DE10305922A1 - New N-azabicyclooctyl bicyclic heteroaryl carboxamides, are alpha 7-nicotinic acetylcholine receptor ligands useful for improving attention, concentration, learning and/or memory performance - Google Patents

Abstract

N-Azabicyclo-(2.2.2)-octyl benzo- or pyrido-furan- or -thiophene-2-carboxamides (I) are new. Azabicyclooctyl-amides of formula (I) and their salts, solvates and solvated salts are new. R1 = 1-aza-bicyclo-(2.2.2)-octyl (optionally substituted (os) at the N by 1-4C alkyl, benzyl or oxy); R2 = H or T; R3 = H, halo or T; R4 = H, halo, CN, NH2, CF3, OCF3, T, COT, NHT, CHO, COOH, OT, COOT, ST, NHCOT, CONHT, 1-4C alkylsulfonylamino, 3-8C cycloalkylcarbonylamino, 3-6C cycloalkylaminocarbonyl, pyrrolyl, NHCONHT, heterocyclylcarbonyl, heterocyclylcarbonylamino, heteroarylcarbonylamino, OH, phenyl or heterocyclyl (where T is os by OH, CN, NH2, NHCONHT, CONHT, heterocyclyl or aryl; CONHT is os by OT or NHT; NHCOT is os by OT; and heterocyclyl is os by =O); A = O or S; ring B = benzo or pyrido (both os by one or more of halo, CN, CHO, CF3, OCF3, NO2, NH2, T or OT); E = -CC-; or arylene or heteroarylene (both os by one or more of halo, CN, CF3, OCF3, NO2, NH2, OT or T); T = 1-6C alkyl. An Independent claim is included for the preparation of (I).

Description

The invention relates to new 2-heteroarylcarboxamides, Process for their production and their use in production of medicines for the treatment and / or prophylaxis of diseases and improve perception, concentration, learning performance and / or memory performance.

Nicotinic acetylcholine receptors (nAChR) form a large one Family of ion channels, by the body's own Messenger acetylcholine activated (Galzi et al., Neuropharmacol. 1995, 34, 563-582). A functional nAChR consists of five subunits that are different (certain combinations of α1-9 and β1-4, γ, δ, ε subunits) or identical (α7-9) could be. this leads to to form a variety of subtypes that are different Distribution in the muscles, nervous system and other organs show (McGehee et al., Annu. Rev. Physiol. 1995, 57, 521-546). activation led by nAChR for the influx of cations into the cell and for the stimulation of nerve or muscle cells. Selective activation of individual nAChR subtypes limited this stimulation to the cell types that have the corresponding subtype and can be so unwanted Side effects such as the stimulation of nAChR in the muscles, avoid. Clinical experiments with nicotine and experiments in Different animal models point to a role of central nicotine Acetylcholine receptors in learning and Memory processes (e.g. Rezvani et al., Biol. Psychiatry 2001, 49, 258-267). nicotinic Acetylcholine receptors of the alpha7 subtype (α7-nAChR) have one in particular high concentration in for Learning and memory important brain regions, such as the hippocampus and cerebral cortex (Séguéla et al., J. Neurosci. 1993, 13, 596-604). The α7-nAChR has a particularly high permeability for calcium ions, increases glutamatergic Neurotransmission, affects neurite growth and modulates in this way the neuronal plasticity (Broide et al., Mol. Neurobiol. 1999, 20, 1-16).

Certain N- (1-aza-bicyclo [2.2.2] oct-3-yl) heteroarylcarboxamides for the treatment of, inter alia, psychoses are in the DE-A 37 24 059 described.

N- (aza-bicycloalkyl) heteroarylcarboxamides, in particular N- (1-aza-bicyclo [2.2.2] oct-4-yl) benzothiophene-3-carboxamides, are described in WO 93/15073 and in EP-A 485 962 disclosed as intermediates for the synthesis of pharmaceutically active compounds.

From the US 4,605,652 and the EP-A 372 335 N- (1-Azabicyclo [2.2.2] oct-3-yl) thiophene-2-carboxamide and its memory-improving effect are known, for example.

In JP-A 14 030 084 describes 1-azabicycloalkanes for the treatment of dementia, attention deficit hyperactivity disorder and learning and memory disorders.

From WO 02/44176, WO 02/085901, WO 01/60821, EP-A 1 231 212 and EP-A 1 219 622 further α7-nicotinic acetylcholine receptor agonists for the treatment of diseases of the central nervous system are known.

in welcher
R¹ 1-Aza-bicyclo[2.2.2]oct-3-yl,
R² Wasserstoff oder C₁-C₆-Alkyl,
R³ Wasserstoff, Halogen oder C₁-C₆-Alkyl,
R⁴ Wasserstoff, Halogen, Cyano, Amino, Trifluormethyl, Trifluormethoxy, C₁-C₆-Alkyl, C₁-C₆-Alkylcarbonyl, C₁-C₆-Alkylamino, Formyl, Hydroxycarbonyl, C₁-C₆-Alkoxy, C₁-C₆-Alkoxycarbonyl, C₁-C₆-Alkylthio, C₁-C₆-Alkylcarbonylamino, C₁-C₄-Alkylsulfonylamino, C₃-C₈-Cycloalkylcarbonylamino, Pynolyl, C₁-C₆-Alkylaminocarbonylamino, Heterocyclylcarbonyl, Phenyl oder Heterocyclyl,
wobei C₁-C₆-Alkyl gegebenenfalls durch Hydroxy, Amino, C₁-C₆- Alkylaminocarbonylamino, C₁-C₆-Alkylaminocarboxyl, Heterocyclyl oder Aryl,
C₁-C₆-Alkylcarbonylamino gegebenenfalls mit C₁-C₆-Alkoxy, und Heterocyclyl gegebenenfalls mit Oxo substituiert sein können,
A Sauerstoff oder Schwefel,
der Ring B Benzo oder Pyrido, die jeweils gegebenenfalls durch Reste aus der Reihe Halogen, Cyano, Formyl, Trifluormethyl, Trifluormethoxy, Nitro, Amino, C₁-C₆-Alkyl und C₁-C₆-Alkoxy substituiert sind, und
E C≡C, Aryl und Heteroaryl, wobei Aryl und Heteroaryl durch Reste aus der Reihe Halogen, Cyano, Trifluormethyl, Trifluormethoxy, Nitro, Amino, C₁-C₆-Alkoxy und C₁-C₆-Alkyl substituiert sein können,
bedeuten, sowie die Solvate, Salze oder Solvate der Salze dieser Verbindungen.The present invention relates to compounds of the formula

in which
R ¹ 1-aza-bicyclo [2.2.2] oct-3-yl,
R ^{2 is} hydrogen or C ₁ -C ₆ alkyl,
R ^{3 is} hydrogen, halogen or C ₁ -C ₆ alkyl,
R ^{4 is} hydrogen, halogen, cyano, amino, trifluoromethyl, trifluoromethoxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkylcarbonyl, C ₁ -C ₆ alkylamino, formyl, hydroxycarbonyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxycarbonyl, C ₁ -C ₆ alkylthio, C ₁ -C ₆ alkylcarbonylamino, C ₁ -C ₄ alkylsulfonylamino, C ₃ -C ₈ cycloalkylcarbonylamino, pynolyl, C ₁ -C ₆ alkylaminocarbonylamino, Heterocyclylcarbonyl, phenyl or heterocyclyl,
where C ₁ -C ₆ alkyl optionally by hydroxy, amino, C ₁ -C ₆ alkylaminocarbonylamino, C ₁ -C ₆ alkylaminocarboxyl, heterocyclyl or aryl,
C ₁ -C ₆ alkylcarbonylamino may optionally be substituted by C ₁ -C ₆ alkoxy, and heterocyclyl may optionally be substituted by oxo,
A oxygen or sulfur,
the ring B benzo or pyrido, which are each optionally substituted by radicals from the series halogen, cyano, formyl, trifluoromethyl, trifluoromethoxy, nitro, amino, C ₁ -C ₆ -alkyl and C ₁ -C ₆ -alkoxy, and
EC≡C, aryl and heteroaryl, where aryl and heteroaryl are radicals from the series halogen, cyano, trifluor methyl, trifluoromethoxy, nitro, amino, C ₁ -C ₆ alkoxy and C ₁ -C ₆ alkyl may be substituted,
mean, and the solvates, salts or solvates of the salts of these compounds.

As solvates within the scope of Invention refers to such forms of connections, which in solid or liquid Condition through coordination with solvent molecules Form complex. Hydrates are a special form of solvate, at which are coordinated with water.

Salts are within the scope of the invention physiologically acceptable salts of the compounds according to the invention prefers.

Physiologically acceptable salts of the compounds (I) Acid addition salts the connections with mineral acids, carboxylic acids or sulfonic acids his. For example, particular preference is given to Salts with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or Benzoic acid.

However, salts with customary salts can also be used Bases are mentioned, such as alkali metal salts (e.g. Sodium or potassium salts), alkaline earth metal salts (e.g. calcium or magnesium salts) or ammonium salts derived from ammonia or organic amines such as diethylamine, triethylamine, ethyldiisopropylamine, Procaine, dibenzylamine, N-methylmorpholine, dihydroabiethylamine, 1-ephenamine or methylpiperidine.

The compounds of the invention can in Stereoisomeric forms (enantiomers, diastereomers) exist. The The invention therefore relates to both the enantiomers or diastereomers as well as those respective mixtures. These enantiomer and diastereomer mixtures can be standardized into the stereoisomerically in a known manner Separate components.

In the context of the present invention, the substituents generally have the following meaning:
C ₁ -C ₆ - and C ₁ -C ₄ alkoxy represent a straight-chain or branched alkoxy radical having 1 to 6, preferably 1 to 4, particularly preferably 1 to 3 carbon atoms. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, n-pentoxy and n-hexoxy.
C ₁ -C ₆ and C ₁ -C ₄ alkyl represent a straight-chain or branched alkyl radical having 1 to 6, preferably 1 to 4, particularly preferably 1 to 3, carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-pentyl and n-hexyl.
C ₁ -C ₆ - and C ₁ -C ₄ alkylamino represents a straight-chain or branched mono- or dialkylamino radical having 1 to 6, preferably 1 to 4, particularly preferably 1 to 3, carbon atoms per alkyl radical. Non-limiting examples include methylamino, dimethylamino, ethylamino, diethylamino, n-propylamino, di-n-propylamino, isopropylamino, diisopropylamino, tert-butylamino, di-tert-butylamino, n-pentylamino, di-n-pentylamino, and n -Hexylamino, di-n-hexylamino, ethylmethylamino, isopropylmethylamino, n-butylethylamino, n-hexyl-i-pentylamino.
C ₁ -C ₆ - and C ₁ -C ₄ -alkylcarbonylamino represents a straight-chain or branched alkylcarbonylamino radical having 1 to 6, preferably 1 to 4 and particularly preferably 1 to 3 carbon atoms. Non-limiting examples include methylcarbonylamino, ethylcarbonylamino, n-propylcarbonylamino, isopropylcarbonylamino, tert-butylcarbonylamino, n-pentylcarbonylamino and n-hexylcarbonylamino.
C ₁ -C ₆ - and C ₁ -C ₄ -alkylaminocarboxyl stands for a straight-chain or branched mono- or dialkylaminocarboxyl radical with 1 to 6, preferably with 1 to 4, particularly preferably with 1 to 3 carbon atoms per alkyl radical. Nonlimiting examples include methylaminocarboxyl, dimethylaminocarboxyl, ethylaminocarboxyl, diethylaminocarboxyl, n-propylaminocarboxyl, di-n-propylaminocarboxyl, isopropylaminocarboxyl, diisopropylaminocarboxyl, tert-butylaminocarboxyl, di-tert-butylaminocarboxyl, n-pentylaminocarboxyl, n-pentylaminocarboxyl, n-pentylaminocarboxyl, n-pentylaminocarboxyl, n-pentylaminocarboxyl, n-pentylaminocarboxyl, n-pentylaminocarboxyl, n-pentylaminocarboxyl, n-pentylaminocarboxyl, n-pentylaminocarboxyl, n-pentylaminocarboxyl, n-pentylaminocarboxyl, n-pentylaminocarboxyl, n-pentylaminocarboxyl, n-pentylaminocarboxyl, n-pentylaminocarboxyl, n-pentylaminocarboxyl, n-pentylaminocarboxyl, and n-pentylaminocarboxyl, -Hexyl aminocarboxyl, di-n-hexylaminocarboxyl, ethylmethylaminocarboxyl, isopropylmethylaminocarboxyl, n-butylethylaminocarboxyl, n-hexyl-i-pentylaminocarboxyl.
C ₁ -C ₆ - and C ₁ -C ₄ -alkylaminocarbonylamino represents a straight-chain or branched mono- or dialkylaminocarbonylamino radical having 1 to 6, preferably 1 to 4, particularly preferably 1 to 3, carbon atoms per alkyl radical. Non-limiting examples include methylaminocarbonylamino, dimethylaminocarbonylamino, ethylaminocarbonylamino, diethylaminocarbonylamino, n-Propylaminocarbonylamino, di-n-propylaminocarbonylamino, Isopropylaminocarbonylamino, Diisopropylaminocarbonylamino, tert.Butylaminocarbonylamino, di-tert-butylaminocarbonylamino, n-Pentylaminocarbonylamino, di-n-pentylaminocarbonylamino, and n -Hexylaminocarbonylamino, di-n-hexylaminocarbonylamino, ethylmethylaminocarbonylamino, isopropylmethylaminocarbonylamino, n-butylethylaminocarbonylamino, n-hexyl-i-pentylaminocarbonylamino.
C ₁ -C ₆ alkylcarbonyl represents a straight-chain or branched alkylcarbonyl radical having 1 to 6, preferably having 1 to 4 carbon atoms. Non-limiting examples include: acetyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, butylcarbonyl, isobutylcarbonyl, pentylcarbonyl and hexylcarbonyl ,
C ₁ -C ₄ -Alkylsulfonylamino represent a straight-chain or branched alkylsulfonylamino radical having 1 to 4, preferably 1 to 3, carbon atoms. For example, and preferably, the following may be mentioned: methanesulfonylamino, ethanesulfonylamino, n-propanesulfonylamino, isopropanesulfonylamino, tert-butanesulfonylamino.
C ₁ -C ₆ - and C ₁ -C ₄ alkoxycarbonyl represents a straight-chain or branched alkoxycarbonyl radical having 1 to 6, preferably 1 to 4 and particularly preferably 1 to 3 carbon atoms. Non-limiting examples include methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl and tert-butoxycarbonyl.
C ₁ -C ₆ - and C ₁ -C ₄ -alkoxycarbonylamino represents a straight-chain or branched alkoxycarbonylamino radical having 1 to 6, preferably 1 to 4 and particularly preferably 1 to 3 carbon atoms. Non-limiting examples include methoxycarbonylamino, ethoxycarbonylamino, n-propoxycarbonylamino, isopropoxycarbonylamino, tert-butoxycarbonylamino, n-pentoxycarbonylamino and n-hexoxycarbonylamino.
C ₃ -C ₈ - and C ₅ -C ₆ -cycloalkylcarbonylamino represents a 3- to 8-membered, preferably 5- to 6-membered cycloalkylcarbonylamino radical. Non-limiting examples include cycloprooylcarbonylamino, cyclobutylcarbonylamino, cyclopentylcarbonylamino, cyclohexylcarbonylamino, cycloheptylcarbonylamino and cyclooctylcarbonylamino.
Heterocyclyl stands for a mono- or polycyclic, preferably mono- or bicyclic, non-aromatic radical with generally 4 to 10, preferably 5 to 8 ring atoms and up to 3, preferably up to 2 hetero-ring members from the series N, O , S, SO, SO ₂ . The heterocyclyl residues can be saturated or partially unsaturated. Non-limiting examples include 5- to 8-membered monocyclic saturated heterocyclyl radicals having up to two hetero ring atoms from the O, N and S series, such as tetrahydrofuran-2-yl, pynolidin-2-yl, pyrrolidin-3-yl, pyrrolinyl, Piperidinyl, morpholinyl and perhydroazepinyl.
Heteroaryl stands for an aromatic, mono- or bicyclic radical with 5 to 10 ring atoms and up to 5 heteroatoms from the series S, O and / or N. 5- to 6-membered heteroaryls with up to 4 heteroatoms are preferred. The heteroaryl radical can be bonded via a carbon or heteroatom. Non-limiting examples include: thienyl, furyl, pyrrolyl, thiazolyl, oxadiazolyl, oxazolyl, imidazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, indolyl, indazolyl, benzofuranyl, benzothiophenyl, quinolinyl, isoquinolinyl.
Heterocyclylcarbonyl stands for a carbonyl group which has a mono- or polycyclic, preferably mono- or bicyclic, non-aromatic radical, generally having 4 to 10, preferably 5 to 8, ring atoms and up to 3, preferably up to 2, hetero-ring members the series N, O, S, SO, SO _{2 is} linked. The heterocyclyl residues can be saturated or partially unsaturated. Non-limiting examples include carbonyl groups linked to 5- to 8-membered monocyclic saturated heterocyclyl radicals having up to two hetero ring atoms from the series O, N and S, such as tetrahydrofuran-2-ylcarbonyl, pynolidin-2-ylcarbonyl, pyrrolidin-3-ylcarbonyl, pyrrolinylcarbonyl , Piperidinylcarbonyl, morpholinylcarbonyl and perhydroazepinylcarbonyl.
Aryl stands for a mono- to tricyclic aromatic, carbocyclic radical with usually 6 to 10 carbon ring atoms. Non-limiting examples include phenyl and naphthyl.
Halogen stands for fluorine, chlorine, bromine and iodine. Fluorine, chlorine and bromine are preferred, particularly preferably fluorine and chlorine.
C ₁ -C ₆ and C ₁ -C ₄ alkylthio represent a straight-chain or branched alkylthio radical having 1 to 6, preferably 1 to 4, particularly preferably 1 to 3 carbon atoms. Non-limiting examples include methylthio, ethylthio, n-propylthio, isopropylthio, tert-butylthio, n-pentylthio and n-hexylthio.

If residues in the compounds of the invention are optionally substituted, the residues, if nothing otherwise, one or more times the same or different be substituted.

Preferred compounds of the formula (n are those in which R ^{1 is} (3R) -1-azabicyclo- [2.2.2] oct-3-yl and R ² , R ³ , R ⁴ , A, E and the ring B have the meanings given above, and the solvates, salts or solvates of the salts of these compounds.

Also preferred are compounds of formula (I) in which R ^{2 is} hydrogen or methyl and R ¹ , R ³ , R ⁴ , A, E and ring B have the meanings given above, and the solvates, salts or solvates of the salts of these connections.

Particular preference is given to compounds of the formula (I) in which R ^{2 is} hydrogen and R ¹ , R ³ , R ⁴ , A, E and the ring B have the meanings given above, and the solvates, salts or solvates of the salts of these compounds ,

Also preferred are compounds of formula (I) in which R ^{3 is} hydrogen or methyl and R ¹ , R ² , R ⁴ , A, E and ring B have the meanings given above, and the solvates, salts or solvates of the salts of these connections.

Particular preference is given to compounds of the formula (I) in which R ^{3 is} hydrogen and R ¹ , R ² , R ⁴ , A, E and the ring B have the meanings given above, and the solvates, salts or solvates of the salts of these compounds ,

Also preferred are compounds of formula (I) in which R ^{4 is} hydrogen, fluorine, chlorine, bromine, trifluoromethoxy, hydroxymethyl, methoxy or 6-membered heterocyclyl and R ¹ , R ² , R ³ , A, E and the ring B. have the meanings given above, and the solvates, salts or solvates of the salts of these compounds.

Also preferred are compounds of formula (I) in which A represents a sulfur atom and R ¹ , R ² , R ³ , R ⁴ , E and the ring B have the meanings given above, and the solvates, salts or solvates of the salts of these compounds.

Also preferred are compounds of formula (I) in which A represents an oxygen atom and R ¹ , R ² , R ³ , R ⁴ , E and ring B have the meanings given above, and the solvates, salts or solvates of the salts thereof Links.

Also preferred are compounds of the formula (I) in which the ring B is benzo, which is optionally substituted by 1 to 3 radicals from the series halogen, cyano, trifluoromethyl, trifluoromethoxy and C ₁ -C ₄ -alkyl, and R ¹ , R ² , R ³ , R ⁴ , A and E have the meanings given above, and the solvates, salts or solvates of the salts of these compounds.

Also preferred are compounds of formula (I) in which E is phenylene which is optionally substituted by radicals from the series fluorine, chlorine, bromine, cyano, trifluoromethoxy, C ₁ -C ₆ alkyl and C ₁ -C ₆ alkoxy , and R ¹ , R ² , R ³ , R ⁴ , A and the ring B have the meanings given above, and the solvates, salts or solvates of the salts of these compounds.

The present invention relates to compounds of the formula (I) in which
R ¹ 1-aza-bicyclo [2.2.2] oct-3-yl,
R ^{2 is} hydrogen or C ₁ -C ₆ alkyl,
R ^{3 is} hydrogen, halogen or C ₁ -C ₆ alkyl,
R ^{4 is} hydrogen, halogen, cyano, trifluoromethyl, trifluoromethoxy, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy or heterocyclyl, alkyl being optionally substituted by a radical hydroxyl,
A oxygen or sulfur,
the ring B benzo or pyrido, which are each optionally substituted by radicals from the series halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, amino, C ₁ -C ₆ -alkyl and C ₁ -C ₆ -alkoxy, and
EC≡C, arylene or heteroarylene, where arylene and heteroarylene can be substituted by radicals from the series halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, amino, C ₁ -C ₆ -alkyl and C ₁ -C ₆ -alkoxy, as well as the solvates, salts or solvates of the salts of these compounds.

in welcher
R¹ (3R)-1-Aza-bicyclo[2.2.2]oct-3-yl,
R² und R³ unabhängig voneinander Wasserstoff oder Methyl,
R⁴ Wasserstoff, Halogen, Cyano, Trifluormethyl, Trifluormethoxy, C₁-C₆-Alkyl, C₁-C₆-Alkoxy oder Heterocyclyl, wobei Alkyl gegebenenfalls durch einen Hydroxyrest substituiert ist, und
R^B Wasserstoff, Halogen, Cyano, Trifluormethyl, Trifluormethoxy, Nitro, Amino, C₁-C₆-Alkyl oder C₁-C₆-Alkoxy
bedeuten, sowie die Solvate, Salze oder Solvate der Salze dieser Verbindungen.Compounds of the formula are also preferred

in which
R ¹ (3R) -1-aza-bicyclo [2.2.2] oct-3-yl,
R ² and R ³ independently of one another are hydrogen or methyl,
R ^{4 is} hydrogen, halogen, cyano, trifluoromethyl, trifluoromethoxy, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy or heterocyclyl, alkyl being optionally substituted by a hydroxyl radical, and
R ^{B is} hydrogen, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, amino, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy
mean, and the solvates, salts or solvates of the salts of these compounds.

Compounds of the formula (Ia) in which
R ¹ (3R) -1-aza-bicyclo [2.2.2] oct-3-yl,
R ² and R ^{3 are} hydrogen,
R ^{4 is} hydrogen, fluorine, chlorine, bromine, trifluoromethoxy, hydroxymethyl, methoxy or 6-membered heterocyclyl and
R ^{B is} hydrogen, halogen, cyano, trifluoromethyl, trifluoromethoxy or C ₁ -C ₄ alkyl
mean, and the solvates, salts or solvates of the salts of these compounds.

in welcher
R¹ (3R)-1-Aza-bicyclo[2.2.2]oct-3-yl,
R² und R³ unabhängig voneinander Wasserstoff oder Methyl,
R⁴ Wasserstoff, Halogen, Cyano, Trifluormethyl, Trifluormethoxy, C₁-C₆-Akyl, C₁-C₆-Alkoxy oder Heterocyclyl, wobei Alkyl gegebenenfalls durch einen Hydroxyrest substituiert ist, und
R^B Wasserstoff, Halogen, Cyano, Trifluormethyl, Trifluormethoxy, Nitro, Amino, C₁-C₆-Alkyl und C₁-C₆-Alkoxy
bedeuten, sowie die Solvate, Salze oder Solvate der Salze dieser Verbindungen.Compounds of the formula are also preferred

in which
R ¹ (3R) -1-aza-bicyclo [2.2.2] oct-3-yl,
R ² and R ³ independently of one another are hydrogen or methyl,
R ^{4 is} hydrogen, halogen, cyano, trifluoromethyl, trifluoromethoxy, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy or heterocyclyl, where alkyl is optionally substituted by a hydroxyl radical, and
R ^{B is} hydrogen, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, amino, C ₁ -C ₆ alkyl and C ₁ -C ₆ alkoxy
mean, and the solvates, salts or solvates of the salts of these compounds.

Also preferred are compounds of formula (Ib) in which
R ¹ (3R) -1-aza-bicyclo [2.2.2] oct-3-yl,
R ² and R ^{3 are} hydrogen,
R ^{4 is} hydrogen, fluorine, chlorine, bromine, trifluoromethoxy, hydroxymethyl, methoxy or 6-membered heterocyclyl and
R ^{B is} hydrogen, halogen, cyano, trifluoromethyl, trifluoromethoxy or C ₁ -C ₄ alkyl
mean, and the solvates, salts or solvates of the salts of these compounds.

in welcher
E Phenylen,
R⁴ C₁-C₆-Alkoxy, Aminomethylen, Hydroxycarbonyl, C₃-C₈-Cycloalkylcarbonylamino, eine Gruppe der Formel

wobei
R⁵ C₁-C₆-Alkyl,
n null, 1, 2, 3 oder 4, oder
5- bis 6-gliedriges Heterocyclyl, das gegebenenfalls mit Oxo substituiert ist,
A Schwefel oder Sauerstoff,
bedeuten, sowie deren Solvate, Salze oder Solvate der Salze.Compounds of the formula are also preferred

in which
E phenylene,
R ⁴ C ₁ -C ₆ alkoxy, aminomethylene, hydroxycarbonyl, C ₃ -C ₈ cycloalkylcarbonylamino, a group of the formula

in which
R ⁵ C ₁ -C ₆ alkyl,
n zero, 1, 2, 3 or 4, or
5- to 6-membered heterocyclyl which is optionally substituted by oxo,
A sulfur or oxygen,
mean, and their solvates, salts or solvates of the salts.

wobei
R⁵ C₁-C₄-Alkyl,
n null, 1 oder 2, oder
5- bis 6-gliedriges Heterocyclyl, das gegebenenfalls mit Oxo substituiert ist,
A Schwefel oder Sauerstoff,
bedeuten, sowie deren Solvate, Salze oder Solvate der Salze.The invention preferably relates to compounds of the formula (I) in which
E phenylene,
R ⁴ C ₁ -C ₄ alkoxy, aminomethylene, hydroxycarbonyl, C ₃ -C ₆ cycloalkylcarbonylamino, a group of the formula

in which
R ⁵ C ₁ -C ₄ alkyl,
n zero, 1 or 2, or
5- to 6-membered heterocyclyl which is optionally substituted by oxo,
A sulfur or oxygen,
mean, and their solvates, salts or solvates of the salts.

sowie die Solvate, Salze oder Solvate der Salze dieser Verbindungen.The invention particularly preferably relates to compounds of the following formulas

as well as the solvates, salts or solvates of the salts of these compounds.

Combinations are very particularly preferred of two or more of the preferred areas mentioned above.

und im Falle, dass E -C≡C- bedeutet, für Wasserstoff steht,
mit einer Verbindung der Formel

in welcher
R¹, R², R³, A und der Ring B die oben genannten Bedeutungen besitzen und
X² für Triflat oder Halogen, bevorzugt Chlor, Brom oder Iod, steht,
und die resultierenden Verbindungen (I) gegebenenfalls mit den entsprechenden (i) Lösungsmitteln und/oder (ii) Basen oder Säuren zu ihren Solvaten, Salzen oder Solvaten der Salze umsetzt.The invention further relates to processes for the preparation of the compounds according to the invention, according to which compounds of the formula X ¹ -ER ⁴ (II), in which
R ^{4 has} the meanings given above and or
X ¹ in the case where E is arylene or heteroarylene, for -B (OH) ₂ or

and in the case where E is -C≡C- stands for hydrogen,
with a compound of the formula

in which
R ¹ , R ² , R ³ , A and the ring B have the meanings given above and
X ^{2 represents} triflate or halogen, preferably chlorine, bromine or iodine,
and optionally reacting the resulting compounds (I) with the corresponding (i) solvents and / or (ii) bases or acids to give their solvates, salts or solvates of the salts.

The implementation of the compounds (II) and (III) generally takes place in an inert solvent in the presence of a transition metal catalyst, in the presence of a base and optionally in the presence of copper (I) iodide instead of.

The method according to the invention is preferred in a temperature range of 70 ° C up to 110 ° C Normal pressure carried out.

Inert solvents are, for example Ethers such as dioxane, tetrahydrofuran or 1,2-dimethoxyethane, hydrocarbons such as benzene, xylene or toluene, nitroaromatics such as nitrobenzene, if appropriate N-alkylated carboxamides such as dimethylformamide, dimethylacetamide, alkyl sulfoxides such as dimethyl sulfoxide or cyclic lactams such as N-methylpyrrolidone. Solvents are preferred from the series dimethylformamide, dimethylacetamide, dimethyl sulfoxide and 1,2-dimethoxyethane.

As transition metal catalysts are preferably palladium (0) - or palladium (II) compounds, in particular bis (diphenylphosphanferrocenyl) palladium (II) chloride, dichlorobis (triphenylphosphine) palladium or Tetrakis (triphenylphosphine) palladium (0), used.

Alkali hydroxides are used as bases or salts such as potassium acetate, sodium hydroxide, sodium hydrogen carbonate or sodium carbonate, optionally in the form of their aqueous Solutions, prefers.

The transition metal catalyzed Reactions can be carried out analogously to known processes, e.g. B. Implementation with alkynes: cf. N. Krause et al., J. Org. Chem. 1998, 63, 8551; with ketones, aromatics and alkenes: cf. e.g. A.

Suzuki, Acc. Chem. Res. 1982, 15, 178 ff; Miyaura et al. J. Am. Chem. Soc. 1989, 111, 314; J. K. Stille, Angew. Chem. 1986, 98, 504 and with substituted amines: cf. S. L. Buchwald et al., J. Organomet. Chem. 1999, 576, 125ff. (see also J. Tsuji, Palladium Reagents and Catalysts, Wiley, New York, 1995).

The compounds (II) are known or can be analogously known methods from the corresponding Synthesize starting materials.

in welcher
R³, X², A und der Ring B die oben genannten Bedeutungen besitzen und
X³ für Hydroxy oder Halogen, bevorzugt Brom oder Chlor, steht,
hergestellt werden.The compounds (III) can be obtained by reacting compounds of the formula R ¹ R ² NH (IV), in which R ¹ and R ^{2 have} the meanings given above,
with a compound of the formula

in which
R ³ , X ² , A and the ring B have the meanings given above and
X ^{3 represents} hydroxy or halogen, preferably bromine or chlorine,
getting produced.

If X ^{3 is} halogen, the compounds (IV) and (V) are generally reacted in inert solvents, if appropriate in the presence of a base, preferably in a temperature range from 0 ° C. to 50 ° C. under atmospheric pressure.

Inert solvents are, for example Halogenated hydrocarbons such as methylene chloride, trichloromethane, carbon tetrachloride, Trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichlorethylene, Ethers such as diethyl ether, methyl tert-butyl ether, dioxane, tetrahydrofuran, Glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, Nitro aromatics such as nitromethane, carboxylic acid esters such as ethyl acetate, ketones such as acetone or 2-butanone, optionally N-alkylated carboxamides such as dimethylformamide or dimethylacetamide, alkyl sulfoxides such as dimethyl sulfoxide, carbonitriles such as acetonitrile or heteroaromatics such as pyridine. Are preferred Dioxane, dimethylformamide or methylene chloride.

