MXPA00006017A - Pharmaceutical composition for antagonizing ccr5 comprising anilide derivative - Google Patents

Abstract

This invention is to provide a pharmaceutical composition for antagonizing CCR5 which comprises a compound of formula (1) wherein R1 is an optionally substituted 5- to 6-membered ring;W is a divalent group of formula (a) or (b) wherein the ring A is an optionally substituted 5- to 6-membered aromatic ring, X is an optionally substituted C, N orO atom, and the ring B is an optionally substituted 5- to 7-membered ring;Z is a chemical bond or a divalent group;R2 is an optionally substituted amino group in which a nitrogen atom may form a quaternary ammonium, etc., or a salt thereof.

Description

DESCRIPTION Pharmaceutical Composition to Antagonize CCR5 comprising a Derivative of Anuide Technical Field The present invention relates to a pharmaceutical composition for antagonizing CCR5 comprising an anuide derivative.

BACKGROUND ART Recently, HIV (human immunodeficiency virus) protease inhibitors are developed for the treatment method of AIDS (acquired immune deficiency syndrome) and the use of protease inhibitors in combination with two transcriptase inhibitors. Inverse HIV, conventional provides additional progress of AIDS treatment. However, these drugs and their use in combination are not sufficient for the eradication of AIDS, and the development of new anti-AIDS drugs that have different activity and mechanism is sought. So far CD4 is known as a receptor from which HIV invades a target cell, and CCR5 was recently discovered as REF .: 33116 a second acrophagous-tropic HIV receptor and CXCR4 as a second T-cell tropic HIV receptor respectively, each of which is a chemokine receptor coupled with protein G that has seven transmembrane domains. It is believed that these chemokine receptors play an essential role in the establishment and spread of HIV infection. In fact, it is reported that a person who is resistant to HIV infection despite several exposures, retains a mutation of homosuppression of the CCR5 gene. Therefore, a CCR5 antagonist is expected to be a new anti-HIV drug. However, until now, it has not been reported that a CCR5 antagonist develops as an AIDS therapeutic agent. In order to analyze an anti-AIDS drug having CCR5 antagonistic activity, it is necessary to clone the CCR5 gene from human tissue derived from a cDNA library, to ligate the gene with a vector for expression in animal cells, to introduce the gene in animal cells and obtain cells that express CCR5. Furthermore, with the use of this transformant, it is necessary to select a compound which strongly inhibits the binding of the CC RANTES chemokine, a natural ligand, to CCR5 (which strongly antagonizes CCR5). However, until now a compound of low molecules that have CCR5 antagonistic activity has not been reported. The present invention is for providing a pharmaceutical composition which is useful for the treatment or prophylaxis of an infectious disease of HIV and, in particular, AIDS and which comprises an anuide derivative having CCR5 antagonistic activity.

Description of the Invention The present inventors extensively conducted extensive studies on compounds having CCR5 antagonistic activity and, as a result, they found that an anuide derivative of the following formula (I ') or a salt thereof [hereinafter referred to as Compound (I ')] unexpectedly possesses potent CCR antagonistic activity and a clinically desirable pharmaceutical effect (eg, remarkable inhibition of HIV infection to mononuclear, peripheral, human, etc. cells). Based on the discovery, the present invention was made. More specifically, the present invention relates to (1) a pharmaceutical composition for antagonizing CCR5 (or a pharmaceutical composition for inhibiting the ligation of a ligand for CCR5 or a pharmaceutical composition for antagonizing the ligament of a CCR5 ligand for the CCR5) which comprises a compound of the formula (! '): wherein R1 is a 5-membered ring, optionally substituted, W is a divalent group of the formula: wherein ring A is an optionally substituted 5 to 6 membered aromatic ring, X is an optionally substituted carbon atom, an optionally substituted nitrogen atom, a sulfur atom or an oxygen atom, ring B is a ring from 5 to 7 members, optionally substituted, Z is a chemical bond or a divalent group, R2 is (1) an optionally substituted amino group in which a nitrogen atom can form a quaternary ammonium, (2) a nitrogen-containing heterocyclic ring group, optionally substituted which may contain a sulfur atom or an oxygen atom as atoms constituting the ring and wherein a nitrogen atom can form a quaternary ammonium, (3) a group that is attached through a sulfur atom or ( 4) A group of the formula: wherein k is 0 or 1, and when k is 0, a phosphorus atom can form a phosphonium; and R5 'and R6' are independently an optionally substituted hydrocarbon group, an optionally substituted hydroxy group or an optionally substituted amino group, and R5 'and R6' may be linked together to form a cyclic group in conjunction with the adjacent phosphorus atom, or a salt of it; (2) a composition of (1) above, wherein R1 is benzene, furan, thiophene, pyridine, cyclopentane, cyclohexane, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine or tetrahydropyran, each of which may be substituted; (3) a composition of (1) above, wherein R1 is an optionally substituted benzene; (4) a composition of (1) above, wherein ring A is furan, thiophene, pyrrole, pyridine or benzene, each of which may be substituted; (5) a composition of (1) above, wherein ring A is an optionally substituted benzene; (6) a composition of (1) above, where is a group of the formula: wherein each symbol is as defined in (1) above; (7) a composition of (1) above, wherein W is a group of the formula: wherein each symbol is as defined in (1) above: (8) a composition of (7) above, wherein ring B is a ring group of 5 to 7 members of the formula: where Y is -Y '- (CH) m- (Y' is -S-, -0-, -NH- or -CH2-, and m is an integer of 0-2), -CH = CH- or -N = CH-), which may have a substituent in any possible position; (9) a composition of (8) above, wherein Y is -Y'- (CH2) 2- (Y 'is -S-, -0-, -NH- or -CH2-); (10) a composition of (8) above, wherein Y is - (CH2) 2-, - (CH2) 3- or -0- (CH2) 2-; (11) a composition of (10) above, wherein ring A is an optionally substituted benzene; (12) a composition of (1) above, wherein Z is an optionally substituted alkylene of 1 to 3 carbon atoms; (13) a composition of (1) above, wherein Z is a divalent group of the formula: -Z '- (CH2) n- (Z' is -CH (OH) -, -C (0) - or - CH2-, and n is an integer of 0-2) in which an optional methylene group may be substituted; (14) a composition of (1) above, wherein Z is methylene; (15) a composition of (1) above, wherein Z is substituted at the para position of the benzene ring; (16) a composition of (1) above, wherein R2 is (1) an optionally substituted amino group in which a nitrogen atom can form a quaternary ammonium, (2) a nitrogen-containing heterocyclic ring group, optionally substituted which can contain a sulfur atom or an oxygen atom as the atoms that make up the ring and where a nitrogen atom can form a quaternary ammonium, (3) a group that binds through a sulfur atom or (4) a group of the formula: wherein k is 0 or 1, and when k is 0, a phosphorus atom can form a phosphonium; and R5 and R6 are independently an optionally substituted hydrocarbon group or an optionally substituted amino group, and R5 and R6 can be linked together to form a cyclic group in conjunction with the adjacent phosphorus atom; (17) a composition of the above (1), wherein R2 is (1) an optionally substituted amino group in which a nitrogen atom can form a quaternary ammonium, (2) a nitrogen-containing heterocyclic ring group, optionally substituted which may contain a sulfur atom or an oxygen atom as ring-forming atoms and wherein the nitrogen atom can form a quaternary ammonium or (3) a group of the formula: wherein R5 and R4 are independently an optionally substituted hydrocarbon group, and R5 and R6 can be linked together to form a cyclic group in conjunction with the adjacent phosphorus atom; (18) a composition of (1) above, wherein R2 is an optionally substituted amino group wherein a nitrogen atom can form a quaternary ammonium; (19) a composition of (1) above, wherein R2 is a group of the formula: -N + RR 'R "wherein R, R' and R" are independently an aliphatic hydrocarbon group, optionally substituted or a group of the heterocyclic, alicyclic, optionally substituted ring; (20) a pharmaceutical composition for antagonizing CCR5 which comprises a compound of the formula: wherein R is an optionally substituted benzene or an optionally substituted thiophene; Y "is -CH2-, -S- or -0-; and R, R 'and R" are independently an optionally substituted aliphatic hydrocarbon group or a heterocyclic, alicyclic, optionally substituted heterocyclic ring group; (21) a composition of (20) above, wherein R and R 'are independently an acyclic hydrocarbon group, optionally substituted; (22) a composition of (20) above, wherein R and R 'are independently an alkyl group of 1 to 6 carbon atoms, optionally substituted; (23) a composition of the above (20), wherein R "is an optionally substituted alicyclic hydrocarbon group or an optionally substituted heterocyclic, alicyclic ring group; (24) a composition of (20) above, wherein R "is a cycloalkyl group of 3 to 8 carbon atoms, optionally substituted; (25) a composition of (20) above, wherein R "is an optionally substituted cyclohexyl; (26) a composition of (20) above, wherein R" is a group of the heterocyclic, alicyclic, saturated, optionally substituted ring; (27) a composition of the above (20), wherein R "is an optionally substituted tetrahydropyranyl, an optionally substituted tetrahydrothiopyranyl or an optionally substituted piperidyl; (28) a composition of the above (20), wherein R" is a tetrahydropyranyl optionally replaced; (29) a pharmaceutical composition for antagonizing CCR5 which comprises a compound of the formula: wherein X "is an anion (30) a composition of (29) above, wherein X is a halogen atom; (31) a pharmaceutical composition for antagonizing CCR5 which comprises N-methyl-N- iodide 4- [[[2- (4-methylphenyl) -6,7-dihydro-5H-benzocyclohepten-8-yl] carbonyl] amino] benzyl] -piperidinium, N-methyl-N- iodide [4- [[[ 7- (4-methylphenyl) -2,3-dihydro-l-benzoxepin-4-yl] carbonyl] amino] benzyl] piperidinium, N- [4- [N-methyl-N- (tetrahydropyran-4-yl) aminomethyl] -phenyl] -7- (4-methylphenyl) -2,3-dihydro-l-benzoxepin-4-carboxamide, N- [ 4- [N-methyl-N- (tetrahydropyran-4-yl) aminomethyl] -phenyl] -7- (4-morpholinophenyl) -2,3-dihydro-l-benzoxepin-4-carboxamide, 7- [4-ethoxyphenyl] ) -N- [4- [N-methyl-N- (tetrahydropyran-4-yl) aminomethyl] phenyl] -2,3-dihydro-l-benzoxepin-4-carboxy ida, N, N-dimethyl-N iodide - [4- [[2- (4-methylphenyl) -6,7-dihydro-5H-benzocyclohepten-8-yl] carbonyl] amino] benzyl] -N- (tetrahydropyran-4-yl) ammonium chloride , N-dimethyl-N- [4- [[[7- (4-methylphenyl) -2, 3-dihydro-l-benzoxepin-4-yl] carbonyl] amino] benzyl] -N- (4-oxocyclohexyl) ammonium , N, N-dimethyl-N- [4 - [[[7- (4-ethoxyphenyl) -2, 3-dihydro-l-benzoxepin-4-yl] carbonyl] amino] benzyl] -N- chloride (tetrahydropyran -4-yl) ammonium, or a salt thereof; (32) a composition of (1) above, which is for the treatment or prophylaxis of infectious diseases of HIV; (33) a composition of (1) above, which is for the treatment or prophylaxis of AIDS; (34) a composition of (1) above, which is for the prevention of the progress of AIDS: (35) a composition of (32) above, which is used in combination with a protease inhibitor and / or an inhibitor of reverse transcriptase; (36) a composition of (35) above, wherein the reverse transcriptase inhibitor is zidovudine, didanosine, zalcitabine, lamivudine, stavudine, nevirapine or delavirdine; (37) a composition of (35) above, wherein the protease inhibitor is saquinavir, ritonavir, indinavir or nelfinavir; (38) use of the compound of (1) above or a salt thereof in combination with a protease inhibitor and / or a reverse transcriptase inhibitor for the treatment or prophylaxis of an infectious disease of HIV; (39) a method for antagonizing CCR5 which comprises administering to a mammal in need thereof an effective amount of a compound of the formula: wherein R1 is an optionally substituted 5 to 6 membered ring; is a divalent group of the formula: wherein ring A is an optionally substituted 5 to 6 membered aromatic ring, X is an optionally substituted carbon atom, an optionally substituted nitrogen atom, a sulfur atom or an oxygen atom, and ring B is a optionally substituted 5 to 7 membered ring; Z is a chemical bond or a divalent group; R2 is (1) an optionally substituted amino group in which a nitrogen atom can form a quaternary ammonium, (2) an optionally substituted nitrogen-containing heterocyclic ring group which may contain a sulfur atom or an oxygen atom as atoms constituting the ring and wherein a nitrogen atom can form a quaternary ammonium, (3) a group that is attached through a sulfur atom or (4) a group of the formula: wherein k is 0 or 1, and when k is 0, a phosphorus atom can form a phosphonium; and R5 'and R6' are independently an optionally substituted hydrocarbon group, an optionally substituted hydroxy group or an optionally substituted amino group, and R5 'and R6' may be linked together to form a cyclic group in conjunction with the adjacent phosphorus atom, or a salt thereof; (40) use of a compound of the formula: wherein R1 is a 5-6 membered ring Optionally substituted; W is a divalent group of the formula: wherein ring A is an optionally substituted 5 to 6-membered aromatic ring, X is an optionally substituted carbon atom, an optionally substituted nitrogen atom, a sulfur atom or an oxygen atom, ring B is a ring from 5 to 7 members optionally substituted; Z is a chemical bond or a divalent group, R2 is (1) an optionally substituted amino group in which a nitrogen atom can form a quaternary ammonium, (2) a nitrogen-containing heterocyclic ring group, optionally substituted which can contain a sulfur atom or an oxygen atom as atoms that make up the ring and where a nitrogen atom can form a quaternary ammonium, (3) a group that binds through a sulfur atom or (4) a group of the formula: wherein k is 0 or 1, and when k is 0, a phosphorus atom can form a phosphonium; and R5 'and R6' are independently an optionally substituted hydrocarbon group, an optionally substituted hydroxy group or an optionally substituted amino group, and R5 'and R6' may be linked together to form a cyclic group in conjunction with the adjacent phosphorus atom, or a salt thereof, for the preparation of a medicament for antagonizing CCR5; etc. In formula (I ') above, the examples of the "5 to 6 membered ring" of the "optionally substituted 5 to 6 membered ring" represented by R1 include a 6 membered aromatic hydrocarbon such as benzene, etc.; a 5- to 6-membered aliphatic hydrocarbon such as cyclopentane, cyclohexane, cyclopentene, cyclohexene, cyclopentandiene, cyclohexanediene, et cetera; a heterocyclic, aromatic, 5- to 6-membered ring containing 1 to 4 heteroatoms consisting of 1 to 2 classes of heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom such as furan, thiophene, pyrrole, imidazole, pyrazole, thiazole, oxazole, isothiazole, isoxazole, tetrazole, pyridine, pyrazine, pyrimidine, pyridazine, triazole, etc .; a heterocyclic, nonaromatic, 5-6 membered heterocyclic ring containing from 1 to 4 heteroatoms consisting of 1 to 2 classes of heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom such as tetrahydrofuran, tetrahydrothiophene, dithiolane, oxathiolane, pyrrolidine, pyrroline, imidazolidine, imidazoline, pyrazolidine, pyrazoline, piperidine, piperazine, oxazine, oxadiazine, thiazine, thiadiazine, morpholine, thiomorpholine, pyran, tetrahydropyran, tetrahydrothiopyran, and the like; etc. Among others, benzene, furan, thiophene, pyridine, cyclopentane, cyclohexane, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, tetrahydropyran (preferentially, 6-membered ring), etc. are preferable and in particular, benzene is preferable. An example of the "substituents", which may have the "5 to 6 membered ring" in the "optionally substituted 5 to 6 membered ring" represented by R1, includes a halogen atom, nitro, cyano, an alkyl optionally substituted, an optionally substituted cycloalkyl, an optionally substituted hydroxy group, an optionally substituted thiol group wherein a sulfur atom may be optionally oxidized to form a sulfinyl group or a sulfonyl group, an optionally substituted amino group, an optionally substituted acyl, an optionally esterified carboxyl group, an optionally substituted aromatic group, and the like. Examples of the halogen as the substituents for R 1 include fluorine, chlorine, bromine, iodine, and the like. Among others, fluorine and chlorine are preferred. Examples of the alkyl in the alkyl optionally substituted as the substituents for R 1 include an alkyl of 1 to 10 carbon atoms, straight or branched such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, etc., and preferably lower alkyl (1 to 6 carbon atoms). Examples of the substituents on the optionally substituted alkyl include halogen (eg, fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, a hydroxy group, a thiol group, an amino group, a carboxyl group, an alkoxy of 1 to 4 optionally halogenated carbon atoms (for example methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, etc.), alkanoyl of 2 to 4 carbon atoms (for example acetyl, propionyl, etc.), alkylsulfonyl of 1 to 4 carbon atoms (by example methanesulfonyl, ethanesulfonyl, etc.), et cetera, and the number of substituents are preferably 1 to 3. Examples of the cycloalkyl in the cycloalkyl optionally substituted as the substituents for R 1 include cycloalkyl of 3 to 7 carbon atoms, etc. such as cyclopropyl , cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and so on. Examples of the substituents in the optionally substituted cycloalkyl include halogen (for example fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, a hydroxy group, a thiol group, an amino group, a carboxyl group, an optionally halogenated alkyl of 1 to 4 carbon atoms (for example trifluoromethyl, methyl, ethyl, etc.), an optionally halogenated alkoxy of 1 to 4 carbon atoms (for example, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, etc.), alkanoyl of 2 to 4 carbon atoms (for example acetyl, pripionyl, etc.) , alkylsulfonyl of 1 to 4 carbon atoms (for example methanesulfonyl, ethanesulfonyl, etc.), and the like, and the number of substituents is preferably 1 to 3. Examples of substituents on the hydroxy group optionally substituted as substituents for R1 include (1) an optionally substituted alkyl (for example, alkyl of 1 to 10 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, hepti lo, octyl, nonyl, decyl, etc., preferably lower alkyl of 1 to 6 carbon atoms, etc.); (2) an optionally substituted cycloalkyl (for example, cycloalkyl of 3 to 7 carbon atoms, etc. such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.); (3) an optionally substituted alkenyl (for example alkenyl of 2 to 10 carbon atoms such as allyl, crotyl, 2-pentenyl, 3-hexenyl, etc., preferably lower alkenyl of 2 to 6 carbon atoms, etc.); (4) an optionally substituted cycloalkenyl (for example cycloalkenyl of 3 to 7 carbon atoms, etc. such as 2-cyclopentenyl, 2-cyclohexenyl, 2-cyclopentenylmethyl, 2-cyclohexenylmethyl, etc.); (5) an optionally substituted aralkyl (for example phenylalkyl of 1 to 4 carbon atoms (eg, benzyl, phenethyl, etc.), etc.); (6) an optionally substituted acyl (for example alkanoyl of 2 to 4 carbon atoms (for example acetyl, propionyl, butyryl, isobutyryl, etc.), alkylsulfonyl of 1 to 4 carbon atoms (for example methanesulfonyl, ethanesulfonyl, etc.), etc); (7) an optionally substituted aryl (for example phenyl, naphthyl, etc.); etc. Examples of the substituents, which may have the (1) alkyl optionally substituted, (2) optionally substituted cycloalkyl, (3) optionally substituted alkenyl, (4) cycloalkenyl, optionally substituted, (5) optionally substituted aralkyl, (6) optionally substituted acyl, and (7) optionally substituted aryl mentioned above, include halogen (e.g. , fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, a hydroxy group, a thiol group, an amino group, a carboxyl group, an optionally halogenated alkyl of 1 to 4 carbon atoms (for example trifluoromethyl, methyl, ethyl, etc.), an optionally halogenated alkoxy of 1 to 4 carbon atoms (for example methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, etc.), alkanoyl of 2 to 4 carbon atoms (for example acetyl, propionyl, et cetera, alkylsulfonyl of 1 to 4 carbon atoms (for example methanesulfonyl, ethanesulfonyl, etc.), and the like, and the number of substituents is preferably 1 to 3.

