 Heterocyclylcarboxamide derivatives and their use as therapeutic agents
专利摘要:
A is methylene or O; B is methylene or O; g is 0, 1, 2, 3 or 4; R 1 is an arbitrary substituent; U is an alkylene chain optionally substituted by one or more alkyl; Q represents a divalent group containing a nitrogen atom; Compounds of formula (I) wherein T represents CO.HET, and pharmaceutically acceptable salts thereof, are useful for the treatment of central nervous system disorders such as depression, anxiety, psychosis (e.g. schizophrenia) The present invention relates to a method of treating a disorder or condition selected from the group consisting of a disease, obesity, hypertension, turret syndrome, sexual dysfunction, drug barriers, substance abuse, cognitive disorders, Alzheimer's disease, senile dementia, obsessive- - Used for the treatment of insulin-dependent diabetes, hyperglycemia, constipation, arrhythmia, disorders of the neuroendocrine system, stress, enlargement of the prostate and convulsions. (I) 公开号:KR19990028918A 申请号:KR1019980700220 申请日:1996-07-02 公开日:1999-04-15 发明作者:알란 마틴 버치；데이비드 존 힐；프랑크 케리간；키이쓰 프랑크 마틴；패트리셔 레슬리 니드햄；브루스 제레미 사전트 申请人:독터. 호르스트 하스칼, 잉에 린스；크놀 아게； IPC主号:
专利说明:
Heterocyclylcarboxamide derivatives and their use as therapeutic agents The present invention relates to novel heteroarylcarboxamide compounds having affinity for 5-HT 1A and / or α 1 and / or α 2 and / or D 2 receptors, processes for their preparation, pharmaceutical compositions containing them and (Eg, schizophrenia), bipolar disorder, Parkinson's disease, obesity, hypertension, turret syndrome, sexual dysfunction, drug barriers, substance abuse, cognitive impairment, Diabetic retinopathy, diabetic neuropathy, neuroendocrine dysfunction, stress, prostate hypertrophy, hyperlipidemia, hyperlipidemia, hyperlipidemia, hypertriglyceridemia, hypertriglyceridemia, And their use in the treatment of convulsions. The present invention provides compounds of formula (I) and pharmaceutically acceptable salts thereof. Wherein A is methylene or O; B is methylene or O; g is 0, 1, 2, 3 or 4; R 1 is a) halo; b) an alkyl group containing from 1 to 3 carbon atoms optionally substituted by one or more halo; c) an alkoxy group containing from 1 to 3 carbon atoms optionally substituted by one or more halo; d) an alkylthio group containing from 1 to 3 carbon atoms optionally substituted by one or more halo; e) hydroxy; f) an acyloxy group containing from 1 to 3 carbon atoms; g) hydroxymethyl; h) cyano; i) an alkanoyl group containing 1 to 6 carbon atoms; j) an alkoxycarbonyl group containing 2 to 6 carbon atoms; k) a carbamoyl group or a carbamoylmethyl group each optionally N -substituted by 1 or 2 alkyl groups each containing 1 to 3 carbon atoms; l) a sulfamoyl or sulfamoylmethyl group optionally N -substituted by one or two alkyl groups each containing 1 to 3 carbon atoms; m) an alkylsulfonyloxy group containing from 1 to 3 carbon atoms optionally substituted by one or more halo; n) furyl group; o) an amino group optionally substituted by one or two alkyl groups each containing from 1 to 3 carbon atoms; Or when g is 2, 3 or 4, two adjacent R < 1 > groups, which are the same or different, together with the carbon atoms to which they are attached form a fused benz ring; R 2 is H, an alkyl group containing from 1 to 3 carbon atoms optionally substituted by one or more halo, or an alkoxy group containing from 1 to 3 carbon atoms optionally substituted by one or more halo; R 3 and R 4 are the same or different and are H or an alkyl group containing 1 to 3 carbon atoms optionally substituted by one or more halo; U is an alkylene chain containing from 1 to 3 carbon atoms, optionally substituted by one or more alkyl groups each containing from 1 to 3 carbon atoms; Q represents a divalent group of chemical formula (IIa), (IIb) or (IIc); V is an alkylene chain containing from 1 to 3 carbon atoms optionally substituted by one or more alkyl groups containing from 1 to 3 carbon atoms, X is an alkylene chain containing from 0 to 2 carbon atoms and X ' is an alkylene chain containing from 1 to 4 carbon atoms, optionally substituted by one or more alkyl groups containing from 1 to 4 carbon atoms, , With the proviso that the total number of carbon atoms in X and X 'is 3 or 4 and R 5 is H or an alkyl group containing 1 to 3 carbon atoms, T is CO.HET wherein HET is selected from 2-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 2- or 3-thienyl, 2- or 3- 2,3- or 7-benzo [b] furanyl, 2,3-dihydro-7-benzo [b] furanyl, 2-, 4- or 5-pyrazolyl, 4- or 5-triazolyl, 5-tetrazolyl, 2-, 3-, 4- or 8-quinolinyl, 2- or 4- 4-, or 5-isoxazolyl, 3-, 4- or 5-isothiazolyl or 2-, 4- or 5-thiazolyl, , Each of which is a) halo, b) an alkyl group containing 1 to 3 carbon atoms optionally substituted by one or more halo, c) an alkoxy group containing 1 to 3 carbon atoms optionally substituted by one or more halo d) an alkylthio group containing 1 to 3 carbon atoms optionally substituted by one or more halo, e) hydroxy, f) an alkyl group containing 1 to 3 carbon atoms I) an alkanoyl group containing 1 to 6 carbon atoms, j) an alkoxycarbonyl group containing 2 to 6 carbon atoms, k) an alkoxycarbonyl group containing 1 to 3 carbon atoms, Carbamoyl or carbamoylmethyl groups each optionally N -substituted by 1 or 2 alkyl groups containing 1 to 3 carbon atoms, 1) 1 or 2 alkyl groups each containing 1 to 3 carbon atoms, optionally N - a substituted sulfamoyl or sulfamoylmethyl group, m) an amino group optionally substituted by one or two alkyl groups each containing from 1 to 5 carbon atoms, n) 1-pyrrolyl or o) 1-pyrrolidinyl or ≪ / RTI > and / or peridino. In a preferred compound of formula (I), A is O. In a preferred compound of formula (I), B is O. In the most preferred compounds of formula (I), A and B are all O. In a preferred compound of formula (I), g is 0, 1 or 2. In a preferred compound of formula (I), g is 1 or 2 and R 1 is halo (e.g. fluoro, chloro, or bromo), 1 to 3 carbon atoms optionally substituted by one or more halo An alkoxy group containing from 1 to 3 carbon atoms, an alkanesulfonyloxy group containing from 1 to 3 carbon atoms optionally substituted by at least one halo, or hydroxy. In a more preferred compound of formula (I), g is 1 or 2 and R 1 represents bromo, chloro, fluoro, trifluoromethyl, trifluoromethanesulfonyloxy, methyl or methoxy. In a preferred compound of formula (I), R 2 is H or an alkyl group containing 1 to 3 carbon atoms. In a more preferred compound of formula (I), R 2 is H. In a preferred compound of formula (I), R 3 and R 4 are the same or different and are H or methyl. In more preferred compounds of formula (I), R 3 and R 4 are both H. In a preferred compound of formula (I), U is methylene. In a preferred compound of formula (I), Q is a group of formula (IIa) or (IIc), V is methylene or ethylene, and X and X 'are both ethylene. In a preferred compound of formula (I), Q is a group of formula (IIb) and V 'is an alkylene chain containing from 2 to 4 carbon atoms. In a more preferred compound of formula (I), Q is a group of formula (IIa) or (IIb) and V is methylene. In a preferred compound of formula (I), R < 5 > is H or methyl. In a more preferred compound of formula (I), R < 5 > In a preferred compound of formula (I), HET is selected from the group consisting of methyl, methoxy, trifluoromethyl, halo, methylthio, 1-pyrrolyl, or one or two alkyl groups each containing 1 to 3 carbon atoms 3- or 4-pyridyl, 8-quinolinyl, or 2-thienyl, each of which is optionally substituted by one or more substituents selected from optionally substituted amino groups. In a more preferred compound of formula (I), HET is selected from the group consisting of 2-pyridyl, 3-pyridyl, 1-pyridyl, 8-quinolinyl, or 2-thienyl. For the most preferred compounds of formula (I), HET is 2-pyridyl optionally substituted by an amino group, or 3-pyridyl. In preferred compounds of formula (I), A and B are both O; g is 0, 1 or 2, R 1 is halo (for example fluoro, chloro or bromo), an alkyl group containing from 1 to 3 carbon atoms optionally substituted by one or more halo, An alkoxy group containing one carbon atom, an alkylsulfonyloxy group containing from 1 to 3 carbon atoms optionally substituted by one or more halo, or hydroxy; R 2 is H or an alkyl group containing 1 to 3 carbon atoms, R 3 and R 4 are the same or different and are H or methyl; U is methylene; Q is a group of formula (IIa) or (IIc); V is methylene; R < 5 > is H or methyl; X and X 'are both ethylene and HET is optionally substituted with one or two alkyl groups containing from 1 to 3 carbon atoms, such as methyl, methoxy, trifluoromethyl, halo, methylthio, 3-, or 4-pyridyl, 8-quinolinyl, or 2-thienyl, each of which is optionally substituted with one or more substituents selected from among the imino groups selected. As used herein, any group containing a chain of three or more atoms will be understood to mean a group in which the chain may be straight-chain or branched. For example, the alkyl group is n-butyl may comprise a comprising a tert-propyl, and n, including propyl and isopropyl-butyl, sec-butyl, isobutyl and tert. The term " halo ", as used herein, refers to fluoro, chloro, bromo and iodo. The compound of formula (I) may be present as a salt with a pharmaceutically acceptable acid. Examples of such salts include, but are not limited to, hydrochloride, bromide, hydrochloride, sulfate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate [ Mixtures thereof, including semisolid mixtures, salts with amino acids such as succinate, benzoate and glutamic acid. The compounds of formula (I) and salts thereof may exist in the form of a solvate (e.g., hydrate). The compounds of formula (I) contain one or more chiral centers and are present in different optically active forms. When the compound of formula (I) contains a single chiral center, the compound is present in two enantiomeric forms and the present invention encompasses both enantiomer and enantiomer mixtures. Enantiomers may be prepared by methods known to those skilled in the art, for example, formation of diastereoisomeric salts which may be separated by crystallization; For example, formation of diastereoisomeric derivatives or complexes which may be separated by crystallization, gas-liquid or liquid chromatography; Selective reaction of an enantiomer and an enantiomer-specific reagent, for example, esterification with an enzyme; Or by chiral environments such as silica with bound chiral ligands, or by gas-liquid or liquid chromatography in the presence of a chiral solvent. If the desired enantiomer is converted to another chemical entity by one of the separation methods described above, it will be appreciated that a further step is required to liberate the desired enantiomeric form. Alternatively, a particular enantiomer may be synthesized by using an optically active agent, substrate, catalyst or solvent, or by converting one enantiomer to another by asymmetric conversion. Compounds of formula (I) may exist in the diastereoisomeric form when they contain more than one chiral center. The diastereoisomer pairs may be separated by methods known to those skilled in the art, for example, by chromatography or crystallization, and individual enantiomers in each pair may be separated as described above. The present invention includes each enantiomer of a compound of formula (I) and mixtures thereof. Certain compounds of formula (I) and salts thereof may exist in more than one crystal form, and the invention includes each crystalline form and mixtures thereof. In addition, certain compounds of formula (I) and salts thereof may exist in the form of a solvate, e.g., hydrate, and the present invention includes each solvate and mixtures thereof. Particular compounds of formula (I) are the following compounds in the form of individual enantiomers, racemates, or other mixtures of enantiomers and the pharmaceutically acceptable salts thereof: 2-Amino- N - {[1- (7-chloro-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} pyridine-3-carboxamide; 2-Amino- N - {[1- (8-chloro-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} pyridine-3-carboxamide; 2-Amino- N - {[1- (1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} pyridine-3-carboxamide; 2-Amino- N - {[1- (7-methyl-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} pyridine-3-carboxamide; N - {[1- (1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} pyridine-2-carboxamide; 2-Amino- N - {[1- (7-methoxy-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} pyridine-3-carboxamide; N - {[1- (1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} quinoline-8-carboxamide; N - {[1- (8-chloro-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -2-methylpyridine-3-carboxamide; 2-Amino- N - {[1- (7-fluoro-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} pyridine-3-carboxamide; 2-Amino- N - {[1- (8-methoxy-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} pyridine-3-carboxamide; N - {[1- (7-chloro-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} pyridine-2-carboxamide; 2-Amino- N - {[1- (8-methyl-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} pyridine-3-carboxamide; 2-Amino- N - {[1- (7-chloro-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -6-methylpyridine-3-carboxamide; 3-Amino- N - {[1- (1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -thiophene-2-carboxamide; 3-Amino- N - {[1- (7-chloro-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} thiophene-2-carboxamide; N - {[1- (7-chloro-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -2-methylpyridine-3-carboxamide; 1- (2-aminonicotinoyl) -4- [ N - (7-chloro-1,4-benzodioxan-2-ylmethyl) aminomethylpiperidine; 2-Amino- N - {[1- (8-trifluoromethyl-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} pyridine-3-carboxamide; 2-Amino- N - {[1- (7-bromo-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} pyridine-3-carboxamide; N - {[1- (7-chloro-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} pyridine-3-carboxamide; N - {[1- (7-chloro-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} quinoline-8-carboxamide; N - {[1- (8-chloro-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} pyridine-3-carboxamide; N - {[1- (7-chloro-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -6-methylpyridine-2-carboxamide; N - {[1- (7-chloro-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -2-methoxypyridine-3-carboxamide; 2-Amino- N - {[1- (7,8-difluoro-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} pyridine-3-carboxamide; 2-Amino- N - {[1- (8-trifluoromethanesulfonyloxy-1,4-benzodioxan-2- ylmethyl) -4-piperidyl] methyl} pyridine-3- carboxamide ; 4- [ N - (7-chloro-1,4-benzodioxan-2-ylmethyl) aminomethyl] -1- (2-pyridylcarbonyl) -piperidine; N - {[1- (7-methyl-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} pyridine-3-carboxamide; 2-methyl- N - {[1- (7-methyl-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} pyridine-3-carboxamide; N - {[1- (7-methyl-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -6- (1-pyrrolyl) pyridine-3-carboxamide; N - {[1- (7-methyl-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -2- (methylthio) pyridine-3-carboxamide; 5-bromo- N - {[1- (7-methyl-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} pyridine-3-carboxamide; N - {[1- (7-bromo-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} pyridine-3-carboxamide; N - {[1- (7-bromo-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -2-methylpyridine-3-carboxamide; N - {[1- (7- bromo-1,4-benzodioxane-2-ylmethyl) -4-piperidyl] methyl} -6- (1-pyrrolyl) pyridine-3-carboxamide ; N - {[1- (7-bromo-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -2- (methylthio) pyridine-3-carboxamide; 5-Bromo- N - {[1- (7-bromo-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} pyridine-3-carboxamide; N - {[1- (7-chloro-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -6- (1-pyrrolyl) pyridine-3-carboxamide; N - {[1- (7-chloro-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -2- (methylthio) pyridine-3-carboxamide; 5-Bromo- N - {[1- (7-chloro-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} pyridine-3-carboxamide; N - {[1- (7-fluoro-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} pyridine-3-carboxamide; N - {[1- (7-fluoro-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -2- (methylthio) pyridine-3-carboxamide; N - {[1- (8-trifluoromethyl-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} pyridine-3-carboxamide; 2-methyl- N - {[1- (8-trifluoromethyl-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} pyridine-3-carboxamide; Methyl] -4-piperidyl] methyl} pyridine-3-carbaldehyde To a solution of 6- (1-pyrrolyl) -N - {[1- (8-trifluoromethyl- ≪ / RTI > 2- (methylthio) - N - {[1- ( 8- trifluoromethyl-1,4-benzodioxane-2-ylmethyl) -4-piperidyl] methyl} pyridine-3-carboxamide ; 5-Bromo- N - {[1- (8-trifluoromethyl-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} pyridine-3-carboxamide; N - {[1- (8-chloro-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -6- (1-pyrrolyl) pyridine-3-carboxamide; N - {[1- (8-chloro-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -2- (methylthio) pyridine-3-carboxamide; And 5-Bromo- N - {[1- (8-chloro-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} pyridine-3- carboxamide. The specific enantiomeric forms of the compounds of formula (I) include the following compounds and their pharmaceutically acceptable salts: (S) -2-amino- N - {[1- (7-chloro-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -pyridine-3- carboxamide; (S) -2-amino- N - {[1- (8-chloro-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -pyridine-3- carboxamide; (S) -2-amino- N - {[1- (8-fluoro-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -pyridine- ; (S) -2-amino- N - {[1- (7-methyl-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -pyridine-3- carboxamide; (S) -2-amino- N - {[1- (7-methoxy-1,4-benzodioxan-2- ylmethyl) -4-piperidyl] methyl} -pyridine- ; (S) - N - {[ 1- (8- chloro-l, 4-benzodioxane-2-ylmethyl) -4-piperidyl] methyl} -2-methylpyridine-3-carboxamide; (S) - N - {[ 1- (7- chloro-1,4-benzodioxane-2-ylmethyl) -4-piperidyl] methyl} pyridine-2-carboxamide; (S) -2-amino- N - {[1- (8-methyl-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -pyridine-3- carboxamide; (S) -2-amino- N - {[1- (7-chloro-1,4-benzodioxan- ≪ / RTI > (S) -2-amino- N - {[1- (1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -pyridine-3-carboxamide; (S) -3-amino- N - {[1- (7-chloro-1,4-benzodioxan-2- ylmethyl) -4-piperidyl] methyl} ; (S) - N - {[ 1- (7- chloro-1,4-benzodioxane-2-ylmethyl) -4-piperidyl] methyl} -2-methylpyridine-3-carboxamide; (S) -2-amino- N - {[1- (8-trifluoromethyl-1,4-benzodioxan- ≪ / RTI > (S) -2-amino- N - {[1- (7-bromo-1,4-benzodioxan-2- ylmethyl) -4-piperidyl] methyl} -pyridine- ; (S) - N - {[ 1- (7- chloro-1,4-benzodioxane-2-ylmethyl) -4-piperidyl] methyl} pyridine-3-carboxamide; (S) - N - {[ 1- (7- chloro-1,4-benzodioxane-2-ylmethyl) -4-piperidyl] methyl} quinoline-8-carboxamide; (S) - N - {[ 1- (8- chloro-l, 4-benzodioxane-2-ylmethyl) -4-piperidyl] methyl} pyridine-3-carboxamide; (S) - N - {[ 1- (7- chloro-1,4-benzodioxane-2-ylmethyl) -4-piperidyl] methyl} -2-methoxy-3-carboxamide; (S) -2-amino- N - {[1- (7,8-difluoro-1,4-benzodioxan- Carboxamide; (S) -2-amino- N - {[1- (8-trifluoromethanesulfonyloxy-1,4-benzodioxan-2- ylmethyl) -4-piperidyl] methyl} 3-carboxamide; (S) - N - {[ 1- (7- methyl-1,4-benzodioxane-2-ylmethyl) -4-piperidyl] methyl} pyridine-3-carboxamide; (S) -2-methyl- N - {[1- (7-methyl-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} pyridine-3-carboxamide; (S) - N - {[ 1- (7- methyl-1,4-benzodioxane-2-ylmethyl) -4-piperidyl] methyl} -6- (1-pyrrolyl) pyridine-3 Carboxamide; (S) - N - {[ 1- (7- methyl-1,4-benzodioxane-2-ylmethyl) -4-piperidyl] methyl} -2 (methylthio) pyridine-3-carboxamide, amides; (S) -5-bromo- N - {[1- (7-chloro-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} pyridine-3-carboxamide; (S) - N - {[ 1- (7- bromo-1,4-benzodioxane-2-ylmethyl) -4-piperidyl] methyl} pyridine-3-carboxamide; (S) - N - {[ 1- (7- bromo-1,4-benzodioxane-2-ylmethyl) -4-piperidyl] methyl} -2-methylpyridine-3-carboxamide; (S) - N - {[ 1- (7- bromo-1,4-benzodioxane-2-ylmethyl) -4-piperidyl] methyl} -6- (1-pyrrolyl) pyridine -3 -Carboxamide; (S) - N - {[ 1- (7- bromo-1,4-benzodioxane-2-ylmethyl) -4-piperidyl] methyl} -2 (methylthio) pyridine-3-carboxamide ≪ / RTI > (S) -5-bromo- N - {[1- (7-bromo-1,4-benzodioxan-2- ylmethyl) -4-piperidyl] methyl} pyridine- ; (S) - N - {[ 1- (7- chloro-1,4-benzodioxane-2-ylmethyl) -4-piperidyl] methyl} -6- (1-pyrrolyl) pyridine-3 Carboxamide; (S) - N - {[ 1- (7- chloro-1,4-benzodioxane-2-ylmethyl) -4-piperidyl] methyl} -2 (methylthio) pyridine-3-carboxamide, amides; (S) -5-bromo- N - {[1- (7-chloro-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} pyridine-3-carboxamide; (S) - N - {[ 1- (-1,4- benzodioxane-2-ylmethyl 7-fluoro) -4-piperidyl] methyl} pyridine-3-carboxamide; (S) - N - {[ 1- (7- fluoro-1,4-benzodioxane-2-ylmethyl) -4-piperidyl] methyl} -2 (methylthio) pyridine-3-carboxamide ≪ / RTI > (S) - N - {[ 1- (8- trifluoromethyl-1,4-benzodioxane-2-ylmethyl) -4-piperidyl] methyl} pyridine-3-carboxamide; Methyl- N - {[1- (8-trifluoromethyl-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} pyridine- amides; (S) -6- (1- pyrrolyl) - N - {[1- (methyl-1,4-benzodioxane-2-yl-methyl-8-trifluoromethyl) -4-piperidyl] methyl} pyridine -3-carboxamide; (S) -2- (methylthio) - N - {[1- (methyl-1,4-benzodioxane-2-yl-methyl-8-trifluoromethyl) -4-piperidyl] methyl} pyridine -3 -Carboxamide; (S) -5-bromo- N - {[1- (8-trifluoromethyl-1,4-benzodioxan-2- ylmethyl) -4-piperidyl] methyl} pyridine- ≪ / RTI > (S) - N - {[ 1- (8- chloro-l, 4-benzodioxane-2-ylmethyl) -4-piperidyl] methyl} -6- (1-pyrrolyl) pyridine-3 Carboxamide; (S) - N - {[ 1- (8- chloro-l, 4-benzodioxane-2-ylmethyl) -4-piperidyl] methyl} -2 (methylthio) pyridine-3-carboxamide, amides; And (S) -5-Bromo- N - {[1- (8-chloro-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} pyridine-3- carboxamide. The present invention also encompasses pharmaceutical compositions containing a therapeutically effective amount of a compound of formula (I) or a salt thereof together with a pharmaceutically acceptable diluent or carrier. The term " active compound " as used below means a compound of formula (I) or a salt thereof. For therapeutic use, the active compounds may be administered orally, rectally, intestinally or topically, preferably orally. Thus, the therapeutic compositions of the present invention may take any form of pharmaceutical composition known for oral, rectal, enteral, or topical administration. Pharmaceutically acceptable carriers suitable for use in such compositions are well known in the art of pharmacy. The composition of the present invention may contain from 0.1 to 99% by weight of active compound. Compositions of the present invention are generally prepared in unit dosage form. Preferably, the unit dose of the active ingredient is 1 to 500 mg. The excipients used in the preparation of these compositions are excipients known in the art of pharmacy. Compositions for oral administration are preferred compositions of the invention, which are in the form of pharmaceutical forms known for such administration, for example tablets, capsules, syrups and aqueous or oily suspensions. The excipients used in the preparation of these compositions are excipients known in the art of pharmacy. Tablets may also be prepared by mixing the active substance with an inert diluent such as calcium phosphate in the presence of a disintegrating agent such as corn starch and a lubricant such as magnesium stearate and purifying the mixture by known methods. Tablets may be formulated in a manner known to those skilled in the art to represent sustained release of the compounds of the present invention. Such tablets may, if desired, be provided for enteric use by known methods, for example, by the use of cellulose acetate phthalate. Similarly, capsules, such as hard or soft gelatin capsules or the like, containing the active compound in the presence or absence of excipients to be added, may be prepared by conventional means and, if desired, May be provided. Tablets and capsules may conveniently contain from 1 to 500 mg of active compound, respectively. Other compositions for oral administration may be presented in the form of, for example, aqueous suspensions containing the active compound in an aqueous medium in the presence of a non-toxic suspending agent, such as sodium carboxymethyl-cellulose, and a suitable vegetable oil, An oily suspension containing the compound of the present invention. The active compound may be formulated into granules in the presence or absence of additional excipients. The granules may be ingested directly by the patient or may be added to a suitable liquid carrier (e. G., Water) prior to ingestion. The granules may contain a disintegrant (e.g., a pharmaceutically acceptable non-equilibrium couple formed from an acid and a carbonate or bicarbonate) to facilitate dispersion in the liquid medium. Compositions of the present invention suitable for rectal administration are in the form of pharmaceuticals known for administration, for example, as suppositories using cocoa butter or polyethylene glycol base. Compositions of the present invention suitable for non-oral administration are known pharmaceutical forms for administration, for example, aseptic suspension or sterile solution in a suitable solvent. The composition for topical administration may be a matrix in which the pharmaceutically active compound of the present invention is dispersed so that the compound is contacted with the skin to be transdermally administered. A suitable percutaneous composition may be prepared by mixing a pharmaceutically active compound with mineral oil, vaseline and / or wax, such as paraffin wax or beeswax, with an effective transdermal accelerator such as dimethylsulfoxide or propylene glycol. Alternatively, the active compound may be dispersed in a pharmaceutically acceptable cream or ointment base. The amount of active compound contained in the topical formulation is such that a therapeutically effective amount of the compound is released over a period of several hours during which the topical formulation is intended on the skin. The compounds of the invention may also be administered by external sources, for example, by intravenous infusion or continuous infusion from any of the sources of the compounds located within the body. Internal sources include implanted reservoirs. The internal source is an implanted reservoir containing infusion compounds that are continuously released by osmosis and (a) a pharmaceutically acceptable diluent, such as a very infrequent aqueous derivative such as a dodecanoate salt or ester, Or (b) an implant that may be a solid, in the form of a grafted support, for example a synthetic resin or wax material for the compound to be injected. The support may be a single portion containing all the compounds or a series of several portions containing a portion of the released compound. The amount of active compound should be such that a therapeutically effective amount of the compound present at the internal source is released over a long period of time. In some formulations, it may be beneficial to use the compounds of the present invention in the form of very small particles, for example as obtained by fluid energy milling. In the compositions of the present invention, the active compound, if desired, may be combined with other commercially available pharmaceutical active ingredients. The invention also encompasses the use of a compound of formula (I) as a medicament. A pharmaceutical composition containing a compound of formula (I) or a salt thereof or a therapeutically effective amount thereof is useful for the treatment and / or prophylaxis of depression, anxiety, psychosis (e.g. schizophrenia), bipolar disorder, Parkinson's disease, obesity, hypertension, Diabetic retinopathy, diabetic retinopathy, constipation, diabetic retinopathy, diabetic retinopathy, diabetic retinopathy, diabetic retinopathy, diabetic retinopathy, diabetic retinopathy, diabetic retinopathy, Arrhythmia, disorders of the neuroendocrine system, stress, prostatic hypertrophy, and convulsions. The precise amount of active compound administered in such treatment depends on a number of factors, such as the age of the patient, the severity of the disease, and the history of the disease, and is always dependent upon the primary care physician, The amount is in the range of 1 to 1000 mg, preferably 5 to 500 mg, which is given once or more per day, by single or divided administration. Preferably, a pharmaceutical composition containing a compound of formula (I) or a salt thereof or a therapeutically effective amount thereof is administered to a mammal, especially a human, for the treatment of depression, anxiety, psychosis (e.g. schizophrenia), bipolar dyskinesia, , Hypertension, turret syndrome, obsessive-compulsive disorder, panic attacks, social phobia, cardiovascular and cerebrovascular disorders, stress and prostate hypertrophy. Another aspect of the present invention is the use of a compound of formula I in the manufacture of a medicament for the treatment and / or prophylaxis of depression, anxiety, psychosis (e.g. schizophrenia), bipolar disorder, Parkinson's disease, obesity, hypertension, turret syndrome, sexual dysfunction, Diabetic retinopathy, diabetic neuropathy, disturbances of the nervous system, stress, diabetes mellitus, diabetes mellitus, diabetes mellitus, cognitive disorders, Alzheimer's disease, senile dementia, obsessive compulsive disorder, panic attacks, social phobia, eating disorders and anorexia, The use of a compound of formula (I) or a salt thereof in the manufacture of a medicament for treating hypertrophy or convulsions. Preferably, the compound of formula (I) or a salt thereof is used for the treatment of depression, anxiety, psychosis (e.g. schizophrenia), bipolar disorder, parkinsonism, hypertension, , Cardiovascular and cerebrovascular disorders, stress and prostate hypertrophy. The present invention also relates to the use of a compound of formula (I) for the manufacture of a medicament for the treatment of depression, anxiety, psychosis (e.g. schizophrenia), bipolar disorder, parkinsonism, obesity, hypertension, Diabetic neuropathy, diabetic neuropathy, cardiovascular and cerebrovascular disorders, non-insulin dependent diabetes mellitus, hyperglycemia, constipation, arrhythmia, neuroendocrine system disorders, such as diabetes mellitus, obesity, substance abuse, cognitive impairment, Alzheimer's disease, senile dementia, obsessive- To a mammal, particularly a human, in need of treatment for a disorder, stress, prostate hypertrophy or convulsions. Preferably, the method is used for the treatment of depression, anxiety, psychosis (e.g. schizophrenia), bipolar dyskinesia, Parkinson's disease, hypertension, turret syndrome, compulsive acts, panic attacks, social phobia, cardiovascular and cerebrovascular disorders, Stress and prostate hypertrophy. Methods for the preparation of compounds of formula (I) are described. These methods constitute a further aspect of the present invention. These methods are preferably carried out at atmospheric pressure. Compounds of formula (I) wherein Q is a group of formula (IIa) wherein R 5 is H, V is (CH 2 ) n + 1 and n is 0, Following the reaction of the compound with a compound of formula (IV), it may be prepared by reaction of the intermediate imine with a reducing agent such as sodium borohydride. Q is formula (Ⅱa) in the presence of (and R 5 is H, V is (CH 2) and n + 1, n is 0, 1 or 2) resulting solvate is optionally suitable for the formula (I), (V) wherein Y is a leaving group, for example toluene-4-sulfonyloxy, optionally in the presence of a base, for example potassium carbonate, in the presence of a base such as potassium carbonate. . Compounds of formula (I) wherein Q is a group of formula (IIa) wherein R 5 is H, V is (CH 2 ) n + 1 and n is 0, 1 or 2 can be prepared optionally in a suitable solvent, Can also be prepared by reaction of a compound of formula (VI) and a compound of formula (VII) wherein Z is a leaving group, for example toluene-4-sulfonyloxy, in the presence of a base, for example potassium carbonate have. Compounds of formula (I) wherein U is methylene and Q is a group of formula (IIa) wherein R 5 is H, V is (CH 2 ) n + 1 and n is 0, ) With a compound of formula (VI), followed by reduction of the intermediate imine to a suitable reducing agent, for example sodium borohydride. Compounds of formula (I) wherein R < 5 > is an alkyl group may be prepared by alkylation of a compound of formula (I) wherein R < 5 > is H with a reducing agent such as formaldehyde and formic acid or aldehydes and sodium cyanoborohydride . Compounds of formula (III) wherein U is (CH 2 ) m + 1 wherein m is 0, 1 or 2 can be obtained by reducing the compound of formula (IX) to a reducing agent such as lithium aluminum hydride . Compounds of formula (IX) wherein both A and B are O may be prepared by reacting a compound of formula (X) with a compound of formula (X) wherein Y is a leaving group such as halo, such as bromo, in the presence of a base, With a nitrile compound of formula (XI). The compound of formula (III) may be prepared by the reaction of E with a nitrogen atom to which it is attached is hydrolyzed with an acid or base catalyst from a cyclic imide, for example phthalimide, of formula (XII) or hydrazine hydrate . ≪ / RTI > Compounds of formula (XII) wherein E is a phthalimide with the nitrogen atom to which it is attached are prepared by reacting a compound of formula (VII) wherein Z is a leaving group such as toluene-4-sulfonyloxy with a compound of formula May also be prepared by reaction. Compounds of formula (III) wherein U is methylene may be prepared by reducing a compound of formula (XIII) to a suitable reducing agent, for example, lithium aluminum hydride. The compound of formula (XIII) may be prepared by the reaction of a compound of formula (XIV) wherein m is 0 and L is an alkyl group containing 1 to 6 carbon atoms with ammonia. Compounds of formula (IV) may be prepared by reacting a compound of formula (XV) wherein R 6 is an alkoxy group containing 1 to 4 carbon atoms with a reducing agent, such as sodium bis (2-methoxyethoxy) aluminum ≪ / RTI > Compounds of formula (XV) can be prepared by reacting a compound of formula (XVI) with a compound of formula X-CO wherein X is a leaving group such as halo, alkoxy, hydroxy or alkoxycarbonyloxy in the presence of a base such as triethylamine. HET, or by reacting it with an amide bond former such as carbonyl diimidazole in a suitable solvent such as dichloromethane. Compounds of formula (IV) may also be prepared by oxidation of compounds of formula (XVII) with a suitable oxidizing agent, for example oxalyl chloride / dimethyl sulfoxide. Compounds of formula (V) wherein Y is toluene-4-sulfonyloxy may be prepared by the reaction of a compound of formula (XVII) with a tosylating agent, such as toluene-4-sulfonyl chloride. Compounds of formula (XVII) may be prepared by reacting a compound of formula (XVIII) with a compound of formula X-CO wherein X is a leaving group such as halo, alkoxy, hydroxy or alkoxycarbonyloxy in the presence of a base such as triethylamine. HET, or by reacting it with an amide bond former such as carbonyl diimidazole in a suitable solvent such as dichloromethane. Compounds of formula (XVIII) may also be prepared by reducing a compound of formula (XVI) wherein R < 6 > is an alkoxy group containing 1-4 carbon atoms with a reducing agent such as lithium aluminum hydride. Compounds of formula (XVI) may be prepared by reacting a compound of formula (XIX) wherein D is a protecting group such as 5-bromo-2-hydroxybenzylidene with a base, such as triethylamine, Is reacted with an acylating agent of the formula X-CO.HET, which is a leaving group, such as halo, alkoxy, hydroxy or alkoxycarbonyloxy, or by subsequent reaction with an amide bond forming agent in a suitable solvent such as dichloromethane , Followed by removal of the protecting group, for example by acid-catalyzed hydrolysis. The compound of formula (XIX) may be prepared by the reaction of a compound of formula (XX) with a protecting agent, for example, 5-bromo-2-hydroxybenzaldehyde. The compounds of formula (XX) is R 6 is NH 2, for the reducing agent, for example a compound of formula (XVI), may be prepared by reduction with lithium aluminum hydride. Compounds of formula (VII) wherein Z is toluene-4-sulfonyloxy may be prepared by reaction of a compound of formula (XXI) with toluene-4-sulfonyl chloride, optionally in the presence of a base, It is possible. Compounds of formula (XXI) wherein U is (CH 2 ) m + 1 are prepared by reacting a compound of formula (XIV) wherein L is an alkyl group containing 1 to 4 carbon atoms and m is 0, 1 or 2, For example, by reduction with lithium aluminum hydride. Compounds of formula (XXI) wherein both A and B are -O- and R 2 , R 3 and R 4 are both H and U is methylene can be prepared by reacting a compound of formula (XXI) with a suitable base such as, for example, (X) with a compound of formula (XXII) wherein Z is a leaving group such as chloro or toluene-4-sulfonyloxy, for example, in the presence of a base such as, for example, water or dimethylformamide have. (S) -enantiomer of a compound of formula (XXI) when an enantiomerically pure form of a compound of formula (XXII) is used, for example, ( R ) -glycidyl-4- toluenesulfonate, . Compounds of formula (XXI) wherein both A and B are -O-, U is methylene, R 2 , R 3 and R 4 are both H and R 1 is an alkoxy group containing 1 to 3 carbon atoms, May also be prepared by alkylation of the corresponding compound of formula (XXI) wherein R < 1 > is hydroxy, in the presence of a base, e.g. sodium hydroxide, by reaction with an alkylating agent, e.g. methyl iodide. Compounds of formula (XXI) wherein both A and B are -O-, U is methylene and R 2 , R 3 and R 4 are both H can be prepared by reacting a compound of formula (XXI) wherein R 1 May be prepared by cyclisation of a compound of formula (XXIII), which is an H or an alkyl group containing 1 to 4 carbon atoms. Compounds of formula (XXIII) may also be prepared by oxidation of compounds of formula (XXIV) with a peroxy acid, for example, 3-chloroperoxybenzoic acid. Compounds of formula (XXIV) can be prepared by reacting a compound of formula (XXV) with a compound of formula (XXII) wherein Z is a leaving group, such as chloro or toluene-4-sulfonyloxy, in the presence of a base, ≪ / RTI > compounds. Compounds of formula (XXI) wherein both A and B are -O-, U is methylene, R 2 is alkyl and R 3 and R 4 are H may be prepared by reacting a compound of formula (XXVI) with an epoxide of a carbonyl compound, For example, with a reagent suitable for conversion to dimethylsulfoxonium methylide. The compound of formula (XXVI) may be prepared by the reaction of a compound of formula (X) with halomethylketone, for example, ClCH 2 COR 2 , in the presence of a base, for example potassium carbonate. Compounds of formula (XXI) wherein A and U are methylene, B is -O- and R 2 is H may be prepared by reducing the compound of formula (XXVII) to a reducing agent, such as a borane-dimethyl sulfide complex, have. The compound of formula (XXVII) may be prepared by reducing a compound of formula (XXVIII) wherein L is H, in the presence of palladium on carbon, with a reducing agent, for example, hydrogen. Compounds of formula (XXVIII) wherein L is H may be prepared by acid or base-catalyzed hydrolysis of compounds of formula (XXVIII) wherein L is an alkyl group containing 1 to 6 carbon atoms. Compounds of formula (XXVIII) wherein L is an alkyl group can be prepared by reacting a compound of formula (XXIX) with L in the presence of a base such as, for example, 1,4-diazabicyclo [2.2.2] octane (DABCO) (XXX) < / RTI > which is an alkyl group containing a carbon atom. Compounds of formula (XXIX) may be prepared by reacting a compound of formula (XXXI) wherein M is an O -protecting group, such as a 1-ethoxyethyl group, with a metallising agent such as n -butyl lithium followed by a formylating agent, For example, by the reaction of dimethylformamide. Compounds of formula (XXI) wherein A, B and U are methylene and R 2 , R 3 , and R 4 are H can be prepared by reducing the compound of formula (XXXII) to a reducing agent such as a borane-dimethyl sulfide complex . The compound of formula (XXXII) may be prepared by subjecting the compound of formula (XXXIII) to Birch reduction using, for example, lithium in liquid ammonia. The compound of formula (XXXIII) may be prepared by the reaction of a compound of formula (XXXIV) with a metallising agent, for example n -butyl lithium, followed by carbon dioxide, followed by acidification of the intermediate carboxylic acid salt. The compound of formula (VIII) can be oxidized with a suitable oxidizing agent of formula (XXI) wherein U is methylene in a solvent, such as toluene, for example, by oxidation with pyridinium chlorochromate or a compound of formula (XIV) For example, by reduction with a suitable reducing agent such as sodium bis (2-methoxyethoxy) aluminum hydride. Compounds of formula (XIV) wherein both A and B are -O- can be prepared by reacting a compound of formula (XIV) wherein Y is a leaving group such as bromo and L is 1 to 6 carbon atoms in the presence of a base, May be prepared by the reaction of a compound of formula (XXXV) with a compound of formula (X). Compounds of formula (XIV) wherein A is methylene, B is -O-, m is 0, R 2 is H and L is an alkyl group containing 1 to 6 carbon atoms may be prepared by reacting a compound of formula , By reducing a compound of formula (XXVIII) wherein L is an alkyl group containing 1 to 6 carbon atoms with a suitable reducing agent, for example, hydrogen. (XIV), wherein A and B are both methylene, m is 0, R 2 is H, and L is an alkyl group containing 1 to 6 carbon atoms, can be prepared