Bases are, for example, alkali metal hydroxides such as sodium or potassium hydroxide, alkali carbonates and bicarbonates like cesium carbonate, Sodium bicarbonate, sodium or potassium carbonate, or amides such as Lithium diisopropylamide, alkylamines such as triethylamine or diisopropylethylamine, preferably diisopropylethylamine or triethylamine, and other bases like DBU.

If X ^{3 is} hydroxy, the reaction is generally carried out in inert solvents; in the presence of condensing agents, if appropriate in the presence of a base, preferably in a temperature range from 20 to 50 ° C. at atmospheric pressure.

The term "inert solvent" includes, for example, halogenated hydrocarbons such as methylene chloride, Trichloromethane, carbon tetrachloride, trichloroethane, carbon tetrachloride, 1,2-dichloroethane or trichlorethylene, ethers such as diethyl ether, methyl tert-butyl ether, Dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, Hydrocarbons such as benzene, xylene, toluene, hexane, cyclo hexane or petroleum fractions, Nitro aromatics such as nitromethane, carboxylic acid esters such as ethyl acetate, ketones such as acetone, optionally N-alkylated carboxamides such as dimethylformamide or dimethylacetamide, alkyl sulfoxides such as dimethyl sulfoxide, carboxylic acid nitriles such as acetonitrile and heteroaromatics such as pyridine. Preferred are tetrahydrofuran, Dimethylformamide, 1,2-dichloroethane or methylene chloride.

Condensing agent in the sense of Examples include carbodiimides such as e.g. N, N'-diethyl, N, N, '- dipropyl, N, N'-diisopropyl, N, N'-dicyclohexylcarbodiimide, N- (3-dimethylaminoisopropyl) -N'-ethylcarbodiimide hydrochloride (EDC), N-cyclohexylcarbodiimide-N'-propyloxymethyl polystyrene (PS-carbodiimide); Carbonyl compounds such as carbonyldiimidazole; 1,2-oxazolium compounds such as 2-ethyl-5-phenyl-1,2-oxazolium-3-sulfate or 2-tert-butyl-5-methyl-isoxazolium perchlorate; acylamino such as 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline; also propanephosphonic anhydride, Isobutyl chloroformate, bis (2-oxo-3-oxazolidinyl) phosphoryl chloride, Benzotriazolyloxy-tri (dimethylamino) phosphonium hexafluorophosphate, O- (benzotriazol-1-yl) -N, N, N ', N'-tetra-methyluronium hexafluorophosphate (HBTU), 2- (2-oxo-1- (2H) pyridyl) -1,1,3,3-tetramethyluronium tetrafluoroborate (TPTU), O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyl uronium hexafluorophosphate (HATU), benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (BOP), and their mixtures.

If necessary, it can be advantageous be the condensing agent in the presence of an auxiliary nucleophile such as For example, 1-hydroxybenzotriazole (HOBt) to use.

Bases are, for example, alkali carbonates and hydrogen carbonates, e.g. Sodium or potassium carbonate or -hydrogen carbonate, organic bases such as alkylamines e.g. triethylamine, or N-methylmorpholine, N-methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamine.

The combination of N- (3-dimethylaminoisopropyl) -N'-ethylcarbodiimide-Hy is particularly preferred hydrochloride (EDC), 1-hydroxybenztriazole (HOBt) and triethylamine in dimethylformamide or of O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyl-uronium hexafluorophosphate (HATU) and diisopropylethylamine in dimethylformamide ,

The compounds (IV) and (V) are known or can be analogous to known methods from the corresponding Synthesize starting materials (see, for example, "Comprehensive Heterocyclic Chemistry", Katritzki et al., Ed.; Elsevier, 1996).

Y = F, Cl, Br
X² = Halogen oder TriflatFor example, substituted benzothiophene-2-carboxylic acids can be obtained from appropriately substituted 2-halobenzaldehydes by reaction with methyl mercaptoacetate (see, for example, AJ Bridges et al., Tetrahedron Lett. 1992, 33, 7499) and subsequent saponification of the ester: Synthesis scheme 1:

Y = F, Cl, Br
X ² = halogen or triflate

For the synthesis of the corresponding pyrido derivatives, a reaction with methyl mercaptoacetic acid to give the 3-aminobenzothiophene-2-carboxylic acid esters is possible starting from 2-halobenzonitriles: Synthesis scheme 2:

The nitrogen atom drawn in the ring can have a CH group at one of the positions 1 to 4 in the aromatic system replace.

The amino function can be achieved by diazotization be removed. Finally the ester can be saponified to the target compound.

Substituted benzofuran-2-carboxylic acids are z. B. according to D. Bogdal et al., Tetrahedron 2000, 56, 8769.

The compounds according to the invention are suitable for use as a medicine for treatment and / or prophylaxis of diseases in humans and animals.

They act as agonists on the α7-nAChR and show an unpredictable, valuable pharmacological spectrum of action.

Because of their pharmacological properties, the compounds according to the invention can be used alone or in combination with other active substances for the treatment and / or prevention of cognitive disorders, in particular Alzheimer's disease. Because of their selective action as α7-nAChR agonists, they are particularly suitable for improving perception and concentration training, learning performance or memory performance, especially after cognitive disorders, such as those associated with "mild cognitive impairment", age-associated learning and memory disorders, age-associated memory loss, vascular dementia, traumatic brain injury, stroke, dementia following strokes occurs ("post stroke dementia"), post-traumatic traumatic brain injury, general concentration disorders, concentration disorders in children with learning and memory problems, attention deficit hyperactivity disorder, Alzheimer's disease, dementia with Lewy bodies, dementia with degeneration of the frontal lobes including des Pick's syndrome, Parkinson's disease, progressive nuclear palsy, dementia with corticobasal degeneration, amyotrophic lateral sclerosis (ALS), Huntington's disease, multiple sclerosis, thalamic degeneration, Creutzfeld-Jacob dementia, HIV dementia, schizophrenia, schizophrenia with dementia or Korsakoff psychosis occur.

The compounds of the invention can be used alone or in combination with other active substances for prophylaxis and treatment acute and / or chronic pain (for a classification see "Classification of Chronic Pain, Descriptions of Chronic Pain Syndromes and Definitions of Pain Terms ", 2nd ed., Meskey and Begduk, eds .; IASP-Press, Seattle, 1994) can be used, especially for the treatment of Cancer-induced pain and chronic neuropathic pain, such as in diabetic neuropathy, postherpetic Neuralgia, peripheral nerve damage, central pain (e.g. as a result of cerebral ischemia) and trigeminal neuralgia, and other chronic pain, such as lumbago, back pain (low back pain) or rheumatic pain. In addition, are suitable these active ingredients also for the treatment of primary acute pain of any kind Genesis and resulting secondary pain conditions, as well for the therapy of chronic, formerly acute pain conditions. The compounds of the invention can alone or in combination with other active substances for treatment used by schizophrenia.

The in vitro effect of the compounds according to the invention can be shown in the following assays:

1. Determination of the Affinity of Test Substances for α7-nAChR by Inhibition of [ ³ H] Methyllycaconitine Binding on Rat Brain Membranes

The [ ³ H] methyllycaconitine binding assay is a modification of that described by Davies et al. in Neuropharmacol. 1999, 38, 679-690.

Rat brain tissue (hippocampus or whole brain) is placed in homogenization buffer (10% w / v, 0.32 M sucrose, 1 mM EDTA, 0.1 mM phenylmethylsulfonyl fluoride (PMSF), 0.01% (w / v) NaN ₃ , pH 7.4, 4 ° C) at 600 rpm homogenized in a glass homogenizer. The homogenate is centrifuged (1000 × g, 4 ° C., 10 min) and the supernatant is removed. The pellet is resuspended (20% w / v) and the suspension is centrifuged (1000 × g, 4 ° C, 10 min). The two supernatants are combined and centrifuged (15,000 × g, 4 ° C., 30 min). The pellet thus obtained is referred to as the P2 fraction.

The P2 pellet is suspended twice in binding buffer (50 mM Tris-HCl, 1 mM MgCl ₂ , 120 mM NaCl, 5 mM KCl, 2 mM CaCl ₂ , pH 7.4) and the suspension is centrifuged (15,000 × g, 4 ° C. , 30 min).

The residue is resuspended in binding buffer and in a volume of 250 μl (membrane protein amount 0.1-0.5 mg) in the presence of 1-5 nM [ ³ H] -methyllycaconitin 0.1% (w / v) BSA (bovine serum albumin) and various concentrations of the test substance for Incubated for 2.5 h at 21 ° C. The mixture is then incubated in the presence of 1 μM α-bungarotoxin or 100 μM nicotine or 10 μM MLA (methyl lycaconitine).

The incubation is carried out by adding 4 ml of PBS (20 mM Na ₂ HPO ₄ , 5 mM KH ₂ PO ₄ , 150 mM NaCl, pH 7.4, 4 ° C.) and filtration through type A / E glass fiber filters (Gelman Sciences), which were previously placed in 0.3% (v / v) polyethyleneimine (PEI) for 3 hours. The filters are washed twice with 4 ml PBS (4 ° C) and the bound radioactivity is determined by scintillation measurement. All tests are carried out as triplicate determinations. The dissociation constant K _{i of} the test substance was calculated from the IC ₅₀ value of the compounds (concentration of the test substance at which 50% of the ligand bound to the receptor is displaced), the dissociation constant K _D and the concentration L of [ ³ H] methyllycaconitin K _i = IC ₅₀ / (1 + L / K _D ) determined.

Instead of [ ³ H] -methyllycaconitin, other α7-nAChR-selective radioligands such as, for example, [ ¹²⁵ I] -α-bungarotoxin or unselective nAChR-radioligands can also be used together with inhibitors of other nAChR.

Representative in vitro activity data for the compounds according to the invention are shown in Table A: Table A

The suitability of the compounds according to the invention for the treatment of cognitive disorders can be shown in the following animal models:

2. Object recognition test

The object recognition test is a memory test. It measures ability of rats (and mice), distinguish between known and unknown objects.

The test is from Blokland et al., NeuroReport 1998, 9, 4205-4208; A. Ennaceur et al ,. Behav. Brain Res. 1988, 31, 47-59; A. Ennaceur et al., Psychopharmacology 1992, 109, 321-330; and Prickaerts et al., Eur. J. Pharmacol. 1997, 337, 125-136.

In a first run, one Rat in an otherwise empty larger observation arena faced two identical objects. The rat becomes both objects investigate extensively, i.e. sniff and touch. In a second run, after a waiting time of 24 hours the rat again placed in the observation arena. Now there is one the known objects are replaced by a new, unknown object. If a rat recognizes the familiar object, it will move forward examine everything the unknown object. After 24 hours one has However, rats usually forget what object they already have has examined in the first pass, and will therefore both objects inspect equally. The gift of a substance with learning and memory-improving Effect can cause that a rat did this 24 hours beforehand in the first run recognizes seen object. It then becomes the new unknown Object more detailed investigate as the already known. This memory performance is in one Discrimination index expressed. A zero discrimination index means that the rat has both Objects, the old and the new, examined at the same time; i.e. she did not recognize the old object and reacts to both objects as if them new. A discrimination index greater than zero means that the Rat the new item longer inspected as the old; i.e. the rat recognized the old object.

3. Social recognition test:

The social recognition test is a test for testing the learning or memory-improving effect of test substances.

Adult rats kept in groups are placed individually in test cages 30 minutes before the start of the test. The test animal is placed in an observation box four minutes before the start of the test brought. After this adaptation period, a juvenile animal becomes the test animal and measured for 2 minutes the time the adult Animal examines the juvenile animal (Trial 1). All are measured behaviors clearly directed towards the young animal, i.e. anogenital Inspection, tracking and grooming, in which the old animal unites Distance of at most 1 cm to the cub. The juvenile animal is then removed and the adult in his test cage left (with 24 hours retention, the animal is returned to its home cage). In front or after the first test, the adult test animal with test substance treated. Depending on the time of treatment, learning or storing information about the young animal can be influenced by the substance. After a set The test period is repeated (Trial 2). The bigger the difference between the investigation times determined in Trials 1 and 2, the better the adult animal remembered the young animal.

The compounds according to the invention are suitable for use as a medicine for humans and animals.

The present invention also includes pharmaceutical preparations which, in addition to inert, non-toxic, pharmaceutically suitable excipients and carriers one or more compounds of the invention contain, or from one or more compounds of the invention exist, as well as processes for the preparation of these preparations.

The compounds of the invention are said to these preparations in a concentration of 0.1 to 99.5% by weight, preferably from 0.5 to 95% by weight of the total mixture.

In addition to the compounds of the invention can the pharmaceutical preparations also include other active pharmaceutical ingredients contain.

The pharmaceutical preparations listed above can in more usual Be prepared by known methods.

The new active ingredients can be used in known way in the usual Formulations are transferred such as tablets, coated tablets, pills, granules, aerosols, syrups, emulsions, Suspensions and solutions, using inert, non-toxic, pharmaceutically suitable excipients or solvent. Here, the therapeutically active compound should be in one Concentration of about 0.5 to 90% by weight of the formulation is present be, i.e. in amounts sufficient to give the indicated dosage range to reach.

The formulations are, for example by stretching the active ingredients with solvents and / or carriers, optionally produced using emulsifiers and / or dispersants, where e.g. in the case of using water as a diluent optionally organic solvents as auxiliary solvent can be used.

The application can be in the usual Mode, preferably orally, transdermally or parenterally, especially perlingually or intravenously, respectively. It can also be inhaled through the mouth or nose, for example with the help of a spray, or topically over the skin.

In general, it has proven to be beneficial proven amounts of about 0.001 to 10 mg / kg, with oral use preferably about 0.005 to 3 mg / kg body weight to achieve more effectively Deliver results.

Nevertheless, it may be necessary be different from the amounts mentioned, depending on of body weight or the type of application route, the individual behavior across from the drug, the type of formulation and the time or interval at which the administration takes place. It can in some cases be sufficient with less than the aforementioned minimum amount get along while in other cases the specified upper limit was exceeded must become. In the case of application of larger quantities it can be recommended be spread over the day in several separate doses.

Unless otherwise stated, refer all quantities refer to percentages by weight. Solvent ratios, dilution ratios and obtain concentration information from liquid / liquid solutions each on the volume. "W / v" means "weight / volume" (Weight / volume). For example, "10% w / v" means 100 ml solution or suspension contain 10 g of substance.

Abbreviations:
DAD diode analyzer
DBU 1,5-diazabicyclo [4.3.0] non-5-ene
DCI direct chemical ionization (for MS)
DMAP 4-N, N-dimethylaminopyridine
DMF N, N-dimethylformamide
DMSO dimethyl sulfoxide
theory the theory (with yield)
EDC N '- (3-dimethylaminopropyl) -N-ethylcarbodiimide × HCl
eq. Equivalent (s)
ESI electrospray ionization (for MS)
HATU O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate
HOBt 1-hydroxy-1H-benzotriazole × H ₂ O
HPLC high pressure / high performance liquid chromatography
conc. concentrated
LC-MS liquid chromatography with coupled mass spectroscopy
MS mass spectroscopy
NMR nuclear magnetic resonance spectroscopy
PBS phosphate buffered saline (phosphate-buffered saline solution)
PdCl ₂ (dppf) bis (diphenylphosphanferrocenyl) palladium (II) chloride
PdCl ₂ (PPh ₃ ) ₂ Dichloro-bis (triphenylphosphine) palladium
Pd (PPh ₃ ) ₄ tetrakis (triphenylphosphine) palladium (0)
Ph phenyl
RT room temperature
R _t retention time (with HPLC)
TBTU O- (benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium tetrafluoroborate
THF tetrahydrofuran
TRIS tris (hydroxymethyl) aminomethane

HPLC and LC-MS methods:

Method 1 (HPLC):

Instrument: HP 1100 with DAD detection; Column: Kromasil RP-18, 60 mm × 2 mm, 3.5 μm; Eluent: A = 5 mL HClO ₄ / LH ₂ O, eluent B = acetonitrile; Gradient: 0 min 2% B, 0.5 min 2% B, 4.5 min 90% B, 6.5 min 90% B; Flow: 0.75 mL / min; Temperature: 30 ° C; Detection: UV 210 nm.

Method 2 (LC-MS):

Device type MS: Micromass ZQ; Device type HPLC: Waters Alliance 2790; Pillar: Symmetry C 18, 50 mm × 2.1 mm, 3.5 µm; Eluent B: acetonitrile + 0.05% formic acid, eluent A: water + 0.05% formic acid; Gradient: 0 min 5% B → 4.5 min 90% B → 5.5 min 90% B; Oven: 50 ° C; Flow: 1.0 mL / min; UV detection: 210 nm.

Method 3 (LC-MS):

Instrument: Micromass Platform LCZ, HP1100; Pillar: Symmetry C18, 50 mm × 2.1 mm, 3.5 µm; Eluent A: water + 0.05% formic acid, eluent B: acetonitrile + 0.05% formic acid; Gradient: 0 min 90% A → 4.0 min 10% A → 6.0 min 10% A; Oven: 40 ° C; Flow: 0.5 mL / min; UV detection: 208-400 nm.

Method 4 (LC-MS):

Device type MS: Micromass ZQ; Device type HPLC: Waters Alliance 2790; Pillar: Grom-Sil 120 ODS-4 HE 50 mm × 2 mm, 3.0 µm; Eluent B: acetonitrile + 0.05% formic acid, eluent A: water + 0.05% formic acid; Gradient: 0.0 min 5% B → 2.0 min 40% B → 4.5 min 90% B → 5.5 min 90% B; Oven: 45 ° C; Flow: 0.0 min 0.75 mL / min → 4.5 min 0.75 mL / min → 5.5 min 1.25 mL / min; UV detection: 210 nm.

Method 5 (LC-MS):

Instrument MS: Micromass TOF (LCT); HPLC instrument: 2-column circuit, Waters 2690; Pillar: YMC-ODS-AQ, 50 mm × 4.6 mm, 3.0 µm; Eluent A: water + 0.1% formic acid, eluent B: acetonitrile + 0.1% formic acid; Gradient: 0.0 min 100% A → 0.2 min 95% A → 1.8 min 25% A → 1.9 min 10% A → 3.2 min 10% A; Oven: 40 ° C; Flow: 3.0 mL / min; UV detection: 210 nm.

Starting Compounds:

General procedure A Synthesis of 1-benzothiophene-2-carboxylic acid methyl esters:

Be under an argon atmosphere 1.5 equivalents Sodium hydride (60% in paraffin oil) in absolute DMSO (0.60–1.26 M Suspension) submitted. At room temperature, 1.1 equivalents slowly become mercaptoacetate added dropwise to the reaction mixture, and the mixture is left until the evolution of hydrogen has ended Stir (approx. 15 min) at room temperature. 1.0 equivalents of the corresponding Benzaldehyde is dissolved in absolute DMSO (1.60–3.36 M solution) and at room temperature added to the reaction mixture. The reaction mixture is up to Completion of the reaction (approx. 5-10 min) stirred and subsequently poured into ice water. The resulting precipitate is suctioned off overnight in a vacuum at 40 ° C dried and further processed raw.

General working instructions B

Synthesis of 1-benzothiophene-2-carboxylic acids:

The corresponding 1-benzothiophene-2-carboxylic acid methyl ester becomes more aqueous with a mixture of equal parts of THF and 2N Potassium hydroxide solution (12:28 to 00:47 M solution) added. You leave stir the reaction mixture at room temperature overnight. The THF is in a vacuum removed and the watery Reaction mixture made acidic with concentrated hydrochloric acid. The resulting one Precipitation is filtered off and dried in vacuo at 40 ° C.

General working instructions C

Amide linkage between 3-quinuclidine amine and 2-benzothiophene or 2-benzofuran carboxylic acids:

1.0 eq. of the corresponding enantiomer 3-quinuclidinamine hydrochloride together with 1 eq. the carboxylic acid and 1.2 eq. HATU at 0 ° C submitted in DMF. After adding 1.2 eq. N, N-diisopropylethylamine the mixture is stirred at RT. After 30 min. another 2.4 eq. N, N-diisopropylethylamine added and over Stirred night at RT.

Example 1A

6-bromo-1-benzofuran-2-carboxylic acid

8.0 g (39.8 mmol) of 4-bromo-2-hydroxybenzaldehyde and 1.47 g (3.98 mmol) of tetra-n-butylammonium iodide are initially introduced together with 22 g (159.19 mmol) of anhydrous potassium carbonate. 9.07 g (83.57 mmol) of methyl chloroacetate are added. The reaction mixture is heated to 130 ° C. for 4 h and then cooled to 0 ° C. using an ice bath. 100 mL THF and a solution of 13.4 g (238.8 mmol) potassium hydroxide in 50 mL water are added and the mixture is then stirred at RT overnight. The THF is removed under reduced pressure. The remaining aqueous phase is washed with water diluted and with conc. Hydrochloric acid made acidic. The precipitated product is filtered off and dried in a high vacuum. For fine cleaning, silica gel 60 (Merck, Darmstadt; eluent: toluene, toluene-acetic acid 50: 1, toluene-acetic acid-methyl acetate 35: 1: 5) is used for cleaning. The solvent is removed under reduced pressure. Finally, the last solvent residues are removed in a high vacuum. 3.8 g (40% of theory) of the title compound are isolated.
¹ H-NMR (400 MHz, methanol-d ₄ ): δ = 7.91 (m, 1H), 7.61-7.51 (m, 3H).
HPLC (method 1): R _t = 4.1 min.
MS (ESIpos): m / z = 258 (M + NH ₄ ) ⁺ .

Example 2A

N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6-bromo-1-benzofuran-2-carboxamide

3.8 g (15.77 mmol) 6-bromobenzofuran-2-carboxylic acid (Example 1A), 3.14 g (15.77 mmol) (R) -3-aminoquinuclidine dihydrochloride, 7.19 g (18.92 mmol) HATU, 7.34 g (56.76 mmol) N, N-Diisopropylethylamine and 50 mL DMF are reacted according to the general working procedure C. The crude product is taken up in methanol and together with acidic ion exchanger (Dowex ^® WX2-200) for about 20 min. long shaken. The loaded ion exchanger is washed successively with methanol, dichloromethane and again with methanol. The product is eluted with methanol-triethylamine 90:10. The solvent is removed on the rotary evaporator under reduced pressure. Finally, the last solvent residues are removed in a high vacuum. 5.14 g (85% of theory) of the title compound are isolated. For analysis, a small amount is converted into the hydrochloride using 4N hydrogen chloride in dioxane.
¹ H-NMR (200 MHz, DMSO-d ₆ ): δ = 10.55 (br. S, 1H), 9.22 (d, 1H), 8.05 (s, 1H), 7.75-7.55 (m, 3H), 4.43- 4.29 (m, 1H), 3.70-3.55 (m, 1H), 3.45-3.10 (m, 5H), 2.25-2.00 (m, 2H), 1.98-1.82 (m, 2H), 1.80-1.60 (m, 1H ).
HPLC (method 1): R _t = 3.9 min.
MS (ESIpos): m / z = 349 (M + H) ⁺ .
LC-MS (Method 2): R _t = 1.49 min.
MS (ESIpos): m / z = 349 (M + H) ⁺ .

Example 3A

N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -5-bromo-1-benzofuran-2-carboxamide hydrochloride

240 mg (0.98 mmol) 5-bromobenzofuran-2-carboxylic acid, 200 mg (0.98 mmol) (R) -3-aminoquinuclidine dihydrochloride, 450 mg (1.18 mmol) HATU, 460 mg (3.54 mmol) N, N-diisopropylethylamine and 2.0 mL DMF are implemented according to general working procedure C. The reaction mixture is purified by preparative HPLC. Finally, the product is mixed with an excess of 1 N hydrochloric acid. The solvent is removed under reduced pressure. 202 mg (53% of theory) of the title compound are isolated.
¹ H-NMR (200 MHz, DMSO-d ₆ ): δ = 9.38 (br. S, 1H), 8.88 (d, 1H), 7.60 (s, 1H), 7.38-7.20 (m, 2H), 7.09 ( dd, 1H), 4.43-4.29 (m, 1H), 3.70-3.55 (m, 1H), 3.45-3.10 (m, 5H), 2.25-2.00 (m, 2H), 1.98-1.82 (m, 2H); 1.80-1.60 (m, 1H).
MS (ESIpos): m / z = 349 (M + H) ⁺ (free base).
LC-MS (Method 3): R _t = 2.71 min.
MS (ESIpos): m / z = 349 (M + H) ⁺ (free base).

Example 4A

7-bromo-5-fluoro-1-benzofuran-2-carboxylic acid

1.0 g (5.24 mmol) of 2-bromo-4-fluorophenol are placed in 4.0 mL of trifluoroacetic acid. There are portions in 20 minutes. 1.47 g (10.47 mmol) of hexamethylenetetramine were added. The mixture is then boiled under reflux for 28 h. At RT, 6 mL water and 3 mL 50% sulfuric acid are added. After 2 h, the mixture is extracted twice with a total of 60 ml of ethyl acetate. The combined organic phases are washed four times with 1N hydrochloric acid and once with water. It is dried over magnesium sulfate and the solvent is removed under reduced pressure. Finally, the last solvent residues are removed in a high vacuum. The crude product (without further purification) and 0.19 g (0.52 mmol) of tetra-n-butylammonium iodide are introduced together with 2.9 g (20.96 mmol) of anhydrous potassium carbonate. 1.19 g (11.0 mmol) of methyl chloroacetate are added. The reaction mixture is heated to 130 ° C. for 4 h and then cooled to 0 ° C. using an ice bath. 18 mL THF and a solution of 1.76 g (31.44 mmol) potassium hydroxide in 18 mL water are added. The mixture is stirred at RT overnight. The solvent is removed under reduced pressure. It is diluted with water and made acidic with concentrated hydrochloric acid. It is extracted twice with ethyl acetate. The combined organic phases are dried over magnesium sulfate and the solvent is removed on a rotary evaporator under reduced pressure. It is purified on silica gel 60 (Merck, Darmstadt; eluent: toluene-acetic acid 40: 1). The solvent is removed under reduced pressure. Finally, the last solvent residues are removed in a high vacuum. 257 mg (19% of theory over both stages) of the title compound are isolated.
¹ H-NMR (400 MHz, methanol-d ₄ ): δ = 7.60 (m, 1H), 7.48-7.35 (m, H).
HPLC (method 1): R _t = 4.1 min.
MS (ESIpos): m / z = 276 (M + NH ₄ ) ⁺ .

Example 5A

N - [(3R) -1-azabicyclo [22.2] oct-3-yl] -5-fluoro-7-bromo-1-benzofuran-2-carboxamide

143 mg (0.55 mmol) 5-fluoro-7-bromo-1-benzofuran-2-carboxylic acid (Example 4A), 100 mg (0.50 mmol) (R) -3-aminoquinuclidine dihydrochloride, 229.14 mg (0.6 mmol) HATU, 234 mg (1.81 mmol) N, N-diisopropylethylamine and 2.0 mL DMF are reacted according to the general working procedure C. DMF is removed under reduced pressure and the crude product is dissolved in 1 N sodium hydroxide solution. The aqueous phase is extracted with ethyl acetate and washed with saturated aqueous sodium chloride solution. The combined organic phases are dried over magnesium sulfate and the solvent is removed under reduced pressure removed on the rotary evaporator. The crude product is taken up in methanol and together with acidic ion exchanger (Dowex ^® WX2-200) for about 20 min. long shaken. The loaded ion exchanger is washed three times with 30 mL methanol, then with water, again with methanol, with dichloromethane and finally again with methanol. The product is eluted with methanol-triethylamine 95: 5. The solvent is removed on the rotary evaporator under reduced pressure. 181 mg (98% of theory) of the title compound are isolated.
¹ H-NMR (400 MHz, methanol-d ₄ ): δ = 7.59 (d, 1H), 7.53-7.46 (m, 2H), 4.24-4.18 (m, 1H), 3.34-3.29 (m, 1H), 3.07-2.97 (m, 1H), 2.93-2.77 (m, 4H), 2.13-2.05 (m, 1H), 1.98-1.86 (m, 1H), 1.84-1.75 (m, 2H), 1.63-1.53 (m , 1H).
MS (ESIpos): m / z = 367 (M + H) ⁺ .
LC-MS (method 3): R _t = 2.92 min.
MS (ESIpos): m / z = 367 (M + H) ⁺ .

Example 6A

7-bromo-1-benzothiophene-2-carbonsäuremethylester

Starting from 27.8 g (137.1 mmol) 3-bromo-2-fluorobenzaldehyde with 8.2 g (205.7 mmol) of sodium hydride (60% in paraffin oil) and 16.0 g (150.9 mmol) of mercaptoacetic acid methyl ester 20.57 g of one Mixture of the title compound and the corresponding acid (approx. 1: 1) according to general working procedure A.

Example 7A

7-bromo-1-benzothiophene-2-carboxylic acid

Starting from 10.0 g (36.9 mmol) of 7-bromo-1-benzothiophene-2-carboxylic acid methyl ester, 8.99 g (91.0% of theory) of the desired product are obtained in accordance with general procedure B.
¹ H-NMR (200 MHz, DMSO-d ₆ ): δ = 13.76 (br. S, 1H), 8.28 (s, 1H), 8.07 (d, 1H), 7.78 (d, 1H), 7.46 (dd, 1H).
HPLC (method 1): R _t = 4.4 min.

Example 8A

N- (1-Azabicyclo [2.2.2] oct-3-yl) -7-bromo-1-benzothiophene-2-carboxamide hydrochloride

903.8 mg (3.52 mmol) 7-bromo-1-benzothiophene-2-carboxylic acid (Example 7A), 700 mg (3.52 mmol) (R) -3-aminoquinuclidine dihydrochloride, 1604.0 mg (4.22 mmol) HATU, 1635.7 mg (12.66 mmol) N, N-diisopropylethylamine and 7.0 mL DMF are reacted according to general working procedure C. The reaction mixture is purified by preparative HPLC. The product is dissolved in a 1: 1 mixture of 4 M hydrogen chloride in dioxane and 1 N hydrochloric acid, then concentrated and dried under high vacuum. 1087 mg (7.7% of theory) of the title compound are obtained.
¹ H-NMR 200 MHz, DMSO-d ₆ ): δ = 10.01 (br. S, 1H), 9.15 (d, 1H), 8.47 (s, 1H), 8.02 (m, 1H), 7.74 (m, 1H) ), 7.43 (dd, 1H), 4.34 (m, 1H), 3.80-3.10 (m, 6H), 2.22 (m, 1H), 2.14 (m, 1H), 1.93 (m, 2H), 1.78 (m, 1H).
HPLC (method 1): R _t = 4.1 min.
MS (ESIpos): m / z = 365 (M + H) ⁺ (free base).

Example 9A

6-bromo-1-benzothiophene-2-carbonsäuremethylester

Starting from 6.54 g (32.2 mmol) of 4-bromo-2-fluorobenzaldehyde, 1.93 g (48.3 mmol) of sodium hydride (60% in paraffin oil) and 3.76 g (35.5 mmol) of methyl mercaptoacetate according to the general procedure A 4.06 g (46% d.Th) received the title compound ..
¹ H-NMR (200 MHz, DMSO-d ₆ ): δ = 8.42 (d, 1H), 8.22 (s, 1H), 7.98 (d, 1H), 7.65 (dd, 1H), 3.90 (s, 3H) ,
HPLC (method 1): R _t = 5.3 min.
MS (ESIpos): m / z = 270 (M ⁺ ).

