( m, 2H), 1.48 (s, 9H), 1.42 (m, 2H). (2) Step B: 4- (furan-3-yl-methoxy) -1H-indole-2-carboxylic acid piperidin-4-yl-amide (165).

The above terbutil-ester (166) (695 milligrams, 1.58 millimoles) is dissolved in 5 milliliters of dioxane. A 4M solution of HCl in dioxane (3.2 milliliters, 12.8 millimoles) is added, and the mixture is stirred for 24 hours. Evaporation gave the hydrochloride as a white powder. Yield: 595 milligrams (100 percent). MS (ESI): 340.2 [M + H] +, 1 H-NMR (DMSO-de): d (ppm) 11.65 (s, 1H), 9.0 (br m, 2H), 8.5 (d, 1H), 7.85 ( s, 1H), 7.71 (s, 1H), 7.3 (s, 1H), 7.09 (t, 1H), 7.02 (d, 1H), 6.62 (d, 1H), 6.64 (s, 1H), 5.05 (d , 2H), 4.07 (m, 1H), 3.31 (m, 2H), 3.0 (m, 2H), 1.96 (m, 2H), 1.78 (m, 2H). Example 134 { 1 - [(S) -2 - ((3R, 4R) -4-hydroxy-3-methyl-piperidin-1-yl) -propl] -piperidin-4-yl} 4- (furan-3-yl-methoxy) -1H-indole-2-carboxylic acid amide.

This compound is synthesized from 4- (furan-3-yl-methoxy) -1H-indole-2-carboxylic acid piperidin-4-yl-amide 165 (see Example 133), and (3R, 4R 2,2-Dimethyl-propionic acid-1 - ((R) -2-hydroxy-propyl) -3-methyl-piperidin-4-yl-ester 164 (for the preparation, see Example 130), from a Analogous to the method described in Example 127, followed by dissociation of pivaloyl as described for amine 55. MS (ESI): 495.2 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 11.46 (s, 1H), 8. 14 (d, 1H), 7.82 (s, 1H), 7.68 (br s, 1H), 7.23 (s, 1H), 7.05 (t, 1H), 6. 99 (d, 1H), 6.6 (d, 1H), 5.03 (s, 2H), 4.43 (d, 1H), 3.72 (m, 1H), 2. 56-2.95 (m, 5H), 2.32 (m, 1H), 2.24 (m, 1H), 2.04-2.19 (m, 2H), 1. 9 (m, 2H), 1.67 - 1.79 (m, 3H), 1.43 - 1.61 (m, 2H), 1.21 - 1.41 (m, 3H), 0.91 (d, 3H), 0.86 (d, 3H). Example 135 [1- (octahydro-quinolizin-1-yl-methyl) -piperidin-4-yl] -amide of acid 4- (2-methyl-thiazol-4-yl-methoxy) -1H-indole-2-carboxylic acid.

This compound is synthesized from 4- (2-methyl-thiazol-4-yl-methoxy) -1H-indole-2-carboxylic acid piperidin-4-yl-amide 167 (for the preparation, see below) ), and (1R, 9aR) -1- (octahydro-quinolizin-1-yl) -methanol, in a manner analogous to the method described in Example 127. MS (ESI): 522 [M + H] +, 1H- NMR (DMSO-d6): d (ppm) 11.5 (s, 1H), 8.15 (d, 1H), 7.57 (s, 1H), 7.25 (s, 1H), 7.05 (dd, 1H), 6.98 (d, 1H), 6.62 (s, 1H), 5.18 (s, 2H), 3.74 (m, 1H), 2.8 (m, 2H), 2.69 (m, 2H), 2.68 (s, 3H), 2.43 - 2.53 (m , 1H), 2.27 (m, 1H), j 2.02 (m, 1H), 1.07-1.95 (m, 19H). Synthesis of 4- (2-methyl-thiazol-4-yl-methoxy) -1H-indole-2-carboxylic acid piperidin-4-yl-amide (167) (1) Step A: (2-methyl- thiazol-4-yl) -methanol (168). The ethyl ester of 2-methyl-thiazole-4-carboxylic acid (966 milligrams, 5.64 mmol) is dissolved in 5 milliliters of diethyl ether, and cooled to -78 ° C. A 1M solution of lithium aluminum hydride in tetrahydrofuran (16.9 milliliters, 16.9 millimoles) is added dropwise, and the mixture is stirred for 3.5 hours at -78 ° C. The mixture is quenched at this temperature with a saturated solution of sodium sulfate, and allowed to warm to room temperature, followed by extraction with ether and evaporation. Yield: 670 milligrams (92 percent). MS (ESI): 130.0 [M-H] ', 1 H-NMR (CDCl 3): d (ppm) 7.20 (s, 1 H), 5.27 (dd, 1 H), 4.50 (d, 2 H), 2. 62 (s, 3H). (2) Step B: 4- (2-m eti I-thiazole -4-I-m ethoxy) 2-ethyl ester of 1-terbutyl ester-n-1,2-d icar boxy I ico (169). The (2-methyl-thiazol-4-yl) -methanol 168 (670 milligrams, 5.2 mmol) is dissolved in 12 milliliters of dry tetrahydrofuran under argon, followed by the addition of the 2-ethyl ester of 1-tert-butyl ester of the tetrahydrofuran. 4-hydroxy-indole-1,2-dicarboxylic acid 102 (see Example 42, 1.58 grams, 5.2 mmol), triphenylphosphine (1.63 grams, 6.2 mmol), and the solution is cooled to 0 ° C. A 40 percent solution of ethyl aza-dicarboxylate in toluene (2.7 milliliters, 6.2 mmol) is added dropwise, and the mixture is stirred for 2.5 hours at 0 ° C. The solvents are removed under reduced pressure, and the residue is dissolved in ethyl acetate, and washed with a sodium hydrogen carbonate solution, and brine. The organic layers are dried over sodium sulfate, filtered, and evaporated. The crude product is purified by evaporation chromatography (silica gel, ethyl acetate / hexanes, 3: 7). Yield: 1.75 grams (81 percent). MS (ESI): 417.2 [M + H] +, 1 H-NMR (DMSO-de): d (ppm) 7.67 (s, 1 H), 7.55 (d, 1 H), 7.41 (dd, 1 H), 7.27 (s) , 1H), 6.99 (d, 1H), 5.27 (s, 2H), 4.31 (q, 2H), 2.68 (s, 3H), 1.57 (s, 9H), 1.32 (t, 3H). (3) Step C: 4- (2-Methy1-thiazol-4-yl-methoxy) -1H-indole-2-carboxylic acid (170). The 4- (2-methyl-thiazol-4-yl-methoxy) -indol-1,2-dicarboxylic acid 1-tert-butyl ester (169) is dissolved (1.75 grams, 4. 2 millimoles) in 20 milliliters of ethanol. After the addition of an aqueous solution of 0.5 M sodium hydroxide (33.6 milliliters, 16.8 millimoles), the solution is heated to 60 ° C, and stirred at this temperature for 18 hours. The reaction mixture is then evaporated, and the residue is dissolved in ethyl acetate. At 0 ° C, concentrated HCl is added until a pH of 1 is reached. The organic phase is washed with water and brine. The organic layers are dried over sodium sulfate, and filtered. The product crystallized after evaporation, and could be filtered. Yield: 1.21 grams (100 percent). MS (ESI): 289.0 [M + H] +, 1 H-NMR (DMSO-de): d (ppm) 11.76 (br s, 11 H), 7.62 (s, 1 H), 7.14 (dd, 1 H), 7.07 ( s, 1H), 7.02 (d, 1H), 6.66 (d, 1H), 5.22 (s, 2H), 2.68 (s, 3H). (4) Step D: Terbutil-acid ester 4-. { [4- (2-methyl-thiazol-4-yl-methoxy) -1 H -i ndol-2-carbonyl] -am i no} -piperid i n-1 -carboxylic (171). The 4- (2-methyl-thiazol-4-yl-methoxy) -1H-indole-2-carboxylic acid (170) (1.21 grams, 4.2 mmol) is dissolved in 10 milliliters of N, N-dimethyl-formamide, and The solution is cooled to 0 ° C. After addition of Hunig's base (2.16 milliliters, 12.6 millimoles), piperidin-4-yl-carbamic acid terbutil ester (3) (841 milligrams, 4.2 millimoles), and PyBOP (2.4 grams, 4.6 millimoles), the mixture was stir at room temperature for 18 hours. Ethyl acetate is added, followed by concentrated sodium hydroxide, until a pH of 11 is reached. The organic layer is washed with brine, dried over sodium sulfate, and evaporated under reduced pressure. The crude product is purified by evaporation chromatography (silica gel, ethyl acetate / cyclohexane, 1: 1). Yield: 1.58 grams (80 percent). MS (ESI): 471.2 [M + H] +, 1 H-NMR (DMSO-de): d (ppm) 11.58 (br s, 1H), 8.25 (d, 1H), 7.61 (s, 1H), 7.27 ( s, 1H), 7.09 (dd, 1H), 7.02 (d, 1H), 6.63 (d, 1H), 5.18 (s, 2H), 3.93 (m, 3H), 2.85 (m, 2H), 2.69 (s) , 3H), 1.78 (m, 2H), 1.4 (s, 9H), 1.38 (m, 2H). (5) Step E: 4- (2-Methyl-thiazol-4-yl-methoxy) -1H-indole-2-carboxylic acid piperidin-4-yl-amide (167). The preceding 171 (1.58 grams, 3.36 mmol) is dissolved in a 4M solution of HCl in dioxane (32 milliliters, 128 mmol), and stirred for 45 minutes at room temperature. Then the reaction mixture is evaporated, dissolved in ethyl acetate, and concentrated sodium hydroxide is added, until a pH of 11 is reached. The aqueous layer is washed with brine, dried over sodium sulfate, and evaporated under reduced pressure. Yield: 1.28 grams (100 percent). MS (ESI): 371.2 [M + H] +, 1 H-NMR (DMSO-de): d (ppm) 11.56 (br, 1H), 8.28 (d, 1H), 7.61 (s, 1H), 7.3 (s, 1H), 7.09 (dd, 1H), 7.02 (d, 1H), 6.62 (d, 1H), 5.19 (s, 2H), 3.90 (m, 1H), 3.07 (m, 2H), 2.70 (s, 3H), 2.62-2.75 (m, 2H), 1. 72-1.85 (m, 3H), 1.4-1.55 (m, 2H). Example 136 { 1- [2- (3,4-Dihydroxy-5-methyl-piperidin-1-yl) -propyl] -piperidin-4-yl} -amide of 4- (benzofuran-3-yl-methoxy) -1 H-indole-2-carboxylic acid.

This compound is synthesized from the 4- (benzofuran-3-yl-methoxy) -1H-indole-2-carboxylic acid piperidin-4-yl-amide 172 (for the preparation, see below), and the amine 35, in a manner analogous to the method described in 54, followed by the dissociation of the protecting group.

MS (ESI): 561 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 11.48 (s, 1 H), 8.16 (s, 1 H), 8.15 (d, 1 H), 7.72 (d , 1H), 7.61 (d, 1H), 7; 35 (dd, 1H), 7.29 (dd, 1H), 7.19 (s, 1H), 7.09 (dd, 1H), 7.01 (d, 1H), 6.71 ( d, 1H), 5.35 (s, 2H), 4.04 (d, 1H), 3.98 (m, 1H), 3.72 (m, 1H), 3.53 (m, 1H), 2.50 - 2.90 (m, 7H), 2.24 -2.38 (m, 2H), 1.88-2.08 (m, 3H), 1.66-1.78 (m, 3H), 1.45-1.58 (m, 2H), 0.86 (d, 3H), 0.83 (d, 3H). Synthesis of 4- (benzofuran-3-yl-methoxy) -1H-indole-2-carboxylic acid piperidin-4-yl-amide (172) (1) Step A: 4- Tert-butyl ester. { [4- (benzo-furan-3-yl-m-ethoxy) -1 H -i ndol-2-carbonyl] -am i no} -piperidin-1 -carboxylic (173).

To an ice-cold solution of 4- (benzofuran-3-yl-methoxy) -1H-indole-2-carboxylic acid 105 (see Example 50) (200 milligrams, 0.651 mmol) in 2 milliliters of dimethyl formamide was added. add base Hunig (334 microliters, 1.95 millimoles). After stirring at 0 ° C for 10 minutes, 4-amino-piperidine-1-carboxylic acid tert-butyl ester (130 milligrams, 0.651 millimole) and PyBOP (356 milligrams, 0.684 millimole) are subsequently added. The mixture is stirred at room temperature overnight. It is then diluted with ethyl acetate, washed with 1N NaOH and brine, dried over anhydrous sodium sulfate, and evaporated to give 980 milligrams of a light brown oil. The crude material is purified by chromatography on silica gel using cyclohexane and ethyl acetate (1: 1). Yield: 318 milligrams (100 percent). MS (ESI): 488.2 [MH] ", 1 H-NMR (CDCl 3): d (ppm) 9.15 (s, 1H), 7.77 (s, 1H), 7.72 (d, 1H), 7.55 (d, 1H), 7.38 (dd, 1H), 7.3 (dd, 1H), 7.23 (d, 1H), 7.08 (d, 1H), 6.91 (s, 1H), 6.7 (d, 1H), 5.96 (d, 1H), 5.34 (s, 2H), 4.04 - 4.2 (overlapping m, 3H), 2.91 (m, 2H), 2.01 (m, 2H), 1.48 (s, 9H), 1.40 (m, 2H). (2) Step B: 4- (Benzo-furan-3-yl-methoxy) -1H-indole-2-carboxylic acid piperidin-4-yl-amide (172) The above terbutil-ester (173) (318 milligrams, 0.65 mmol) ) is dissolved in a 4M solution of HCl in dioxane (6 milliliters, 1.2 mmol), and stirred for 1 hour at room temperature.The evaporation gave the hydrochloride as a white powder, which is dissolved in water, treated with a Concentrated NaOH solution at 0 ° C to a pH of 11, and extract with ethyl acetate.The organic layers are washed with brine, dried over sodium sulfate, and evaporated Yield: 248 milligrams (98 percent) of a light yellow solid MS (ESI): 390.2 [M + H] +. 137. 1- [2- (3,4-Dihydroxy-piperidin-1-yl) -propyl] -piperidin-4-yl} 4- (5-fIuoro-benzofuran-3-yl-methoxy) -1H-indole-2-carboxylic acid amide.

This compound is synthesized from 4- (5-fluoro-benzofuran-3-yl-m-ethoxy) -1H-indol-2-carboxylic acid piperidin-4-yl-amide 174 (for the preparation, see below), and to the amine 34, in a manner analogous to the method described for 54, followed by the dissociation of the protecting group. MS (ESI): 565 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 11.52 (s, 1H), 8.28 (s, 1H), 7.68 (dd, 1H), 7.52 (d , 1H), 7.23 (s, 1H), 7.21 (dd, 1H), 7.11 (dd, 1H), 7.03 (d, 1H), 6.72 (d, 1H), 5.35 (s, 2H), 4.19 (m, 1H), 4.13 (d, 1H), 3.73 (m, 1H), 3.52 (br s, 1H), 3.44 (br s, 1H), 2.9 (m, 3H), 2.52 (, 2H), 2.33 (m, 3H), 2.11 (m, 1H), 2.03 (dd, 1H), 1.84 (dd, 1H), 1.75 (d, 1H), 1.45 - 1.65 (m, 5H), 0.9 (d, 3H). Synthesis of 4- (5-fluoro-benzofuran-3-yl-m-ethoxy) -1H-in-l-2-carboxylic acid piperidin-4-yl-amide (174) (1) Step A: Terbutil - acid ester 4 { [4- (5-fluoro-benzo-furan-3-yl-methoxy) -1H-indoI-2-carbonyl] -amino} -piperidine-1-carboxylic acid (175). A solution of 4- (5-fluoro-benzo-furan-3-yl-methoxy) -1H-indole-2-carboxylic acid 113 (see Example 60, 160 milligrams, 0.49 mmol), is dissolved in 1.5 milliliters of N, N-dimethyl formamide, and cooled to 0 ° C. After addition of Hunig's base (252 microliters, 1.5 mmol), the mixture is stirred for 15 minutes, and then piperidin-4-yl-carbamic acid terbutil-ester 3 (98.5 milligrams, 0.49 mmol) is added, followed by PyBOP (269 milligrams, 0.51 millimoles). The mixture is stirred at room temperature for 18 hours. The mixture is then diluted with ethyl acetate, washed with a 1N sodium hydroxide solution, and salted. The organic layers are dried over sodium sulfate, and evaporated under reduced pressure. The crude product (581 m ilig ram os) is purified by chromathography by evaporation (silica gel, cyclohexane / ethyl acetate, 1: 1). Yield: 250 milligrams (100 percent). MS (ESI): 506.2 [M-H] " (2) Step B: 4- (5-Fluoro-benzofuran-3-yl-methoxy) -1H-indole-2-carboxylic acid piperidin-4-yl-amide (174). The above terbutil-ester (175) (250 milligrams, 0.49 mmol) is dissolved in a 4M solution of HCl in dioxane (4 milliliters, 16 mmol), and the mixture is stirred for 1 hour at room temperature. Evaporation gave the hydrochloride as a yellow solid, which is dissolved in 5 milliliters of water, and the pH is adjusted to 1 1 by the addition of concentrated sodium hydroxide. The solution is extracted with ethyl acetate, the organic layers are washed with brine and dried over sodium sulfate. Evaporation gave 200 milligrams (1 00 percent) of a white solid. MS (ESI): 408.2 [M + H] +.

Example 138 { 1 - [2- (3,4-Dihydroxy-piperidin-1-yl) -propyl] -piperidin-4-yl} -amide of 4- (5-chloro-benzofuran-3-yl-methoxy) -1 H-indole-2-carboxylic acid.

This compound is synthesized from the 4- (5-chloro-benzo-furan-3-yl-methoxy) -1H-indole-2-carboxylic acid piperidin-4-yl-amide 176 (for the preparation, see below), and amine 34, in a manner analogous to the method described for 54, followed by the dissociation of the protecting group. MS (ESI): 581 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 11.5 (br s, 1H), 8.28 (s, 1H), 8.17 (d, 1H), 7.79 ( s, 1H), 7.68 (d, 1H), 7.39 (d, 1H), 7.22 (s, 1H), 7.10 (dd, 1H), 7.03 (d, 1H), 6.7 (d, 1H), 5.36 (s) , 2H), 4.18 (m, 1H), 4.12 (d, 1H), 3.72 (m, 1H), 3.52 (m, 1H), 3.45 (m, 1H), 2. 45-2.9 (m, 4H), 2.33 (m, 4H), 1.88-2.14 (m, 3H), 1.73 (m, 2H), 1.42-1.65 (m, 4H), 0.89 (d, 3H). Synthesis of 4- (5-chloro-benzo-furan-3-yl-methoxy) -1H-indole-2-carboxylic acid piperidin-4-yl-amide (176) (1) Step A: Terbutil-acid ester 4-. { [4- (5-chloro-benzo-furan-3-yl-methoxy) -1 H -indodo-2-carbonyl] -amino} -piperidine-1-carboxylic acid (177). This compound is synthesized from 4- (5-chloro-benzofuran-3-yl-methoxy) -1H-indole-2-carboxylic acid 113 (see Example 60), and amine 3, in a manner analogous to the method described for 175. Yield: 270 milligrams (60 percent). MS (ESI): 522 [MH] ", 1 H-NMR (DMSO-d 6): d (ppm) 11.58 (m, 1H), 8.28 (s, 1H), 8.20 (d, 1H), 7.8 (s, 1H ), 7.69 (d, 1H), 7.4 (d, 1H), 7.2 (s, 1H), 7.11 (dd, 1H), 7.03 (d, 1H), 6.72 (d, 1H), 5.36 (s, 2H) , 3.93 (m, 3H), 2.7-2.9 (m, 2H), 1.76 (d, 2H), 1.4 (s, 9H), 1.29 - 1.42 (m, 2H). (2) Step B: Piperidin-4- 4- (5-Chloro-benzo-furan-3-yl-methoxy) -1H-indole-2-carboxylic acid il-amide (176) This compound is synthesized from 177 in a manner analogous to the method described for 175. MS (ESI): 424.2 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 11.38 (s, 1H), 8.14 (s, 1H), 8.02 (d, 1H), 7.66 (s, 1H), 7.55 (d, 1H), 7.27 (d, 1H), 7.09 (s, 1H), 6.98 (d, 1H), 6.91 (d, 1H), 6.59 (d, 1H), 5.23 (s, 2H), 3.68 (m, 1H), 2.8 (m, 1H), 2.37 (m, 3H), 1.57 (m, 1H), 1.25 (m, 3H), Example 139 { 1 - [( 9S, 9aS) -1- (octahydro-pyrido [2,1-c] [1,4] oxazin-9-yl) -methyl] -piperidin-4-yl} -amide of 4- (5 -chloro-benzo-furan-3-yl-methoxy) -1H-indole-2-carboxylic acid.