by reacting a compound of formula May also be prepared by esterifying a compound of formula (XXXII) with an alcohol of formula LOH. (I) wherein Q is a group of formula (IIa) may be prepared by reaction of a compound of formula (XXXVI) wherein D 'is H, optionally in the presence of a base such as potassium carbonate and optionally in a solvent such as acetonitrile (VII) wherein Z is a leaving group such as toluene-4-sulfonyloxy. D 'is H, a compound of formula (XXXVI) is D' is a protecting group, e.g., t-butoxycarbonyl in the presence of acetic acid for deprotection, examples of the compound of formula (XXXVI) with g., Trifluoromethyl under May be prepared by acid hydrolysis. D 'the protecting groups A compound of formula (XXXVI) is D' is a protecting group, e.g., tert-butoxycarbonyl is, for the base, for a compound of formula (XXXVII), in the presence of triethylamine, X Is reacted with a compound of formula X.CO.HET wherein R < 1 > is a leaving group such as halo, alkoxy, hydroxy or alkoxycarbonyloxy, or by reaction with an amide bond former in a suitable solvent such as dichloromethane, Carbonyldiimidazole. ≪ / RTI > (XXXVI) wherein D 'is a protecting group and HET completes a heteroaromatic ring and R is H or alkyl is a group of formula (XXXVIII) can be prepared from a compound of formula (XXXVI) in a solvent such as 1,2-dimethoxyethane May be prepared by reaction of a compound of formula (XXXVII) with a compound of formula (XXXIX) wherein Y is a heteroaromatic ring and R is H or an alkyl group. Compounds of formula (I) wherein Q is a group of formula (IIb) may be prepared by treating a compound of formula (XL) with a leaving group such as, for example, halo, alkoxy, hydroxy Or with an acylating agent of the formula X-CO.HET, which is alkoxycarbonyloxy, or by reaction with an amide bond former such as carbonyldiimidazole in a suitable solvent such as dichloromethane. Compounds of formula (I) wherein Q is a group of formula (IIb) may be obtained by reaction of a compound of formula (VII) wherein Z is a leaving group such as toluene-4-sulfonyloxy, optionally in the presence of a base, (XLI) < / RTI > in the presence of a base. The compound of formula (XL) may be prepared from an acid or base catalyzed hydrolysis or reagent from a compound of formula (XLII) wherein E is a cyclic imide, for example phthalimide, with the nitrogen atom to which it is attached, For example, by decomposition with hydrazine hydrate. Compounds of formula (XLII) wherein E is, for example, phthalimide and R < 5 > is H, together with the nitrogen atom to which it is attached, may optionally be reacted with a compound of formula (III) in the presence of a base, May also be prepared by reacting a compound with a haloalkyl phthalimide, for example N - (3-bromopropyl) phthalimide. The formula of formula (I) wherein Q is a group of formula (IIb) can be prepared by reacting a compound of formula (XLIII) wherein D 'is H, optionally in the presence of a base such as potassium carbonate, optionally in a solvent such as acetonitrile, With a compound of formula (VII) wherein Z is a leaving group such as toluene-4-sulfonyloxy. D 'is H, a compound of formula (XLIII) is D' is a protecting group, e.g., tert-butoxycarbonyl is e. Deprotection, examples of the compound of formula (XLIII), in the presence of trifluoroacetic acid May be prepared by acid hydrolysis. D 'a protecting group Compounds of formula (XLIII) is D' is a protecting group, e.g., tert-butoxycarbonyl the base of a compound of formula (XLIV), for example, the X in the presence of triethylamine Is reacted with a compound of formula X.CO.HET which is a leaving group such as halo, alkoxy, hydroxy or alkoxycarbonyloxy, or by reaction with an amide bond former such as, for example, Lt; / RTI > with a boron diimidazole. (XLIII) wherein D 'is a protecting group and HET is a group of formula (XXXVIII) wherein Y is a heteroaromatic ring and R is H or alkyl may be prepared by reacting a compound of formula (XLIII) May be prepared by reaction of a compound of formula (XLIV) with a compound of formula (XXXIX) wherein Y is a heteroaromatic ring and R is H or an alkyl group. (I) wherein Q is a group of formula (IIc) can be prepared by reacting a compound of formula (XLV) wherein D 'is H, optionally in the presence of a base such as potassium carbonate and optionally in a solvent such as acetonitrile (VII) wherein Z is a leaving group such as toluene-4-sulfonyloxy. The presence of such butoxycarbonyl is e. Deprotection, examples of the compound of formula (XLV), trifluoroacetic acid - D 'is H, a compound of formula (XLV) is D' is a protecting group, for example, tertiary Lt; / RTI > acid hydrolysis. D 'the protecting groups A compound of formula (XLV) is D' is a protecting group, e.g., tert-butoxycarbonyl is, for the base, for a compound of formula (XLVI), in the presence of triethylamine, X Is reacted with a compound of formula X.CO.HET wherein R < 1 > is a leaving group such as halo, alkoxy, hydroxy or alkoxycarbonyloxy, or by reaction with an amide bond former in a suitable solvent such as dichloromethane, Carbonyldiimidazole. ≪ / RTI > (XLV) wherein D 'is a protecting group, HET completes a heteroaromatic ring and R is H or alkyl is a group of the formula (XXXVIII) can be prepared from a compound of formula (XLV) in a solvent such as 1,2-dimethoxyethane , A compound of formula (XLVI) may be prepared by reacting a compound of formula (XXXIX) wherein Y is a heteroaromatic ring and R is H or alkyl. Compounds of formula (I) wherein Q is a group of formula (IIc) can be prepared by reacting a compound of formula (XLVII) with a compound of formula (XXXIX), optionally in the presence of a solvent, for example 1,2-dimethoxyethane, , The pyrido [2,3- d ] [1,3] oxazine-2,4 (1H) -dione. Compounds of formula (XLVII) wherein R < 5 > is H may be prepared by acid or base catalyzed hydrolysis of compounds of formula (XLVIII) wherein D is a protecting group, for example 5-bromo-2-hydroxybenzylidene . Compounds of formula (XLVIII) may be prepared by reaction of a compound of formula (XLIX) wherein D is a protecting group, for example 5-bromo-2-hydroxybenzylidene, with a compound of formula XLVIII, optionally in the presence of a base, Lt; RTI ID = 0.0 > (VII) < / RTI > Compounds of formula (XLIX) may be prepared by the reaction of a compound of formula (L) with a protecting group, for example, 5-bromo-2-hydroxybenzaldehyde. Compounds of formula (I) wherein Q is of formula (IIc) may also be prepared by reacting a compound of formula (XLVII) with a leaving group such as halo, alkoxy, hydroxy Or with an acylating agent of the formula X-CO.HET, which is alkoxycarbonyloxy, or by reaction with an amide bond former such as carbonyl diimidazole or N , N ' -diisobutyl ketone in a suitable solvent such as dichloromethane Lt; / RTI > with carbodiimide The present inventors have found that compounds that inhibit the binding of tritium screen on 5-hydroxy tryptamine (5-HT) the ability of the Formula (I) that interacts with the receptor, in vitro 5-HT receptor, especially 5-HT 1A receptors ≪ RTI ID = 0.0 > ability. ≪ / RTI > Hippocampal tissues from the brains of male Sprague-Dawley rats (150-250 g body weight range) were suspended in ice-cold 50 mM Tris-HCl buffer (pH 7.7, 1:40 w / v when measured at 25 ° C) Homogenized and centrifuged at 30,000 g for 10 minutes at 4 ° C. The pellet was re-homogenized in the same buffer, incubated at 37 ° C for 10 minutes, and centrifuged at 30,000 g at 4 ° C for 10 minutes. The final pellet was reconstituted in 50 mM Tris-HCl buffer (pH 7.7) containing 4 mM CaCl 2 , 0.1% L-ascorbic acid and 10 μM pargyline hydrochloride (amount corresponding to 6.25 mg wet mass / Lt; / RTI > and used immediately for binding analysis. (50 μl; 2 nM) and distilled water (50 μl total binding) or 5-HT (50 μl; 10 μM) were added to this suspension (400 μl; 2.5 mg wet weight / ; it was added to the tube containing from 10 -6 M 10 gae concentration of 10 -11 to 10 -3 M range or at a single concentration); non-specific binding) or test compound (50 ㎕. The ligand was [ 3 H] 8-hydroxy-2- (dipropylamino) tetralin ([ 3 H] 8-OH-DPAT), and the mixture was incubated at 25 ° C. for 30 minutes, The culture was terminated. The filter was washed with ice cold Tris-HCl buffer and dried. The filter was punched into the vial, scintillation fluid added, and radioactivity determined by liquid scintillation counting. Percentage substitution of the specific binding of the tritiated ligand was calculated for a single concentration (10 -6 M) of the test compound. Subsequently, substitution curves were generated for compounds in which more than 50% of the specific binding of the tritiated ligand at 10 <" 6 > M was substituted using a range of concentrations of the compound. Concentration (IC 50 ) representing 50% inhibition of specific binding was obtained from the curve. The inhibitory correlation coefficient K i was then calculated using the equation: [ligand] is the concentration of the tritiated ligand used and K D is the equilibrium dissociation constant for the ligand. The present inventors have found that the ability of the compounds of formula (I) to interact with adrenoceptor binding sites, in vitro-adrenergic receptor, in particular, α 1 - examination of the following to determine the ability of compounds to inhibit the tritium screen ligand binding to the adrenergic receptors Lt; / RTI > Whole cortical tissue from the brains of male Charles River CD rats weighing 150 to 250 g was homogenized in ice-cold 50 mM Tris-HCl, pH 7.6 (at 25 ° C; 1:40 w / v) , And centrifuged at 4 ° C for 10 minutes. The pellet was re-homogenized in 50 mM Tris-HCl, pH 7.6 (1:40 w / v) and centrifuged at 30,000 g at 4 ° C for 10 minutes. The final pellet was re-homogenized in 50 mM Tris-HCl, pH 7.6 (an amount corresponding to 6.25 mg wet weight / ml of tissue) and used immediately for binding analysis. (50 μl; 0.1 μM) and distilled water (50 μl; total binding) or phentolamine (50 μl; 5 μM) were added to this suspension (400 μl; amount corresponding to 5 mg wet weight / ; it was added to the tube containing from 10 -6 M 10 gae concentration of 10 -11 to 10 -3 M range or at a single concentration); non-specific binding) or test compound (50 ㎕. Ligands - was [7-methoxy-3 H] prazosin and the mixture was cultured at 30 ℃ for 30 minutes to terminate the culture by rapid filtration. The filter was washed with ice cold Tris-HCl buffer and dried. The filter was punched into the vial, scintillation fluid added, and radioactivity determined by liquid scintillation counting. Percentage substitution of the specific binding of the tritiated ligand was calculated for a single concentration (10 -6 M) of the test compound. Subsequently, substitution curves were generated for compounds in which more than 50% of the specific binding of the tritiated ligand at 10 <" 6 > M was substituted using a range of concentrations of the compound. Concentration (IC 50 ) representing 50% inhibition of specific binding was obtained from the curve. The inhibitory correlation coefficient K i was then calculated using the equation: [ligand] is the concentration of the tritiated ligand used and K D is the equilibrium dissociation constant for the ligand. The inventors have demonstrated the ability of compounds of formula (I) to interact with an a 2 -adrenergic receptor binding site by the ability of a compound to inhibit tritiated ligand binding to in vitro α 1 -adrenergic receptors, particularly α 2A -adrenoceptors ≪ / RTI > The post-hoc cerebral cortex was homogenized in ice-cold 0.25 M sucrose (1:30 w / v) and centrifuged at 1000 g at 4 ° C for 12 minutes. The supernatant was stored on ice and the pellet was re-homogenized in 0.25 M sucrose (1:15 w / v) and centrifuged at 850 g, 4 ° C for 12 minutes. The combined supernatants were diluted with 5 mM Tris-HCl containing 5 mM ethylenediaminetetraacetic acid (EDTA) and readjusted to pH 7.5 (at 25 ° C) using 1:80 w / v 1 M sodium hydroxide , And centrifuged at 11,000 g and 4 ° C for 10 minutes. The resulting pellet was resuspended in 50 mM Tris-HCl (pH 7.5) containing 5.68 mM L-ascorbic acid and 0.5 mM EDTA and eluted with 1:80 w / v 1 M sodium hydroxide to pH 7.5 (25 Lt; 0 > C) and centrifuged at 11,000 g for 10 minutes. The pellet was stored at -80 < 0 > C. On the day of analysis, the pellet was thawed and resuspended in 50 mM Tris-HCl (pH 7.5) containing 5.68 mM L-ascorbic acid and 1: 80 w / v 5 mM EDTA and incubated at 11,000 g for 10 min And centrifuged. The final pellet was resuspended in 50 mM Tris-HCl (pH 7.5) containing 5.68 mM L-ascorbic acid and 5 mM EDTA (an amount corresponding to 25 mg wet weight / ml of tissue). (50 μl; 0.2 μM) and distilled water (50 μl; total binding) or phentolamine (50 μl; 50 μM) were added to the aliquot of the suspension (400 μL; ; it was added to the tube containing from 10 -6 M 10 gae concentration of 10 -11 to 10 -3 M range or at a single concentration); non-specific binding) or test compound (50 ㎕. Ligands tritium screen RX 821002 - was (2- (2-methoxy -1,4- [6,7 (n) 3 H ] benzodioxane-2-yl) -2-imidazoline), and the mixture After culturing at 0 DEG C for 75 minutes, the culture was terminated by rapid filtration. The filter was washed with ice cold Tris-HCl buffer and dried. The filter was punched into the vial, scintillation fluid added, and radioactivity determined by liquid scintillation counting. Percentage substitution of the specific binding of the tritiated ligand was calculated for a single concentration (10 -6 M) of the test compound. Subsequently, substitution curves were generated for compounds in which more than 50% of the specific binding of the tritiated ligand at 10 <" 6 > M was substituted using a range of concentrations of the compound. Concentration (IC 50 ) representing 50% inhibition of specific binding was obtained from the curve. The inhibitory correlation coefficient K i was then calculated using the equation: [ligand] is the concentration of the tritiated ligand used and K D is the equilibrium dissociation constant for the ligand. We have tested the ability of a compound of formula (I) to interact with an adrenergic receptor binding site in the following tests to determine the ability of a compound to inhibit tritiated ligand binding to in vitro adrenergic receptors, in particular to the 2D -adrenergic receptor Lt; / RTI > Frontal cortical tissue from the brain of male Charles River CD rats weighing 150 to 250 g was homogenized in ice-cold 0.25 M sucrose (1:30 w / v) and centrifuged at 1000 g for 12 minutes at 4 ° C. The supernatant was stored on ice and the pellet was re-homogenized in 0.25 M sucrose (1:15 w / v) and centrifuged at 850 g, 4 ° C for 12 minutes. The combined supernatants were diluted in 5 mM Tris-HCl, pH 7.5 (25 캜) containing 5 mM ethylenediaminetetraacetic acid (EDTA) and diluted with 1:80 w / v 1 M sodium hydroxide at pH 7.5 ), And centrifuged at 30,000 g for 10 minutes. The resulting pellet was resuspended in 50 mM Tris-HCl (pH 7.5) containing 5.68 mM L-ascorbic acid and 0.5 mM EDTA and resuspended to pH 7.5 (at 25 ° C) with 1 M sodium hydroxide to give 30,000 g Lt; / RTI > for 10 minutes. The final pellet was resuspended in 50 mM Tris-HCl (pH 7.5) containing 5.68 mM L-ascorbic acid and 5 mM EDTA (the amount corresponding to 12.5 mg wet weight / ml of tissue) Respectively. The suspension (50 μl; 1 nM) and distilled water (50 μl; total binding) or phentolamine (50 μl; 5 μM) were added to the aliquot of this suspension (400 μL; ; it was added to the tube containing from 10 -6 M 10 gae concentration of 10 -11 to 10 -3 M range or at a single concentration); non-specific binding) or test compound (50 ㎕. Ligands tritium screen is joksan - was ((1,4- [6,7 (n) 3 H] benzodioxane-2-yl) -2-imidazoline hydrochloride), for 75 minutes the mixture at 0 ℃ After culturing, the culture was terminated by rapid filtration. The filter was washed with ice cold Tris-HCl buffer and dried. The filter was punched into the vial, scintillation fluid added, and radioactivity determined by liquid scintillation counting. Percentage substitution of the specific binding of the tritiated ligand was calculated for a single concentration (10 -6 M) of the test compound. Subsequently, substitution curves were generated for compounds in which more than 50% of the specific binding of the tritiated ligand at 10 <" 6 > M was substituted using a range of concentrations of the compound. Concentration (IC 50 ) representing 50% inhibition of specific binding was obtained from the curve. The inhibitory correlation coefficient K i was then calculated using the equation: [ligand] is the concentration of the tritiated ligand used and K D is the equilibrium dissociation constant for the ligand. We have tested the ability of compounds of formula (I) to interact with dopamine receptor binding sites by the following test to determine the ability of compounds to inhibit tritiated ligand binding to in vitro dopamine receptors, particularly the D2 dopamine receptor Proved Line tissue from the brains of male Charles River CD rats weighing 140-250 g was homogenized in ice-cold 50 mM Tris-HCl (pH 7.7 when measured at 25 ° C) and centrifuged at 40,000 g for 10 min. The pellet tris salt buffer solution; the (120 mM NaCl with the addition of 6 mM ascorbic acid, 5 mM KCl, 2 mM CaCl 2 and 1 mM MgCl 2 50 mM Tris -HCl pH 7.7 containing, as measured at 25 ℃) Re-homogenized and similarly centrifuged at 40,000 g for 10 min. The final pellet was stored at -80 < 0 > C. Prior to each test, the pellet was resuspended in Tris salt buffer (an amount corresponding to 2 mg wet weight / ml of tissue). The suspension (40 μl; 10 nM) and Tris-salt buffer (40 μl; total binding) or spiroperi- stone (10 μM) were added to the aliquot of this suspension (720 μl; 1.44 mg wet weight / 40 [mu] l; 1 nM; non-specific binding) or the test compound (40 [mu] l at 6 concentrations ranging from 10 -11 to 10 -4 M at a single concentration of 10 -6 M). The ligand was tritiated ( S ) -sulfuride, and the mixture was incubated at 4 ° C for 40 minutes and then terminated by rapid filtration. The filter was washed with ice cold Tris-HCl buffer and dried. The filter was punched into the vial, scintillation fluid added, and radioactivity determined by liquid scintillation counting. Percentage substitution of the specific binding of the tritiated ligand was calculated for a single concentration (10 -6 M) of the test compound. Subsequently, substitution curves were generated for compounds in which more than 50% of the specific binding of the tritiated ligand at 10 <" 6 > M was substituted using a range of concentrations of the compound. Concentration (IC 50 ) representing 50% inhibition of specific binding was obtained from the curve. The inhibitory correlation coefficient K i was then calculated using the equation: [ligand] is the concentration of the tritiated ligand used and K D is the equilibrium dissociation constant for the ligand. The K i values obtained in the above test for the 5-HT 1A , α 1 , α 2A , α 2D and D 2 bonds for each final product are shown in Tables 1a, 1b and 1c below. The percentages of Tables 1a, 1b and 1c are% substitutions of the appropriate radioligand at 10-6 M. NT means not tested. The invention is illustrated by the following examples given by way of example only. The final product of each of these embodiments may be one or more of the following methods; Gas-liquid chromatography; High performance liquid chromatography; Elemental analysis, nuclear magnetic resonance spectroscopy and infrared spectroscopy. ≪ Example 1 > A mixture of 10.0 g of ( R ) -glycidyl 4-toluenesulfonate, 8.92 g of 5-chloro-2-hydroxybenzaldehyde and 7.87 g of potassium carbonate in 200 ml of dimethylformamide was stirred and heated at 60 DEG C for 5 hours And allowed to stand for 18 hours. Water (200 mL) was added and the resulting mixture was extracted with ether (3 x 150 mL). The combined ether extracts were washed with brine (3 x 150 mL), dried over magnesium sulfate, and the solvent was evaporated. The oily residue was purified by flash chromatography on silica eluting with petroleum ether (boiling point 40-60 ° C) and 25: 1, then 10: 1 mixture of ethyl acetate to give 10% R) -5-chloro-2- (2,3-epoxypropoxy) benzaldehyde, 8.1 g, which was used without further purification. A mixture of 8.1 g of the product from the previous reaction and 9.2 g of 3-chloroperoxybenzoic acid (85%) in 100 ml of dichloromethane was heated at reflux temperature for 20 hours and then cooled in ice water. The precipitate was filtered and the filtrate was washed with a saturated aqueous sodium metabisulfite solution (100 ml), a saturated aqueous sodium bicarbonate solution (2 x 100 ml) and brine (100 ml), and then dried over magnesium sulfate. The solvent was evaporated to give 7.98 g of (R) -5-chloro-2- (2,3-epoxypropoxy) phenyl formate, containing less than 10% of undetermined impurities, as an orange oil which was used without further purification . 