Example 10A

6-bromo-1-benzothiophene-2-carboxylic acid

Starting from 4.0 g (14.8 mmol) of 6-bromo-1-benzothiophene-2-carboxylic acid methyl ester (from Example 9A), 3.55 g (94% of theory) of the desired product are obtained according to general working procedure B.
¹ H-NMR 400 MHz, DMSO-d ₆ ): δ = 13.48 (br. S, 1H), 8.38 (s, 1H), 8.22 (s, 1H), 7.96 (d, 1H), 7.63 (m, 1H ).
HPLC (method 1): R _t = 4.5 min.

Example 11A

N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6-bromo-1-benzothiophene-2-carboxamide hydrochloride

900.0 mg (3.50 mmol) 4-bromo-1-benzothiophene-2-carboxylic acid (Example 10A), 697.0 mg (3.50 mmol} (R) -3-aminoquinuclidine dihydrochloride, 1597.1 mg (4.20 mmol) HATU, 1628.7 mg (12.60 mmol) N, N-diisopropylethylamine and 8.0 mL DMF are reacted according to general working procedure C. The reaction mixture is purified by preparative HPLC. The product is dissolved in a 1: 1 mixture of 4 M hydrogen chloride in dioxane and 1 N hydrochloric acid and the solution is then concentrated. Recrystallization from methanol / ethanol (1:10) gives 594 mg (42% of theory) of the title compound in the form of yellow-brown crystals.
¹ H-NMR (300 MHz, DMSO-d ₆ ): δ = 9.81 (br. S, 1H), 8.76 (m, 1H), 8.33 (s, 1H), 8.22 (s, 1H), 7.91 (d, 1H), 7.59 (dd, 1H), 4.15 (m, 1H), 3.51-2.93 (m, 6H), 2.12-1.92 (m, 2H), 1.79 (m, 2H), 1.58 (m, 1H).
HPLC (method 1): R _t = 4.1 min.
MS (ESIpos): m / z = 364 (M ⁺ ) (free base).

Example 12A

5-bromo-1-benzothiophene-2-carbonsäuremethylester

Starting from 2.99 g (14.7 mmol) of 5-bromo-2-fluorobenzaldehyde, 0.88 g (22.1 mmol) of sodium hydride (60%) and 1.72 g (16.2 mmol) of methyl mercaptoacetate according to the general procedure A 2.76 g (69.1% of theory). Th) of the title compound.
¹ H-NMR (200 MHz, DMSO-d ₆ ): δ = 8.29 (d, 1H), 8.18 (s, 1H), 8.08 (d, 1H), 7.69 (dd, 1H), 3.90 (s, 3H) ,
HPLC (method 1): R _t = 5.2 min.
MS (ESIpos): m / z = 270 (M ⁺ ).

Example 13A

5-bromo-1-benzothiophene-2-carboxylic acid

Starting from 2.7 g (9.96 mmol) of 5-bromo-1-benzothiophene-2-carboxylic acid methyl ester (from Example 12A), 2.41 g (94% of theory) of the desired product are obtained according to general working procedure B.
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 13.67 (br. S, 1H), 8.27 (m, 1H), 8.10 (s, 1H), 8.05 (d, 1H), 7.66 (dd, 1H).
HPLC (method 1): R _t = 4.5 min.

Example 14A

N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -5-bromo-1-benzothiophene-2-carboxamide hydrochloride

133.7 mg (0.52 mmol) 5-bromo-1-benzothiophene-2-carboxylic acid (Example 13A), 155.4 mg (0.78 mmol) (R) -3-aminoquinuclidine dihydrochloride, 296.7 mg (0.78 mmol) HATU, 369.8 mg (2.86 mmol) N, N-diisopropylethylamine and 1.5 mL DMF are reacted according to the general working procedure C. The reaction mixture is purified by preparative HPLC. The product is dissolved in acetonitrile and an excess of 1N hydrochloric acid is added. Finally the solvent is removed. 175 mg (84% of theory) of the title ver bond isolated.
¹ H-NMR (200 MHz, DMSO-d ₆ ): δ = 9.44 (br. S, 1H), 8.95 (d, 1H), 8.30-8.10 (m, 2H), 8.03 (d, 1H), 7.60 ( m, 1H), 4.3 8-4.20 (m, 1H), 3.80-3 .5 5 (m, 1H), 3.42-3.05 (m, 5H), 2.25-2.00 (m, 2H), 1.98-1.62 (m, 3H).
HPLC (method 1): R _t = 4.1 min.
MS (ESIpos): m / z = 365 (M + H) ⁺ (free base).

Example 15A

4- (4-bromophenyl) morpholine

A solution of 6.94 mL (134.8 mmol) bromine in 25 mL acetic acid is added to a solution of 20 g (122.5 mmol) N-phenylmorpholine in 170 mL acetic acid at room temperature over a period of 40 min. slowly added dropwise. After 30 min. Stirring at room temperature, the reaction mixture is stirred into 750 ml of water and adjusted to pH 11 with 45% sodium hydroxide solution. The resulting precipitate is filtered off, washed with water and dried in a high vacuum. After recrystallization from ethanol, 18.6 g (62.9% of theory) of the title compound are obtained.
¹ H NMR (200 MHz, DMSO-d ₆ ): δ = 7.37 (m, 2H), 6.89 (m, 2H), 3.73 (m, 4H), 3.08 (m, 4H).
HPLC (method 1): R _t = 3.9 min.
MS (ESIpos): m / z = 242 (M + H) ⁺ .

Example 16A

4- (4-bromophenyl) -3-morpholinone

1.41 g (6.20 mmol) of benzyltriethylammonium chloride and 0.98 g (6.20 mmol) of potassium permanganate are added to a solution of 500 mg (2.07 mmol) of 4- (4-bromophenyl) morpholine (Example 15A) in 10 mL of dichloromethane. After 5 hours under reflux, the contents of the flask are concentrated in vacuo and the residue is purified by preparative HPLC. The concentrated product is dried in a high vacuum. 217 mg (35.7% of theory) of the title compound are obtained.
LC-MS (Method 4): R _t = 2.9 min, m / z = 255 (M ⁺ ).

Example 17A

3- (4-morpholinyl) phenyl trifluoromethanesulfonate

2.18 mL (12.9 mmol) of trifluoromethanesulfonic anhydride are slowly added dropwise to a solution of 1.54 g (8.6 mmol) of 3- (4-morpholinyl) phenol and 3.59 mL (25.8 mmol) of triethylamine in 10 mL of dichloromethane, cooled to -10 ° C. It will take 30 min. at -10 ° C and then 30 min. stirred at 0 ° C. It is gradually washed with 10% sodium hydrogen carbonate solution, water and saturated sodium chloride solution , dried over sodium sulfate, concentrated in vacuo and the residue dried in a high vacuum. 2.41 g (90.1% of theory) of the title compound are obtained.
¹ H-NMR (200 MHz, CDCl ₃ ): δ = 7.28 (m, 1H), 6.88 (m, 1H), 6.73 (m; 2H), 3.86 (m, 4H), 3.18 (m, 4H):
HPLC (method 1): R _t = 4.8 min.
MS (ESIpos): m / z = 312 (M + H) ⁺ .

Example 18A

4- (4-morpholinylcarbonyl) phenyl trifluoromethanesulfonate

1.23 mL (7.24 mmol) of trifluoromethanesulfonic anhydride are slowly added dropwise to a solution of 1.0 g (4.83 mmol) of 4- (4-morpholinylcarbonyl) phenol and 2.02 mL (14.48 mmol) of triethylamine in 20 mL of dichloromethane, cooled to -10 ° C. It will take 30 min. at -10 ° C and then 30 min. stirred at 0 ° C. It is washed successively with 10% sodium hydrogen carbonate solution, water and saturated sodium chloride solution, dried over sodium sulfate, concentrated in vacuo and the residue is dried under high vacuum. 1.71 g (94.6% of theory) of the title compound are obtained.
¹ H NMR (400 MHz, methanol-d ₄ ): δ = 7.62 (m, 2H), 7.49 (m, 2H), 3.86-3.34 (m, 8H).
HPLC (method 1): R _t = 4.2 min.
MS (ESIpos): m / z = 357 (M + NH ₄ ) ⁺ .

Example 19A

7- [4- (4-morpholinyl) phenyl] -1-benzothiophene-2-carbonsäuremethylester

To a solution of 619.1 mg (2.28 mmol) of 7-bromo-1-benzothiophene-2-carboxylic acid methyl ester (Example 6A) and 520 mg (2.51 mmol) of 4- (4-morpholinyl) phenylboronic acid in 10 mL of DMF are gradually added 3.42 mL of 2 M Sodium carbonate solution and 83.5 mg (0.11 mmol) of PdCl ₂ (dppf) were added. The mixture is heated to 80 ° C. for 16 h. After cooling, it is filtered through kieselguhr and purified by preparative HPLC. The concentrated product is dried in a high vacuum. 146.7 mg (16.4% of theory) of the title compound are obtained.
HPLC (method 1): R _t = 4.6 min.
MS (ESIpos): m / z = 354 (M + H) ⁺ .

Example 20A

7- [4- (4-morpholinyl) phenyl] -1-benzothiophene-2-carboxylic acid

A solution of 330 mg (0.77 mmol) 7- [4- (4-morpholinyl) phenyl] -1-benzothiophene-2-carbonsäuremethylester (Example 19A) in 6 mL of a 1: 1 mixture of methanol and 2 N potassium hydroxide solution is stirred for 2 h at room temperature and 1 h at 50 ° C. The reaction mixture is concentrated in vacuo, mixed with water and then with conc. hydrochloric acid acidified. The resulting precipitate is filtered off, twice with water washed and dried in a high vacuum. 292 mg are obtained Crude product that is implemented without further purification.

Example 21A

7- (2-methoxyphenyl) -1-benzofuran-2-carboxylic acid

5.0 g (20.7 mmol) of 7-bromo-1-benzofuran-2-carboxylic acid (Example 29A) and 3.78 g (24.9 mmol) of 2-methoxyphenylboronic acid are placed in 50 mL DMF. After adding 31.1 mL of 2 M sodium carbonate solution and 1.2 g (1.04 mmol) of Pd (PPh ₃ ) ₄ , the mixture is heated to 90 ° C. After 18 h the solvent is distilled off. The residue is partitioned between 1N hydrochloric acid and ethyl acetate and extracted three times with 200 mL ethyl acetate each. The organic phase is dried over sodium sulfate and concentrated in vacuo. The residue is purified by means of flash chromatography (silica gel, mobile phase: dichloromethane / methanol / acetic acid 100: 10: 1). After concentration and drying in a high vacuum, 2.97 g (53.2% of theory) of the title compound are obtained.
¹ H-NMR (300 MHz, DMSO-d ₆ ): δ = 13.46 (s, 1H), 7.73 (dd, 1H), 7.59 (s, 1H), 7.48-7.33 (m, 4H), 7.20 (d, 1H), 7.09 (m, 1H), 3.75 (s, 3H).
HPLC (method 1): R _t = 4.5 min.
MS (ESIpos): m / z = 286 (M + NH ₄ ) ⁺ .

Example 22A

N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -7-bromo-1-benzothiophene-2-carboxamide hydrochloride

To a solution of 4.0 g (15.6 mmol) cooled to 0 ° C 7-bromo-1-benzothiophene-2-carboxylic acid (example 7A) and 3.10 g (15.6 mmol) of (S) -3-aminoquinuclidine dihydrochloride in 50 mL DMF are 3.58 g (18.7 mmol) EDC, 2.52 g (18.7 mmol) HOBt and 7.8 mL (56 mmol) triethylamine were added. At room temperature Stirred for 18 h. The reaction is stopped by adding 10% sodium hydrogen carbonate solution. The one after the addition of ethyl acetate the resulting precipitate is filtered off. The aqueous phase is mixed with ethyl acetate extracted, the combined organic phases are over sodium sulfate dried, concentrated and the residue dried in a high vacuum. 4.70 g (68% of theory) of the title compound are obtained.

The spectroscopic data are correct with those of the enantiomeric compound (Example 8A).

Example 23A

N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (4-formylphenyl) -1-benzothiophene-2-carboxamide hydrochloride

200 mg (0.50 mmol) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6-bromo-1-benzothiophene-2-carboxamide hydrochloride (Example 11A) and 74.6 mg (0.50 mmol) 4-formylphenylboronic acid are placed in 2 mL DMF. After addition of 0.75 mL 2 M sodium carbonate solution and 20.3 mg (0.02 mmol) PdCl ₂ (dppf) the mixture is heated to 80 ° C. After 18 h, the reaction mixture is filtered through kieselguhr and purified by preparative HPLC. The product fractions are concentrated, a 5: 1 mixture of methanol and 4 N hydrogen chloride in dioxane is added and the mixture is concentrated again. After drying in a high vacuum, 163.8 mg (75.0% of theory) of the title compound are obtained.
¹ H-NMR (200 MHz, DMSO-d ₆ ): δ = 10.09 (s, 1H), 10.07 (br. S, 1H), 9.10 (d, 1H), 8.50 (m, 1H), 8.37 (s, 1H), 8.15-7.97 (m, 5H), 7.87 (dd, 1H), 4.33 (m, 1H), 3.68 (m, 1H), 3.45-3.12 (m, 5H), 2.23 (m, 1H), 2.16 (m, 1H), 1.91 (m, 2H), 1.76 (m, 1H).
HPLC (method 1): R _t = 4.1 min.

MS (ESIpos): m / z = 391 (M + H) ⁺ (free base).

Example 24A

6-Cyano-1-benzothiophene-2-carbonsäuremethylester

4.08 g (23.2 mmol) of 4-cyano-2-nitrobenzaldehyde, 2.46 g (23.2 mmol) of methyl mercaptoacetate and 6.46 mL (46.4 mmol) of triethylamine are heated to 80 ° C in 12.3 mL of DMSO for 2.5 h. The reaction solution is poured onto 400 mL ice water. After the addition of 4 mL acetic acid, the precipitate formed is suction filtered, washed twice with water and dried in vacuo at 50 ° C. overnight. 4.19 g (83.2% of theory) of the title compound are obtained.
¹ H-NMR (200 MHz, DMSO-d ₆ ): δ = 8.73 (d, 1H), 8.32 (s, 1H), 8.21 (d, 1H), 7.85 (dd, 1H), 3.92 (s, 3H) ,
HPLC (method 1): R _t = 4.4 min.
MS (ESIpos): m / z = 218 (M + H) ⁺ .

Example 25A

6-Cyano-1-benzothiophene-2-carboxylic acid

According to general working procedure B, 0.49 g (61.6% of theory) of the desired product is obtained starting from 0.6 g (2.76 mmol) of 6-cyano-1-benzothiophene-2-carboxylic acid methyl ester (Example 24A).
HPLC (method 1): R _t = 3.9 min.
MS (ESIpos): m / z = 222 (M + H) ⁺ .

Example 26A

N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6-cyano-1-benzothiophene-2-carboxamide hydrochloride

320.8 mg (1.1 mmol) 6-cyano-1-benzothiophene-2-carboxylic acid (Example 25A), 200 mg (1.0 mmol) (R) -3-aminoquinuclidine dihydrochloride, 458.3 mg (1.21 mmol) HATU, 467.3 mg (3.62 mmol) N, N-diisopropylethylamine and 4.0 mL DMF are reacted according to the general working procedure C. The reaction mixture is purified by means of preparative HPLC. The product is dissolved in a mixture of methanol and 4 M hydrogen chloride in dioxane, then concentrated and dried in a high vacuum. 222.1 mg (64% of theory) of the title compound are obtained.
¹ H-NMR (300 MHz, DMSO-d ₆ ): δ = 9.80 (m, 1H), 9.12 (d, 1H), 8.68 (s, 1H), 8.37 (s, 1H), 8.16 (d, 1H) , 7.83 (dd, 1H), 4.33 (m, 1H), 3.76-3.05 (m, 6H), 2.23 (m, 1H), 2.13 (m, 1H), 1.92 (m, 2H), 1.76 (m, 1H) ).
HPLC (method 1): R _t = 3.6 min.
MS (ESIpos): m / z = 312 (M + H) ⁺ (free base).

Example 27A

6 - [(Z) -amino (hydroxyimino) methyl] -N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -1-benzothiophene-2-carboxamide dihydrochloride

800 mg (2.0 mmol) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6-cyano-1-benzothiophene - 2-carboxamide hydrochloride (Example 26A), 278.1 mg ( 4.0 mmol) of hydroxylamine hydrochloride and 829.5 mg (6.0 mmol) of potassium carbonate are heated in 8 mL of an 8: 1 mixture of water and ethanol at 80 ° C. for 3 h. The mixture is purified by column chromatography on silica gel (mobile phase: dichloromethane / methanol / 25% ammonia solution 100: 20: 4). The product fractions are combined, concentrated, mixed with methanol and 4 M hydrogen chloride in dioxane, then concentrated again and dried in a high vacuum. 447.3 mg (53.6% of theory) of the title compound are obtained.
¹ H-HMR (200 MHz, DMSO-d ₆ ): δ = 11.15 (m, 1H), 10.22 (m, 1H), 9.36 (d, 1H), 8.52 (s, 1H), 8.46 (m, 1H) , 8.14 (d, 1H), 7.73 (dd, 1H), 4.33 (m, 1H), 3.93-3.10 (m, 6H), 2.32-2.05 (m, 2H), 1.93 (m, 2H), 1.75 (m , 1H).
HPLC (method 1): R _t = 2.9 min.
MS (ESIpos): m / z = 345 (M + H) ⁺ (free base).

Example 28A

3-bromo-2-hydroxybenzaldehyde

20.0 g (115.6 mmol) of 2-bromophenol are placed in 500 ml of dry acetonitrile. 16.84 g (176.87 mmol) of dry magnesium chloride, 23.4 g of paraformaldehyde granules and 41.9 mL (300.6 mmol) of triethylamine are added. The reaction mixture is heated under reflux for 4 h, then cooled to 0 ° C. and mixed with 300 ml of 2N hydrochloric acid. The aqueous phase is extracted three times with 200 mL diethyl ether. The organic phase is dried over magnesium sulfate and the solvent is removed in vacuo. 24 g (64% of theory, content 62% according to HPLC) of the title compound are isolated, which is reacted further without further purification.
HPLC (method 1): R _t = 4.25 min.
MS (ESIpos): m / z = 202 (M + H) ⁺ .

Example 29A

7-bromo-1-benzofuran-2-carboxylic acid

13.5 g (40.3 mmol) of 3-bromo-2-hydroxybenzaldehyde (example 28A, content 62%) together with 9.18 g (84.62 mmol) of methyl chloroacetate, 1.49 g (4.03 mmol) of tetra-n-butylammonium iodide and 22.28 g (161.18 mmol) Potassium carbonate heated to 130 ° C for 6 h. After cooling to RT, 100 ml of water and 100 ml of THF and 13.57 g (241.77 mmol) of potassium hydroxide are added and the mixture is stirred at RT overnight. The solvent is removed under reduced pressure, the residue is taken up in 400 ml of water and washed four times with a total of 400 ml of diethyl ether. While cooling with ice, the pH is adjusted to 0 with concentrated hydrochloric acid and extracted five times with a total of 700 ml of ethyl acetate. The organic phase is washed with 100 mL saturated sodium chloride solution and then dried over magnesium sulfate. The crude product is completely freed from solvent residues in a high vacuum and stirred with 80 mL diethyl ether. The product is filtered off and washed with a little ice-cold diethyl ether. 4.8 g (47% of theory) of the title compound are isolated.
¹ H-NMR (200 MHz, DMSO-d ₆ ): δ = 13.5 (br. S, 1H), 7.86-7.72 (m, 2H), 7.79 (s, 1H), 7.31 (t, 1H).
MS (DCI / NH ₃ ): m / z = 258 (M + NH ₄ ) ⁺ .

Example 30A

N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -7-bromo-1-benzofuran-2-carboxamide

5.20 g (21.57 mmol) 7-bromobenzofuran-2-carboxylic acid (Example 29A), 4.3 g (21.57 mmol) (R) -3-aminoquinuclidine dihydrochloride, 9.84 g (25.89 mmol) HATU, 13.53 mL (74.68 mmol) N, N-Diisopropylethylamine and 21 mL DMF are reacted according to general working procedure C. The solvent is removed under reduced pressure, the crude product is taken up in 100 ml of ethyl acetate and washed 15 times with a total of 1.5 l of 1N sodium hydroxide solution. The organic phase is dried over magnesium sulfate and freed from the solvent. 5.2 g (69% of theory) of the title compound are isolated.
¹ H-NMR (300 MHz, DMSO-d ₆ ): δ = 8.48 (d, 1H), 7.85-7.65 (m, 3H), 7.25 (t, 1H), 3.95 (m, 1H), 3.15 (m, 1H), 2.95 (m, 1H), 2.80-2.60 (m, 4H), 1.90 (m, 1H), 1.70 (m, 1H), 1.58 (m, 2H), 1.35 (m, 1H).
HPLC (method 1): R _t = 3.79 min.
MS (ESIpos): m / z = 349 (M + H) ⁺ [α] ²⁰ _D = 26.9 ° (c = 0.50, methanol).

In some embodiments, the corresponding Hydrochloride used, which by moving the title compound with a 5: 1 mixture of methanol and 1 N hydrochloric acid and subsequent concentration and drying in a high vacuum is obtained.

Example 31A

N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -7-bromo-1-benzofuran-2-carboxamide

4.0 g (16.59 mmol) 7-bromobenzofuran-2-carboxylic acid (Example 29A), 3.3 g (16.59 mmol) (S) -3-aminoquinuclidine dihydrochloride, 7.57 g (19.91 mmol) HATU, 10.41 mL (59.74 mmol) N, N-Diisopropylethylamine and 21 mL DMF are reacted according to general working procedure C. The solvent is removed under reduced pressure, the crude product is taken up in 100 ml of ethyl acetate and washed 15 times with a total of 1: 5 L of 1N sodium hydroxide solution. The organic phase is dried over magnesium sulfate and Solvents exempt. 5.0 g (85% of theory) of the title compound are isolated.

The analytical data correspond to those from Example 30A.
[α] ²⁰ _D = -28.0 ° (c = 0.1, methanol).

Example 32A

2- (4-morpholinyl) phenyl trifluoromethanesulfonate

2.78 mL (16.4 mmol) of trifluoromethanesulfonic anhydride are slowly added dropwise to a solution of 2 g (10.9 mmol) of 2- (4-morpholinyl) phenol and 4.57 mL (32.8 mmol) of triethylamine in 15 mL of dichloromethane, cooled to -10 ° C. It will take 30 min. at -10 ° C and then 30 min. stirred at 0 ° C. It is washed successively with 10% sodium hydrogen carbonate solution, water and saturated sodium chloride solution, dried over sodium sulfate, concentrated in vacuo and the residue is dried under high vacuum. 3.48 g (87.6% of theory) of the title compound are obtained.
HPLC (method 1): R _t = 4.9 min.
MS (ESIpos): m / z = 312 (M + H) ⁺ .

EXAMPLES

General working instructions D:

1.5 eq. Bis (pinacolato) dibor, 3.25 eq. dry potassium acetate, 1.3 eq. the substituted halogen aromatic or the substituted aryl trifluoromethanesulfonate are dissolved in DMF (approx. 1 mL / mmol halogen aromatic or aryl trifluoromethanesulfonate). Argon is passed through the reaction mixture for 15 minutes, then with 0.05 eq. PdCl ₂ (dppf) was added and the mixture was heated to 90 ° C. for 2 h. Then 1.0 eq. of the corresponding bromo-substituted N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] benzothiophene-2-carboxamide or N - [(3R) -1-azabicyclo [2.2.2] oct- 3-yl] benzofuran-2-carboxamids, 5 eq. aqueous 2 - M sodium carbonate solution and another 0.05 eq. PdCl ₂ (dppf) added. The reaction mixture is heated to 90 ° C for 6-12 h. The purification is carried out by preparative HPLC. The product obtained (free base) is dissolved in methanol and an excess of 1N hydrochloric acid is added. The solvent is removed under reduced pressure.

example 1

N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- [2- (hydroxymethyl) phenyl] -1-benzofuran-2-carboxamide

A mixture of 130 mg (0.86 mmol) 2- (hydroxymethyl) phenylboronic acid, 200 mg (0.57 mmol) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6-bromo-1- benzofuran-2-carboxamide (Example 2A), 1.72 mL (1.72 mmol) 1 N Sodium hydroxide solution, 40 mg (0.06 mmol) 1,1'-bis (diphenylphosphino) ferrocene palladium (II) chloride and 2 mL DMF is heated to 80–85 ° C for 18 h. The solvent is removed under reduced pressure. The crude product is purified on silica gel 60 (Merck, Darmstadt; eluent: dichloromethane, dichloromethane-methanol 20: 1, dichloromethane-methanol-ammonia 80: 20: 2). The solvent is removed under reduced pressure. Finally, the last solvent residues are removed in a high vacuum. 149 mg (63% of theory) of the title compound are isolated.
¹ H-NMR (200 MHz, CDCl ₃ ): δ = 7.71-7.28 (m, 8H), 6.77 (d, 1H), 4.62 (s, 2H), 4.28-4.12 (m, 1H), 3.56-3.38 ( m, 1H), 3.04-2.78 (m, 4H), 2.75-2.59 (m, 1H), 2.16-2.02 (m, 1H), 1.93-1.66 (m, 3H), 1.66-1.45 (m, 1H).
HPLC (method 1): R _t = 3.6 min.
LC-MS (Method 2): R _t = 1.49 min.
MS (ESIpos): m / z = 377 (M + H) ⁺ .

Example 2

N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- [3- (hydroxymethyl) phenyl] -1-benzofuran-2-carboxamide

A mixture of 130 mg (0.86 mmol) of 3- (hydroxymethyl) phenylboronic acid, 200 mg (0.57 mmol) of N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6-bromo-1- benzofuran-2-carboxamide (Example 2A), 1.72 mL (1.72 mmol) 1 N sodium hydroxide solution, 40 mg (0.06 mmol) 1,1'-bis (diphenylphosphino) ferrocene palladium (II) chloride and 2 mL DMF is 18 to 80- Heated to 85 ° C. The solvent is removed under reduced pressure. The crude product is purified on silica gel 60 (Merck, Darmstadt; eluent: dichloromethane, dichloromethane-methanol 20: 1, dichloromethane-methanol-ammonia 80: 20: 2). The solvent is removed under reduced pressure. Finally, the last solvent residues are removed in a high vacuum. 127 mg (54% of theory) of the title compound are isolated.
¹ H-NMR (200 MHz, CDCl ₃ ): δ = 7.86 (d, 1H), 7.72-7.28 (m, 7H), 6.77 (d, 1H), 4.62 (s, 2H), 4.28-4.12 (m, 1H), 3.56-3.38 (m, 1H), 3.04-2.78 (m, 4H), 2.75-2.59 (m, 1H), 2.16-2.02 (m, 1H), 1.93-1.66 (m, 3H), 1.66- 1.45 (m, 1H).
HPLC (method 1): R _t = 3.5 min.
LC-MS (method 2): R _t = 1.50 min.
MS (ESIpos): m / z = 377 (M + H) ⁺ .

Example 3

N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- [4- (hydroxymethyl) phenyl] -1-benzofuran-2-carboxamide

A mixture of 130 mg (0.86 mmol) 4- (hydroxymethyl) phenylboronic acid, 200 mg (0.57 mmol) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6-bromo-1- benzofuran-2-carboxamide (Example 2A), 1.72 mL (1.72 mmol) 1 N sodium hydroxide solution, 40 mg (0.06 mmol) 1,1'-bis (diphenylphosphino) ferrocene palladium (II) chloride and 2 mL DMF is 18 to 80- Heated to 85 ° C. The solvent is removed under reduced pressure. The crude product is purified on silica gel 60 (Merck, Darmstadt; eluent: dichloromethane, dichloromethane-methanol 20: 1, dichloromethane-methanol-ammonia 80: 20: 2). The solvent is removed under reduced pressure. Finally, last ones Residual solvents removed in a high vacuum. 55 mg (23% of theory) of the title compound are isolated.
¹ H-NMR (200 MHz, CDCl ₃ ): δ = 7.83 (d, 1H), 7.69-7.28 (m, 7H), 6.77 (d, 1H), 4.62 (s, 2H), 4.28-4.12 (m, 1H); 3.56-3.38 (m, 1H), 3.04-2.78 (m, 4H), 2.75-2.59 (m, 1H), 2.16-2.02 (m, 1H), 1.93-1.66 (m, 3H), 1.66-1.45 (m , 1H).
HPLC (method 1): R _t = 3.5 min.
LC-MS (Method 2): R _t = 1.46 min.
MS (ESIpos): m / z = 377 (M + H) ⁺ .

Example 4

N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- [4- (4-morpholinyl) phenyl] -1-benzofuran-2-carboxamide

A mixture of 180 mg (0.86 mmol) of 4- (4-morpholinyl) phenylboronic acid, 200 mg (0.57 mmol) of N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6-bromo -1-benzofuran-2-carboxamide (Example 2A), 1.72 mL (1.72 mmol) 1 N sodium hydroxide solution, 40 mg (0.06 mmol) 1,1'-bis (diphenylphosphino) ferrocene palladium (II) chloride and 2 mL DMF is 18 h heated to 80-85 ° C. The solvent is removed under reduced pressure. The crude product is purified on silica gel 60 (Merck, Darmstadt; eluent: dichloromethane, dichloromethane-methanol 20: 1, dichloromethane-methanol-ammonia 80: 20: 2). The solvent is removed under reduced pressure. Finally, the last solvent residues are removed in a high vacuum. 79 mg (32% of theory) of the title compound are isolated.
¹ H-NMR (200 MHz, CDCl ₃ ): δ = 7.84-7.29 (m, 7H), 6.99 (d, 1H), 6.84-6.70 (m, 1H), 4.28-4.13 (m, 1H), 3.97- 3.83 (m, 2H), 3.59-3.36 (m, 1H), 3.29-3.13 (m, 2H), 3.04-2.78 (m, 4H), 2.75-2.59 (m, 1H), 2.16-2.02 (m, 1H) ), 1.93-1.66 (m, 3H), 1.66-1.45 (m, 1H).
HPLC (method 1): R _t = 3.5 min.
LC-MS (method 2): R _t = 1.74 min.
MS (ESIpos): m / z = 432 (M + H) ⁺ .

Example 5

N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- [4- (methoxy) phenyl] -1-benzofuran-2-carboxamide

A mixture of 130 mg (0.86 mmol) of 4-methoxyphenylboronic acid, 200 mg (0.57 mmol) of N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6-bromo-1-benzofuran-2 -carboxamide (Example 2A), 1.72 mL (1.72 mmol) 1 N sodium hydroxide solution, 40 mg (0.06 mmol) 1,1'-bis (diphenylphosphino) ferrocene palladium (II) chloride and 2 mL DMF is at 80-85 ° C for 18 h heated. The solvent is removed under reduced pressure. The crude product is purified on silica gel 60 (Merck, Darmstadt; eluent: dichloromethane, dichloromethane-methanol 20: 1, dichloromethane-methanol-ammonia 80: 20: 2). The solvent is removed under reduced pressure. Finally, the last solvent residues are removed in a high vacuum. 160 mg (68% of theory) of the title compound are isolated.
¹ H-NMR (200 MHz, CDCl ₃ ): δ = 7.84-7.75 (m, 1H), 7.62-7.45 (m, 5H), 6.99 (m, 2H), 6.84-6: 70 (m, 1H), 4.28-4.13 (m, 1H), 3.87 (s, 3H), 3.59-3.36 (m, 1H), 3.04-2.78 (m, 4H), 2.75-2.59 (m, 1H), 2.16-2.02 (m, 1H) ), 1.93-1.66 (m, 3H), 1.66-1.45 (m, 1H).
HPLC (method 1): R _t = 4.0 min.
LC-MS (Method 3): R _t = 3.2 min.
MS (ESIpos): m / z = 377 (M + H) ⁺ .