This compound is synthesized from compound 176 (see Example 138), and (9RS, 9aSR) -1- (octahydro-pyrido [2,1-c] [1,4-oxazin-9-yl] -methanol (63), in a manner analogous to the method described in Example 127. Yield: 7.7 milligrams (12 percent) of a white solid. MS (ESI): 575/577 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 11.5 (s, 1H), 8.11 (d, 1H), 7.78 (d, 1H), 7.67. (d, 1H), 7.38 (dd, 1H), 7.18 (d, 1H), 7.10 (m, 1H), 7.03 (d, 1H), 6.70 (d, 1H), 5.36 (s, 2H), 3.75 - 3.60 (m, 2H), 3.50 - 3.30 (m, 4H), 2.80 - 2.55 (m, 2H), 2.60 - 2.50 (m, 2H), 2.32 (d, 2H), 2.10 - 1.65 (m, 9H), 1.60-1.40 (m, 3H), 1.35-1.20 (m, 2H). Example 140 { 1 - [(8S, 8aS) -1- (hexahydro-pyrrolo [2,1-c] [1,4] oxazin-8-yl) -methyl] -piperidin-4-yl} 4- (5-Chloro-benzo-furan-3-yl-methoxy) -1H-indole-2-carboxylic acid amide.

This compound is synthesized from compound 176 (see Example 138) and (9RS, 9aSR) -1- (octahydro-pyrido- [2,1-c] [1,4] oxazin-9-yl) -methanol (67), in a manner analogous to the method described in Example 127. Yield: 82 milligrams (14.6 percent) of a white solid. MS (ESI): 563/565 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 11.5 (s, 1H), 8.25 (s, 1H), 8.10 (d, 1H), 7.78 (d, 1H), 7.67 (d, 1H), 7.38 (bd, 1H), 7.19 (s, 1H), 7.10 - 7.00 (m, 2H), 6.70 (d, 1H), 5.35 (s, 2H), 4.00 (m, 1H), 3.90 (m, 1H), 3.75 -3.60 (m, 2H), 3.40 - 3.30 (m, 2H), 2.95 -2.70 (m, 1H), 2.40 -2.20 (m, 2H), 2.10 - 1.70 (, 8H), 1.55 - 1.25 (m, 4H), 1.15 (t, 1H), 1.07 (t, 1H). Example 141 { 1 - [(1S, 9aR) -1- (Octahydro-quinolizin-1-yl) -methyl] -piperidin-4-yl} 4- (4-methoxy-phenyl) -1H-indole-2-carboxylic acid amide.

This compound is synthesized from compound 178 (for the preparation, see below), and octahydro-2H-quinolizin-1-yl-methanol, in a manner analogous to the method described in Example 127. Yield: 350 milligrams (33.7 percent). MS (ESI): 501 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 11.6 (s, 1 H), 8.22 (d, 1 H), 7.56 (d, 2 H), 7.37 (d , 1H), 7.31 (m, 1H), 7.20 (dd, 1H), 7.07 (d, 2H), 7.01 (d, 1H), 3.81 (s, 3H), 3.75 (m, 1H), 3.16 (d, 1H), 2.80 (m, 2H), 2.67 (m, 2H), 2.46 (dd, 1H), 2.28 (m, 1H), 1.1 - 2.1 (m, 19H). Synthesis of 4- (4-methoxy-phenyl) -1H-indole-2-carboxylic acid piperidin-4-yl-amide (178): (1) Step A: 4- (4-methoxy-phenyl) -1 H-Indole-2-carboxylic acid (128). 4-Bromo-1 H-indole-2-carboxylic acid (5 grams, 20.8 mmol), and 4-methoxy-phenyl-boronic acid (3.2 grams, 20.8 mmol) are dissolved in 1-propanol (100 milliliters), and The mixture is flooded with argon for 30 minutes. Then bis (triphenylphosphine) palladium chloride (11) (200 milligrams, 1 millimole), and Na 2 CO 3 (4.4 grams, 40.2 mmol) are added, and the reaction mixture is stirred at 85 ° C for 3 hours. After cooling to room temperature, ethyl acetate and 2M HCl were added. The organic layers are dried over sodium sulfate. Evaporation gave 6 grams of a beige solid, which is further purified by crystallization from ethyl acetate. Yields.7 grams (84 percent). MS (ESI): 266 [MH] ". (2) Step B: 4- (4-methoxy-phenyl) -1H-indole-2-carboxylic acid (1-benzyl-piperidin-4-yl) -amide. (179) Dissolve 128 (4.7 grams, 1 7.6 mmol) and 1-benzyl-piperidin-4-yl-amine (3.3 grams, 17.6 mmol) in N, N-dimethyl-formamide (70 milliliters), and then of the addition of TBTU (6.4 grams, 1 9.4 millimoles) and ethyl-di-isopropylamine (1 2 milliliters, 70.4 millimoles), the mixture is stirred at room temperature for 2 hours, then the solvent is evaporated in a high vacuum The residue is dissolved in ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate, and brine.The organic layers are dried over sodium sulfate, and evaporated under reduced pressure.The crude mixture is crystallized from methanol. Yield: 4.1 grams (53 percent) MS (ESI): 440 [M + H] +, 1 H-NMR (DMSO-de): d (ppm) 11.6 (s, 1H), 8.26 (d, 1H), 7.56 (d, 2H), 7.38 (d, 1H), 7.15-7.35 (m, 7H), 7.08 (d, 2H), 7.01 (d, 1H), 4.07 (m, 1H), 3.81 (s, 3H), 3.47 (s, 2H), 2.8 (m, 2H), 2.04 (m, 2H), 1.77 (m, 2H), 1.58 (m, 2H). (3) Step C: 4- (4-methoxy-phenyl) -1H-indole-2-carboxylic acid piperidin-4-yl-amide (178). Dissolve the 179 (4 grams, 9.1 mmol) in 100 milliliters of methanol, flood with argon, and, after the addition of Pd-C (100 milligrams) and 2M HCl (5.5 milliliters, 11 mmol), the mixture is hydrogenated at room temperature for 3 hours. The mixture is filtered over Celite, and evaporated. Yield: 1 gram of a white solid (29 percent). MS (ESI): 350 [M + H] +. Example 142 { 1 - [(1S, 9aR) -1- (Octahydro-quinolizin-1-yl) -methyl] -piperidin-4-yl} 4- (4-ethoxy-phenyl) -1H-indoI-2-carboxylic acid amide.

This compound is synthesized from compound 180 (for the preparation, see below), and octahydro-2H-quinolizin-1-yl-methanol, in a manner analogous to the method described in Example 127. Yield: 23 milligrams (16.2) percent). MS (ESI): 515 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 11.67 (s, 1H), 8.28 (d, 1H), 7.56 (d, 2H), 7.33 (d , 1H), 7.3 (m, 1H), 7.20 (dd, 1H), 7.0-7.07 (m, 3H), 4.08 (q, 2H), 3.77 (m, 1H), 2.80 (dd, 2H), 2.67 ( m, 2H), 2.46 (dd, 1H), 2.28 (dd, 1H), 2.01 (dd, 1H), 1.36 (t, 3H), 1.1-2.1 (m, 19H).

Synthesis of 4- (4-ethoxy-phenyl) -1H-n-dol-2-carboxylic acid piperidin-4-yl-amide (180): This compound has been synthesized from 4-ethoxy-phenyl-boronic acid, in a manner analogous to the method described in the synthesis of 178 (see Example 141). MS (ESI): 364 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 11.64 (s, 1 H), 8.28 (d, 1 H), 7.55 (d, 2 H), 7.35 (d , 1H), 7.31 (s, 1H), 7.19 (dd, 1H), 7.06 (d, 2H), 7.02 (d, 1H), 4.09 (q, 2H), 3.81 (m, 1H), 3.4 (m, 1H), 2.92 (m, 2H), 2.46 (m, 2H), 1.77 (m, 2H), 1.4 (m, 2H), 1.37 (t, 3H).

Example 143 { 1 - [(S) -2 - ((3S, 4S) -4-hydroxy-3-methyl-piperidin-1-yl) -propyl] -piperidin-4-yl} 4- (6-methoxy-pyridin-3-yl) -1 H-indole-2-carboxylic acid amide.

This compound is synthesized from the 4- (6-methoxy-pyridin-3-yl) -4H-indole-2-carboxylic acid piperidin-4-ylamide 181 (for the preparation, see below), and the amine 164, in a manner analogous to the method described for 54, followed by the dissociation of the protecting group. MS (ESI): 504 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 11.7 (s, 1H), 8. 48 (br s, 1H), 8.28 (d, 1H), 7.97 (d, 1H), 7.41 (d, 1H), 7.36 (s, 1H), 7. 24 (dd, 1H), 7.09 (d, 1H), 6.96 (d, 1H), 4.44 (d, 1H), 3.93 (s, 3H), 3.68 - 3.82 (m, 1H), 2.61 - 2.96 (m, 6H), 2.04 - 2.39 (m, 4H), 1.85 - 1.96 (m, 2H), 1.66 - 1.82 (m, 3H), 1.45 - 1.65 (m, 2H), 1.2 - 1.44 (m, 2H), 0.91 (d, 3H), 0.86 (d, 3H). Synthesis of 4- (6-methoxy-pyridin-3-yl) -1H-indole-2-carboxylic acid piperidin-4-yl-amide (181) (1) Step A: 4 - [( 4-bromo-1H-indole-2-carbonyl) -am and no] -piperidine-1-carboxylic acid (182). 4-Bromo-1 H-indole-2-carboxylic acid is dissolved (3 grams, 12. 5 mmol) in 30 milliliters of N, N-dimethyl formamide, and the solution is cooled to 0 ° C. After addition of Hunig's base (6.4 milliliters, 37.5 millimoles), the mixture is stirred for 15 minutes. The terbutil-ester of piperidin-4-yl-carbamic acid 3 (2.5 grams, 12.5 millimoles) is added, followed by PyBOP (7.2 grams, 13.7 millimoles). The reaction mixture is stirred for 18 hours at room temperature. Then, ethyl acetate and concentrated sodium hydroxide are added until a pH of 11 is reached. The organic layers are washed with brine, dried over sodium sulfate and evaporated. The crude product is further purified by evaporation chromatography (silica gel, ethyl acetate / cyclohexane, 1: 1). Yield: 5.13 grams (97 percent). MS (ESI): 420, 422 [M-H] ", 1 H-NMR (DMSO-de): d (ppm) 11.9 (m, 1H), 8.48 (d, 1H), 7.45 (d, 1H), 7.27 (d, 1H), 7.21 (s, 1H), 7.11 ( dd, 1H), 2.86 (m, 2H), 1.81 (m, 2H), 1.42 (s, 9H), 1.42 (m, 2H). (2) Step B: Terbutil-acid ester 4-. { [-4- (6-methoxy-pyridin-3-yl) -1H-indole-2-carbonyl] -amino} -piperidine-1-carboxylic acid (183). A stream of argon was bubbled through a solution of 182 above (500 milligrams, 1.2 millimoles), and 2-methoxy-5-pyridine boronic acid (181 milligrams, 1.2 millimoles) in 4 milliliters of 1-propanol for 15 minutes. . Then add an aqueous solution of 2M sodium carbonate (1.2 milliliters, 2.4 millimoles) and bis- (triphenylphosphine) -palladium chloride (ll) (50 milligrams, 0.07 millimoles), and the reaction mixture is stirred at 85 ° C for 3 hours. The mixture is then cooled to 0 ° C, and ethyl acetate and a concentrated solution of sodium hydroxide are added until a pH of 11 is reached. The solution is washed with brine, and the organic layers are dried over sodium sulfate and dried. evaporate. The crude product is purified by evaporation chromatography (silica gel, cyclohexane / ethyl acetate, 7: 3). Yield: 290 milligrams (69 percent). MS (ESI): 451.2 [M + H] +, 1 H-NMR (CDCl 3): d (ppm) 9.3 (s, 1 H), 8.53 (s, 1 H), 7.96 (d, 1H), 7.46 (d, 1H), 7.38 (dd, 1H), 7.17 (d, 1H), 6.98 (s, 1H), 6.86 (d, 1H), 6.12 (d, 1H), 4.13 (m, 2H) ), 4.08 (s, 3H), 2.91 (m, 2H), 2.01 (m, 2H), 1.48 (s, 9H), 1.42 (m, 2H), 1.27 (m, 1H). (3) Step C: 4- (6-Methoxy-pyridin-3-yl) -1H-indole-2-carboxylic acid piperidin-4-yl-amide (181). The above 183 (370 milligrams, 0.82 millimoles) is dissolved in a 4M solution of HCl in dioxane (7.5 milliliters, 30 millimoles), and stirred for 1 hour at room temperature. The reaction mixture is then evaporated, dissolved in ethyl acetate, and concentrated sodium hydroxide is added until a pH of 11 is reached. The organic layer is washed with brine, dried over sodium sulfate, and evaporated under reduced pressure. . Yield: 300 milligrams (100 percent). MS (ESI): 351.2 [M + H] \ 1 H-NMR (DMSO-de): d (ppm) 11.74 (m, 1H), 8.51 (s, 1H), 8.35 (d, 1H), 8.00 (d, 1H), 7.44 (d, 1H), 7.41 (s, 1H), 7.27 (dd, 1H), 7. 11 (d, 1H), 7.00 (d, 1H), 3.95 (s, 3H), 3.84 (m, 1H), 2.96 (m, 2H), 2.31 (m, 1H), 2.01 (m, 2H), 1.75 (m, 2H), 1.4 (m, 2H). Example 144 { 1- [2 - ((3S, 4S) -4-hydroxy-3-methyl-piperidin-1-yl) -ethyl] -piperidin-4-yl} 4- (6-methoxy-pyridin-3-yl) -1H-indole-2-carboxylic acid amide.

This compound is synthesized from 4- (6-methoxy-pyridin-3-yl) -1H-indole-2-carboxylic acid [1- (2-hydroxy-ethyl) -piperidin-4-yl] -amide. 184 (for the preparation, see below), and (3S, 4S) -3-methyl-piperidin-4-yl-ester of 2,2-dimethyl-propionic acid (17), in a manner analogous to the method described in Example 150, followed by the cleavage of the protecting group. MS (ESI): 492 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 11.70 (s, 1 H), 8.48 (br s, 1 H), 8.30 (d, 1 H), 7.97 ( dd, 1H), 7.42 (d, 1H), 7.36 (s, 1H), 7.24 (t, 1H), 7.09 (d, 1H), 6.97 (d, 1H), 4.47 (d, 1H), 3.92 (s) , 3H), 3.75 (m, 1H), 2.70 - 2.90 (m, 5H), 2.31 - 2.41 (m, 4H), 1.86 -2.04 (m, 3H), 1.66 - 1.82 (m, 3H), 1.46 - 1.62 ( m, 3H), 1.3-1.44 (m, 2H), 0.86 (d, 3H). Synthesis of 4- (6-methoxy-pyridin-3-yl) -1H-indole-2-carboxylic acid ri- (2-hydroxy-ethyl) -piperidin-4-yl-amide (184) Piperidine is dissolved 4- (6-Methoxy-pyridin-3-yl) -1H-indole-2-carboxylic acid (4-yl) -amide (181), (150 milligrams, 0.43 mmol) in 3 milliliters of ethanol under argon. After the addition of sodium carbonate (182 milligrams, 1.7 millimoles) and 2-bromoethanol (61 microliters, 0.85 millimoles), the reaction mixture is stirred at 80 ° C for 13 hours. The mixture is diluted with methylene chloride, filtered, and the filtrate is evaporated. Evaporation under reduced pressure gave 128 milligrams of the crude product, which is further purified by evaporation chromatography (dichloromethane / methanol / 25 percent ammonia (90: 9: 1) Yield: 90 milligrams (53 percent). (ESI): 395.2 [M + H] +. Example 145 { 1 - [(1S, 9aR) -1- (Octahydro-quinolizin-1-yl) -methyl] -piperidin-4-yl}. 4-p-tolyloxy-1H-indole-2-carboxylic acid amide.

This compound is synthesized from compound 185 (for the preparation, see below), and octahydro-2H-quinolizin-1-yl-methanol, in a manner analogous to the method described in Example 127. Yield: 86 milligrams ( 34.9 percent). MS (ESI): 501 [M + H] +, 1 H-NMR (DMSO-de): d (ppm) 11.7 (s, 1H), 8.2 (d, 1H), 7.2 (d, 2H), 7.15 (d , 2H), 7.1 (s, 1H), 6.85 (d, 2H), 6.47 (d, 1H), 3.72 (m, 1H), 2.8 (dd, 2H), 2.70 (d, 2H), 2.45 (m, 1H), 2.3 (s, 3H), 2.28 (m, 1H), 2.03 (dd, 1H), 1.1-2.1 (m, 19H). Synthesis of 4-p-tolyloxy-1 H-indole-2-carboxylic acid piperidin-4-yl-amide (185): Reaction Scheme 18: (1) Step A: 4-p-tolyloxy-1 H -i ndol-2-carboxylic acid (1-benzyl-piperidin-4-yl) -amide (1 86). 4-p-Tolyloxy-1 H-indole-2-carboxylic acid is dissolved (1 37) (850 milligram, 3.2 millimoles), and 4-amino-N-benzyl-piperidine (605 milligrams, 3.2 millimoles) in 5 milliliters of N, N-dimethylformamide, and after the addition of TBTU (1.2 grams) , 3.5 mmol) and ethyl-di-isopropyl-amine (2.2 milliliters, 12.8 mmol), the mixture is stirred at room temperature for 2 hours. Then the mixture is evaporated in a high vacuum. The residue is dissolved in ethyl acetate and washed with a saturated solution of NaHCO 3, and brine. The organic layers are dried over Na 2 SO 4, filtered, and evaporated under reduced pressure. Yield: 1.47 grams (100 percent) of a yellow foam.

MS (ES I): 438 [M-H] \ (2) Step B: 4-p-Tolyloxy-1 H-indole-2-carboxylic acid piperidin-4-yl-amide (1 85). Pd-C (1 gram) is placed in a flask filled with argon and covered with methanol. Dissolve 1 86 (1.4 grams, 3.2 mmol) in 100 milliliters of methanol, and add 1.6 milliliters of 2M HCl. After hydrogenation at room temperature for 5 hours, the mixture is filtered on Celite and evaporated. Yield: 1.1 grams (96 percent) of a white foam. MS (ESI): 350 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 11.75 (s, 1 H), 8.43. (d, 1H), 7.2 (d, 1H), 7.1 - 7.2 (m, 4H), 6.85 (d, 2H), 6.47 (d, 1H), 4.05 (m, 1H), - 3.26 (m, 2H) , 2.90 (m, 2H), 2.73 (s, 1H), 2.28 (s, 3H), 1.9 (m, 2H), 1.7 (m, 2H). Alternatively, the branched indole-2-carboxamides could be prepared as shown in the reaction template 19.