0.25 g of sodium metal was dissolved in 20 ml of methanol under nitrogen and a solution of 2.0 g of the product from the previous reaction in 30 ml of methanol was added dropwise. The resulting mixture was stirred for 1 hour, then heated at reflux temperature for 2 hours and allowed to stand at ambient temperature for 18 hours. The solvent was removed in vacuo and the residue partitioned between 100 mL ether and 100 mL water. The ether layer was washed with 100 ml of water and dried over magnesium sulfate. The solvent was evaporated to give (S) -7-chloro-1,4-benzodioxan-2-ylmethanol as a yellow oil (1.67 g). 5.9 g of 4-toluenesulfonyl chloride was added to a solution of 6.0 g of (S) -7-chloro-1,4-benzodioxan-2-ylmethanol (prepared by the method described above) in 40 ml of pyridine, The mixture was stirred for 4 hours. Another 250 mg of 4-toluenesulfonyl chloride was added and stirring was continued for 2 hours, then 250 mg of additional 4-toluenesulfonyl chloride was added and stirring was continued for 1 hour. The mixture was poured into 200 ml of water and extracted with ethyl acetate (2 x 200 ml). The combined extracts were washed with hydrochloric acid (2 M; 2 x 200 mL), saturated aqueous sodium bicarbonate (2 x 200 mL) and brine (200 mL) and then dried over magnesium sulfate. The solvent was removed in vacuo and the residue was recrystallized from ether to give 7.00 g of (R) -7-chloro-1,4-benzodioxan-2-ylmethyl 4-toluenesulfonate with a melting point of 90-91 占 폚. A mixture of 170 g of 5-bromo-2-hydroxybenzaldehyde and 96.9 g of 4- (aminomethyl) piperidine in 2.5 L of ethanol was stirred at ambient temperature for 3 hours. The solvent was removed under vacuum to obtain 267 g of 4-bromo-2- [ N - (4-piperidylmethyl) iminomethyl] phenol with a melting point of 35-38 DEG C as a yellow solid. A mixture of 6.87 g of the product from the previous reaction in 160 ml of acetonitrile, 4.1 g of (R) -7-chloro-1,4-benzodioxan-2-ylmethyl 4-toluenesulfonate and 1.6 g of potassium carbonate was stirred at reflux temperature And heated for 18 hours. After cooling and filtration, the solvent was removed in vacuo and the residue was purified by flash chromatography on silica eluting with a 1: 2 mixture of ethyl acetate and petroleum ether (boiling point 60-80 ° C) followed by pure ethyl acetate. The appropriate fractions were combined and the solvent was removed in vacuo to give (S) -4-bromo-2- { N- [1- (7-chloro-1,4-benzodioxan- Ylmethyl] iminomethyl} phenol (4.0 g) as a yellow oil. 4.0 g of the product from the previous reaction in a mixture of 30 ml of aqueous potassium hydrogen sulfate solution (1 M) and 5 ml of industrial methyl alcohol was heated at 70 DEG C for 5 minutes and then stirred at ambient temperature for 1 hour. The mixture was washed with ether (3 x 50 mL), and then a saturated aqueous solution of sodium carbonate was added to obtain a pH of 11. The mixture was extracted with dichloromethane (3 x 50 mL) and the combined extracts were dried over magnesium sulfate and the solvent was evaporated to give (S) -4- (aminomethyl) -1- (7- , 4-benzodioxan-2-ylmethyl) piperidine (1.94 g) as a colorless oil. 1.0 g of the product from the previous reaction and 0.55 g of pyrido [2,3- d ] [1,3] oxazine-2,4- (1 H ) -dione in 30 ml of 1,2- ≪ / RTI > for 16 hours. The solvent was removed in vacuo and the residue was purified by flash chromatography on silica eluting with a 97: 3, then 95: 5 mixture of dichloromethane and methanol. The appropriate fractions were combined and the solvent was removed in vacuo. Trituration of the residue with ether, melting point 150-152 ℃, [α] D -50.65 ° (c = 0.918, MeOH) (S) - (-) - 2- amino - N - {[1- (7- chloro- Benzodioxan-2-ylmethyl) -4-piperidyl] methyl} pyridine-3-carboxamide (0.80 g). ≪ Example 2 > A stirred mixture of 4.4 g of 2-chloro-6-hydroxybenzaldehyde, 5.0 g of (R) -glycidyl 4-toluenesulfonate and 3.9 g of potassium carbonate in 120 ml of dimethylformamide was heated at 60 DEG C for 5 hours , And allowed to stand at ambient temperature for 18 hours. The solvent was removed in vacuo, 60 mL of water was added, and the mixture was extracted with ether (3 x 100 mL). The combined extracts were dried over magnesium sulfate and the solvent was evaporated. The residue was purified by flash chromatography on silica eluting with petroleum ether (boiling point 60-80 占 폚) and 1: 1 mixture of dichloromethane followed by a 19: 1 mixture of dichloromethane and industrial methyl alcohol. The appropriate fractions were combined and the solvent removed in vacuo to give 2.8 g of (R) -2-chloro-6- (2,3-epoxypropoxy) benzaldehyde, mp 62-64 ° C. The product from the previous reaction in 200 ml of dichloromethane 2.8. and 4.8 g of 3-chloroperoxybenzoic acid (85%) in acetonitrile (5 ml) was heated at reflux for 18 hours. Additional 4.8 g of 3-chloroperoxybenzoic acid was added and refluxing was continued for 6 hours. The mixture was washed with a saturated aqueous sodium bicarbonate solution (3 x 200 mL) and then dried over magnesium sulfate. The solvent was evaporated in vacuo to give 2.8 g of (R) -2-chloro-6- (2,3-epoxypropoxy) phenyl formate as a yellow solid. A stirred solution of 2.8 g of the product from the previous reaction in 20 ml of aqueous sodium hydroxide solution (2.5 M) was heated at reflux temperature for 1.5 hours. The cooled solution was extracted with dichloromethane (2 x 30 mL) and the combined extracts were dried over magnesium sulfate and the solvent was removed in vacuo to give (S) -8-chloro-1,4-benzodioxan- -One methanol (1.63 g) as a yellow oil. A solution of 1.7 g of 4-toluenesulfonyl chloride in 10 ml of pyridine is added dropwise to a solution of 1.63 g of the product of the previous reaction in 30 ml of pyridine and the mixture is stirred at ambient temperature for 4 hours and then at 50 DEG C for 30 minutes Lt; / RTI > The cooled solution was poured into 50 mL of hydrochloric acid (5 M) and then extracted with dichloromethane (3 x 50 mL). The combined extracts were dried over magnesium sulfate and the solvent removed in vacuo to give (R) -8-chloro-1,4-benzodioxan-2-ylmethyl 4-toluenesulfonate as an orange oil (2.33 g). 1,2-dimethoxyethane and 30 ㎖ of 4- (aminomethyl) -1- (tert-butoxycarbonyl) piperidine 2.0 g and pyrido [2,3 d] [1,3] oxazin- 2,4- (1 H) - dione a mixture of 1.53 g was stirred for 3 h at ambient temperature. The solvent was removed in vacuo and the residue was purified by flash chromatography on silica eluting with dichloromethane, followed by a 19: 1 mixture of dichloromethane and industrial methyl alcohol. The appropriate fractions were combined, the solvent was removed in vacuo 2-amino-N - [(1- 3-tert-butoxycarbonyl-4-piperidyl) methyl] pyridine-3-carboxamide was obtained a 1.7 g. Of acetic acid 9 ㎖ dichloromethane 50 ㎖ trifluoroacetate 2-Amino-N - [(1- 3-tert-butoxycarbonyl-4-piperidyl) methyl] pyridine-3-carboxamide (similar to that described above 2.2 g) and heated at ambient temperature for 1 hour. The solvent was evaporated in vacuo to give crude 2-amino- N- (4-piperidylmethyl) pyridine-3-carboxamide trifluoroacetate. A mixture of this material in 70 ml of acetonitrile, 2.3 g of (R) -8-chloro-1,4-benzodioxan-2-ylmethyl 4-toluenesulfonate and 3.6 g of potassium carbonate was heated at reflux temperature for 6 hours Respectively. The solvent was removed in vacuo, 50 ml of water was added to the residue, and the mixture was extracted with dichloromethane (2 x 30 ml). The combined organic layers were extracted with hydrochloric acid (2.5 M; 2 x 30 mL), and the combined extracts were basified with aqueous sodium hydroxide (5 M) and extracted with dichloromethane (2 x 30 mL). The combined organic layers were dried over magnesium sulfate and the solvent was removed in vacuo. The residue was purified by flash chromatography eluting with silica in a 9: 1 mixture of dichloromethane and methanol. The appropriate fractions were combined, the solvent was removed in a vacuum melting point 62-70 ℃, [α] D -35.47 ° (c = 0.888, MeOH) (S) -2- amino - N - {[1- (8- chloro -1,4-benzodioxan-2-ylmethyl) -piperidyl] methyl} -pyridine-3-carboxamide (1.0 g). ≪ Example 3 > 15.9 mL of a solution of butyllithium in hexane (2.5 M) was added to a stirred solution of 5.0 g of 3-fluoroanisole in 100 mL of tetrahydrofuran anhydride at -78 < 0 > C and the mixture was stirred at that temperature for 30 minutes . 3.1 ml of dimethylformamide anhydride were added and the mixture was stirred and warmed to ambient temperature for 1 hour. 150 ml of water were added and the mixture was extracted with ethyl acetate (3 x 100 ml). The combined extracts were washed with 100 ml brine, dried over magnesium sulfate and the solvent evaporated in vacuo. The residue was distilled off under reduced pressure to obtain 4.6 g of 2-fluoro-6-methoxybenzaldehyde having a boiling point of 120 DEG C at 10.66 mbar as an oil. 20.15 mL of a solution of boron tribromide (1 M) in dichloromethane was added dropwise to a stirred solution of 4.66 g of 2-fluoro-6-methoxybenzaldehyde (prepared as described above) in 40 mL of dichloromethane at -78 < . The mixture was allowed to warm to ambient temperature and then 150 mL of water was added and the mixture was extracted with dichloromethane (3 x 100 mL). The combined extracts were washed with 100 ml of water, then brine (100 ml) and the solvent was evaporated. The residue was evaporated under reduced pressure to give 2.0 g of 2-fluoro-6-hydroxybenzaldehyde at a boiling point of 60 DEG C at 4.66 mbar contaminated with 7% starting methoxy compound, which was used without further purification A mixture of 1.7 g of the product from the previous reaction in 50 ml of dimethylformamide, 2.1 g of (R) -glycidyl 4-toluenesulfonate and 1.68 g of potassium carbonate was stirred and heated at 60 DEG C for 5 hours. After stirring at ambient temperature for 18 hours, the mixture was poured into 150 mL of water and then extracted with ethyl acetate (3 x 100 mL). The combined extracts were washed with 100 ml brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the oily residue was passed through a pad of silica gel, eluting with a 1: 2 mixture of ethyl acetate and petroleum ether (boiling point 60-80 [deg.] C). The solvent was removed under vacuum to obtain 0.71 g of (R) -2- (2,3-epoxypropoxy) -6-fluorobenzaldehyde as an oil. A mixture of 0.71 g of the product from the previous reaction and 0.87 g of 3-chloroperoxybenzoic acid (85%) in 100 ml of dichloromethane was heated at reflux temperature for 3 hours. Additional 0.87 g of 3-chloroperoxybenzoic acid was added and refluxing was continued for 18 hours. The mixture was poured into 250 mL of a saturated aqueous solution of sodium carbonate and extracted with dichloromethane (3 x 100 mL). The combined extracts were washed with 100 ml of brine then dried over magnesium sulfate and the solvent was evaporated in vacuo to give 0.34 g of (R) -2- (2,3-epoxypropoxy) -6-fluorophenylformate as an oil . 0.89 g of sodium metal was dissolved in 100 ml of methanol and 6.56 g of (R) -2- (2,3-epoxypropoxy) -6-fluorophenylformate (prepared as described above) in 100 ml of methanol The solution was added dropwise. The mixture was stirred at ambient temperature for 1 hour, then heated at reflux temperature for 2 hours, allowed to stand for 3 days and then heated at reflux temperature for 4 hours. The solvent was removed in vacuo, 100 ml of water were added, and the mixture was extracted with ethyl acetate (4 x 100 ml). The combined extracts were washed with brine (100 mL), dried over magnesium sulfate and the solvent was evaporated in vacuo to give 3.85 g of (S) -8-fluoro-1,4-benzodioxan- It was used without purification. 4.1 g of 4-toluenesulfonyl chloride was added to a solution of 3.85 g of the crude product from the previous reaction in 50 ml of pyridine and the mixture was stirred for 18 hours and then poured into 100 ml of hydrochloric acid (5 M). The mixture was extracted with ethyl acetate (3x100ml) and the combined extracts were washed with brine (100ml) and dried over magnesium sulfate. The solvent was removed in vacuo to give 4.1 g of (R) -8-fluoro-1,4-benzodioxan-2-ylmethyl 4-toluenesulfonate which was used without further purification. 7.21 g of crude 2-amino- N- (4-piperidylmethyl) pyridine-3-carboxamide (prepared by a method similar to that described in Example 2), 4.15 g of potassium carbonate and R) -8-fluoro-1,4-benzodioxan-2-ylmethyltoluene-4-sulfonate was heated under reflux for 16 hours. After cooling and filtration, the solvent was removed in vacuo and the residue was purified by chromatography on silica eluting with pure ethyl acetate. The appropriate fractions were combined and the solvent removed in vacuo to give 1.5 g of a solid. 0.78 g of this solid was dried under vacuum and polishing with a melting point 115-116 ℃, [α] D -39.09 ° solvate of (c = 0.967, methanol), (S) - (- ) - 2- amino - N - { 4-piperidyl] methyl} pyridine-3-carboxamide 0.5 hydrate 0.15 Ethyl acetate (610 mg) was obtained. <Example 4> 0.82 g of 1,4-benzodioxan-2-ylmethyltoluene-4-sulfonate in 50 ml of acetonitrile was added dropwise to a solution of 2-amino- N- (4-piperidylmethyl) pyridine-3- Acetate (prepared by a method similar to that described in Example 2) and 1.4 g of potassium carbonate was heated at reflux temperature for 6 hours. After cooling, the solvent was removed in vacuo, 60 ml of water was added to the residue, and the product was extracted with dichloromethane (2 x 30 ml). The extract was dried over magnesium sulfate and the solvent was removed in vacuo to give an oil. The oil was purified by flash chromatography eluting with silica in a 1: 1 mixture of dichloromethane and methanol. The appropriate fractions were combined and the solvent removed under vacuum to give an oil. Ethyl maleic acid (20 mL) was added to obtain a white solid. The solid was collected by filtration, washed with ether and the solvent removed in vacuo to give 2-amino- N - {[1- (1,4-benzodioxan-2- ylmethyl) -4-piperidyl] methyl} pyridine-3-carboxamide 0.5 maleate (95 mg). ≪ Example 5 > A mixture of 7.1 g of 2-hydroxy-5-methylbenzaldehyde, 11.9 g of (R) -glycidyl 4-toluenesulfonate and 7.25 g of potassium carbonate in 150 ml of 1,2-dimethoxyethane anhydride was stirred, For 5 hours, allowed to stand at ambient temperature for 18 hours, heated at 60 < 0 > C for an additional 8 hours and then cooled for 18 hours. The solvent was removed in vacuo and the residue was partitioned between 250 mL of water and 250 mL of ether. The mixture was filtered through Celite, the ether layer was separated, washed with water and dried over magnesium sulfate. The solvent was evaporated and the residue was purified by flash chromatography eluting on silica with a 1: 1 mixture of ether and petroleum ether (boiling point 40-60 C). The appropriate fractions were combined and the solvent was evaporated in vacuo to give 8.91 g of (R) -2- (2,3-epoxypropoxy) -5-methylbenzaldehyde as an oil A solution of 8.91 g of the product from the previous reaction and 19.6 g of 3-chlorooxybenzoic acid (86%) in 250 ml of dichloromethane was heated at ambient temperature for 18 hours. The solution was washed with dilute sodium bicarbonate solution (2 x 200 mL) followed by 150 mL of water and dried over magnesium sulfate. The solvent was evaporated in vacuo to give 14.0 g of (R) -2- (2,3-epoxypropoxy) -5-methylphenylformate still containing some 3-chlorobenzoic acid and used without further purification. 14.0 g of the crude product from the previous reaction was dissolved in 100 ml of aqueous sodium hydroxide solution (2.5 M) and the mixture was stirred and heated at 95-100 C for 1.5 h. The cooled solution was extracted with dichloromethane (2 x 200 mL) and the combined extracts were dried over magnesium sulfate and the solvent was evaporated. The residue was purified by chromatography on silica eluting with a 1: 1 mixture of ether and petroleum ether (boiling point 40-60 [deg.] C). The appropriate fractions were combined and the solvent was evaporated to give 4.71 g of (S) -7-methyl-1,4-benzodioxan-2-ylmethanol as an oil. A solution of 5.5 g of 4-toluenesulfonyl chloride in 50 ml of pyridine anhydride is added dropwise to a solution of 4.7 g of the product from the previous reaction in 50 ml of pyridine anhydride and the mixture is stirred at ambient temperature for 2 hours, Lt; / RTI > The mixture was poured on ice, acidified with hydrochloric acid (5 M) and extracted with dichloromethane (2 x 200 mL). The combined extracts were washed with saturated brine and then dried over magnesium sulfate. The solvent was evaporated and the residue was purified by chromatography on silica eluting with a 1: 1 mixture of ether and petroleum ether (boiling point 40-60 [deg.] C). The appropriate fractions were combined and the solvent was evaporated to give 4.53 g of (R) -7-methyl-1,4-benzodioxan-2-ylmethyl 4-toluenesulfonate as a solid. Of 2-acetic acid 5 ㎖ 10 ㎖ dichloromethane trifluoromethyl-Amino-a - [(butoxycarbonyl-4-piperidyl 1-3-tert-) methyl] pyridine-3-carboxamide (2 to an exemplary N Prepared in a manner analogous to that described), the mixture was heated at ambient temperature for 2 hours and the solvent was removed in vacuo. Subsequently, the prepared crude 2-amino- N- (4-piperidylmethyl) pyridine-3-carboxamide trifluoroacetate was dissolved in 10 ml of acetonitrile anhydride, 1.5 g of potassium carbonate was added, Was added to a solution of 0.9 g of (R) -7-methyl-1,4-benzodioxan-2-ylmethyl 4-toluenesulfonate in 5 ml of acetonityl anhydride. The mixture was heated at reflux for 18 h, then poured onto water and extracted with ether (2 x 100 mL). The combined extracts were washed with water and then extracted with 50 mL of hydrochloric acid (1M). The acid extract was washed with 100 ml of water, basified with sodium bicarbonate and extracted with ether (2 x 100 ml). The extracts were combined, washed with water, and dried over magnesium sulfate. The solvent was evaporated and the residue was purified by flash chromatography eluting with a 20: 1 mixture of dichloromethane and methanol on silica. The appropriate fractions were combined and evaporated to give a melting point 143-146 ℃, [α] D -46.23 ° (c = 0.53, methanol) of (S) -2- amino - N - {[1- (7- methyl-1,4 -Benzodioxan-2-ylmethyl) -4-piperidyl] methyl} pyridine-3-carboxamide (0.36 g) as a colorless solid. ≪ Example 6 > A mixture of 2.7 g of pyridine-2-carboxylic acid and 5.0 g of 4- (aminomethyl) -1- tert -butoxycarbonylpiperidine in 50 ml of xylene anhydride was treated with Dean and Stark at reflux temperature, Was heated under a water separator for 6 hours. The cooled solution was diluted with 150 mL of ethyl acetate and washed with aqueous oxalic acid solution (2 M; 2 x 100 mL) followed by aqueous sodium bicarbonate (5 M; 2 x 100 mL) and dried over magnesium sulfate . The solvent was removed in vacuo to N - [(1- 3-tert-butoxycarbonyl-4-piperidyl) methyl] pyridine-2-carboxamide 2.53 g was obtained as an oil. 16 ml of trifluoroacetic acid are added to a solution of 2.5 g of the product from the previous reaction in 50 ml of dichloromethane, and the mixture is stirred at ambient temperature for 2 hours. The solvent was removed in vacuo and the residue was dissolved in 25 ml acetonitrile anhydride. 7.0 g of potassium carbonate and 2.4 g of 1,4-benzodioxan-2-ylmethyl 4-toluenesulfonate were added and the mixture was heated at reflux temperature for 18 hours, then cooled and poured into water. The resulting mixture was extracted with dichloromethane (2 x 100 mL) and the combined extracts were washed with water and then dried over magnesium sulfate. The solvent was evaporated and the residue was purified by flash chromatography eluting with ethyl acetate on silica. The appropriate fractions were combined and the solvent removed in vacuo to give N - {[1- (1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} pyridin- 2- Carboxamide (2.43 g) as a colorless solid. ≪ Example 7 > A mixture of 6.65 g of 2-hydroxy-5-methoxybenzaldehyde, 10.0 g of (R) -glycidyl 4-toluenesulfonate and 6.1 g of potassium carbonate in 100 ml of dimethylformamide anhydride was stirred and heated at 60 DEG C for 5 hours Lt; / RTI > The solvent was removed in vacuo, water was added to the residue, and the mixture was extracted with ether (2 x 200 mL). The combined extracts were washed with water and dried over magnesium sulphate. The solvent was evaporated and the residue was purified by flash chromatography eluting on a silica with a 2: 1 mixture of ether and petroleum ether (boiling point 40-60 C). The appropriate fractions were combined and the solvent was evaporated in vacuo to give 7.25 g of (R) -2- (2,3-epoxypropoxy) -5-methoxybenzaldehyde as a clear oil A solution of 7.25 g of the product from the previous reaction and 14.85 g of 3-chloroperoxybenzoic acid (86%) in 200 ml of dichloromethane was heated at ambient temperature for 20 hours. Water (200 mL) was added, and the organic layer was separated, washed with sodium bicarbonate (5 M; 3 times x 200 mL), then with water, and dried over magnesium sulfate. The solvent was evaporated to obtain 7.1 g of (R) -2- (2,3-epoxypropoxy) -5-methoxyphenyl formate as a transparent oil. A solution of 7.1 g of the product from the previous reaction in 100 ml of an aqueous solution of sodium hydroxide (2.5 M) was heated at 95-100 < 0 > C for 1.5 h. The cooled solution was extracted with ether (2 x 200 mL) and the combined extracts were dried over magnesium sulfate. The solvent was evaporated to obtain 3.64 g of (S) -7-methoxy-1,4-benzodioxan-2-yl methanol as a solid. A solution of 3.54 g of 4-toluenesulfonyl chloride in 35 ml of pyridine anhydride was added to a solution of 3.64 g of the product from the previous reaction in 60 ml of pyridine anhydride, the mixture was stirred at ambient temperature for 18 hours, . The mixture was acidified with hydrochloric acid (5 M) and then extracted with 200 mL of dichloromethane. The combined extracts were dried over magnesium sulfate and the solvent was evaporated to give 5.1 g of (R) -7-methoxy-1,4-benzodioxan-2-ylmethyl 4-toluenesulfonate as a colorless solid. 