Example 6

N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- [3- (methoxy) phenyl] -1-benzofuran-2-carboxamide

A mixture of 130 mg (0.86 mmol) 3-methoxyphenylboronic acid, 200 mg (0.57 mmol) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6-bromo-1-benzofuran-2 -carboxamide (Example 2A), 1.72 mL (1.72 mmol) 1 N sodium hydroxide solution, 40 mg (0.06 mmol) 1,1'-bis (diphenylphosphino) ferrocene palladium (II) chloride and 2 mL DMF is at 80-85 ° C for 18 h heated. The solvent is removed under reduced pressure. The crude product is purified on silica gel 60 (Merck, Darmstadt; eluent: dichloromethane, dichloromethane-methanol 20: 1, dichloromethane-methanol-ammonia 80: 20: 2). The solvent is removed under reduced pressure. Finally, the last solvent residues are removed in a high vacuum. 151 mg (64% of theory) of the title compound are isolated.
¹ H-NMR (200 MHz, CDCl ₃ ): δ = 7.90-7.80 (m, 1H), 7.72-7.08 (m, 5H), 6.95-6.85 (m, 1H), 6.84-6.70 (m, 1H), 428-4.13 (m, 1H), 3.87 (s, 3H), 3.59-3.36 (m, 1H), 3.04-2.78 (m, 4H), 2.75-2.59 (m, 1H), 2.16-2.02 (m, 1H ), 1.93-1.66 (m, 3H), 1.66-1.45 (m, 1H).
HPLC (method 1): R _t = 4.0 min.
LC-MS (method 2): R _t = 1.87 min.
MS (ESIpos): m / z = 377 (M + H) ⁺ .

Example 7

N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (4-fluorophenyl) -1-benzofuran-2-carboxamide

A mixture of 120 mg (0.86 mmol) 4-fluorophenylboronic acid, 200 mg (0.57 mmol) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6-bromo-1-benzofuran-2 -carboxamide (Example 2A), 1.72 mL (1.72 mmol) 1 N sodium hydroxide solution, 40 mg (0.06 mmol) 1,1'-bis (diphenylphosphino) ferrocene palladium (II) chloride and 2 mL DMF is at 80-85 ° C for 18 h ; heated. The solvent is removed under reduced pressure. The crude product is purified on silica gel 60 (Merck, Darmstadt; eluent: dichloromethane, dichloromethane-methanol 20: 1, dichloromethane-methanol-ammonia 80: 20: 2). The solvent is removed under reduced pressure. Finally, the last solvent residues are removed in a high vacuum. 155 mg (68% of theory) of the title compound are isolated.
¹ H-NMR (200 MHz, CDCl ₃ ): δ = 7.99 (s, 1H), 7.64-7.46 (m, 5H), 7.22-7.07 (m, 2H), 6.84-6.70 (m, 1H), 4.28- 4.13 (m, 1H), 3.59-3.36 (m, 1H), 3.04-2.78 (m, 4H), 2.75-2.59 (m, 1H), 2.16-2.02 (m, 1H), 1.93-1.66 (m, 3H ), 1.66-1.45 (m, 1H).
HPLC (method 1): R _t = 4.1 min.
LC-MS (Method 2): R _t = 1.92 min.
MS (ESIpos): m / z = 365 (M + H) ⁺ .

Example 8

N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (4-trifluoromethoxyphenyl) -1-benzofuran-2-carboxamide

A mixture of 180 mg (0.86 mmol) 4- (trifluoromethoxy) phenylboronic acid, 200 mg (0.57 mmol) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6-bromo-1- benzofuran-2-carboxamide (Example 2A), 1.72 mL (1.72 mmol) 1 N sodium hydroxide solution, 40 mg (0.06 mmol) 1,1'-bis (diphenylphosphino) ferrocene palladium (II) chloride and 2 mL DMF is 18 to 80- Heated to 85 ° C. The solvent is removed under reduced pressure. The crude product is purified on silica gel 60 (Merck, Darmstadt; eluent: dichloromethane, dichloromethane-methanol 20: 1, dichloromethane-methanol-ammonia 80: 20: 2). The solvent is removed under reduced pressure. Finally, the last solvent residues are removed in a high vacuum. 155 mg (68% of theory) of the title compound are isolated.
¹ H-NMR (200 MHz, CDCl ₃ ): δ = 7.82 (s, 1H), 7.72-7.45 (m, 5H), 7.36-7.27 (m, 2H), 6.84-6.70 (m, 1H), 4.28- 4.13 (m, 1H), 3.59-3.36 (m, 1H), 3.04-2.78 (m, 4H), 2.75-2.59 (m, 1H), 2.16-2.02 (m, 1H), 1.93-1: 66 (m , 3H), 1.66-1.45 (m, 1H).
HPLC (method 1): R _t = 4.4 min.
LC-MS (Method 2): R _t = 2.22 min.
MS (ESIpos): m / z = 431 (M + H) ⁺ .

Example 9

N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (3-hydroxy-1-propynyl) -1-benzofuran-2-carboxamide

A mixture of 289 mg (5.15 mmol) propargyl alcohol, 150 mg (0.43 mmol) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6-bromo-1-benzofuran-2-carboxamide (Example 2A), 1.6 mg (0.01 mmol) copper (I) iodide, 15 mg (0.02 mmol) bis (triphenylphosphine) palladium (II) chloride, 61 mg (0.86 mmol) pyrrolidine and 1 mL THF is heated under reflux overnight , The crude product is mixed with 10 ml of 1 N sodium hydroxide solution and extracted three times with a total of 100 ml of ethyl acetate. The combined organic phases are dried over magnesium sulfate and the solvent is removed under reduced pressure. The crude product is over silica gel 60 (Merck, Darmstadt; eluent: dichloromethane-triethylamine 100: 1, then dichloromethane-methanol-triethylamine 100: 1: 1 to dichloromethane-methanol-triethylamine 100 : 10: 1) cleaned. The solvent is removed under reduced pressure. Finally, the last solvent residues are removed in a high vacuum. 40 mg (27% of theory) of the title compound are isolated.
HPLC (method 1): R _t = 3.3 min.
LC-MS (method 3): R _t = 2.6 min.
MS (ESIpos): m / z = 325 (M + H) ⁺ .

Example 10

N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -5-fluoro-7- (4-fluorophenyl) -1-benzofuran-2-carboxamide

A mixture of 40 mg (0.29 mmol) 4-fluorophenylboronic acid, 70 mg (0.19 mmol) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -5-fluoro-7-bromo-1 -benzofuran-2-carboxamide (Example 5A), 0.57 mL (0.57 mmol) 1 N sodium hydroxide solution, 14 mg (0.02 mmol) 1,1'-bis (diphenylphosphino) ferrocene palladium (II) chloride and 2 mL DMF is brought to 85 overnight ° C heated. The solvent is removed under reduced pressure. The crude product is mixed with 1 N sodium hydroxide solution and extracted three times with a total of 100 mL ethyl acetate. The combined organic phases are dried over magnesium sulfate and the solvent is removed under reduced pressure. The crude product is taken up in methanol and together with an acidic ion exchanger (Dowex ^® WX2-200) for about 20 minutes. long shaken. The loaded ion exchanger is washed three times with 30 mL methanol, then with water, again with methanol, with dichloromethane, again with methanol, with THF and finally again with methanol. The product is eluted with methanol-triethylamine 95: 5. The solvent is removed on the rotary evaporator under reduced pressure. For fine cleaning, silica gel 60 (Merck, Darmstadt; eluent: dichloromethane-triethylamine 100: 1, then dichloromethane-methanol-triethylamine 100: 1: 1 to dichloromethane-methanol-triethylamine 100: 10: 1) is used for cleaning. The solvent is removed under reduced pressure. Finally, the last solvent residues are removed in a high vacuum. 51 mg (70% of theory) of the title compound are isolated.
¹ H-NMR (400 MHz, methanol-d ₄ ): δ = 7.99-7.90 (m, 2H), 7.59 (s, 1H), 7.45-7.35 (m, 2H), 7.30-7.22 (m, 2H), 4.24-4.18 (m, 1H), 3.34-3.29 (m, 1H), 3.07-2.97 (m, 1H), 2.93-2.77 (m, 4H), 2.13-2.05 (m, 1H), 1.98-1.86 (m , 1H), 1.84-1.75 (m, 2H), 1.63-1.53 (m, 1H).
HPLC (method 1): R _t = 4.3 min.
LC-MS (Method 3): R _t = 3.08 min.
MS (ESIpos): m / z = 383 (M + H) ⁺ .

Example 11

N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -5-fluoro-7- (4-trifluoromethoxyphenyl) -1-benzofuran-2-carboxamide

A mixture of 40 mg (0.29 mmol) 4- (trifluoromethoxy) phenylboronic acid, 70 mg (0.19 mmol) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -5-fluoro-7- bromo-1-benzofuran-2-carboxamide (Example 5A), 0.57 mL (0.57 mmol) 1 N sodium hydroxide solution, 14 mg (0.02 mmol) 1,1'-bis (diphenylphosphino) ferrocene palladium (II) chloride and 2 mL DMF is heated to 85 ° C. overnight. The solvent is removed under reduced pressure. The crude product is mixed with 1 N sodium hydroxide solution and extracted three times with a total of 100 mL ethyl acetate. The combined organic phases are dried over magnesium sulfate and the solvent is removed under reduced pressure. The crude product is taken up in methanol and together with acidic ion exchanger (Dowex ^® WX2-200) for about 20 min. long shaken. The loaded ion exchanger is washed three times with 30 mL methanol, then with water, again with methanol, with dichloromethane, again with methanol, with THF and finally again with methanol. The product is eluted with methanol-triethylamine 95: 5. The solvent is removed on the rotary evaporator under reduced pressure. For fine cleaning, silica gel 60 (Merck, Darmstadt; eluent: dichloromethane-triethylamine 100: 1, then dichloromethane-methanol-triethylamine 100: 1: 1 to dichloromethane-methanol-triethylamine 100: 10: 1) is used for cleaning. The solvent is removed under reduced pressure. Finally, the last solvent residues are removed in a high vacuum. 52 mg (61% of theory) of the title compound are isolated.
¹ H-NMR (400 MHz, methanol-d ₄ ): δ = 8.08-8.00 (m, 2H), 7.59 (s, 1H), 7.49-741 (m, 4H), 4.24-4.18 (m, 1H), 3.34-3.29 (m, 1H), 3.07-2.97 (m, 1H), 2.93-2.77 (m, 4H), 2.13-2.05 (m, 1H), 1.98-1.86 (m, 1H), 1.84-1.75 (m , 2H), 1.63-1.53 (m, 1H).
HPLC (method 1): R _t = 4.6 min.
LC-MS (Method 3): R _t = 3.37 min.
MS (ESIpos): m / z = 449 (M + H) ⁺ .

Example 12

N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -5-phenyl-1-benzothiophene-2-carboxamide hydrochloride

To a mixture of 40 mg (0.10 mmol) of N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -5-bromo-1-benzothiophene-2-carboxamide hydrochloride (Example 14A) and 12.1 mg (0.10 mmol) phenylboronic acid in 1 mL DMF are added 0.15 mL 2 M aqueous sodium carbonate solution and 4.1 mg (0.005 mmol) PdCl ₂ (dppf). The reaction mixture is heated to 80 ° C. for 14 h, filtered through diatomaceous earth and concentrated to dryness. After purification of the crude product by means of preparative HPLC, subsequent addition with 1 N hydrochloric acid and drying in a high vacuum, 7.3 mg (18% of theory) of the title compound are obtained.
HPLC (method 1): R _t = 4.2 min.
MS (ESIpos): m / z = 363 (M + H) ⁺ (free base).

Example 13

N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6-phenyl-1-benzothiophene-2-carboxamide hydrochloride

To a mixture of 40 mg (0.10 mmol) of N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6-bromo-1-benzothiophene-2-carboxamide hydrochloride (Example 11A) and 12.1 mg (0.10 mmol) phenylboronic acid in 1 mL DMF are added 0.15 mL 2 M aqueous sodium carbonate solution and 4.1 mg (0.005 mmol) PdCl ₂ (dppf). The reaction mixture is heated to 80 ° C. for 14 h, filtered through diatomaceous earth and concentrated to dryness. After purification of the crude product by means of preparative HPLC, subsequent addition with 1 N hydrochloric acid and drying in a high vacuum, 14.5 mg (37% of theory) of the title compound are obtained.
¹ H-NMR (200 MHz, DMSO-d ₆ ): δ = 9.91 (m, 1H), 9.02 (d, 1H), 8.38 (m, 1H), 8.32 (m, 1H), 8.06 (d, 1H) , 7.78 (m, 3H), 7.58-7.37 (m, 3H), 4.32 (m, 1H), 3.78-3.03 (m, 6H), 2.28-2.05 (m, 2H), 1.93 (m, 2H), 1.78 (m, 1H).
HPLC (method 1): R _t = 4.2 min.
MS (ESIpos): m / z = 363 (M + H) ⁺ (free base).

Example 14

N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (3-methoxyphenyl) -1-benzothiophene-2-carboxamide hydrochloride

To a mixture of 40 mg (0.10 mmol) of N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6-bromo-1-benzothiophene-2-carboxamide hydrochloride (Example 11A) and 15.1 mg (0.10 mmol) 3-methoxyphenylboronic acid in 1 mL DMF are added 0.3 mL 2 M aqueous sodium carbonate solution and 4.1 mg (0.005 mmol) PdCl ₂ (dppf). The reaction mixture is heated to 80 ° C. for 14 h, filtered through diatomaceous earth and concentrated to dryness. After purification of the crude product by means of preparative HPLC, subsequent addition with 1 N hydrochloric acid and drying in a high vacuum, 25.5 mg (57% of theory) of the title compound are obtained.
¹ H-NMR (200 MHz, DMSO-d ₆ ): δ = 9.70 (s, 1H), 8.97 (d, 1H), 8.38 (m, 1H), 8.28 (m, 1H), 7.99 (m, 1H) , 7.78 (m, 1H), 7.37 (m, 3H), 6.98 (m, 1H), 4.33 (m, 1H), 3.86 (s, 3H), 3.79-3.12 (m, 6H), 2.28-2.00 (m , 2H), 1.99-1.68 (m, 3H).
HPLC (method 1): R _t = 4.2 min.
MS (ESIpos): m / z = 393 (M + H) ⁺ (free base).

Example 15

N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (3-hydroxy-1-propynyl) -1-benzothiophene-2-carboxamide

120 mg (0.30 mmol) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6-bromo-1-benzothiophene-2-carboxamide hydrochloride (Example 11A), 10.5 mg (0.01 mmol) PdCl ₂ (PPh ₃ ) ₂ and 4.6 mg (0.02 mmol) copper (I) iodide are dissolved in 1.5 mL triethylamine / DMF (2: 1) under argon and stirred at 60 ° C for 1 h. After adding 25.1 mg (0.45 mmol) of propargyl alcohol, the mixture is heated to 70 ° C. for a further 16 h. After cooling, it is filtered through kieselguhr and purified by preparative HPLC, concentrated and the product is dried under high vacuum. 12 mg (11% of theory) of the title compound are obtained.
¹ H-NMR (200 MHz, DMSO-d ₆ ): δ = 8.73 (d, 1H), 8.20 (m, 2H), 7.96 (d, 1H), 7.46 (dd, 1H), 4.34 (s, 2H) , 4.09 (m, 1H), 3.32 (m, 1H), 3.16-2.77 (m, 5H), 1.99 (m, 1H), 1.91 (m, 1H), 1.70 (m, 2H), 1.49 (m, 1H ).
HPLC (method 1): R _t = 3.4 min.
MS (ESIpos): m / z = 341 (M + H) ⁺ .

Example 16

N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -7-phenyl-1-benzothiophene-2-carboxamide hydrochloride

To a mixture of 56 mg (0.14 mmol) of N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -7-bromo-1-benzothiophene-2-carboxamide hydrochloride (Example 8A) and 18.7 mg (0.15 mmol) phenylboronic acid in 1 mL DMF are added 0.14 mL 2 M aqueous sodium carbonate solution and 5.7 mg (0.007 mmol) PdCl ₂ (dppf). The reaction mixture is heated to 80 ° C. After 3 h at this temperature, a further 5.7 mg (0.007 mmol) of PdCl ₂ (dppf) are added and the mixture is stirred at 80 ° C. for a further 12 h. The reaction mixture is filtered through kieselguhr and evaporated to dryness. After purification of the crude product by means of preparative HPLC, subsequent addition with 1 N hydrochloric acid and drying in a high vacuum, 10.6 mg (18% of theory) of the title compound are obtained.
HPLC (method 1): R _t = 4.2 min.
MS (ESIpos): m / z = 363 (M + H) ⁺ (free base).

Example 17

N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -7- (3-methoxyphenyl) -1-benzothiophene-2-carboxamide hydrochloride

To a mixture of 49 mg (0.10 mmol) of N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -7-bromo-1-benzothiophene-2-carboxamide hydrochloride (Example 8A) and 15.8 mg (0.10 mmol) 3-methoxyphenylboronic acid in 1 mL DMF are added 0.16 mL 2 M aqueous sodium carbonate solution and 4.2 mg (0.005 mmol) PdCl ₂ (dppf). The reaction mixture is heated to 80 ° C. for 14 h, then filtered through diatomaceous earth and concentrated to dryness. After purification of the crude product by means of preparative HPLC, subsequent addition with 1 N hydrochloric acid and drying in a high vacuum, 8.0 mg (18% of theory) of the title compound are obtained.
HPLC (method 1): R _t = 4.2 min.
MS (ESIpos): m / z = 393 (M + H) ⁺ (free base).

Example 18

N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -7- (2-methoxyphenyl) -1-benzothiophene-2-carboxamide hydrochloride

To a mixture of 60 mg (0.15 mmol) of N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -7-bromo-1-benzothiophene-2-carboxamide hydrochloride (Example 8A) and 22.7 mg (0.15 mmol) 2-methoxyphenylboronic acid in 1 mL DMF are added 0.22 mL 2 M aqueous sodium carbonate solution and 6.1 mg (0.007 mmol) PdCl ₂ (dppf). The reaction mixture is heated to 80 ° C. for 14 h, then filtered through diatomaceous earth and concentrated to dryness. After purification of the crude product by means of preparative HPLC, subsequent addition with 1 N hydrochloric acid and drying in a high vacuum, 12.8 mg (18% of theory) of the title compound are obtained.
HPLC (method 1): R _t = 4.2 min.
MS (ESIpos): m / z = 393 (M + H) ⁺ (free base).

Example 19

N - [(3R) -1-azabicyclo [2.2: 2] oct-3-yl] -7- [4- (4-morpholinyl) phenyl] -1-benzothiophene-2-carboxamide hydrochloride

To a mixture of 60 mg (0.15 mmol) of N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -7-bromo-1-benzothiophene-2-carboxamide hydrochloride (Example 8A) and 30.9 mg (0.15 mmol) 4- (4-morpholinyl) -phenylboronic acid in 1 mL DMF are added 0.22 mL 2 M aqueous sodium carbonate solution and 6.1 mg (0.007 mmol) PdCl ₂ (dppf). The reaction mixture is heated to 80 ° C. After 4.5 h, another 6.1 mg (0.007 mmol) of PdCl ₂ (dppf) are added. After a further 12 h, the reaction mixture is filtered through diatomaceous earth and concentrated to dryness. The crude product is purified by means of preparative HPLC. The product is dissolved in methanol and an excess of 4 N hydrogen chloride in dioxane is added. After drying in a high vacuum, 20.6 mg (25% of theory) of the title compound are obtained.
¹ H-NMR (300 MHz, methanol-d ₄ ): δ = 8.21 (s, 1H), 7.97 (m, 2H), 7.93 (s, 1H), 7.83 (m, 2H), 7.57 (dd, 1H) , 7.52 (m, 1H), 4.46 (m, 1H), 4.13 (m, 4H), 3.83 (m, 1H), 3.78 (m, 4H), 3.49 (m, 1H), 3.43-3 .17 (m, 4H), 2.3 8 (m, 1H), 2.28 (m, 1H), 2.10 (m, 2H), 1.96 (m, 1H).
HPLC (method 1): R _t = 4.3 min.
MS (ESIpos): m / z = 448 (M + H) ⁺ (free base).

Example 20

N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -7- [4- (hydroxymethyl) phenyl] -1-benzothiophene-2-carboxamide hydrochloride

60 mg (0.15 mmol) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -7-bromo-1-benzothiophene-2-carboxamide hydrochloride (Example 8A) and 22.7 mg (0.15 mmol) 4- (hydroxymethyl) phenylboronic acid are placed in 1 mL DMF. After adding 0.22 mL 2 M aqueous sodium carbonate solution and 6.1 mg (0.01 mmol) PdCl ₂ (dppf) the mixture is heated to 80 ° C. After 14 h the reaction mixture is filtered through kieselguhr and evaporated to dryness. The crude product is purified by means of preparative HPLC. The product is dissolved in methanol and an excess of 4 N hydrogen chloride in dioxane is added. After drying in a high vacuum, 9 mg (9% of theory) of the title compound are obtained.
HPLC (method 1): R _t = 3.8 min.
MS (ESIpos): m / z = 393 (M + H) ⁺ (free base).

The compounds listed in the following table are obtained in an analogous manner: Table 2:

Example 51

7- [3- (acetylamino) phenyl] -N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -1-benzothiophene-2-carboxamide hydrochloride

To a mixture of 200 mg (0.50 mmol) of N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -7-bromo-1-benzothiophene-2-carboxamide hydrochloride (Example 8A) and 89.1 mg (0.50 mmol) 3- (acetamido) phenylboronic acid in 2 mL DMF are added 0.75 mL 2 M aqueous sodium carbonate solution and 20.3 mg (0.02 mmol) PdCl ₂ (dppf). The reaction mixture is heated to 80 ° C for 17 h. A further 89.1 mg (0.50 mmol) of 3- (acetamido) phenylboronic acid, 1.5 mL of 1 N sodium hydroxide solution and 81.3 mg (0.1 mmol) of PdCl ₂ (dppf) are added and the mixture is heated at 80 ° C. for a further 18 h. After cooling, it is filtered through kieselguhr and purified by means of preparative HPLC. The crude product obtained is further purified by flash chromatography on silica gel (mobile phase: dichloromethane / methanol / ammonia 100: 10: 2). The product fractions are concentrated, taken up in a 5: 1 mixture of methanol and 1N hydrochloric acid and concentrated again. After drying in a high vacuum, 243.2 mg (86.6% of theory) of the title compound are obtained.
¹ H-NMR (300 MHz, DMSO-d ₆ ): δ = 10.16 (s, 1H), 10.10 (br. S, 1H), 9.03 (d, 1H), 8.38 (s, 1H), 8.06 (m, 1H), 7.98 (dd, 1H), 7.65 (m, 1H), 7.59 (dd, 1H), 7.51 (m, 1H), 7.48 (m, 1H), 7.37 (m, 1H), 4.33 (m, 1H) ), 3.66 (m, 1H), 3.45-3.13 (m, 5H), 2.22 (m, 1H), 2.14 (m, 1H), 2.08 (s, 3H), 1.91 (m, 2H), 1.75 (m, 1H).
HPLC (method 1): R _t = 3.9 min.
MS (ESIpos): m / z = 420 (M + H) ⁺ (free base).

Example 52

N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- [4- (4-morpholinyl) phenyl] -1-benzothiophene-2-carboxamide hydrochloride

100 mg (0.25 mmol) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6-bromo-1-benzothiophene-2-carboxamide hydrochloride (Example 11A) and 51.5 mg (0.25 mmol) 4-morpholinophenylboronic acid are placed in 1 mL DMF. After adding 0.37 mL 2 M sodium carbonate solution and 10.2 mg (0.01 mmol) PdCl ₂ (dppf) the mixture is heated to 80 ° C. After 16 h, a further 51.5 mg (0.25 mmol) of 4-morpholinophenylboronic acid, 0.37 mL of 2 M sodium carbonate solution and 10.2 mg (0.01 mmol) of PdCl ₂ (dppf) are added. The mixture is heated to 80 ° C. for a further 4 h. After cooling, the reaction mixture is filtered through kieselguhr and purified by preparative HPLC. The product fractions are concentrated, a 5: 1 mixture of methanol and 4 M hydrogen chloride in dioxane is added and the mixture is concentrated again. After drying in a high vacuum, 83 mg (69% of theory) of the title compound are obtained.
¹ H-NMR (200 MHz, DMSO-d ₆ ): δ = 10.20 (br. S, 1H), 9.07 (d, 1H), 8.33 (s, 1H), 8.27 (s, 1H), 7.97 (d, 1H), 7.71 (m, 3H), 7.10 (m, 2H), 4.33 (m, 1H), 3.78 (m, 4H), 3.73-3.07 (m, 10H), 2.22 (m, 1H), 2.17 (m , 1H), 1.93 (m, 2H), 1.75 (m, 1H).
HPLC (method 1): R _t = 3.8 min.
MS (ESIpos): m / z = 448 (M + H) ⁺ (free base).

Example 53

N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (5-methyl-1,2,4-oxadiazol-3-yl) -1-benzothiophene-2-carboxamide hydrochloride

154 mg (0.37 mmol) 6 - [(amino (hydroxyimino) methyl] -N - ((3R) -1-azabicyclo [2.2.2] -oct-3-yl] -1-benzothiophene-2-carboxamide dihydrochloride ( Example 27A) is dissolved in 2 ml of DMF and 0.75 ml of THF, 250 mg of 4 Å molecular sieve are added and the mixture is stirred at room temperature for 30 minutes After the addition of 44.4 mg (1.11 mmol) of sodium hydride (60% suspension in mineral oil) The mixture is heated to 60 ° C. for 20 minutes and then cooled to room temperature, after which a solution of 90 μL (1.11 mmol) of methyl acetate in 1 ml of THF is added to the reaction mixture, and the mixture is then heated to 80 ° C. for 14 hours 29.6 mg (0.74 mmol) sodium hydride (60% suspension in mineral oil) and 0.88 mL (11.1 mmol) methyl acetate in 1 mL THF is heated for a further 24 h to 70 ° C. The reaction is stopped by adding water The product fractions are concentrated using a 5: 1 mixture of methanol and 4 N hydrogen chloride f added in dioxane and concentrated again. After drying in a high vacuum, 41.9 mg (23.6% of theory) of the title compound are obtained.
¹ H NMR (300 MHz, DMSO-d ₆ ): δ = 10.15 (br. S, 1H), 9.14 (d, 1H); 8.70 (m, 1H), 8.41 (s, 1H), 8.13 (d, 1H), 8.05 (m, 1H), 4.34 (m, 1H), 3.75-3.13 (m, 6H), 2.70 (s, 3H), 2.23 (m, 1H), 2.15 (m, 1H), 1.92 (m, 2H), 1.77 (m, 1H).
HPLC (method 1): R _t = 3.8 min.
MS (ESIpos): m / z = 369 (M + H) ⁺ (free base).

Example 54

N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- [2- (hydroxymethyl) phenyl] -1-benzothiophene-2-carboxamide hydrochloride

100 mg (0.25 mmol) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6-bromo-1-benzothiophene-2-carboxamide hydrochloride (Example 11A) and 37.8 mg (0.25 mmol) 2- (hydroxymethyl) phenylboronic acid are placed in 1 mL DMF. After adding 0.37 mL 2 M sodium carbonate solution and 10.2 mg (0.01 mmol) PdCl ₂ (dppf) the mixture is heated to 80 ° C. After 14 h, the reaction mixture is filtered through kieselguhr and purified by separation twice using preparative HPLC. The product fractions are concentrated, a 5: 1 mixture of methanol and 4 N hydrogen chloride in dioxane is added and the mixture is concentrated again. After drying in a high vacuum, 27 mg (24.4% of theory) of the title compound are obtained.
¹ H-NMR (200 MHz, DMSO-d ₆ ): δ = 10.10 (br. S, 1H), 9.06 (d, 1H), 8.36 (s, 1H), 8.02 (m, 2H), 7.61 (m, 1H), 7.54-7.36 (m, 4H), 4.43 (s, 2H), 4.33 (m, 1H), 3.67 (m, 1H), 3.55-3.12 (m, 5H), 2.23 (m, 1H), 2.16 (m, 1H), 1.92 (m, 2H), 1.77 (m, 1H).
HPLC (method 1): R _t = 3.9 min.
MS (ESIpos): m / z = 393 (M + H) ⁺ (free base).

Example 55

N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (5-phenyl-1,2,4-oxadiazol-3-yl) -1-benzothiophene-2-carboxamide hydrochloride

110 mg (0.26 mmol) 6- [Amino (hydroxyimino) methyl] -N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -1-benzothiophene-2-carboxamide dihydrochloride (example 27A) are dissolved in 2 mL DMF and 0.75 mL THF. 250 mg of 4 Å molecular sieve are added and the mixture is stirred for 30 min. at room temperature. After the addition of 31.2 mg (0.79 mmol) sodium hydride (60% suspension in mineral oil), 20 min. heated to 60 ° C and then cooled to room temperature. A solution of 100 μL (0.79 mmol) methyl benzoate in 1 mL THF is added to the reaction mixture and the mixture is heated at 80 ° C. for 14 h. A further 20.8 mg (0.52 mmol) sodium hydride (60% suspension in mineral oil) and 0.99 mL (7.91 mmol) methyl benzoate in 1 mL THF are added and the mixture is heated to 70 ° C. for a further 24 h. The reaction is stopped by adding water. The cleaning is done by preparative HPLC. The product fractions are concentrated, a 5: 1 mixture of methanol and 4 N hydrogen chloride in dioxane is added and the mixture is concentrated again. After drying in a high vacuum, 45.7 mg (32% of theory) of the title compound are obtained.
HPLC (method 1): R _t = 4.5 min.
MS (ESIpos): m / z = 431 (M + H) ⁺ (free base).

Example 56

N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (5-benzyl-1,2,4-oxadiazol-3-yl) -1-benzothiophene-2-carboxamide hydrochloride

110 mg (0.26 mmol) 6- [amino (hydroxymino) methyl] -N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -1-benzothiophene-2-carboxamide dihydrochloride (example 27A) are dissolved in 2 mL DMF and 0.75 mL THF. 250 mg of 4 Å molecular sieve are added and the mixture is stirred for 30 min. at room temperature. After adding 31.2 mg (0.79 mmol) sodium hydride (60% suspension in mineral oil), 20 min. heated to 60 ° C and then cooled to room temperature. A solution of 110 μL (0.79 mmol) methyl phenylacetate in 1 mL THF is added and the mixture is heated to 80 ° C. for 14 h. After adding a further 20.8 mg (0.52 mmol) sodium hydride (60% suspension in mineral oil) and 1.14 mL (7.91 mmol) methyl phenylacetate in 1 mL THF, the mixture is heated at 70 ° C. for a further 24 h. The reaction is stopped by adding water. The cleaning is done by preparative HPLC. The product fractions are concentrated, a 5: 1 mixture of methanol and 4 N hydrogen chloride in dioxane is added and the mixture is concentrated again. After drying in a high vacuum, 4.1 mg (3% of theory) of the title compound are obtained.
¹ H-NMR (300 MHz, methanol-d ₄ ): δ = 8.63 (s, 1H), 8.11 (m, 2H), 8.04 (d, 1H), 7.43-7.27 (m, 5H), 4.47 (m, 1H), 4.38 (s, 2H), 3.87 (m, 1H), 3.52-3.20 (m, 5H), 2.40 (m, 1H), 2.28 (m, 1H), 2.11 (m, 2H), 1.97 (m , 1H).
HPLC (method 1): R _t = 4.4 min.
MS (ESIpos): m / z = 445 (M + H) ⁺ (free base).