Reaction Scheme 19: Example 146 4-Isobutoxy-1H-indoI-2-carboxylic acid 1- (2-azepan-1-yl-1S-methyl-ethyl) -piperidin-4-yl] -amide. (1) Step A: 4-Isobutoxy-1H-indole-2-carboxylic acid [1- (2R-hydroxy-propyl) -piperidin-4-yl] -amide (187). A solution of 4-isobutoxy-1H-indole-2-carboxylic acid piperidin-4-yl-amide hydrochloride (161) of Example 127 (300 milligrams, 0.85 millimoles) in 5 milliliters of ethanol, and triethylamine (0.472 milliliters, 3.4 mmol), treated with R (+) - propylene oxide (0.59 milliliters, 4.25 mmol), and stirred at room temperature in a sealed container for 14 hours. Another portion of R (+) - propylene oxide (0.59 milliliters, 4.25 millimoles) is added, and stirring is continued for 24 hours. Then the solvents evaporate. The crude is redissolved in DCM, and washed with 2N NaOH and brine. The organic layer is dried over anhydrous sodium sulfate and evaporated to give a white powder. Yield: 290 milligrams (91 percent). MS (ESI): 374.1 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 11.45 (s, 1H), 8.22 (d, 1H), 7. 22 (s, 1H), 7.03 (t, 1H), 6.97 (d, 1H), 6.45 (d, 1H), 4.25 (br s, 1H), 3.84 (d, 2H), 3.75 (overlapping m, 2H) , 2.87 (m, 2H), 1.98-2.39 (m, 5H), 1.76 (m, 2H) 1.58 (m, 2H), 1.05 (m, 9H). (2) Step B: 4-Isobutoxy-1H-indole-2-carboxylic acid [1- (2-azepan-1-yl-1S-methyl-ethyl) -piperidin-4-yl] -amide.

The alcohol (187) above (100 milligrams, 0.27 millimoles) is mixed with azepane (0.033 milliliters, 0.298 millimoles), DIEA (0.227 milliliters, 1.34 millimoles), and cyanomethyl-triphenyl-phosphonium iodide (156 milligrams, 0.648 millimoles) in 2 milliliters of propionitrile. The suspension is heated to 90 ° C for 3 hours. The resulting solution is cooled, diluted with EtOAc, washed with 2N NaOH, and brine, dried over anhydrous sodium sulfate, and evaporated. The crude material is purified by chromatography on silica gel using DCM (saturated with ammonia) and MeOH (from 0 percent to 10 percent). Yield: 74 milligrams (61 percent). MS (ESI): 455.4 [M + H] +, 1 H-NMR (DMSO-de): d (ppm) 11.43 (s, 1H), 8.2 (d, 1H), 7.22 (s, 1H), 7.02 (t , 1H), 6.96 (d, 1H), 6.44 (d, 1H), 3.84 (d, 2H), 3.72 (brm, 1H), 2.52-2.95 (m, 8H), 2.15-2.4 (m, 3H) , 2.1 (m, 1H), 1.77 (m, 2H), 1.45 - 1.67 (m, 10H) 1.05 (d, 6H), 0.95 (d, 3H). Example 147 [1- (2-azepan-1-yl-1R-methyl-ethyl) -piperidin-4-yl] -amide of 4-isobutoxy-1H-indole-2-carboxylic acid.

The title compound is prepared as described in Example 83 from 4-isobutoxy-1H-indole-2-carboxylic acid piperidin-4-yl-amide (161), S (-) - propylene oxide, and azepano. The intermediate of [1- (2S-hydroxy-propyl) -piperidin-4-yl] -amide of 4-isobutoxy-1H-indole-2-carboxylic acid (188) and the final product, had spectra of MS and NMR identical to those of the enantiomers- (R) of Example 146. Example 148 [1- (2S-azepan-1-yl-propyl) -piperidin-4-yl] -amide of 4- (furan- 3-l-methoxy) -1H-? NdoJ-2-carboxylic acid.

S (-) - propylene oxide (21.2 milliliters, 302.5 millimoles), and azepam (3.41 milliliters, 30.25 millimoles) are mixed in 10 milliliters of ethanol, and stirred in a sealed container for 24 hours. The solvents are then evaporated, and the crude oil of 1-azepan-1-yl-propan-2S-ol (189) is used as such without further purification. Yield: 2.25 grams (47 percent). The above alcohol (189) (63 milligrams, 0.408 millimoles) is mixed with the 4- (furan-3-yl-methoxy) -1H-indole-2-carboxylic acid piperidin-4-yl-amide 165 (see Example 133) of Step B (100 milligrams, 0.27 millimoles), DIEA (0.227 milliliters, 1.35 millimoles), and cyanomethyl-triphenyl-phosphonium iodide (193 milligrams, 0.81 millimoles) in 2 milliliters of propionitrile. The suspension is heated at 90 ° C for 3 hours. The resulting solution is cooled, diluted with EtOAc, washed with 2N NaOH and brine, dried over anhydrous sodium sulfate, and evaporated. The crude material is purified by chromatography on silica gel using DCM (saturated with ammonia) and MeOH (from 0 percent to 10 percent). Rendimienío: 45 milligrams (35 percent). MS (ESI): 479.1 [M + H] +, 1 H-NMR (DMSO-de): d (ppm) 11.46 (s, 1H), 8.14 (d, 1H), 7.82 (s, 1H), 7.68 (s, 1H), 7.22 (s, 1H), 7.05 (t, 1H), 6.99 (d, 1H), 6.62 (s, 1H), 6.59 (d, 1H), 5.03 (d, 2H), 3.72 (m, 1H), 2.75-2.95 (m, 3H), 2.58 (m, 4H), 2.33 (m, 1H), 2.0-2.2 (m, 2H), 1.92 (m, 1H), 1.74 (m, 2H), 1.45-1.6 (m, 10H), 0.91 (d, 3H). Example 149 4- (furan-3-l-methoxy) -1H-indoI-2-carboxylic acid 1- (2R-azepan-1-yl-propyl) -piperidin-4-yl] -amide.

The title compound is prepared by starting with 4- (furan-3-yl-meioxy) -1H-indole-2-carboxylic acid (4,6-pyridin-4-yl-amide) (165), as described in Example 133, using R (+) - propylene oxide instead of the enanlimer- (S). The MS and NMR specimens are identical to those of their enantiomeric example 148. Alternatively, the 4-alkoxy-indole-2-carboxamides are prepared as shown in reaction template 20.

Reaction Scheme 20: Example 150 { 1- [2- (3,6-dihydro-2 H -pyridin-1-yl) -etl] -piperidin-4-yl} -amide of 4-isobutoxy-1H-indole-2-carboxylic acid.

Subsequently, 1,2,5,6-pherahydro-pyridine (25.4 microliths, 0.279 mmol), cyano-methyl-triphenyl-phosphonium iodide (162.5 milligrams, 0.6686 mmol), and Hünig's base (171 microliters, 1 millimole) are added. , to a suspension of 190 (for the preparation, see below) (100 milligrams, 0.279 millimoles) in 4 milliliters of propioniírilo. The mixture was stirred for 2 hours at 100 ° C, then diluted with ethyl acetate, washed with a 1N sodium hydroxide solution and brine, and dried over sodium sulfalous. The evaporation gave 138 milligrams of the crude product, which is further purified by means of preparative HPLC (RP, aceionitrile / water). Rendimienfo: 55 milligrams (47 per cent). MS (ESI): 443.3 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 11.45 (s, 1 H), 8.2 (d, 1 H), 7.23 (d, 1 H), 7.04 (t) , 1H), 6.97 (d, 1H), 6.45 (d, 1H), 4.5 (d, 1H), 3.85 (d, 2H), 3.74 (m, 1H), 3.41 (m, 1H), 2.88 (m, 2H), 2.71 (m, 2H), 2.38 (m, 4H), 2.1 (m, 1H), 2.0 (m, 4H), 1.76 (m, 2H), 1.68 (m, 2H), 1.55 (m, 2H) ), 1.35 (m, 2H), 1.06 (d, 6H). Synthesis of 4-isobutoxy-1H-indole-2-carboxylic acid ri- (2-hydroxy-ethyl) -piperidin-4-yl-amide (190) (1) Step A: Terbutil-ester of [1- ( 2-hydroxy-ethyl) -piperidin-4-yl] -carbamic acid (191). The terpene-ester of piperidin-4-yl-carbamic acid (5 grams, 25 mmol) is dissolved in 100 milliliters of ethanol. After the addition of sodium carbonate (10.6 grams, 100 millimoles), 2-bromo-ethanol (3.55 milliliters, 50 millimoles) is added dropwise. The reaction mixture is refluxed for 16 hours, and then evaporated. The residue is dissolved in 100 milliliters of dichloromethane, and filtered. The residue is washed with DCM. The combined filtrates are evaporated, which gives 10.1 grams of a yellow oil, which is further purified by chromatography by evaporation (silica gel, DCM / mefanol / concentrated ammonia, 90: 9: 1). Yield: 4.02 grams (66 percent) of a white solid. MS (ESI): 443.3 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 11.45 (s, 1H), 8.2 (d, 1H), 7.23 (d, 1H), 7.04 (t , 1H), 6.97 (d, 1H), 6.45 (d, 1H), 4.5 (d, 1H), 3.85 (d, 2H) 3.74 (m, 1H), 3.41 (m, 1H), 2.88 (m, 2H ), 2.71 (m, 2H), 2.38 (m, 4H), 2.1 (m, 1H), 2.0 (m, 4H), 1.76 (m, 2H), 1.68 (m, 2H), 1.55 (m, 2H), 1.35 (m, 2H) ), 1.06 (d, 6H). (2) Step B: 2- (4-amino-piperidin-1-yl) -ethanol (192). Compound 191 (4.02 grams, 16.46 mmol) was brought with 4M HCl in dioxane (60 milliliters, 240 mmol), and the mixture was stirred at ambient temperature for 1 hour. The white precipitate is filtered, washed with water, and dried under an empty dish. The mother liquor was concentrated and ran dry. The white solid is filtered and dried under an empty dish. Rendimienío: 3.42 grams (95.9 per cent). MS (ESI): 443.3 [M + H] +, 1 H-NMR (DMSO-dβ): d (ppm) 11.45 (s, 1H), 8.2 (d, 1H), 7.23 (d, 1H), 7. 04 (f, 1H), 6.97 (d, 1H), 6.45 (d, 1H), 4.5 (d, 1H), 3.85 (d, 2H) 3.74 (m, 1H), 3.41 (m, 1H), 2.88 (m, 2H), 2.71 (m, 2H), 2.38 (m, 4H), 2.1 (m, 1H), 2.0 (m, 4H), 1.76 (m, 2H), 1.68 (m, 2H), 1.55 (m, 2H), 1.35 (m, 2H), 1.06 (d, 6H). (3) Step C: 4-Isobutoxy-1H-indole-2-carboxylic acid [1- (2-hydroxy-ethyl) -piperidin-4-yl] -amide (190). The 4-isobutoxy-1 H-indole-2-carboxylic acid 80 (for the preparation, see Example 8, 1 gram, 4.29 mmol) is suspended in 5 milliliters of N, N-dimethyl formamide, cooled to 0 °. C, and it is based on Hünig (1.46 milliliters), 8.58 millimoles). The mixture was stirred for 15 min. At 0 ° C. In a separate reaction mixture, the compound 192 (931 milligrams, 4.29 millimoles) in 10 milliliters of N, N-dimethyl formamide was cooled to 0 ° C, brought with an aqueous 10M sodium hydroxide solution (0.858 milliliters, 8.58 millimoles), and it is stirred for 15 minutes at the same time. This solution is added to the abovementioned mixture, followed by benzotriazole-1-l-oxy-fri-pyrrolidin-phosphonium hexafluorophosphate (PyBOP, 2.34 grams, 4.5 mmol), and is stirred for 4 hours at ambient temperature. The reaction mixture is diluted with ethyl efflux and washed with a 2N sodium hydroxide solution, water, and brine. The evaporation gave a crude yellow semi-solid product, which is treated with ether, filtered, and washed with ether. Yield: 657 milligrams (83 per cent). MS (ESI): 443.3 [M + H] +, 1 H-NMR (DMSO-de): d (ppm) 11.45 (s, 1H), 8.2 (d, 1H), 7.23 (d, 1H), 7.04 (s) , 1H), 6.97 (d, 1H), 6.45 (d, 1H), 4.5 (d, 1H), 3.85 (d, 2H) 3.74 (m, 1H), 3.41 (m, 1H), 2.88 (m, 2H ), 2.71 (m, 2H), 2.38 (m, 4H), 2.1 (m, 1H), 2.0 (m, 4H), 1.76 (m, 2H), 1.68 (m, 2H), 1.55 (m, 2H) , 1.35 (m, 2H), 1.06 (d, 6H). Example 151 { 1- [2- (4-hydroxy-azepan-1-yl) -ethyl] -piperidin-4-yl} -amide of 4-isobutoxy-1H-indole-2-carboxylic acid.

This compound is synthesized in a manner analogous to Example 150, to form 4- [1- (2-hydroxy-ethyl) -piperidin-4-yl] -amide of 4-isobuhioxy-1H-indole-2-carboxylic acid 190, and azepan-4-ol Rendimienfo: 36 milligrams (80 per cent). MS (ESI): 457 [M + H] +, 1 H-NMR (DMSO-de): d- (ppm) 11.45 (s, 1H), 8.19 (d, 1H), 7.23 (s, 1H), 7.02 ( i, 1H), 6.96 (d, 1H), 6.44 (d, 1H), 4.35 (d, 1H), 3.84 (d, 2H), 3.80 - 3.62 (m, 2H), 3.29 (s, 1H), 2.88 (d, 2H), 2.68 - 2.30 (m, 8H), 2.14 - 2.06 (m, 1H), 2 ^ 0 (1, 2H), 1.83 - 1.34 (m, 9H), 1.05 (d, 6H). Example 152 { 1- [2- (3-amino-azepan-1-yl) -ethyl] -piperidin-4-yl} -amide of 4-isobutyl-1 H-indole-2-carboxylic acid.

This compound is synthesized in a manner analogous to Example 150, to parifir of [1- (2-hydroxy-ethyl) -piperidin-4-yl] -amide of 4-isobuoyoxy-1H-indole-2-carboxylic acid 190, and azepan-3-yl-amine. Rendimienío: 48 milligrams (38 per cent). MS (ESI): 456.3 [M + H] +, 1 H-NMR (DMSO-de): d (ppm) 11.5 (s, 1H), 8.27 (d, 1H), 7.24 (s, 1H), 7.05 (s) , 1H), 6.97 (d, 1H), 6.46 (d, 1H), 3.84 (d, 2H), 3.80 - 3.70 (m, 1H), 2.89 (m, 2H), 2.79 (m, 1H), 2.68 - 2.62 (m, 1H), 2.60 - 2.52 (m, 4H), 2.43-2.27 (m, 3H), 2.15 - 2.05 (m, 1H), 2.05 - 1.95 (m, 2H), 1.78 - 1.72 (m, 2H) ), 1.70 - 1.68 (m, 2H), 1.60 - 1.50 (m, 6H), 1.43 - 1.35 (m, 1H), 1.32 - 1.22 (m, 1H), 1.05 (d, 6H). Example 153 { 1- [2- (3-Fluoro-piperidin-1-yl) -ethyl] -piperidin-4-yl} -amide of 4-isobutyl-1 H-indole-2-carboxylic acid.

To a suspension of 190 (see Example 150) (100 milligrams, 0.28 millimoles), 3-fluoropiperidine hydrochloride (43 milligrams, 0.208 millimoles), and DIEA (0.189 milliliters, 1.12 millimoles) in 0.5 milliliters of propionitrile, is added cyano-methyl-triphenyl-phosphonium iodide (81 milligrams, 0.336 mmol). The mixture was heated at 90 ° C for 14 hours. Then the resulfanie solution is diluted with EOAc (20 milliliters), and washed twice with saturated sodium bicarbonate, dried over sodium sulfate, and evaporated. The crude product is further purified by preparative HPLC. Rendimienío: 30 milligrams (24 per cent). MS (ESI): 445.3 [M + H] +, 1 H-NMR (DMSO-de): d (ppm) 11.43 (s, 1H), 8.19 (d, 1H), 7.22 (s, 1H), 7.02 (l , 1H), 6.96 (d, 1H), 6.45 (d, 1H), 4.45 - 4.7 (m, 1H), 3.84 (d, 2H), 3.74 (m, 1H), 2.88 (m, 2H), 2.76 ( m, 1H), 2.18-2.48 (m, 8H), 2.1 (m, 1H), 2.0 (m, 2H), 1.34-1.9 (m, 7H), 1.05 (d, 6H). Example 4 4- (5-Chlorobenzofuran-3-yl-methoxy) -1H-indole-2-carboxylic acid [4- (2-piperidin-1-yl-ethyl-ethyl) -phenyl] -amide.

This compound is synthesized in a manner analogous to Example 150, from 4- (5-chlorobenzofuran-3-yl-methoxy) -1H-indole-2-carboxylic acid 4- (2-hydroxy-eyl) -phenyl] -amide 193 (for the preparation, see more ahead), and piperidine. Yield: 140 milligrams (67 percent). MS (ESI): 528/530 [M + H] +, 1 H-NMR (DMSO-de): d (ppm) 11.69 (s, 1H), 10.00 (s, 1H), 8. 28 (s, 1H), 7.85-7.35 (m, 6H), 7.25-7.00 (m, 4H), 6.75 (d, 1H), 5.40 (2, 2H), 2.70 (m, 4H), 2.60-2.20 ( m, 4H), 1.55-1.40 (m, 6H). Synthesis of 4- (5-chlorobenzofuran-3-yl-methoxy) -1H-indole-2-carboxylic acid (4-hydroxy-ethyl) -phenyl-1-amino acid ester (193) This compound is synthesized from a manner analogous to the Example 42, from 4- (5-chloro-benzofuran-3-yl-methoxy) -1H-indole-2-carboxylic acid (97) and 2- (4-amino-phenyl) -ethanol. Yield: 1.59 grams (69 percent) of a white solid. MS (ESI): 461/463 [M + HJ +, 1 H-NMR (DMSO-d 6): d (ppm) 11.68 (s, 1 H), 9.99 (s, 1 H), 8.27 (s, 1 H), 7.80 (d , 1H), 7.70-7.60 (m, 3H), 7.46 (d, 1H), 7.39 (dd, 1H), 7.20-7.10 (m, 3H), 7.06 (d, 1H), 6.75 (d, 1H), . 37 (s, 2H), 4.59 (m, 1H), 3.57 (m, 2H), 2.67 (1, 2H). Example 155 { 4- [2- (4-hydroxy-piperidin-1-yl) -etii] -phenyl} 4- (5- Chloro-benzofuran-3-yl-methoxy) -1H-indole-2-carboxylic acid amide.

This compound is synthesized in a manner analogous to Example 154, starting from 4- (5-chlorobenzofuran-3-yl-meioxy) -1H-indole-2 [4- (2-hydroxy-eyl) -phenyl] -amide. -carboxylic (193), and piperidin-4-yl-ester of acid 2, 2-dimethyryl propionic acid, followed by the removal of the pro-active group by means of sodium methylation. Rendimienío: 38 milligrams (34.9 per cent). MS (ESI): 528/530 [M + H] +, 1 H-NMR (DMSO-de): d (ppm) 11.68 (s, 1H), 8.27 (s, 1H), 7.63 (d, 1H), 7.70. - 7.60 (m, 3H), 7.45 (d, 1H), 7.38 (dd, 1H) (s, 1H), 7.20 - 7.00 (m, 4H), 6.75 (d, 1 H), 5.37 (s, 2H) , 4.49 (d, 1H), 3.42 (m, 1H), 2.80 - 2.60 (m, 4H), 2.45 - 2.40 (m, 1H), 2.10 - 1.95 (m, 3H), 1.75 - 1.65 (m, 2H) 1.45-1.30 (m, 2H). The 4-aryl-indole-2-carboxamides are prepared in general by a Suzuki coupling of the 4-bromo-indole-2-carboxamides with the corresponding aryl-boronic acids (Reaction Esquema 15).