Examples of the substituents on the thiol group optionally substituted as the substituents for R 1 are similar to the substituents described above in the optionally substituted hydroxy group as the substituents for R 1, and inter alia, (1) an optionally substituted alkyl (e.g., alkyl of 1 to 10 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, etc., in the form preferred lower alkyl of 1 to 6 carbon atoms, etc.); (2) an optionally substituted cycloalkyl (for example, cycloalkyl of 3 to 7 carbon atoms, etc. such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.); (3) an optionally substituted aralkyl (for example phenylalkyl of 1 to 4 carbon atoms (for example, benzyl, phenethyl, etc.), etc.); (4) an optionally substituted aryl (for example phenyl, naphthyl, etc.); etcetera, they are the preferred ones. Examples of substituents, which may have the (1) optionally substituted alkyl, (2) optionally substituted cycloalkyl, optionally substituted (3) aralkyl, and optionally substituted (4) aryl mentioned above, include halogen (eg, fluorine, chlorine , bromine, iodine, etc.), nitro, cyano, a hydroxy group, a thiol group, an amino group, a carboxyl group, an optionally halogenated alkyl of 1 to 4 carbon atoms (for example trifluoromethyl, methyl, ethyl, etc.) , an optionally halogenated alkoxy of 1 to 4 carbon atoms (for example methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, etc.), alkanoyl of 2 to 4 carbon atoms (for example acetyl, propionyl, etc.), alkylsulfonyl of 1 to 4 atoms of carbon (for example methanesulfonyl, ethanesulfonyl, etc.), and the like, and the number of substituents is preferably 1 to 3. Examples of substituents on the amino group optionally substituted with or the substituents for R1 are similar to the substituents described above in the optionally substituted hydroxy group as the substituents for R1, and examples of the optionally substituted amino group as the substituents for R1 include an amino group which may have one or two substituents selected of the substituents described above in the optionally substituted hydroxy group as the substituents for R1, et cetera. Among others, as the substituents on the optionally substituted amino group as the substituents for R1, (1) an optionally substituted alkyl (eg, alkyl of 1 to 10 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl , sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, etc., preferably lower alkyl of 1 to 6 carbon atoms, etc.); (2) an optionally substituted cycloalkyl (for example, cycloalkyl of 3 to 7 carbon atoms, etc. such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.); (3) an optionally substituted alkenyl (for example alkenyl of 2 to 10 carbon atoms such as allyl, crotyl, 2-pentenyl, 3-hexenyl, etc., preferably lower alkenyl of 2 to 6 carbon atoms, etc.); (4) an optionally substituted cycloalkenyl (for example cycloalkenyl of 3 to 7 carbon atoms, etc. such as 2-cyclopentenyl, 2-cyclohexenyl, 2-cyclopentenylmethyl, 2-cyclohexenylmethyl, etc.); (5) an optionally substituted acyl (for example, alkanoyl of 2 to 4 carbon atoms (for example acetyl, propionyl, butyryl, isobutyryl, etc.), alkylsulfonyl of 1 to 4 carbon atoms (for example methanesulfonyl, ethanesulfonyl, etc.) , etc); (6) an optionally substituted aryl (e.g., phenyl, naphthyl, etc.); etc. are preferable. Examples of substituents, which each have the optionally substituted (1) alkyl, (2) optionally substituted cycloalkyl, (3) optionally substituted alkenyl, (4) optionally substituted cycloalkenyl, (5) optionally substituted acyl, and (6) optionally substituted aryl mentioned above, include halogen (for example, fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, a hydroxy group, a thiol group, an amino group, a carboxyl group, an optionally halogenated alkyl of 1 to 4 carbon atoms (for example trifluoromethyl) , methyl, ethyl, etc.), an optionally halogenated alkoxy of 1 to 4 carbon atoms (for example methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, etc.), alkanoyl of 2 to 4 carbon atoms (for example acetyl, propionyl, etc.) , alkylsulfonyl of 1 to 4 carbon atoms (for example methanesulfonyl, ethanesulfonyl, etc.), and the like, and the number of substituents is preferably 1 to 3.

Substituents on the optionally substituted amino group as the substituents for R1 may be linked together to form a cyclic amino group (eg, 5- to 6-membered cyclic amino, etc. such as tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole, imidazole , etc) . The cyclic amino group may have a substituent, and examples of substituents include halogen (e.g., fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, a hydroxy group, a thiol group, an amino group, a group carboxy, an optionally halogen of 1 to 4 carbon atoms (for example trifluoromethyl, methyl, ethyl, etc.), an optionally halogenated alkoxy of 1 to 4 carbon atoms (for example methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, etc.), alkanoyl of 2 to 4 carbon atoms (for example acetyl, propionyl, etc.), alkylsulfonyl of 1 to 4 carbon atoms (for example methanesulfonyl, ethanesulfonyl, etc.), etcetera, and the number of substituents is preferably 1 to 3. Examples of the acyl optionally substituted as the substituents for R 1 include a carbonyl group or a sulfonyl group that binds to (1) hydrogen; (2) an optionally substituted alkyl (for example, alkyl of 1 to 10 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl , octyl, nonyl, decyl, etc., preferably lower alkyl of 1 to 6 carbon atoms, etc.); (3) an optionally substituted cycloalkyl (for example, cycloalkyl of 3 to 7 carbon atoms, etc. such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.); (4) an optionally substituted alkenyl (for example alkenyl of 2 to 10 carbon atoms such as allyl, crotyl, 2-pentenyl, 3-hexenyl, etc., preferably lower alkenyl of 2 to 6 carbon atoms, etc.); i (5) an optionally substituted cycloalkenyl (for example cycloalkenyl of 3 to 7 carbon atoms, etc. such as 2-cyclopentenyl, 2-cyclohexenyl, 2-cyclopentenylmethyl, 2-cyclohexenylmethyl, etc.); (6) an aromatic, monocyclic, 5- to 6-membered, optionally substituted group (for example phenyl, pyridyl, etc.); etc. Examples of the acyl include acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, octanoyl, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl, crotonyl, 2-cyclohexencarbonyl, benzoyl, nicotinoyl, methanesulfonyl, ethanesulfonyl, and the like. Examples of substituents, which may have the (2) alkyl optionally substituted, (3) optionally substituted cycloalkyl, (4) optionally substituted alkenyl, (5) optionally substituted cycloalkenyl, and (6) an aromatic, monocyclic, 5-6 membered, optionally substituted group mentioned above, include halogen (eg, fluorine, chlorine , bromine, iodine, etc.), nitro, cyano, a hydroxy group, a thiol group, an amino group, a carboxyl group, an optionally halogenated alkyl of 1 to 4 carbon atoms (for example trifluoromethyl, methyl, ethyl, etc.) , an optionally halogenated alkoxy of 1 to 4 carbon atoms (for example methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, etc.), alkanoyl of 2 to 4 carbon atoms (for example acetyl, propionyl, etc.), alkylsulfonyl of 1 to 4 atoms of carbon (for example methanesulfonyl, ethanesulfonyl, etc.), et cetera, and the number of substituents is preferably 1 to 3.

Examples of the optionally esterified carboxyl group as the substituents for R1 include a carbonyloxy group that binds to (1) hydrogen; (2) an optionally substituted alkyl (for example, alkyl of 1 to 10 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl , octyl, nonyl, decyl, etc., preferably lower alkyl of 1 to 6 carbon atoms, etc.); (3) an optionally substituted cycloalkyl (for example, cycloalkyl of 3 to 7 carbon atoms, etc. such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.); (4) an optionally substituted alkenyl (for example alkenyl of 2 to 10 carbon atoms such as allyl, crotyl, 2-pentenyl, 3-hexenyl, etc., preferably lower alkenyl of 2 to 6 carbon atoms, etc.); (5) an optionally substituted cycloalkenyl (for example cycloalkenyl of 3 to 7 carbon atoms, etc. such as 2-cyclopentenyl, 2-cyclohexenyl, 2-cyclopentenylmethyl, 2-cyclohexenylmethyl, etc.); (6) an optionally substituted aryl (for example phenyl, naphthyl, etc.); et cetera, and preferably carboxyl, lower alkoxycarbonyl of 1 to 6 carbon atoms, aryloxycarbonyl (for example methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, phenoxycarbonyl, naphthoxycarbonyl, etc.), etcetera. Examples of substituents, which may have optionally substituted (2) alkyl, (3) optionally substituted cycloalkyl, (4) optionally substituted alkenyl, (5) optionally substituted cycloalkenyl, and (6) optionally substituted aryl mentioned above, include halogen (for example, fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, a hydroxy group, a thiol group, an amino group, a carboxyl group, an optionally halogenated alkyl of 1 to 4 carbon atoms (for example trifluoromethyl) , methyl, ethyl, etc.), an optionally halogenated alkoxy of 1 to 4 carbon atoms (for example methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, etc.), alkanoyl of 2 to 4 carbon atoms (for example acetyl, propionyl, etc.) , alkylsulfonyl of 1 to 4 carbon atoms (for example methanesulfonyl, ethanesulfonyl, etc.), and the like, and the number of substituents is preferably 1 to 3.

Examples of the aromatic group in the aromatic group optionally substituted as the substituents for R 1 include an aromatic ring of heterocyclic or heterocyclic ring, of 5 to 6 members, etc. such as phenyl, pyridyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl , oxazolyl, isothiazolyl, isoxazolyl, tetrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazolyl, and the like. Examples of the substituents for these aromatic groups include halogen (for example fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, a hydroxy group, a thiol group, an amino group, a carboxyl group, an alkyl of 1 to 4 carbon atoms optionally halogenated (for example trifluoromethyl, methyl, ethyl, etc.), an alkoxy of 1 to 4 carbon atoms optionally halogenated (for example methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, etc.), alkanoyl of 2 to 4 carbon atoms carbon (for example acetyl, propionyl, etc.), alkylsulfonyl of 1 to 4 carbon atoms (for example methanesulfonyl, ethanesulfonyl, etc.), and the like, and the number of substituents is preferably 1 to 3. The number of substituents mentioned above for R1 it is 1-4 (preferably 1-2) and these may be the same or different and may be present in any possible position in the ring represented by R1. When two or more substituents are present on the 5- to 6-membered ring on the "optionally substituted 5 to 6 membered ring" represented by R1, two substituents therebetween may be joined together to form a lower alkylene of 1 to 6 carbon atoms. carbon (for example trimethylene), tetra ethylene, etc.), a lower alkyleneoxy of 1 to 6 carbon atoms (for example -CH2-0-CH2-, -0-CH2-CH2-, etc.), a lower alkylenedioxy of 1 to 6 carbon atoms ( for example -0-CH2-0-, -0-CH2-CH2-0-, etc.), a lower alkenylene of 2 to 6 carbon atoms (for example -CH2-CH = CH-, -CH2-CH2-CH = CH-, -CH2-CH = CH-CH2-, etc.), a lower alkydienylene of 4 to 6 carbon atoms (for example -CH = CH-CH = CH-, etc.), et cetera. Preferred examples of the "substituents", which may have the "5 to 6 membered ring" in the "optionally substituted 5 to 6 membered ring" represented by R1, include a lower alkyl of 1 to 4 carbon atoms optionally halogenated (for example methyl, ethyl, t-butyl, trifluoromethyl, etc.), an optionally halogenated lower alkoxy of 1 to 4 carbon atoms (for example methoxy, ethoxy, t-butoxy, trifluoromethoxy, etc.), halogen (for example fluorine) , chlorine, etc.), nitro, cyano, an amino group optionally substituted with 1-2 lower alkyl groups of 1 to 4 carbon atoms (for example amino, methylamino, dimethylamino, etc.), cyclic amino of 5 to 6 members ( for example 1-pyrrolidinyl, 1-piperazinyl, 1-piperidinyl, 4-morpholino, 4-thiomorpholino, 1-imidazolyl, 4-tetrahydropyranyl, etc.), and so on, and when R1 is a benzene, the "substituent" is present in the form present in the position for. In formula (I ') above, examples of the "5- to 6-membered aromatic ring" in the "optionally substituted 5 to 6-membered aromatic ring" represented by A include a 6-membered aromatic hydrocarbon such as benzene, etc.; a heterocyclic, aromatic, 5- to 6-membered ring containing 1 to 3 heteroatoms consisting of 1 to 2 classes of heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom such as furan, thiophene, pyrrole, imidazole, pyrazole, thiazole, oxazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, triazole, etc .; etc. Among others, benzene, furan, thiophene, pyridine (preferentially, a 6-membered ring) etc. are preferable, and in particular benzene is preferable. Examples of the "substituents", which may have the "5- to 6-membered aromatic ring" in the "optionally substituted 5 to 6 membered aromatic ring" represented by A, are similar to the "substituents", which may having the "5 to 6 member ring" in the "optionally substituted 5 to 6 member ring" represented by R1. The number of substituents for ring A is 1-4 (preferably 1-2), and these may be the same or different and may be present in any possible position (eg the position of group X and the other positions ) in the ring represented by A. In the formula (I ') above, a group of the formula: represented by W joins the adjacent groups as follows: In formula (I ') above, examples of the "5 to 7 membered ring" in the "optionally substituted 5 to 7 membered ring" represented by B include a ring group of 5 to 7 members of the formula: , which can have a substituent in any possible position, etcetera. In the above formula, the divalent group represented by Y can be any divalent group as to the B ring forms a 5- to 7-membered ring, optionally substituted, and preferred examples of the divalent groups include (1) - (CH2) at -0- (CH2) a2- (ai and a2 are the same or different and 0, 1 or 2, with the proviso that the sum of ai and a2 is 2 or less), -0- (CH = CH) -, - (CH = CH) -0-; (2) - (CH2) bi-S- (CH2) 2- (bi and b2 are the same or different and 0, 1 or 2, provided that the sum of bi and b2 is 2 or less), -S - (CH = CH) -, - (CH = CH) -S-; (3) - (CH2) d? - (di is 1, 2 or 3), -CH2- (CH = CH) -, - (CH = CH) -CH2-, -CH = CH-; (4) - (CH2) e? -NH- (CH2) e2- (ex and e2 are the same or different and 0, 1 or 2, provided that the sum of ex and e2 is 2 or less), - NH- (CH = CH) -, - (CH = CH) -NH-, - (CH2) e6- (N = CH) - (CH2) e7-, - (CH2) e7 ~ (CH = N) - (CH2) e6- (one of e6 and e7 is 0, and the other is 1) , - (CH2) is- (N = N) - (CH2) eS- (one of is and e9 is 0, and the other is 1); etc. More preferred examples of the divalent groups include -O-, -0-CH2-, -0-CH2-CH2-, -0-CH = CH-, -S-, -S-CH-, -S-CH-CH2-, -S-CH-CH-, -CH-, - (CH) 2-, - (CH2) 3-, -CH = CH-, -CH = CH -CH2-, -CH2-CH = CH-, -NH-, -N = CH-, -CH = N-, -N = N- (in which each of the above formulas represents that it binds to ring A through its left chemical link), et cetera. The divalent group may have a substituent. Examples of the substituent include those for the "5 to 6 membered ring" in the "optionally substituted 5 to 6 membered ring" represented by R 1 and an oxo group, and the like. Among others, lower alkyl of 1 to 3 carbon atoms (for example methyl, ethyl, propyl, etc.), a phenyl group, an oxo group, a hydroxy group, and the like are preferable. In addition, the divalent group can be -O-C (O) - (in which each of the above formulas represents that it binds to ring A through its left chemical bond), and so on. The number of substituents is preferably 1 to 4 (preferably 1-2), and these may be the same or different and bind to the divalent group in any possible position. As the divalent group represented by Y, a group of the formula is preferred: -Y '- (CH2) m- (Y' is -S-, -O-, -NH- or -CH2- and m is an integer of 0.2), -CH = CH-, -N = CH-, - (CH2) m-Y '~ (Y' is -S-, -0-, -NH- or -CH2-, and m is an integer of 0-2), -CH = N- (in which each of the above formulas represents that it joins ring A through its left chemical bond), and so on. Among others, a group of the formula is preferred: -Y '- (CH2) m- (Y' is -S-, -O-, -NH- or -CH2-, and m is an integer of 0-2) , -CH = CH-, -N = CH- (in which each of the above formulas represents that it joins ring A through its chemical bond), and so on. In particular, Y is preferably a group of the formula: -Y '- (CH2) 2- (Y' is -S-, -O-, -NH- or -CH2- (preferably -S-, -0- or -CH2-, more preferably -O- or -CH2-)) in which the formula binds to ring A through its left chemical bond, etc.; and ring B is preferably a 7-membered ring. As the divalent group represented by Y, a group of the formula is preferable: - (CH2) 2-, - (CH2) 3- or -0- (CH2) 2-. Examples of the "substituents", which may have the "5 to 7 membered ring" in the "optionally substituted 5 to 7 membered ring" represented by B, include those for the "5 to 6 membered ring" in the "optionally substituted 5 to 6 membered ring" represented by R1 and an oxo group, and the like. The number of substituents is preferably 1 to 4 (preferably 1-2) and these may be the same or different and bind to the divalent group in any possible position. In a group of the formula: represented by, a carbon atom in position a is preferably unsubstituted. In formula (I ') above, examples of the divalent group represented by Z include an optionally substituted divalent group whose straight chain is composed of 1 to 4 carbon atoms (eg, alkylene of 1 to 4 carbon atoms, alkenylene of 2 to 4 carbon atoms, etc., preferably alkylene of 1 to 3 carbon atoms, more preferably methylene), and the like. The group Z can be attached to any possible position of the benzene ring, and preferably to the para position of the benzene ring. The divalent group represented by Z can be any divalent group whose straight chain is constructed by 1 to 4 atoms and is exemplified by an alkylene chain of the formula: - (CH2) k? - (ki is an integer of 1-4) ), an alkenylene chain of the formula: - (CH2) k2- (CH = CH) - (CH2) k3- (k2 and k3 are the same or different and 0, 1 or 2, with the proviso that the sum of k2 and k3 is 2 or less), and so on. Examples of the substituent for the divalent group represented by Z include any that is capable of binding to the straight chain of the divalent group, and preferably lower alkyl of 1 to 6 carbon atoms (e.g., methyl, ethyl, propyl, isopropyl) , butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, etc.), lower cycloalkyl of 3 to 7 carbon atoms (eg cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.), a optionally esterified phosphono group, an optionally esterified carboxyl group, a hydroxy group, oxo, etc., and more preferably lower alkyl of 1 to 6 carbon atoms (preferably alkyl of 1 to 3 carbon atoms), a group hydroxy, oxo, et cetera. Examples of the optionally esterified phosphono group include a group of the formula: P (0) (OR7) (OR8) wherein R7 and R8 are independently hydrogen, an alkyl group of 1 to 6 carbon atoms, or a cycloalkyl group of 3 to 7 carbon atoms, and R7 and R8 can be bonded together to form a 5- to 7-membered ring. In the above formula, examples of the alkyl group of 1 to 6 carbon atoms represented by R7 and R8 include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl , et cetera, and examples of the cycloalkyl of 3 to 7 carbon atoms include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like. Among others, lower alkyl of 1 to 6 carbon atoms is preferred, straight and lower alkyl of 1 to 3 carbon atoms is more preferred. The groups R7 and R8 can be the same or different and preferably the groups R7 and R8 are the same. When R7 and R8 can be joined together to form a 5- to 7-membered ring, the groups R7 and R8 are bonded together to represent an alkylene chain of 2 to 4 carbon atoms, straight of the formula: - (CH2 )2-, - (CH2) 3-, - (CH2) 4-, and so on. The chain may have a substituent, and examples of the substituent include a hydroxy group, halogen, and the like. Examples of the optionally esterified carboxyl group include a carboxy group and an ester group formed by linking a carboxy group to an alkyl group of 1 to 6 carbon atoms or a cycloalkyl group of 3 to 7 carbon atoms (for example methoxycarbonyl, ethoxycarbonyl , propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, etc.). As the divalent group represented by Z, an optionally substituted alkylene of 1 to 3 carbon atoms is preferable, and alkylene of 1 to 3 carbon atoms which may be substituted by alkyl of 1 to 3 carbon atoms, is more preferable, hydroxy or oxo group. Among others, as the divalent group represented by Z, a group of the formula is preferable: -Z '- (CH2) n- or - (CH2) n -Z'- (Z' is -CH (OH) -, -C (0) - or -CH2-, and n is an integer of 0-2) in which each of the above formulas shows that it binds to the benzene ring through its left chemical bond and each of the methylene groups can be substituted by 1-2 substituents the same or different, more preferably a group of the formula: -Z '- (CH2) n (Z' is -CH (OH) -, -C (O) - or -CH2-, and n is an integer of 0-2 (preferably, n is 0)) in which the formula is attached to the benzene ring through its left chemical bond and each of the methylene groups is it can be substituted by 1-2 substituents the same or different, and methylene is particularly preferable. In the formula mentioned above (I) / the examples of the "amino group" in the "optionally substituted amino group in which a nitrogen atom can form a quaternary ammonium" represented by R2 include an amino group which may have 1-2 substituents, an amino group having 3 substituents wherein the nitrogen atom forms a quaternary ammonium, and so on. When the number of substituents on the nitrogen atom is 2 or more, these substituents may be the same or different. When the total number of substituents and hydrogen atoms in the nitrogen atom is 3, the "amino group" represented by R2 can be any type of an amino group represented by the formula: -N + R3, -N + R2R 'or -N + RR'R' '(R, R' and R "are independently a hydrogen atom or a substituent). Examples of the counterion of the amino group in which the nitrogen atom forms a quaternary ammonium include an anion of a halogen atom (for example Cl ", Br", I ", etc.), and also an anion derived from an acid inorganic such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc.; an anion derivative of an organic acid such as formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid , etc; an anion derived from an acidic amino acid such as aspartic acid, glutamic acid, etc.; etc. Among others, Cl ", Br", I ", etc. are preferable Examples of substituents for the amino group include (1) an optionally substituted alkyl (eg, alkyl of 1 to 10 carbon atoms such as methyl, ethyl). , propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, etc., preferably lower alkyl of 1 to 6 carbon atoms, etc.) (2) an optionally substituted cycloalkyl (for example cycloalkyl of 3 to 8 carbon atoms, etc. such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc.), with the proviso that (2-1) cycloalkyl can contain a heteroatom selected from a sulfur atom, an oxygen atom and a nitrogen atom to form oxirane, thiorane, aziridine, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, tetrahydropyran, tetrahydrothiopyran, tetrahydrothiopyran-1-oxide, piperidine, etc. (preferably a 6-membered ring such as tetrahydropyran, tetrahydrothiopyran, piperidine, etc.) and these groups are preferably linked to the amino group in its 3 or 4 position (preferably, the 4-position), that (2-2) the cycloalkyl can be fused with a benzene ring to form indane, tetrahydronaphthalene, etc. (preferably, indane, etc.), and that (2-3) the cycloalkyl can have a bridge comprising a chain Straight consisting of 1-2 carbon atoms to form a bridged hydrocarbon residue such as bicyclo [2.2.1] heptyl, bicyclo [2.2.2] octyl, bicyclo [3.2.1] octyl, bicyclo [3.2.2] nonyl , etc., preferably, a cyclohexyl group, etc. having a bridge comprising a straight chain consisting of 1-2 carbon atoms, and more preferably bicyclo [2.2.1] heptyl, etc.; (3) an optionally substituted alkenyl (for example alkenyl of 2 to 10 carbon atoms such as allyl, crotyl, 2-pentenyl, 3-hexenyl, etc., preferably lower alkenyl of 2 to 6 carbon atoms, etc.); (4) an optionally substituted cycloalkenyl (for example cycloalkenyl of 3 to 7 carbon atoms, etc. such as 2-cyclopentenyl, 2-cyclohexenyl, 2-cyclopentenylmethyl, 2-cyclohexenylmethyl, etc.); (5) an optionally substituted aralkyl (for example phenyl-alkyl of 1 to 4 carbon atoms (for example benzyl, phenethyl, etc.), etc.); (6) an optionally substituted acyl (for example alkanoyl of 2 to 4 carbon atoms (for example acetyl, propionyl, butyryl, isobutyryl, etc.), alkylsulfonyl of 1 to 4 carbon atoms (for example methanesulfonyl, ethanesulfonyl, etc.), etc); (7) an optionally substituted aryl (for example phenyl, naphthyl, etc.); (8) a heterocyclic ring group, optionally substituted (for example the 5-6 membered aromatic heterocyclic ring containing 1 to 4 heteroatoms consisting of 1 to 2 kinds of heteroatoms selected from an oxygen atom, an sulfur and a nitrogen atom such as furan, thiophene, pyrrole, imidazole, pyrazole, thiazole, oxazole, isothiazole, isoxazole, tetrazole, pyridine, pyrazine, pyrimidine, pyridazine, triazole, etc., a heterocyclic, nonaromatic ring of 5 to 6 members containing 1 to 4 heteroatoms consisting of 1 to 2 classes of heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom such as tetrahydrofuran, tetrahydrothiophene, dithiolane, oxathiolane, pyrrolidine, pyrroline, imidazolidine, imidazoline , pyrazolidine, pyrazoline, piperidine, piperazine, oxazine, oxadiazine, thiazine, thiadizine, morpholine, thiomorpholine, pyran, tetrahydropyran, etc., preferably, the ani Heterocyclic, non-aromatic, 5-6 members, etcetera; more preferably a 5-6 membered heterocyclic, non-aromatic ring containing a heteroatom, etc. such as tetrahydrofuran, piperidine, tetrahydropyran, tetrahydrothiopyran, etc.); etc.