Example 57 N - [(3R) -1-Azabicyclo [2.2.2] oct-3-yl] -6- [4- (4-morpholinylmethyl) phenyl] -1-benzothiophene-2-carboxamide dihydrochloride

To a solution of 80 mg (0.19 mmol) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (4-formylphenyl) -1-benzothiophene-2-carboxamide hydrochloride ( Example 23A) in 1.5 mL of a 6: 1 mixture of methanol and acetic acid, 330 mg (3.75 mmol) of morpholine and 40 mg (0.56 mmol) of sodium cyanoborohydride are successively added. After 2 h at room temperature and 6 h at 80 ° C, it is purified by means of preparative HPLC. The product fractions are concentrated, a 5: 1 mixture of methanol and 1 N hydrochloric acid is added and the mixture is concentrated again. After drying in a high vacuum, 87.7 mg (88% of theory) of the title compound are obtained.
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 11.26 (br. S, 1H), 10.29 (br. S, 1H), 9.18 (d, 1H), 8.41 (m, 2H), 8.06 ( d, 1H), 7.89 (m, 2H), 7.81 (d, 1H), 7.74 (m, 2H), 4.39 (m, 2H), 4.34 (m, 1H), 4.05-3.03 (m, 6H), 2.23 (m, 1H), 2.16 (m, 1H), 1.92 (m, 2H), 1.76 (m, 1H).
HPLC (method 1): R _t = 3.5 min.
MS (ESIpos): m / z = 462 (M + H) ⁺ (free base).

Example 58 N - [(3R) -1-Azabicyclo [2.2.2] oct-3-yl] -7- [4- (dimethylamino) phenyl] -1-benzothiophene-2-carboxamide hydrochloride

To a mixture of 100 mg (0.22 mmol) of N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -7-bromo-1-benzothiophene-2-carboxamide hydrochloride (Example 8A) and 36.8 mg (0.22 mmol) 4- (dimethylamino) phenylboronic acid in 1 mL DMF are added 0.33 mL 2 M sodium carbonate solution and 9.1 mg (0.01 mmol) PdCl ₂ (dppf). The reaction mixture is heated to 80 ° C. for 16 h. A further 36.8 mg (0.22 mmol) of 4- (dimethylamino) phenylboronic acid, 36.5 mg (0.04 mmol) of PdCl ₂ (dppf) and 0.67 mL of 1 N sodium hydroxide solution are added and the mixture is heated at 80 ° C. for a further 3 h. After cooling, it is filtered through kieselguhr and purified by means of preparative HPLC. The product fractions are concentrated, taken up in a 5: 1 mixture of methanol and 1N hydrochloric acid and concentrated again. After drying in a high vacuum, 50.6 mg (47% of theory) of the title compound are obtained.
¹ H-NMR (300 MHz, methanol-d ₄ ): δ = 8.26 (s, 1H), 7.95 (m, 3H), 7.80 (m, 2H), 7.58 (dd, 1H), 7.53 (m, 1H) , 4.46 (m, 1H), 3.82 (m, 1H), 3.51 (m, 1H), 3.45-3.16 (m, 10H), 2.37 (m, 1H), 2.29 (m, 1H), 2.10 (m, 2H ), 1.95 (m, 1H).
HPLC (method 1): R _t = 3.6 min.
MS (ESIpos): m / z = 406 (M + H) ⁺ (free base).

Example 59 N - [(3R) -1-Azabicyclo [2.2.2] oct-3-yl] -7- (2-thienyl) -1-benzothiophene-2-carboxamide formate

100 mg (0.25 mmol) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -7-bromo-1-benzothiophene-2-carboxamide hydrochloride (Example 8A) and 31.9 mg (0.25 mmol) 2-thiophene boronic acid are placed in 1.5 mL DMF. After adding 0.37 mL 2 M sodium carbonate solution and 9.11 mg (0.01 mmol) PdCl ₂ (dppf) the mixture is heated to 85 ° C. After 14 h, the reaction mixture is filtered through kieselguhr and purified by preparative HPLC (eluent A: acetonitrile, eluent B: water + 0.1% formic acid; gradient: 10% A → 95% A). The product fractions are concentrated and dried in a high vacuum. 30 mg (28% of theory) of the title compound are obtained.
¹ H-NMR (200 MHz, DMSO-d ₆ ): δ = 8.80 (d, 1H), 8.33 (s, 1H), 8.23 (s, 1H), 7.97 (m, 1H), 7.72 (m, 3H) , 7.55 (dd, 1H), 7.28 (dd, 1H), 4.12 (m, 1H), 3.36 (m, 1H), 3.18-2.80 (m, 5H), 2.03 (m, 1H), 1.95 (m; 1H ), 1.74 (m, 2H), 1.52 (m, 1H).
HPLC (method 1): R _t = 4.2 min.
MS (ESIpos): m / z = 369 (M + H) ⁺ (free base).

Example 60 7- (5-Acetyl-2-thienyl) -N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -1-benzothiophene-2-carboxamide hydrochloride

100 mg (0.25 mmol) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -7-bromo-1-benzothiophene-2-carboxamide hydrochloride (Example 8A) and 42.3 mg (0.25 mmol) 5-acetyl-2-thienylboronic acid are placed in 1.5 mL DMF. After adding 0.37 mL 2 M sodium carbonate solution and 9.11 mg (0.01 mmol) PdCl ₂ (dppf) the mixture is heated to 85 ° C. After 14 h, the reaction mixture is filtered through kieselguhr and purified by preparative HPLC. The product fractions are concentrated, taken up in a 5: 1 mixture of methanol and 1 N hydrochloric acid, concentrated again and dried in a high vacuum. 52 mg (46% of theory) of the title compound are obtained.
¹ H-NMR (200 MHz, DMSO-d ₆ ): δ = 10.25 (br. S, 1H), 9.23 (d, 1H), 8.49 (s, 1H), 8.08 (d, 1H), 8.06 (m, 1H), 7.89 (m, 1H), 7.82 (d, 1H), 7.61 (dd, 1H), 4.36 (m, 1H), 3.73-3.13 (m, 5H), 2.60 (s, 3H), 2.23 (m , 1H), 2.15 (m, 1H), 1.93 (m, 2H), 1.76 (m, 1H).
HPLC (method 1): R _t = 4.1 min.
MS (ESIpos): m / z = 411 (M + H) ⁺ (free base).

Example 61 N - [(3R) -1-Azabicyclo [2.2.2] oct-3-yl] -7- [4- (6-oxo-2-piperidinyl) phenyl] -1-benzothiophene-2-carboxamide hydrochloride

According to the general working procedure D, 123.4 mg (0.49 mmol) 6- (4-bromophenyl) -2-piperidinone, 142.2 mg (0.56 mmol) bis (pinacolato) dibor, 146.6 mg (1.49 mmol) potassium acetate, 13.7 mg (0.02 mmol) PdCl ₂ (dppf), 150 mg (0.37 mmol) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -7-bromo-1-benzothiophene-2-carboxamide hydrochloride (Example 8A ), 0.93 mL 2 M sodium carbonate solution and another 13.7 mg (0.02 mmol) PdCl ₂ (dppf) in 2 mL DMF. After drying in a high vacuum, 7.3 mg (4% of theory) of the title compound are obtained.
HPLC (method 1): R _t = 3.9 min.
MS (ESIpos): m / z = 460 (M + H) ⁺ (free base).

Example 62 N - [(3R) -1-Azabicyclo [2.2.2] oct-3-yl] -7- [3- (hydroxymethyl) phenyl] -1-benzothiophene-2-carboxamide hydrochloride

200 mg (0.45 mmol) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -7-bromo-1-benzothiophene-2-carboxamide hydrochloride (Example 8A) and 74.6 mg (0.49 mmol) 3- (hydroxymethyl) phenylboronic acid are placed in 3 mL DMF. After addition of 0.67 mL 2 M sodium carbonate solution and 18.2 mg (0.02 mmol) PdCl ₂ (dppf) the mixture is heated to 80 ° C. After 14 h, the reaction mixture is filtered through kieselguhr and purified by separation using preparative HPLC. The product fractions are concentrated, a 5: 1 mixture of methanol and 4 N hydrogen chloride in dioxane is added and the mixture is concentrated again. After drying in a high vacuum, 40 mg (19% of theory) of the title compound are obtained.
¹ H-NMR (300 MHz, DMSO-d ₆ ): δ = 10.47 (br. S, 1H), 9.17 (d, 1H), 8.47 (s, 1H), 7.96 (d; 1H), 7.67 (s, 1H), 7.63-7.47 (m, 4H), 7.43 (d, 1H), 4.61 (s, 2H), 4.33 (m, 1H), 3.62 (m, 1H), 3.3 9 (m, 2H), 3.20 ( m, 3H), 2.11 (m, 1H), 2.15 (m, 1H), 1.91 (m, 2H), 1.75 (m, 1H).
HPLC (method 1): R _t = 3.9 min.
MS (ESIpos): m / z = 393 (M + H) ⁺ (free base).

Example 63 N - [(3R) -1-Azabicyclo [2.2.2] oct-3-yl] -7- [2- (4-morpholinyl) phenyl] -1-benzothiophene-2-carboxamide hydrochloride

According to the general working procedure D 100 mg (0.41 mmol) 4- (2-bromophenyl) morpholine, 121.0 mg (0.48 mmol) bis (pinacolato) dibor, 101.3 mg (1.03 mmol) potassium acetate, 11: 6 mg (0.02 mmol) PdCl ₂ (dppf), 127.6 mg (0.32 mmol) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -7-bromo-1-benzothiophene-2-carboxamide hydrochloride (Example 8A) , 0.79 mL 2 M sodium carbonate solution and a further 11.6 mg (0.02 mmol) PdCl ₂ (dppf) in 2 mL DMF. After drying under high vacuum, 38.9 mg (48% of theory) of the title compound are obtained.
¹ H-NMR (200 MHz, DMSO-d ₆ ): δ = 10.20 (br. S, 1H), 9.04 (d, 1H), 8.36 (s, 1H), 7.93 (dd, 1H), 7.55 (m, 2H), 7.45 (d, 1H), 7.37 (dd, 1H), 7.17 (m, 2H), 4.32 (m, 1H), 3.62 (m, 1H), 3.48-3.10 (m, 9H), 2.69 (m , 4H), 2.19 (m, 1H), 2.10 (m, 1H), 1.90 (m, 2H), 1.73 (m, 1H).
HPLC (method 1): R _t = 4.3 min.
MS (ESIpos): m / z = 448 (M + H) ⁺ (free base).

Example 64 2- (2 - {[(3R) -1-Azabicyclo [2.2.2] oct-3-ylamino] carbonyl} -1-benzothien-7-yl) benzyl ethyl carbamate hydrochloride

To a suspension of 50 mg (0.12 mmol) of N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -7- [2- (hydroxymethyl) phenyl] -1-benzothiophene-2-carboxamide -Hydrochloride (Example 131) in 1 mL of a 5: 1 mixture of THF and DMF, 32.5 μL (0.23 mmol) triethylamine and 16.6 mg (0.23 mmol) ethyl isocyanate are added. After 18 h at room temperature, a further 16.6 mg (0.23 mmol) of ethyl isocyanate and a catalytic amount of 4-N, N-dimethylaminopyridine are added. The mixture is stirred at room temperature for a further 18 h. The reaction mixture is concentrated in vacuo and purified by preparative HPLC. The product fractions are concentrated, a 5: 1 mixture of methanol and 1 N hydrochloric acid is added and the mixture is concentrated again: after drying in a high vacuum, 28 mg (47% of theory) of the title compound are obtained.
HPLC (method 1): R _t = 4.2 min.
MS (ESIpos): m / z = 464 (M + H) ⁺ (free base).

Example 65 2- (2 - {[(3R) -1-Azabicyclo [2.2.2] oct-3-ylamino] carbonyl} -1-benzothien-7-yl) benzyl methyl carbamate hydrochloride

To a suspension of 50 mg (0.12 mmol) of N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -7- [2- (hydroxymethyl) phenyl] -1-benzothiophene-2-carboxamide Hydrochloride (Example 131) in 1 mL of a 5: 1 mixture of THF and DMF, 32.5 μL (0.23 mmol) of triethylamine and 13.3 mg (0.23 mmol) of methyl isocyanate are added. After 18 h at room temperature, a further 16.6 mg (0.23 mmol) of methyl isocyanate and a catalytic amount of 4-N, N-dimethylaminopyridine are added. The mixture is stirred at room temperature for a further 18 h. The reaction mixture is concentrated in vacuo and purified by preparative HPLC. The product fractions are concentrated, a 5: 1 mixture of methanol and 1 N hydrochloric acid is added and the mixture is concentrated again. After drying in a high vacuum, 18 mg (30% of theory) of the title compound are obtained.
¹ H-NMR (400 MHz, methanol-d ₄ ): δ = 8.18 (s, 1H), 7.95 (m, 1H), 7.63-7.42 (m, 4H), 7.38 (m, 2H), 4.42 (m, 1H), 3.81 (m, 1H), 3.47 (m, 1H), 3.40-3.25 (m, 4H), 2.57 (m, 3H), 2.37 (m, 1H), 2.26 (m, 1H), 2.09 (m , 2H), 1.94 (m; 1H).
LC-MS (Method 4): R _t = 2.7 min., M / z = 464 (M + H) ⁺ (free base).

Example 66 N - [(3R) -1-Azabicyclo [2.2.2] oct-3-yl] -7- [4- (2-oxo-1-pyrrolidinyl) phenyl] -1-benzothiophene-2-carboxamide hydrochloride

According to the general working procedure D 116.5 mg (0.49 mmol) 1- (4-bromophenyl) -2-pyrrolidinone, 142.2 mg (0.56 mmol) bis (pinacolato) dibor, 119.1 mg (1.21 mmol) potassium acetate, 13.7 mg (0.02 mmol) PdCl ₂ (dppf), 150 mg (0.37 mmol) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -7-bromo-1-benzothiophene-2-carboxamide hydrochloride (Example 8A ), 0.93 mL 2 M sodium carbonate solution and another 13.7 mg (0.02 mmol) PdCl ₂ (dppf) in 2 mL DMF. After drying in a high vacuum, 71 mg (39% of theory) of the title compound are obtained.
¹ H-NMR (400 MHz, methanol-d ₄ ): δ = 8.16 (s, 1H), 7.91 (d, 1H), 7.80 (m, 2H), 7.75 (m, 2H), 7.54 (dd, 1H) , 7.51 (dd, 1H), 4.46 (m, 1H), 4.01 (m, 2H), 3.85 (m, 1H), 3.47 (m, 1H), 3.42-3.26 (m, 4H), 2.65 (m, 2H ), 2.39 (m, 1H), 2.24 (m, 3H), 2.10 (m, 2H), 1.96 (m, 1H).
HPLC (method 1): R _f = 4.0 min.
MS (ESIpos): m / z = 446 (M + H) ⁺ (free base).

Example 67 N - [(3R) -1-Azabicyclo [2.2.2] oct-3-yl] -7- (4- (1-piperazinyl) phenyl] -1-benzothiophene-2-carboxamide dihydrochloride

According to the general procedure D 165.6 mg (0.49 mmol) of tert-butyl 4- (4-bromophenyl) -1-piperazinecarboxylate, 142.2 mg (0.56 mmol) of bis- (pinacolato) dibor, 119.1 mg (1.21 mmol) of potassium acetate, 13.7 mg (0.02 mmol) PdCl ₂ (dppf), 150 mg (0.37 mmol) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -7-bromo-1-benzothiophene-2- carboxamide hydrochloride (Example 8A), 0.93 mL 2 M sodium carbonate solution and another 13.7 mg (0.02 mmol) PdCl ₂ (dppf) in 2 mL DMF. The compound purified by preparative HPLC is dissolved in 3 ml of methanol, mixed with 3 ml of 4 M hydrogen chloride in dioxane and 30 min. stirred at room temperature. The contents of the flask are concentrated in vacuo and the residue is azeotroped twice with toluene. After drying under high vacuum, 54 mg (28% of theory) of the title compound are obtained.
¹ H-NMR (300 MHz, methanol-d ₄ ): δ = 8.17 (s, 1H), 7.87 (dd, 1H), 7.66 (m, 2H), 7.52 (dd, 1H), 7.45 (dd, 1H) , 7.18 (m, 2H), 4.45 (m, 1H), 3.83 (m, 1H), 3.75-3.13 (m, 13H), 2.38 (m, 1H), 2.28 (m, 1H), 2.10 (m, 2H ), 1.95 (m, 1H).
HPLC (method 1): R _t = 3.7 min.
MS (ESIpos): m / z = 447 (M + H) ⁺ (free base).

Example 68 N - [(3R) -1-Azabicyclo [2.2.2] oct-3-yl] -7- [4- (3-oxo-4-morpholinyl) phenyl] -1-benzothiophene-2-carboxamide hydrochloride

According to the general procedure D 120 mg (0.39 mmol) 4- (4-bromophenyl) -3-morpholinone, 115.3 mg (0.45 mmol) bis (pinacolato) dibor, 96.6 mg (0.98 mmol) potassium acetate, 11.1 mg (0.02 mmol) PdCl ₂ (dppf), 121.6 mg (0.30 mmol) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -7-bromo-1-benzothiophene-2-carboxamide hydrochloride (Example 8A ), 0.76 mL 2 M sodium carbonate solution and another 11.1 mg (0.02 mmol) PdCl ₂ (dppf) in 2 mL DMF. After drying in a high vacuum, 24 mg (16% of theory) of the title compound are obtained.
¹ H-NMR (400 MHz, methanol-d ₄ ): δ = 8.17 (s, 1H), 7.93 (d, 1H), 7.80 (m, 2H), 7.55 (m, 4H), 4.46 (m, 1H) , 4.33 (s, 2H), 4.09 (m, 2H), 3.88 (m, 2H), 3.84 (m, 1H), 3.47 (m, 1H), 3.41-3.26 (m, 4H), 2.39 (m, 1H ), 2.28 (m, 1H), 2.10 (m, 2H), 1.95 (m, 1H).
HPLC (method 1): R _t = 3.8 min.
MS (ESIpos): m / z = 462 (M + H) ⁺ (free base).

Example 69 N - [(3R) -1-Azabicyclo [2.2.2] oct-3-yl] -7- [3- (1-pyrrolidinyl) phenyl] -1-benzothiophene-2-carboxamide hydrochloride

According to the general working procedure D 109.8 mg (0.49 mmol) 1- (3-bromophenyl) pyrrolidine, 142.2 mg (0.56 mmol) bis (pinacolato) dibor, 119.1 mg (1.21 mmol) potassium acetate, 13.7 mg (0.02 mmol) PdCl ₂ ( dppf), 150.0 mg (0.37 mmol) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -7-bromo-1-benzothiophene-2-carboxamide hydrochloride (Example 8A), 0.93 mL 2 M sodium carbonate solution and another 13.7 mg (0.02 mmol) PdCl ₂ (dppf) reacted in 2 mL DMF. After drying in a high vacuum, 88.4 mg (51% of theory) of the title compound are obtained.
¹ H-NMR (200 MHz, DMSO-d ₆ ): δ = 10.28 (br. S, 1H), 9.11 (d, 1H), 8.42 (s, 1H), 7.95 (dd, 1H), 7.55 (m, 2H), 7.36 (dd, 1H), 6.96 (d, 1H), 6.87 (s, 1H), 6.68 (m, 1H), 4.33 (m, 1H), 3.80-3.10 (m, 10H), 2.21 (m , 1H), 2.11 (m, 1H), 2.95 (m, 6H), 1.75 (m, 1H).
HPLC (method 1): R _t = 4.2 min.
MS (ESIpos): m / z = 432 (M + H) ⁺ (free base).

Example 70 N - [(3R) -1-Azabicyclo [2.2.2] oct-3-yl] -7- [3- (4-morpholinyl) phenyl] -1-benzothiophene-2-carboxamide hydrochloride

According to the general procedure D 151.1 mg (0.49 mmol) of 3- (4-morpholinyl) phenyl trifluoromethanesulfonate (Example 17A), 142.2 mg (0.56 mmol) of bis (pinacolato) dibor, 119.1 mg (1.21 mmol) of potassium acetate, 13.7 mg ( 0.02 mmol) PdCl ₂ (dppf), 150.0 mg (0.37 mmol) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -7-bromo-1-benzothiophene-2-carboxamide hydrochloride (Example 8A), 0.93 ml of 2 M sodium carbonate solution and a further 13.7 mg (0.02 mmol) of PdCl ₂ (dppf) in 2 ml of DMF. After drying in a high vacuum, 125.3 mg (68% of theory) of the title compound are obtained.
¹ H-NMR (400 MHz, methanol-d ₄ ): δ = 8.26 (s, 1H), 7.99 (m, 2H), 7.86 (d, 1H), 7.75 (m, 2H), 7.59 (m, 2H) , 4.47 (m, 1H), 4.10 (m, 4H), 3.83 (m, 1H), 3.76 (m, 4H), 3.73 (m, 1H), 3.52 (m, 1H), 3.37 (m, 3H), 2.3 8 (m, 1H), 2.29 (m, 1H), 2.10 (m, 2H), 1.96 (m, 1H).
HPLC (method 1): R _t = 3.9 min.
MS (ESIpos): m / z = 448 (M + H) ⁺ (free base).

Example 71 N - [(3R) -1-Azabicyclo [2.2.2] oct-3-yl] -7- [4- (1-pyrrolidinyl) phenyl] -1-benzothiophene-2-carboxamide dihydrochloride

According to the general working procedure D, 109.8 mg (0.49 mmol) of 1- (4-bromophenyl) pyrrolidine, 142.2 mg (0.56 mmol) of bis (pinacolato) dibor, 119.1 mg (1.21 mmol) of potassium acetate, 13.7 mg (0.02 mmol) of PdCl ₂ ( dppf), 150.0 mg (0.37 mmol) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -7-bromo-1-benzothiophene-2-carboxamide hydrochloride (Example 8A), 0.93 mL 2 M sodium carbonate solution and another 13.7 mg (0.02 mmol) PdCl ₂ (dppf) in 2.5 mL DMF. After drying in a high vacuum, 24.8 mg (13% of theory) of the title compound are obtained.
¹ H-NMR (400 MHz, methanol-d ₄ ): δ = 8.26 (s, 1H), 7.98 (d, 1H), 7.92 (m, 2H), 7.75 (m, 2H), 7.5.8 (dd, 1H), 7.53 (d, 1H), 4.47 (m, 1H), 3.92-3.76 (m; 5H), 3.51 (m, 1H), 3.45-3.18 (m, 4H), 2.42-2.23 (m, 6H) , 2.10 (m, 2H), 1.96 (m, 1H).
HPLC (method 1): R _t = 4.1 min.
MS (ESIpos): m / z = 432 (M + H) ⁺ (free base).

Example 72 N - [(3R) -1-Azabicyclo [2.2.2] oct-3-yl] -7- [4- (4-morpholinylcarbonyl) phenyl] -1-benzothiophene-2-carboxamide hydrochloride

According to general working procedure D, 164.7 mg (0.49 mmol) of 4- (4-morpholinylcarbonyl) phenyl trifluoromethanesulfonate (Example 18A), 142.2 mg (0.56 mmol) of bis (pinacolato) dibor, 119.1 mg (1.21 mmol) of potassium acetate, 13.7 mg ( 0.02 mmol) PdCl ₂ (dppf), 150.0 mg (0.37 mmol) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -7-bromo-1-benzothiophene-2-carboxamide hydrochloride (Example 8A), 0.93 ml of 2 M sodium carbonate solution and a further 13.7 mg (0.02 mmol) of PdCl ₂ (dppf) in 2.5 ml of DMF. Following a first purification using preparative HPLC, column chromatography on silica gel (mobile phase: dichloromethane-methanol-ammonia 90: 9: 1) is carried out. After drying in a high vacuum, 24.8 mg (13% of theory) of the title compound are obtained.
¹ H-NMR (400 MHz, methanol-d ₄ ): δ = 8.22 (s, 1H), 7.97 (d, 1H), 7.83 (m, 2H), 7.62 (m, 2H), 7.55 (m, 2H) , 4.47 (m, 1H), 3.90-3.26 (m, 14H), 2.38 (m, 1H), 2.28 (m, 1H), 2.10 (m, 2H), 1.96 (m, 1H).
HPLC (method 1): R _t = 3.8 min.
MS (ESIpos): m / z = 476 (M + H) ⁺ (free base).

Example 73 7- [2- (Aminomethyl) phenyl] -N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -1-benzothiophene-2-carboxamide dihydrochloride

According to the general procedure D 534.2 mg (1.87 mmol) of tert-butyl-2-bromobenzylcarbamate, 474.1 mg (1.87 mmol) of bis (pinacolato) dibor, 397.0 mg (4.04 mmol) of potassium acetate, 45.5 mg (0.06 mmol) of PdCl ₂ ( dppf), 500 mg (1.24 mmol) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -7-bromo-1-benzothiophene-2-carboxamide hydrochloride (Example 8A), 3.11 mL 2 M sodium carbonate solution and another 45.5 mg (0.06 mmol) PdCl ₂ (dppf) reacted in 6.0 mL DMF. Following the purification by means of preparative HPLC, the combined product fractions are concentrated, taken up in methanol, 1 N hydrochloric acid is added and the mixture is stirred for 30 min. stirred at room temperature. After concentration and drying in a high vacuum, 121 mg (20% of theory) of the title compound are obtained.
HPLC (method 1): R _t = 3.6 min.
MS (ESIpos): m / z = 392 (M + H) ⁺ (free base).

Example 74 N - [(3R) -1-Azabicyclo [2.2.2] oct-3-yl] -7- {3 - [(2,2-dimethylpropanoyl) amino] phenyl} -1-benzothiophene-2-carboxamide- hydrochloride

According to the general working procedure D 143.5 mg (0.56 mmol) N- (3-bromophenyl) -2; 2-dimethylpropanamide, 142.2 mg (0.56 mmol) bis (pinacolato) dibor, 119.1 mg (1.21 mmol) potassium acetate, 13.7 mg (0.02 mmol) PdCl ₂ (dppf), 150.0 mg (0.37 mmol) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -7-bromo-1-benzothiophene-2-carboxamide hydrochloride ( Example 8A), 0.93 ml of 2 M sodium carbonate solution and a further 13.7 mg (0.02 mmol) of PdCl ₂ (dppf) in 2.0 ml of DMF. Following a first purification using preparative HPLC, column chromatography on silica gel (mobile phase: dichloromethane-methanol-ammonia 90: 9: 1) is carried out. After drying in a high vacuum, 32.4 mg (17% of theory) of the title compound are obtained.
¹ H-NMR (400 MHz, methanol-d ₄ ): δ = 8.16 (s, 1H), 8.01 (m, 1H), 7.92 (m, 1H), 7.63-7.48 (m, 3H), 7.47 (m, 2H), 4.44 (m, 1H), 3.84 (m, 1H), 3.47 (m, 1H), 3.41-3.27 (m, 4H), 2.38 (m, 1H), 2.28 (m, 1H), 2.10 (m , 2H), 1.96 (m, 1H), 1.32 (s, 9H).
HPLC (method 1): R _t = 4.3 min.
MS (ESIpos): m / z = 462 (M + H) ⁺ (free base).

Example 75 3- (2 - {[(3R) -1-Azabicyclo [2.2.2] oct-3-yl-amino] carbonyl} -1-benzothien-7-yl) -benzoic acid hydrochloride

200 mg (0.50 mmol) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -7-bromo-1-benzothiophene-2-carboxamide hydrochloride (Example 8A) and 82.6 mg (0.50 mmol) 3-carboxyphenylboronic acid are placed in 1.5 mL DMF. After adding 0.78 mL 2 M sodium carbonate solution and 20.3 mg (0.02 mmol) PdCl ₂ (dppf) the mixture is heated to 60 ° C. After 18 h, a further 20.3 mg (0.02 mmol) of PdCl ₂ (dppf) are added and the mixture is heated to 90 ° C. for a further 18 h. After cooling, the reaction mixture is filtered through kieselguhr and purified by means of preparative HPLC. The product fractions are concentrated, a 3: 1 mixture of acetonitrile and 1 N hydrochloric acid is added and the mixture is concentrated again. After drying in a high vacuum, 103 mg (45% of theory) of the title compound are obtained.
¹ H-NMR (300 MHz, DMSO-d ₆ ): δ = 10.28 (br. S, 1H), 9.13 (d, 1H), 8.46 (s, 1H), 8.29 (m, 1H), 8.08-7.95 ( m, 3H), 7.71 (dd, 1H), 7.60 (m, 2H), 4.33 (m, 1H), 3.85-3.12 (m, 6H), 2.22 (m, 1H), 2.15 (m, 1H), 1.91 (m, 2H), 1.75 (m, 1H).
HPLC (method 1): R _t = 3.9 min.
MS (ESIpos): m / z = 407 (M + H) ⁺ (free base).

Example 76 N - [(3R) -1-Azabicyclo [2.2.2] oct-3-yl] -7- [2 - ({[(methylamino) carbonyl] amino} methyl) phenyl] -1-benzothiophene-2 -carboxamide hydrochloride

To a suspension of 85 mg (0.18 mmol) 7- [2- (aminomethyl) phenyl] -N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -1-benzothiophene-2-carboxamide Dihydrochloride (Example 73) in 1 mL of a 5: 1 mixture of THF and DMF, 51.0 μL (0.37 mmol) triethylamine and 43.5 μL (0.73 mmol) methyl isocyanate are added. After 18 h at room temperature, the reaction mixture is concentrated in vacuo and purified by means of preparative HPLC. The product fractions are concentrated, a 5: 1 mixture of methanol and 1 N hydrochloric acid is added and the mixture is concentrated again. After drying in a high vacuum, 65.5 mg (74% of theory) of the title compound are obtained.
¹ H-NMR (400 MHz, methanol-d ₆ ): δ = 8.18 (s, 1H), 7.94 (d, 1H), 7.58-7.44 (m, 3H), 7.43-7.29 (m, 3H), 4.43 ( m, 1H), 4.15 (m, 2H), 3.82 (m, 1H), 3.47 (m, 1H), 3.41-3.27 (m, 4H), 2.62 (s, 3H), 2.37 (m, 1H), 2.26 (m, 1H), 2.08 (m, 2H), 1.94 (m, 1H).
HPLC (method 1): R _t = 3.8 min. LC-MS (Method 4): R _t = 2.5 min.
MS (ESIpos): m / z = 448 (M + H) ⁺ (free base).

Example 77 N - [(3R) -1-Azabicyclo [2.2.2] oct-3-yl] -7- [3- (1H-pyrrol-1-yl) phenyl] -1-benzothiophene-2-carboxamide hydrochloride

According to the general working procedure D 124.4 mg (0.56 mmol) 1- (3-bromophenyl) -1H-pyrrole, 142.2 mg (0.56 mmol) bis (pinacolato) dibor, 119.1 mg (1.21 mmol) potassium acetate, 13.7 mg (0.02 mmol) PdCl ₂ (dppf), 150.0 mg (0:37 mmol) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -7-bromo-1-benzothiophene-2-carboxamide hydrochloride ( Example 8A), 0.93 ml of 2 M sodium carbonate solution and a further 13.7 mg (0.02 mmol) of PdC1 ₂ (dppf) in 2.0 ml of DMF. After drying in a high vacuum, 86.9 mg (48% of theory) of the title compound are obtained.
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 9.92 (br. S, 1H), 9.03 (d, 1H), 8.39 (m, 1H), 8.02 (m, 1H), 7.88 (s, 1H), 7.77-7.57 (m, 5H), 7.49 (m, 2H), 6.31 (m, 2H), 4.32 (m, 1H), 3.67 (m, 1H), 3.57-3.13 (m, 5H), 2.21 (m, 1H), 2.13 (m, 1H), 1.90 (m, 2H), 1.75 (m, 1H).
HPLC (method 1): R _t = 4.5 min.
MS (ESIpos): m / z = 428 (M + H) ⁺ (free base).