Reaction Scheme 21: Example 156 4-phenyl-1 H-indole-2-carboxylic acid [1- (2-azepane-1-ethyl-ethyl) -piperidin-4-yl] -amide.

Bromindol 1 94 (for preparation, see below) (1 50 milligrams, 0.335 millimole), phenyl boronic acid (82 milligrams, 0.67 millimole), and triphenyl phosphine (26.4 milligrams, 0.1 12 millimole), are dissolved in 1 0 milliliters of ileol. After the addition of 1 milliliter of ethanol, argon is injected through the mixture for 30 minutes. Then, acetylation of Pd (I I) (3 milligrams, 1 3.4 micromoles), and 2M aqueous sodium carbonate (0.67 milliliters, 1.34 millimoles) are added. The mixture was stirred under reflux for 3 hours. After cooling to ambient temperature, the mixture was sprayed with 30 milliliters of ethyl alcohol, and a 5% aqueous solution of NaHC03, and filtered over Celite. The organic layer is separated, and evaporation under reduced pressure gives 1 70 milligrams of the crude product, which is further purified by chromatography by evaporation (silica gel, effilo kephir / meianol, concentrated NH3, 90: 10: 2), and by crisíalización to paríir aceiaío de éíilo. Rendimienío: 45 milligrams (30 per cent) of a white solid; MS (ESI): 445.4 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 11.64 (s, 1 H), 8.25. (d, 1H), 7.63 (d, 2H), 7.50 (dd, 2H), 7.40 (m, 2H), 7.31 (s, 1H), 7.23 (dd, 1H), 7.08 (d, 1H), 3.73 (m, 1H), 2.85 (m, 2H), 2.57 (m, 6H), 2.36 (m, 2H), 1.99 (m, 2H), 1.74 (m, 2H), 1.52 (m, 10H). (1) 4-Bromo-1 H-indole-2-carboxylic acid (1-4) - (1- (2-azepan-1-yl-ethyl) -piperidin-4-yl] -amide. 4-Bromo-1 H-indole-2-carboxylic acid (1.5 grams, 3.1 mmol), trichlorhydride of 1- (2-azepan-1-yl-eyl) -piperidin-4-yl-amine (5) are dissolved ( 2.1 grams, 3.1 millimoles), and DIEA (4.3 milliliters, 12.4 millimoles), under an argon atmosphere, in N, N-dimefilformamide (25 milliliters). TBTU (2.3 grams, 3.4 millimoles) is added to the ambient temperature. The reaction mixture is stirred for 2 hours at room temperature, evaporated under an empty ally, dissolved in ethyl acetate, and washed twice with an aqueous solution of 5 percent NaHCO 3. The organic layers are dried over sodium sulfate. Evaporation under reduced pressure gave 1.3 grams (93 percent) of a beige solid. MS (ESI): 447.1, 449.1 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 11.9 (s, 1H), 8.4 (d, 1H), 7.4 (d, 1H), 7.25 (d, 1H), 7.2 (s, 1H), 7.08 (dd, 1H), 3. 76 (m, 1H), 2.88 (m, 2H), 2.55 - 2.68 (m, 6H), 2.4 (m, 2H), 2.05 (m, 2H), 1.78 (m, 2H), 1.5-1.62 (m, 10H). Example: 4- (4-trifluoromethyl-phenyl) -1H-indole-2-carboxylic acid 1- (2-azepan-1-yl-ethyl) -piperidin-4-yl] -amide.

This compound is synthesized to form part of compound 194 (see Example 146) and 4-trifluoromethyl-phenyl-boronic acid, in a manner analogous to the method described in Example 156. Yield: 35 milligrams (20 percent) of white chrysolics; MS (ESI): 513 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 11.75 (s, 1 H), 8.25 (d, 1 H), 7.85 (s, 4 H), 7.48 (d, 1H), 7.32 (s, 1H), 7.28 (dd, 1H), 7.15 (d, 1H), 3.75 (m, 1H), 2.87 (m, 2H), 2.5-2.6 (m, 6H), 2.38 (m, 2H), 2. 0 (m, 2H), 1.78 (m, 2H), 1.48-1.55 (m, 10H). Example 158 4-p-Tol l-1 H -indole-2-carboxylic acid 1- (2-azepan-1-yl-ethyl) -piperidin-4-yl] -amide.

This compound is synthesized from compound 194 (see Example 156) and 4-p-tolyl boronic acid, in a manner analogous to the method described in Example 156. Delivery: 40 milligrams (26 percent) of a white foam; MS (ESI): 459 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 11.6 (s, 1H), 8. 25 (d, 1H), 7.53 (d, 2H), 7.48 (d, 1H), 7.32 (d, 2H), 7.3 (s, 1H), 7.2 (dd, 1H), 7.05 (d, 1H), 3.75 (m, 1H), 2.5-2.6 (m, 8H), 2.38 (s, 3H), 2.33-2.4 (m, 2H), 2.0 (m, 2H), 1.75 (m, 2H), 1.48 - 1.55 (m , 10H). Example 159 1- (2-azepan-1-yl-ethyl) -piperidin-4-yl] -amide of 4- (4-dimethylamino-phenyl) -1 H -indole-2-carboxylic acid.

This compound is synthesized from compound 194 (see Example 156) and (4-dimethylamino-phenyl) -boronic acid, in a manner analogous to the method described in Example 156. Yield: 45 milligrams (28 percent) of a white foam; MS (ESI): 488.2 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 11.55 (s, 1H), 8. 25 (d, 1H), 7.3 - 7.4 (m, 2H), 7.15 - 7.25 (m, 3H), 7.07 (m, 2H), 3.8 (s, 3H), 3.78 (s, 3H), 3.75 (m, 1H), 2.88 (m, 2H), 2.57 (m, 6H), 2.38 (m, 2H), 2.0 (m, 2H), 1.75 (m, 2H), 1.5 (m, 4H), 1.75 (m, 10H). Example 1-4-Benzo [1,2,5] oxadiazoI-5-yl-1H-indole-2-carboxylic acid 1- (2-azepan-1-yl-ethyl) -piperidin-4-yl] -amide. .

This compound is synthesized from the compound 194 (see Example 156) and benzo [1,2,5] oxadiazol-5-yl-boronic acid, in a manner analogous to the method described in Example 156. Yield: 85 milligrams ( 39 per cent) of white crystals; MS (ESI): 487.1 [M + H] +, 1 H-NMR (DMSO-de): d (ppm) 11.8 (s, 1 H), 8.3 (d, 1 H), 8.2 (s, 1 H), 8.18 (d , 1H), 7.95 (d, 1H), 7.52 (m, 1H), 7.38 (s, 1H), 7.3 (d, 1H), 3.75 (m, 1H), 2.87 (m, 2H), 2.5 - 2.6 ( m, 6H), 2.36 (m, 2H), 2.0 (m, 2H), 1.75 (m, 2H), 1.47-1.58 (m, 10H).

Example 161 4- (4-methoxy-phen? I) -1H-indole-2-carboxylic acid [1- (2-azepan-1-yl-ethyl) -piperidin-4-yl] -amide.

This compound is synthesized from compound 194 (see Example 156) and (4-methoxy-phenyl) -boronic acid, in a manner analogous to the method described in Example 156. Yield: 22 milligrams (38 percent) of a white foam; MS (ESI): 475.4 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 11.59 (s, 1H), 8. 23 (d, 1H), 7.49 (d, 2H), 7.32 (m, 2H), 7.18 (dd, 1H), 7.0 (d, 1H), 6.85 (d, 2H), 3.75 (m, 1H), 2.97 (s, 6H), 2.87 (m, 2H), 2.56 (m, 6H), 2.48 (m, 2H), 2.0 (m, 2H), 1.77 (m, 2H), 1.52 (m, 10H). Example 162 4- (3-cyano-phenyl) -1H-indoI-2-carboxylic acid 1- (2-azepan-1-yl-ethyl) -piperidin-4-yl] -amide.

This compound is synthesized from compound 194 (see Example 156) and 3-cyano-phenyl-boronic acid, in a manner analogous to the method described in Example 156. Yield: 115 milligrams (55 percent) of white crystals; MS (ESI): 470.1 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 11.75 (s, 1 H), 8.38 (d, 1 H), 8.05 (s, 1 H), 7.98 (dd) , 1H), 7.88 (m, 1H), 7.72 (dd, 1H), 7.47 (d, 1H), 7.3 (d, 1H), 7.25 (d, 1H), 7.15 (d, 1H), 3.75 (m, 1H), 2.87 (m, 2H), 2.48-2.6 (m, 6H), 2.37 (m, 2H), 2.0 (m, 2H), 1.75 (m, 2H), 1.47 - 1.58 (m, 10H). Example 163 4- (4-Ethoxy-phenyl) -1H-indole-2-carboxylic acid 1- (2-azepan-1-yl-ethyl) -piperidin-4-yl] -amide.

This compound is synlelated from compound 194 (see Example 156) and (4-ethoxy-phenyl) -boronic acid, in a manner analogous to the method described in Example 156. Yield: 40 milligrams (24 percent) of crystals beiges; MS (ESI): 487 [MH] ", 1 H-NMR (DMSO-d 6): d (ppm) 11.6 (s, 1H), 8.25 (d, 1H), 7.57 (d, 2H), 7.38 (d, 1H ), 7.32 (s, 1H), 7.2 (dd, 1H), 7.05 (d, 2H), 7.02 (d, 1 H), 4.07 (q, 2H), 3.75 (m, 1H), 2.85 (m, 2H) ), 2.50 -2.58 (m, 6H), 2.38 (m, 2H), 2.0 (m, 2H), 1.75 (m, 2H), 1.48 - 1.58 (m, 8H), 1.38 (t, 3H). [4- (3- (3-methoxy-propoxy) -phenyl] -1H-indole-2-carboxylic acid [1- (2-azepan-1-yl-ethyl) -piperidin-4-yl] -amide.

This compound is synthesized from compound 194 (see Example 156) and [3- (3-methoxy-propoxy) -phenyl] -boronic acid, in a manner analogous to the method described in Example 156. Yield: 160 milligrams ( 67 percent) of a beige foam; MS (ESI): 533.2 [M + H] +, 1 H-NMR (DMSO-ds): d (ppm), 11.65 (s, 1H), 8. 28 (d, 1H), 7.38-7.4 (m, 2H), 7.32 (s, 1H), 7.2-2.25 (m, 2H), 7.15 (m, 1H), 7.08 (d, 1H), 6.95 (dd, 1H), 4.1 (t, 2H), 3.75 (m, 1H), 3.48 (t, 2H), 3.25 (s, 3H), 2.85 (m, 2H), 2.48 - 2.58 (m, 8H), 2.35 (m , 2H), 1.95 - 2.04 (m, 4H), 1.75 (m, 2H), 1.48 - 1.6 (m, 10H). Example 165 4- (4-Trifluoromethoxy-phenyl) -1H-indole-2-carboxylic acid [1- (2-azepan-1-yl-ethyl) -piperidin-4-yl] -amide.

This compound is synthesized from compound 194 (see Example 156) and 4-urea-phenyl-boronic acid, in a manner analogous to the method described in Example 156. Delivery: 75 milligrams (42 percent) of a white foam; MS (ESI): 529 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 11.7 (s, 1H), 8. 28 (d, 1H), 7.78 (d, 2H), 7.50 (d, 2H), 7.44 (d, 1H), 7.3 (s, 1H), 7. 25 (dd, 1H), 7.08 (d, 1H), 3.75 (m, 1H), 2.87 (m, 2H), 2.5-2.6 (m, 6H), 2.38 (m, 2H), 2.0 (m, 2H), 1.75 (m, 2H), 1.48 - 1.6 (m, 10H). Example 166 4- (2,4-dimethoxy-phenyl) -1H-indole-2-carboxylic acid 1- (2-azepan-1-yl-ethyl) -piperidin-4-yl] -amide.

This compound is synthesized from compound 194 (see Example 156) and acid (2,4-dimethoxy-phenyl) -boronic acid 1 in a manner analogous to the method described in Example 156. Yield: 120 milligrams (53 percent) of a beige foam; MS (ESI): 505.1 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 11.45 (s, 1 H), 8.15 (d, 1 H), 7.34 (d, 1 H), 7.2 (d , 1H), 7.15 (dd, 1H), 6.93 (d, 1H), 6.9 (d, 1H), 6.7 (d, 1H), 6.65 (dd, 1H), 3.84 (s, 3H), 3.73 (m, 1H), 3.68 (s, 3H), 2.85 (m, 2H), 2.47-2.58 (m, 8H), 2.35 (m, 2H), 1.98 (m, 2H), 1.75 (m, 2H), 1.47 - 1.58 (m, 8H). Example 167 4- (3,4-Dimethoxy-phenyl) -1H-indole-2-carboxylic acid 1- (2-azepan-1-yl-ethyl) -piperidin-4-yl] -amide.

This compound is synthesized from compound 194 (see Example 156) and (3,4-dimethoxy-phenyl) -boronic acid, in a manner analogous to the method described in Example 156. Delivery: 65 milligrams (29 percent) of white crlisles; MS (ESI): 505.2 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 11.6 (s, 1 H), 8.25 (d, 1 H), 7.3 - 7.4 (m, 2 H), 7.15 - 7.25 (m, 3H), 7.07 (m, 2H), 3.8 (s, 3H), 3.78 (s, 3H), 3.75 (m, 1H), 2.88 (m, 2H), 2.57 (m, 6H), 2.38 (m, 2H), 2.0 (m, 2H), 1.75 (m, 2H), 1.5 (m, 4H), 1.75 (m, 10H). Example: 4-benzo [1, 3] dioxol-5-yl-1-H-indole-2-carboxy I [1- (2-azepane-1-yl-ethyl) -piperidin-4-yl] -amide ico This compound is synthesized from compound 194 (see Example 156) and benzo [1,3] dioxol-5-yl-boronic acid, in a manner analogous to the method described in Example 156.

Rendimienío: 75 milligrams (34 per cent) of white chrysanthemums; MS (ESI): 489.1 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 11.6 (s, 1 H), 8.28. (d, 1H), 7.38 (d, 1H), 7.3 (m, 1H), 7.2 (d, 1H), 7.18 (m, 1H), 7.1 (dd, 1H), 7.04 (dd, 1H), 6.08 (s, 2H), 3.75 (m, 1H), 2.87 (m, 2H), 2.48-2.6 (m, 6H), 2.37 (m, 2H), 2.0 (m , 2H), 1.75 (m, 2H), 1.47 - 1.58 (m, 10H). Example 169 4-pyridin-4-yl-1H-indole-2-carboxylic acid 1- (2-azepan-1-yl-ethyl) -piperidin-4-yl] -amide.

This compound is synthesized from compound 194 (see Example 156) and pyridin-4-yl-boronic acid, in a manner analogous to the method described in Example 156. Yield: 35 milligrams (53 percent) of beige chrysolics; MS (ESI): 446.2 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 11.8 (s, 1 H), 8.68 (d, 2 H), 8.3 (d, 1 H), 7.68 (d , 1H), 7.5 (d, 1H), 7.38 (s, 1H), 7.3 (m, 1H), 7.2 (d, 1H), 3.75 (m, 1H), 2.88 (m, 2H), 2.45 - 2.6 ( m, 6H), 2.38 (m, 2H), 2.0 (m, 2H), 1.75 (m, 2H), 1.48 - 1.6 (m, 10H).

Example: 4- (6-methoxy-pyridin-3-yl) -1H-indole-2-carboxylic acid 1- (2-azepan-1-yl-ethyl) -piperidin-4-yl] -amide.

This compound is synthesized from compound 194 (see Example 156) and (6-methoxy-pyridin-3-yl) -boronic acid, in a manner analogous to the method described in Example 156. Yield: 125 milligrams (59%) cienío) of white chrysalis; MS (ESI): 476.4 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 11.65 (s, 1 H), 8.48. (d, 1H), 8.3 (d, 1H), 7.98 (dd, 1H), 7.42 (d, 1H), 7.35 (s, 1H), 7.24 (dd, 1H), 7.08 (d, 1H), 6.97 ( d, 1H), 3.93 (s, 3H), 3.75 (m, 1H), 2.87 (m, 2H), 2.48-2.6 (m, 6H), 2.35 (m, 2H), 2.0 (m, 2H), 1.75 (m, 2H), 1.47-1.58 (m, 10H). Example 171 4- (4-Ethoxy-phenyl) -1H-indole-2-carboxylic acid 1- (2-piperidin-1-yl-ethyl) -piperidin-4-yl] -amide.

This compound is synthesized from compound 195 (for the preparation, see below) and (4-eioxy-phenyl) -boronic acid, in a manner analogous to the method described in Example 156.

Rendimienfo: 100 milligrams (46 per cent) of yellow chrysalis; MS (ESI): 475 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 11.6 (s, 1H), 8.25 (d, 1H), 7.55 (d, 2H), 7.35 (d , 1H), 7.3 (s, 1H), 7.2 (dd, 1H), 7.05 (d, 2H), 7.02 (d, 1H), 4.08 (q, 2H), 3.73 (m, 1H), 2.87 (m, 2H), 2.25-2.4 (m, 8H), 2.0 (m, 2H), 1.75 (m, 2H), 1.3-1.57 (m, 8H), 1.38 (t, 3H). (1) 4-bromo-1H-indole-2-carboxylic acid (1- (2-piperidin-1-yl-ethyl) -piperidin-4-yl] -amide (195).

This compound is synthesized from 4-bromo-1H-indole-2-carboxylic acid, and amine 4, in a manner analogous to the method described above for the synthesis of 194 (see Example 156). MS (ESI): 433, 435 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 11.9 (s, 1 H), 8.4 (d, 1 H), 7.4 (d, 1 H), 7.23 (d, 1H), 7.19 (s, 1H), 7.08 (dd, 1H), 3.76 (m, 1H), 2.88 (m, 2H), 2.3-2.4 (m, 8H), 2.0 (m, 2H), 1.78 (m, 2H), 1.3-1.6 (m, 8H). Example 172 { 1- [2- (4-hydroxy-piperidin-1-yl) -ethyl] -piperidin-4-yl} 4- (4-methoxy-phenyl) -1H-indoI-2-carboxylic acid amide.

This compound is synthesized from compound 196 (for the preparation, see below), and acid (4-methoxy-phenyl) -boronic acid, in a manner analogous to the method described in Example 156. Yield: 55 milligrams (35 ppm) cienío) of a white foam; MS (ESI): 477.2 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 11.6 (s, 1 H), 8.25 (d, 1 H), 7.58 (d, 2 H), 7.36 (d , 1H), 7.3 (s, 1H), 7.2 (dd, 1H), 7.05 (d, 2H), 7.02 (d, 1H), 4.55 (br, 1H), 3.85 (s, 3H), 3.78 (m, 1H), 3.45 (, 1H), 2.9 (m, 2H), 2.78 (m, 2H), 2.45 (m, 4H), 2.15 (m, 2H), 2.05 (m, 2H), 1.3 - 1.8 (m, 8H). (1) . { 1- [2- (4-hydroxy-piperidin-1-yl) -ethyl] -piperidin-4-yl} 4-bromo-1H-indole-2-carboxylic acid amide (196).

This compound is synthesized by parfing 4-bromo-1H-indole-2-carboxylic acid and amine 21, in a manner analogous to the method described for 194 (see Example 156). MS (ESI): 449 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 11.9 (s, 1 H), 8.42 (d, 1 H), 7.4 (d, 1 H), 7.23 (d , 1H), 7.2 (s, 1H), 7.08 (dd, 1H), 3.8 (m, 1H), 3.5 (, 1H), 2.88 (m, 2H), 2.95 (m, 2H), 2.86 (m, 2H) ), 2.6 (m, 2H), 2.52 (m, 2H), 2.3 (m, 2H), 2.12 (m, 2H), 1.8 (m, 2H), 1.75 (m, 2H), 1.58 (m, 2H) , 1.43 (m, 2H). Example 173. { 1- [2- (4-hydroxy-piperidin-1-yl) -ethyl] -piperidin-4-yl} 4- (4-Ethoxy-phenyl) -1H-indole-2-carboxylic acid amide.