Examples of the substituents, which may have the (1) optionally substituted alkyl, (2) optionally substituted cycloalkyl, (3) optionally substituted alkenyl, (4) optionally substituted cycloalkenyl, (5) optionally substituted aralkyl, (6) acyl optionally substituted, (7) optionally substituted aryl and (8) a group of the optionally substituted heterocyclic ring mentioned above, include halogen (eg, fluorine, chlorine, bromine, iodine, etc.), a lower alkyl of 1 to 4 carbon atoms optionally halogenated, an optionally halogenated alkoxy of 1 to 4 carbon atoms (for example, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, etc.), alkylenedioxy of 1 to 4 carbon atoms (for example -0-CH2-0-, -0 -CH2-CH2-0-, etc.), alkanoyl of 2 to 4 carbon atoms (for example acetyl, propionyl, etc.), alkylsulfonyl of 1 to 4 carbon atoms (for example methanesulfonyl, ethanesulfonyl, etc.), fe nyl-lower alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, cyano, nitro, a hydroxy group, a thiol group, an amino group, a carboxyl group, lower alkoxycarbonyl of 1 to 4 atoms of carbon (preferably halogen, a lower alkyl of 1 to 4 carbon atoms optionally halogenated, a lower alkoxy of 1 to 4 carbon atoms optionally halogenated, phenyl-lower alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, cyano, a hydroxy group, etc.), etc., and the number of substituents is preferably 1 to 3. In formula (I ') above, preferred examples of "optionally substituted amino group in which a nitrogen atom can form a quaternary ammonium "represented by R 2 include an amino group which may have 1-3 substituents selected from (1) a straight or branched lower alkyl of 1 to 6 carbon atoms which may have 1 to 3 substituents selected from halogen, cyano, a hydroxy or cycloalkyl group of 3 to 7 carbon atoms; (2) a cycloalkyl of 5 to 8 carbon atoms which may have 1 to 3 substituents selected from halogen, a lower alkyl of 1 to 4 carbon atoms optionally halogenated or phenyl-lower alkyl of 1 to 4 carbon atoms, which may contain a heteroatom selected from a sulfur atom, an oxygen atom and a nitrogen atom, which may be fused with a benzene ring, and which may have a bridge comprising a straight chain constructed of 1 -2 carbon atoms (for example, cyclopentyl, cyclohexyl, cyclopentyl, cyclooctyl, tetrahydropyranyl, tetrahydrothiapyranyl, piperidinyl, indanyl, tetrahydronaphthalenyl, bicyclo [2.2.1] heptyl, etc., each of which may be substituted); (3) a phenyl-lower alkyl of 1 to 4 carbon atoms which may have 1 to 3 substituents selected from halogen, a lower alkyl of 1 to 4 carbon atoms optionally halogenated or a lower alkoxy of 1 to 4 carbon atoms optionally halogenated; (4) a phenyl which may have 1 to 3 substituents selected from halogen, a lower alkyl of 1 to 4 optionally halogenated carbon atoms or a lower alkoxy of 1 to 4 optionally halogenated carbon atoms; and (5) an aromatic 5- to 6-membered heterocyclic ring (eg, furan, thiophene, pyrrole, pyridine, etc.) which may have 1 to 3 substituents selected from halogen, a lower alkyl of 1 to 4 carbon atoms, optionally halogenated carbon, a lower alkoxy of 1 to 4 carbon atoms optionally halogenated, a lower alkoxy of 1 to 4 carbon atoms optionally halogenated-lower alkoxy of 1 to 4 carbon atoms, phenyl-lower alkyl of 1 to 4 carbon atoms carbon, cyano or a hydroxy group.

In formula (I ') above, examples of the "nitrogen-containing heterocyclic ring" in the "optionally substituted nitrogen-containing heterocyclic ring group which may contain a sulfur atom or an oxygen atom as ring-forming atoms and wherein a nitrogen atom can form a quaternary ammonium "include a heterocyclic, aromatic, 5- to 6-membered ring which may contain 1 to 3 heteroatoms consisting of 1 to 2 kinds of heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom other than a nitrogen atom such as pyrrole, imidazole, pyrazole, thiazole, oxazole, isothiazole, isoxazole, tetrazole, pyridine, pyrazine, pyrimidine, pyridazine, triazole, etc.; a heterocyclic, non-aromatic, 5-8 membered ring which may contain 1 to 3 heteroatoms consisting of 1 to 2 classes of heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom different from a nitrogen atom nitrogen such as pyrrolidine, pyrroline, imidazolidine, imidazoline, pyrazolidine, pyrazoline, piperidine, piperazine, oxazine, oxadiazine, thiazine, thiadiazine, morpholine, thio-morpholine, azacycloheptane, azacyclooctane (azocan), etc .; etc. These heterocyclic rings containing nitrogen may have a bridge comprising a straight chain consisting of 1-2 carbon atoms to form a bridged heterocyclic ring containing nitrogen azabicyclo [2.2.1] heptane, azabicyclo [2.2.2] octane (quinuclidine) , etc. (preferably, piperidine having a bridge comprising a straight chain consisting of 1-2 carbon atoms, etc.). Among the nitrogen-containing heterocyclic rings, exemplified above, pyridine, imidazole, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, azabicyclo [2.2.2] octane (preferably a 6-membered ring) are preferable. The nitrogen atom of the "nitrogen-containing heterocyclic ring" can form a quaternary ammonium or can be oxidized. When the nitrogen atom of the "nitrogen-containing heterocyclic ring" forms a quaternary ammonium, examples of the counterion of the "nitrogen-containing heterocyclic ring wherein the nitrogen atom forms a quaternary ammonium" include an anion of a halogen atom (for example Cl ", Br", I ", etc.), and so on, and also an anion derived from an inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc., an anion derived from an organic acid such as formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc., a derivative anion of an acidic amino acid such as aspartic acid, glutamic acid, etc., etc. Among others, Cl ", Br", I ", etc. are preferable. The "nitrogen-containing heterocyclic ring" can be attached to the divalent group represented by Z through either a carbon atom or a nitrogen atom, and can be 2-pyridyl, 3-pyridyl, 2-piperidinyl, etc. joins the divalent group represented by Z through a carbon atom. Preferably, the "nitrogen-containing heterocyclic ring" is attached to the divalent group represented by Z via a nitrogen atom, as exemplified by the following formulas; Examples of the substituents, which may have the "nitrogen-containing heterocyclic ring", include halogen (for example fluorine, chlorine, bromine, iodine, etc.), an optionally substituted lower alkyl of 1 to 4 carbon atoms, an alkoxy optionally substituted lower of 1 to 4 carbon atoms, an optionally substituted phenyl, a mono- or di-phenyl-lower alkyl of 1 to 4 optionally substituted carbon atoms, optionally substituted cycloalkyl of 3 to 7 carbon atoms, cyano, nitro, a hydroxy group, a thiol group, an amino group, a carboxyl group, lower alkoxy of 1 to 4 carbon atoms, carbonyl, lower alkanoyl of 2 to 4 carbon atoms, lower alkylsulfonyl of 1 to 4 carbon atoms, an optionally substituted heterocyclic ring group (for example an aromatic, 5-6 membered heterocyclic ring containing 1 to 4 heteroatoms consisting of 1 to 2 classes of heteroatoms selected from an oxygen atom, an atom sulfur and a nitrogen atom such as furan, thiophene, pyrrole, imidazole, pyrazole, thiazole, oxazole, isothiazole, isoxazole, tetrazole, pyridine, pyrazine, pyrimidine, pyridazine, triazole, etc.; a heterocyclic, non-aromatic, 5-6 membered ring containing 1 to 4 heteroatoms consisting of 1 to 2 classes of heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom such as tetrahydrofuran, tetrahydrothiophene, dithiolane , oxathiolane, pyrrolidine, pyrroline, imidazolidine, imidazoline, pyrazolidine, pyrazoline, piperidine, piperazine, oxazine, oxadiazine, thiazine, thiadiazine, morpholine, thiomorpholine, pyran, tetrahydropyran, tetrahydrothiopyran, and the like; etcetera), et cetera, and the number of substituents is preferably 1-3.