2 in acetic acid 10 ㎖ 10 ㎖ dichloromethane trifluoromethyl-Amino-a - [(butoxycarbonyl-4-piperidyl 1-3-tert-) methyl] pyridine-3-carboxamide (2 to an exemplary N Prepared in a manner analogous to that described), the mixture was heated at ambient temperature for 2 hours and the solvent was removed in vacuo. The residue was dissolved in 75 ml of acetonitrile and then 15 g of potassium carbonate and 2.5 g of the product from the previous reaction were added and the mixture was heated at reflux temperature for 20 hours. The cooled mixture was poured onto 200 ml of water and then extracted with dichloromethane (2 x 200 ml). The combined extracts were dried over magnesium sulfate, the solvent was evaporated and the residue was purified by chromatography on silica eluting with a 9: 1 mixture of ethyl acetate and methanol. The appropriate fractions were combined and the solvent was removed in vacuo. Melting the residue was recrystallized from ethyl acetate 156-158 ℃, [α] D -46.5 ° (S) -2- amino (c = 0.505, methanol) - N - {[1- ( 7- methoxy-l , 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} pyridine-3- carboxamide ≪ Example 8 > Quinoline-8-carboxylic acid (0.74 g) and thionyl chloride (10 ml) were stirred and heated together at 50 ° C for 2 hours. Excess thionyl chloride was removed under vacuum, and the residue was suspended in 20 mL of dichloromethane. A solution of 0.98 g of 4- (aminomethyl) -1- tert -butoxycarbonylpiperidine in 10 ml of dichloromethane was added and the mixture was heated at ambient temperature for 4 hours, then a solution of sodium bicarbonate (1 M). The organic layer was separated, washed with an aqueous oxalic acid solution (2M; 2 x 50 mL) and dried over magnesium sulfate. Evaporation of the solvent N - [(1- 3-tert-butoxycarbonyl-4-piperidyl) methyl] quinoline-8-carboxamide 0.59 g of a colorless solid. Of acetic acid 5 ㎖ 20 ㎖ dichloromethane trifluoroacetate N - [(1- 3-tert-butoxycarbonyl-4-piperidyl) methyl] quinoline-8-carboxamide (prepared in a manner similar to that described above ) Was added to a solution of 1.11 g and the mixture was heated at reflux temperature for 2 hours, then cooled and the solvent was removed in vacuo. The residue was dissolved in 50 ml of acetonitrile anhydride, 3.0 g of potassium carbonate and 0.92 g of 1,4-benzodioxan-2-ylmethyl 4-toluenesulfonate were added and the mixture was heated at reflux temperature for 20 hours . The cooled mixture was poured onto 100 ml of water and extracted with dichloromethane (2 x 100 ml). The combined extracts were washed with water and dried over magnesium sulphate. The solvent was evaporated and the residue was purified by flash chromatography eluting with ethyl acetate on silica. The appropriate fractions were combined and the solvent removed in vacuo to afford N - {[1- (1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} quinolin- Carboxamide 2.5 g fumarate was obtained (softened at 78 < 0 > C). ≪ Example 9 > A mixture of 4.4 g of 2-chloro-6-hydroxybenzaldehyde, 5.0 g of (R) -glycidyl 4-toluenesulfonate and 3.9 g of potassium carbonate in 120 ml of dimethylformamide was stirred and heated at 60 DEG C for 5 hours And allowed to cool over 18 hours. The solvent was removed in vacuo, 60 ml of water was added to the residue, and the mixture was extracted with ether (3 x 100 ml). The combined extracts were dried over magnesium sulfate and the solvent was evaporated. The residual oil was purified by flash chromatography on silica eluting with petroleum ether (boiling point 40-60 DEG C) and a 1: 1 mixture of dichloromethane, followed by pure dichloromethane, followed by a 19: 1 mixture of dichloromethane and industrial methyl alcohol Lt; / RTI > The appropriate fractions were combined and the solvent removed in vacuo to give (R) -2-chloro-6- (2,3-epoxypropoxy) benzaldehyde as light yellow solid 2.8 g. The other fractions which were incompletely purified were chromatographed to give 0.5 g of the product of the second crop. A solution of 2.8 g of the product from the previous reaction and 4.8 g of 3-chloroperoxybenzoic acid (86%) in 200 ml of dichloromethane was stirred and heated at reflux temperature for 18 hours. 4.8 g of additional 3-chloroperoxybenzoic acid (86%) was added and the solution was heated at reflux temperature for 6 hours. The mixture was washed with saturated aqueous sodium bicarbonate solution (3 x 200 mL), dried over magnesium sulfate and the solvent was evaporated to give (R) -2-chloro-6- (2,3-epoxypropoxy) phenyl Formate (2.8 g) as a yellow solid. A solution of 2.8 g of the product from the previous reaction in 20 ml of aqueous sodium hydroxide solution (2.5 M) was stirred and heated at reflux temperature for 1.5 hours. The cooled solution was extracted with dichloromethane (2 x 30 mL) and the combined extracts were dried over magnesium sulfate and the solvent was evaporated to give (S) -8-chloro-1,4-benzodioxan- Methanol 1.63 g as a yellow oil. A solution of 3.15 g of 4-toluenesulfonyl chloride in 15 ml of pyridine anhydride was added to a solution of (S) -8-chloro-1,4-benzodioxan-2-ylmethanol (prepared by a method similar to that described above) in 40 ml of pyridine anhydride ), And the mixture was stirred at ambient temperature for 18 hours, then poured onto ice, and dilute hydrochloric acid was added to obtain a pH of 4. The mixture was extracted with dichloromethane (2 x 200 mL) and the combined extracts were washed with brine and dried over magnesium sulfate. The solvent was evaporated to obtain 5.21 g of (R) -8-chloro-1,4-benzodioxan-2-ylmethyl 4-toluenesulfonate as a light yellow solid. A mixture of 2.5 g of the product from the previous reaction in 50 ml of acetonitrile anhydride, 1.42 g of N - (benzylidene-l- (4-piperidyl) methylamine and 2.0 g of potassium carbonate was stirred and refluxed for 24 hours The combined extracts were washed with brine and dried over magnesium.The solvent was evaporated and the residue was triturated with ether < RTI ID = 0.0 > The solvent was evaporated to give partially purified (S) -N -benzylidene-1- [1- (8-chloro-1,4-benzodioxan- Ylmethyl) -4-piperidyl] methylamine (1.72 g) as a cream solid. 1.7 g of the product from the previous reaction were stirred in 100 ml of aqueous potassium hydrogen sulfate solution (1 M) at ambient temperature for 2 hours. The solution was washed with 100 mL of ether, basified with aqueous sodium hydroxide (5 M), and extracted with dichloromethane (2 x 200 mL). The combined extracts were washed with 100 ml of water and then dried over magnesium sulfate. The solvent was evaporated to obtain 0.65 g of (S) -4- (aminomethyl) -1- (8-chloro-1,4-benzodioxan-2- ylmethyl) piperidine as an oil. 0.22 g of triethylamine and then 0.24 g of ethyl chloroformate were added to a solution of 0.3 g of 2-methylpyridine-3-carboxylic acid in 20 ml of dichloromethane, and the mixture was stirred at ambient temperature for 18 hours. A solution of 0.65 g of the product from the previous reaction in 10 ml of dichloromethane was then added dropwise, the mixture was stirred at ambient temperature for 24 hours, then washed with 100 ml of water and dried over magnesium sulfate. The solvent was evaporated and the residue was purified by flash chromatography eluting with a 15: 1 mixture of dichloromethane and methanol on silica. The appropriate fractions were combined, the solvent was removed in a vacuum melting point 147-149 ℃, [α] D -37.9 ° (c = 1.0035, methanol) (S) - N - { [1- (8- Chloro-1,4 -Benzodioxan-2-ylmethyl) -4-piperidyl] methyl} pyridine-2-methylpyridine-3- carboxamide as a solid. ≪ Example 10 > 38 g of epichlorohydrin were added to a stirred solution of 20.9 g of 5'-fluoro-2'-hydroxyacetone phenone in 20 ml of ethanol. Then a solution of 9.5 g of potassium hydroxide in a mixture of 30 ml of ethanol and 5 ml of water was added and stirring was continued for 1 hour. The solvent was removed in vacuo, the residue was poured into water and extracted with ethyl acetate. The combined extracts were washed with brine and dried over magnesium sulfate. The solvent was removed in vacuo and the residue was purified by chromatography on silica eluting with petroleum ether (boiling point 40-60 [deg.] C) and a 3: 2 mixture of ethyl acetate. The appropriate fractions were combined and the solvent removed in vacuo to give 4.68 g of 2 ' - (2,3-epoxypropoxy) -5 ' -fluoroacetophenone as an oil. A solution of 4.68 g of the product from the previous reaction in 50 ml of chloroform and 5.86 g of 3-chloroperoxybenzoic acid (80%) was heated at reflux for 18 hours. After cooling, the mixture was washed with a saturated aqueous solution of sodium hydrogencarbonate followed by brine and the solvent was removed in vacuo to give 4.44 g of 2- (2,3-epoxypropoxy) -5-fluorophenylacetate, It was used without purification. 4.0 g of the crude product from the previous reaction and 7.3 ml of aqueous sodium hydroxide solution (10%) were heated together at reflux temperature for 5 hours. The cooled mixture was poured into water and extracted with ethyl acetate. The combined organic layers were washed with brine, then dried over magnesium sulfate. The solvent was removed under vacuum to obtain 2.0 g of 7-fluoro-1,4-benzodioxan-2-ylmethanol. 2.14 g of 4-toluenesulfonyl chloride was added to a solution of 2.0 g of the product from the previous reaction in 50 ml of pyridine and the mixture was stirred at ambient temperature for 18 hours. The mixture was poured into a mixture of ice and dilute hydrochloric acid and then extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, and the solvent was evaporated to yield a contaminated product with a significant amount of starting material. The crude product is purified by flash chromatography, which is carried out as described above, by reacting with 2.14 g of 4-toluenesulfonyl chloride in 50 ml of additional pyridine and eluting with a 20: 1 mixture of dichloromethane and methanol on silica An impure product was obtained. The appropriate fractions were combined and the solvent was removed under vacuum to give 0.78 g of 7-fluoro-1,4-benzodioxan-2-ylmethyl 4-toluenesulfonate as a clear oil. Acid 5 ㎖ trifluoromethyl-dichloro-2-amino methane ㎖ 25 - in [(butoxycarbonyl-4-piperidyl 1-3-tert-) methyl] pyridine-3-carboxamide (Example 2 N Was prepared in a manner similar to that described), and the mixture was stirred at ambient temperature for 2 hours. The solvent was removed in vacuo and the residue was dissolved in 20 ml of acetonitrile. To this solution was added a solution of 0.75 g of the product from the previous reaction in 3.0 g of potassium carbonate and 10 ml of acetonitrile, then the mixture was stirred and heated at reflux temperature for 18 hours. The cooled mixture was filtered and the resulting solid was washed with 100 mL of dichloromethane. The filtrate and washings were combined, washed with water (2 x 100 mL), and dried over magnesium sulfate. The solvent was removed in vacuo and the residue was purified by flash chromatography eluting with a 25: 1 mixture of dichloromethane and methanol on silica. The appropriate fractions were combined and the solvent removed in vacuo to give 2-amino- N - {[1- (7-fluoro-1, 4-benzodioxan- Peridyl] methyl} pyridine-3-carboxamide (0.56 g) as a colorless solid. ≪ Example 11 > 2 in acetic acid 10 ㎖ dichloromethane 50 ㎖ trifluoromethyl-Amino-N - [(1- 3-tert-butoxycarbonyl-4-piperidyl) methyl] pyridine-3-carboxamide (Example 2 Was prepared in a manner similar to that described), and the mixture was stirred at ambient temperature for 2 hours. The solvent was removed in vacuo and the residue was dissolved in 50 ml of acetonitrile. To this solution was added a solution of 3.0 g of potassium carbonate and 8-methoxy-1,4-benzodioxan-2-ylmethyl 4-toluenesulfonate (prepared by a method similar to that described in WO 95/07274) in 20 ml of acetonitrile ) Was added. The resulting suspension was stirred and heated at reflux for 20 hours, cooled and then poured into 100 ml of water, and the mixture was extracted with dichloromethane (2 x 100 ml). The combined extracts were washed with 100 ml of water, dried over magnesium sulfate and the solvent was evaporated to give an oil. The product was purified by flash chromatography using a 9: 1 mixture of ethyl acetate and methanol on silica as the eluent. The appropriate fractions were combined and the solvent was removed in vacuo to afford 2-amino- N - {[1- (8-methoxy-1,4-benzodioxan- Peridyl] methyl} pyridine-3-carboxamide 0.4 Ethyl acetate solvate 0.5 The hydrate was obtained as a colorless solid 1.55 g. ≪ Example 12 > Of acetic acid 25 ㎖ 50 ㎖ dichloromethane trifluoroacetate N - [(1- 3-tert-butoxycarbonyl-4-piperidyl) methyl] pyridine-2-carboxamide was added to a solution of 5.2 g, and the mixture Was stirred at ambient temperature for 2 hours. The solvent was removed in vacuo and the residue was dissolved in 50 ml of acetonitrile anhydride. 6.0 g of potassium carbonate and 25 g of (R) -7-chloro-1,4-benzodioxan-2-ylmethyl 4-toluenesulfonate (prepared by a method similar to that described in Example 1) Was stirred and heated at reflux temperature for 24 hours. The cooled reaction mixture was filtered and the solvent was removed in vacuo. The residue was dissolved in ethyl acetate, the solution was washed with water and then dried over magnesium sulfate. The solvent was removed in vacuo and the residue was purified by flash chromatography eluting with ethyl acetate on silica, then with a 20: 1 mixture of ethyl acetate and methanol. The appropriate fractions were combined, the solvent was removed under vacuum melting point 110-112 ℃, [α] D 47.7 (c = 1.005, methanol) of (S) -. N - { [1- (7- chloro-1,4 Benzodioxan-2-ylmethyl) -4-piperidyl] methyl} pyridine-2-carboxamide (4.42 g). ≪ Example 13 > A mixture of 60.0 g of 2-benzyloxy-3-hydroxybenzaldehyde, 60.0 g of (R) -glycidyl 4-toluenesulfonate and 74 g of potassium carbonate in 600 ml of dimethylformamide anhydride was stirred and heated at 60 DEG C for 14 hours Lt; / RTI > After cooling, the solvent was removed in vacuo, and 250 mL of water was added and the mixture was extracted with ether (2 × 200 mL) followed by ethyl acetate (2 × 400 mL). The combined extracts were washed with brine (2 x 500 mL) and dried over magnesium sulfate. The solvent was removed in vacuo and the residue was first adsorbed onto silica by evaporative drying from solution in dichloromethane over silica and then eluted with a 3: 1 mixture of petroleum ether (boiling point 40-60 C) and ether Purified by flash chromatography. The appropriate fractions were combined and the solvent removed in vacuo to give 14.22 g of (R) -2-benzyloxy-3- (2,3-epoxypropoxy) benzaldehyde. 33.37 g of the product of the further harvest was obtained by extraction of the silica used in the chromatography using ether (6 x 500 ml), followed by concentration of the combined extracts to a volume of about 500 ml, cooling overnight, The precipitate was then washed with a 1: 1 mixture of petroleum ether (bp 40-60 C) and ether. The solvent was removed from the filtrate under vacuum and the residue was purified by flash chromatography according to the procedure described above to give 9.68 g of a third crop of the product. The combined yield of the product was 57.27 g. 57.27 g of the combined product from the previous reaction, 2.75 g of palladium on carbon (10%), 81.4 ml of cyclohexene and 2 L of ethyl acetate were heated and stirred together under nitrogen and also at reflux for 24 hours. The solvent was evaporated and the residue was dissolved in 1 L of ethyl acetate and then filtered through a pad of celite. The solvent was removed in vacuo to give an orange oil which was dissolved in a mixture of 500 ml of ethanol, 500 ml of water and 55.2 ml of triethylamine. The mixture was stirred and heated at reflux temperature for 3 hours. After cooling, the ethanol was removed in vacuo and the residual aqueous mixture was extracted with ethyl acetate (2 x 250 mL). The combined extracts were washed with hydrochloric acid (1 M; 2 x 250 mL) followed by water, then dried over magnesium sulfate. The solvent was removed in vacuo and the residue was purified by flash chromatography on silica eluting with a petroleum ether and a 3: 1 mixture of (boiling point 40-60 DEG C) ethyl acetate followed by a 1: 1 mixture. The appropriate fractions were combined and the solvent removed in vacuo to give 8.02 g of (S) -2-hydroxymethyl-1,4-benzodioxane-8-carboxaldehyde. A mixture of 2.0 g of the product from the previous reaction, 0.16 g of potassium carbonate, 1.0 ml of hydrazine hydrate and 50 ml of ethane-1,2-diol was stirred and heated at reflux temperature for 1 hour. The excess hydrazine hydrate was distilled until the internal temperature reached 185 캜, then the remaining mixture was heated under reflux for an additional 2 hours, cooled, and poured into water. The mixture was extracted with 100 ml of ethyl acetate, and the combined extracts were washed with 100 ml of dilute hydrochloric acid, then 100 ml of sodium hydrogencarbonate, and dried over magnesium sulfate. The solvent was removed in vacuo and the residue was purified by chromatography on silica eluting with a 20: 1 mixture of dichloromethane and methanol to give (S) -8-methyl-1,4-benzodioxan- g. A solution of 0.96 g of 4-toluenesulfonyl chloride in 10 ml of pyridine anhydride was added to an ice-cooled solution of 0.9 g of the product from the previous reaction in 40 ml of pyridine anhydride, the mixture was stirred, warmed at ambient temperature for 18 hours, Poured onto ice. The mixture was acidified with dilute hydrochloric acid and then extracted with ether (2 x 200 mL). The combined extracts were washed with water and dried over magnesium sulphate. The solvent was evaporated and the residue was purified by chromatography on silica eluting with petroleum ether (boiling point 40-60 [deg.] C) and a 4: 1 mixture of ether. The appropriate fractions were combined and the solvent was evaporated to obtain 0.91 g of (R) -8-methyl-1,4-benzodioxan-2-ylmethyl 4-toluenesulfonate. Of acetic acid 5 ㎖ 30 ㎖ dichloromethane trifluoroacetate N - [(1- 3-tert-butoxycarbonyl-4-piperidyl) methyl] pyridine-2-carboxamide was added to a solution of 0.9 g, and the mixture Was stirred at ambient temperature for 2 hours. The solvent was removed in vacuo and the residue was dissolved in 20 ml of acetonitrile anhydride. 0.85 g of the product from the previous reaction and 2.0 g of potassium carbonate were added to this solution and the mixture was stirred and heated at reflux for 24 hours. The cooled solution was filtered, and the filtrate was partitioned between 100 mL of dichloromethane and 100 mL of water. The organic layer was washed with water, then dried over magnesium sulfate and the solvent was removed in vacuo. The residue was purified by flash chromatography eluting with silica in a 9: 1 mixture of dichloromethane and methanol. The appropriate fractions were combined, evaporation of the solvent melting point of 56-58 ℃, [α] D ( c = 0.869, methanol) (S) -2- amino - N - {[1- (8- Chloro-1,4- Benzodioxan-2-ylmethyl) -4-piperidyl] methyl} pyridine-3-carboxamide 0.42 g. ≪ Example 14 > A mixture of 19.75 g of 6-methylpyridine-2,3-dicarboxylic acid and 51 ml of acetic anhydride was stirred and heated in an oil bath (at a bath temperature of 110 ° C) for 5 hours. The solvent was removed in vacuo and a 2: 1 mixture of dichloromethane and ether was added to give a dark brown solid. A solution of this solid in dichloromethane was passed through a pad of silica gel eluting with dichloromethane and the solvent was evaporated to give 12.1 g of partially purified 6-methylpyridine-2,3-dicarboxylic acid anhydride. 