This compound is synthesized according to compound 196 (see Example 172) and (4-eioxy-phenyl) -boronic acid, in a manner analogous to the method described in Example 156. Yield: 45 milligrams (21 percent) of crystals whites; MS (ESI): 491 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 11.6 (s, 1H), 8.24 (d, 1H), 7.54 (d, 2H), 7.34 (d, 1H), 7.3 (s, 1H), 7.19 (dd, 1H), 7.06 (d, 2H), 7.0 (d, 1H), 4.47 (d, 1H), 4.08 (q, 2H), 3.73 (m, 1H) ), 3.40 (m, 1H), 2.85 (m, 2H), 2.68 (m, 2H), 2.36 (m, 4H), 1.98 (m, 4H), 1.74 (m, 2H), 1.65 (m, 2H) , 1.51 (m, 2H), 1.37 (t, 3H), 1.32 (m, 2H). Example 174 { 1- [2- (4-hydroxy-piperidin-1-yl) -ethyl] -piperidin-4-yl} 4- (6-methoxy-pyridin-3-yl) -1H-indole-2-carboxylic acid amide.

This compound is synthesized from compound 196 (see Example 172) and acid (6-methoxy-pyridin-3-yl) -boronic acid, in a manner analogous to the method described in Example 156. Rendimienio: 28 milligrams ( 18 per cent) of white chrysalis; MS (ESI): 478.1 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 11.68 (s, 1H), 8.47 (d, -1H), 8.27 (d, 1H), 7.95 ( dd, 1H), 7.40 (d, 1H), 7.35 (s, 1H), 7.23 (dd, 1H), 7.09 (d, 1H), 6.97 (d, 1H), 4.48 (d, 1H), 3.92 (s) , 3H), 3.75 (m, 1H), 3.39 (m, 1H), 2.85 (m, 2H), 2.68 (m, 2H), 2.36 (m, 4H), 1.99 (m, 4H), 1.75 (m, 2H), 1.65 (m, 2H), 1.54 (m, 2H), 1.35 (m, 2H). Example 175 { 1- [2- (3-hydroxy-8-aza-bicyclo [3.2.1] oct-8-yl) -ethyl] -piperidin-4-yl} 4- (4-methoxy-phenyl) -1H-indole-2-carboxylic acid amide.

This compound is synthesized from compound 197 (for the preparation, see below), and (4-methoxy-phenyl) -boronic acid, in a manner analogous to the method described in Example 156. Yield: 90 milligrams (57 ppm) cent) of a white foam; MS (ESI): 503.2 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 11.6 (s, 1H), 8.25 (d, 1H), 7.55 (d, 2H), 7.35 (d , 1H), 7.3 (m, 1H), 7.2 (dd, 1H), 7.05 (d, 2H), 7.02 (d, 1H), 4.25 (br s, 1H), 3.82 (s, 3H), 3.78 (m , 1H), 3.75 (m, 1H), 3.1 (m, 2H), 2.88 (m, 2H), 2.38 (m, 4H), 2.0 (m, 4H), 1.85 (m, 2H), 1.77 (m, 4H), 1.55 (m, 4H). (1) . { 1- [2- (3-hydroxy-8-aza-bicyclo [3.2.1] oct-8-yl) -ethyl] -piperidin-4-yl} 4-bromo-1H-indole-2-carboxylic acid amide (197).

This compound is synthesized from 4-bromo-1H-indole-2-carboxylic acid and amine 24, in a manner analogous to the method described for 194 (see Example 156). MS (ESI): 475.3 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 11.7 (br s, 1 H), 8.28 (br s, 1 H), 7.49 (d, 1 H), 7.25 (d, 1H), 7.15 (s, 1H), 7.1 (dd, 1H), 4.1 (br s, 1H), 3.97 (m, 3H), 3.5 (m, 2H), 3.0 (m, 2H), 2.5 (m, 6H), 1.9-2.2 (m, 10H).

Example 176 { 1- [2- (3-hydroxy-8-aza-bicyclo [3.2.1] oct-8-yl) -ethyl] -piperidin-4-yl} 4- (6-methoxy-pyridin-3-yl) -1H-indole-2-carboxylic acid amide.

This compound is sinieized from compound 197 (see Example 175) and (6-methoxy-pyridin-3-yl) -boronic acid, in a manner analogous to the method described in Example 156. Yield: 90 milligrams (57 ppm) cent) of a white foam; MS (ESI): 504.2 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 11.6 (s, 1 H), 8.48 (d, 1 H), 8.28 (d, 1 H), 7.97 (dd) , 1H), 7.4 (d, 1H), 7.35 (m, 1H), 7.23 (dd, 1H), 7.08 (d, 1H), 6.95 (d, 1H), 4.23 (br, 1H), 3.93 (s, 3H), 3.78 (m, 1H), 3.75 (m, 1H), 3.1 (m, 2H), 2.88 (m, 2H), 2.38 (m, 4H), 2.0 (m, 4H), 1.8 (m, 6H) ), 1.53 (m, 4H). Alternatively, the 4-alkoxy-indole-2-carboxamides are prepared as shown in Reaction Run 22.

Reaction Scheme 22: Example 177 4-hydroxy-1H-indole-2-carboxylic acid [1- (2-azepan-1-yl-ethyl) -piperidin-4-yl] -amide.

The methoxyl derivative of Example 1 (100 milligrams, 0.25 mmol) is dissolved in 5 milliliters of DCM. A solution of BBr3 (1M in DCM, 2.5 milliliters, 2.5 mmol) is added, and the mixture is stirred for 18 hours. It is then poured onto ice, and washed with EtOAc (30 milliliters). The pH of the water layer is adjusted to 9, and extracted twice with EtOAc. The organic layers are combined, washed with brine, dried over anhydrous sodium sulfate, and evaporated. Rendimienío: 24 milligrams (25 per cent). MS (ESI): 385.3 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 9.62 (s, 1H), 8. 14 (d, 1H), 7.2 (d, 1H), 6.94 (t, 1H), 6.86 (d, 1H), 6.37 (d, 1H), 3.75 (m, 1H), 2.89 (m, 2H), 2.53 - 2.65 (m, 6H), 2.39 (m, 2H), 2.03 (m, 2H), 1.78 (m, 2H), 1.47-1.68 (m, 10H), 1.25 (m, 1H).

Synthesis of the benzothiophen-2-carboxamides The 4-alkoxy-benzothiophen-2-carboxylates are synthesized starting from 4-thiophen-2-yl-butyric acid (Reaction Scheme 23).

Reaction Scheme 2312: (204) (205) (1) 6,7-dihydro-5H-benzo [b] thiophen-4-one (198). Dissolve ortho-phosphoric acid (85 percent, 0.27 milliliters, 3.7 millimoles) in acetic acid anhydride (13 milliliters), and after the addition of 4-iiophen-2-yl-butyric acid (9 grams, 52.9 millimoles) , the mixture is stirred at 1 20 ° C for 2.5 hours. The brown solution is cooled using an ice bath, water is added, and the reaction mixture is extracted with dichloromethane. The organic layers are washed with a 2M NaOH solution, and twice with water, until a neutral pH is reached. The solution is dried over Na 2 SO, and evaporated under reduced pressure. The crude product is obtained as a chamomile oil (7.84 grams), which is further purified by means of chromatography by evaporation (silica gel, ethyl acetate / hexane, 9: 1). Yield: 5.83 grams (72 percent) of a slightly yellow solid. MS (ESI): 1 52 [M] +, 1 H-NMR (DMSO-d 6): d (ppm) 7.38 (d, 1 H), 7.25 (d, 1 H), 3.03 (i, 2H), 2.48 (m, 2H), 2.12 (t, 2H). (2) 5-brom or-6J7-dihydro-5H-benzo [b] thiophen-4-one (199). 6,7-Dihydro-5H-benzo [b] thiophen-4-one (1 98, 5.8 grams, 38.3 mmol) is dissolved in 200 milliliters of dry diethyl ether, and cooled to -10 ° C. Slowly add a solution of bromine (6.1 grams, 38.3 millimoles) in 30 milliliters of tetrachloromean and 2 to 3 gofas of diethyl ether. The mixture is agitated for 1 5 minutes at -10 ° C, for 15 minutes at 0 ° C, and 18 hours at room temperature. Then water and diethyl ether are slowly added. The organic layers are washed with water, dried over Na2SO4, and evaporated.

Performance: 8.7 grams of a solid yellow (containing 23 percent of the starting material). M S (ES I): 230, 232 [M] +, 1 H-RM N (DMSO-d6): d (ppm) 7.46 (d, 1 H), 7.3 (d, 1 H), 4.87 (dt, 1 H), 3.1 (m, 2H), 2.45 (m, 2H). (3) Benzo [b] thiophen-4-ol (200). 5-Bromo-6,7-dihydro-5H-benzo [b] thiophen-4-one (99.99, 77 pure percent, 8.7 grams, 28.9 mmol), LiBr (5.7 grams, 65.1 mmol), and Li2CO3 are placed. (4.3 grams, 57.8 mmol) under argon in 300 milliliters of N, N-dimethyl formamide, and refluxed for 3 hours. The reaction mixture is allowed to cool to room temperature, and is evaporated under a high vacuum. After the addition of ice water and cold aqueous 2M HCl solution, the mixture is extracted with diethyl ether. The organic layers are extracted with 2M NaOH, and the combined aqueous layers are acidified with concentrated HCl. The product is extracted twice with ethyl acetate, and the organic layers are washed with a saturated NaCl solution, dried over Na2SO, and evaporated under reduced pressure. Yield: 4.7 grams of a solid chestnut, which is used without further purification. MS (ES I): 149.0 [MH] \ 1 H-RM N (DMSO-ds): d (ppm) 9.95 (br s, 1 H), 7.55 (d, 1 H), 7.45 (d, 1 H) 7.38 (d, 1 H), 7.15 (dd, 1 H), 6.72 (d, 1 H). (4) 4-isobutoxy-benzo [b] thiophene (201). Benzo [b] thiophen-4-ol (200, 4.3 grams, 28.9 millimoles) and iso-butanol (3.2 milliliters, 34.7 millimoles) are dissolved under argon in 150 milliliters of foluene. After the addition of triphenylphosphine (9.1 grams, 34.7 millimoles) and 40% DEAD solution in toluene (16.8 milliliters, 34.7 millimoles), the mixture was agitated at 120 ° C overnight. After cooling, the reaction mixture is subsequently washed with a saturated aqueous solution of NaHCO 3 and a solution of NaCl, dried over Na 2 SO 4, and evaporated under reduced pressure. The triphenylphosphine oxide is removed by crystallization from ethyl acetate and hexane, and the crude product is further purified by evaporation chromatography (silica gel, hexane / ethyl acetate, 9: 1). Yield: 5.4 grams (91 percent) of a yellow oil. MS (ESI): 206 [M] +, 1 H-NMR (DMSO-d 6): d (ppm) 7.62 (d, 1H), 7.5 (d, 1H), 7.44 (d, 1H), 7.27 (dd, 1H ), 6.85 (d, 1H), 3.88 (d, 2H), 2.12 (m, 1H), 1.05 (d, 6H). (5) 4-Isobutoxy-benzo [b] thiophene-2-carboxylic acid (202). A 1.6 M solution of n-butyllithium in hexane (18 milliliters, 28.8 millimoles) is dissolved under an argon atmosphere in 100 milliliters of dry diethyl ether, followed by the dropwise addition of a solution of 4-isobutoxy. benzo- [b] -thiophene (201, 5.4 grams, 26.1 mmol) in 40 milliliters of diethyl ether. The reaction mixture is refluxed for 45 minutes, then cooled and transferred by syringe to a mixture of excess dry ice (115 grams, 2.61 moles) in diethyl ether (the dry ice is washed twice before with diethyl ether). The mixture is left stirring during the night at ambient temperature, then it is distributed between diethyl ether and water.

The ether layers are re-extracted with water. The aqueous layers are acidified with an aqueous 2M HCl solution, and the precipitate is filtered, washed with water, and dried under a high vacuum. Yield: 3.72 grams (57 percent) of a white solid. MS (ESI): 250 [M] +, 1 H-NMR (DMSO-d 6): d (ppm) 13.4 (br s, 1 H), 7.98 (s, 1H), 7.55 (d, 1H), 7.43 (dd, 1H), 6.9 (d, 1H), 3.9 (d, 2H), 2.14 (m, 1H), 1.05 (d, 6H). Example 178 4-methoxy-benzo [b] thiophene-2-carboxylic acid [1- (2-azepan-1-yl-ethyl) -piperidin-4-yl] -amide.

A solution of a mixture of 4- and 6-methoxy-benzo [b] thiophene-2-carboxylic acid (CR Hebd, Seances Acad, Sel 1965, 261, 705) (440 milligrams, 1.05 mmol), amine 5 ( 357 milligrams, 1.05 millimoles) in 10 milliliters of N, N-dimethyl formamide, is treated with EDC (178 milligrams, 1.05 millimoles), HOBT hydrate (178 milligrams, 1.15 millimoles), and triethylamine (0.44 milliliters, 3.15 millimoles). The mixture is stirred overnight, and then evaporated under an empty dish. The crude residue is dissolved in ethyl acetate, and washed twice with sodium bicarbonate (10 percent), brine, and dried over sodium sulfate. The crude product is then purified by evaporation chromatography (ethyl acetate / meihanol / ammonia, 90: 10: 1). Rendimienlo: 45 milligrams (10 percent) of a yellow solid (and 84 milligrams of the 6-substituted isomer). MS (ESI): 416.1 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 8.53 (d, 1H), 8.2 (s, 1H), 7. 5 (d, 1H), 7.37 (dd, 1H), 6.9 (d, 1H), 3.94 (s, 3H), 3.7 (br m, 1H), 2. 88 (m, 2H), 2.6 (m, 6H), 2.4 (m, 2H), 2.0 (m, 2H), 1.75 (m, 2H), 1. 47-1.6 (m, 10H). Example 179 [1- (2-azepan-1-yl-ethyl-ethyl) -piperidin-4-yl] -amide of 4-isobutoxy-benzo [b] thiof in -2-carboxylic acid.

This compound is synthesized from compound 202 and amine 5, in a manner analogous to the method described in Example 178. Yield: 340 milligrams (53 percent) of a beige powder. MS (ESI): 458.4 [M + H] +, 1 H-NMR (DMSO-d 6): d (ppm) 8.58 (d, 1H), 8.15 (s, 1H), 7.5 (d, 1H), 7.35 (dd) , 1H), 6.88 (d, 1H), 3.9 (d, 2H), 3.7 (br m, 1H), 2.9 (m, 2H), 2.6 (m, 6H), 2.4 (m, 2H), 2.15 (m , 1H), 2.0 (m, 2H), 1.78 (m, 2H), 1.5 - 1.65 (m, 10H), 1.05 (d, 6H). Example 4-Isobutoxy-benzo [b] thiophene-2-carboxylic acid [1- (2-piperidin-1-yl-ethyl) -piperidin-4-yl] -amide.

This compound is synthesized from compound 202 and amine 1, in a manner analogous to the method described in Example 178. Yield: 93 milligrams (26 percent) of a beige powder. MS (ESI): 444.3 [M + H] +, 1 H-NMR (DMSO-dβ): d (ppm) 8.58 (d, 1H), 8.15 (s, 1H), 7.48 (d, 1H), 7.35 (dd, 1H), 6.88 (d, 1H), 3.9 (d, 2H), 3.7 (br m, 1H), 2.88 (m, 2H), 2.3 - 2.4 (m, 8H), 2.15 (m, 1H), 1.98 (m, 2H), 1.78 (m, 2H), 1.58 (m, 2H), 1.47 (m, 4H), 1.35 (m, 2H), 1.05 (d, 6H). Synthesis of the benzofuran-2-carboxamides Example 181 [1- (2-azepan-1-yl-ethyl) -piperidin-4-yl] -amide of 4-methoxy-benzofuran -2-carboxylic acid.

This compound is synthephized in a manner analogous to Example 1, starting from 4-methoxy-benzofuran-2-carboxylic acid and amine 5. MS (ESI): 400.2 [M + H] +, 1 H-NMR (DMSO-d6 ): d (ppm) 8.42 (d, 1H), 7.5 (s, 1H), 7.37 (t, 1H), 7.21 (d, 1H), 6.84 (d, 1H), 3.92 (s, 3H), 3.72 ( m, 1H), 2.88 (m, 2H), 2.35-2.68 (m, 8H), 2.02 (m, 2H), 1.76 (m, 2H), 1.48-1.67 (m, 10H). The compounds of formula I in free form or in pharmaceutically acceptable salt form exhibit valuable pharmacological properties, for example as an anonymity of CCR2 and CCR5, as indicated in the in vitro tests described below. a) CCR2 membrane bond assay. The SPA technology (Scintillation Proximity Assay) is used to demonstrate that the test compounds prevent MCP-1 from binding to the cell membranes expressing the CCR2 receptor. Transfected CHO-dukX cells that expressly express the hCCR2b gene are grown in an alpha MEM medium to a confluence of between 70 and 80 percent. After discarding the medium, 30 milliliters of an ice cold physiological buffer containing 1 mM EDTA, and the cells are removed from the pill by using a scraper. The cell suspension is centrifuged at 800 g for 10 minutes at 4 ° C, and the cell pellet is re-suspended in the regulator. Cell lysis is done using a Polyfron PTI300D at 28,000 revolutions per minute for 30 seconds twice on ice. The membranes are harvested by centrifugation at 42,000 g for 20 minutes at 4 ° C, and subjected to a second round of lysis (Polylron, 28,000 revolutions per minute, 30 seconds, twice, on ice). Following the sterilization at 42,000 g for 20 minutes at 4 ° C, the membranes are re-suspended in the regulator at a concentration of 2 m ilig ram / m ililiter, and stored at -80 ° C. 1 0 μM supply solutions are prepared from the test compounds in 1 percent ethyl d-sulfoxide. The test compounds are further diluted in the regulator, to produce the solutions concentrated four times, for the tests that tested an interval of 10"1 0 to 1 0" 5 M. The S PA assay is carried out in a final volume of 200 microliters per well in 96-well plates. The components are added, per well, in the following order: 50 microliters of Regulator (+/- test compound 50 microlives of wheat germ agglutinin beads-SPA (1.25 milligrams / well) in the regulator. microliters of CCR2B membrane suspension diluted with the regulator to 0.04 milligrams / milliliter (2 micrograms / well), al- ternatively 50,000 cells per well 50 microliters of [125I] MCP-1 in the regulator (final concentration of 60 pM, 2.5 μCi / plate) After the addition of all the components, the plate is sealed and incubated for 90 minutes at room temperature with constant agitation.After incubation, the plate is centrifuged at 1 000 revolutions per minute in a Sorvall RC3B centrifuge for 4 minutes at room temperature, and is counted for 3 minutes per well in a TOP COUNT instrument (Packard) .The corrected counts are used when switching off for radioligand analysis. Ormula I have an I C50 of between 0.0003 and 1 0 μM. In a similar way, binding assays have been established for rat, mouse, and Rhesus monkey CCR2 receptors. Due to the species specificity of the CCR2 antagonisms, the compounds of the formula I have an I C50 of between 0.01 5 and 1.0 μM on mouse CCR2, and between 0.020 and 1.0 μM on rat CCR2. b) Functional assay of CCR2 - Mobilization of Ca2 + Cells hCCR2b-C HO # 84: A CHOdukX cell line expressing the hCCR2 gene is cultivated in MEMa to an 80% confluence. On the day before the experiment, the cells are harvested from the tissue culture flask by trypsinization, washed, applied to a 96-well black / clear well plate at 5 x 114 cells per well, and culminated last overnight at 37 ° C in a humid atmosphere enriched with 5 percent C02. The following day, cells are washed twice and loaded for 1 hour at room temperature in the dark with 2 μM Fluo-4 in regulator C. After two additional washes, cells are resuspended in regulator D The serial dilutions of the compounds, in regulator D, are mixed with the cells, and incubated for half an hour at room temperature in the dark. The cells are then stimulated by injection of MCP-1 and calcium fluxes are monitored using the Flexsiation ™ R, a bench-top fluorometer with an integrated fluid transfer work station.