Examples of the substituent, which may have "optionally substituted lower alkyl of 1 to 4 carbon atoms", "optionally substituted lower alkoxy of 1 to 4 carbon atoms", "optionally substituted phenyl", mono- or di-phenyl-lower alkyl of 1 to 4 optionally substituted carbon atoms ", the" cycloalkyl of 3 to 7 optionally substituted carbon atoms "and the" optionally substituted heterocyclic ring group "as a substituent for the" heterocyclic ring containing nitrogen, "include halogen (for example fluorine, chlorine, bromine, iodine, etc.), an optionally halogenated lower alkyl of 1 to 4 carbon atoms, an optionally halogenated alkoxy of 1 to 4 carbon atoms (eg, methoxy, ethoxy) , trifluoromethoxy, trifluoroethoxy, etc.), alkanoyl of 2 to 4 carbon atoms (for example acetyl, propionyl, etc.), alkylsulfonyl of 1 to 4 carbon atoms (for example methanesulfonyl, ethanesulfonium lo, et cetera), alkylenedioxy of 1 to 3 carbon atoms (for example methylenedioxy, ethylenedioxy, etc.), cyano, nitro, a hydroxy group, a thiol group, an amino group, a carboxyl group, lower alkoxy of 1 to 4 atoms of carbon-carbonyl, etc., and the number of substituents is preferably 1 to 3. In formula (I ') above, the preferred example of substituents for the "nitrogen-containing heterocyclic ring" in the "heterocyclic ring group" which contains optionally substituted nitrogen which may contain a sulfur atom or an oxygen atom as ring-forming atoms and wherein a nitrogen atom can form a quaternary ammonium "includes (1) halogen, (2) cyano, (3) ) a hydroxy group, (4) a carboxyl group, (5) lower alkoxy of 1 to 4 carbon atoms, (6) lower alkyl of 1 to 4 carbon atoms which may be substituted with halogen, a hydroxy group or lower alkoxy of 1 to 4 atoms carbon, (7) lower alkoxy of 1 to 4 carbon atoms which may be substituted by halogen, a hydroxy or lower alkoxy group of 1 to 4 carbon atoms, (8) phenyl which may be substituted by halogen, lower alkyl of 1 to 4 carbon atoms, a hydroxy group, lower alkoxy of 1 to 4 carbon atoms or alkylenedioxy of 1 to 3 carbon atoms, (9) mono- or di-phenyl-lower alkyl of 1 to 4 carbon atoms whose benzene ring can be substituted by halogen, lower alkyl of 1 to 4 carbon atoms, a hydroxy group, lower alkoxy of 1 to 4 carbon atoms or alkylenedioxy of 1 to 3 carbon atoms, (10) a heterocyclic, aromatic, 5- to 6-membered ring such as furan, thiophene, pyrrole, pyridine, etc., etcetera. In formula (I ') above, the examples of the "group that binds through a sulfur atom" represented by R2 include a group of the formula: -S (0) m-Rs where m is an integer of 0-2, and Rs is a substituent. In the above formula, preferred examples of the "substituent" represented by Rs include (1) an optionally substituted alkyl (eg, alkyl of 1 to 10 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec- butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, etc., preferably lower alkyl of 1 to 6 carbon atoms, etc.); (2) an optionally substituted cycloalkyl (for example cycloalkyl of 3 to 7 carbon atoms, etc. such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.); (3) an optionally substituted aralkyl (for example phenyl-alkyl of 1 to 4 carbon atoms (for example benzyl, phenethyl, etc.), etc.); (4) an optionally substituted aryl (for example phenyl, naphthyl, etc.) and so on. Examples of the substituent, which may have the (1) optionally substituted alkyl, (2) optionally substituted cycloalkyl, (3) optionally substituted aralkyl, and (4) an optionally substituted aryl mentioned above, include halogen (for example fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, a hydroxy group, a thiol group, an amino group, a carboxy group, an optionally halogenated alkyl of 1 to 4 carbon atoms (for example trifluoromethyl, methyl, ethyl, etc.), an optionally halogenated alkoxy of 1 to 4 carbon atoms (for example methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, etc.), alkanoyl of 2 to 4 carbon atoms (for example acetyl, propionyl, etc.), alkylsulfonyl of 1 to 4 carbon atoms (for example methanesulfonyl, ethanesulfonyl, etc.), and the like, and the number of substituents is preferably 1 to 3. In formula (I ') above, the examples of the "hydrocarbon group" in the "optionally substituted hydrocarbon group" represented by R5 'and R6' of the group of the formula: wherein k is 0 or 1, and when k is 0, a phosphorus atom can form a phosphonium; and R5 'and R6' are independently an optionally substituted hydrocarbon group, an optionally substituted hydroxy group or an optionally substituted amino group, and R5 'and R6' may be joined together to form a cyclic group in conjunction with the adjacent phosphorus atom " represented by R2 include (1) an optionally substituted alkyl (eg, alkyl of 1 to 10 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl , hexyl, heptyl, octyl, nonyl, decyl, etc., preferably lower alkyl of 1 to 6 carbon atoms, etc.) (2) an optionally substituted cycloalkyl (for example cycloalkyl of 3 to 7 carbon atoms, etc.) as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.) (3) an optionally substituted alkenyl (for example alkenyl of 2 to 10 carbon atoms such as allyl, crotyl, 2-pentenyl, 3-hexe nyl, etc., preferably lower alkenyl of 2 to 6 carbon atoms, etc.); (4) an optionally substituted cycloalkenyl (for example cycloalkenyl of 3 to 7 carbon atoms, etc., such as 2-cyclopentenyl, 2-cyclohexenyl, 2-cyclopentenylmethyl, 2-cyclohexenylmethyl, etc.); (5) an optionally substituted alkynyl (for example alkynyl of 2 to 10 carbon atoms such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-pentynyl, 3-hexynyl, etc., preferably lower alkynyl of 2 to 6 carbon atoms, etc.); (6) an optionally substituted aralkyl (for example phenyl-alkyl of 1 to 4 carbon atoms (for example benzyl, phenethyl, etc.), etc.); (7) an optionally substituted aryl (e.g., phenyl, naphthyl, etc.); etc. Examples of the substituents, which may have the (1) alkyl optionally substituted, (2) optionally substituted cycloalkyl, (3) optionally substituted alkenyl, (4) optionally substituted cycloalkenyl, (5) optionally substituted alkynyl, (6) optionally substituted aralkyl, and (7) optionally substituted aryl mentioned above, include halogen (eg fluorine) , chlorine, bromine, iodine, etc.), nitro, cyano, a hydroxy group, a thiol group, an amino group, a carboxyl group, an optionally halogenated alkyl of 1 to 4 carbon atoms (for example trifluoromethyl, methyl, ethyl, etc.), an optionally substituted alkoxy of 1 to 4 carbon atoms (for example methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, etc.), alkanoyl of 2 to 4 carbon atoms (for example acetyl, propionyl, etc.), alkylsulfonyl of 1 to 4 carbon atoms (for example methanesulfonyl, ethanesulfonyl, etc.), and the like, and the number of substituents is preferably 1 to 3. Examples of the "optionally substituted hydroxy group" "represented by R5 'and R6' include a hydroxy group which may have (1) an optionally substituted alkyl (for example alkyl of 1 to 10 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec. -butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, etc., preferably lower alkyl of 1 to 6 carbon atoms, etc.); (2) an optionally substituted cycloalkyl (for example cycloalkyl of 3 to 7 carbon atoms, etc., such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.); (3) an optionally substituted alkenyl (for example alkenyl of 2 to 10 carbon atoms such as allyl, crotyl, 2-pentenyl, 3-hexenyl, etc., preferably lower alkenyl of 2 to 6 carbon atoms, etc.); (4) an optionally substituted cycloalkenyl (for example cycloalkenyl of 3 to 7 carbon atoms, etc., such as 2-cyclopentenyl, 2-cyclohexenyl, 2-cyclopentenylmethyl, 2-cyclohexenylmethyl, etc.); (5) an optionally substituted aralkyl (for example phenyl-alkyl of 1 to 4 carbon atoms (for example benzyl, phenethyl, etc.), etc.); (6) an optionally substituted acyl (for example alkanoyl of 2 to 4 carbon atoms (for example acetyl, propionyl, butyryl, isobutyryl, etc.), alkylsulfonyl of 1 to 4 carbon atoms (for example methanesulfonyl, ethanesulfonyl, etc.), etc); (7) an optionally substituted aryl (for example phenyl, naphthyl, etc.); etc.

Examples of the substituents, which may have the (1) optionally substituted alkyl, (2) optionally substituted cycloalkyl, (3) optionally substituted alkenyl, (4) optionally substituted cycloalkenyl, (5) optionally substituted aralkyl, (6) acyl optionally substituted and (7) optionally substituted aryl mentioned above, include halogen (for example fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, a hydroxy group, a thiol group, an amino group, a carboxyl group, an alkyl from 1 to 4 carbon atoms optionally halogenated (for example trifluoromethyl, methyl, ethyl, etc.), an alkoxy of 1 to 4 carbon atoms optionally halogenated (for example methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, etc.), alkanoyl 2 4 carbon atoms (for example acetyl, propionyl, etc.), alkylsulfonyl of 1 to 4 carbon atoms (for example methanesulfonyl, ethanesulfonyl, etc.), et cetera, and the number of substituents is preferably 1 to 3. In the above formula, the groups R5 'and R6' may be linked together to form a cyclic group (preferably, a 5- to 7-membered ring) together with the adjacent phosphorus atom. The cyclic group may have a substituent. Examples of the substituent include halogen (for example fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, a hydroxy group, a thiol group, an amino group, a carboxyl group, an alkyl of 1 to 4 carbon atoms optionally halogenated (for example trifluoromethyl, methyl, ethyl, etc.), an optionally halogenated alkoxy of 1 to 4 carbon atoms (for example methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, etc.), alkanoyl of 2 to 4 carbon atoms (for example acetyl) , propionyl, etc.), alkylsulfonyl of 1 to 4 carbon atoms (for example methanesulfonyl, ethanesulfonyl, etc.), and the like, and the number of substituents is preferably 1 to 3. In formula (I ') above, the examples of the counter-anion, when the phosphorus atom forms a phosphonium, includes an anion of a halogen atom (eg, Cl ", Br", I ", etc.), and so on, and also an anion derived from an inorganic acid such as hydrochloric acid , acid or hydrobromic, nitric acid, sulfuric acid, phosphoric acid, etcetera; an anion derived from an organic acid such as formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc; an anion derived from an acidic amino acid such as aspartic acid, glutamic acid, etc.; etc. Among others, Cl ", Br", I ", etc. are preferred, examples of the optionally substituted amino group represented by R5 'and R6' include an amino group which may have 1-2 substituents selected from (1) an alkyl optionally substituted (for example alkyl of 1 to 10 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, etc., preferably lower alkyl of 1 to 6 carbon atoms, etc.) (2) an optionally substituted cycloalkyl (for example cycloalkyl of 3 to 7 carbon atoms, etc., such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl , etc.): (3) an optionally substituted alkenyl (for example alkenyl of 2 to 10 carbon atoms such as allyl, crotyl, 2-pentenyl, 3-hexenyl, etc., preferably lower alkenyl of 2 to 6 carbon atoms , etc); (4) an optionally substituted cycloalkenyl (for example cycloalkenyl of 3 to 7 carbon atoms such as 2-cyclopentenyl, 2-cyclohexenyl, 2-cyclopentenylmethyl, 2-cyclohexenylmethyl, etc., etc.); (5) an optionally substituted acyl (for example alkanoyl of 2 to 4 carbon atoms (for example acetyl, propionyl, butyryl, isobutyryl, etc.), alkylsulfonyl of 1 to 4 carbon atoms (for example methanesulfonyl, ethanesulfonyl, etc.), etc); (6) an amino group which may have 1-2 optionally substituted aryl groups (for example phenyl, naphthyl, etc.); etc. Examples of the substituent, which may have the optionally substituted (1) alkyl, (2) optionally substituted cycloalkyl, (3) optionally substituted alkenyl, optionally substituted (4) cycloalkenyl, optionally substituted (5) acyl, and optionally substituted (6) aryl substituted above mentioned, include halogen, (for example fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, a hydroxy group, a thiol group, an amino group, a carboxy group, an alkyl of 1 to 4 carbon atoms optionally halogenated, (for example trifluoromethyl, methyl, ethyl, etc.), an alkoxy of 1 to 4 carbon atoms, optionally halogenated (for example methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, etc.), alkanoyl of 2 to 4 carbon atoms ( for example acetyl, propionyl, etc.), alkylsulfonyl of 1 to 4 carbon atoms (for example methanesulfonyl, ethanesulfonyl, etc.), and the like, and the number of substituents is preferably 1 to 3. As In the group R2, preferred are (1) an optionally substituted amino group wherein a nitrogen atom can form a quaternary ammonium, (2) a group of the optionally substituted nitrogen-containing heterocyclic ring which may contain a sulfur atom or a oxygen atom as the atoms that make up the ring and wherein a nitrogen atom can form a quaternary ammonium, (3) a group that binds through a sulfur atom and (4) a group of the formula: wherein k is 0 or 1, and when k is 0, a phosphorus atom can form a phosphonium; and R5 'and R6' are independently an optionally substituted hydrocarbon group or an optionally substituted amino group, and R 'and R6' may be linked together to form a cyclic group in conjunction with the adjacent phosphorus atom. As the group R2, an optionally substituted amino group in which a nitrogen atom can form a quaternary ammonium is most preferable, (2) an optionally substituted nitrogen-containing heterocyclic ring group which may contain a nitrogen atom. sulfur or an oxygen atom such as the atoms that make up the ring and where a nitrogen atom can form a quaternary ammonium, (3) a group of the formula: wherein R5 and R6 are independently an optionally substituted hydrocarbon group, and R5 and R6 can be linked together to form a cyclic group together with the adjacent phosphorus atom, and so on. As the group R2, it is preferable (1) an optionally substituted amino group in which a nitrogen atom can form a quaternary ammonium, and a group of the formula: -N + RR'R "wherein R, R is more preferable 'and R' 'are independently an optionally substituted aliphatic hydrocarbon group or an optionally substituted heterocyclic, alicyclic ring group .. Among Compound (I') / - a compound of the formula is preferable: wherein R1 is an optionally substituted benzene or an optionally substituted thiophene; And "is -CH2-, -S- or -0-; and R, R 'and R "are independently an optionally substituted aliphatic hydrocarbon group or an optionally substituted heterocyclic, alicyclic ring group Examples of the" optionally substituted aliphatic hydrocarbon group "and the" heterocyclic ring, alicyclic, optionally substituted "represented by R, R 'or R" include those exemplified by the substituents for the "optionally substituted amino" represented by R2.

Among these, as the group R or R ', an optionally substituted acyclic hydrocarbon group is preferable, an optionally substituted alkyl group of 1 to 6 carbon atoms is more preferable, and methyl is much preferable; and as the group R ", an optionally substituted alicyclic hydrocarbon group (more preferably, an optionally substituted cycloalkyl group of 3 to 8 carbon atoms, more preferably, an optionally substituted cyclohexyl) or a group of the heterocyclic, alicyclic, optionally substituted ring (most preferably, a heterocyclic, alicyclic, saturated, optionally substituted heterocyclic ring group (preferably a 6-membered ring group), more preferably, an optionally substituted tetrahydropyranyl, a optionally substituted tetrahydrothiopyranyl or an optionally substituted piperidyl, much more preferably, an optionally substituted tetrahydropyranyl.) Among Compound (I '), a compound of the formula is preferable: where X "is an anion Examples of the anion include that of a halogen atom, which is derived from an inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc., that derived from an organic acid such as formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.; an acidic amino acid such as aspartic acid, glutamic acid, etc., etc. Anion of a halogen atom is preferable Among the Compound (I '), the following compounds and their salts are preferable: N-methyl iodide -N- [4- [[[2- (4-methylphenyl) -6,7-dihydro-5H-benzocyclohepten-8-yl] carbonyl] amino] benzyl] -piperidinium; N-methyl-N- [4 - [[[7- (4-methylphenyl) -2,3-dihydro-l-benzoxepin-4-yl] carbonyl] amino] benzyl] -peridinium iodide; N- [4- [N-methyl-N- (tetrahydropyran-4-yl) minomethyl] -phenyl] -7- (4-methylphenyl) -2,3-dihydro-l-benzoxepin-4-carboxamide; N- [4- [N-methyl-N- (tetrahydropyran-4-yl) aminomethyl] -phenyl] -7- (4-morpholinophenyl) -2,3-dihydro-l-benzoxepin-4-carboxamide; 7- (4-ethoxyphenyl) -N- [4- [N-methyl-N- (tetrahydropyran-4-yl) aminomethyl] phenyl] -2,3-dihydro-l-benzoxepin-4-carboxamide; N, N-methyl-N- [4 - [[[2- (4-methylphenyl) -6,7-dihydro-5H-benzocyclohepten-8-yl] carbonyl] amino] benzyl] -N- (tetrahydropyran 4-yl) ammonium; N, N-dimethyl-N- [4 - [[[7- (4-methylphenyl) -2,3-dihydro-l-benzoxepin-4-yl] carbonyl] amino] benzyl] -N- (4-) chloride oxocyclohexyl) ammonium; N, N-dimethyl-N- [4- [[[7- (4-ethoxyphenyl) -2, 3-dihydro-l-benzoxepin-4-yl] carbonyl] amino] benzyl] -N- (tetrahydropyran-) chloride 4-yl) ammonium; etc.

Examples of salts of the compound represented by the formula (I ') include a pharmaceutically acceptable salt such as a salt with an inorganic base, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, a salt with an amino acid basic or acidic, et cetera. Examples of the salt with the inorganic base include a salt with alkali metal (for example sodium, potassium, etc.), alkaline earth metal (for example calcium, magnesium, etc.), aluminum, ammonium, and the like. Examples of the salt with the organic base include a salt with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N'-dibenzylethylenediamine, and the like. Examples of the salt with the inorganic acid include a salt with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like. Examples of the salt with the organic acid include a salt with formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and so on. Examples of the salt with the basic amino acid include a salt with arginine, lysine, ornithine, and the like. Examples of the salt with the acidic amino acid include a salt with aspartic acid, glutamic acid, and the like. The compound of the formula (I ') of the present invention can be hydrated or solvated. When the compound of the formula (I ') of the present invention exists as a configuration isomer, diastereomer, conformer, etc., it is possible to isolate the individual isomers with a known separation per se and a purification method, if desired. When the compound of the formula (I ') of the present invention is racemate, it can be separated into a compound (S) and a compound (R) with a usual optical resolution and individual optical isomers and a mixture thereof are included. in the scope of the present invention. The present compound of the formula (I ') or a salt thereof (hereinafter, the "Compound (I')" includes the compound of the formula (I ') and its salt; and also a compound of the formula (I) and its salt) alone or as a mixture with a pharmaceutically acceptable carrier (e.g. solid formulations such as tablets, capsules, granules, powders, etc.), liquid formulations such as syrups, injections, etc.) can be administered orally or not orally. Examples of non-oral formulations include injections, drops, suppositories, pessaries, and the like. In particular, the pessary is useful for the -prophylaxis of an infectious HIV disease. Examples of carriers include various organic or inorganic carriers which are generally used in this field. For example, an excipient, a lubricant, a binder, a disintegrating agent, etc., are used in the solid formulations, and a solvent, a solubilizer, a suspending agent, an isotonicity agent, a buffer, a triggering agent, etc. are used in liquid formulations. In addition, if desired, an appropriate additive such as a preservative, an antioxidant, a colorant, a sweetener, etc. can be used in the above formulations. Examples of the excipient include lactose, sucrose, D-mannitol, starch, crystalline cellulose, clear silicic acid anhydride, and the like. Examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica, and the like. Examples of the binder include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinyl pyrrolidone, and the like. Examples of the disintegrating agent include starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, sodium carboxymethyl starch, and so on. Examples of the solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, and the like. Examples of the solubilizer include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, and the like. Examples of the suspending agent include surfactants such as stearyl triethanolamine, sodium laurisulfate, acid. laurylaminopropionic, lecithin, benzalkonium chloride, benzethonium chloride, glycerin monostearate, etc .; hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, and the like; etc. Examples of the isotonicity agent include sodium chloride, glycerin, D-mannitol, and the like. Examples of the buffer include a buffer solution of phosphate, acetate, carbonate, citrate, and the like. Examples of the triggering agent include benzyl alcohol, et cetera. Examples of the preservative include esters of para-oxybenzoic acid, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid, and the like. Examples of the antioxidant include sulfites, ascorbic acid, and the like. The compound of the formula (I ') or a salt thereof of the present invention can be used in combination with another drug of the treatment or prophylaxis of infectious diseases of HIV (in particular, a pharmaceutical composition for the treatment or prophylaxis of AIDS) . In this case, these drugs can be formulated by mixing individually or simultaneously with pharmaceutically acceptable carriers, excipients, binders, diluents or the like, which can be administered orally or non-orally as a pharmaceutical composition for the treatment or prophylaxis of a disease infectious of HIV. In the case of the formulation of these effective components individually, while the individually formulated agents can be administered in the form of their prepared mixture when using, for example a diluent when administered, the individually formulated agents can also be administered separately or simultaneously or with time intervals to one or the same subject. A device for administering the effective components individually formulated in the form of their mixture prepared by using for example a diluent when administered (for example an injection equipment comprising two or more ampoules, each comprising a powder component and a diluent for mixing and dissolving two or more components when administered, etc.), a device for administering the individually formulated agents in a manner simultaneous or at time intervals to one or the same subject (e.g., a device for tablets that are administered simultaneously or at intervals of time, characterized by having two or more tablets each comprising an agent and tablets that are put in a separate bag (s) and, if necessary, a column to describe the time to be administered to each agent, etc.), et cetera are also included by the pharmaceutical composition of the present invention. An example of the other pharmaceutical agent for the treatment or prophylaxis of an infectious disease of HIV to be used in combination with the compound of the formula (I ') or a salt thereof of the present invention includes a reverse transcriptase inhibitor of nucleotides such such as zidovudine, didanosine, zalcitabine, lamivudine, etaudine, abacavir, adefovir, adefovir dipivoxil, fozivudine tidoxil, etc .; an inhibitor of non-nucleotide reverse transcriptases (including an agent having anti-oxidant activity such as immunocal, oltipraz, etc.) such as nevirapine, delavirdine, efavirenz), loviride, immunocal, oltipraz, et cetera; protease inhibitors such as saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, palinavir, lasinavir, et cetera; etc. As the inhibitor of nucleotide reverse transcriptase, zidovudine, didanosine, zalcitabine, lamivudine, stavudine, etc. are preferable; As the non-nucleotide reverse transcriptase inhibitor, nevirapine, delavirdine, etc. are preferable; and 'as the protease inhibitor, saquinavir, ritonavir, indinavir, nelfinavir, and the like are preferable. A compound of the formula (I): wherein R1 is an optionally substituted 5 to 6 membered ring, W is a divalent group of the formula: (wherein ring A is an optionally substituted 5 to 6 membered aromatic ring, X is an optionally substituted carbon atom, an optionally substituted nitrogen atom, a sulfur atom or an oxygen atom, and ring B is a optionally substituted 5 to 7 membered ring), Z is a chemical bond or a divalent group, and R1 is (1) an optionally substituted amino group wherein a nitrogen atom can form a quaternary ammonium, (2) a ring group heterocyclic containing optionally substituted nitrogen which may contain a sulfur atom or an oxygen atom such as the atoms constituting the ring and wherein a nitrogen atom can form a quaternary ammonium, (3) a group that is attached through a sulfur atom or (4) a group of the formula: wherein k is 0 or 1, and when k is 0, a phosphorus atom can form a phosphonium; R 5 -y. Rpe are independently an optionally substituted hydrocarbon group or an optionally substituted amino group, and R5 and R6 can be linked together to form a cyclic group together with the adjacent phosphorus atom, or a salt thereof is a novel compound, and the of production thereof is described later.