1.63 ml of trimethylsilyl azide was added to a solution of 2.0 g of the product of the previous reaction in 10 ml of ethanol solvent chloroform under nitrogen to give a milky suspension which became clear by heating for 10 minutes. After 1 hour at ambient temperature, the mixture was heated at 95-100 < 0 > C for 1 hour, cooled and 0.72 ml of ethanol was added. The mixture was cooled in ice, and the precipitated yellow solid was collected to obtain 1.2 g of 7-methylpyrido [2,3- d ] [1,3] oxazine-2,4- (1 H ) -dione. A mixture of 0.35 g of the product from the previous reaction in 15 ml of 1,2-dimethoxyethane and 0.58 g of [1- (7-chloro-1,4-benzodioxan-2-methyl) Was stirred at ambient temperature for 24 hours. The solvent was removed in vacuo and the residue was purified by flash chromatography eluting with a 95: 5 mixture of dichloromethane and methanol on silica. (S) of the appropriate fractions were combined, (c = 0.036, methanol) and the solvent removed under vacuum melting point 160-163 ℃, [α] D -50.7 -2- Amino -. N - {[1- ( 7- chloro -1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} pyridine-3-carboxamide. ≪ Example 15 > Acid 8 ㎖ trifluoromethyl dichloromethane 50 ㎖ of N - added to a solution of [(1-tert-butoxycarbonyl-4-piperidyl) methyl] pyridine-2-carboxamide 1.0 g, and the The mixture was stirred at ambient temperature for 1 hour. The solvent was removed in vacuo and the residue was dissolved in 50 ml of acetonitrile anhydride. 1.5 g of potassium carbonate and 0.89 g of (R) -1,4-benzodioxan-2-ylmethyl 4-toluenesulfonate were added and the mixture was stirred and heated at reflux for 4 hours. The solvent was removed in vacuo and the residue was partitioned between 40 mL of water and 40 mL of dichloromethane. The organic phase was extracted with 40 ml of hydrochloric acid (2 M) and then the extract was basified with aqueous sodium hydroxide (5 M) and extracted with dichloromethane (3 x 20 ml). The combined organic extracts were dried over magnesium sulfate and the solvent was removed in vacuo. The residue was purified by flash chromatography on silica eluting with a 9: 1 mixture of dichloromethane and industrial methyl alcohol. The appropriate fractions were combined and the solvent removed in vacuo to give an oil which was treated with an ethereal maleic acid solution. The resulting salt was recovered but was very moisturized and absorbed in aqueous sodium hydroxide solution (2 M) and the mixture was extracted with dichloromethane. The The extract was dried over magnesium sulfate, the solvent was removed under vacuum melting point 102-105 ℃, [α] D -29.36 ° (c = 0.6845, methanol) (S) -2- amino - N - {[1- ( Benzodioxan-2-ylmethyl) -4-piperidyl] methyl} pyridine-3-carboxamide (0.182 g) as a colorless foam. ≪ Example 16 > 1,2-dimethoxyethane and 50 ㎖ of 2 H - thieno [3,2- d] [1,3] oxazine -2,4 (1 H) - dione, and 3.1 g 4- (aminomethyl) -1 - tert -butoxycarbonylpiperidine in 50 ml of tetrahydrofuran was stirred at ambient temperature for 5 hours. The solvent was removed in vacuo and the residue was purified by flash chromatography, eluting with ether on silica. The appropriate fractions were combined and evaporation of the solvent, 3-amino - N - (1- 3-tert-butoxycarbonyl-4-piperidyl-methyl) thiophene-2-carboxamide was obtained as a colorless solid 2.57 g. 10 ml of trifluoroacetic acid are added to a suspension of 2.0 g of the product from the previous reaction in dichloromethane and the mixture is stirred at ambient temperature for 18 hours. The solvent was removed in vacuo and the residue was dissolved in 100 ml of acetonitrile. To this solution, 3.1 g of potassium carbonate, 2 ml of triethylamine and 1.8 g of 1,4-benzodioxan-2-ylmethyl 4-toluenesulfonate were added. The mixture was stirred and heated at reflux temperature for 6 hours, additional 4 mL of triethylamine was added and refluxing was continued for an additional 6 hours. The cooled mixture was filtered and the solvent was removed in vacuo. The residue was dissolved in dichloromethane, washed with water (2 x 50 mL), dried over magnesium sulfate, and the solvent removed in vacuo. The residue was purified by flash chromatography on silica eluting with dichloromethane, followed by a 19: 1 mixture of dichloromethane and industrial methyl alcohol. The appropriate fractions were combined and the solvent removed in vacuo to give an oil which was triturated with ether to give 3-amino- N - {[1- (1,4-benzodioxan- Piperidyl] methyl} thiophene-2-carboxamide (0.22 g) as a solid. ≪ Example 17 > Of acetic acid 5 ㎖ 100 ㎖ dichloromethane trifluoromethyl 3-amino - N - (1- 3-tert-butoxycarbonyl-4-piperidyl-methyl) thiophene-2-carboxamide was added to a suspension of 3.8 g , And the mixture was stirred at ambient temperature for 18 hours. The solvent was removed in vacuo and the residue was dissolved in 100 ml of acetonitrile. 1.4 g of potassium carbonate, 4 ml of triethylamine and 3.5 g of (R) -7-chloro-1,4-benzodioxan-2-ylmethyl 4-toluenesulfonate were added to this solution, and the mixture was stirred Was heated at reflux temperature for 3 days. The mixture was filtered and the solvent removed in vacuo to give an oil which was dissolved in 100 mL dichloromethane and washed with water (2 x 50 mL). The solution was dried over magnesium sulfate and the solvent was removed in vacuo. The residue was purified by flash chromatography on silica eluting with dichloromethane, followed by a 19: 1 mixture of dichloromethane and industrial methyl alcohol. The appropriate fractions were combined and the solvent was removed in vacuo to give a light yellow solid which was triturated with ether to give (S) -3-amino-benzoic acid of melting point 200-202 ° C, [ ] D -30 ° (c = 0.024, N - {[1- (7- chloro-1,4-benzodioxane-2-ylmethyl) -4-piperidyl] methyl} thiophene-2-carboxamide was obtained as a light yellow solid carboxamide 100 ㎎. ≪ Example 18 > 0.47 ml of triethylamine was added to a suspension of 0.46 g of 2-methylpyridine-3-carboxylic acid in dichloromethane and the mixture was cooled in ice water. 0.33 g of ethyl chloroformate were added with stirring and the mixture was allowed to warm to ambient temperature for 18 hours. 1.0 g of (S) -4- (aminomethyl) -1- (7-chloro-1,4-benzodioxan-2-ylmethyl) piperidine was added and stirring was continued for 24 hours. The solvent was evaporated, the residue was triturated with water, collected by filtration and purified by flash chromatography on silica eluting with 3: 1 then 2: 1 mixture of ethyl acetate and methanol. The appropriate fractions were combined and the solvent was removed in vacuo to give still impure product. Flash chromatography on a silica eluting with a 10: 1 mixture of dichloromethane and methanol followed by an 18: 1: 1 mixture of dichloromethane, methanol and triethylamine was followed by removal of the solvent from the appropriate fractions under vacuum to give a melting point 133-136 ℃, [α] D -46.6 ° (c = 0.837, methanol) of (S) -N - {[1- (7- chloro-1,4-benzodioxane-2-ylmethyl) -4 -Piperidyl] methyl} -2-methylpyridine-3-carboxamide (330 mg) as a colorless solid. ≪ Example 19 > A solution of 4.09 g of 2-chloropyridine-3-carboxylic acid in 100 ml of dichloromethane and 2.7 ml of 1-methylmorpholine was stirred at -5 [deg.] C under nitrogen and 2.4 ml of ethyl chloroformate was added dropwise. After 10 minutes, 5.0 g of N-benzylidene-l- (4-piperidyl) methylamine in 25 ml of dichloromethane was added and stirring continued at -5 ° C for 2 hours and then at ambient temperature for 18 hours Respectively. The solvent was removed in vacuo and the residue was stirred with 250 mL of potassium hydrogen sulphate solution (1 M) for 5 hours. The mixture was filtered and the filtrate was washed with dichloromethane (2 x 150 ml), basified with aqueous sodium hydroxide solution (5 M) and extracted with dichloromethane (3 x 150 ml). The combined extracts were dried over magnesium sulfate and the solvent was evaporated to yield 4.81 g of 4- (aminomethyl) -2- (2-chloro-3-pyridylcarbonyl) -piperidine contaminated with some 1- methylmorpholine ≪ / RTI > This material was used in the next reaction without further purification. 4.75 g of the crude product from the previous reaction in 100 ml of acetonitrile anhydrous, 12.93 g of potassium carbonate and 6.64 g of (R) -7-chloro-1,4-benzodioxan-2-ylmethyl 4- And heated at reflux temperature for 48 hours. The mixture was cooled, filtered and the solvent was removed in vacuo to give an oil which was purified by flash chromatography eluting with silica in a 25: 1 mixture of dichloromethane and industrial methyl alcohol. The appropriate fractions were combined and the solvent removed in vacuo to give (S) -4- [ N- (7-chloro-1,4-benzodioxan-2- ylmethyl) aminomethyl] -1- Yl) piperidine ethanol solvate (2.49 g) as a gum. 2.49 g of the product from the previous reaction, 10 ml of industrial methyl alcohol, 100 ml of aqueous ammonia solution (SG 0.88) and 0.5 g of copper lining powder were stirred and heated at 150 캜 for 18 hours in a pressure vessel. After cooling, 400 ml of dichloromethane and 400 ml of water were added and the mixture was filtered through celite and washed with water (4 x 50 ml) followed by dichloromethane (4 x 50 ml). The filtration layer was separated and the aqueous layer was extracted with 400 mL of dichloromethane. The combined organic layers were dried over magnesium sulfate and the solvent was evaporated to give a red oil which was purified by flash chromatography eluting with a 9: 1 mixture of dichloromethane and ethanol. The appropriate fractions were combined and the solvent removed in vacuo to give the product as a red gum which was dissolved in 20 ml of hot ethanol and a hot solution of 340 mg of fumaric acid in 5 ml of ethanol was added. Removed under vacuum, and grinding the residue with ether having a melting point of 110 ℃ (dec.), [ Α] D 0 ° racemic 1- (2-amino-nicotinoyl) and the solvent -4- [N - (7- Chloro-1,4-benzodioxan-2-ylmethyl) aminomethyl] piperidine 1.6 fumarate 0.7 hydrate 0.7 0.85 g of ethanol solvate was obtained. ≪ Example 20 > A mixture of 25 g of 2-fluoro-6-trifluoromethylbenzaldehyde and 866 ml of sodium hydroxide (0.5 M) was stirred and heated at 80 占 폚 under nitrogen for 43 hours. The cooled solution was washed with ether (2 x 350 mL), acidified with concentrated hydrochloric acid and then extracted with ether (2 x 500 mL). The combined extracts were dried over magnesium sulfate and the solvent was removed in vacuo. The residue was purified by flash chromatography eluting with a 95: 5 mixture of dichloromethane and methanol on silica. The appropriate fractions were combined and the solvent was removed in vacuo to afford 6.2 g of 2-hydroxy-6-trifluoromethylbenzaldehyde as an oil. A mixture of 5.95 g of the product from the previous reaction in 150 ml of dimethylformamide, 6.05 g of (R) -glycidyl 4-toluenesulfonate and 4.3 g of potassium carbonate was stirred and heated at 60 DEG C for 24 hours. The cooled solution was poured into 600 mL of ice-water and extracted with ether (3 x 300 mL). The combined extracts were washed with brine (2 x 400 mL), dried over magnesium sulfate and the solvent removed in vacuo to give 7.0 g of solid which was recrystallized from 30 mL ether to give (R) -2- (2 , 3-epoxypropoxy) -6-trifluoromethylbenzaldehyde as a solid (5.4 g). A mixture of 5.4 g of the product from the previous reaction in 300 ml of chloroform and 13.84 g of 3-chloroperoxybenzoic acid (57%) was stirred and heated at reflux temperature for 18 hours and then allowed to stand at ambient temperature for 3 days, And poured into 400 ml of a saturated aqueous sodium hydrogen carbonate solution. The mixture was extracted with 200 mL of dichloromethane and the organic phase was washed with saturated aqueous sodium bicarbonate solution (3 x 400 mL), then dried over magnesium sulfate and the solvent removed in vacuo to give crude 2- (2,3-epoxy Propoxy) -6-trifluoromethylphenylformate (6.26 g) as a yellow solid. A solution of 6.26 g of the crude product from the previous reaction in 75 ml of methanol was added dropwise to a solution of sodium methoxide prepared by the melting of 0.69 g of metallic sodium in 75 ml of methanol and the mixture was stirred at ambient temperature for 18 hours Then, it was left for 24 hours. The solvent was removed in vacuo and the residue was added to 300 mL of water. The mixture was extracted with ethyl acetate (3 × 200 ml) and the combined extracts were dried over magnesium sulfate and the solvent was removed in vacuo to give a crude oil (1 g) of petroleum ether (mp 40-60 ° C.) and ethyl acetate A brown oil was obtained which was purified by flash chromatography eluting with a mixture. The appropriate fractions were combined and the solvent removed in vacuo to give 1.80 g of (S) -8-trifluoromethyl-1,4-benzodioxan-2-ylmethanol as a yellow oil. 1.29 g of 4-toluenesulfonyl chloride was added to a solution of 1.26 g of the product from the previous reaction in 50 ml of pyridine anhydride under nitrogen at -10 DEG C and the mixture was allowed to warm to ambient temperature for 18 hours with stirring. Additional 0.7 g of 4-toluenesulfonyl chloride was added and stirring was continued for 3 days, then the mixture was poured into 200 ml of dilute hydrochloric acid and extracted with ethyl acetate (2 x 200 ml). The combined extracts were washed with dilute hydrochloric acid (2 x 200 mL), dried over magnesium sulphonate and the solvent removed in vacuo to give crude (R) -8-trifluoromethyl-l, 4-benzodioxane -2-ylmethyl 4-toluenesulfonate (1.27 g). Acid 15 ㎖ trifluoromethyl-dichloro 2-amino methane ㎖ 15 - in [(butoxycarbonyl-4-piperidyl 1-3-tert-) methyl] pyridine-3-carboxamide (Example 2 N Prepared in a manner similar to that described), and the mixture was stirred at ambient temperature for 3 hours and the solvent was removed in vacuo. The residue was dissolved in 100 ml of acetonitrile, 4.5 g of potassium carbonate and 1.27 g of the product from the previous reaction were added and the mixture was stirred and heated at reflux temperature for 72 hours. The cooled mixture was filtered and the solid was washed with 200 mL of ethyl acetate. The filtrate was evaporated in vacuo and purified by flash chromatography, eluting with ethyl acetate and methanol in a 3: 1 mixture on silica. The appropriate fractions were combined, the solvent was removed in a vacuum melting point 101-103 ℃, [α] D -16.2 ° (c = 0.56, dichloromethane) (S) -2- amino - N - {[1- (8- Trifluoromethyl-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} pyridine-3-carboxamide (870 mg) as a colorless solid. ≪ Example 21 > A mixture of 68.75 g of 5-bromo-2-hydroxybenzaldehyde, 65 g of ( R ) -glycidyl 4-toluenesulfonate and 47.3 g of potassium carbonate in 1.5 L of dimethylformamide anhydride was stirred at 60 占 폚 under nitrogen Heated for 24 hours, then cooled and left at ambient temperature for 24 hours. The mixture was poured into 2 L of water and then extracted with ether (4 x 400 mL). The combined extracts were washed with brine (4 x 500 mL), dried over magnesium sulfate and the solvent removed in vacuo and flash chromatographed eluting with petroleum ether (boiling point 60-80 ° C) and ethyl acetate 4: An oil was obtained which was purified by means of a < RTI ID = 0.0 > The appropriate fractions were combined and the solvent was removed in vacuo to give an oil which was triturated with 150 mL of ether to give 43.3 g of ( R ) -5-bromo-2- (2,3-epoxypropoxy) benzaldehyde as a colorless solid . A solution of 42.6 g of the product from the previous reaction in 1.5 L of chloroform and 69.4 g of 3-chloroperoxybenzoic acid (86%) was heated at reflux temperature for 24 hours and then allowed to stand at ambient temperature for 48 hours. The solution was washed with water (5 x 300 mL), saturated aqueous sodium bicarbonate (600 mL) and brine (2 x 500 mL) and then dried over magnesium sulfate. The solvent was removed in vacuo to give 47.8 g of crude ( R ) -5-bromo-2- (2,3-epoxypropoxy) phenyl formate which was continuously crystallized as a yellow oil. A solution of 47.8 g of the crude product from the previous reaction in 400 ml of methanol was added dropwise to a solution of sodium methoxide prepared by dissolving 5.3 g of sodium metal in 400 ml of methanol and the mixture was stirred at ambient temperature for 18 hours. The solvent was removed in vacuo, 800 ml of water was added to the residue, and the mixture was extracted with ethyl acetate (4 x 500 ml). The combined extracts were dried over magnesium sulfate and the solvent was removed in vacuo to give a brown oil which was purified by flash chromatography on silica eluting with a petroleum ether (boiling point 60-80 ° C) and a 5: 1 mixture of ethyl acetate . The appropriate fractions were combined and the solvent was removed under vacuum to give 29.2 g of (S) -7-bromo-1,4-benzodioxan-2-ylmethanol as an orange oil. 7.63 g of 4-toluenesulfonyl chloride was added to 7.0 g of the ice-cold solution of the product from the previous reaction in 50 ml of pyridine and the mixture was stirred at ambient temperature for 20 hours and then poured into 200 ml of hydrochloric acid (1 M) . The mixture was extracted with ethyl acetate (3 x 200 mL) and the combined extracts were washed with 200 mL of hydrochloric acid (1 M) and dried over magnesium sulfate. The solvent was removed in vacuo and the residue was recrystallized from a 3: 1 mixture of ether and ethyl acetate to give 6.9 g (R) -7-bromo-1,4-benzodioxan-2-ylmethyl 4-toluenesulfonate As a colorless solid. 2-acetic acid in dichloromethane to 17 ㎖ 17 ㎖ trifluoromethyl-Amino-a - [(butoxycarbonyl-4-piperidyl 1-3-tert-) methyl] pyridine-3-carboxamide (2 to an exemplary N Prepared in a manner analogous to that described), and the mixture was stirred at ambient temperature for 2 hours and the solvent was removed in vacuo. The residue was dissolved in 170 ml of acetonitrile and then 7.6 g of potassium carbonate and 2.21 g of the product from the previous reaction were added and the mixture was heated at reflux temperature for 24 hours and then allowed to stand for 36 hours at ambient temperature, And poured into 300 ml of an aqueous sodium hydroxide solution (5 M). The mixture was extracted with 100 mL of ethyl acetate and the organic phase was washed with hydrochloric acid (1 M; 2 x 300 mL). The combined acid extracts were basified with 200 mL of aqueous sodium hydroxide solution (5 M) and the mixture was washed with ethyl acetate (3 x 200 mL). The combined extracts were dried over magnesium sulfate and the solvent was removed in vacuo to give 1.3 g of a colorless solid which was recrystallized from 7 mL of a 5: 1 mixture of ethyl acetate and petroleum ether (boiling point 40-60 DEG C) ℃, [α] d -25.5 ° (c = 79, dichloromethane) of (S) -2-amino - N - {[1- (7- bromo-1,4-benzodioxane-2-ylmethyl ) -4-piperidyl] methyl} pyridine-3-carboxamide (0.82 g). ≪ Example 22 > A solution of 3.87 g of 3-pyridinecarbonyl chloride hydrochloride in 100 ml of dichloromethane is added to a suspension of 5.0 g of 4- (aminomethyl) -1- tert -butoxycarbonylpiperidine and 10 g of potassium carbonate in 100 ml of dichloromethane And the mixture was stirred at ambient temperature for 2 hours and then poured into 500 ml of water. The organic layer was washed with 250 ml of water, dried over magnesium sulfate and the solvent was evaporated. The residue was purified by flash chromatography eluting with silica in a 20: 1 mixture of dichloromethane and methanol. The appropriate fractions were combined, the solvent was removed in vacuo to N - [(1- 3-tert-butoxycarbonyl-4-piperidyl) methyl] pyridine-3-carboxamide 3.22 g of were obtained as an orange oil. 10 ml of trifluoroacetic acid are added to a solution of 0.95 g of the product from the previous reaction in 25 ml of dichloromethane, the mixture is stirred for 2 hours and then the solvent is removed under vacuum. The residue was dissolved in 25 ml of acetonitrile anhydride, and 5.0 g of potassium carbonate and 1.0 g of (R) -7-chloro-1,4-benzodioxan-2-methyl-4-toluenesulfonate were added, And heated at reflux temperature for 24 hours. The cooled mixture was filtered and the filtrate was evaporated in vacuo. The residue was purified by flash chromatography eluting with silica in a 20: 1 mixture of dichloromethane and methanol. The appropriate fractions were combined, the solvent was removed under vacuum melting point 172-174 ℃, [α] D -48 ° (c = 0.9945, methanol) of (S) - N - {[ 1- (7- chloro-1,4 -Benzodioxan-2-ylmethyl) -4-piperidyl] methyl} piperidine-3-carboxamide (0.75 g). ≪ Example 23 > Of acetic acid 10 ㎖ 50 ㎖ dichloromethane trifluoroacetate N - [(1- 3-tert-butoxycarbonyl-4-piperidyl) methyl] method similar to that described in quinoline-8-carboxamide (8 in the embodiment , And the mixture was stirred for 2 hours and then the solvent was removed under vacuum. The residue was dissolved in 30 ml of acetonitrile anhydride, and 3.0 g of potassium carbonate and 1.51 g of (R) -7-chloro-1,4-benzodioxan-2-ylmethyl 4-toluenesulfonate were added thereto. Was stirred and heated at reflux temperature for 24 hours. The mixture was filtered and the solvent was removed in vacuo. The residue was dissolved in dichloromethane and the solution was washed with water (2 x 50 mL) and then dried over magnesium sulfate. The solvent was removed in vacuo and the residue was purified by flash chromatography on silica eluting with dichloromethane, then a 100: 1 mixture of dichloromethane and methanol followed by a 20: 1 mixture. The appropriate fractions were