HBSS X Hepes 20mM BSA 0.1% Probenecid 625μM BSA 0.5% Regulator A X X Controller B X X X Controller C X X X Controller D X X X X * Hank's balanced alt solution (10X) without phenol red (# 14065-049, G ibco BRL).

HCCR2b-300.19 cells: Pre-B 300-1 9 cell line is stably expressing the hCCR2 gene (Loetscher et al., J. Biol.

Chem. 276 (5), 2986-91 (2001)), in RPMl 1 640 with glutamax-l supplemented with non-essential amino acid M EM 1 X, 1 mM sodium pyruvate, 5 x 1 0"5 ß-mercaptoethanol, and fetal calf serum at 10 percent For the experiment, the cells are used in the exponential growth phase, at a maximum concentration of 1.5 x 1 06 cells per milliliter.The cells are washed in regulator A, and They charge in approximately 2.1 06 cells per milliliter in 2 μM fluo-4 in regulator B for 30 minutes in the dark, at 37 ° C in a water bath After two washes with regulator A, the cells are applied to a 96-well plate of black / clear bottom, at 2 x 1 05 cells per well in regulator B. All the following steps, including the compound and chemokine dilutions, are carried out as described above for hCCR2b cells -CHO # 84, except that regulator B is used instead of regulator D. In this test, the You have an IC50 of formula 0.0005 and 1.0 μM. c) Functional assay of CCR2 - chemotaxis. An in vitro cell migration assay is used for CCR2-dependent chemotaxis based on membrane inserts Transwell R, to profile the compounds. The assay is carried out with the human monocytic cell line TH P-1, and with activated peripheral blood lymphocytes (PBL). THP-1 cells are cultured in RPMl 1640 supplemented with 1 0 percent heat-inactivated calf fetal serum. Activated peripheral blood lymphocytes are prepared from human blood by elutriation, and then activated by culturing on culture plates coated with human-like CD3, and expanded by a subsequent culture in a medium supplemented with I L-2. Aliquots of activated peripheral blood lymphocytes are frozen in liquid nitrogen and used in migration experiments after thawing and culinating at night. Cells from the cultures at a density of less than 1.2 x 106 cells / milliliter are counted, washed, and resuspended at an appropriate density in RPM 1 1640 with 0.5 percent bovine serum albumin. TranswellM R membrane inserts of 6.5 millimeters in diameter, a pore size of 3 or 8 microns, and a polycarbonate membrane trayed with tissue culture are used for migration tests. The trans-well inserts are loaded with cells and compounds in a final volume of 1 00 microliters in RPMl 1 640 / 0.5 percent bovine serum albumin. For TH P-1 cells, inserts with a pore size of 8 micras are used. For peripheral blood lymphocytes, the use of inserts with a pore size of 3 microns resulted in lower non-specific counts. The inserts are placed in a 24-well tissue culture plate containing recombinant human MCP-1 and compounds in a final volume of 600 microliters. After allowing the cells to migrate to the bottom compartment, the assay is stopped by removing and discarding the trans-well inserts. The cells of the fundus are collected and counted in a FACScan flow cytometer, acquiring all the sludge for 30 seconds, with the positions established for each type of cell. The migration is expressed as absolute cell counts / 30 seconds, in relation to the number of cells introduced measured under the same conditions. In this test, the compounds of the formula I have an IC 50 of between 0.001 2 and 1 0 μM. d) CCR5 membrane bond assay. Human CCR5 is used to generate stable transfectants in CH O K1 cells. The membranes prepared from these CCR5 transfectants, are used in a radio binding test using 1 25-l-M I P-1 as a binding, and the compounds of formula I are tested to determine their inhibitory activity. The data are reported as IC 50, that is, the required concentration of the compound to achieve a 50 percent inhibition of the [I-1 25] M I P-1 a binding. The Agents of the Invention are effective as double antagonists of CCR-2 and CCR-5. Accordingly, the Agents of the Invention are useful for the prophylaxis and treatment of diseases or medical conditions mediated by CCR-2 and CCR-5. The CCR-2 and CCR-5 have an important role in leukocyte trafficking, in particular in the migration of monocytes to the inflammatory sites, and consequently, the agents of the invention can be used to inhibit the migration of monocytes, by example, in the treatment of inflammatory conditions, allergies and allergic conditions, autoimmune diseases, chronic pain, graft rejection, cancers that involve leukocyte filtration, stenosis or restenosis, atherosclerosis, rheumatoid arthritis, osteoarthritis, and chronic pain. The diseases or conditions that can be treated with the Agents of the Invention include: Inflammatory or allergic conditions, including allergic respiratory diseases such as asthma, allergic rhinitis, COPD, pulmonary hypersensitivity diseases, hypersensitivity pneumonitis, interstitial lung disease (LD), (for example, idiopathic pulmonary fibrosis). , or I LD associated with autoimmune diseases such as RA, S LE, etc.); chronic disease, chronic obstructive anaphylaxis and hypersensitivity responses, drug allergies (for example, to penicillins or cephalosporins), and allergies to insect bites; inflammatory conditions of the osteosine, such as Crohn's disease and ulcerative colitis; spondyloarthropathies, sclerodoma; inflammatory psoriasis and dermatoses such as dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, urticaria; vasculitis; autoimmune diseases, in particular autoimmune diseases with an etiology including an inflammatory component, such as arthritis (for example, rheumatoid arthritis, chronic progredient arthritis, psoriatic arthritis and arthritis deformans), and rheumatic diseases, including inflammatory conditions and rheumatic diseases involving loss bony, inflammatory pain, hypersensitivity (including both hypersensitivity of the respiratory tract and dermal hypersensitivity), and allergies. Specific autoimmune diseases for which can be employed Antibodies R nvención include autoimmune haematological disorders (including eg hemolytic anemia, aplásfica anemia, pure red cell anemia and idiopathic trombociíopenia), systemic eritemafoso lupus, polychondritis, sclerodoma , Wegener's granulomatosis, dermaíomiositis, chronic hepaíitis acíiva, gravis miasíenia, psoriasis, Sfeven-Johnson syndrome, idiopathic pruritus, inflammatory disease autoinm binds bowel (including, for exam ple, ulcerative colitis, Crohn's disease, and S índrome intestine Irritable), thyroiditis autoinm une, Behcet's disease, endocrine ophthalmology, G raves disease, sarcoidosis, multiple sclerosis, primary biliary cirrhosis, juvenile diabetic (diabetes mellitus type I), uveitis (anterior and posterior), keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial pulmonary fibrosis, and glomerulus nephritis (with and without nephrotic syndrome, for example including idiopathic nephrotic syndrome or minimal change nephropathy); graft rejection (for example, in transplantation, including heart, lung, heart-lung, liver, kidney, pancreas, skin, or cornea transplants), including allograft rejection or xenograft rejection, or graft-versus-host disease , and arcleosclerosis associated with organ transplantation; atherosclerosis; cancer with leukocyte infiltration of the skin or organs; breast cancer; sphenosis or restenosis of the vasculature, in particular of the arteries, for example the coronary artery, including stenosis or restenosis resulting from vascular intervention, as well as neointimal hyperplasia; embolism; and hears diseases or conditions that involve inflammatory responses, including reperfusion injury, hematologic malignancies, cytokine-induced toxicity (eg, septic shock or endo-toxic shock), polymyositis, dermatomyosis, and ulomacyanal gaseous diseases including sarcoidosis; infectious diseases, including VI H and S I DA. It should be understood that the term "treatment", as used in the present, includes the epipeuic mode as a prophylactic of therapy, for example in connection with the neoplasm fratamieny, therapy to prevent the establishment of clinically or preclinically evident neoplasia, or for the prevention of the onset of malignant cells, or to stop or reverse the progress of pre malignant to malignant cells, as well as the prevention or inhibition of growth of neoplasia or metastasis. In this context, it should be understood that the present invention encompasses in particular the use of the compounds of the present invention to inhibit or prevent the development of skin cancer, for example squamous or basal cell carcinoma as a result of exposure to ultraviolet light, for example. result from chronic exposure to the sun. The agents of the invention are particularly useful for the treatment of diseases of bone and cartilage metabolism, including osteoarteries and other inflammatory arteries, for example rheumatoid arthritis, and bone loss in general, including bone loss related to age, and in particular periodontal disease. The Agents of the invention can also be used in ocular applications, which include the treatment of ocular diseases, in particular of inflammatory or ocular disorders, of ocular pain, including pain associated with ocular surgery, such as PRK or surgery of cataracts, of ocular allergy, of photophobia of diverse etiology, of high intraocular pressure (in glaucoma) by inhibiting the production of the glucocorticoid response protein inducible by the trabecular meshwork (TIG R), and of dry eye For the above indications, the appropriate dosage will, of course, vary depending on, for example, the particular Agent of the Invention to be employed, the subject to be delivered, the mode of administration, and the nature and severity of the the condition that is fratando. However, in prophylactic use, it is generally indicated that satisfactory results are obtained in dosages from about 0.05 milligrams to about 10 milligrams per kilogram of body weight, more usually from about 0.1 milligrams to about 5 milligrams per kilogram of body weight. The dosage frequency for prophylactic use will normally be in the range of about once a week to about once every 3 months, more usually in the interval from about once every 2 weeks to about once every 10 weeks, for example , once every 4 or 8 weeks. The Agent of the Invention is conveniently administered in a parenteral, intravenous fashion, for example in the antecubital or peripheral vein, intramuscularly, or subcutaneously. For example, a prophylactic treatment normally involves administering the Agency of the invention from once a month to once every 2 to 3 months, or with less frequency. Aggregates of the invention can be administered in conjunction with another active agent. Suitable acidic agents include antimetabolites (e.g., methotrexate), ani-TN F agents (e.g. Remicade® (infliximab), Enbrel® (Etanercepí), Humira® (adalumimab)), anti-I L-1 agents (e.g. pralnacasan, ACZ885), reverse transcriptase inhibitors that are nucleosides and non-nucleosides, inhibitors of VI H protease, fusion inhibitors and other anti-retroviral agents. The agent or agents can be administered simultaneously, separately, or in sequence with the Agent of the Invention. The pharmaceutical compositions of the invention can be manufactured in a conventional manner. A composition according to the invention is preferably provided in a lyophilized form. For immediate administration, it is dissolved in a suitable aqueous vehicle, for example, sterile water for injection or sterile regulated physiological saline. It is considered advisable to form a solution of a larger volume to be administered medianfe infusion, instead of doing it as a bolus injection, and it is convenient to incorporate human serum albumin or the patient's own heparinized blood in the serum at the time of formulation. The presence of an excess of this physiologically inert protein prevents the loss of the antibody by adsorption on the walls of the container and the tubing used with the solution for infusion. If you use ina album, a suitable concentration is 0.5 to 4.5 percent by weight of the saline solution. The Agencies of the Invention can be administered by any conventional route, for example orally, for example in the form of solvents for drinking, tablets or capsules, or parenterally, for example in the form of injectable solutions or suspensions. Normally, oral dosage forms are preferred for systemic administration, although, for some indications, the Agents of the Invention may also be administered topically or dermally, for example in the form of a dermal cream or gel or similar preparation, or, for the purposes of applying to the eye, in the form of an eye cream, gel, or preparation of eye drops; or they can be administered by inhalation, for example for the treatment of asthma. Unit dosage forms suitable for oral administration comprise, for example, 25 to 250 milligrams of the Agent of the invention per unit dosage. 304 the substitution or optional substituents on Y are independently selected from the group consisting of halogen, hydroxyl, alkyl of 1 to 7 carbon atoms, mono- or dialkyl of 1 to 7 carbon atoms, aminocarbonyl , mono- or di-alkyl of 1 to 7 carbon atoms - ammoncarbonyl, amino, carboxyl of 1 to 7 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, heterocycloalkyl of 3 to 18 carbon atoms, alkyl from 1 to 7 carbon atoms-carbonyl, alkoxy from 1 to 7 carbon atoms-carbonyl, nitrile, aryl; all of which, except halogen, are optionally substituted in an independent manner by one or more substituents selected from the group consisting of halogen, hydroxyl, alkyl of 1 to 7 carbon atoms, mono- or di-alkyl of 1 to 7. carbon-amino, aminocarbonyl, mono- or di-alkyl atoms of 1 to 7 carbon atoms-aminocarbonyl, amino, carboxyl of 1 to 7 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, heterocycloalkyl of 3 to 1 8 carbon atoms, alkyl of 1 to 7 carbon atoms, carbonyl, alkoxy of 1 to 7 carbon atoms, carbonyl, nihil, aryl. 2. A compound of the formula (I), or a pharmaceutically acceptable salt, ester, or prodrug thereof: (ll) 305 where: Z 'is NH, N CH3l CH2, S or O. R' is hydroxyl, an alkoxy of 1 to 7 carbon atoms optionally substituted, alkenyloxy of 2 to 7 carbon atoms, cycloalkyl-alkyloxy of 1 to 7 carbon, aryloxy, heteroaryloxy, hephenoaryl-alkyloxy, atoms of 1 to 7 carbon atoms, or aryl-alkyloxy of 1 to 7 carbon atoms, an optionally substituted aryl, heteroaryl, or an aryl-alkyl group of 1 to 7 carbon atoms carbon optionally susíiuuido; X 'is selected from the group consisting of: QC is selected from the group consisting of: -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH (CH3) -CH2-, -CH2-CH (CH3) -, -CH2-N H2-, -CH (CH3) -N H-, -CH2-N (CH3) -, -CH2-CH (CH2OH) -, or -CH (CH3) -NH (CH3) -; Y 'is selected from the group consisting of: cycloalkyl of 3 to 18 carbon atoms, heterocycloalkyl, bridged cycloalkyl, benzened heterocycloalkyl, aryl, heetroaryl, aryl-heyerocycloalkyl fused, all of which are optionally substituted in an independent manner once or more; the substituent or the optional substituents on R 'are independently selected from the group consisting of 306 halogen, hydroxyl, alkoxy of 1 to 7 carbon atoms, mono- or dialkyl of 1 to 7 carbon atoms, aminocarbonyl, mono- or di-alkyl of 1 to 7 carbon atoms; aminocarbonyl, amino, carboxyl of 1 to 7 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, heyerocycloalkyl of 3 to 18 carbon atoms, alkyl of 1 to 7 carbon atoms, carbonyl of 1 to 7 carbon atoms - carbonyl, nitrile, aryl; all of which, except halogen, are optionally substituted independently by one or more substituents selected from the group consisting of halogen, hydroxyl, alkyl of 1 to 7 carbon atoms, mono- or di-alkyl of 1 to 7. carbon-amino, aminocarbonyl, mono- or di-alkyl atoms of 1 to 7 carbon atoms-aminocarbonyl, amino, carboxyl of 1 to 7 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, heterocycloalkyl of 3 to 1 8 carbon atoms, alkyl of 1 to 7 carbon atoms-carbonyl, alkoxy of 1 to 7 carbon atoms-carbonyl, nitrile, aryl; The optional or optional substrates on Y 'are independently selected from the group consisting of halogen, hydroxyl, alkyl of 1 to 7 carbon atoms, mono- or di-alkyl of 1 to 7 carbon-amino atoms, aminocarbonyl, mono- or di-alkyl of 1 to 7 atoms of carbon-aminocarbonyl, amino, carboxyl of 1 to 7 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, heterocycloalkyl of 3 to 18 carbon atoms, alkyl of 1 to 7 carbon-carbonyl atoms, alkoxyl of 1 to 7 carbon-carbonyl, nitryl, aryl; all of which, except halogen, 307 they are optionally substituted in an independent manner by one or more substituents selected from the group consisting of halogen, hydroxyl, alkyl of 1 to 7 carbon atoms, m or di- or di-alkyl of 1 to 7 carbon atoms. carbon-amino, aminocarbonyl, mono- or di-alkyl of 1 to 7 carbon atoms-aminocarbonyl, amino, carboxyl of 1 to 7 carbon atoms, cycloalkyl of 3 to 1 2 carbon atoms, heterocycloalkyl of 3 to 1 8 carbon atoms, alkyl of 1 to 7 carbon-carbonyl atoms, alkoxyl of 1 to 7 carbon-carbonyl atoms, nihilil, aryl. 3. A compound according to any of the preceding claims, selected from: [1- (2-azepane-1-yl-ellyl) -piperidin-4-yl] -amide of 4-methoxy-1 H- acid indole-2-carboxylic; 4-isopropoxy-1 H-indole-2-carboxylic acid [1 - (2-azepan-1-yl-efyl) -piperidin-4-yl] -amide; . { 1 - [2- (4-hydroxy-piperidin-1-yl) -ethyl] -piperidin-4-yl} -amide of 4-isopropoxy-1 H-indole-2-carboxylic acid; 4-Cyclopropylmethyl-1 H-indole-2-carboxylic acid [1 - (2-azepan-1-yl-eyl) -piperidin-4-yl] -amide; . { 1 - [2- (4-hydroxy-piperidin-1-yl) -ethyl] -piperidin-4-yl} 4-cyclopropylmethoxy-1H-indole-2-carboxylic acid amide; . { 1 - [(S) -2- (4-hydroxy-piperidin-1-yl) -propyl] -piperidin-4-yl} -amide of 4-cyc-opropyl methoxy-1 H -i ndol-2-carboxylic acid; . { 1 - [(S) -2- [3S, 4S) -4-hydroxy-piperidin-1-yl) -propyl] -piperidin-4-yl} 4-cyclopropylmethoxy-1 H-indole-2-carboxylic acid amide; 308 [1- (2-azepan-1-yl-eyl) -piperidin-4-yl] -amide of 4-isobuoxy-1 H-indole-2-carboxylic acid; [1- (2-piperidin-1-yl-ethyl) -piperidin-4-yl] -amide of 4-isobutoxy-1H-indole-2-carboxylic acid; . { 1- [2- (RS) -2-methyl-piperidin-1-yl] -ethyl] -piperidin-4-yl} -amide of acid 4-butabuxy-1 H-indole-2-carboxylic acid; . { 1- [2- (4-meityl-piperidin-1-yl) -ethyl] -piperidin-4-yl} 4- Isobutoxy-1H-indole-2-carboxylic acid amide; . { 1- [2 - ((2S, 6R) -2,6-dimethyl-piperidin-1-yl) -ethyl] -piperidin-4-yl} 4-isobutoxy-1 H-indole-2-carboxylic acid amide; . { 1- [2 - ((R) -3-hydroxy-piperidin-1-yl) -ethyl] -piperi in-4-yl} -amide of acid 4-sodiumbuzoxy-1H-indole-2-carboxylic acid; . { 1- [2 - ((S) -3-hydroxy-piperidin-1-yl) -ethyl] -piperidin-4-yl} -amide of acid 4-isobutoxy-1 H -indo l-2-carboxylic acid; . { 1- [2- (4-hydroxy-piperidin-1-yl) -yl] -piperidin-4-yl} 4-isobuzoxy-1H-indole-2-carboxylic acid amide; . { 1- [2 - ((1R, 3S, 5S) -3-hydroxy-8-aza-bicyclo [32.1] oct-8-yl) -yl] -piperidin-4-yl} 4-isobutoxy-1 H-indole-2-carboxylic acid amide; . { 1 - [(S) -2- (4-hydroxy-piperidin-1-yl) -propyl] -piperidin-4-yl} 4-isobutoxy-1 H-indole-2-carboxylic acid amide; [4- (2-azepan-1-yl-efyl) -phenyl] -amide of 4-isobutoxy-H-indole-2-carboxylic acid; 4-Isobutoxy-1 H-indole-2-carboxylic acid (4- ({[methyl- (tetrahydro-pyran-4-yl) -amino] -methyl} -cyclohexyl) -amide; (4- ({[[methyl- (terahydro-pyran-4-yl) -amino] -methyl} -phenyl) -amide of acid 309 4-isobutoxy-1 H-indole-2-carboxylic acid; (4- { (R) -1- [Methyl- (1-tetrahydro-pyran-4-yl) -amno] -ethyl) -phenyl) -amide of the acid 4-isobutoxy-1 H -indole-2-carboxylic acid; [4- (2-azepan-1-ethyl-ethyl) -piperidin-4-yl] -amide of 4-cyclobuyl-ethoxy-1 H-indole-2-carboxylic acid; . { 1 - [2- (3- (R) -hydroxy-piperidin-1-yl) -ethyl] -piperidin-4-yl} -amide of acid 4-cyclobutylmethoxy-1 H-indole-2-carboxylic acid; . { 1 - [2- (4-hydroxy-piperidin-1-yl) -yl] -piperidin-4-yl} 4-cyclobuylmethyl-1 H-indole-2-carboxylic acid amide; . { 1 - [2 - ((3S, 4S) -4-hydroxy-3-methyl-piperidin-1-yl) -ethyl] -piperidin-4-yl} 4-cyclobutylmethoxy-1 H-indole-2-carboxylic acid amide; . { 1 - [2 - ((1 R, 3S, 5S) -3-hydroxy-8-aza-bicyclo [3.2.1] oct-8-yl) -ethyl] -piperidin-4-yl} 4-cyclobutylmethoxy-1 H-indole-2-carboxylic acid amide; . { 1 - [8S) -2- (4-Hydroxy-piperidin-1-yl) -propyl] -piperidin-4-yl} 4-cyclobutylmethoxy-1 H-indole-2-carboxylic acid amide; . { 1 - [(S) -2 - ((3S, 4S) -4-hydroxy-3-mephyl-piperidin-1-yl) -propyl] -piperidin-4-yl} 4-cyclobutylmethoxy-1 H-indole-2-carboxylic acid amide; dihydrochloride. { 1 - [2- (4-hydroxy-piperidin-1-yl) -ethyl] -p -peridin-4-yl} 4- (3-methyl-butyloxy) -1 H-indole-2-carboxylic acid amide; . { 1 - [2- (4-hydroxy-piperidin-1-yl) -ethyl] -piperidin-4-yl} 4-cyclopentylmethoxy-1 H-indole-2-carboxylic acid amide; [1- (1, 2-dimethylapropoxy) -1H-indole-2-carboxylic acid [1- (2-azepan-1-ethyl-ethyl) -piperidin-4-yl] -amide; [1- (2-azepan-1-yl-eyl) -piperidin-4-yl] -amide of 4- (2,2-dimethyl-propoxy) -1H-indole-2-carboxylic acid; 310 . { 1- [2- (4-hydroxy-piperidin-1-yl) -efil] -piperidin-4-yl} -amide of 4- (4- methyl I-pe nti I oxy) - 1 H-indole-2-carboxylic acid; dihydrochloride. { 1- [2- (4-hydroxy-ipiperidin-1-yl) -ethyl] -piperidin-4-yl} - 4- (3,3-dimethyl-butoxy) -1H-indole-2-carboxylic acid amide; [1- (2-azepan-1-yl-ethyl) -piperidin-4-yl] -amide of 4- (furan-2-ylmeyoxy) -1 H-2-carboxylic acid; [4 (furan-3-ylmeyoxy) -1H-2-carboxylic acid [1- (2-azepan-1-yl-ethyl) -p -peridin-4-yl] -amide; . { 1- [2- (4-hydroxy-piperidin-1-yl) -yl] -piperidin-4-yl. { 4- (furan-3-ylmethoxy) -1H-indole-2-carboxylic acid amide; . { 1- [2 - ((3S, 4S) -4-hydroxy-3-methyl-piperidin-1-yl) -ethyl] -p -peridin-4-yl} 4- (furan-3-ylmethoxy) -1 H-indole-2-carboxylic acid amide; . { 1 - [(S) -2- (4-hydroxy-piperidin-1-yl) -propyl] -piperidin-4-yl} 4- (furan-3-ylmethoxy) -1H-indole-2-carboxylic acid amide; . { 1 - [(S) -2 - ((3S, 4S) -4-hydroxy-3-methyl-piperidin-1-yl) -propyl] -piperidin-4-yl} 4- (furan-3-ylmethoxy) -1H-indole-2-carboxylic acid amide; 4-Benzyloxy-1H-indole-2-carboxylic acid [1- (2-azepan-1-yl-eyl) -p -perdin-4-yl] -amide; dihydrochloride. { 1 - [(1S, 9aR) -1- (octahydro-quinolizin-1-yl) meily] -piperidin-4-yl} 4- (5-Choro-benzofuran-3-ylmeyoxy) -1H-indole-2-carboxylic acid amide; [4- (5-Choro-benzofuran-3-i-methoxy) -1H-indole-2-carboxylic acid [1- (2-azepan-1-yl-ethyl) -piperidin-4-yl] -amide; . { 1- [2- (4-hydroxy-piperidin-1-yl) -ethyl] -piperidin-4-yl} 