The compound of the formula (I) or a salt thereof can be produced according to the methods known per se, for example, the methods described below, the methods described in JP-A-73476/1996, or methods analogous to same. A salt of the compound of the formulas (I), (II), (III), (IV), (V), (1-1), (1-2) and (1-3) can be similar to that of the composed of the formula (I '). In the following reaction steps, when the starting compounds have, as substituents, an amino group, a carboxyl group and / or a hydroxy group, these groups can be protected by ordinary protecting groups such as those generally employed in peptide chemistry., etc. After the reaction, if necessary, the protecting groups can be removed to obtain the desired compound. Examples of the amino protecting group include an optionally substituted alkylcarbonyl of 1 to 6 carbon atoms (for example, formyl, methylcarbonyl, ethylcarbonyl, etc.), phenylcarbonyl, alkyloxycarbonyl of 1 to 6 carbon atoms (for example methoxycarbonyl, ethoxycarbonyl, -butoxycarbonyl, etc.), aryloxycarbonyl (for example phenoxycarbonyl, etc.), aralkyloxycarbonyl of 7 to 10 carbon atoms (for example benzyloxycarbonyl, etc.), trityl, phthaloyl, and the like. These protecting groups can be substituted by 1 to 3 substituents such as a halogen atom (for example fluorine, chlorine, bromine, iodine, etc.), alkylcarbonyl of 1 to 6 carbon atoms (for example acetyl, propionyl, butyryl, etc.) , a nitro group, etcetera. Examples of the carboxyl protecting group include an optionally substituted alkyl of 1 to 6 carbon atoms (for example methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.), phenyl, trityl, silyl, and the like. These protecting groups can be substituted by 1 to 3 substituents such as a halogen atom (for example fluorine, chlorine, bromine, iodine, etc.), alkylcarbonyl of 1 to 6 carbon atoms (for example formyl, acetyl, propionyl, butyryl, etcetera), a nitro group, etcetera. Examples of the hydroxy protecting group include an optionally substituted alkyl of 1 to 6 carbon atoms (for example methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.), phenyl, aralkyl of 7 to 10 carbon atoms ( for example benzyl, etc.), alkylcarbonyl of 1 to 6 carbon atoms (for example formyl, acetyl, propionyl, etc.), phenyloxycarbonyl, aralkyloxycarbonyl of 7 to 10 carbon atoms (for example benzyloxycarbonyl, etc.), pyranyl, furanyl, silyl , etc. These protecting groups can be substituted by 1 to 4 substituents such as a halogen atom (for example fluorine, chlorine, bromine, iodine, etc.), alkyl of 1 to 6 carbon atoms, phenyl, aralkyl of 7 to 10 carbon atoms. , a nitro group, etcetera. These protecting groups can be introduced or eliminated by methods known per se (for example, a method described in Protective Groups in Organic Chemistry (J. F. McOmie et al.; Plenum Press Inc.) or methods analogous thereto. For example, the method that can be used to remove the protecting groups is a method using an acid, a base, a reduction, ultraviolet rays, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, and the like.

[Method A] Cl l] [l l l] where each symbol is as defined above. This production method is carried out by reacting the compound [II] with the aniline derivative [III] to obtain the anuide compound [I-13. The condensation reaction of the compounds [II] and [III] is carried out by usual methods for the synthesis of peptides. Methods for the synthesis of peptides are used according to known, optional methods, for example, the methods described in "Peptide Synthesis" written by M. Bodansky and M. A. Ondetti, Interscience, New York, 1966; "The Proteins", volume 2, written by FM Finn and K. Hofmann, H. Nenrath and RL Hill edition, Academic Press Inc., New York, 1976: "Peputido-gssei no kiso to jikken (Basis and Experiment of Peptide Synthesis ) "written by Nobou Izumiya et al., Maruzen KK, 1985; etcetera, as well as the azide method, chlorine method, acid anhydride method, mixed acid anhydride method, DCC method, active ester method, method using Woodward K reagent, carbonyldiimidazole method, of oxidation-reduction, DCC / HONB method, etc. and also the WSC method, method that uses diethyl cyanophosphate (DEPC), and so on. The condensation reaction can be carried out in a solvent. Examples of the solvents that are employed in the reaction include anhydrous N, N-dimethylformamide (DMF), dimethyl sulfoxide, pyridine, chloroform, dichloromethane, tetrahydrofuran, dioxane, acetonitrile or a suitable mixture of these solvents. The reaction temperature is generally about -20 ° C to about 50 ° C, preferably about -10 ° C to about 30 ° C, and the reaction time is generally about 1 to about 100 hours, preferably about 2 to about 40 hours. The anuide derivative obtained in this way [1-1] can be isolated and purified by known separation and purification methods such as concentration, concentration under reduced pressure, extraction, crystallization, recrystallization, solvent cover, chromatography, and the like. [Method B] ammonization © tertiary amination - ^ - reductive amination, or @ oxidation F When the group R2"in Compound [1-2] is, for example, a tertiary amine residue, Compound [I-1] wherein the group R2 'is a quaternary ammonium can be produced by reacting the Compound [1-2] with halogenated alkyl or halogenated aralkyl Examples of a halogen atom include chlorine, bromine, iodine, etc. and usually about 1 to 5 moles of the halogenated alkyl (for example lower alkyl of 1 to 4 carbon atoms) are used. carbon, halogenated, etc.) or halogenated aralkyl (eg lower alkyl of 1 to 4 carbon atoms, halogenated phenyl, etc.) per mole of Compound [1-2] The reaction is carried out in an inert solvent such as toluene, benzene, xylene, dichloromethane, chloroform, 1,2-dichloroethane, dimethylformamide, dimethylacetamide, etc., or a suitable mixture of these solvents The reaction temperature is generally about 10 ° C to about 160 ° C, preferably Approximately 20 ° C to approximate 120 ° C and the reaction time is generally about 1 hour to about 100 hours, preferably about 2 hours to about 40 hours. This reaction is preferably carried out under an inert gas atmosphere (for example nitrogen, argon, etc.). When the group R2"in Compound [1-2] is, for example, a secondary amine residue, Compound [Il] wherein the group R2 'is a tertiary amino can be produced by reacting Compound [1]. -2] with halogenated alkyl or halogenated aralkyl Examples of a halogen atom include chlorine, bromine, iodine, etc. and usually about 1 to 2 moles of the halogenated alkyl or halogenated aralkyl are used per mole of Compound [1-2]. If required, the reaction proceeds smoothly by adding about once to three times the moles of a base such as triethylamine, diisopropylethylamine, pyridine, lithium hydride, sodium hydride, sodium methoxide, sodium ethoxide, sodium carbonate, carbonate potassium, sodium hydrogen carbonate and additional sodium iodide, potassium iodide, and so on. This tertiary amination reaction is carried out in an inert solvent such as methanol, ethanol, propanol, isopropanol, n-butanol, tetrahydrofuran, diethyl ether, dimethoxyethane, 1,4-dioxane, toluene, benzene, xylene, dichloromethane, chloroform, 1,2-dichloroethane, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), pyridine, etc., or a suitable mixture of these solvents. The reaction temperature is generally about 0 ° C to 180 ° C, and the reaction time is generally about 1 hour to about 40 hours. This reaction is preferably carried out under an inert gas atmosphere (for example, nitrogen, argon, etc.). T When the group R2"in Compound [1-2] is, for example, a secondary amine residue, Compound [1-1] wherein the group R1 'is a tertiary amino can be produced by reacting the Compound [1-2] with the aldehyde compound in the presence of a reductive amination reagent such as triacetoxysodium boron hydride, cyanoodium boron hydride, sodium boron hydride, etc. The conditions of this reductive amination reaction vary depending on the reagent For example, when triacetoxysodium boron hydride is used, the reaction is carried out in an inert solvent such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, diethyl ether, dioxane, acetonitrile, dimethylformamide (DMF). etc., or a suitable mixture of these solvents In this case, about 1 to 2 moles of the reagent are used per mole of Compound [1-2] The reaction temperature is generally about 0 ° C to about 80 ° C , Y the reaction time is generally about 1 hour to about 40 hours. This reaction is preferably carried out under an inert gas atmosphere (for example nitrogen, argon, etc.). When the group R2"in Compound [1-2] is, for example, a sulfur residue or a tertiary amine residue, Compound [1-1] where the R2 'group is a sulfinyl group, a group sulfonyl or a group of amine oxide can be produced by reacting Compound [1-2] with an oxidizing agent such as m-chloroperbenzoic acid, perbenzoic acid, p-nitroperbenzoic acid, magnesium monoperoxyphthalate, paracetic acid, peroxide hydrogen, sodium periodate, potassium periodate, etc. The conditions of this oxidation reaction vary depending on the oxidation agent used, for example, when m-chloroperbenzoic acid is used, the reaction is carried out in a solvent Inert such as dichloromethane, chloroform, 1,2-dichloroethane, diethyl ether, tetrahydrofuran, acetone, ethyl acetate, etc., or a suitable mixture of these solvents, usually about 1-3 moles of oxidation agent are used per mole. 1 of Compound [1-2]. The reaction temperature is generally about -25 ° C to about 80 ° C (preferably -25 ° C to 25 ° C), and the reaction time is generally about 1 hour to about 40 hours.

[Method C] f ammonization or phosphonization (D substitution wherein V in Compound [IV] is a halogen atom (chlorine, bromine, iodine, etc.), or a sulfonyloxy group (a methanesulfonyloxy group, a trifluoromethanesulfonyloxy group, a benzenesulfonyloxy group, a toluenesulfonyloxy group, etc.), and the other symbols are as defined above.

F Compound [1-1] wherein the group R2 'is a quaternary ammonium can be produced by reacting Compound [IV] and a tertiary amine. The reaction is carried out in an inert solvent such as toluene, benzene, xylene, dichloromethane, chloroform, 1,2-dichloroethane, dimethylformamide (DMF), dimethylacetamide, et cetera, or a suitable mixture of these solvents. Usually, about 1-3 moles of the tertiary amine are used per mole of Compound [IV]. The reaction temperature is generally about 10 ° C to about 120 ° C, and the reaction time is generally about 1 hour to about 40 hours. This reaction is preferably carried out under an inert gas atmosphere (for example nitrogen, argon, etc.). Compound [1-1] wherein the group R2 'is a quaternary phosphonium can be produced by reacting Compound [IV] and a tertiary phosphine. The reaction is carried out in an inert solvent such as toluene, benzene, xylene, dichloromethane, chloroform, 1,2-dichloroethane, acetonitrile, dimethylformamide (DMF), or a suitable mixture of these solvents. Usually, about 1-2 moles of the tertiary phosphine are used per mole of Compound [IV]. The reaction temperature is generally about 20 ° C to about 150 ° C, and the reaction time is generally about 1 hour to about 50 hours. This reaction is preferably carried out under an inert gas atmosphere (for example nitrogen, argon, etc.).

Q) Compound [1-1] wherein the group R2 'is a secondary or tertiary amino group or a thio group can be produced by reacting Compound [IV] and the primary or secondary amine compound or the thiol compound. Usually, about 1 to 3 moles of the primary or secondary amine compound or the thiol compound is used per mole of Compound [IV]. If necessary, the reaction proceeds smoothly by adding about once to three times the moles of a base such as triethylamine, diisopropylethylamine, pyridine, lithium hydride, sodium hydride, sodium methoxide, sodium ethoxide, sodium carbonate. , potassium carbonate, sodium hydrogen carbonate and additional sodium iodide, potassium iodide, and so on. This substitution reaction is carried out in an inert solvent such as methanol, ethanol, propanol, isopropanol, n-butanol, tetrahydrofuran, diethyl ether, dimethoxyethane, 1,4-dioxane, toluene, benzene, xylene, dichloromethane, chloroform, , 2-dichloroethane, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), pyridine, etc., or a suitable mixture of these solvents. The reaction temperature is generally about -10 ° C to about 180 ° C, and the reaction time is generally about 1 hour to about 40 hours.

The reaction is preferably carried out under an inert gas atmosphere (for example nitrogen, argon, etc.). [Method D] Suzuki reaction wherein V is a halogen atom (bromine, iodine, etc.) or a sulfonyloxy group (a trifluoromethanesulfonyloxy group, etc.), and the other symbols are as defined above. Compound [1-3] wherein the group R1 'is a group of the 5- to 6-membered aromatic ring can be produced by binding Compound [V] to, for example, the Suzuki reaction [through the reaction of condensation of aryl borate with, for example, aryl halide or aryloxytrifluoromethanesulfonate in the presence of a palladium catalyst; A. Suzuki et al., Synth. Commun. 1981, 11, 513]. Usually, about 1-1.5 times the moles of aryl borate are used per mole of Compound [V]. Compound [II] used as a starting material can be produced by a known method (for example the method described in JP-A-73476/1996, etc.) or methods analogous thereto. For example, Compound [II] can be produced by a method described in the following Reaction Scheme I, a method described in the following Reference Examples or methods analogous thereto. [1 - 1] wherein R 9 is an alkyl group of 1 to 4 carbon atoms, Y '' is a divalent group, which does not contain an unsaturated bond and whereby ring B forms a ring of 5 to 7 members, and the other symbols are as defined above. In this reaction, the compound of formula [VI] is heated with a polyphosphoric acid, or Compound [VII] is converted to acid chloride with thionyl chloride, oxalyl chloride, phosphorus oxychloride, phosphorus pentachloride, and the like, followed by subjecting the resulting acid chloride to the usual Friedel-Crafts reaction and cycling through it to produce Compound [VII]. The compound [VII] is reacted with carbonate ester in the presence of a base to produce the ketoester [VIII]. Compound [VIII] is subjected to reduction with catalytic hydrogenation or boron sodium hydride, etc. to produce Compound [IX]. Compound [IX] is subjected to dehydration and ester hydrolysis by the method known per se to produce unsaturated carboxylic acid [II-1]. Compound [III] can be produced by a known method (for example the method described in JP-A-73476/1996, etc.) or methods analogous thereto. For example, Compound [III] can be produced by a method described in the following Reaction Scheme II, a method described in the following Reference Examples or analogous methods thereto.

Reaction SchemeII [X] [III] reduction The reduction of compound [X] can be carried out by methods known per se, for example, reduction with metal, reduction with metal hydride, reduction with a complex compound of metal hydride , the reduction with diborane or substituted borane, the catalytic hydrogenation, and so on. That is, this reaction is carried out by treating Compound [X] with a reducing agent. Examples of the reducing agent include metal such as reduced iron, zinc powder, etc.; boron alkali metal hydride (eg boron sodium hydride, boron lithium hydride, etc.); complex metal hydride compound such as lithium aluminum hydride, etc.; metal hydride such as sodium hydride, etc .; composed of organic tin (triphenyltin hydride, etc.), complex metal compound and metal salt such as nickel compound, zinc compound and so on; a catalytic reduction agent using hydrogen and a transit metal catalyst such as palladium, plutino, rhodium, etc.; diborane; etc. Among others, as the reducing agent, a catalytic reduction agent utilizing hydrogen and transit metal catalyst such as palladium, plutype, rhodium, etc., is preferable; reduced iron, etcetera. The reaction is carried out in a solvent which does not affect the reaction. Examples of the solvent include benzene, toluene, xylene, chloroform, carbon tetrachloride, dichloromethane, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, diethyl ether, tetrahydrofuran, dioxane, methanol, ethanol, propanol, isopropanol, 2-methoxyethanol, N, N-dimethylformamide, acetic acid, or a suitable mixture of these solvents, etcetera. The solvent is appropriately selected depending on the kind of reducing agent. The reaction temperature is generally about -20 ° C to about 150 ° C, preferably about 0 ° C to about 100 ° C, and the reaction time is generally about 1 to about 24 hours. The resulting Compound [III] can be separated and purified with known separation and purification methods such as concentration, concentration under reduced pressure, extraction, crystallization, recrystallization with, solvent conversion, chromatography, and the like. The compound of the formula (I ') or a salt thereof of the present invention has potent CCR5 antagonistic activity and can therefore be used for the treatment or prophylaxis of various infectious diseases of HIV, for example, AIDS in humans. The compound of the formula (I ') or a salt thereof of the present invention is of low toxicity and is used safely as a CCR5 antagonist for the treatment or prophylaxis of AIDS and also for the prevention of the progression of AIDS. The dose per day of the compound of the formula (I ') or a salt thereof varies depending on the condition and body weight of a patient, the route of administration, and so on. The typical, daily dose per adult patient (body weight: 50 kg) for oral administration is about 5-10O0 mg, preferably about 10-600 mg, most preferably about 10-300 mg, and in particular about 15 mg. -150 mg, as the active ingredient [the compound of the formula (I ') or a salt thereof] and the compound of the formula (I') or a salt thereof is administered once or 2-3 times per day. When the compound of the formula (I ') or a salt thereof is used in combination with a reverse transcriptase inhibitor and / or a protease inhibitor, the dose of the reverse transcriptase inhibitor or the protease inhibitor varies, for example, about 1 / 200-1 / 2 or more of usual dose to about 2-3 times or less than usual dose. If two or more drugs are used in combination, each dose of the drugs is adjusted appropriately if one drug affects the metabolism of the other drug, while each dose of the drugs, when used in combination, is generally the same. as the dose when these are used alone. The daily dose, typical of the reverse transcriptase inhibitor and the protease inhibitor is as follows: zidovudine 100 mg didanosine 125-200 mg zalcitabine 0.75 mg lamivudine 150 mg stavudine 30-40 mg saquinavir 600 mg ritonavir 600 mg indinavir 800 mg nelfinavir 750 mg In the case of the combination use of the compound of the formula (I ') or a salt thereof with a reverse transcriptase inhibitor and / or a protease inhibitor, the preferred embodiments are shown below. F A drug containing about 10-300 mg of the compound of the formula (I ') or a salt thereof and a drug containing about 50-200 mg of zidovudine is administered to an adult patient (body weight: 50 kg). Each of the drugs can be administered to one and the same subject simultaneously or at time intervals of 12 hours or less. @ A drug containing approximately 10-300 mg of the compound of the formula (I ') or a salt thereof and a drug containing approximately 300-1200 mg of saquinavir is administered to an adult patient (body weight: 50 kg). Each of the drugs can be administered to one and the same subject simultaneously or at time intervals of 12 hours or less.