combined, the solvent was removed in a vacuum melting point 51-54 ℃, [α] D -39.7 ° (c = 0.7230, methanol) (S) - N - { [1- (7- chloro-1,4 -Benzodioxan-2-ylmethyl) -4-piperidyl] methyl} quinoline-8-carboxamide (1.33 g). ≪ Example 24 > Of acetic acid 10 ㎖ 25 ㎖ dichloromethane trifluoroacetate N - [(1- 3-tert-butoxycarbonyl-4-piperidyl) methyl] pyridine-3-carboxamide was added to a solution of 1.56 g, and the mixture Was stirred for 2 hours and then the solvent was removed under vacuum. The residue was dissolved in 10 ml of acetonitrile anhydride, and to the solution was added 5.0 g of potassium carbonate and then 1.7 g of (R) -7-chloro-1,4-benzodioxan-2- And the mixture was stirred and heated at reflux temperature for 6 hours. The cooled mixture was poured into water and extracted with dichloromethane (2 x 50 mL). The combined extracts were washed with 100 ml brine, dried over magnesium sulfate and the solvent removed in vacuo. The residue was purified by flash chromatography eluting with silica in a 20: 1 mixture of dichloromethane and methanol. The appropriate fractions were combined, the solvent was removed in a vacuum melting point 52-54 ℃, [α] D -35.3 ° (c = 1.024, methanol) (S) - N - { [1- (8- Chloro-1,4 Methyl-4-piperidyl] methyl} pyridine-3-carboxamide as a colorless solid. ≪ Example 25 > 0.57 g of (S) -4- (aminomethyl) -1-7- (chloro-1,4-benzodioxan-2-ylmethyl) -piperidine and 0.57 g of 6-methylpyridine- A mixture of 0.27 g of the carboxylic acid was heated under a Dean and Stark water separator for 6 hours. The solvent was removed from the cooled mixture under vacuum and the residue was dissolved in 100 mL of dichloromethane. The solution was washed with water (2 x 100 mL), dried over magnesium sulfate, and the solvent was evaporated. The residue was purified by flash chromatography eluting with silica in a 20: 1 mixture of dichloromethane and methanol. The appropriate fractions were combined, the solvent was removed in a vacuum melting point 81-83 ℃, [α] D -39.6 ° (c = 0.389, methanol) (S) - N - { [1- (7- chloro-1,4 -Benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -6-methylpyridine-2-carboxamide di fumarate as a beige solid. ≪ Example 26 > 4.86 g of 2-methoxypyridine-3-carboxylic acid was added in small portions to 50 ml of thionyl chloride, and the mixture was stirred and heated at reflux temperature for 2 hours. After cooling, the excess thionyl chloride was removed in vacuo and the residue was dissolved in 100 ml of dichloromethane. A solution of 7.3 g of 4- (aminomethyl) -1- tert -butoxycarbonylpiperidine in 100 ml of dichloromethane was added and the mixture was stirred at ambient temperature for 4 hours and then poured into 200 ml of water . The organic phase was washed with water (100 mL), aqueous oxalic acid solution (2 M; 2 x 100 mL), hydrochloric acid (1 M: 100 mL), aqueous sodium bicarbonate solution (2 M; 2 x 150 mL) . The solvent was removed in vacuo and the residue was purified by flash chromatography eluting on silica with a 1: 1 mixture of ethyl acetate and petroleum ether (boiling point 60-80 占 폚). The appropriate fractions were combined, the solvent was removed in vacuo to N - [(1- 3-tert-butoxycarbonyl-4-piperidyl) methyl] 2-methoxy-3-carboxamide 2.06 g was obtained. 10 ml of trifluoroacetic acid are added to a solution of 2.06 g of the product from the previous reaction in 25 ml of dichloromethane, the mixture is stirred for 2.5 hours and then the solvent is removed in vacuo. The residue was dissolved in 50 ml of acetonitrile anhydride and a solution of (R) -7-chloro-1,4-benzodioxan-2-ylmethyl 4-toluenesulfonate 2.33 g, and the mixture was stirred and heated at reflux temperature for 24 hours. The cooled mixture was filtered and the solvent was removed in vacuo. The residue was dissolved in dichloromethane (200 mL) and the solution was washed with water (2 x 200 mL) and dried over magnesium sulfate. The solvent was removed in vacuo and the residue was purified by flash chromatography eluting with a 20: 1 mixture of dichloromethane and methanol on silica. The appropriate fractions were combined, the solvent was removed under vacuum melting point 72-75 ℃, [α] D -47.3 ° (c = 0.226, methanol) of (S) - N - {[ 1- (7- chloro-1,4 -Benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -2-methoxypyridine-3-carboxamide as a solid. ≪ Example 27 > The solvent was evaporated from a solution of butyllithium in 55.6 mL of hexane (2.5 M) under vacuum and at ambient temperature to give a viscous oil which was cooled to -78 C under nitrogen and treated with potassium tertiary- A pre-cooled solution of 15.6 g of butoxide was added slowly. 20.0 g of 3,4-difluoroanisole was then added dropwise while maintaining the reaction temperature below -60 캜 to obtain a brown solution. After stirring at -78 [deg.] C for 2 hours, 10.8 ml of dimethylformamide anhydride was added and the mixture was allowed to warm to ambient temperature over 18 hours. Water (200 mL) was added and the mixture was extracted with ether (3 x 300 mL). The combined extracts were washed with 100 mL of aqueous lithium chloride solution (40%), 200 mL of water and dried over magnesium sulfate. Evaporation of the solvent gave an orange oil which was purified by flash chromatography eluting with silica on a petroleum ether (boiling point 40-60 DEG C) and a 9: 1 mixture of ethyl acetate. The appropriate fractions were combined and the solvent was removed in vacuo to give 10.1 g of 2,3-difluoro-6-methoxybenzaldehyde as a yellow solid. A solution of boron tribromide (1.0 M) in dichloromethane (197.4 mL) was added to a solution of 2,3-difluoro-6-methoxybenzaldehyde (prepared analogously to that described above) in 100 mL of dichloromethane under nitrogen and also at- ≪ / RTI > was added with stirring to a solution of 10.4 g. The resulting solution was allowed to warm to ambient temperature overnight, then 200 mL of methanol and then 100 mL of water were added and the mixture was heated at 40 < 0 > C for 2 h. The aqueous layer was separated and extracted with dichloromethane (2 x 300 mL). The combined organic extracts were extracted with aqueous sodium hydroxide (1 M; 3 x 400 ml), the combined extracts were acidified with concentrated hydrochloric acid and extracted with ethyl acetate (3 x 300 ml). The combined extracts were dried over magnesium sulfate and the solvent was removed under vacuum to give 8.12 g of 2,3-difluoro-6-hydroxybenzaldehyde as a solid. A mixture of 8.1 g of the product from the previous reaction in 250 ml of dimethylformamide, 11.4 g of (R) -glycidyl 4-toluenesulfonate and 7.03 g of potassium carbonate was stirred and heated at 60 ° C under nitrogen for 3 days. Water (300 mL) was added and the mixture was extracted with ether (3X x 400 mL). The combined extracts were washed with 200 mL of aqueous lithium chloride solution (40%), 200 mL of water and dried over magnesium sulfate. Evaporation of the solvent gave an oil which was added to a 1: 1 mixture of ether and petroleum ether (boiling point 40-60 C) and poured slowly from the dark brown oil to give an orange solution. The solvent was removed under vacuum to obtain 9.0 g of (R) -6- (2,3-epoxypropoxy) -2,3-difluorobenzaldehyde as an oil. A solution of 9.0 g of the product from the previous reaction and 26.47 g of 3-chloroperoxybenzoic acid (57%) in 500 ml of chloroform was heated at reflux for 18 hours. 300 ml of a saturated aqueous solution of sodium hydrogencarbonate and 500 ml of dichloromethane were added and the organic layer was separated, washed with a saturated aqueous solution of sodium hydrogencarbonate (3 times x 300 ml), brine (300 ml) and dried over magnesium sulfate. The solvent was removed under vacuum to obtain 11.9 g of (R) -6- (2,3-epoxypropoxy) -2,3-difluorophenylformate as a solid. A solution of 11.9 g of the crude product from the previous reaction in 140 ml of methanol was added dropwise to a stirred solution of sodium methoxide prepared by melting 1.22 g of sodium metal in 140 ml of methanol under nitrogen and the solution was stirred at ambient temperature for 18 hours Lt; / RTI > The solvent was removed in vacuo, 500 mL of water was added to the residue, and the mixture was extracted with ethyl acetate (3 x 400 mL). The combined extracts were washed with brine (300 mL), dried over magnesium sulfate and the solvent was removed in vacuo. The residue was purified by flash chromatography eluting with ethyl acetate in petroleum ether and a 1: 1 mixture of petroleum ether (boiling point 40-60 [deg.] C). The appropriate fractions were combined and the solvent was removed under vacuum to give 0.7 g of (S) -7,8-difluoro-1,4-benzodioxan-2-yl methanol as an oil. A solution of 0.74 g of 4-toluenesulfonyl chloride in 10 ml of dichloromethane was added dropwise at 0 [deg.] C under nitrogen to a solution of 0.7 g of the product from the previous reaction and 0.52 g of 4- (dimethylamino) pyridine in 10 ml of dichloromethane. The solution was stirred at 0 < 0 > C for 2 h, then at ambient temperature for 1 h. Water (50 mL) was added, and the mixture was extracted with dichloromethane (3X100 mL). The combined extracts were dried over magnesium sulfate and the solvent was evaporated, yielding 1.1 g of (R) -7,8-difluoro-1,4-benzodioxan-2-ylmethyl 4-toluenesulfonate, Oil. Acid 10 ㎖ trifluoromethyl-dichloro 2-amino 10 ㎖ methane-on - [(butoxycarbonyl-4-piperidyl 1-3-tert-) methyl] pyridine-3-carboxamide (Example 2 N Was prepared in a manner similar to that described), and the mixture was stirred at ambient temperature for 5 hours, and the solvent was removed under vacuum. The residue was added to a mixture of 4.3 g of potassium carbonate in 100 ml of acetonitrile, 10 mg of potassium iodide and 1.1 g of the product from the previous reaction, and the mixture was stirred and heated at reflux temperature for 16 hours. The solvent was removed from the cooled mixture under vacuum and the residue partitioned between 300 mL saturated aqueous sodium bicarbonate and 300 mL ethyl acetate. The aqueous layer was further extracted with ethyl acetate (3 x 300 mL) and the combined organic layers were washed with brine (400 mL) and dried over magnesium sulfate. The solvent was removed in vacuo and the residue was purified by flash chromatography on silica eluting with a 9: 1 mixture of ethyl acetate and methanol. The appropriate fractions were combined, the solvent was removed in a vacuum melting point 127-128 ℃, [α] D -25.8 ° (c = 0.80, methanol, dichloromethane) (S) -2- amino - N - {[1- (7 , 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} pyridine-3-carboxamide 0.2 Ethyl acetate solvate was obtained as a solid 0.47 g. ≪ Example 28 > A mixture of 8.2 g of pyrogallol carbonate, 5.0 g of (S) -epichlorohydrin and 0.2 ml of pyridine anhydride in 50 ml of ethyl acetate anhydride was heated at reflux temperature for 2 hours. The solvent was heated under vacuum, 30 mL of water was added, and the mixture was heated at reflux for 30 minutes. A solution of 10 g of potassium hydroxide in 20 ml of water was added dropwise and the mixture was heated under nitrogen at reflux temperature for another 30 min. The cooled mixture was diluted with water (100 mL), acidified with hydrochloric acid (5 M) and extracted with ethyl acetate (3 x 200 mL). The combined extracts were washed with water (2 x 100 mL) and dried over magnesium sulfate. The solvent was removed in vacuo and the residue was purified by chromatography eluting with a 1: 1 mixture of ethyl acetate and petroleum ether (boiling point 60-80 C) followed by pure ethyl acetate. The appropriate fractions were combined and the solvent removed in vacuo to give 0.8 g of (S) -8-hydroxy-1,4-benzodioxan-2-ylmethanol. 2.48 g of trifluoromethanesulfonic anhydride was added dropwise at 0 [deg.] C to a stirred solution of 0.8 g of the product from the previous reaction and 0.64 g of 4- (dimethylamino) pyridine in 50 ml of dichloromethane under nitrogen. The mixture was allowed to warm to ambient temperature with continued stirring for 18 hours, then washed with 100 ml of water and dried over magnesium sulfate. The solvent was removed in vacuo and the residue was purified by flash chromatography eluting with dichloromethane on silica. The appropriate fractions were combined and the solvent removed in vacuo to give 1.10 g of (R) -8- (trifluoromethanesulfonyloxy) -1,4-benzodioxan-2-ylmethyltrifluoromethanesulfonate. Acid 5 ㎖ trifluoromethyl-dichloro-2-amino methane ㎖ 25 - in [(butoxycarbonyl-4-piperidyl 1-3-tert-) methyl] pyridine-3-carboxamide (Example 2 N Prepared in a manner analogous to that described), and the mixture was stirred at ambient temperature for 2 hours and the solvent was removed under vacuum. The residue was dissolved in 25 ml of acetonitrile anhydride and a solution of 1.03 g of the product from the previous reaction in 5.0 g of potassium carbonate and then 10 ml of acetonitrile anhydride was added. The mixture was stirred, heated at reflux temperature for 1.5 hours, cooled, filtered and the solvent removed in vacuo. The residue was dissolved in 100 mL of dichloromethane, washed with water (2 x 100 mL), and dried over magnesium sulfate. The solvent was removed in vacuo and the residue was purified by flash chromatography eluting with a 20: 1 mixture of ethyl acetate and methanol on silica. (S) of the combined appropriate fractions were removed in a vacuum melting point 52-55 ℃, [α] D -21.9 ° (c = 0.2925, methanol) and the solvent 2-amino - N - {[1- (8- tree Methyl-4-piperidyl] methyl} pyridine-3-carboxamide as a colorless solid. ≪ Example 29 > 6.58 g of N, N'-carbonyldiimidazole was added to a suspension of 5.0 g of pyridine-2-carboxylic acid in 75 ml of dichloromethane under nitrogen and at ambient temperature with stirring. Stirring was continued (about 2 hours) until gas evolution ceased and then 8.2 g of N -benzylidene-l- (4-piperidyl) methylamine was added and the reaction mixture was stirred for 18 hours. The solvent was evaporated to give a viscous yellow oil which was stirred with 200 ml of aqueous potassium hydrogen sulfate (1 M) solution for 18 hours. The mixture was washed with dichloromethane (2 x 250 mL), adjusted to pH 14 with aqueous sodium hydroxide solution (5 M) and extracted with dichloromethane (3 x 250 mL). The combined extracts were dried over magnesium sulfate and the solvent was removed in vacuo to give 5.2 g of 4- (aminomethyl) -1- (2-pyridylcarbonyl) piperidine as a viscous yellow oil. 3.0 g of the product from the previous reaction in acetonitrile anhydride, 4.86 g of (R) -7-chloro-1,4-benzodioxan-2-ylmethyl 4-toluenesulfonate, 200 mg of potassium iodide and 9.45 g of The mixture was stirred and heated at reflux temperature for 18 hours. The mixture was cooled and filtered, and the solvent was removed in vacuo. The residue was purified by flash chromatography eluting on silica with a 20: 1 mixture of dichloromethane and industrial methyl alcohol. The appropriate fractions were combined and the solvent removed in vacuo to give 2.87 g of a viscous yellow oil which was dissolved in 10 ml of hot ethanol and treated with a solution of 0.76 g of fumaric acid in 10 ml of hot ethanol. The solvent was removed under vacuum, and grinding the residue with ether, 250 ㎖ about 55 ℃ Melting point (dec.), [Α] D -42.9 ° 4- [N in (c = 0.8135, methanol) - (7-chloro-l , 4-benzodioxan-2-ylmethyl) aminomethyl] -1- (2-pyridylcarbonyl) piperidine 1.2 fumarate 0.5 hydrate 0.4 Solvent of ethanol was obtained as a solid. ≪ Examples 30 to 52 > The following compounds of formula (I) are prepared by the method detailed below. Six different formula (XLVII) (g is 1; A is O; B is O; U is methylene; X is ethylene and; X 'is ethylene, and; V is methylene; R 5 is H and; R 1 is 7-methyl, 7-bromo, 7-chloro, 7-fluoro, 8-trifluoromethyl, or 8-chloro-Im), and formula 5 different formula R-HET-CO 2 H ( HET of Is 3-pyridyl and R is H, 2-methyl, 6- (1-pyrrolyl), 2-methylthio or 5-bromo) as starting materials. Example No.designation 30 (S) - N - {[ 1- (7- methyl-1,4-benzodioxane-2-ylmethyl) -4-piperidyl] methyl} pyridine-3-carboxamide 31Methyl- N - {[1- (7-methyl-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} pyridine-3- carboxamide 32 (S) - N - {[ 1- (7- methyl-1,4-benzodioxane-2-ylmethyl) -4-piperidyl] methyl} -6- (pyrrolyl) pyridine-3-carboxamide, amides 33 (S) - N - {[ 1- (7- methyl-1,4-benzodioxane-2-ylmethyl) -4-piperidyl] methyl} -2 (methylthio) pyridine-3-carboxamide, amides 34(S) -5-bromo- N - {[1- (7-methyl-1,4-benzodioxan-2- ylmethyl) -4-piperidyl] methyl} pyridine- 35 (S) - N - {[ 1- (7- bromo-1,4-benzodioxane-2-ylmethyl) -4-piperidyl] methyl} pyridine-3-carboxamide 36 (S) - N - {[ 1- (7- bromo-1,4-benzodioxane-2-ylmethyl) -4-piperidyl] methyl} -2-methylpyridine-3-carboxamide 37 (S) - N - {[ 1- (7- bromo-1,4-benzodioxane-2-ylmethyl) -4-piperidyl] methyl} -6- (1-pyrrolyl) pyridine -3 - carboxamide 38 (S) - N - {[ 1- (7- bromo-1,4-benzodioxane-2-ylmethyl) -4-piperidyl] methyl} -2 (methylthio) pyridine-3-carboxamide Vox amide 39(S) -5-bromo- N - {[1- (7-bromo-1,4-benzodioxan-2- ylmethyl) -4-piperidyl] methyl} pyridine- 40 (S) - N - {[ 1- (7- chloro-1,4-benzodioxane-2-ylmethyl) -4-piperidyl] methyl} -6- (1-pyrrolyl) pyridine-3 Carboxamide 41 (S) - N - {[ 1- (7- chloro-1,4-benzodioxane-2-ylmethyl) -4-piperidyl] methyl} -2 (methylthio) pyridine-3-carboxamide, amides 42(S) -5-bromo- N - {[1- (7-chloro-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} pyridine- 43 (S) - N - {[ 1- ( 7-fluoro-l, 4-benzodioxane-2-ylmethyl) -4-piperidyl] methyl} pyridine-3-carboxamide 44 (S) - N - {[ 1- (7- fluoro-1,4-benzodioxane-2-ylmethyl) -4-piperidyl] methyl} -2 (methylthio) pyridine-3-carboxamide Vox amide 45 (S) - N - {[ 1- (8- trifluoromethyl-1,4-benzodioxane-2-ylmethyl) -4-piperidyl] methyl} pyridine-3-carboxamide 46Methyl- N - {[1- (8-trifluoromethyl-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} pyridine- amides 47(S) -6- (1- pyrrolyl) - N - {[1- (methyl-1,4-benzodioxane-2-yl-methyl-8-trifluoromethyl) -4-piperidyl] methyl} pyridine -3-carboxamide 48(S) -2- (methylthio) - N - {[1- (methyl-1,4-benzodioxane-2-yl-methyl-8-trifluoromethyl) -4-piperidyl] methyl} pyridine -3 - carboxamide 49(S) -5-bromo- N - {[1- (8-trifluoromethyl-1,4-benzodioxan-2- ylmethyl) -4-piperidyl] methyl} pyridine- Vox amide 50 (S) - N - {[ 1- (8- chloro-l, 4-benzodioxane-2-ylmethyl) -4-piperidyl] methyl} -6- (1-pyrrolyl) pyridine-3 Carboxamide 51 (S) - N - {[ 1- (8- chloro-l, 4-benzodioxane-2-ylmethyl) -4-piperidyl] methyl} -2 (methylthio) pyridine-3-carboxamide, amides 52(S) -5-bromo- N - {[1- (8-chloro-1,4-benzodioxan-2- ylmethyl) -4-piperidyl] methyl} pyridine- ≪ Formula XLVII > < EMI ID = 0.1 mmol of the compound of formula R-HET-CO 2 H was weighed into a 2 ml reaction vial. 0.1 mmol of the compound of formula (XLVII) was dissolved in 0.5 ml of dichloromethane anhydride and added to the vial. Subsequently, 0.1 mmol of N , N' -diisopropylcarbodiimide was added and the mixture was stirred at 20 < 0 > C for 5.5 hours under nitrogen. The vial was exposed to reduced pressure in a vacuum desiccator for 20 minutes to remove the solvent. 1 ml of digol was added and stirring was continued until the reaction residue was redissolved / resuspended (0.1 M concentration). 20 μl of this material was added to 1.98 ml of digol to obtain a 0.001 M solution to be tested for receptor binding affinity for 5HT 1A , α 1 , and D 2 receptors. ≪ Example 53 > The use of the compounds of the invention in the manufacture of pharmaceutical compositions is illustrated by the following description. In this description, the term " active compound " means any compound, especially any compound, which is the final product of any of the preceding embodiments. a) Capsules In the preparation of the capsules, 10 parts by weight of active compound and 240 parts by weight of lactose were deagglomerated and mixed. This mixture was filled into each hard gelatine capsule containing a unit dose or a unit dose of the active compound. b) Tablets Tablets were made with the following ingredients: Weight portion The active compound 10 Lactose 190 Corn starch 22 Polyvinylpyrrolidone 10 Magnesium stearate 3 The active compound, lactose and some starch were deagglomerated and mixed, and the resulting mixture was granulated with a solution of polyvinylpyrrolidone in ethanol. The granular anhydride was mixed with magnesium stearate and the remaining starch. This mixture was compressed on a tablet machine to obtain each tablet containing a unit dose or a part of the unit dose of the active compound. c) Intestinal purgative Tablets were prepared as described in (b) above. The tablets were coated with the enteric coating in a conventional manner using a solution of 20% cellulose acetate phthalate and 3% diethyl phthalate in ethanol: dichloromethane (1: 1). d) Suppositories In the manufacture of suppositories, 100 parts by weight of the active compound is incorporated into 1300 parts by weight of a triglyceride suppository base, which mixture is formed with each suppository containing a therapeutically effective amount of the active ingredient.