4- (5-Choro-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid amide; 311 . { 1- [2 - ((3S, 4S) -4-hydroxy-3-methyl-piperidin-1-yl) -ethyl] -piperidin-4-yl} - 4- (5-chloro-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid amide; dihydrochloride. { 1 - [(S) -2- (4-Hydroxy-piperidin-1-yl) -propyl] -piperidin-4-yl} 4- (5-Chloro-benzofuran-3-ylmeyoxy) -1 H-indole-2-carboxylic acid amide; dihydrochloride of. { 1 - [(S) -2 - ((3S, 4S) -4-hydroxy-3-methyl-piperidin-1-yl) -propyl] -piperidin-4-yl} 4- (5-Chloro-benzofuran-3-I-methoxy) -1H-indole-2-carboxylic acid amide; dihydrochloride. { 1 - [(1S, 9aR) - (octahydro-quinolizin-1-yl) -methyl] -piperidin-4-yl} 4- (4-Fluoro-benzofuran-3-ylmeloxy) -1H-indole-2-carboxylic acid amide; dihydrochloride. { 1- [2- (4-hydroxy-piperidin-1-yl) -ethyl] -piperidin-4-yl} 4- (4-Fluoro-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid amide; dihydrochloride of. { 1 - [(1S, 9Ar) -1- (ociahydro-quinolizin-1-yl) methyl] -piperidin-4-yl} 4- (benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid amide; . { 1- [2- (4-hydroxy-piperidin-1-yl) -yl] -piperidin-4-yl} 4- (benzofuran-3-i-methoxy) -1H-indole-2-carboxylic acid amide; . { 1- [2 - ((3S, 4S) -4-hydroxy-3-methyl-piperidin-1-yl) -ethyl] -piperidin-4-yl} 4- (benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid amide; . { 1 - [(S) -2- (4-hydroxy-piperidin-1-yl) -propyl] -piperidin-4-yl} 4- (benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid amide; . { 1 - [(S) -2 - ((3S, 4S) -4-hydroxy-3-meityl-piperidin-1-yl) -propyl] -piperidin-4- 312 il} 4- (benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid amide; dihydrochloride. { 1 - [(1S, 9aR) -1- (octahydro-quinolizin-1-yl) -methyl] -piperidin-4-yl} 4- (6-Fluoro-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid dihydrochloride. { 1- [2- (4-hydroxy-piperidin-1-yl) -ethyl] -p-per-dine-4-yl} - 4- (6-fluoro-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid amide; dihydrochloride. { 1- [2 - ((3S, 4S) -4-hydroxy-3-methyl-piperidin-1-yl) -ethyl] -piperidin-4-yl} 4- (6-Fluoro-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid amide; dihydrochloride. { 1 - [(S) -2- (4-hydroxy-piperidin-1-yl) -propl] -p] per-dine-4- l} 4- (6-fluoro-benzofuran-3-ylmethoxy) -1 H-indole-2-carboxylic acid amide; . { 1 - [(S) -2 - ((3S, 4S) -4-hydroxy-3-methyl-piperidin-1-yl) -propyl] -piperidin-4-yl} 4- (6-Fluoro-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid amide; . { 1 - [(1S, 9aR) -1- (Octahydro-quinolizin-1-yl) methyl] -piperidin-4-yl} 4- (5-Fluoro-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid amide; dihydrochloride. { 1- [2- (4-hydroxy-piperidin-1-yl) -ethyl] -piperidin-4-yl} 4- (5-Fluoro-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid amide; dihydrochloride. { 1- [2 - ((3R, 4R, 5S) -4-hydroxy-3,5-dimethyl-piperidin-1-yl) -efil] -piperidin-4-yl} 4- (5-Fluoro-benzofuran-3-ylmeyoxy) -1H-indole-2-carboxylic acid amide; dihydrochloride of. { 1 - [(S) -2- (4-hydroxy-piperidin-1-yl) -propyl] -pperidine-4-313 il} 4- (5-Fluoro-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid amide; . { 1 - [(S) -2 - ((3S, 4S) -4-hydroxy-3-meityl-piperidin-1-yl) -propyl] -piperidin-4-yl} 4- (5-Fluoro-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid amide; dihydrochloride. { 1 - [(1S, 9aR) -1- (ociahydro-quinolizin-1-yl) mephyl] -piperidin-4-yl} 4- (7-Fluoro-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid amide; dihydrochloride. { 1 - [(1S, 9aR) -1- (O-Hydro-quinolizin-1-ylmethyl] -piperidin-4-yl} -amide of 4- (4,6-difluoro-benzofuran-3-ylmethoxy) - 1H -indol-2-carboxylic acid; 4- (4, 4- (4-hydroxy-piperidin-1-yl) -ethyl) -piperidin-4-yl} -amide. 6-difluoro-benzofuran-3-ylmeyoxy) -1H-indole-2-carboxylic acid; dichlorhydride of. {1- [2 - ((3S, 4S) -4-hydroxy-3-meityl-piperidin-1-yl) -elyl] -piperidin-4-yl.} - amide of 4- (4,6-difluoro-benzofuran-3-ylmethoxy) -1 H-indole-2-carboxylic acid; dihydrochloride of. (S) -2- (4-hydroxy-piperidin-1-yl) -propyl] -piperidin-4-yl}. -amide of 4- (4,6-difluoro-benzofuran-3-ylmethoxy) -1H -indol-2-carboxylic acid, dichlorhydram of {.1 - [(S) -2 - ((3S, 4S) -4-hydroxy-3-methyl-piperidin-1-yl) -propyl] -piperidin-4- il.) 4- (4,6-difluoro-benzofuran-3-i-methoxy) -1H-indol-2-carboxylic acid amide; dihydrochloride of. {1 - [(1S, 9a R)] -1- (octahi ro-quinolizin-1-yl) methyl] -piperidin-4-yl. {- -amide of 4- (7-chloro-benzofuran-3-ylmethoxy) - 1H- 314 indole-2-carboxylic; dihydrochloride of. { 1 - [(1S, 9a R) -1 - (ocia h ~ dro-qu mol izin- 1-yl) mephyl] -piperidin-4-yl} 4- (6-chloro-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid amide; . { 1- [2- (4-hydroxy-piperidin-1-yl) -ery] -piperidin-4-yl} 4- (6-chloro-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid amide; . { 1- [2 - ((3S, 4S) -4-hydroxy-3-methyl-piperidin-1-yl) -ethyl] -piperidin-4-yl} - 4- (6-Chloro-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid amide; dihydrochloride. { 1 - [(S) -2- (4-hydroxy-piperidin-1-yl) -propyl] -piperidin-4-yl} 4- (6-chloro-benzofuran-3-ylmethoxy) -1 H-indole-2-carboxylic acid amide; dihydrochloride. { 1 - [(1S, 9aR) -1- (octahydro-quinolizin-1-yl) meily] -piperidin-4-yl} 4- (4-Choro-benzofuran-3-ylmethoxy) -1 H-indole-2-carboxylic acid amide; dihydrochloride. { 1- [2- (4-hydroxy-piperidin-1-yl) -ethyl] -piperidin-4-yl} 4- (4-chloro-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid amide; dihydrochloride. { 1- [2 - ((3R, 4R, 5S) -4-hydroxy-3,5-dimethyl-piperidin-1-yl) -ethyl] -piperidin-4-yl} 4- (4-chloro-benzofuran-3-ylmeloxy) -1H-indole-2-carboxylic acid amide; . { 1 - [(S) -1- (4-hydroxy-pyperidin-1-yl) -propyl] -piperidin-4-yl} 4- (4-chloro-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid amide; dihydrochloride from. { 1 - [(1S, 9a R) -1- (octah id ro-quinol izin-1-yl) meti!] - piperidin-4-yl} -amide of 4- (7-methoxy-benzofuran-3-ylmethoxy) -1 H- 315 acid indole-2-carboxylic; [1- (2-piperidin-1-ylmethyl) -piperidin-4-yl] -amide of 4- (7-methoxy-benzofu-ran-3-yl-ethoxy) -1H-indole-2-carboxylic acid ico; dihydrochloride. { 1 - [2- (4-hydroxy-piperidin-1-yl) -ethyl] -piperidin-4-yl} - amide of 4- (7-methoxy-benzofuran-3-ylmethoxy) -1 H-ind ol-2-carboxylic acid; dihydrochloride. { 1 - [2 - ((3S, 4S) -4-hydroxy-3-methyl-piperidin-1-yl) -ethyl] -piperidin-4-yl} 4- (7-meioxy-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid amide; dihydrochloride. { 1 - [(S) -2- (4-hydroxy-piperidin-1 -I) -propyl] -piperidin-4-yl} 4- (7-methoxy-benzofuran-3-ylmethoxy) -1 H-indole-2-carboxylic acid amide; . { 1 - [(S) -2 - ((3S, 4S) -4-hydroxy-3-methyl-piperidin-1-yl) -propyl] -piperidin-4-yl} 4- (7-methoxy-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid amide; . { 1 - [(1S, 9aR) -1 - (Octahydro-quinolizin-1-yl) methyl] -piperidin-4-yl} -amide of 4- (6-methoxy-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid; [1- (2-azepan-1-yl-ethyl) -piperidin-4-yl] -amide of 4- (6-methoxy-benzofuran-3-i-methoxy) -1H-indole-2-carboxylic acid; . { 1 - [2- (4-hydroxy-piperidin-1-yl) -ethyl] -piperidin-4-yl} 4- (6-methoxy-benzofuran-3-ylmethoxy) -1 H-indole-2-carboxylic acid amide; dihydrochloride. { 1 - [2 - ((3S, 4S) -4-hydroxy-3-methyl-piperidin-1-yl) -ethyl] -piperidin-4-yl} 4- (6-methoxy-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid amide; . { 1 - [(S) -2- (4-hydroxy-piperidin-1-yl) -propyl] -piperidin-4-yl} -amide of 316 4- (6-meioxy-benzofuran-3-ylm-ethoxy) -1H-indole-2-carboxylic acid; . { 1 - [(S) -2 - ((3S, 4S) -4-hydroxy-3-methyl-piperidin-1-yl) -propyl] -piperidin-4-yl} 4- (6-mephoxy-benzofuran-3-ylmeloxy) -1H-indole-2-carboxylic acid amide; [4- (5-Myoxy-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid [1- (2-azepan-1-yl-efyl) -piperidin-4-yl] -amide; . { 1- [2- (4-hydroxy-piperidin-1-yl) -yl] -piperidin-4-yl} 4- (5-meioxy-benzofuran-3-ylmeloxy) -1H-indole-2-carboxylic acid amide; . { 1 - [(S, 9aR) -1- (Octahydro-quinolizin-1-yl) methyl] -piperidin-4-yl} 4- (4-methoxy-benzofuran-3-ylmeloxy) -1H-indole-2-carboxylic acid amide; . { 1- [2- (4-hydroxy-piperidin-1-yl) -efil] -p -peridin-4-yl} 4- (4-methoxy-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid amide; . { 1- [2 - ((3S, 4S) -4-hydroxy-3-meityl-piperidin-1-yl) -ethyl] -piperidin-4-yl} 4- (4-methoxy-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid amide; . { 1 - [(S) -2- (4-hydroxy-piperidin-1-yl) -propyl] -piperidin-4-yl} 4- (4-methoxy-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid amide; . { 1 - [(S) -2 - ((3S, 4S) -4-hydroxy-3-methyl-piperidin-1-yl) -propyl] -piperidin-4-yl} 4- (4-mephoxy-benzofuran-3-ylmethoxy) -1 H-indole-2-carboxylic acid amide; dihydrochloride from. { 1 - [(1S, 9aR) -1- (ociahydro-quinolizin-1-yl) methyl] -piperidin-4-yl} 4- (4,6-dimethoxy-benzofuran-3-y1-meioxy) -1H-indole-2-carboxylic acid amide; . { 1- [2- (4-hydroxy-piperidin-1-yl) -efil] -piperidin-4-yl} 4- (4,6-dimethoxy-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid amide; 317 dihydrochloride of. { 1- [2 - ((3S, 4S) -4-hydroxy-3-methyl-piperidin-1-yl) -eiyl] - p -peridin-4-yl] -amide of acid 4- (4,6 -dimefoxy-benzofuran-3-ylmeyoxy) -1H-indole-2-carboxylic acid; . { 1 - [(S) -2- (4-hydroxy-piperidin-1-yl-propyl] -piperidin-4-yl} -amide of 4- (4,6-dimethoxy-benzofuran-3-ylmeyoxy) -1H-indole-2-carboxylic acid; . { 1 - [(S) -2 - ((3S, 4S) -4-hydroxy-3-methyl-piperidin-1-yl) -propyl] -piperidn-4-yl} 4- (4,6-dimethoxy-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid amide; dihydrochloride. { 1 - [(1S, 9aR) -1- (Octahydro-quinolizin-1-yl) methyl] -piperidin-4-yl} 4- (5,6-dimethyl-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid amide; . { 1- [2- (4-hydroxy-piperidin-1-yl) -yl] -piperidin-4-yl} 4- (5,6-d i -meiylbenzofuran-3-I-methoxy) -1H-indole-2-carboxylic acid amide; dihydrochloride. { 1- [2 - ((3S, 4S) -4-hydroxy-3-methyl-piperidin-1-yl) -ethyl] -piperidin-4-yl} 4- (5,6-dimethyl-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid amide; . { 1 - [(S) -2- (4-hydroxy-piperidin-1-yl) -propyl] -piperidin-4-yl} -amide of 4- (5,6-dimethyl-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid; dihydrochloride. { 1 - [(S) -2 - ((3S, 4S) -4-hydroxy-3-methyl-piperidin-1-yl) -propyl] -piperidin-4-yl} 4- (5,6-dimethyl-benzofuran-3-ylmeyoxy) -1H-indole-2-carboxylic acid amide; . { 1 - [(S) -2- (4-hydroxy-piperidin-1-yl) -propl] -p -peridin-4-yl} 4- (4-ethoxy-phenyl) -1H-indole-2-carboxylic acid amide; . { 1 - [(S) -2- (4-hydroxy-piperidin-1-yl) -propyl] -piperidin-4-yl} -arnide of 4- (4-mephoxy-phenyl) -1H-indole-2-carboxylic acid; 318 4-Phenoxy-1H-indole-2-carboxylic acid [1- (2-azepane-1-yl-etyl) -pyridin-4-yl] -amide; 4-M-Tolyloxy-1 H-indole-2-carboxylic acid [1- (2-azepan-1-yl-eyl) -piperidin-4-yl] -amide; . { 1- [2- (3- (RS) -hydroxy-piperidin-1-yl) -ethyl] -piperidin-4-yl} 4-m-yloxyloxy-1 H-indole-2-carboxylic acid amide; . { 1- [2- (4-hydroxy-piperidin-1-yl) -ethyl] -piperidin-4-yl} 4- m-tolyloxy-1 H-indole-2-carboxylic acid amide; 4-p-yloxy-1H-indole-2-carboxylic acid [1- (2-azepan-1-yl-eyl) -piperidin-4-yl] -amide; . { 1- [2- (3- (RS) -hydroxy-piperidin-1-yl) -yl] -piperidin-4-yl} 4-p-yloxyloxy-1 H-indole-2-carboxylic acid amide; . { 1- [2- (4-hydroxy-piperidin-1-yl) -yl] -piperidin-4-yl} 4-p-yloxyloxy-1 H-indole-2-carboxylic acid amide; [1- (2-azepan-1-yl-eyl) -piperidin-4-yl] -amide of 4- (3-fluoro-phenoxy) -1H-indole-2-carboxylic acid; . { 1- [2- (4-hydroxy-piperidin-1-yl) -yl] -piperidin-4-yl} 4- (3-fluoro-phenoxy) -1H-indole-2-carboxylic acid amide; [4- (4-Fluoro-phenoxy) -1 H -indole-2-carboxylic acid [1- (2-azepan-1-yl-ethyl) -piperidin-4-yl] -amide; . { 1- [2- (4-hydroxy-piperidin-1-yl) -ethyl] -piperidin-4-yl} 4- (4-fluoro-phenoxy) -1H-indole-2-carboxylic acid amide; [1- (2-azepan-1-yl-ethyl) -piperidin-4-yl] -amide of 4- (3,4-difluoro-phenoxy) -1H-indole-2-carboxylic acid; [1- (2-azepan-1-yl-ethyl) -piperidin-4-yl] -amide of 4- (3,5-difluoro- 319) f enoxy) - 1 H -i ndol-2-carboxylic; . { 1- [2- (3-RS-hydroxy-piperidin-1-yl) -yl] -piperidin-4-yl} -amide of acid 4- (3,5-difluoro-phenoxy) -1H-indole-2-carboxylic acid; . { 1- [2- (4-hydroxy-piperidin-1-yl) -ethyl] -piperidin-4-yl} -amide of 4- (3,5-difluoro-f in oxy) -1H-indole-2-carboxylic acid; [1- (2-azepan-1-yl-ethyl) -piperidin-4-yl} 4- (6-chloro-pyridin-2-yloxy) -1H-indole-2-carboxylic acid amide; dihydrochloride of 4-isobutoxy-1H-indole-2-carboxylic acid [1- (ociahydro-quinolizin-1-ylmethyl) -piperidin-4-yl] -amide; 4-iobutoxy-1H-indole-2-carboxylic acid [1- (1-methyl-piperidin-3-ylmethyl) -piperidin-4-yl] -amide; . { 1 - [(1S, 9aR) -1- (octahydro-quinolizin-1-yl) methyl] -piperidin-4-yl} 4-cyclobutylmethoxy-1 H-indole-2-carboxylic acid amide; . { 1 - [(S) -2 - ((3R, 4R) -4-hydroxy-3-methyl-piperidin-1-yl) -propyl] -piperidin-4-yl} 4-cyclobutylmethoxy-1H-indole-2-carboxylic acid amide; . { 1 - [(S) -2 - ((3S, 4R, 5S) -34-dihydroxy-5-methyl-piperidin-1-yl) -propl] -piperidin-4-yl} 4-cyclobutylmethoxy-1 H -indole-2-carboxylic acid amide; . { 1 - [(R) -3-hydroxy-2 - ((3S, 4S) -4-hydroxy-3-methyl-piperidin-1-yl) -propyl] -piperidin-4-yl} 4-cyclobutylmethoxy-1H-indole-2-carboxylic acid amide; . { 1 - [(1S, 9aR) -1- (octahydro-quinolizin-1-yl) meily] -piperidin-4-yl} 4- (furan-3-ylmethoxy) -1H-indole-2-carboxylic acid amide; . { 1 - [(S) -2 - ((3R, 4R) -4-Hydroxy-3-meityl-piperidin-1-yl) -propyl] -piperidin-4-yl} 4- (furan-3-ylmethoxy) -1H-indole-2-carboxylic acid amide; 320 [4- (2-methyl-thiazol-4-ylmethoxy] -1H-indole-2-carboxylic acid [1- (octahydro-quinolizin-1-ylmeryl) -piperidin-4-yl] -amide; . { 1- [2- (3,4-Dihydroxy-5-methyl-piperidin-1-yl) -propyl] -piperidin-4-yl} 4- (benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid amide; . { 1 - [(S) -2 - ((3RS, 4SR) -3,4-dihydroxy-piperidin-1-yl) -propyl] -piperidin-4-yl} 4- (5-fluoro-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid amide; . { 1 - [(S) -2- (3RS, 4SR) -3,4-dihydroxy-piperidin-1-yl) -propyl] -piperidin-4-yl} - 4- (5-chloro-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid amide; . { 1 - [(9S, 9aS) -1- (Octahydro-pyrido [2,1-c] [1,4] oxazin-9-yl) methyl] -piperidin-4-yl} 4- (5-chloro-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid amide; . { 1 - [(8S, 8aS) -1- (hexahydro-pyrrolo [2,1-c] [1,4] oxazin-8-yl) meiyl] -piperidin-4-yl} 4- (5-chloro-benzofuran-3-ylmethoxy) -1H-indole-2-carboxylic acid amide; . { 1 - [(1S, 9aR) -1- (ociahydro-quinolizin-1-yl) meily] -piperidin-4-yl} 4- (4-methoxy-phenyl) -1H-indole-2-carboxylic acid amide; . { 1 - [(1S, 9aR) -1- (Octahydro-quinolizin-1-yl) methyl] -piperidin-4-yl} 4- (4-ethoxy-phenyl) -1H-indole-2-carboxylic acid amide; . { 1 - [(S) -2 - ((3S, 4S) -4-hydroxy-3-methyl-piperidin-1-yl) -propyl] -piperidin-4-yl} 4- (6-meioxy-pyridin-3-yl) -1 H-indole-2-carboxylic acid amide; . { 1- [2 - ((3S, 4S) -4-hydroxy-3-mephyl-piperidin-1-yl) -ethyl] -piperidin-4-yl} 4- (6-meioxy-pyridin-3-yl) -1 H-indole-2-carboxylic acid amide; . { 1 - [(1S, 9a R) -1- (octahydro-quinol izin-1-yl) methyl] -piperid i n-4-yl} -a measure 321 of 4-p-tolyloxy-1H-indole-2-carboxylic acid; [1- (2-azepan-1-yl-1S-methyl-ethyl) -piperidin-4-yl] -amide of 4-isobutoxy-1 H-indole-2-carboxylic acid; [1- (2-azepan-1-yl-1R-methyl-ethyl) -piperidin-4-yl] -amide of 4-isobutoxy-1 H -ind-ol-2-carboxylic acid; [1- (2S-azepan-1-yl-propyl) -piperidin-4-yl] -amide of 4- (furan-3-ylmethoxy) -1H-indole-2-carboxylic acid; [1- (2R-azepan-1-yl-propyl) -piperidin-4-yl] -amide of 4- (furan-3-i-methoxy) -1H-indole-2-carboxylic acid; . { 1- [2- (3,6-Dihydro-2H-pyridin-1-yl) -ethyl] -piperidin-4-yl} -amide of the acid 4-isobuloxy-1 H-indole-2-carboxylic acid; . { 1- [2- (4-hydroxy-azepan-1-yl) -ethyl] -piperidin-4-yl} 4-isobutoxy-1H-indole-2-carboxylic acid amide; . { 1- [2- (3-amino-azepan-1-yl) -ethyl] -piperidin-4-yl} 4-isobutoxy-1 H-indole-2-carboxylic acid amide; . { 1- [2- (3-fluoro-piperidin-1-yl) -ethyl] -piperidin-4-yl} -amide of 4-isobutoxy-1 H-indole-2-carboxylic acid; [4- (5-Chloro-benzofuran-3-ylmefoxy) -1H-indole-2-carboxylic acid [4- (2-piperidin-1-yl-ethyl) -phenyl] -amide; . { 4- [2- (4-hydroxy-piperidin-1-yl) -ethyl] -phenyl} 4- (5-chloro-benzofuran-3-ylmefoxy) -1H-indole-2-carboxylic acid amide; 4-phenyl-1H-indole-2-carboxylic acid [1- (2-azepane-1-yl-elyl) -piperidin-4-yl] -amide; [4- (4-trifluoromethyl-phenyl) -1H-indole-2-carboxylic acid [1- (2-azepan-1-yl-ethyl) -piperidin-4-yl] -amide; 322 4-p-tolyl-1H-indole-2-carboxylic acid [1- (2-azepan-1-yl-ethyl) -piperidin-4-yl] -amide; [1- (2-azepan-1-yl-ethyl) -piperidin-4-yl] -amide of 4- (4-di-ethylamino-phenyl) -1H-indole-2-carboxylic acid; [4,5-Benzo [12,5] oxadiazol-5-yl-1H-indole-2-carboxylic acid [1- (2-azepan-1-yl-ethyl) -piperidin-4-yl] -amide; [1- (2-azepan-1-yl-elyl) -piperidin-4-yl] -amide of 4- (4-methioxyphenyl) -1 H -indole-2-carboxylic acid; [1- (2-azepan-1-yl-ethyl) -piperidin-4-yl] -amide of 4- (3-cyano-phenyl) -1H-indole-2-carboxylic acid; [4- (4-Ethoxy-phenyl) -1H-indole-2-carboxylic acid [1- (2-azepan-1-yl-ethyl) -piperidin-4-yl] -amide; [4- (3- (3-methoxy-propoxy) -phenyl] -1H-indole-2-carboxylic acid [1- (2-azepan-1-yl-ethyl) -piperidin-4-yl] -amide; 4- (4-Trifluoromethoxy-phenyl) -1H-indole-2-carboxylic acid [1- (2-azepan-1-yl-ethyl) -piperidin-4-yl] -amide; [1- (2-azepan-1-yl-ethyl) -piperidin-4-yl] -amide of 4- (2,4-dimethoxy-phenyl) -1H-indole-2-carboxylic acid; [1- (2-azepan-1-yl-ethyl) -piperidin-4-yl] -amide of 4- (3,4-dimethoxy-phenyl) -1H-indole-2-carboxylic acid; 4-Benzo [1, 3] dioxol-5-yl-1 H-indole-2-carboxylic acid [1- (2-azepan-1-yl-ethyl) -piperidin-4-yl] -amide; 4-Pyridin-4-yl-1H-indole-2-carboxylic acid [1- (2-azepan-1-yl-ethyl) -piperidin-4-yl] -amide; [1- (2-azepan-1-yl-ethyl) -piperidin-4-yl] -amide of 4- (6-methoxy-323) pyridin-3-yl) -1 H -indole-2-carboxylic acid; [1- (2-piperidin-1-yl-ethyl) -piperidin-4-yl] -amide of 4- (4-ethoxy-phenyl) -1H-indole-2-carboxylic acid; . { 1- [2- (4-hydroxy-piperidin-1-yl) -ethyl] -piperidin-4-yl} 4- (4-methoxy-phenyl) -1H-indole-2-carboxylic acid amide; . { 1- [2- (4-hydroxy-piperidin-1-yl) -ethyl] -piperidin-4-yl} 4- (4-efoxy-phenyl) -1 H-indole-2-carboxylic acid amide; . { 1- [2- (4-hydroxy-piperidin-1-yl) -ethyl] -piperidin-4-yl} 4- (6-methoxy-pyridin-3-yl) -1H-indole-2-carboxylic acid amide; . { 1- [2- (3-hydroxy-8-aza-bicyclo [3.2.1] oct-8-yl) -ethyl] -piperidin-4-yl} 4- (4-methoxy-phenyl) -1H-indole-2-carboxylic acid amide; . { 1- [2- (3-hydroxy-8-aza-bicyclo [3.2.1] oct-8-yl) -ethyl] -piperidin-4-yl} 4- (6-methoxy-pyridin-3-yl) -1 H-indole-2-carboxylic acid amide; [1- (2-azepan-1-yl-eyl) -piperidin-4-yl] -amide of 4-hydroxy-1H-indole-2-carboxylic acid; 4-Methioxy-benzo [b] thiophene-2-carboxylic acid [1- (2-azepan-1-yl-ethyl) -piperidin-4-yl] -amide; [1- (2-azepan-1-yl-ethyl) -piperidin-4-yl] -amide of 4-isobuzoxy-benzo [b] thiophene-2-carboxylic acid; 4-Butyloxy-benzo [b] thiophene-2-carboxylic acid [1- (2-piperidin-1-yl-ethyl) -piperidin-4-yl] -amide; 4-Myoxy-benzofuran-2-carboxylic acid [1- (2-azepan-1-yl-ethyl) -p -peridin-4-yl] -amide. 4. A compound according to any of the preceding claims, to be used as a product 324 Pharmaceutical for the prevention, reduction, or treatment of an autoimmune or inflammatory disease or condition. 5. A compound according to any one of claims 1 to 3 above, to be used as a pharmaceutical prod- uct for the prevention, reduction, or treatment of HIV infection or AIDS. 6. A process for the preparation of a compound of the formula (I), which comprises: (a) reacting a compound of the formula (III): (lll) wherein R "is H or a lower alkyl group, with a compound of the formula NH2-XQY, the groups R, R9, Z, X, Q, and Y being as defined in claim 1; or (b) for the preparation of the compounds of the formula (I) wherein X is piperidin-4-yl and Q is -CH2-CH2-, and Y is a group having the formula -NR7R8, wherein R7 and R8 are linked to define collectively a fused heterocycloalkyl, bridged cycloalkyl, bridged heterocycloalkyl, heteroaryl, or aryl-heterocycloalkyl, reacting a compound of the formula (IV): (IV) with a compound of the formula N H R 7 R 8, wherein R 7 and R 8 are as defined above, and R, R 9, and Z are as defined above; or (c) for the preparation of compounds of the formula (1), wherein X is piperidin-4-yl and Q is CH2-, reacting a compound of the formula (V): (V) wherein R, R9 and Z are as defined above, with a compound of the formula HO-CH2-Y, wherein Y is as defined above; or (d) for the preparation of compounds of the formula (I), wherein R is an optionally substituted aryl group, use appropriately the Br group in a compound of the formula (VI) for 326 susfiíuir a esíe g ru po arilo substituted: (VI) where Z, R9, X, Q and Y are as defined above; and recovering the resulting compounds of formula (I) in free or salt form. 7. A compound obtainable by the process of claim 5. 8. A pharmaceutical composition comprising a compound according to claim 1, in association with a pharmaceutically acceptable diluent or vehicle. 9. The use of a compound according to claim 1, in the manufacture of a medicament for use in the treatment of an autoimmune or inflammatory disease or condition. 10. The use of a compound according to claim 1, in the manufacture of a medicament for use in the treatment of infection by VI H or SI DA. eleven . A method for inhibiting chemokine receptors or the macrophage protein, or for reducing inflammation in a subject in need of such treatment, whose method comprises administering 327 to said subject is an effective amount of a compound according to claim 1. 12. A method for the treatment of an inflammatory or autoimmune disease or condition, which comprises administering to this subject an effective amount of a compound according to claim 1. 1. A method for the treatment of HIV infection or AIDS, which comprises administering to this subject an effective amount of a compound according to claim 1. 14. The use of a compound according to the claim 1, in combination with one or more agents selected from: methotrexate, an anti-TNF agent, an anti-IL-1 agent, a reverse transcriptase inhibitor that is nucleoside or non-nucleoside, an HIV protease inhibitor , a fusion inhibitor, and an anti-retroviral agent for the treatment of an inflammatory or autoimmune disease or condition, or HIV or AIDS. 328 SUMMARY A compound of the formula (I), or a pharmaceutically acceptable salt or prodrug ester thereof: ) wherein the variants R, R9, Z, X, Q, and Y are defined in the specification. * * * * *