BEST MODE FOR CARRYING OUT THE INVENTION The present invention is described below in more detail by means of the following Test Example, Reference Example and Working Example, which are only examples of the present invention and are not constructed as limiting factors. for the present invention. The following gene manipulation is carried out according to the methods described in the textbook (Maniatis et al., Molecular Cloning, Cold Spring Harbor Laboratory, 1989) or a protocol attached to the reagents.

Test Example (1) Cloning of the human CCR5 chemokine receptor Cloning of the CCR5 gene was carried out by PCR (polymerase chain reaction) of human spleen cDNA. With the use of 0.5 ng of spleen cDNA (Toyobo, QUICK-Clone cDNA) as a model, PCR was performed on a Thermal Cycler 480 DNA (Perkin-Elmer) (reaction conditions: 30 cycles of 95 ° C for 1 minute , 60 ° C for 1 minute, and 75 ° C for 5 minutes) when adding a set of primers, 5 '-CAGGATCCGATG GAT ATCAAGTGTCAAGTCCAA-3' (25 pmol) and 5 '-TCTAGATCACAAGCC CACAGATATTTCCTGCTCC-3' (25 pmol), which were designed with reference to the nucleotide sequence of the CCR5 gene reported by Samson et al. (Biochemistry, 35 (11), 3362-3367 (1996)) and by using TaKaRa EX Taq (Takara Shuzo). The resulting PCR product was subjected to agarose gel electrophoresis to collect approximately 1.0 kg of DNA fragment, which was attached to the Original TA Cloning Kit (Funakoshi) to carry out the cloning of the CCR5 gene. (2) Preparation of the plasmid for the expression of human CCR5 The plasmid obtained in (1) above was digested with restriction enzymes Xbal (Takara Shuzo) and BamHI (Takara Shuzo) and subjected to agarose gel electrophoresis for Collect approximately 1.0 kg of DNA fragment. The DNA fragment was mixed with the pcDNA3.1 plasmid (Funakoshi) for expression in animal cells, the plasmid that is digested with Xbal and BamHI, and these were ligated with the DNA Ligation Kit Ver.2 (Takara Shuzo) The resulting plasmid was subjected to the transformation of the competent cell of E. coli JM109 (Takara Shuzo) to obtain the plasmid pCKR5. (3) Introduction of the plasmid for the expression of human CCR5 in a CHO-K1 cell and the expression of the plasmid in a CHO-K1 cell CHO-K1 cells were cultured in 750 ml of the tissue culture flask (Becton Dickinson) using a Ham's F12 medium (Nihon Pharmaceutical) containing 10% fetal bovine serum (Life Tech Oriental) and collected with 0.5 g / L trypsin-2. Og / L EDTA (Life Tech Oriental). The cells were washed with PBS (Life Tech Oriental), centrifuged (1000 rpm, 5 minutes) and suspended in PBS. With the use of Gene Pulser (Bio-Rad Laboratories), the DNA was introduced into the cells under the conditions shown below. That is, to the tube or specimen from an aperture of 0.4 cm, 8 x 10 6 cells and 10 μg of plasmid pCKR5 were added for the expression of human CCR5, and the electroporation was carried out under 0.25 kV of voltage and 960 μF of capacitance. . Cells were transferred in Ham's F12 medium (Nihon Phamaceutical) containing 10% fetal bovine serum, and cultured for 24 hours. Cells were harvested again and centrifuged, and suspended in Ham's F12 medium (Nihon Pharmaceutical) containing 10% fetal bovine serum and 500 μg / ml geneticin (Life Tech Oriental). The suspension was diluted to give 104 cells / ml of suspension, which was inoculated into a 96-well plate (Becton Dickinson) to give geniticin-resistant cells. The resulting geniticin-resistant cells were cultured in a 96-well plate (Becton Dickinson) and the cells expressing CCR5 were selected from the geniticin-resistant cells. That is, in test buffer (medium Ham's F12 containing 0.5% BSA and 20 mM HEPES (Wako Puré chemical, pH7.2) to which 200 pM of [125 I] -RANTES (Amersham) was added as a ligand, the binding reaction was carried out at room temperature for 40 minutes, and the buffer was washed with chilled PBS . To the buffer 50 μg / well of 1M NaOH was added, and the mixture was stirred. The radioactivity was determined with the? -counter to select the CHO / CCR5 cells which bind specifically to the ligand. (4) Evaluation of the Test Compounds based on the antagonistic activity of CCR5 The CHO / CCR5 were inoculated into a 96-well microplate (5xl04 cells / well) and cultured for 24 hours. The medium was removed by means of suction and to each well was added the assay buffer containing the Test Compound (1 μM) and then 100 pM of [125 I] -RANTES (Amersham) as a ligand. The binding assay was carried out at room temperature for 30 minutes, and the test buffer was removed by suction. Each well was washed twice with chilled PBS, and 200 μl of Microscint-20 was added.

(Packard Instrument, Inc.) to each well. The radio activity was determined with the Top-Count Micro Scintillation Counter (Packard Instrument, Inc.). According to the method described above, the rate of inhibition of the Test Compound (which number is referenced in the following Examples) to the binding of the CCR5 The results are shown in Table 1 Table 1 Compound Number Inhibition Rate (%) 16 88 92 100 96 93 97 94 100 100 128 87 180 99 209 80 248 99 249 96 250 96 Ex. of Ref. 51 73 (5) Inhibitory effect on HIV-1 infection in the MAGI-CCR5 cell The plasmid where the β-galactosidase gene was ligated downstream of the HIV-1 LTR was introduced into a positive CD4 HeLa cell, to which the Human CCR5 was additionally introduced to obtain the MAGI-CCR5 transformant. When using the MAGI-CCR5 transformant, the degree of infection of HIV-l was calculated from the activity of β-galactosidase (blue color due to the decomposition of 5-bromo-4-chloro-3-indolyl-β -D-galactopyranoside). Specifically, the MAGI-CCR5 cells were suspended in the DMEM medium containing 10% serum to prepare a suspension of 5 × 10 04 cells / ml. 200 μl of the suspension was inoculated to each well of a 96-well plate, and the cells were cultured at 37 ° C overnight. The medium was removed by suction and 100 μl of the above medium containing 1.6 μM of Test Compound 96 or 0.064 μM of Test Compound 248 and 100 μl of the above medium containing 300 PFU of HIV-cells were added to the residue. l BA-L. The cells were cultured at 37 ° C for 2 days. The medium was eliminated by means of suction. To the residue was added 200 μl of cell fixative (PBS containing 1% formaldehyde and 0.2% glutaraldehyde) and the mixture was allowed to stand at room temperature for 5 minutes and was washed twice with PBS. To the mixture was added 100 μl of coloring solution (PPS containing 4 μM of potassium ferrocyanide, 4 μM of potassium ferricyanide, 2 μM of MgCl 2 and 0.4 mg / ml of X-gal), and the mixture was allowed to stand 37 ° C for 50 minutes and washed twice with PBS. The number of blue cells was counted by the microscope and was defined as the number of cells infected with HIV-1. In accordance with this method, the rate of inhibition in HIV-1 infection was determined and it was found that Compounds 96 and 248 respectively show 92% and 100% inhibition in HIV-1 infection. (6) Inhibitory effect on HIV-1 infection of human PBMC From a normal person mononuclear cells were separated from peripheral blood of human (PBMC), and the cells were stimulated with 10 μg / ml of PHA (Phytohemagglutinin) and 20U / ml of interleukin-2 (IL-2) for 3 days. The cells were suspended in the medium RPMI-1640 containing 20% serum to prepare a suspension of lxl06 / ml. The HIV-1 BA-L cells (20 ng as an amount of p24 antigen) were infected to the suspension., and the viruses were absorbed at 37 ° C for 2 hours. The cells were washed and suspended in RPMI-1640 medium containing 20% serum and 20U IL-2 / ml to prepare a suspension of lxl05 / ml. To the PBMC suspension was added the same amount of a solution which contains 2.0 μM of Test Compound 96 or 0.32 μM of Test Compound 248, and the cells were cultured at 37 ° C for 7 days in a gas incubator of carbon dioxide. The amount of the p24 antigen in the supernatant of the cultured medium was determined by the enzyme-linked immunosorbent assay (ELISA) and was defined as the degree of HIV-1 infection. According to this method, the rate of inhibition in HIV-1 infection was determined and it was found that Compounds 96 and 248 respectively show 96% and 74% inhibition in HIV-1 infection. The pharmaceutical composition for antagonizing CCR5 (for example a medicament for the treatment or prophylaxis of an infectious disease of HIV, a medicament for the treatment or prophylaxis of AIDS, etc.) comprising the compound of the formula (I ') or a salt of the same of the present invention, as an active ingredient, can be prepared, for example, by the following prescriptions: 1. Capsule (1) Compound obtained in the Working Example 128 40 mg (2) lactose 70 mg (3) Fine crystalline cellulose 9 mg (4) Magnesium stearate 1 mg 1 capsule 120 mg The (1), (2), (3) and 1/2 (4) were mixed and then granulated. The remainder of (4) is added to the granules, and the whole is filled into a gelatin capsule. 2. Tablet (1) Compound obtained in Working Example 128 40 mg (2) lactose 58 mg (3) corn starch 18 mg (4) crystalline cellulose, fine 3.5 mg (5) magnesium stearate 0.5 mg 1 tablet 120 mg Mix (1), (2), (3), 2/3 of (4) and 1/2 of (5) and then granulate. The remains of (4) and (5) are added to the granules, followed by the clamping of the mixture to compression molding. 3. Injection A mixture of the Compound obtained in the Working Example 248 (500 mg), mannitol (1000 mg) and polysorbate 80 (100 mg) is dissolved in distilled water (10 ml) and to the solution distilled water is added to make the total volume 20 ml. The solution is filtered under sterile conditions. Each 2 ml of the solution is filled into a vial for injection under sterile conditions.

Working Example Reference Example 1 In THF (50 ml) 4-nitrobenzyl chloride (5.00 g) was dissolved, and piperidine (6.20 g) was added to the mixture. The reaction mixture was stirred at room temperature for 20 hours. To the mixture was added water (500 ml), and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was separated and purified by column chromatography (ethyl acetate / hexane = 1/2) to give 1- (4-nitrobenzyl) piperidine (6.41 g) as a pale yellow oil. NMR aH (200MHz, CDC13) d: 1.38-1.70 (6H, m), 2.30-2.45 (4H, m), 3.55 (2H, s), 7.51 (2H, d, J = 8.8 Hz), 8.17 (2H, d, J = 8.8 Hz).

Reference Example 2 In ethanol (50 ml), the l- (4-nitrobenzyl) -piperidine (6.41 g) was dissolved, and 10% dry palladium on carbon (0.33 g) was added to the mixture. Under a hydrogen atmosphere, the mixture was stirred at room temperature under atmospheric pressure for 24 hours. The palladium was filtered and the filtrate was concentrated.

The residue was recrystallized from hexane to give l- (4-amino-benzyl) piperidine (1.01 g) as pale yellow crystals, m.p. 87-88 ° C Elemental Analysis for C? 2H18N2 Calculated: C, 75.74; H, 9.53; N, 14.72. Found: C, 75.82; H, 9.58; N, 14.61. IR (KBr) cm "1: 3417, 2935, 1614, 1518, 1290, 1117, 1038, 991 aH NMR (200MHz, CDC13) d: 1.35-1.65 (6H, m), 2.28-2.45 (4H,), 3.37 (2H, s), 3.61 (2H, broad s), 6.64 (2H, d, J = 8.6 Hz), 7.09 (2H, d, J = 8.6Hz).

Reference Example 3 In THF (3 ml) 7-cyclohexyl-3,4-dihydro-naphthalene-2-carboxylic acid (100 mg) was dissolved, and oxalyl chloride (41 μl) and one drop of DMF were added to mix. The mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The residue was dissolved in THF (3 ml), and 4-aminobenzyl phosphonate of diethyl (99 mg) and triethylamine (60 μl) were added to the mixture at room temperature. The reaction mixture was stirred at room temperature for 3 hours. To the mixture was added water (100 ml), and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was separated and purified by column chromatography (ethyl acetate / hexane = 3/1) to give 7-cyclohexyl-N- [4- (diethoxyphosphoryl) benzyl] -3,4-dihydronaphthalene-2-carboxamide ( 85 mg) as colorless crystals. p.f. 169-170 ° C Analysis is The emental for C27H34NO2P • 0. 2H20 Calculated: C, 68. 83; H, 7 32; N, 2 97 Found: C, 68.83; H, 7.34; N, 3.00. IR (KBr) cm "1: 3301, 2927, 1670, 1591, 1522, 1317, 1227, 1136, 1053, 1026, 966 aH NMR (200MHz, CDC13) d: 1.05-1.95 (16H, m), 2.40-2.56 (1H, m), 2.60-2.73 (2H, m), 2.80-3.00 (2H, m ), 4.00-4.22 (4H, m), 7.05-7.15 (3H, m), 7.31 (1H, s), 7.68-7.88 (5H, m).

Reference Example 4 In thionyl chloride (5.8 ml) 4-nitrobenzylphosphonic acid (1.50 g) was dissolved, and a drop of DMF was added to the mixture. The mixture was refluxed for 5 hours, and the thionyl chloride was evaporated under reduced pressure. The residue was dissolved in THF (15 ml), and a solution of ethylamine (excess amount) and pyridine (1.2 ml) in acetonitrile (2 ml) at -78 ° C was poured into the mixture. The reaction mixture was stirred at room temperature for 24 hours. The precipitated products were filtered and the filtrate was concentrated. The residue was separated and purified by column chromatography (ethyl acetate / methanol = 5 μl) to give N, N '-diethyl-p- (4-nitrobenzyl) -phosphon-diamide (1.88 g) as colorless crystals. p.f. 102-103 ° C Elemental Analysis for CnH18N3? 3P Calculated: C, 48.71; H, 6.69; N, 15.49. Found: C, 48.51; H, 6.40; N, 15.37. IR (KBr) cm "1: 3244, 2970, 1520, 1348, 1173, 1128, 966 H-NMR (200MHz, DMSO-d6) d: 0.99 (6H, t, J = 7.1Hz), 2.65-2.85 (4H, m), 3.11 (2H, d, J = 18.8Hz), 3.99-4.15 (2H, m) 7.52 (2H, dd, J = 2.2, 8.6Hz), 8.15 (2H, d, J = 8.6Hz).

Reference Example 5 In ethanol (20 ml) N, N'-diethyl-p- (4-nitrobenzyl) phosphonthiamide (1.71 g) was dissolved and palladium on dry carbon 10% (0.09 g) was added to the solution.

Under a hydrogen atmosphere, the mixture was stirred at room temperature under atmospheric pressure for 72 hours. The palladium was filtered and the filtrate was concentrated. The residue was recrystallized from diisopropyl ether to give p- (4-aminobenzyl) -N, N'-diethylphosphon-amide (1.28 g) as colorless crystals. p.f. 109-111 ° C Elemental Analysis for C11H20N3OP • 0. 1H20 Calculated: C, 54. 35; H, 8 4 6; N, 17 29 Found: C, 54.39; H, 8.42; N, 17.00 IR (KBr) cm "1: 3205, 2968, 1515, 1408, 1182, 1122, 1074, 829, 785 1H NMR (200MHz, CDC13) d: 1.10 (6H, t, J = 7.1Hz), 1.95- 2.10 (2H, m), 2.80-3.03 (6H, m), 3.30-3.90 (2H, broad) , 6. 64 (2H, d, J = 8.4Hz), 7.07 (2H, d, J = 8.4Hz).

Reference Example 6 In xylene (450 ml) 7-methoxy-1-tetralone (50.0 g) was dissolved under an argon atmosphere. Aluminum chloride (75.7 g) was added to the mixture and the mixture was heated to reflux for 4.5 hours. The mixture was cooled to room temperature. To the mixture was added 3N hydrochloric acid (500 ml), and the mixture was extracted with ethyl acetate. The organic layer was separated and concentrated under reduced pressure. The residue was separated and purified by column chromatography (ethyl acetate) to give 7-hydroxy-l-tetralone (36.4 g) as dark green crystals. p.f. 162-163 ° C NMR aH (200MHz, CDC13) d: 2.02-2.20 (2H, m), 2.65 (2H, t, J = 6.6Hz), 2.90 (2H, t, J = 6.0Hz), 6.00-6.20 (1H, broad), 7.04 (1H, dd, J = 2.8, 8.4Hz), 7.16 (1H, d, J = 8.4Hz), 7.61 (1H, d, J = 2.8Hz).

Reference Example 7 In dichloromethane (500 ml) 7-hydroxy-1-tetralone (15.0 g) and triethylamine (38.9 ml) were dissolved under an argon atmosphere, and trifluoromethanesulfonic acid anhydride was added dropwise to the mixture. (15.6 ml) at 0 ° C. The reaction mixture was stirred for 2 hours at 0 ° C, and water (500 ml) was added to the mixture.

The organic layer was separated, washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was separated and purified by column chromatography (ethyl acetate / hexane = 1/7) to give 7- (trifluoromethanesulfoxy) -1-tetralone (23.3 g) as a pale brown oil. NMR aH (200MHz, CDC13) d: 2.10-2.25 (2H,), 2.69 (2H, t, J = 6.6Hz), 3.00 (2H, t, J = 6.0Hz), 7.37 (2H, s), 7.91 ( 1H, s).

Reference Example 8 A mixture of 7- (trifluoromethanesulfoxy) -1-tetralone (23.3 g), phenyl borate (11.8 g), potassium carbonate (21.9 g), toluene (500 ml), ethanol (50 ml) and water (50 ml) was stirred for 30 minutes at room temperature under an argon atmosphere and tetracis (triphenylphosphine) aladium (3.66 g) was added to the mixture. The mixture was refluxed for 20 hours and then cooled to room temperature. The organic layer was separated, washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by column chromatography (ethyl acetate / toluene / hexane = 1/5/5) to give 7-phenyl-1-tetralone (15.1 g) as a pale brown oil.