Example 78 N - [(3R) -1-Azabicyclo [2.2.2] oct-3-yl] -7- [3- (4-morpholinylcarbonyl) phenyl] -1-benzothiophene-2-carboxamide hydrochloride

To a solution of 50 mg (0.11 mmol) of 3- (2 - {[(3R) -1-azabicyclo [2.2.2] oct-3-yl-amino] carbonyl} -1-benzothien-7-yl) -benzoic acid -Hydrochloride (Example 75) and 19.7 μL (0.23 mmol) morpholine in 0.5 mL DMF are given 103 mg (0.27 mmol) HATU and 70.8 μL (0.41 mmol) N, N-diisopropylethylamine at 0 ° C. The mixture is stirred at room temperature for 18 h. After purification by means of preparative HPLC, the product fractions are concentrated, a 3: 1 mixture of acetonitrile and 1 N hydrochloric acid is added and the mixture is concentrated again. After drying in a high vacuum, 43 mg (74% of theory) of the title compound are obtained.
¹ H-NMR (200 MHz, DMSO-d ₆ ): δ = 10.66 (br. S, 1H), 9.33 (d, 1H), 8.56 (s, 1H), 7.98 (dd, 1H), 7.87-7.45 ( m, 6H), 4.34 (m, 1H), 3.87-3.06 (m, 14H), 2.18 (m, 2H), 1.90 (m, 2H), 1.74 (m, 1H).
HPLC (method 1): R _t = 3.8 min.
MS (ESIpos): m / z = 476 (M + H) ⁺ (free base).

Example 79 N - [(3S) -1-Azabicyclo [2.2.2] oct-3-yl] -7- [4- (4-morpholinyl) phenyl] -1-benzothiophene-2-carboxamide hydrochloride

To a mixture of 144.3 mg (0.72 mmol) S-3-aminoquinuclidine dihydrochloride and 300 mg (0.72 mmol) 7- [4- (4-Morpholinyl) phenyl] -1-benzothiophene-2-carboxylic acid (example 20A) in 3 mL DMF at 0 ° C 330.7 mg (0.87 mmol) HATU and 112.4 mg (0.87 mmol) N, N-diisopropylethylamine given. After 30 min. at 0 ° C 224.8 mg (1.74 mol) of N, N-diisopropylethylamine are added and 19 h stirred at room temperature. The reaction solution is mixed with a little water and acetonitrile and by means of preparative HPLC purified. The product fractions are concentrated with a 3: 1 mixture of methanol and 1 N hydrochloric acid was added and the mixture was concentrated again. Obtained after drying in a high vacuum 158 mg (45% of theory) of the title compound.

The spectroscopic data are correct with those of the enantiomeric compound (Example 19).

Example 80 N - [(3R) -1-Azabicyclo [2.2.2] oct-3-yl] -7- [3- (4-morpholinyl) phenyl] -1-benzofuran-2-carboxamide hydrochloride

According to the general procedure D 151.1 mg (0.49 mmol) of 3- (4-morpholinyl) phenyl trifluoromethanesulfonate (Example 17A), 142.2 mg (0.56 mmol) of bis (pinacolato) dibor, 119.1 mg (1.21 mmol) of potassium acetate, 13.7 mg ( 0.02 mmol) PdCl ₂ (dppf), 144 mg (0.37 mmol) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -7-bromo-1-benzofuran-2-carboxamide hydrochloride (Example 30A), 0.93 ml of 2 M sodium carbonate solution and a further 13.7 mg (0.02 mmol) of PdCl ₂ (dppf) in 2 ml of DMF. After drying under high vacuum, 32 mg (18% of theory) of the title compound are obtained.
¹ H-NMR (300 MHz, DMSO-d ₆ ): δ = 10.27 (br. S, 1H), 8.96 (d, 1H), 7.85 (s, 1H), 7.78 (m, 1H), 7.68 (m, 1H), 7.62 (m, 1H), 7.43 (m, 3H), 7.17 (m, 1H), 4.36 (m, 1H), 3.82 (m, 4H), 3.63 (m, 1H), 3.44-3.10 (m , 9H), 2.22 (m, 1H), 2.12 (m, 1H), 1.91 (m, 2H), 1.75 (m, 1H).
HPLC (method 1): R _t = 3.8 min.
MS (ESIpos): m / z = 432 (M + H) ⁺ (free base).

Example 81 7- (3-Aminophenyl) -N - [(3R) -1-azabicyelo [2.2.2] oct-3-yl] -1-benzothiophene-2-carboxamide hydrochloride

200 mg (0.50 mmol) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -7-bromo-1-benzothiophene-2-carboxamide hydrochloride (Example 8A) and 68.2 mg (0.50 mmol) 3-aminophenylboronic acid are placed in 1.5 mL DMF. After adding 0.78 mL 2 M sodium carbonate solution and 20.3 mg (0:02 mmol) PdCl ₂ (dppf), the mixture is heated to 60 ° C. for 18 h. After cooling, the reaction mixture is filtered through kieselguhr and purified by separation using preparative HPLC. The product fractions are concentrated, a 3: 1 mixture of acetonitrile and 1 N hydrochloric acid is added and the mixture is concentrated again. After drying in a high vacuum, 201 mg (98% of theory) of the title compound are obtained.
¹ H-NMR (200 MHz, DMSO-d ₆ ): δ = 10.63 (br. S, 1H), 9.33 (d, 1H), 8.57 (s, 1H), 8.00 (dd, 1H), 7.76-7.5 8 (m, 4H), 7.5 5 (m, 1H), 7.43 (m, 1H), 4.34 (m, 1H), 3.62 (m, 1H), 3.42 (m, 2H), 3.19 (m, 3H) , 2.19 (m, 2H), 1.90 (m, 2H), 1.73 (m, 1H).
HPLC (method 1): R _t = 3.5 min.
MS (ESIpos): m / z = 378 (M + H) ⁺ (free base).

Example 82 N - [(3R) -1-Azabicyclo [2.2.2] oct-3-yl] -7- {3 - [(methoxyacetyl) amino] phenyl} -1-benzothiophene-2-carboxamide hydrochloride

To a solution of 50 mg (0.12 mmol) 7- (3-aminophenyl) -N - [(3R) -1-azabicyclo- [2.2.2] oct-3-yl] -1-benzothiophene-2-carboxamide hydrochloride (Example 81) and 18.5 μL (0.24 mmol) methoxyacetic acid in 0.5 mL DMF are added at 0 ° C 96.4 mg (0.25 mmol) HATU and 71.5 μL (0.41 mmol) N, N-diisopropylethylamine. The mixture is stirred at room temperature for 3 h. After purification by means of preparative HPLC, the product fractions are concentrated, a 3: 1 mixture of acetonitrile and 1 N hydrochloric acid is added and the mixture is concentrated again. After drying in a high vacuum, 7 mg (11% of theory) of the title compound are obtained.
¹ H-NMR (300 MHz, DMSO-d ₆ ): δ = 10.13 (br. S, 1H), 9.97 (s, 1H), 9.04 (d, 1H), 8.39 (s, 1H), 8.13 (m, 1H), 7.98 (d, 1H), 7.76 (d, 1H), 7.58 (dd, 1H), 7.50 (m, 2H), 7.42 (m, 1H), 4.33 (m, 1H), 4.03 (s, 2H ), 3.66 (m, 1H), 3.56-3.12 (m, 8H), 2.22 (m, 1H), 2.14 (m, 1H), 1.91 (m, 2H), 1.75 (m, 1H).
HPLC (method 1): R _t = 4.0 min.
MS (ESIpos): m / z = 450 (M + H) ⁺ (free base).

Example 83 N - [(3R) -1-Azabicyclo [2.2.2] oct-3-yl] -7- [4- (2-oxo-1-pyrrolidinyl) phenyl] -1-benzofuran-2-carboxamide hydrochloride

According to general working procedure D, 161.9 mg (0.67 mmol) 1- (4-bromophenyl) -2-pyrrolidinone, 197.5 mg (0.78 mmol) bis (pinacolato) dibor, 165.4 mg (1.69 mmol) potassium acetate, 19.0 mg (0.03 mmol) PdCl ₂ (dppf), 200 mg (0.52 mmol) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -7-bromo-1-benzofuran-2-carboxamide hydrochloride (Example 30A ), 1.30 mL 2 M sodium carbonate solution and another 19.0 mg (0.03 mmol) PdCl ₂ (dppf) in 2.5 mL DMF. After drying in a high vacuum, 166.6 mg (65% of theory) of the title compound are obtained.
¹ H-NMR (200 MHz, DMSO-d ₆ ): δ = 10.06 (br. S, 1H), 8.96 (d, 1H), 7.97 (m, 1H), 7.94 (s, 1H), 7.83 (m, 3H), 7.78 (dd, 1H), 7.69 (dd, 1H); 7.43 (dd, 1H), 4.33 (m, 1H), 4.00-3.75 (m, 2H), 3.66 (m, 1H), 3.49-3.10 (m, 5H), 2.55 (m, 2H), 2.23 (m, 1H), 2.10 (m, 3H), 1.91 (m, 2H), 1.75 (m, 1H).
HPLC (method 1): R _t = 4.0 min.
MS (ESIpos): m / z = 430.5 (M + H) ⁺ (free base).

Example 84 7- [3- (Acetylamino) phenyl] -N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1-benzothiophene-2-carboxamide hydrochloride

To a mixture of 200 mg (0.45 mmol) of N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -7-bromo-1-benzothiophene-2-carboxamide hydrochloride (Example 22A) and 80.2 mg (0.45 mmol) of 3- (acetamido) phenylboronic acid in 2 mL DMF are added to 0.67 mL 2 M sodium carbonate solution and 18.3 mg (0.02 mmol) PdCl ₂ (dppf). The reaction mixture is heated to 80 ° C for 17 h. A further 40.1 mg (0.22 mmol) of 3- (acetamido) phenylboronic acid, 1.34 ml of 1 N sodium hydroxide solution and 73.2 mg (0.09 mmol) of PdCl ₂ (dppf) are added and the mixture is heated at 70 ° C. for a further 18 h. After cooling, it is filtered through kieselguhr and purified by preparative HPLC. The product fractions are concentrated, taken up in a 5: 1 mixture of methanol and 1N hydrochloric acid and concentrated again. After drying in a high vacuum, 124.5 mg (59% of theory) of the title compound are obtained.

The spectroscopic data are correct with those of the enantiomeric compound (Example 51).

Example 85 N - [(3S) -1-Azabicyclo [2: 2.2] oct-3-yl] -7- (3-methoxyphenyl) -1-benzothiophene-2-carboxamide hydrochloride

To a mixture of 200 mg (0.45 mmol) of N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -7-bromo-1-benzothiophene-2-carboxamide hydrochloride (Example 22A) and 68.1 mg (0.45 mmol) 3-methoxyphenylboronic acid in 2 mL DMF are added 0.67 mL 2 M aqueous sodium carbonate solution and 18.3 mg (0.02 mmol) PdCl ₂ (dppf). The reaction mixture is heated to 80 ° C. for 17 h, filtered through diatomaceous earth and evaporated to dryness. Following purification by means of preparative HPLC, column chromatography on silica gel (mobile phase: dichloromethane-methanol-ammonia 90: 9: 1) is carried out. The product fractions are concentrated, taken up in a 5: 1 mixture of methanol and 1N hydrochloric acid and concentrated again. After drying in a high vacuum, 97.7 mg (48% of theory) of the title compound are obtained.
¹ H-NMR (200 MHz, DMSO-d ₆ ): δ = 10.25 (br. S, 1H), 9.11 (d, 1H), 8.42 (s, 1H), 7.97 (dd, 1H), 7.56 (m, 2H), 7.47 (d, 1H), 7.30 (d, 1H), 7.24 (m, 1H), 7.06 (m, 1H), 4.32 (m, 1H), 3.83 (s, 3H), 3.63 (m, 1H) ), 3.49-3.10 (m, 5H), 2.20 (m, 1H), 2.13 (m, 1H), 1.90 (m, 2H), 1.74 (m, 1H).

The analytical data agree. those of the enantiomeric compound (Example 17) correspond.

Example 86 4- (2 - {[(3R) -1-Azabicyclo [2.2.2] oct-3-yl-amino] carbonyl} -1-benzofuran-7-yl) -benzoic acid hydrochloride

150 mg (0.43 mmol) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -7-bromo-1-benzofuran-2-carboxamide hydrochloride (Example 30A) and 71.3 mg (0.43 mmol) 4-carboxyphenylboronic acid are placed in 1.5 mL DMF. After adding 0.64 mL 2 M sodium carbonate solution and 17.5 mg (0.02 mmol) PdCl ₂ (dppf) the mixture is heated to 80 ° C for 18 h. After cooling, the reaction mixture is filtered through kieselguhr, the filtrate is concentrated and partitioned between water and ethyl acetate. The aqueous phase is washed with ethyl acetate and then concentrated. The crude product is purified using preparative HPLC. The product fractions are combined, concentrated, mixed with a 3: 1 mixture of acetonitrile and 1N hydrochloric acid and concentrated again. The crude product is stirred with acetonitrile. After filtering off the precipitate and drying in a high vacuum, 37 mg (20% of theory) of the title compound are obtained.
¹ H NMR (300 MHz, DMSO-d ₆ ): δ = 10.37 (br. S, 1H), 9.15 (d, 1H); 8.08 (m, 4H), 7.93 (s, 1H), 7.85 (dd, 1H), 7.76 (dd, 1H), 7.47 (dd, 1H), 4.36 (m, 1H), 3.77-3.32 (m, 3H) , 3.32 (m, 3H), 2.23 (m, 1H), 2.12- (m, 1H), 1.92 (m, 2H), 1.76 (m, 1H).
HPLC (method 1): R _t = 3.9 min.
MS (ESIpos): m / z = 391 (M + H) ⁺ (free base).

Example 87 N - [(3R) -1-Azabicyclo [2.2.2] oct-3-yl] -7- [3- (trifluoromethoxy) phenyl] -1-benzofuran-2-carboxamide hydrochloride

200 mg (0.52 mmol) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -7-bromo-1-benzofuran-2-carboxamide hydrochloride (Example 30A) and 106.8 mg (0.52 mmol) 3- (trifluoromethoxy) -phenylboronic acid are placed in 2.0 mL DMF. After adding 0.78 mL 2 M sodium carbonate solution and 21.2 mg (0.03 mmol) PdCl ₂ (dppf) the mixture is heated to 70 ° C for 17 h. After cooling, the reaction mixture is filtered through kieselguhr and purified by means of preparative HPLC. The product fractions are combined, concentrated, mixed with a 5: 1 mixture of methanol and 1 N hydrochloric acid and concentrated again. After drying in a high vacuum, 48.8 mg (20% of theory) of the title compound are obtained.
¹ H-NMR (200 MHz, DMSO-d ₆ ): δ = 10.18 (br. S, 1H), 9.00 (d, 1H), 7.95 (m, 2H), 7.89 (s, 1H), 7.86 (m, 1H), 7.77 (m, 1H), 7.68 (m, 1H), 7.47 (m, 2H), 4.34 (m, 1H), 3.65 (m, 1H), 3.35 (m, 2H), 3.23 (m, 3H) ), 2.22 (m, 1H), 2.12 (m, 1H), 1.92 (m, 2H), 1.76 (m, 1H).
HPLC (method 1): R _t = 4.5 min.
MS (ESIpos): m / z = 431 (M + H) ⁺ (free base).

Example 88 N - [(3S) -1-Azabicyclo [2.2.2] oct-3-yl] -7- (2-methoxyphenyl) -1-benzothiophene-2-carboxamide hydrochloride

To a mixture of 200 mg (0.45 mmol) of N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -7-bromo-1-benzothiophene-2-carboxamide hydrochloride (Example 22A) and 68.1 mg (0.45 mmol) 2-methoxyphenylboronic acid in 2 mL DMF are added 0.67 mL 2 M sodium carbonate solution and 18.3 mg (0.02 mmol) PdCl ₂ (dppf). The reaction mixture is heated to 70 ° C. for 17 h, filtered after cooling through diatomaceous earth and purified by means of preparative HPLC. The product fractions are concentrated, taken up in a 5: 1 mixture of methanol and 1N hydrochloric acid and concentrated again. After drying in a high vacuum, 112 mg (58% of theory) of the title compound are obtained.
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 10.38 (br. S, 1H), 9.07 (d, 1H), 8.38 (s, 1H), 7.95 (m, 1H), 7.50 (dd, 1H), 7.47 (m, 1H), 7.37 (m, 2H), 7.20 (d, 1H), 7.09 (dd, 1H), 4.31 (m, 1H), 3.73 (s, 3H), 3.62 (m, 1H ), 3.35 (m, 2H), 3.19 (m, 3H), 2.19 (m, 1H), 2.13 (m, 1H), 1.90 (m, 2H), 1.73 (m, 1H).

The other analytical data are correct with those of the enantiomeric compound (Example 18).

Example 89 N - [(3R) -1-Azabicyclo [2.2.2] oct-3-yl] -7- [3- (hydroxymethyl) phenyl] -1-benzofuran-2-carboxamide hydrochloride

150 mg (0.43 mmol) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -7-bromo-1-benzofuran-2-carboxamide hydrochloride (Example 30A) and 65.3 mg (0.43 mmol) of 3- (hydroxymethyl) phenylboronic acid are placed in 1.5 mL DMF. After addition of 0.64 mL 2 M sodium carbonate solution and 17.5 mg (0.02 mmol) PdCl ₂ (dppf) the mixture is heated to 60 ° C for 18 h. A further 17.5 mg (0.02 mmol) of PdCl ₂ (dppf) are added and the mixture is stirred at 90 ° C. for a further 18 h. After cooling, the reaction mixture is filtered through kieselguhr. Following a first purification using preparative HPLC, column chromatography on silica gel (mobile phase: dichloromethane-methanol-ammonia 90: 9: 1) is carried out. The product fractions are combined, concentrated, mixed with a 5: 1 mixture of methanol and 4 N hydrogen chloride in dioxane and concentrated again. After drying in a high vacuum, 45 mg (24% of theory) of the title compound are obtained.
¹ H-NMR (400 MHz, methanol-d ₄ ): δ = 7.98 (m, 1H), 7.74 (m, 2H), 7.65 (m, 2H), 7.52 (dd, 1H), 7.42 (m, 2H) , 4.72 (s, 2H), 4.51 (m, 1H), 3.87-3.26 (m, 6H), 2.39 (m, 1H), 2.23 (m, 1H), 2.10 (m, 2H), 1.95 (m, 1H ).
HPLC (method 1): R _t = 3.9 min.
MS (ESIpos): m / z = 377 (M + H) ⁺ (free base).

Example 90 N - [(3R) -1-Azabicyclo [2.2.2] oct-3-yl] -7- [4- (3-oxo-4-morpholinyl) phenyl] -1-benzofuran-2-carboxamide hydrochloride

According to the general procedure D 205.4 mg (0.70 mmol) of 4- (4-bromophenyl) -3-morpholinone (Example 16A), 204.4 mg (0.81 mmol) of bis (pinacolato) -dibor, 171.2 mg (1.74 mmol) of potassium acetate, 19.6 mg (0.03 mmol) PdCl ₂ (dppf), 207 mg (0.54 mmol) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -7-bromo-1-benzofuran-2-carboxamide Hydrochloride (Example 30A), 1.34 ml of 2 M sodium carbonate solution and a further 19.6 mg (0.03 mmol) of PdCl ₂ (dppf) in 2 ml of DMF. After drying in a high vacuum, 233 mg (85% of theory) of the title compound are obtained.
¹ H-NMR (200 MHz, DMSO-d ₆ ): δ = 10.32 (br. S, 1H), 9.07 (d, 1H), 7.95 (m, 3H), 7.80 (dd, 1H), 7.70 (dd, 1H), 7.59 (m, 2H), 7.44 (dd, 1H), 4.33 (m, 1H), 4.26 (s, 2H), 4.02 (m, 2H), 3.83 (m, 2H), 3.64 (m, 1H) ), 3.37 (m, 2H), 3.21 (m, 3H), 2.23 (m, 1H), 2.11 (m, 1H), 1.91 (m, 2H), 1.74 (m, 1H).
HPLC (method 1): R _t = 4.5 min.
MS (ESIpos): m / z = 446 (M + H) ⁺ (free base).

Example 91 N - [(3R) -1-Azabicyclo [2.2.2] oct-3-yl] -7- [2- (4-morpholinyl) phenyl] -1-benzofuran-2-carboxamide hydrochloride

According to general working procedure D, 225 mg (0.93 mmol) of 2- (4-morpholinyl) phenyl trifluoromethanesulfonate (Example 32A), 272 mg (1.07 mmol) of bis (pinacolato) dibor, 228 mg (2:33 mmol) of potassium acetate, 26 mg (0.04 mmol) PdCl ₂ (dppf), 250 mg (0.72 mmol) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -7-bromo-1-benzofuran-2- carboxamide (Example 30A), 1.8 mL 2 M sodium carbonate solution and another 26 mg (0.04 mmol) PdCl ₂ (dppf) in 2 mL DMF. After drying in a high vacuum, 82 mg (24% of theory) of the title compound are obtained.
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 9.76 (s, 1H), 8.82 (d, 1H), 7.79 (s, 1H), 7.77 (d, 1H), 7.55 (d, 1H) , 7.46-7.37 (m, 3H), 7.23-7.14 (m, 2H), 4.33 (m, 1H), 3.83-3.04 (m, 6H), 3.55 (s, 4H), 2.68 (s, 4H), 2.16 (m, 1H), 2.04 (m, 1H), 1.95-1.84 (m, 2H), 1.79-1.67 (m, 1H).
HPLC (method 1): R _t = 4.1 min.
MS (ESIpos): m / z = 432 (M + H) ⁺ (free base).

Example 92 N - [(3R) -1-Azabicyclo [2.2.2] oct-3-yl] -7- [4- (4-morpholinyl) phenyl] -1-benzofuran-2-carboxamide hydrochloride

To a mixture of 500 mg (0.143 mmol) of N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -7-bromo-1-benzofuran-2-carboxamide hydrochloride (Example 30A) and 105 mg (0.14 mmol) PdCl ₂ (dppf) in 5 mL DMF are added 444 mg (2.15 mmol) 4- (4-morpholinyl) -phenylboronic acid and 4.3 mL 1 N sodium hydroxide solution. The reaction mixture is heated to 100 ° C. overnight. The solvent is removed under reduced pressure and the crude product is taken up in methanol and filtered through diatomaceous earth. The cleaning is done by preparative HPLC. The product fractions are concentrated, dissolved in methanol and an excess of 1 N hydrochloric acid is added. The solvent is removed under reduced pressure. After drying in a high vacuum, 393 mg (59% of theory) of the title compound are obtained.
¹ H-NMR (200 MHz, DMSO-d ₆ ): δ = 10.45 (s, 1H), 9.10 (d, 1H), 7.91 (s, 1H), 7.87 (d, 1H), 7.75-7.55 (m, 2H), 7.40 (t, 1H), 7.18 (d, 2H), 4.40 (m, 1H), 3.80 (m, 4H), 3.75-3.00 (m, 6H), 3.20 (m, 4H), 2.30-2.02 (m, 2H), 2.00-1.62 (m, 3H).
HPLC (method 1): R _t = 3.79 min.
MS (ESIpos): m / z = 432 (M + H) ⁺ (free base).

Example 93 N - [(3R) -1-Azabicyclo [22.2] oct-3-yl] -5- [4- (4-morpholinyl) phenyl] -1-benzofuran-2-carboxamide hydrochloride

To a mixture of 250 mg (0.72 mmol) of N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -5-bromo-1-benzofuran-2-carboxamide (Example 3A) and 52 mg (0.07 mmol) PdCl ₂ (dppf) in 3 mL DMF 177 mg (0.86 mmol) 4- (4-morpholinyl) phenylboronic acid and 2.15 mL 1 N sodium hydroxide solution are added. The reaction mixture is heated to 90 ° C. overnight. The solvent is removed under reduced pressure and the crude product is taken up in methanol and filtered through diatomaceous earth. The cleaning is done by preparative HPLC. The product fractions are concentrated, dissolved in acetonitrile / water and an excess of 1 N hydrochloric acid is added. The Solvent is removed under reduced pressure. After drying in a high vacuum, 23 mg (7% of theory) of the title compound are obtained.
¹ H-NMR (200 MHz, DMSO-d ₆ ): δ = 10.40 (s, 1H), 9.15 (d, 1H), 7.98 (s, 1H), 7.76-7.68 (m, 2H), 7.67-7.58 ( m, 2H), 7.20-7.10 (d, 2H), 4.45 (m, 1H), 3.80 (m, 4H), 3.75-3.30 (m, 6H), 3.20 (m, 4H), 2.30-2.02 (m, 2H), 2.00-1.62 (m, 3H).
HPLC (method 1): R _t = 3.52 min.
MS (ESIpos): m / z = 432 (M + H) ⁺ (free base).

Example 94 N - [(3R) -1-Azabicyclo [2.2.2] oct-3-yl] -5- [4- (hydroxymethyl) phenyl] -1-benzofuran-2-carboxamide

To a mixture of 170 mg (0.49 mmol) of N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -5-bromo-1-benzofuran-2-carboxamide (Example 3A) and 35 mg (0.05 mmol) PdCl ₂ (dppf) in 2 mL DMF, 110 mg (0.73 mmol) 4- (hydroxymethyl) phenylboronic acid and 1.46 mL 1 N sodium hydroxide solution are added. The reaction mixture is heated to 85 ° C. overnight. The solvent is removed under reduced pressure. After adding a mixture of 1N sodium hydroxide solution and ethyl acetate to the residue, the aqueous phase is extracted again with ethyl acetate. The combined organic phases are each washed twice with 1 N sodium hydroxide solution and saturated sodium chloride solution, dried over magnesium sulfate and concentrated on a rotary evaporator under reduced pressure. The crude product is taken up in methanol and together with acidic ion exchanger (Dowex ^® WX2-200) for about 20 min. long shaken. The loaded ion exchanger is washed three times with 30 mL methanol, then with DMF, again with methanol, with dichloromethane, again with methanol, with water and finally again with methanol. The product is eluted with methanol-triethylamine 95: 5. The solvent is removed on the rotary evaporator under reduced pressure. 148 mg (80% of theory) of the title compound are isolated.
¹ H-NMR (200 MHz, CDCl ₃ ): δ = 7.85 (s, 1H), 7.70-7.35 (m, 7H), 6.77 (d, 1H), 4.62 (s, 2H), 4.28-4.12 (m, 1H), 3.56-3.38 (m, 1H), 3.04-2.78 (m, 4H), 2.75-2.59 (m, 1H), 2.16-2.02 (m, 1H), 1.93-1.66 (m, 3H), 1.66- 1.50 (m, 1H).
HPLC (method 1): R _t = 3.65 min.
MS (ESIpos): m / z = 377 (M + H) ⁺ .

Example 95 N - [(3R) -1-Azabicyclo [2.2.2] oct-3-yl] -5- [2- (hydroxymethyl) phenyl] -1-benzofuran-2-carboxamide

To a mixture of 170 mg (0.49 mmol) of N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -5-bromo-1-benzofuran-2-carboxamide (Example 3A) and 35 mg (0.05 mmol) PdCl ₂ (dppf) in 2 mL DMF, 110 mg (0.73 mmol) 2- (hydroxymethyl) phenylboronic acid and 1.46 mL 1 N sodium hydroxide solution are added. The reaction mixture is heated to 85 ° C. overnight. The solvent is removed under reduced pressure. After adding a mixture of 1N sodium hydroxide solution and ethyl acetate to the residue, the aqueous phase is extracted again with ethyl acetate. The combined organic phases are each washed twice with 1 N sodium hydroxide solution and saturated sodium chloride solution, dried over magnesium sulfate and concentrated on a rotary evaporator under reduced pressure. The crude product is taken up in methanol and together with acidic ion exchanger (Dowex ^® WX2-200) for about 20 min. long shaken. The loaded ion exchanger is washed three times with 30 mL methanol; then washed with DMF, again with methanol, with dichloromethane, again with methanol, with water and finally again with methanol. The product is eluted with methanol-triethylamine 95: 5. The solvent is removed on the rotary evaporator under reduced pressure. 140 mg (76% of theory) of the title compound are isolated.
¹ H-NMR (300 MHz, CDCl ₃ ): δ = 7.70-7.25 (m, 8H), 6.75 (d, 1H), 4.62 (s, 2H), 4.28-4.12 (m, 1H), 3.56-3.38 ( m, 1H), 3.04-2.78 (m, 4H), 2.75-2.59 (m, 1H), 2.16-2.02 (m, 1H), 1.93-1.66 (m, 3H), 1.66-1.50 (m, 1H).
HPLC (method 1): R _t = 3.76 min.
MS (ESIpos): m / z = 377 (M + H) ⁺ .

Example 96 N - [(3R) -1-Azabicyclo [2.2.2] oct-3-yl] -5- [4- (dimethylamino) phenyl] -1-benzofuran-2-carboxamide

To a mixture of 170 mg (0.49 mmol) of N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -5-bromo-1-benzofuran-2-carboxamide (Example 3A) and 35 mg (0.05 mmol) PdCl ₂ (dppf) in 2 mL DMF are added 120 mg (0.73 mmol) 4- (dimethylamino) phenylboronic acid and 1.46 mL 1 N sodium hydroxide solution. The reaction mixture is heated to 85 ° C. overnight. The solvent is removed under reduced pressure. After adding a mixture of 1N sodium hydroxide solution and ethyl acetate to the residue, the aqueous phase is extracted again with ethyl acetate. The combined organic phases are each washed twice with 1 N sodium hydroxide solution and saturated sodium chloride solution, dried over magnesium sulfate and concentrated on a rotary evaporator under reduced pressure. The crude product is taken up in methanol and together with acidic ion exchanger (Dowex ^® WX2-200) for about 20 min. long shaken. The loaded ion exchanger is washed three times with 30 mL methanol, then with DMF, again with methanol, with dichloromethane, again with methanol, with water and finally again with methanol. The product is eluted with methanol-triethylamine 95: 5. The solvent is removed on the rotary evaporator under reduced pressure. 138 mg (73% of theory) of the title compound are isolated.
¹ H NMR (200 MHz, CDCl ₃ ): δ = 7.78 (d, 1H) 7.70-7.39 (m, 4H), 6.88-6.75 (m, 3H), 4.28-4.12 (m, 1H), 3.56-3.38 (m, 1H), 3.04-2.78 (m, 4H), 3.00 (s, 6H), 2.75-2.59 (m, 1H), 2.16-2.02 (m, 1H), 1.93-1.66 (m, 3H), 1.66 -1.50 (m, 1H).
HPLC (method 1): R _t = 3.36 min.
MS (ESIpos): m / z = 390 (M + H) ⁺ .