Claims

301 REIVI NDICATIONS

1 . A compound of the formula (I), or a pharmaceutically acceptable salt or prodrug ester thereof: (0 wherein: Z is CR, R2, O or S; R is selected from the group consisting of hydroxyl, an optionally substituted alkoxy of 1 to 7 carbon atoms, alkenoxyl of 2 to 7 carbon atoms, alkyloxy, aryloxy, heteroaryloxy, arylalkoxy of 1 to 7 carbon atoms, or heteroaryl-alkoxy of 1 to 7 carbon atoms, an alkyl of 1 to 7 carbon atoms, or alkenyl of 2 to 7 carbon atoms optionally substituted , an optionally substituted aryl, heeroaryl, or an aryl-alkyl group of 1 to 7 carbon atoms optionally substituted; R 9 represents one or more ring sushituites selected from the group consisting of H, hydroxyl, an alkoxy of from 1 to 7. carbon atoms optionally substituted, alkenoxyl of 2 to 7 carbon atoms, cycloalkyloxy, aryloxy, heteroaryloxy, aryl-alkoxy of 1 to carbon atoms or heteroaryl-alkoxy of 1 to 7 carbon atoms, an alkyl of 1 to 7 carbon atoms 302 carbon or alkenyl of 2 to 7 optionally substituted carbon atoms, an optionally substituted aryl, heteroaryl, or an aryl-alkyl group of 1 to 7 carbon atoms optionally substituted; R i, R 2, and R 3 are independently selected from the group consisting of H and alkyl of 1 to 7 carbon atoms; X is cycloalkyl of 3 to 1 8, heterocycloalkyl, aryl, or heeroaryl, each of which may optionally be substituted; Q is a linker of between 1 and 3 atoms in length; Y is cycloalkyl of 3 to 18 carbon atoms, heterocycloalkyl, bridged cycloalkyl, bridged heterocycloalkyl, aryl, heteroaryl, aryl-heterocycloalkyl fused, all of which are optionally subsituted independently one or more times; the substituent or the optional substituents on R and R9 are independently selected from the group consisting of halogen, hydroxyl, alkyl of 1 to 7 carbon atoms, mono- or di-lower alkyl-amino, aminocarbonyl, mono- or di-lower alkyl-aminocarbonyl, amino, carboxyl , alkoxy of 1 to 7 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, heterocycloalkyl of 3 to 18 carbon atoms, alkyl of 1 to 7 carbon atoms-carbonyl, alkoxy of 1 to 7 carbon atoms-carbonyl, nitrile, aryl; all of which, except halogen, are optionally subsituted in an independent manner by one or more employees, selected from a group that consists of 303 Halogen, hydroxyl, alkoxy of 1 to 7 carbon atoms, mono-or dialkyl of 1 to 7 carbon atoms-amino, aminocarbonyl, mono- or di-alkyl of 1 to 7 carbon atoms -aminocarbonyl, amine, carboxyl of 1 to 7 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, heterocycloalkyl of 3 to 1 8 carbon atoms, alkyl of 1 to 7 carbon atoms carbonyl, alkoxy from 1 to 7 carbon-carbonyl, nitrile, aryl; the substituent or optional substituents on X are independently selected from the group consisting of halogen, hydroxyl, alkyl of 1 to 7 carbon atoms, mono- or dialkyl of 1 to 7 carbon-amino, aminocarbonyl, mono- or di-alkyl of 1 to 7 carbon-aminocarbonyl, amino, carboxyl of 1 to 7 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, heterocycloalkyl of 3 to 18 carbon atoms, alkyl of 1 to 7 carbon atoms -carbonyl, alkoxy of 1 to 7 carbon atoms-carbonyl, nitrile, aryl; all of which, except halogen, are optionally substituted independently by one or more substituents selected from the group consisting of halogen, hydroxyl, alkyl of 1 to 7 carbon atoms, mono- or di-alkyl of 1 to 7 carbon-amino, aminocarbonyl, mono- or di-alkyl atoms of 1 to 7 carbon-aminocarbonyl, amino, carboxyl of 1 to 7 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, heterocycloalkyl of 3 to 1 8 carbon atoms, alkyl of 1 to 7 carbon atoms carbonyl, alkoxy of 1 to 7 carbon atoms carbonyl, nitrile, aryl;