NMR aH (200MHz, CDC13) d: 2.10-2.25 (2H, m), 2.65-2.75 (2H, m), 2.96-3.05 (2H, m), 7.31-7.50 (4H, m), 7.57-7.67 (2H , m), 7.73 (1H, dd, J = 2.2, 8.0Hz), 8.30 (1H, d, J = 2.2Hz).

Reference Example 9 A mixture of sodium methoxide (18.3 g), dimethyl carbonate (107 ml) and 7-phenyl-1-tetralone (15.1 g) was heated to reflux for 30 minutes. The reaction mixture was cooled to 0 ° C. To the mixture was added 3N hydrochloric acid (200 ml), and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure to give a brown solid. The solid was dissolved in dichloromethane (100 ml) and boron sodium hydride (1.60 g) was added to the mixture at 0 ° C. To the mixture methanol (10 ml) was added dropwise over 30 minutes, and the reaction mixture was stirred for 4 hours at 0 ° C. To the mixture was added water (500 ml), and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was dissolved in methanol (45 ml). To the mixture was added 2N sodium hydroxide (50 ml), and the mixture was heated to reflux for 2 hours. The reaction mixture was cooled to room temperature, acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was dissolved in Digly e (1, 1'-oxybis [2-methoxyethane]) (50 ml), and concentrated hydrochloric acid (10 ml) was added to the mixture. The mixture was stirred for 2 hours at 100 ° C, and water (500 ml) was added to the mixture. The mixture was extracted with ethyl acetate, and the organic layer was washed with a saturated sodium chloride solution and concentrated under reduced pressure. The residue was dissolved in IN sodium hydroxide (200 ml), washed with diethyl ether, acidified by adding concentrated hydrochloric acid to the aqueous layer and extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate, concentrated under reduced pressure. The residue was recrystallized with ethanol-water to give 7-phenyl-3,4-dihydronaphthalene-2-carboxylic acid (7.47 g) as brown crystals, m.p. 204-208 ° C 1E NMR (200MHz, CDC13) d: 2.61-2.73 (2H, m), 2.88-3.00 (2H, m), 7.23-7.60 (8H, m), 7.74 (1H, s).

Reference Example 10 In THF (200 ml) the 4-nitrobenzyl bromide (25.0 g) was dissolved, and morpholine (25.2 ml) was added to the mixture at 0 ° C. The reaction mixture was stirred for 15 hours at room temperature. To the mixture was added water (500 ml) and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was separated and purified by column chromatography (ethyl acetate) to give 4- (4-nitrobenzyl) morpholine (25.5 g) as pale yellow crystals. A portion of the crystals was recrystallized with diisopropyl ether to give pale yellow crystals which were used for various analyzes, m.p. 79-80 ° C Elemental Analysis for C 11 H 14 N 2 O 3 Calculated: C, 59.45; H, 6.35; N, 12.60. Found: C, 59.68; H, 6.25; N, 12.75. IR (KBr) cm "1: 3350, 1518, 1344, 1111, 1009, 864, 744 NMR tE (200MHz, CDCl3) d: 2.37-2.55 (4H, m), 3.59 (2H, s), 3.65-3.80 ( 4H, m), 7.53 (2H, d, J = 8.4Hz), 8.18 (2H, d, J = 8.4Hz).

Reference Example 11 In ethanol (300 ml) was dissolved 4- (4-nitrobenzyl) -morpholine (25.8 g), and palladium on dry carbon 10% (Pd-C) (1.00 g) was added to the mixture. Under a hydrogen atmosphere, the mixture was stirred at room temperature under atmospheric pressure for 20 hours. The palladium was filtered and the filtrate was concentrated. The residue was separated and purified by column chromatography (ethyl acetate) to give 4- (4-aminobenzyl) -morpholine (430 mg) as pale yellow crystals. p.f. 98-99 ° C Elemental Analysis for CnH? 6N20 Calculated: C, 68.72; H, 8.39; N, 14.57. Found: C, 68.57; H, 8.25; N, 14.59. IR (KBr) cm "1: 3350, 2804, 1635, 1516, 1282, 1111, 1005, 860 RMN tR (200MHz, CDC13) d: 2.32-2.52 (4H, m), 3.39 (2H, s), 3.45-3.80 (6H,), 6.64 (2H, d, J = 8.2Hz), 7.09 (2H, d, J = 8.2Hz).

Reference Example 12 In THF (250 ml) 4-nitrobenzyl bromide (25.0 g) was dissolved, and pyrrolidine (24.1 ml) was added to the mixture at 0 ° C. The reaction mixture was stirred at room temperature for 60 hours. To the mixture was added water (500 ml) and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was separated and purified by column chromatography (ethyl acetate) to give 1- (4-nitrobenzyl) pyrrolidine (23.5 g) as an orange oil. NMR aH (200MHz, CDC13) d: 1.75-1.85 (4H, m), 2.43-2.58 (4H, m), 3.71 (2H, s), 7.51 (2H, d, J = 8.6 Hz), 8.18 (2H, d, J = 8.6 Hz).

Reference Example 13 In ethanol (100 ml) the l- (4-nitrobenzyl) -pyrrolidine (23.5 g) was dissolved, and 10% dry palladium on carbon (1.00 g) was added to the mixture. Under a hydrogen atmosphere, the mixture was stirred at room temperature under atmospheric pressure for 20 hours. The palladium was filtered and the filtrate was concentrated. The residue was separated and purified by column chromatography (ethyl acetate / triethylamine = 10 / L) to give l- (4-aminobenzyl) pyrrolidine (8.54 g) as an orange-colored oil. NMR E (200MHz, CDC13) d: 1.60-1.90 (4H, m), 2.35-2.55 (4H, m), 3.45-3.70 (4H, m), 6.64 (2H, d, J = 8.4 Hz), 7.11 ( 2H, d, J = 8.4 Hz).

Reference Example 14 In THF (250 ml) 4-nitrobenzyl bromide (25.0 g) was dissolved, and a 50% solution of dimethylamine (29 ml) at 0 ° C was added to the mixture. The reaction mixture was stirred at room temperature for 60 hours. To the mixture was added water (500 ml), and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by column chromatography (ethyl acetate) to give dimethyl-4-nitrobenzylamine (20.7 g) as an orange oil). NMR aH (200MHz, CDCl 3) d: 2.26 (6H, s), 3.52 (2H, s), 7.50 (2H, d, J = 8.8 Hz), 8.19 (2H, d, J = 8.8 Hz).

Reference Example 15 In ethanol (100 ml), dimethyl-4-nitro-benzylamine (20.7 g) was dissolved and 10% dry palladium on carbon (1.00 g) was added to the mixture. Under a hydrogen atmosphere, the mixture was stirred at room temperature under atmospheric pressure for 20 hours. The palladium was filtered and the filtrate was concentrated. The residue was separated and purified by column chromatography (ethyl acetate) to give 4-aminobenzyldimethylamine (8.75 g) as a pale yellow oil. 2 H NMR (200MHz, CDC13) d: 2.21 (6H, s), 3.31 (2H, s), 3.53-3.70 (2H, broad), 6.65 (2H, d, J = 8.4 Hz), 7.08 (2H, d, J = 8.4).

Reference Example 16 In THF (250 ml) 3-nitrobenzyl chloride (25.0 g) was dissolved and piperidine (36 ml) was added to the mixture. The reaction mixture was stirred at room temperature for 20 hours. To the mixture was added water (500 ml), and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by column chromatography (ethyl acetate) to give 1- (3-nitrobenzyl) iperidine (32.2 g) as a pale yellow oil. NMR aH (200MHz, CDC13) d: 1.40-1.66 (6H,), 2.33-2.44 (4H, m), 3.54 (2H, s), 7.47 (1H, t, J = 8.0Hz, 7.67 (1H, d, J = 8.0Hz), 8.10 (1H, d, J = 8.0Hz), 8.20 (1H, s).

Reference Example 17 In ethanol (100 ml) l- (3-nitrobenzyl) -piperidine (32.2 g) was dissolved, and 10% dry palladium on carbon (1.61 g) was added to the mixture. Under a hydrogen atmosphere, the mixture was stirred at room temperature under atmospheric pressure for 24 hours. The palladium was filtered, and the filtrate was concentrated. The residue was recrystallized from diisopropyl ether-hexane to give l- (3-aminobenzyl) piperidine (15.8 g) as colorless crystals. p.f. 109-110 ° C Elemental Analysis for C? 2H? 8N2 Calculated: C, 75.74; H, 9.53; N, 14.72. Found: C, 75.81; H, 9.13; N, 14.87. IR (KBr) cm "1: 3398, 3184, 2948, 1643, 1606, 1454, 1302, 1101, 995, 795, 775, 698 aH NMR (200MHz, CDC13) d: 1.35-1.65 (6H, m), 2.25 -2.45 (4H, m), 3.38 (2H, s), 3.50-3.75 (2H, broad), 6.57 (1H, broad d, J = 7.9Hz), 6.65-6.75 (2H, m), 7.08 (1H, t, J = 7.9Hz).

Reference Example 18 In DMF (100 ml), 4- (2-bromoethyl) nitrobenzene (25.0 g) was dissolved, and piperidine (12.9 ml) and potassium carbonate were added to the solution. (18.0 g). The mixture was stirred at 70 ° C for 15 hours, and to the mixture water (900 ml) was added and then the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by column chromatography (ethyl acetate) to give 1- [2- (4-nitro-phenyl) ethyl] piperidine (24.8 g) as an orange oil. NMR aH (200MHz, CDC13) d: 1.39-1.75 (6H, m), 2.35-2.65 (6H, m), 2.85-3.00 (2H, m), 7.36 (2H, d, J = 8.8 Hz), 8.14 (2H, d, J = 8.8Hz).

Reference Example 19 In ethanol (100 ml) l- [2- (4-nitrophenyl) ethyl] piperidine (24.8g) was dissolved, and 10% dry palladium on carbon (1.24 g) was added to the mixture. Under a hydrogen atmosphere, the mixture was stirred at room temperature under atmospheric pressure for 86 hours. The palladium was filtered, and the filtrate was concentrated to give 1- [2- (4-aminophenyl) ethyl] -piperidine (21.7 g) as a pale brown oil. NMR aH (200MHz, CDCl3) d: 1.40-1.80 (6H, m), 2.35-2.60 (6H, m), 2.60-2.80 (2H, m), 3.40-3.70 (2H, broad), 6.62 (2H, d, J = 8.4 Hz), 7.00 (2H, d, J = 8.4Hz).

Reference Example 20 In methanol (35 ml) 7-phenyl-3,4-dihydro-naphthalene-2-carboxylic acid (1.50 g) was dissolved, and the mixture was added concentrated sulfuric acid (0.1 ml), and then the mixture it was heated to reflux for 9 hours. The reaction mixture was cooled to room temperature, and a 5% sodium hydrogen carbonate solution was added to the mixture, and then the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (100 ml) and activated manganese dioxide (9 g) was added to the mixture. The mixture was refluxed for 48 hours and then cooled to room temperature. The manganese dioxide was filtered and the filtrate was concentrated. The residue was dissolved in methanol (15 ml), and 1N sodium hydroxide (10 ml) was added to the mixture. The mixture was refluxed for 4 hours and then cooled to room temperature. The mixture was acidified with dilute hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was recrystallized with ethyl acetate-diisopropyl ether to give 7-phenylnaphthalene-2-carboxylic acid (783 mg) as colorless crystals, m.p. 244-245 ° C Elemental Analysis for C? 7H? 202 Calculated: C, 82.24; H, 4.87. Found: C, 82.10; H, 4.85. IR (KBr) cm "1: 3053, 1701, 1684, 1429, 1302, 860, 756, 696 NMR aH (200MHz, CDC13) d: 7.37-7.57 (3H, m), 7.70-7.77 (2H, m), 7.86-8.02 (3H, m), 8.10-8.20 (2H, m), 8.77 (1H, s).

Reference Example 21 To a solution of 4-nitrobenzyl alcohol (4.59 g) in methanol (300 ml) was added copper (I) chloride (17.8 g) at room temperature, and then boron potassium hydride (11.3 g) was gradually added. ) for 40 minutes. The reaction mixture was stirred at room temperature for 2 hours and concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by column chromatography (ethyl acetate / hexane = 3/1) to give 4-aminobenzyl alcohol (1.31 g) as pale yellow crystals. p.f. 53-55 ° C Elemental Analysis for C7H9NO Calculated: C, 68.27; H, 7.37; N, 11.37. Found: C, 68.43; H, 7.43; N, 11.49. IR (KBr) cm "1: 3375, 3219, 1614, 1514, 1470, 1259, 1041, 854, 827, 748, 509 2 H NMR (200 MHz, CDCl 3) d: 3.50-3.85 (2 H, broad), 4.56 (2 H, s), 6.68 (2 H, d, J = 8.4 Hz), 7.17 (2 H, d, J = 8.4Hz).

Reference Example 22 In THF (10 ml) 7-phenyl-3,4-dihydro-naphthalene-2-carboxylic acid (500 mg) was dissolved and to the solution were added oxalyl chloride (262 μl) and one drop of DMF. The mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The residue was dissolved in DMF (5 ml), and a solution of 4-aminobenzyl alcohol (246 mg) in pyridine (10 ml) at 0 ° C was added dropwise to the mixture. The reaction mixture was stirred at 0 ° C for 3 hours. To the mixture was added water (500 ml) and then the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-acetone to give N- [4- (hydroxymethyl) phenyl] -7-phenyl-3,4-dihydronaphthalene-2-carboxamide (486 mg) as pale brown crystals, m.p. 207-210 ° C Elemental Analysis for C24H21NO2 • 0.5H20 Calculated: C, 79.10; H, 6.08; N, 3.84. Found: C, 79.35; H, 5.97; N, 3.86. IR (KBr) cm-1: 3332, 1651, 1618, 1597, 1527, 1412, 1317, 831, 764, 700 XH NMR (200MHz, DMSO-d6) d: 2.50-2.66 (2H, m), 2.80-2.95 (2H, m), 4.46 (2H, s), 7.23-7.72 (13H, m), 9.91 (1H, s).

Reference Example 23 Under an argon atmosphere, a mixture of 7- (trifluoromethanesulfoxy) -1-tetralone (9.02 g), 4-methylphenyl borate (5.00 g), potassium carbonate (8.46 g), toluene (300 ml) , ethanol (30 ml) and water (30 ml) was stirred at room temperature for 30 minutes, and tetracis (triphenylphosphine) palladium (1.06 g) was added to the mixture. The mixture was refluxed for 14 hours. The reaction mixture was cooled to room temperature. The organic layer was separated, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was separated and purified by column chromatography (ethyl acetate / toluene = 1/10) to give 7- (4-methylphenyl) -1-tetralone (5.23 g) as colorless crystals. p.f. 86-87 ° C Elemental Analysis for C? 7H? EO Calculated: C, 86.41; H, 6.82. Found: C, 86.30; H, 6.69. IR (KBr) cm "1: 2947, 1682, 1606, 1489, 1435, 1323, 1223, 1178, 810 NMR tE (200MHz, CDC13) d: 2.10-2.24 (2H, m), 2.39 (3H, s), 2.69 (2H, t, J = 6.6Hz), 3.00 (2H, t, J = 6.0Hz ), 7.21-7.35 (3H, m), 7.52 (2H, d, J = 8.4Hz), 7.71 (1H, dd, J = 2.2, 8.2Hz), 8.27 (1H, d, J = 2.2Hz).

Reference Example 24 Under an argon atmosphere, a mixture of 7- (trifluoro-methanesulfoxy) -1-tetralone (17.5 g), 4-fluorophenyl borate (10.0 g), potassium carbonate (16.6 g), toluene (500 ml), ethanol (50 ml) and water (50 ml) was stirred at room temperature for 30 minutes, and tetracis (triphenylphosphine) palladium was added to the mixture. (2.08 g). The mixture was refluxed for 14 hours. The reaction mixture was cooled to room temperature. The organic layer was separated, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by column chromatography (ethyl acetate / toluene = 1/10) to give 7- (4-fluorophenyl) -1-tetralone (13.8 g) as a brown oil. NMR aH (200MHz, CDC13) d: 2.10-2.24 (2H,), 2.70 (2H, t, J = 6.6Hz), 3.01 (2H, t, J = 6.0Hz), 7.07-7.19 (2H, m), 7.30 (1H, d, J = 7.6 Hz), 7.53-7.62 (2H, m), 7.67 (1H, dd, J = 2.2, 8.2Hz), 8.23 (1H, d, J = 2.2Hz).

Reference Example 25 A mixture of sodium methoxide (5.63 g), dimethyl carbonate (33 ml) and 7- (4-methylphenyl) -1-tetralone (4.93 g) was heated to reflux for 30 minutes. The reaction mixture was cooled to 0 ° C and 3N hydrochloric acid (80 ml) was added gradually to the mixture. The mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was dissolved in THF (30 ml), and boron sodium hydride (494 mg) was added to the mixture at 0 ° C and then methanol (3 ml) was added dropwise during 30 minutes. The reaction mixture was stirred at 0 ° C for 4 hours and water (500 ml) was added to the mixture. The mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was dissolved in methanol (20 ml), and 1N sodium hydroxide (20 ml) was added to the mixture. The mixture was refluxed for 4 hours, cooled, acidified with concentrated hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was dissolved in Diglyme (20 ml) and concentrated hydrochloric acid (4 ml) was added to the mixture. The mixture was stirred at 100 ° C for 2 hours and water (500 ml) was added to the mixture. The mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution and concentrated under reduced pressure. The residue was dissolved in 0.5N sodium hydroxide (400 ml), and the mixture was washed with diethyl ether. The aqueous layer was separated and acidified with concentrated hydrochloric acid. The mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-diisopropyl ether to give 7- (4-methyl-phenyl) -3,4-dihydronaphthalene-2-carboxylic acid (1.96 g) as pale brown crystals. p. f. 230-231 ° C Elemental Analysis for C? 8H? 602 Calculated: C, 81. 79; H, 6 10 Found: C, 81.62; H, 6.11. IR (KBr) c "1: 3023, 2908, 1697, 1682, 1626, 1431, 1300, 928, 810 H NMR (200MHz, CDC13) d: 2.40 (3H, s), 2.61-2.71 (2H, m), 2.89-2.98 (2H, m), 7.22-7.28 (3H, m), 7.45-7.51 ( 4H, m), 7.73 (1H, s).