Example 97 N - [(3R) -1-Azabicyclo [2.2.2] oct-3-yl] -5- [4- (methoxy) phenyl] -1-benzofuran-2-carboxamide hydrochloride

To a mixture of 250 mg (0.72 mmol) of N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -5-bromo-1-benzofuran-2-carboxamide (Example 3A) and 52 mg (0.07 mmol) PdCl ₂ (dppf) in 3 mL DMF, 130 mg (0.86 mmol) 4- (methoxy) phenylboronic acid and 2.15 mL 1 N sodium hydroxide solution are added. The reaction mixture is heated to 90 ° C. overnight. The solvent is removed under reduced pressure and the crude product is taken up in methanol and filtered through diatomaceous earth. The cleaning is done by preparative HPLC. The product fractions are mixed with an excess of 1 N hydrochloric acid. The solvent is removed under reduced pressure. After drying in a high vacuum, 127 mg (39% of theory) of the title compound are obtained.
¹ H-NMR (200 MHz, DMSO-d ₆ ): δ = 9.90 (s, 1H), 9.10 (d, 1H), 7.95 (m, 2H), 7.75-7.60 (m, 4H), 7.10-7.02 ( m, 2H), 4.40 (m, 1H), 3.85 (m, 3H), 3.75-3.00 (m, 6H), 3.20 (m, 4H), 2.30-2.02 (m, 2H), 2.00-1.62 (m, 3H).
HPLC (method 1): R _t = 4.15 min.
MS (ESIpos): m / z = 377 (M + H) ⁺ (free base).

Example 98 N - [(3R) -1-Azabicyclo [2.2.2] oct-3-yl] -5- [3- (methoxy) phenyl] -1-benzofuran-2-carboxamide hydrochloride

To a mixture of 250 mg (0.72 mmol) of N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -5-bromo-1-benzofuran-2-carboxamide (Example 3A) and 52 mg (0.07 mmol) PdCl ₂ (dppf) in 3 mL DMF, 130 mg (0.86 mmol) 3- (methoxy) phenylboronic acid and 2.15 mL 1N sodium hydroxide solution are added. The reaction mixture is heated to 90 ° C. overnight. The solvent is removed under reduced pressure and the crude product is taken up in methanol and filtered through diatomaceous earth. The cleaning is done by preparative HPLC. The product fractions are mixed with an excess of 1 N hydrochloric acid. The solvent is removed under reduced pressure. After drying under high vacuum, 208 mg (63% of theory) of the title compound are obtained.
¹ H-NMR (300 MHz, DMSO-d ₆ ): δ = 10.0 (s, 1H), 9.10 (d, 1H), 8.05 (s, 1H), 7.80-7.65 (m, 3H), 7.42-7.18 ( m, 3H), 6.93 (m, 1H), 4.35 (m, 1H), 3.85 (s, 3H), 3.75-3.00 (m, 6H), 3.20 (m, 4H), 2.30-2.02 (m, 2H), 2.00 -1.62 (m, 3H).
HPLC (method 1): R _t = 4.19 min.
MS (ESIpos): m / z = 377 (M + H) ⁺ (free base).

Example 99 N - [(3R) -1-Azabicyclo [2.2.2] oct-3-yl] -7- [4- (methoxy) phenyl] -1-benzofuran-2-carboxamide hydrochloride

To a mixture of 300 mg (0.86 mmol) of N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -7-bromo-1-benzofuran-2-carboxamide (Example 30A) and 63 mg (0.09 mmol) PdCl ₂ (dppf) in 4 mL DMF, 130 mg (0.86 mmol) 4- (methoxy) phenylboronic acid and 2.58 mL 1 N sodium hydroxide solution are added. The reaction mixture is heated to 95 ° C overnight. The solvent is removed under reduced pressure and the crude product is taken up in methanol and filtered through diatomaceous earth. The cleaning is done by preparative HPLC. The product fractions are mixed with an excess of 1 N hydrochloric acid. The solvent is removed under reduced pressure. After drying under high vacuum, 165 mg (47% of theory) of the title compound are obtained.
¹ H-NMR (300 MHz, DMSO-d ₆ ): δ = 10.4 (s, 1H), 9.00 (d, 1H), 8.05 (s, 1H), 7.90-7.82 (m, 3H), 7.75 (d, 1H), 7.62 (d, 1H), 7.40 (t, 1H), 7.15-7.05 (m, 2H), 4.35 (m, 1H), 3.85 (s, 3H), 3.65 (m, 1H), 3.48-3.30 (m, 2H), 3.25-3.10 (m, 3H), 2.25 (m, 1H), 2.18-2.05 (m, 1H), 1.98-1.88 (m, 2H), 1.80-1.63 (m, 1H).
HPLC (method 1): R _t = 4.18 min.
MS (ESIpos): m / z = 377 (M + H) ⁺ (free base).

Example 100 N - [(3S) -1-Azabicyclo [2.2.2] oct-3-yl] -7- (2-methoxyphenyl) -1-benzofuran-2-carboxamide hydrochloride

To a mixture of 890 mg (4.47 mmol) S-3-aminoquinuclidine dihydrochloride and 1000 mg (3.73 mmol) 7- (2-methoxyphenyl) -1-benzofuran-2-carboxylic acid (Example 21A) in 10 mL DMF are at 0 ° C 3.4 g (8.95 mmol) of HATU and 2.34 mL (13.42 mmol) of N, N-diisopropylethylamine given. After stirring for 18 h at room temperature the reaction solution is preparative HPLC cleaned. The product fractions are concentrated, with 5 mL 1N hydrochloric acid added and concentrated again. After drying in a high vacuum, 209 is obtained mg (13.6% of theory) of the title compound.

The analytical data agree those of the enantiomeric compound (Example 102) correspond.

Example 101 N - [(3R) -1-Azabicyclo [2.2.2] oct-3-yl] -7- [3- (methoxy) phenyl] -1-benzofuran-2-carboxamide hydrochloride

To a mixture of 150 mg (0.43 mmol) of N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -7-bromo-1-benzofuran-2-carboxamide (Example 30A) and 31 mg (0.04 mmol) PdCl ₂ (dppf) in 2 mL DMF are added 98 mg (0.64 mmol) 3- (methoxy) phenylboronic acid and 1.29 mL 1 N sodium hydroxide solution. The reaction mixture is heated to 90 ° C. overnight. The solvent is removed under reduced pressure and the crude product is taken up in methanol and filtered through diatomaceous earth. The cleaning is done by preparative HPLC. The product is dissolved in methanol and an excess of 1N hydrochloric acid is added. The solvent is removed under reduced pressure and the residue is recrystallized from a little isopropanol. After drying in a high vacuum, 159 mg (85% of theory) of the title compound are obtained.
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 10:05 (s, 1H), 8.95 (d, 1H), 7.85 (s, 1H), 7.80, (d, 1H), 7.70 (d , 1H), 7.50-7.40 (m, 4H), 7.00 (m, 1H), 4.35 (m, 1H), 3.85 (s, 3H), 3.65 (m, 1H), 3.48-3.30 (m, 2H), 3.25-3.15 (m, 3H), 2.25 (m, 1H), 2.18-2.05 (m, 1H), 1.98-1.88 (m, 2H), 1.80-1.63 (m, 1H).
HPLC (method 1): R _t = 4.21 min.
MS (ESIpos): m / z = 377 (M + H) ⁺ (free base).

Example 102 N - [(3R) -1-Azabicyclo [2.2.2] oct-3-yl] -7- [2- (methoxy) phenyl] -1-benzofuran-2-carboxamide hydrochloride

Method a):

To a mixture of 150 mg (0.43 mmol) of N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -7-bromo-1-benzofuran-2-carboxamide (Example 30A) and 31 mg (0.04 mmol) PdCl ₂ (dppf) in 2 mL DMF, 98 mg (0.64 mmol) 2- (methoxy) phenylboronic acid and 1.29 mL 1 N sodium hydroxide solution are added. The reaction mixture is heated to 85 ° C. overnight. The solvent is removed under reduced pressure and the crude product is taken up in methanol and filtered through diatomaceous earth. Further purification is done by preparative HPLC. The product is dissolved in methanol and an excess of 1N hydrochloric acid is added. The solvent is removed under reduced pressure and the residue is recrystallized from a little isopropanol. After drying in a high vacuum, 100 mg (62% of theory) of the title compound are obtained.
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 10.08 (s, 1H), 8.91 (d, 1H), 7.87 (s, 1H), 7.84-7.74 (m, 2H), 7.53-7.33 ( m, 3H), 7.25-7.00 (m, 2H), 4.35 (m, 1H), 3.75 (s, 3H), 3.65 (m, 1H), 3.48-3.30 (m, 2H), 3.25-3.15 (m, 3H), 2.25 (m, 1H), 2.18-2.05 (m, 1H), 1.98-1.88 (m, 2H), 1.80-1.63 (m, 1H).
HPLC (method 1): R _t = 4.16 min.
MS (ESIpos): m / z = 377 (M + H) ⁺ (free base).

Method b):

To a solution of 2.92 g (10.9 mmol) of 7- (2-methoxyphenyl) -1-benzofuran-2-carboxylic acid (example 21A) and 2.17 g (1.0.9 mmol) of (R) -3-aminoquinuclidine dihydrochloride in 35 mL DMF, 2.51 g (13.1 mmol) EDC, 1.77 g (13.1 mmol) HOBt and 5.47 mL (39.2 mmol ) Added triethylamine. After stirring for 18 hours at room temperature, a further 434 mg (2.2 mmol) of (R) -3-aminoquinuclidine dihydrochloride and 418 mg (2.2 mmol) of EDC are added. After 2 h at 55 ° C., the reaction solution is concentrated and the residue is partitioned between 200 ml of ethyl acetate and 2 N sodium hydroxide solution. The organic phase is washed 15 times with 100 mL 2N sodium hydroxide solution each. The combined aqueous phases are back-extracted with 250 mL ethyl acetate. The combined organic phases are dried over sodium sulfate, concentrated, the residue is mixed with a 5: 1 mixture of methanol and 1 N hydrochloric acid, concentrated again and dried under high vacuum. After recrystallization of the residue from 10 mL of a 10: 1 mixture of isopropanol and ethanol, 2.73 g (60.5% of theory) of the title compound are obtained.

Example 103 N - [(3R) -1-Azabicyclo [2.2.2] oct-3-yl] -7- [4- (methoxy) -3-pyridinyl] -1-benzofuran-2-carboxamide hydrochloride

To a mixture of 100 mg (0.29 mmol) of N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -7-bromo-1-benzofuran-2-carboxamide (Example 30A) and 21 mg (0.03 mmol) PdCl ₂ (dppf) in 2 mL DMF are added 98 mg (0.64 mmol) 4-methoxy-3-pyridinylboronic acid and 0.86 mL 1 N sodium hydroxide solution. The reaction mixture is heated to 85 ° C. overnight. The solvent is removed under reduced pressure and the crude product is taken up in methanol and filtered through diatomaceous earth. The cleaning is done by preparative HPLC. The product fractions are mixed with an excess of 1 N hydrochloric acid. The solvent is removed under reduced pressure. After drying in a high vacuum, 58 mg (49% of theory) of the title compound are obtained.
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 10.55 (s, 1H), 9.20 (d, 1H), 9.05 (s, 1H), 8.95 (d, 1H), 7.96-7.89 (m, 2H), 7.82 (d, 1H), 7.65 (d, 1H), 7.50 (t, 1H), 4.35 (m, 1H), 4.10 (s, 3H), 3.65-3.15 (m, 6H), 2.20 (m , 1H), 2.18-2.05 (m, 1H), 1.98-1.88 (m, 2H), 1.80-1.63 (m, 1H).
HPLC (method 1): R _t = 3.35 min.
MS (ESIpos): m / z = 37.8 (M + H) ⁺ (free base).

Example 104 N - [(3R) -1-Azabicyclo [2.2.2] oct-3-yl] -7- [4- (4-morpholinylcarbonyl) phenyl] -1-benzofuran-2-carboxamide hydrochloride

According to the general procedure D 631 mg (1.43 mmol) of 4- (4-morpholinylcarbonyl) phenyl trifluoromethanesulfonate (Example 18A), 545 mg (2.15 mmol) of bis (pinacolato) dibor, 456 mg (4.65 mmol) potassium acetate, 52 mg (0.07 mmol) PdCl ₂ (dppf), 500 mg (1.43 mmol) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -7-bromo-1- benzofuran-2-carboxamide (Example 30A), 3.6 mL 2 M sodium carbonate solution and a further 52 mg (0.07 mmol) PdCl ₂ (dppf) in 8 mL DMF. After drying under high vacuum, 455 mg (61% of theory) of the title compound are obtained.
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 10.45 (s, 1H), 9.10 (d, 1H), 8.02-7.92 (m, 3H), 7.78 (d, 1H), 7.71 (d, 1H), 7.60 (d, 2H), 7.45 (t, 1H), 4.35 (m, 1H), 3.75-3.35 (m, 11H), 3.25-3.15 (m, 3H), 2.25 (m, 1H), 2.18 -2.05 (m, 1H), 1.98-1.88 (m, 2H), 1.80-1.63 (m, 1H).
HPLC (method 1): R _t = 3.79 min.
MS (ESIpos): m / z = 460 (M + H) ⁺ (free base).

Example 105 N - [(3R) -1-Azabicyclo [2.2.2] oct-3-yl] -7- [3- (1-piperidinyl) phenyl] -1-benzofuran-2-carboxamide dihydrochloride

To a mixture of 300 mg (0.86 mmol) of N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -7-bromo-1-benzofuran-2-carboxamide (Example 30A) and 63 mg (0.09 mmol) PdCl ₂ (dppf) in 4 mL DMF add 3.11 mg (1.29 mmol) 3- (1-piperidinyl) phenylboronic acid and 3.44 mL 1 N sodium hydroxide solution. The reaction mixture is heated to 95 ° C overnight. The solvent is removed under reduced pressure and the crude product is taken up in methanol and filtered through diatomaceous earth. The cleaning is done by preparative HPLC. The product is dissolved in methanol and an excess of 1N hydrochloric acid is added. The solvent is removed under reduced pressure. After drying in a high vacuum, 164 mg (41% of theory) of the title compound are obtained.
¹ H-NMR (200 MHz, DMSO-d ₆ ): δ = 10.55 (s, 1H), 9.10 (d, 1H), 8.75 (s, 1H), 7.95-7.63 (m, 7H), 7.45 (t, 1H), 4.35 (m, 1H), 4.13-3.40 (m, 7H), 3.35-3.10 (m, 3H), 2.15-1.50 (m, 11H).
HPLC (method 1): R _t = 3.72 min.
MS (ESIpos): m / z = 430 (M + H) ⁺ (free base).

Example 106 N - [(3R) -1-Azabicyclo [2.2.2] oct-3-yl] -7- (3-pyridinyl) -1-benzofuran-2-carboxamide dihydrochloride

To a mixture of 100 mg (0.86 mmol) of N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -7-bromo-1-benzofuran-2-carboxamide (Example 30A) and 63 mg (0.09 mmol) PdCl ₂ (dppf) in 4 mL DMF are added 70 mg (0.57 mmol) 3-pyridineboronic acid and 0.86 mL 1 N sodium hydroxide solution. The reaction mixture is heated to 95 ° C overnight. The solvent is removed under reduced pressure and the crude product is taken up in methanol and filtered through diatomaceous earth. The cleaning is done by preparative HPLC. The product is dissolved in methanol and an excess of 1N hydrochloric acid is added. The solvent is removed under reduced pressure. After drying in a high vacuum, 49 mg (45% of theory) of the title compound are obtained.
¹ H-NMR (300 MHz, DMSO-d ₆ ): δ = 10.55 (s, 1H), 9.51 (s, 1H), 9.30 (d, 1H), 9.20 (s, 1H), 8.94-8.80 (m, 2H), 8.07-7: 80 (m, 4H), 7.55 (t, 1H), 4.35 (m, 1H), 3.65-3.15 (m, 6H), 2.20 (m, 1H), 2.18-2.05 (m, 1H), 1.98-1.88 (m, 2H), 1.80-1.63 (m, 1H).
HPLC (method 1): R _t = 3.27 min.
MS (ESIpos): m / z = 348 (M + H) ⁺ (free base).

Example 107 N - [(3R) -1-Azabicyclo [2.2.2] oct-3-yl] -7- (3 - {[(methylamino) carbonyl] amino} phenyl) -1-benzofuran-2-carboxamide hydrochloride

63 mg (0.18 mmol) 7- (3-aminophenyl) -N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -1-benzofuran-2-carboxamide (Example 114), 40 mg (0.70 mmol) methyl isocyanate and 0.12 mL (0.88 mmol) triethylamine are heated in 3 mL THF / DMF (1: 1) at 40 ° C overnight. A further 40 mg (0.70 mmol) of methyl isocyanate and a catalytic amount of DMAP are added and the mixture is heated to 50 ° C. overnight. After cooling, water is added, the mixture is filtered and the solvent is removed under reduced pressure. The cleaning is done by preparative HPLC. The product is dissolved in methanol and an excess of 1N hydrochloric acid is added. The solvent is removed under reduced pressure. After drying in a high vacuum, 18 mg (23% of theory) of the title compound are obtained.
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 9.98 (s, 1H), 8.85 (s, 1H), 8.63 (d, 1H), 8.15 (s, 1H), 7.80 (m, 2H) , 7.65 (d, 1H), 7.45 (t, 1H), 7.38 (s, 2H), 6.20 (m, 1H), 4.35 (m, 1H), 3.75-3.63 (m, 1H), 3.60-3.15 (m , 5H), 2.65 (s, 3H), 2.30 (m, 1H), 2.18-2.05 (m, 1H), 1.98-1.88 (m, 2H), 1.80-1.63 (m, 1H).
HPLC (method 1): R _t = 3.89 min.
MS (ESIpos): m / z = 419 (M + H) ⁺ (free base).

Example 108 N - [(3R) -1-Azabicyclo [2.2.2] oct-3-yl] -7- (3 - {[(ethylamino) carbonyl] amino} phenyl) -1-benzofuran-2-carboxamide hydrochloride

63 mg (0.18 mmol) 7- (3-aminophenyl) -N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -1-benzofuran-2-carboxamide (Example 114), 50 mg (0.70 mmol) ethyl isocyanate and 0.12 mL (0.88 mmol) triethylamine are heated in 3 mL THF / DMF (1: 1) at 40 ° C overnight. A further 50 mg (0.70 mmol) of ethyl isocyanate and a catalytic amount of DMAP are added and the mixture is heated to 50 ° C. overnight. After cooling, water is added, the mixture is filtered and the solvent is removed under reduced pressure. The cleaning is done by preparative HPLC. The product is dissolved in methanol and an excess of 1N hydrochloric acid is added. The solvent is removed under reduced pressure. After drying in a high vacuum, 15 mg (18% of theory) of the title compound are obtained.
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 9.80 (s, 1H), 8.74 (s, 1H), 8.63 (d, 1H), 8.10 (s, 1H), 7.80 (m, 2H) , 7.60 (d, 1H), 7.45 (t, 1H), 7.38 (s, 2H), 6.20 (m, 1H), 4.35 (m, 1H), 3.75-3.63 (m, 1H), 3.60-3.15 (m , 5H), 3.10 (m, 2H), 2.65 (s, 3H), 2.30 (m, 1H), 2.18-2.05 (m, 1H), 1.98-1.88 (m, 2H), 1.80-1.63 (m, 1H ), 1.05 (t, 3H).
HPLC (method 1): R _t = 4.01 min.
MS (ESIpos): m / z = 433 (M + H) ⁺ (free base).

Example 109 N - [(3R) -1-Azabicyclo [2.2.2] oct-3-yl] -7- [3 - ({[(1-Methylethyl) amino] carbonyl} amino) phenyl] -1-benzofuran -2-carboxamide hydrochloride

50 mg (0.14 mmol) 7- (3-aminophenyl) -N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -1-benzofuran-2-carboxamide (Example 114), 47 mg (0.55 mmol) isopropyl isocyanate and 0.12 mL (0.88 mmol) triethylamine are heated in 3 mL THF / DMF (1: 1) at 40 ° C overnight. A further 47 mg (0.55 mmol) of isopropyl isocyanate and a catalytic amount of DMAP are added and the mixture is heated to 50 ° C. overnight. After cooling, water is added, the mixture is filtered and the solvent is removed under reduced pressure. The cleaning is done by preparative HPLC. The product is dissolved in methanol and an excess of 1N hydrochloric acid is added. The solvent is removed under reduced pressure. After drying in a high vacuum, 13 mg (18% of theory) of the title compound are obtained.
¹ H NMR (400 MHz, DMSO-d ₆ ): δ = 9.80 (s, 1H), 8.70 (d, 1H); 8.65 (s, 1H), 8.05 (s, 1H), 7.80 (m, 2H), 7.60 (d, 1H), 7.45 (t, 1H), 7.38 (s, 2H), 6.20 (m, 1H), 4.35 (m, 1H), 3.80 = 3.72 (m, 1H), 3.70-3.63 (m, 1H), 3.50-3.05 (m, 5H), 2.30 (m, 1H), 2.18-2.05 (m, 1H), 1.98 -1.88 (m, 2H), 1.80-1.63 (m, 1H), 1.10 (d, 6H).
HPLC (method 1): R _t = 4.12 min.
MS (ESIpos): m / z = 447 (M + H) ⁺ (free base).

Example 110 N - [(3R) -1-Azabicyclo [2.2.2] oct-3-yl] -7- [3 - ({[(1,1-dimethylethyl) amino] carbonyl} amino) phenyl] -1 benzofuran-2-carboxamide hydrochloride

63 mg (0.14 mmol) 7- (3-aminophenyl) -N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -1-benzofuran-2-carboxamide (Example 114), 69 mg (0.70 mmol) tert-butyl isocyanate and 0.12 mL (0.88 mmol) triethylamine are heated in 3 mL THF / DMF (1: 1) at 40 ° C overnight. A further 69 mg (0.70 mmol) of tert-butyl isocyanate and a catalytic amount of DMAP are added and the mixture is heated to 50 ° C. overnight. After cooling, water is added, the mixture is filtered and the solvent is removed under reduced pressure. The cleaning is done by preparative HPLC. The product is dissolved in methanol and an excess of 1N hydrochloric acid is added. The solvent is removed under reduced pressure. After drying under high vacuum, 8 mg (9% of theory) of the title compound are obtained.
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 9.70 (s, 1H), 8.80 (d, 1H), 8.55 (s, 1H), 7.85 (s, 1H), 7.80 (m, 2H) , 7.60 (d, 1H), 7.45 (t, 1H), 7.38 (s, 2H), 6.10 (m, 1H), 4.35 (m, 1H), 3.70-3.63 (m, 1H), 3.50-3.05 (m , 5H), 2.30 (m, 1H), 2.18-2.05 (m, 1H), 1.98-1.88 (m, 2H), 1.80-1.63 (m, 1H), 1.30 (s, 9H).
HPLC (method 1): R _t = 4.27 min.
MS (ESIpos): m / z = 461 (M + H) ⁺ (free base).

Example 111 N - [(3R) -1-Azabicyclo [2.2.2] oct-3-yl] -7- {3 - [(methylsulfonyl) amino] phenyl} -1-benzofwan-2-carboxamide hydrochloride

73 mg (0.20 mmol) 7- (3-aminophenyl) -N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -1-benzofuran-2-carboxamide (Example 114), 69 mg (0.61 mmol) methanesulfonic acid chloride and 0.14 mL (1.01 mmol) triethylamine are heated in 3 mL THF / DMF (1: 1) at 50 ° C overnight. After cooling, water is added, the mixture is filtered and the solvent is removed under reduced pressure. The cleaning is done by preparative HPLC. The product is dissolved in methanol and an excess of 1N hydrochloric acid is added. The solvent is removed under reduced pressure. After drying in a high vacuum, 16 mg (14% of theory) of the title compound are obtained.
¹ H-NMR (300 MHz, DMSO-d ₆ ): δ = 10.15 (s, 1H), 9.90 (s, 1H), 8.76 (d, 1H), 7.90 (s, 1H), 7.85-7.75 (m, 2H), 7.66-7.60 (m, 2H), 7.55-7.53 (m, 2H), 7.25 (m, 1H), 4.37 (m, 1H), 3.70-3.63 (m, 1H), 3.45-3.05 (m, 5H), 3.10 (s, 3H), 2.30 (m, 1H), 2.18-2.05 (m, 1H), 1.98-1.88 (m, 2H), 1.80-1.63 (m, 1H).
HPLC (method 1): R _t = 3.97 min.
MS (ESIpos): m / z = 440 (M + H) ⁺ (free base).

Example 112 N - [(3R) -1-Azabicyclo [2.2.2] oct-3-yl] -7- {2 - [(cyclobutylcarbonyl) amino] phenyl} -1-benzofuran-2-carboxamide hydrochloride

60 mg (0.15 mmol) 7- (2-aminophenyl) -N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -1-benzofuran-2-carboxamide (Example 132), 26 mg (0.22 mmol) cyclobutane carboxylic acid chloride and 0.06 mL (0.44 mmol) triethylamine are shaken in 2 mL THF / DMF (1: 1) at RT overnight. The solvent is removed under reduced pressure. The cleaning is done by preparative HPLC. The product is dissolved in methanol and an excess of 1N hydrochloric acid is added. The solvent is removed under reduced pressure. After drying in a high vacuum, 39 mg (56% of theory) of the title compound are obtained.
¹ H-NMR (300 MHz, DMSO-d ₆ ): δ = 10.15 (s, 1H), 9.05 (s, 1H), 8.40 (d, 1H), 7.95 (s, 1H), 7.80-7.70 (m, 2H), 7.55-7.30 (m, 6H), 4.32 (m, 1H), 3.70-3.63 (m, 1H), 3.45-3.05 (m, 5H), 2.98-2.88 (m, 1H), 2.30 (m, 1H), 2.18-2.05 (m, 1H), 1.98-1.55 (m, 9H).
HPLC (method 1): R _t = 3.95 min.
MS (ESIpos): m / z = 444 (M + H) ⁺ (free base).

Example 113 N - [(3R) -1-Azabicyclo [2.2.2] oct-3-yl] -5- (5-pyrimidinyl) -1-benzofuran-2-carboxamide hydrochloride

To a mixture of 250 mg (0.72 mmol) of N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -5-bromo-1-benzofuran-2-carboxamide (Example 3A) and 52 mg (0.07 mmol) PdCl ₂ (dppf) in 3 mL DMF become 177 mg (0.86 mmol) 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyrimidine and 2.15 mL Given 1 N sodium hydroxide solution. The reaction mixture is heated to 90 ° C. overnight. The solvent is removed under reduced pressure and the crude product is taken up in methanol and filtered through diatomaceous earth. The cleaning is done by preparative HPLC. The product is dissolved in methanol and an excess of 1N hydrochloric acid is added. The solvent is removed under reduced pressure. After recrystallization of the residue from isopropanol and drying in a high vacuum, 28 mg (10% of theory) of the title compound are obtained.
¹ H-NMR (300 MHz, DMSO-d ₆ ): δ = 10.30 (s, 1H), 9: 22-9.13 (m, 4H), 8.24 (m, 1H), 7.93-7.81 (m, 3H), 4.39 (m, 1H), 3.68-3.48 (m, 1H), 3.45-3.13 (m, 5H), 2.28-2.20 (m, 1H), 2.18-2.07 (m, 1H), 1.97-1.88 (m; 2H ), 1.80-1.57 (m, 1H).
HPLC (method 1): R _t = 3.26 min.
MS (ESIpos): m / z = 349 (M + H) ⁺ (free base).

Example 114 7- (3-aminophenyl) -N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -1-benzofuran-2-carboxamide

Method a):

To a mixture of 978 mg (2.80 mmol) of N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -7-bromo-1-benzofuran-2-carboxamide (Example 30A) and 205 mg (0.28 mmol) PdCl ₂ (dppf) in 15 mL DMF are added 622 mg (1.68 mmol) 3-aminophenylboronic acid hemisulfate and 11.2 mL 1 N sodium hydroxide solution. The reaction mixture is heated to 95 ° C overnight. The crude product is filtered through kieselguhr, washed with DMF and freed from the solvent under reduced pressure. The residue is mixed with 200 ml of 1 N sodium hydroxide solution and 200 ml of ethyl acetate. After separating the phases, the organic phase is washed twice with 100 ml of 1N sodium hydroxide solution and then again with 100 ml of a saturated sodium chloride solution. After drying over magnesium sulfate, the crude product is purified by preparative HPLC. After removing the solvent on a rotary evaporator, 875 mg (73% of theory) of the title compound can be obtained in the form of a white foam by adding dichloromethane twice and concentrating again.
¹ H-NMR (300 MHz, DMSO-d ₆ ): δ = 8.48 (d, 1H), 8.21 (s, 1H), 7.76-7.69 (m, 1H), 7.54 (d, 1H), 7.45-7.37 ( m, 1H), 7.20-7.00 (m, 3H), 6.67-6.61 (m, 1H), 4.13-4.06 (m, 1H), 3.48-3.26 (m, 1H), 3.10-3.01 (m, 1H), 2.93-2.79 (m, 4H), 2.03 (m, 1H), 2.00-1.88 (m, 1H), 1.79-1.67 (m, 2H), 1.58-1.42 (m, 1H).
HPLC (method 1): R _t = 3.46 min.
MS (ESIpos): m / z = 362 (M + H) ⁺ .

Method b):

To a mixture of 660 mg (1.89 mmol) of N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -7-bromo-1-benzofuran-2-carboxamide (Example 30A) and 138 mg (0.19 mmol) PdCl ₂ (dppf) in 8 mL DMF, 419 mg (1.13 mmol) bis [3- (dihydroxyboranyl) -benzolaminium] sulfate and 7.56 mL 1 N sodium hydroxide solution are added. The reaction mixture is heated to 95 ° C overnight. The solvent is removed under reduced pressure, the crude product is taken up in methanol and filtered through diatomaceous earth. Further purification is done by preparative HPLC. The solvent is removed from the product fractions under reduced pressure. After drying in a high vacuum, 485 mg (71% of theory) of the title compound are obtained.
¹ H-NMR (300 MHz, DMSO-d ₆ ): δ = 8.48 (d, 1H), 8.21 (s, 1H), 7:70 (s, 1H), 7.55 (m, 1H), 7.40 (t, 1H), 7.18 (t, 1H), 7.10-7.00 (m, 2H), 6.66 (m, 1H), 4.20 (br. S, 2H), 4.05 (m, 1H), 3.25 (m, 1H) , 3.05 (m, 1H), 2.90-2.70 (m, 4H), 2.05 (m, 1H), 1.70 (m, 1H), 1.65 (m, 2H), 1.45 (m, 1H).
HPLC (method 1): R _t = 3.50 min.
MS (ESIpos): m / z = 362 (M + H) ⁺ .

Example 115 7- [3- (Acetylamino) phenyl] -N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -1-benzofuran-2-carboxamide hydrochloride

75 mg (0.16 mmol) 7- (3-aminophenyl) -N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -1-benzofuran-2-carboxamide (Example 114), 18 µL (0.24 mmol) acetyl chloride and 68 μL (0.49 mmol) triethylamine are stirred in 2 mL THF at RT overnight. The solvent is removed under reduced pressure. The cleaning is done by preparative HPLC. The product is dissolved in methanol and an excess of 1N hydrochloric acid is added. After removal of the solvent under reduced pressure and drying in a high vacuum, 51 mg (72% of theory) of the title compound are obtained.
¹ H-NMR (300 MHz, DMSO-d ₆ ): δ = 10.37 (s, 1H), 10.30 (br. S, 1H), 8.67-8.59 (m, 2H), 7.82-7.68 (m, 3H), 7.58-7.41 (m, 4H), 4.40 (m, 1H), 3.73-3.60 (m, 1H), 3.48-3.37 (m, 1H), 3.78-3.15 (m, 4H), 2.29 (m, 1H), 2.19-2.09 (m, 1H), 2.13 (s, 3H), 1.98-1.90 (m, 2H), 1.81-1.69 (m, 1H).
HPLC (method 1): R _t = 4.04 min.
MS (ESIpos): m / z = 404 (M + H) ⁺ (free base).