权利要求:
Claims (14) [1" claim-type="Currently amended] (I) < / RTI > comprising a pharmaceutically acceptable salt thereof. (I) Wherein A is methylene or -O-; B is methylene or -O-; g is 0, 1, 2, 3 or 4; R 1 is a) halo; b) an alkyl group containing from 1 to 3 carbon atoms optionally substituted by one or more halo; c) an alkoxy group containing from 1 to 3 carbon atoms optionally substituted by one or more halo; d) an alkylthio group containing from 1 to 3 carbon atoms optionally substituted by one or more halo; e) hydroxy; f) an acyloxy group containing from 1 to 3 carbon atoms; g) hydroxymethyl; h) cyano; i) an alkanoyl group containing 1 to 6 carbon atoms; j) an alkoxycarbonyl group containing 2 to 6 carbon atoms; k) a carbamoyl group or a carbamoylmethyl group each optionally N -substituted by 1 or 2 alkyl groups each containing 1 to 3 carbon atoms; l) a sulfamoyl or sulfamoylmethyl group optionally N -substituted by one or two alkyl groups each containing 1 to 3 carbon atoms; m) an alkylsulfonyloxy group containing from 1 to 3 carbon atoms optionally substituted by one or more halo; n) furyl group; o) an amino group optionally substituted by one or two alkyl groups each containing from 1 to 3 carbon atoms; Or when g is 2, 3 or 4, two adjacent R < 1 > groups, which are the same or different, together with the carbon atoms to which they are attached form a fused benz ring; R 2 is H, an alkyl group containing from 1 to 3 carbon atoms optionally substituted by one or more halo, or an alkoxy group containing from 1 to 3 carbon atoms optionally substituted by one or more halo; R 3 and R 4 are the same or different and are H or an alkyl group containing from 1 to 3 carbon atoms optionally substituted by one or more halo; U is an alkylene chain containing from 1 to 3 carbon atoms, optionally substituted by one or more alkenyl groups each containing from 1 to 3 carbon atoms; Q represents a divalent group of formula (IIa), (IIb) or (IIc); <Formula IIa> <Formula IIb> <Formula IIc> V is an alkylene chain containing from 1 to 3 carbon atoms optionally substituted by one or more alkyl groups containing from 1 to 3 carbon atoms, X is an alkylene chain containing from 0 to 2 carbon atoms and X ' is an alkylene chain containing from 1 to 4 carbon atoms, optionally substituted by one or more alkyl groups containing from 1 to 4 carbon atoms, , With the proviso that the total number of carbon atoms in X and X 'is 3 or 4 and R 5 is H or an alkyl group containing 1 to 3 carbon atoms, T is CO.HET wherein HET is selected from 2-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 2- or 3-thienyl, 2- or 3- 2,3- or 7-benzo [b] furanyl, 2,3-dihydro-7-benzo [b] furanyl, 2-, 4- or 5-pyrazolyl, 4- or 5-triazolyl, 5-tetrazolyl, 2-, 3-, 4- or 8-quinolinyl, 2- or 4- 4-, or 5-isoxazolyl, 3-, 4- or 5-isothiazolyl or 2-, 4- or 5-thiazolyl, , Each of which is a) halo, b) an alkyl group containing 1 to 3 carbon atoms optionally substituted by one or more halo, c) an alkoxy group containing 1 to 3 carbon atoms optionally substituted by one or more halo d) an alkylthio group containing 1 to 3 carbon atoms optionally substituted by one or more halo, e) hydroxy, f) an alkyl group containing 1 to 3 carbon atoms I) an alkanoyl group containing 1 to 6 carbon atoms, j) an alkoxycarbonyl group containing 2 to 6 carbon atoms, k) an alkoxycarbonyl group containing 1 to 3 carbon atoms, Carbamoyl groups or carbamoylmethyl groups each optionally N -substituted by one or more alkyl groups containing 1 to 3 carbon atoms, l) optionally N -substituted by 1 or 2 alkyl groups each containing 1 to 3 carbon atoms, A sulfamoylmethyl group, m) an amino group optionally substituted by one or two alkyl groups each containing 1 to 5 carbon atoms, n) 1-pyrrolyl or o) 1-pyrrolidinyl or piperidino ≪ / RTI > [2" claim-type="Currently amended] 2. The compound of claim 1, wherein A and B are both O; wherein g is 0, 1 or 2, R 1 is halo (for example fluoro, chloro or bromo), an alkyl group containing from 1 to 3 carbon atoms optionally substituted by one or more halo, An alkoxy group containing one carbon atom, an alkylsulfonyloxy group containing from 1 to 3 carbon atoms optionally substituted by one or more halo, or hydroxy; R 2 is H or an alkyl group containing 1 to 3 carbon atoms, R 3 and R 4 are the same or different from each other and are H or methyl; U is methylene; Q is a group of formula (IIa) or (IIc); V is methylene; R < 5 > is H or methyl; X and X 'are both ethylene and HET is optionally substituted by methyl, methoxy, trifluoromethyl, halo, methylthio, 1-pyrrolyl and one or two alkyl groups each containing from 1 to 3 carbon atoms 3-or 4-pyridyl, 8-quinolinyl or 2-thienyl, each of which is optionally substituted by one or more substituents selected from imino groups. [3" claim-type="Currently amended] 3. A compound according to claim 1 or 2, wherein HET is 2-pyridyl, 3-pyridyl, 8-pyridyl, or 3-pyridyl optionally substituted with an amino group, methyl, methoxy, 1- pyrrolyl, trifluoromethyl, methylthio or bromo, -Quinolinyl or 2-thienyl. ≪ / RTI > [4" claim-type="Currently amended] 4. Compounds of formula (I) according to any one of claims 1 to 3, wherein HET is 2-pyridyl or 3-pyridyl optionally substituted by an amino group. [5" claim-type="Currently amended] 3. A compound according to claim 1, in the form of the individual enantiomers, racemates or other mixtures of enantiomers 2-Amino- N - {[1- (7-chloro-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} pyridine-3-carboxamide; 2-Amino- N - {[1- (8-chloro-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} pyridine-3-carboxamide; 2-Amino- N - {[1- (8-fluoro-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} pyridine-3-carboxamide; 2-Amino- N - {[1- (1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} pyridine-3-carboxamide; 2-Amino- N - {[1- (7-methyl-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} pyridine-3-carboxamide; N - {[1- (1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} pyridine-2-carboxamide; 2-Amino- N - {[1- (7-methoxy-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} pyridine-3-carboxamide; N - {[1- (1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} quinoline-8-carboxamide; N - {[1- (8-chloro-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -2-methylpyridine-3-carboxamide; 2-Amino- N - {[1- (7-fluoro-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} pyridine-3-carboxamide; 2-Amino- N - {[1- (8-methoxy-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} pyridine-3-carboxamide; N - {[1- (7-chloro-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} pyridine-2-carboxamide; 2-Amino- N - {[1- (8-methyl-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} pyridine-3-carboxamide; 2-Amino- N - {[1- (7-chloro-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -6-methylpyridine-3-carboxamide; 3-Amino- N - {[1- (1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -thiophene-2-carboxamide; 3-Amino- N - {[1- (7-chloro-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} thiophene-2-carboxamide; N - {[1- (7-chloro-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -2-methylpyridine-3-carboxamide; 1- (2-aminonicotinoyl) -4- [ N - (7-chloro-1,4-benzodioxan-2-ylmethyl) aminomethylpiperidine; 2-Amino- N - {[1- (8-trifluoromethyl-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} pyridine-3-carboxamide; 2-Amino- N - {[1- (7-bromo-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} pyridine-3-carboxamide; N - {[1- (7-chloro-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} pyridine-3-carboxamide; N - {[1- (7-chloro-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} quinoline-8-carboxamide; N - {[1- (8-chloro-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} pyridine-3-carboxamide; N - {[1- (7-chloro-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -6-methylpyridine-2-carboxamide; N - {[1- (7-chloro-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -2-methoxypyridine-3-carboxamide; 2-Amino- N - {[1- (7,8-difluoro-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} pyridine-3-carboxamide; 2-Amino- N - {[1- (8-trifluoromethanesulfonyloxy-1,4-benzodioxan-2- ylmethyl) -4-piperidyl] methyl} pyridine-3- carboxamide ; 4- [ N - (7-chloro-1,4-benzodioxan-2-ylmethyl) aminomethyl] -1- (2-pyridylcarbonyl) -piperidine; N - {[1- (7-methyl-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} pyridine-3-carboxamide; 2-methyl- N - {[1- (7-methyl-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} pyridine-3-carboxamide; N - {[1- (7-methyl-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -6- (1-pyrrolyl) pyridine-3-carboxamide; N - {[1- (7-methyl-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -2- (methylthio) pyridine-3-carboxamide; 5-bromo- N - {[1- (7-methyl-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} pyridine-3-carboxamide; N - {[1- (7-bromo-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} pyridine-3-carboxamide; N - {[1- (7-bromo-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -2-methylpyridine-3-carboxamide; N - {[1- (7- bromo-1,4-benzodioxane-2-ylmethyl) -4-piperidyl] methyl} -6- (1-pyrrolyl) pyridine-3-carboxamide ; N - {[1- (7-bromo-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -2- (methylthio) pyridine-3-carboxamide; 5-Bromo- N - {[1- (7-bromo-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} pyridine-3-carboxamide; N - {[1- (7-chloro-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -6- (1-pyrrolyl) pyridine-3-carboxamide; N - {[1- (7-chloro-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -2- (methylthio) pyridine-3-carboxamide; 5-Bromo- N - {[1- (7-chloro-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} pyridine-3-carboxamide; N - {[1- (7-fluoro-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} pyridine-3-carboxamide; N - {[1- (7-fluoro-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -2- (methylthio) pyridine-3-carboxamide; N - {[1- (8-trifluoromethyl-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} pyridine-3-carboxamide; 2-methyl- N - {[1- (8-trifluoromethyl-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} pyridine-3-carboxamide; Methyl] -4-piperidyl] methyl} pyridine-3-carbaldehyde To a solution of 6- (1-pyrrolyl) -N - {[1- (8-trifluoromethyl- ≪ / RTI > 2- (methylthio) - N - {[1- ( 8- trifluoromethyl-1,4-benzodioxane-2-ylmethyl) -4-piperidyl] methyl} pyridine-3-carboxamide ; 5-Bromo- N - {[1- (8-trifluoromethyl-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} pyridine-3-carboxamide; N - {[1- (8-chloro-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -6- (1-pyrrolyl) pyridine-3-carboxamide; N - {[1- (8-chloro-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -2- (methylthio) pyridine-3-carboxamide; And 5-bromo - N - {[1- (8- chloro-l, 4-benzodioxane-2-ylmethyl) -4-piperidyl] methyl} pyridine-3-carboxamide, and their pharmaceutically (I) < / RTI > selected from pharmaceutically acceptable salts. [6" claim-type="Currently amended] A composition comprising a therapeutically effective amount of a compound of formula (I) or a salt thereof according to claim 1 together with a pharmaceutically acceptable diluent or carrier. [7" claim-type="Currently amended] The use according to claim 1 for the treatment of depression, anxiety, psychosis, bipolar dyskinesia, Parkinson's disease, hypertension, Turret's syndrome, compulsive acts, panic attacks, social phobia, cardiovascular and cerebrovascular disorders, A compound of formula (I) used in the treatment of hypertrophy. [8" claim-type="Currently amended] 8. Compounds of formula (I) according to claim 7 for use in the treatment of schizophrenia. [9" claim-type="Currently amended] The use of a compound of formula (I) according to claim 1 for the treatment of a disorder or condition selected from the group consisting of depression, anxiety, psychosis, bipolar disorder, parkinsonism, hypertension, tullet syndrome, obsession, panic attacks, Use in the manufacture of a medicament for treating vascular disorders, stress and prostate hypertrophy. [10" claim-type="Currently amended] A method for the treatment of anxiety, psychosis, bipolar disorder, parkinsonism, hypertension, tourette syndrome, obsessive compulsive disorder, panic attacks, social phobia, cardiovascular and cerebrovascular disorders, stress and prostate hypertrophy by administering a therapeutically effective amount of a compound of formula (I) To a mammal, particularly a human, in need thereof. [11" claim-type="Currently amended] 11. The method of claim 10, wherein the treatment of schizophrenia. [12" claim-type="Currently amended] The compound of formula (XXXVI) is reacted with a leaving group such as, for example, toluene-4-sulfonyloxy (R), in the presence of a base such as potassium carbonate and optionally in a solvent such as acetonitrile (I) according to claim 1, wherein Q is a group of formula < RTI ID = 0.0 > (IIa) < / RTI > <Formula XXXVI> In the above formula, D 'is H. [13" claim-type="Currently amended] Compounds of formula (XLV) may be prepared by reacting a compound of formula (XLV) optionally in the presence of a base, such as potassium carbonate, and optionally in a solvent such as acetonitrile, with a leaving group such as toluene- (I) according to claim 1, wherein Q is a group of formula (IIc), comprising reacting a compound of formula (VIII) <XLV> In the above formula, D 'is H. [14" claim-type="Currently amended] A) optionally in the presence of a solvent, for example 1,2-dimethoxyethane, a compound of formula (XXXIX), for example pyrido [2,3- d ] [1 , 3] oxazine-2,4 ( 1H ) -dione; Or b) in the presence of a base, for example triethylamine, with an acylating agent of the formula X-CO.HET wherein X is a leaving group such as halo, alkoxy, hydroxy or alkoxycarbonyloxy, (IIc), which comprises reacting a compound of formula (IIc) with an amide bond former such as carbonyl diimidazole or N , N' -diisopropyl carbodiimide in a suitable solvent such as dichloromethane. Lt; RTI ID = 0.0 > (I) < / RTI > <XLVII>
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同族专利:
公开号 | 公开日 TW454006B|2001-09-11| BG62771B1|2000-07-31| BR9609506A|1999-06-01| WO1997003071A1|1997-01-30| JPH11508599A|1999-07-27| DE69630604T2|2004-09-23| TR199800041T1|1998-05-21| CA2223472A1|1997-01-30| NZ313164A|1999-07-29| EP0839145B1|2003-11-05| NO980129D0|1998-01-12| AU6517296A|1997-02-10| HRP960348A2|1998-04-30| ZA9605921B|1998-01-12| NO980129L|1998-01-12| SK2498A3|1998-09-09| AT253573T|2003-11-15| EP0839145A1|1998-05-06| IL122540A|2001-10-31| IL122540D0|1998-06-15| BG102145A|1998-11-30| RU2169147C2|2001-06-20| US5935973A|1999-08-10| HU9901485A3|2001-03-28| CZ388497A3|1998-06-17| CN1071755C|2001-09-26| PL324529A1|1998-06-08| GB9514380D0|1995-09-13| CN1190967A|1998-08-19| HU9901485A2|2000-07-28| MX9800084A|1998-03-29| AU708890B2|1999-08-12| DE69630604D1|2003-12-11|
引用文献:
公开号 | 申请日 | 公开日 | 申请人 | 专利标题
法律状态:
1995-07-13|Priority to GBGB9514380.6A 1995-07-13|Priority to GB9514380.6 1996-07-02|Application filed by 독터. 호르스트 하스칼, 잉에 린스, 크놀 아게 1999-04-15|Publication of KR19990028918A
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申请号 | 申请日 | 专利标题 GBGB9514380.6A|GB9514380D0|1995-07-13|1995-07-13|Therapeutic agents| GB9514380.6|1995-07-13| 相关专利
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