Example 116 N - [(3R) -1-Azabicyclo [2.2.2] oct-3-yl] -7- {3 - [(cyclopropylcarbonyl) amino] phenyl} -1-benzofuran-2-carboxamide hydrochloride

75 mg (0.21 mmol) 7- (3-aminophenyl) -N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -1-benzofuran-2-carboxamide (Example 114), 28 µL (0.31 mmol) cyclopropylcarboxylic acid chloride and 87 μL (0.62 mmol) triethylamine are stirred in 2 mL THF at RT overnight. After adding water, the solvent is reduced under decorated print removed. The cleaning is done by preparative HPLC. The product is dissolved in methanol and an excess of 1N hydrochloric acid is added. After removal of the solvent under reduced pressure and drying in a high vacuum, 55 mg (57% of theory) of the title compound are obtained.
¹ H-NMR (300 MHz, DMSO-d ₆ ): δ = 10.53 (s, 1H), 10.08 (br. S, 1H), 8.83 (m, 1H), 8.28 (s, 1H), 7.82-7.75 ( m, 2H), 7.71 (d, 1H), 7.62 (d, 1H), 7.58-7.50 (m, 1H), 7.48- 7.41 (m, 2H), 4.38 (m, 1H), 3.71-3.60 (m, 1H), 3.50-3.15 (m, 5H), 2.27 (m, 1H), 2.21-2.11 (m, 1H), 1.99-1.82 (m, 3H), 1.80-1.71 (m, 1H), 0.88-0.77 ( m, 4H).
HPLC (method 1): R _t = 4.07 min.
MS (ESIpos): m / z = 430 (M + H) ⁺ (free base).

Example 117 N - [(3R) -1-Azabicyclo [2.2.2] oct-3-yl] -7- (3 - {[(methoxy) acetyl] amino} phenyl) -1-benzofuran-2-carboxamide hydrochloride

75 mg (0.21 mmol) 7- (3-aminophenyl) -N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -1-benzofuran-2-carboxamide (Example 114), 21 µL (0.31 mmol) methoxyacetic acid chloride and 87 μL (0.62 mmol) triethylamine are stirred in 2 mL THF at RT overnight. After adding water, the solvent is removed under reduced pressure. The cleaning is done by preparative HPLC. The product is dissolved in methanol and an excess of 1N hydrochloric acid is added. After removal of the solvent under reduced pressure and drying in a high vacuum, 56 mg (55% of theory) of the title compound are obtained.
¹ H-NMR (300 MHz, DMSO-d ₆ ): δ = 10.17 (br. S, 1H), 10.10 (s, 1H), 8.63-8.55 (m, 2H), 7.82-7.68 (m, 3H), 7.64-7.57 (m, 2H), 7.52-7.41 (m, 2H), 4.39 (m, 1H), 4.10 (s, 2H), 3.71-3.61 (m, 1H), 3.49-3.14 (m, 5H), 3.41 (s, 3H), 2.29 (m, 1H), 2.19-2.05 (m, 1H), 1.99-1.89 (m, 2H), 1.80-1.69 (m, 1H).
HPLC (method 1): R _t = 4.07 min.
MS (ESIpos): m / z = 434 (M + H) ⁺ (free base).

Example 118 N - [(3R) -1-Azabicyclo [2.2.2] oct-3-yl] -7- {3 - [(cyclobutylcarbonyl) amino] phenyl} -1-benzofuran-2-carboxamide hydrochloride

75 mg (0.21 mmol) 7- (3-aminophenyl) -N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -1-benzofuran-2-carboxamide (Example 114), 37 mg (0.31 mmol) cyclobutane carboxylic acid chloride and 87 μL (0.62 mmol) triethylamine are stirred in 2 mL THF at RT overnight. After adding water, the solvent is removed under reduced pressure. The cleaning is done by preparative HPLC. The product is dissolved in methanol and an excess of 1N hydrochloric acid is added. After removal of the solvent under reduced pressure and drying in a high vacuum, 57 mg (57% of theory) of the title compound are obtained.
¹ H-NMR (300 MHz; DMSO-d ₆ ): δ = 10.14 (br. S, 1H), 10.07 (s, 1H), 8.82 (d, 1H), 8.35 (s, 1H), 7.80-7.78 ( m, 2H), 7.74-7.61 (m, 2H), 7.57-7.41 (m, 3H), 4.36 (m, 1H), 3.70-3.61 (m, 1H), 3.45-3.13 (m, 5H), 2.30-1.67 ( m, 12H).
HPLC (method 1): R _t = 4.22 min.
MS (ESIpos): m / z = 444 (M + H) ⁺ (free base).

Example 119 N - [(3R) -1-Azabicyclo [2.2.2] oct-3-yl] -7- {2 - [(cyclopropylcarbonyl) amino] phenyl} -1-benzofuran-2-carboxamide hydrochloride

60 mg (0.15 mmol) 7- (2-aminophenyl) -N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -1-benzofuran-2-carboxamide (Example 132), 20 µL (0.31 mmol) cyclopropylcarboxylic acid chloride and 87 μL (0.62 mmol) triethylamine are stirred in 2 mL THF / DMF (1: 1) at RT overnight. After adding water, the solvent is removed under reduced pressure. The cleaning is done by preparative HPLC. The product is dissolved in methanol and an excess of 1N hydrochloric acid is added. After removal of the solvent under reduced pressure and drying in a high vacuum, 27 mg (40% of theory) of the title compound are obtained.
¹ H-NMR (300 MHz, DMSO-d ₆ ): δ = 10.07 (br. S, 1H), 9.48 (s, 1H), 8.84 (d, 1H), 7.83-7.77 (m, 1H), 7.72 ( m, 1H), 7.54-7.31 (m, 6H), 4.30 (m, 1H), 3.70-3.61 (m, 1H), 3.37-3.03 (m, 5H), 2.23 (m, 1H), 2.14-2.03 ( m, 1H), 1.95-1.83 (m, 2H), 1.79-1.68 (m, 1H), 1.53 (m, 1H), 1.31-1.15 (m, 4H).
HPLC (method 1): R _t = 3.85 min.
MS (ESIpos): m / z = 430 (M + H) ⁺ (free base).

Example 120 N - [(3R) -1-Azabicyclo [2.2.2) oct-3-yl] -7- (2 - {[(methoxy) acetyl) amino} phenyl) -1-benzofuran-2-carboxamide hydrochloride

60 mg (0.15 mmol) 7- (2-aminophenyl) -N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -1-benzofuran-2-carboxamide (Example 132), 20 µL (0.22 mmol) methoxyacetic acid chloride and 61 μL (0.44 mmol) triethylamine are stirred in 2 mL THF / DMF (1: 1) at RT overnight. After adding water, the solvent is removed under reduced pressure. The cleaning is done by preparative HPLC. The product is dissolved in methanol and an excess of 1N hydrochloric acid is added. After removal of the solvent under reduced pressure and drying in a high vacuum, 29 mg (40% of theory) of the title compound are obtained.
¹ H-NMR (300 MHz, DMSO-d ₆ ): δ = 10.15 (br. S, 1H), 9.05 (s, 1H), 8.53 (d, 1H), 7.88-7.73 (m, 3H), 7.52- 7.34 (m, 5H), 4.33 (m, 1H), 3.77 (s, 2H), 3.69-3.59 (m, 1H), 3.44-3.14 (m, 5H), 3.04 (s, 3H), 2.22 (m, 1H), 2.18-2.05 (m, 1H), 1.96-1.84 (m, 2H), 1.80-1.67 (m, 1H).
HPLC (method 1): R _t = 3.84 min.
MS (ESIpos): m / z = 434 (M + H) ⁺ (free base).

Example 121 N - [(3S) -1-Azabicyclo [2.2.2] oct-3-yl] -7- [4- (4-morpholinyl) phenyl] -1-benzofuran-2-carboxamide hydrochloride

To a mixture of 150 mg (0.43 mmol) of N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -7-bromo-1-benzofuran-2-carboxamide (Example 31A) and 35 mg (0.04 mmol) PdCl ₂ (dppf) in 4 mL DMF, 107 mg (0.52 mmol) 4-morpholinophenylboronic acid and 1.72 mL 1 N sodium hydroxide solution are added. The reaction mixture is heated to 95 ° C overnight. The crude product is filtered through kieselguhr, washed with DMF and freed from the solvent under reduced pressure. To remove the last catalyst residues, filter again through silica gel and wash with dichloromethane and methanol. The crude product is purified by preparative HPLC. The product is dissolved in methanol and an excess of 1N hydrochloric acid is added. After removal of the solvent under reduced pressure and drying in a high vacuum, 84 mg (42% of theory) of the title compound are obtained.
¹ H-NMR (300 MHz, DMSO-d ₆ ): δ = 10.48 (br. S, 1H), 9.05 (d, 1H), 7.90-7.82 (m, 3H), 7.70 (d, 1H), 7.63 ( d, 1H), 7.42-7.35 (m, 1H), 7.20-7.12 (m, 2H), 4.40-4.31 (m, 1H), 3.84-3.77 (m, 4H), 3.69-3.57 (m, 1H), 3.48-3.12 (m, 9H), 2.22 (m, 1H), 2.19-2.08 (m, 1H), 1.96-1.85 (m, 2H), 1.80-1.71 (m, 1H).
HPLC (method 1): R _t = 3.82 min.
MS (ESIpos): m / z = 432 (M + H) ⁺ .

Example 122 N - [(3S) -1-Azabicyclo [2.2.2] oct-3-yl] -7- [2- (hydroxymethyl) phenyl] -1-benzofuran-2-carboxamide

To a mixture of 150 mg (0.43 mmol) N - [(3S) -1-azabicyclo [2.22] oct-3-yl] -7-bromo-1-benzofuran-2-carboxamide (Example 31A) and 35 mg (0.04 mmol) of PdCl ₂ (dppf) in 3 mL DMF are added 78 mg (0.52 mmol) 2- (hydroxymethyl) phenylboronic acid and 1.72 mL 1 N sodium hydroxide solution. The reaction mixture is heated to 95 ° C overnight. The crude product is filtered through kieselguhr, washed with DMF and freed from the solvent under reduced pressure. To remove the last catalyst residues, filter again through silica gel and wash with dichloromethane and methanol. The crude product is purified by preparative HPLC. The product is dissolved in methanol and an excess of 1N hydrochloric acid is added. After removal of the solvent under reduced pressure and drying in a high vacuum, 81 mg (46% of theory) of the title compound are obtained.
¹ H-NMR (300 MHz, DMSO-d ₆ ): δ = 10.12 (br. S, 1H), 8.94 (d, 1H), 7.91-7.79 (m, 3H), 7.69 (d, 1H), 7.53- 7.32 (m, 5H), 4.33-4.22 (m, 3H), 3.68-3.57 (m, 1H), 3.48-3.12 (m, 5H), 2.19 (m, 1H), 2.15-2.04 (m, 1H), 1.94-1.83 (m, 2H), 1.79-1.67 (m, 1H).
HPLC (method 1): R _t = 3.87 min.
MS (ESIpos): m / z = 377 (M + H) ⁺ .

Example 123 N - [(3S) -1-Azabicyclo [2.2.2] oct-3-yl] -7- (3-pyridinyl) -1-benzofuran-2-carboxamide hydrochloride

To a mixture of 150 mg (0.43 mmol) of N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -7-bromo-1-benzofuran-2-carboxamide (Example 31A) and 35 mg (0.04 mmol) PdCl ₂ (dppf) in 4 mL DMF, 63 mg (0.57 mmol) 3-pyridineboronic acid and 1.72 mL 1N sodium hydroxide solution are added. The reaction mixture is heated to 95 ° C overnight. The solvent is removed under reduced pressure and the crude product is taken up in methanol and filtered through diatomaceous earth. To remove the last catalyst residues, filter again through silica gel and wash with dichloromethane and methanol. The cleaning is done by preparative HPLC. The product is dissolved in methanol and an excess of 1N hydrochloric acid is added. The solvent is removed under reduced pressure. After drying in a high vacuum, 76 mg (42% of theory) of the title compound are obtained.
¹ H-NMR (300 MHz, DMSO-d ₆ ): δ = 10.49 (s, 1H), 9.51 (s, 1H), 9.30 (d, 1H), 8.94-8.80 (m, 2H), 8.07-7.80 ( m, 4H), 7.55 (t, 1H), 4.35 (m, 1H), 3.65-3.15 (m, 6H), 2.20 (m, 1H), 2.18-2.05 (m, 1H), 1.98-1.88 (m, 2H), 1.80-1.63 (m, 1H).
HPLC (method 1): R _t = 3.30 min.
MS (ESIpos): m / z = 348 (M + H) ⁺ (free base).

Example 124 N - [(3S) -1-Azabicyclo [2.2.2] oct-3-yl] -7- [4- (methoxy) phenyl] -1-benzofuran-2-carboxamide hydrochloride

To a mixture of 150 mg (0.43 mmol) of N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -7-bromo-1-benzofuran-2-carboxamide (Example 31A) and 35 mg (0.04 mmol) PdCl ₂ (dppf) in 4 mL DMF, 78 mg (0.52 mmol) 4- (methoxy) phenylboronic acid and 1.72 mL 1 N sodium hydroxide solution are added. The reaction mixture is heated to 95 ° C overnight. The solvent is removed under reduced pressure, the crude product is taken up in methanol and filtered through diatomaceous earth. To remove the last catalyst residues, filter again through silica gel and wash with dichloromethane and methanol. The cleaning is done by preparative HPLC. The product fractions are mixed with an excess of 1 N hydrochloric acid. The solvent is removed under reduced pressure. After drying in a high vacuum, 27 mg (15% of theory) of the title compound are obtained.

The analytical data agree those of the enantiomeric compound (Example 99) match.

Example 125 N - [(3S) -1-Azabicyclo [2.2.2] oct-3-yl] -7- [3- (methoxy) phenyl] -1-benzofuran-2-carboxamide hydrochloride

To a mixture of 150 mg (0.43 mmol) of N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -7-bromo-1-benzofuran-2-carboxamide (Example 31A) and 35 mg (0.04 mmol) PdCl ₂ (dppf) in 3 mL DMF are added 78 mg (0.52 mmol) 3- (methoxy) phenylboronic acid and 1.72 mL 1 N sodium hydroxide solution. The reaction mixture is heated to 95 ° C overnight. The solvent is removed under reduced pressure, the crude product is taken up in methanol and filtered through diatomaceous earth. To remove the last catalyst residues, filter again through silica gel and wash with dichloromethane and methanol. The cleaning is done by preparative HPLC. The product is dissolved in methanol and an excess of 1N hydrochloric acid is added. The solvent is removed under reduced pressure. After drying in a high vacuum, 23 mg (13% of theory) of the title compound are obtained.

The analytical data agree those of the enantiomeric compound (Example 101) correspond.

Example 126 N - [(3R) -1-Azabicyclo [2.2.2] oct-3-yl] -7- [2 - ({[(1-methylethyl) amino] carbonyl} amino) phenyl] -1-benzofuran -2-carboxamide hydrochloride

75 mg (0.16 mmol) 7- (2-aminophenyl) -N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -1-benzofuran-2-carboxamide (Example 132), 65 µL (0.66 mmol) isopropyl isocyanate and 114 μL (0.82 mmol) triethylamine in 3 mL THF / DMF (1: 1) for 48 h at 50 ° C heated. After cooling water is added, the mixture is filtered and the solvent is reduced Pressure removed: The cleaning is done by preparative HPLC.

The product is dissolved in methanol and an excess of 1N hydrochloric acid is added. The solvent is removed under reduced pressure. After drying in a high vacuum, 21 mg (26% of theory) of the title compound are obtained.
¹ H-NMR (300 MHz, DMSO-d ₆ ): δ = 10.09 (br. S, 1H), 8.60 (d, 1H), 7.88-7.77 (m, 3H), 7.46-7.33 (m, 3H), 7.29 (dd, 1H), 7.19-7.10 (m, 1H), 6.22 (br. S, 1H), 4.29 (m, 1H), 3.75-3.54 (m, 2H), 3.39-3.13 (m, 5H), 2.22 (m, 1H), 2.15-2.02 (m, 1H), 1.96-1.86 (m, 2H), 1.80-1.69 (m, 1H), 0.96 (d, 6H).
HPLC (method 1): R _t = 3.92 min.
MS (ESIpos): m / z = 447 (M + H) ⁺ (free base).

Example 127 N - [(3R) -1-Azabicyclo [2.2.2] oct-3-yl] -7- (2 - {[(ethylamino) carbonyl] amino} phenyl) -1-benzofuran-2-carboxamide hydrochloride

75 mg (0.16 mmol) 7- (2-aminophenyl) -N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -1-benzofuran-2-carboxamide (Example 132), 50- μL (0.66 mmol) ethyl isocyanate and 110 μL (0.82 mmol) triethylamine together with a catalytic amount of DMAP in 3 mL THF / DMF (1: 1) are heated to 50 ° C for 48 h. After cooling, water is added, the mixture is filtered and the solvent is removed under reduced pressure. The cleaning is done by preparative HPLC. The product is dissolved in methanol and an excess of 1N hydrochloric acid is added. The solvent is removed under reduced pressure. After drying in a high vacuum, 10 mg (12% of theory) of the title compound are obtained.
¹ H-NMR (300 MHz, DMSO-d ₆ ): δ = 10.41 (br. S, 1H), 9.30 (d, 1H), 8.69 (d, 1H), 7.96-7.78 (m, 3H), 7.59- 7.11 (m, 4H), 4.30 (m, 1H), 3.69-3.54 (m, 1H), 3.40-3.13 (m, 5H), 2.99 (q, 2H), 2.24-2.19 (m, 1H), 2.17- 2.04 (m, 1H), 1.96-1.84 (m, 2H), 1.80-1.64 (m, 1H), 0.92 (t, 3H).
HPLC (method 1): R _t = 3.86 min.
MS (ESIpos): m / z = 433 (M + H) ⁺ (free base).

Example 128 N - [(3R) -1-Azabicyclo [2.2.2] oct-3-yl] -7- (2 - {[(methylamino) carbonyl] amino} phenyl) -1-benzofuran-2-carboxamide hydrochloride

75 mg (0.16 mmol) 7- (2-aminophenyl) -N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -1-benzofuran-2-carboxamide (Example 132), 37 mg (0.66 mmol) methyl isocyanate and 110 μL (0.82 mmol) triethylamine are heated together with a catalytic amount of DMAP in 3 mL THF / DMF (1: 1) to 50 ° C overnight. After cooling, water is added, the mixture is filtered and the solvent is removed under reduced pressure. The cleaning is done by preparative HPLC. The product is dissolved in methanol and an excess of 1N hydrochloric acid is added. The solvent is removed under reduced pressure. After drying in a high vacuum, 29 mg (35% of theory) of the title compound are obtained.
¹ H-NMR (300 MHz, DMSO-d ₆ ): δ = 10.22 (br. S, 1H), 8.60 (d, 1H), 8.69 (d, 1H), 7.86-7.74 (m, 3H), 7.51- 7.28 (m, 5H), 7.18-7.11 (m, 1H), 6.21 (br. S, 1H), 4.29 (m, 1H), 3.69-3.58 (m, 1H), 3.38-3.13 (m, 5H), 2:51 (s, 3H), 2.28-2.22 (m, 1H), 2.18-2.04 (m, 1H), 1.99-1.87 (m, 2H), 1.82-1.68 (m, 1H).
HPLC (method 1): R _t = 3.72 min.
MS (ESIpos): m / z = 419 (M + H) ⁺ (free base).

Example 129 N - [(3R) -1-Azabicyclo [2.2.2] oct-3-yl] -7- [2 - ({[(1,1-dimethylethyl) amino] carbonyl} amino) phenyl] -1 benzofuran-2-carboxamide hydrochloride

75 mg (0.16 mmol) 7- (2-aminophenyl) -N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -1-benzofuran-2-carboxamide (Example 132), 65 mg (0.66 mmol) (1,1-dimethylethyl) isocyanate and 110 μL (0.82 mmol) triethylamine are heated together with a catalytic amount of DMAP in 3 mL THF / DMF (1: 1) at 50 ° C overnight. After cooling, water is added, the mixture is filtered and the solvent is removed under reduced pressure. The cleaning is done by preparative HPLC. The product is dissolved in methanol and an excess of 1N hydrochloric acid is added. The solvent is removed under reduced pressure. After drying in a high vacuum, 10 mg (12% of theory) of the title compound are obtained.
HPLC (method 1): R _t = 4.06 min.
MS (ESIpos): m / z = 461 (M + H) ⁺ (free base).

Example 130 N - [(3R) -1-Azabicyclo [2.2.2] oct-3-yl] -7- [2- (methoxy) phenyl] -1-benzofuran-2-carboxamide

600 mg (1.45 mmol) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -7- [2- (methoxy) phenyl] -1-benzofuran-2-carboxamide hydrochloride (example 102) are dissolved in 15 mL ethyl acetate and extracted three times with 1 N sodium hydroxide solution. The organic phase is dried over sodium sulfate and then concentrated. After drying in a high vacuum, 534 mg (97.6% of theory) of the title compound are obtained.
¹ H-NMR (200 MHz, DMSO-d ₆ ): δ = 8.34 (d, 1H), 7.72 (dd, 1H), 7.70 (s, 1H), 7.50-7.30 (m, 4H), 7.20 (m, 1H), 7.08 (m, 1H), 3.93 (m, 1H), 3.76 (s, 3H), 3.11 (m, 1H), 2.86 (m, 1H), 2.69 (m, 4H), 1.86 (m, 1H) ), 1.75 (m, 1H), 1.58 (m, 2H), 1.32 (m, 1H).
HPLC (method 1): R _t = 4.1 min.
MS (ESIpos): m / z = 377 (M + H) ⁺ .

Example 131 N - [(3R) -1-Azabicyclo [2.2.2] oct-3-yl] -7- [2- (hydroxymethyl) phenyl] -1-benzothiophene-2-carboxamide hydrochloride

200 mg (0.45 mmol) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -7-bromo-1-benzothiophene-2-carboxamide hydrochloride (Example 8A) and 67.9 mg (0.45 mmol) 2- (hydroxymethyl) phenylboronic acid are placed in 2 mL DMF. After addition of 0.67 mL 2 M sodium carbonate solution and 18.2 mg (0.02 mmol) PdCl ₂ (dppf) the mixture is heated to 80 ° C. After 18 h, the reaction mixture is filtered through kieselguhr and purified by separation using preparative HPLC. The product fractions are concentrated, a 5: 1 mixture of methanol and 4 N hydrogen chloride in dioxane is added and the mixture is concentrated again. After drying in a high vacuum, 148 mg (72% of theory) of the title compound are obtained.
¹ H-NMR (300 MHz, DMSO-d ₆ ): δ = 10.30 (br. S, 1H), 9.10 (d, 1H), 8.47 (s, 1H), 8.07 (d; 1H), 7.78 (d, 1H), 7.68-7.54 (m, 2H), 7.52-7.39 (m, 3H), 4.40 (m, 1H), 4.36 (s, 2H), 3.72 (m, 1H), 3.53-3.20 (m, 5H) , 2.29 (m, 1H), 2.21 (m, 1H), 2.00 (m, 2H), 1.82 (m, 1H).
HPLC (method 1): R _t = 3.9 min.
MS (ESIpos): m / z = 393 (M + H) ⁺ (free base).

Example 132 7- (2-aminophenyl) -N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -1-benzofuran-2-carboxamide

To a mixture of 1.0 g (2.86 mmol) of N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -7-bromo-1-benzofuran-2-carboxamide (Example 30A) and 234 mg (0.29 mmol) PdCl ₂ (dppf) in 15 mL DMF become 752 mg (3.44 mmol) 2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenylamine and 11.45 mL 1 N sodium hydroxide solution. The reaction mixture is heated to 95 ° C. overnight and then filtered through diatomaceous earth. The solvent is then removed under reduced pressure and the residue is taken up in 100 ml of ethyl acetate and 100 ml of 1N sodium hydroxide solution. The organic phase is washed twice with 1 N sodium hydroxide solution and once with saturated sodium chloride solution. The combined organic phases are dried over magnesium sulfate and the solvent is distilled off under reduced pressure on a rotary evaporator. The crude product is taken up in methanol and together with an acidic ion exchanger (Dowex ^® WX2-200) for about 30 minutes. long shaken. The loaded ion exchanger is washed three times with 30 mL methanol, then with DMF. It is washed successively with methanol, dichloromethane, methanol, water, methanol, dichloromethane, methanol, THF and finally again with methanol. The product is eluted with methanol-triethylamine 95: 5. The solvent is removed on the rotary evaporator under reduced pressure. After drying in a high vacuum, 601 mg (48% of theory) of the title compound are obtained in sufficient purity for the further reactions.
HPLC (method 1): R _t = 3.51 min.
MS (ESIpos): m / z = 362 (M + H) ⁺ .

Claims (14)

Compounds of the formula

in which R ¹ 1-azabicyclo [22.2] oct-3-yl, R ^{2 is} hydrogen or C ₁ -C ₆ alkyl, R ^{3 is} hydrogen, halogen or C ₁ -C ₆ alkyl, R ^{4 is} hydrogen, halogen, Cyano, amino, trifluoromethyl, trifluoromethoxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkylcarbonyl, C ₁ -C ₆ alkylamino, formyl, hydroxycarbonyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ - Alkoxycarbonyl, C ₁ -C ₆ alkylthio, C ₁ -C ₆ alkylcarbonylamino, C ₁ -C ₄ alkylsulfonylamino, C ₃ -C ₈ cycloalkylcarbonylamino, pyrrolyl, C ₁ -C ₆ alkylaminocarbonylamino, heterocyclylcarbonyl, phenyl or heterocyclyl, where C ₁ -C ₆ alkyl optionally by hydroxy, amino, C ₁ -C ₆ alkylaminocarbonylamino, C ₁ -C ₆ alkylaminocarboxyl, heterocyclyl or aryl, C ₁ -C ₆ alkylcarbonylamino optionally with C ₁ -C ₆ alkoxy , and heterocyclyl are optionally substituted with oxo, A oxygen or sulfur, the ring B benzo or pyrido; which are each optionally substituted by radicals from the series halogen, cyano, formyl, trifluoromethyl, trifluoromethoxy, nitro, amino, C ₁ -C ₆ alkyl and C ₁ -C ₆ alkoxy, and EC≡C, aryl and heteroaryl, where Aryl and heteroaryl are optionally substituted by radicals from the series halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, amino, C ₁ -C ₆ alkoxy and C ₁ -C ₆ alkyl, and the solvates, salts or solvates of the salts of these connections. Compounds of the formula (n according to claim 1, in which R ¹ 1-aza-bicyclo [2.2.2] oct-3-yl, R ² hydrogen or C ₁ -C ₆ alkyl, R ³ hydrogen, halogen or C ₁ - C ₆ alkyl, R ⁴ hydrogen, halogen, cyano, trifluoromethyl, trifluoromethoxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy or heterocyclyl, where alkyl is optionally substituted by a radical hydroxy, A oxygen or sulfur, the ring B benzo or pyrido, which are each optionally substituted by radicals from the series halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, amino, C ₁ -C ₆ -alkyl and C ₁ -C ₆ -alkoxy, and EC≡C, Arylene or heteroarylene, where arylene and heteroarylene are optionally substituted by radicals from the series halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, amino, C ₁ -C ₆ alkyl and C ₁ -C ₆ alkoxy, and the solvates, Salts or solvates of the salts of these compounds. Compounds according to claim 1 of the formula

in which R ¹ (3R) -1-aza-bicyclo [2.2.2] oct-3-yl, R ² and R ³ independently of one another are hydrogen or methyl, R ^{4 is} hydrogen, halogen, cyano, trifluoromethyl, trifluoromethoxy, C ₁ - C ₆ alkyl, C ₁ -C ₆ alkoxy or heterocyelyl, where alkyl is optionally substituted by a hydroxyl radical, and R ^{B is} hydrogen, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, amino, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy, and the solvates, salts or solvates of the salts of these compounds. Compounds according to claim 1 of the formula

in which R ¹ (3R) -1-aza-bicyclo [2.2.2] oct-3-yl, R ² and R ³ independently of one another are hydrogen or methyl, R ^{4 is} hydrogen, halogen, cyano, trifluoromethyl, trifluoromethoxy, C ₁ - C ₆ alkyl, C ₁ -C ₆ alkoxy or heterocyclyl, where alkyl is optionally substituted by a hydroxy radical, and R ^{B is} hydrogen, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, amino, C ₁ -C ₆ alkyl and C ₁ -C ₆ alkoxy, and the solvates, salts or solvates of the salts of these compounds. Compounds according to claims 3 and 4, wherein R ¹ (3R) -1-aza-bicyclo [2.2.2] oct-3-yl, R ² and R ³ hydrogen, R ⁴ hydrogen, fluorine, chlorine, bromine, trifluoromethoxy, hydroxymethyl , Methoxy or 6-membered heterocyclyl and R ^{B is} hydrogen, halogen, cyano, trifluoromethyl, trifluoromethoxy or C ₁ -C ₄ -alkyl, and the solvates; Salts or solvates of the salts of these compounds. Compounds according to claim 1, of the formula

in which E phenylene, R ⁴ C ₁ -C ₆ alkoxy, aminomethylene, hydroxycarbonyl, C ₃ -C ₈ cycloalkylcarbonylamino, a group of the formula

where R ^{5 is} C ₁ -C ₆ alkyl, n is zero, 1, 2, 3 or 4, or 5- to 6-membered heterocyclyl, which is optionally substituted with oxo, A is sulfur or oxygen, and their solvates, salts or solvates of the salts. Compounds according to claim 1, of the formula (Ic), in which E is phenylene, R ⁴ C ₁ -C ₄ alkoxy, aminomethylene, hydroxycarbonyl, C ₃ -C ₆ cycloalkylcarbonylamino, a group of the formula

where R ^{5 is} C ₁ -C ₄ alkyl, n is zero, 1 or 2, or 5- to 6-membered heterocyclyl, which is optionally substituted with oxo, A is sulfur or oxygen, and their solvates, salts or solvates of the salts , Compounds according to claim 1, of the following formulas

as well as the solvates, salts or solvates of the salts of these compounds. Process for the preparation of the compounds according to the invention, after which compounds of the formula X ¹ -ER ⁴ (II), in which R ^{4 has} the meaning given above and X ¹ in the case that E denotes arylene or heteroarylene for -B (OH) ₂ or

and in the case where E is -C≡C- represents hydrogen, with a compound of the formula

in which R ¹ , R ² , R ³ , A and the ring B have the meanings given above and X ^{2 represents} triflate or halogen, preferably chlorine, bromine or iodine, and the resulting compounds (I) optionally with the corresponding ( i) solvents and / or (ii) bases or acids to their solvates, salts or solvates of the salts. Compounds according to one of claims 1 to 8 for treatment and / or prophylaxis of diseases. Medicament containing at least one compound after one of claims 1 to 8 and at least one pharmaceutically acceptable essentially non-toxic carrier or excipients. Use of compounds according to one of claims 1 to 8 for producing a means for improving perception, Concentration performance, learning performance and / or memory performance. Use of compounds according to one of claims 1 to 8 for the manufacture of a medicament for treatment and / or prophylaxis of disorders perception, concentration, learning and / or memory. Medicament according to Claim 11 for the treatment and / or prophylaxis of disorders perception, concentration, learning and / or memory.