Reference Example 26 A mixture of sodium methoxide (15.5 g), dimethyl carbonate (91 ml) and 7- (4-fluorophenyl) -1-tetralone (13.8 g) was heated to reflux for 30 minutes. The reaction mixture was cooled to 0 ° C and 3N hydrochloric acid (200 ml) was added gradually to the mixture. The mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in THF (90 ml) and to the mixture boron sodium hydride (1.36 g) was added at 0 ° C and then methanol (9 ml) was added dropwise during 30 minutes. The reaction mixture was stirred at 0 ° C for 4 hours and water (500 ml) was added to the mixture. The mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, and concentrated under reduced pressure. The residue was dissolved in methanol (80 ml), and 1N sodium hydroxide (100 ml) was added to the mixture. The mixture was refluxed for 4 hours and cooled to room temperature. The mixture was acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was dissolved in Diglyme (50 ml), and concentrated hydrochloric acid (10 ml) was added to the mixture. The mixture was stirred at 100 ° C for 2 hours, and water (500 ml) was added to the mixture. The mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution and concentrated under reduced pressure. The residue was dissolved in 0.5N sodium hydroxide (400 ml), and the mixture was washed with diethyl ether. The aqueous layer was separated, acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-diisopropyl ether to give 7- (4-fluorophenyl) -3,4-dihydronaphthalene-2-carboxylic acid (6.01 g) as pale brown crystals. p.f. 213-214 ° C Analysis The emental for C? 7H? 302F Calculated: C, 76. eleven; H, 4 88 Found: C, 76.02; H, 4.97. IR (KBr) cm "1: 2953, 1695, 1518, 1431, 1300, 1281, 1246, 930, 824 aH NMR (200MHz, CDC13) d: 2.61-2.71 (2H, m), 2.90-2.99 (2H, m), 7.08-7.19 (2H, m), 7.23-7.29 (1H, m), 7.41-7.58 (4H, m), 7.72 (1H, s).

Reference Example 27 To a mixture of N- [4- (hydroxymethyl) phenyl] -7-phenyl-3,4-dihydronaphthalene-2-carboxamide (566 mg), lithium chloride (135 mg), triethylamine (446 μl) and dichloromethane (50 ml) was added methanesulfonyl chloride (172 μl), and the mixture was stirred at room temperature for 2 hours. Dilute hydrochloric acid was added to the reaction mixture. The organic layer was separated, washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give N- [4- (chloromethyl) phenyl] -7-phenyl-3,4-dihydronaphthalene-2-carboxamide (494 mg) as colorless crystals. p.f. 176-177 ° C Elemental Analysis for C24H20NOCI Calculated: C, 77. 10; H, 5 39; N, 3 75 Found: C, 76.95; H, 5.47; N, 3.82. IR (KBr) cm "1: 3327, 1649, 1618, 1527, 1412, 1317, 831, 764, 700 NMR aH (200MHz, DMSO-d6) d: 2.55-2.68 (2H, m), 2.85-2.95 (2H, m), 4.74 (2H, s), 7.30-7.80 (13H,), 10.05 (1H, s).

Reference Example 28 A mixture of 4-nitrobenzyl alcohol (10.0 g), tert-butyl-dimethylsilyl chloride (11.8 g), imidazole (11.2 g) and DMF (50 ml) was stirred at room temperature for 1.5 hours. Water was added to the mixture (500 ml), and the mixture was extracted with ethyl acetate.

The organic layer was washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by column chromatography (ethyl acetate / hexane = 1/7) to give tert-butyldimethyl-4-nitrobenzyloxysilane (17.5 g) as a pale yellow oil.

NMR aH (200MHz, CDC13) d: 0.13 (6H, s), 0.96 (9H, s), 4.83 (2H, s), 7.48 (2H, d, J = 8.2 Hz), 8.20 (2H, d, J = 8.6Hz).

Reference Example 29 In ethanol (80 ml) was dissolved tert-butyldimethyl-4-nitrobenzyloxysilane (16.5 g), and to the mixture was added palladium on carbon 5% dry (0.83 g). Under a hydrogen atmosphere, the mixture was stirred at room temperature under atmospheric pressure for 7.5 hours. The palladium was filtered and the filtrate was concentrated. The residue was separated and purified by column chromatography (ethyl acetate / hexane = 1/4) to give 4-aminobenzyloxy-tert-butyldimethylsilane (13.8 g) as a colorless oil. IR (pure) cm "1;: 3359, 2954 ,, 2856, 1626, 1518, 1471, 1375, 1257, 1072, 837, 777 2H NMR (200MHz, CDC13) d: 0.07 (6H, s), 0.92 (9H , s), 3.50-3.70 (2H, broad), 4.62 (2H, s), 6.65 (2H, d, J = 8.4Hz), 7.11 (2H, d, J = 8.4Hz).

Reference Example 30 In THF (60 ml), 7- (4-methylphenyl) -3,4-dihydro-naphthalene-2-carboxylic acid (4.02 g) was dissolved. To the solution were added oxalyl chloride (1.99 ml) and one drop of DMF, and the mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The residue was dissolved in THF (30 ml), and a solution of 4-amino-benzyloxy-tert-butyldimethylsilane (3.97 g) and triethylamine (2.56 ml) in THF (30 ml) was added dropwise to the mixture. room temperature. The reaction mixture was stirred at room temperature for 19 hours. To the mixture was added water (300 ml), and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by column chromatography (ethyl acetate / toluene / hexane = 1/5/5). The resulting oil was dissolved in acetone (60 ml), and 6N hydrochloric acid (2 ml) was added to the mixture. The mixture was stirred at room temperature for 30 minutes. To the reaction mixture were added 0.5% sodium hydroxide (500 ml) and diisopropyl ether (200 ml), and the mixture was stirred at room temperature for 5 minutes. The resulting precipitate was filtered and recrystallized with acetone-diisopropyl ether to give N- [4- (hydroxy-methyl) phenyl] -7- (4-methylphenyl) -3, -dihydro-naphthalene-2-carboxamide (4.54 g) as pale brown crystals. p.f. 219-220 ° C Elemental Analysis for C25H23NO2 Calculated: C, 81. 27; H, 6 27; N, 3 79 Found: C, 81.23; H, 5.99; N, 3.80. IR (KBr) cm "1: 3315, 1647, 1618, 1597, 1531, 1414, 1321, 810 NMR XH (200MHz, DMSO-d6) d: 2.35 (3H, s), 2.55-2.65 (2H, m), 2.83-2.93 (2H, m), 4.46 (2H, d, J = 5.6Hz), 5.13 (1H, t, J = 5.6Hz), 7.23-7.33 (5H, m), 7.44-7.58 (5H, m), 7.69 (2H, d, J = 8.4Hz), 9.93 (1H, s).

Reference Example 31 To a mixture of N- [4- (hydroxymethyl) phenyl] -7- (4-methylphenyl) -3,4-dihydronaphthalene-2-carboxamide (2.20 g), lithium chloride (505 mg), triethylamine (1.67 ml), DMAP [4-dimethylaminopyridine] (catalytic amount) and dichloromethane (200 ml) were added methanesulfonyl chloride (645 μl), and the mixture was stirred at room temperature for 42 hours and concentrated under reduced pressure. To the residue 0.5N hydrochloric acid (200 ml) was added and the mixture was extracted with ethyl acetate. The organic layer was dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give N- [4- (chloromethyl) -phenyl] -7- (4-methylphenyl) -3,4-dihydronaphthalene-2-carboxamide 973 g. as colorless crystals. p.f. 178-179 ° C Elemental Analysis for C25H22N0C1 Calculated: C, 77. 41; H, 5 72; N, 3 61 Found: C, 77.34; H, 5.89; N, 3.65. IR (KBr) cm "1: 3332, 1651, 1620, 1529, 1412, 1319, 812 NMR aH (200MHz, DMSO-d6) d: 2.35 (3H, s), 2.55-2.68 (2H, m), 2.83-2.93 (2H, m), 4.74 (2H, s), 7.24-7.60 (10H, m ), 7. 76 (2H, d, J = 8.6Hz), 10.04 (1H, s).

Reference Example 32 Under an argon atmosphere, 6-methoxy-1-indanone (10.0 g) was dissolved in xylene (100 ml), and aluminum chloride (16.4 g) was added to the mixture. The mixture was refluxed for 2 hours and then cooled to room temperature. To the mixture was added 3N hydrochloric acid (100 ml), and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by column chromatography (ethyl acetate) to give 6-hydroxy-l-indanone (7.36 g) as pale brown crystals.

TR NMR (200MHz, CDC13) d: 2.67-2.76 (2H, m), 3.02-3.11 (2H, m), 5.61 (1H, s), 7.10-7.21 (2H, m), 7.36 (1H, d, J) = 8.0 Hz).

Reference Example 33 Under an argon atmosphere, 6-hydroxy-l-indanone (7.36 g) and triethylamine (20.9 ml) were dissolved in dichloromethane (120 ml), and trifluoromethanesulfonic acid anhydride was added dropwise to the mixture ( 8.78 ml) at 0 ° C. The reaction mixture was stirred at 0 ° C for 1 hour, and water (200 ml) was added to the mixture. The organic layer was separated, washed with water, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was separated and purified by column chromatography (ethyl acetate / hexane = 1/4) to give 6- (trifluoromethanesulfoxy) -1-indanone (11.5 g) as a brown oil. 1H-NMR (200MHz, CDC13) d: 2.75-2.83 (2H, m), 3.17-3.24 (2H, m), 7.50 (1H, dd, J = 2.4, 8.4Hz), 7.60 (1H, d, J = 8.4 Hz), 7.64 (1H, d, J = 2.4Hz).

Reference Example 34 Under an argon atmosphere, a mixture of the 6- (trifluoro-methanesulfoxy) -1-indanone (11.5 g), 5-methylphenyl borate (6.69 g), potassium carbonate (11.3 g), toluene (400 ml), ethanol (40 ml) and water (40 ml) ) was stirred at room temperature for 30 minutes, and tetracis (triphenylphosphine) palladium (1.42 g) was added to the mixture. The mixture was refluxed for 17 hours and cooled to room temperature. The organic layer was separated, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by column chromatography (ethyl acetate / toluene = 1/10) and recrystallized from ethyl acetate-hexane to give 6- (4-methylphenyl) -1-indanone (5.20 g) as colored glasses V. pale coffee. p.f. 121-122 ° C Elemental Analysis for C? 6H? 40 Calculated: C, 86.45; H, 6.35. Found: C, 86.46; H, 6.23. IR (KBr) c "1: 1703, 1614, 1483, 1448, 1404, 1304, 814 aH NMR (200MHz, CDC13) d: 2.40 (3H, s), 2.70-2.79 (2H, m), 3.13-3.22 ( 2H,), 7.23-7.29 (2H, m), 7.48-7.57 (3H, m), 7.83 (1H, dd, J = 1.8, 8.0Hz), 7.96 (1H, s).

Reference Example 35 A solution of 6- (4-methylphenyl) -1-indanone (4.97 g) in THF (33 ml) was added dropwise to a refluxed mixture of 60% sodium hydride (3.26 g), potassium hydride (catalytic amount), dimethyl carbonate (6.65 ml) and THF ( 100 ml), and the mixture was heated to reflux for 6 hours. The reaction mixture was cooled to 0 ° C, and 2N hydrochloric acid (150 ml) was added gradually to the mixture. The mixture was extracted with ethyl acetate, and the organic layer was washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was separated and purified by column chromatography (ethyl acetate / toluene = 1/3) to give a brown solid. The solid was dissolved in dichloromethane (100 ml), and to the mixture boron sodium hydride (391 mg) was added at 0 ° C and then methanol (10 ml) was added dropwise. The reaction mixture was stirred at 0 ° C for 1.5 hours, and water (500 ml) was added to the mixture. The mixture was extracted with ethyl acetate and the organic layer was washed with a saturated sodium chloride solution., dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in methanol (30 ml), and IN sodium hydroxide (40 ml) was added to the mixture. The mixture was refluxed for 2 hours and cooled to room temperature. Water was added to the mixture, and the mixture was washed with diethyl ether. The aqueous layer was acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in Diglyme (30 ml), and concentrated hydrochloric acid (6 ml) was added to the mixture. The mixture was stirred at 100 ° C for 2 hours, and a solution of 0.5% sodium hydrogen carbonate (500 ml) and hexane (500 ml) were added to the solution. The resulting precipitate was filtered to give 5- (4-methylphenyl) -inden-2-carboxylic acid (2.72 g) as brown crystals, m.p. 226-229 ° C (decomp.) Elemental Analysis for Ci7H? 402 • 0.1H20 Calculated: C, 80.99; H, 5.68. Found: C, 80.92; H, 5.55. IR (KBr) cm-1: 2999, 1670, 1572, 1259, 808 1N NMR (200MHz, DMS0-d6) d: 2.35 (3H, s), 3.63-3.70 (2H, m), 7.28 (2H, d, J = 8.0Hz), 7.53-7.73 (5H, m), 7.83 (1H, d, J = 6.0Hz).

Reference Example 36 A mixture of hexamethyleneimine (15.0 g), ethyl iodide (14.5 ml), potassium carbonate (31.3 g) and ethanol (300 ml) was heated to reflux for 6 hours and concentrated under reduced pressure. Diethyl ether was added to the residue, and the insoluble material was filtered.

The filtrate was under reduced pressure to give 1-ethylperhydroazepine (4.56 g) as a colorless oil. p.f. 73-76 ° C / 70mmHg IR (pure) cm "1: 2927, 1452, 1352, 1190, 1140, 1093 tR NMR (200MHz, CDC13) d: 1.05 (3H, t, J = 7.2Hz), 1.55-1.72 (8H, m), 2.47-2.65 (6H, m).

Reference Example 37 A mixture of hexamethyleneimine (15.0 g), 1-propyl iodide (29.5 ml), potassium carbonate (31.3 g) and ethanol (300 ml) was refluxed for 42 hours and concentrated under reduced pressure. Diethyl ether was added to the residue and the insoluble material was filtered. The filtrate was under reduced pressure to give 1-propylperhydroazepine (2.50 g) as a colorless oil, m.p. 70.74 ° C / 50 mmHg IR (pure) cm "1: 2926, 1749, 1458, 1375, 1259, 1184, 1138, 1082 tR NMR (200MHz, CDCl3) d: 0.87 (3H, t, J = 7.5Hz), 1.40-1.80 (10H, m), 2.36-2.46 (2H, m), 2.55-2.67 (4H, m).

Reference Example 38 A mixture of heptamethyleneimine (10.0 g), ethyl iodide (8.48 ml), potassium carbonate (18.3 g) and ethanol (200 ml) was heated to reflux for 13 hours and concentrated under reduced pressure. Diethyl ether was added to the residue and the insoluble material was filtered. The filtrate was under reduced pressure to give 1-ethylperhydroazocine (2.29 g) as a colorless oil. p.f. 76-78 ° C / 40 mmHg IR (pure) cm "1: 2920, 1475, 1446, 1371, 1252, 1225, 1161, 1093 NMR aH (200MHz, CDCl3) d: 1.03 (3H, t, J = 6.9Hz ), 1.48-1.72 (10H, m), 2.42-2.60 (6H, m).

Reference Example 39 Under an argon atmosphere, a mixture of methyl (E) -3- (trifluoromethanesulfoxy) cinnamate (9.00 g), 4-methyl-phenyl borate (4.73 g), potassium carbonate (8.02 g), toluene (300 ml), ethanol (30 ml) and water (30 ml) was stirred at room temperature for 30 minutes. To the mixture was added tetracis (triphenylphosphine) palladium (1.01 g) and the mixture was heated to reflux for 24 hours. The reaction mixture was cooled to room temperature, and the organic layer was separated, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was separated and purified by column chromatography (ethyl acetate / toluene / hexane = 1/5/5) to give a colorless oil, which was dissolved in methanol (50 ml). To the mixture was added IN sodium hydroxide (50 ml), and the mixture was heated to reflux for 1 hour. The reaction mixture was cooled to room temperature, acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized with ethyl acetate-diisopropyl ether to give (E) -3- (4-methyl-phenyl) cinnamic acid (5.15 g) as colorless crystals, m.p. 192-194 ° C Elemental Analysis for C? 6H1? 2 • 0.1H20 Calculated: C, 80.04; H, 5.96. Found: C, 80.13; H, 5.94. IR (KBr) cm "1: 2922, 1687, 1628, 1435, 1321, 1282, 1225, 798 aH NMR (200MHz, CDC13) d: 2.41 (3H, s), 6.52 (1H, d, J = 16.0Hz) , 7.23-7.30 (2H, m), 7.40-7.53 (4H, m), 7.56-7.65 (1H, m), 7.73 (1H, s), 7.85 (1H, d, J = 16.0Hz).

Reference Example 40 In THF (50 ml), (E) -3- (4-methylphenyl) -cinnamic acid (5.00 g) was dissolved, and to the solution were added oxalyl chloride (2.38 ml) and one drop of DMF. The mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The residue was dissolved in THF (50 ml), and 4-aminobenzyloxy-tert-butyl-dimethylsilane (5.48 g) and triethylamine (3.53 ml) were added to the mixture at room temperature. The reaction mixture was stirred at room temperature for 3 hours, and water (200 ml) was added to the mixture. The mixture was extracted with ethyl acetate and the organic layer was washed with a saturated sodium chloride solution., dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was separated and purified by column chromatography (ethyl acetate / toluene / hexane = 1/5/5) to give an oil, which was dissolved in acetone (50 ml). To the mixture was added 6N hydrochloric acid (1 ml), and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added 0.5% sodium hydroxide (500 ml) and diisopropyl ether (200 ml), and the mixture was stirred at room temperature for 5 minutes. The resulting precipitate was filtered and recrystallized with acetone-diisopropyl ether to give (E) -N- [4- (hydroxymethyl) -phenyl] -3- (4-methylphenyl) -cinnamide (6.18 g) as pale yellow crystals. . p.f. 220-223 ° C Elemental Analysis for C23H21N02 Calculated: C, 80. 44; H, 6 1 6; N, 4 08 Found: C, 80.12; H, 6.15; N, 4.00. IR (KBr) cm "1: 3294, 1662, 1624, 1603, 1541, 1516, 1414, 13. 46, 1250, 1184, 999, 787 aH NMR (200MHz, DMSO-d6) d: 2.36 (3H, s), 4.46 (2H, s), 6. 93 (1H, d, J = 15.4Hz), 7.22-7.33 (4H, m), 7.46-7.71 (8H, m), 7.89 (1H, s), 10.18 (1H, s).

Reference Example 41 To a mixture of (E) -N- [4- (hydroxymethyl) phenyl] -3- (4-methylphenyl) cinnamamide (3.00 g), lithium chloride (741 mg), triethylamine (3.06 ml), DMAP (catalytic amount) and dichloromethane (300 ml) were added methanesulfonyl chloride (1.15 ml), and the mixture was stirred at room temperature for 13 hours. To the reaction mixture was added a solution of ethyl acetate 4N hydrochloric acid (3.3 ml), and the mixture was purified with column chromatography (ethyl acetate) and recrystallized with ethyl acetate-diisopropyl ether to give the E) -N- [4- (chloromethyl) phenyl] -3- (4-methylphenyl) cinnamamide (2.00 g) as colorless crystals. p.f. 178-180sC Elemental Analysis for C23H20NOC1 • 0.1H20 Calculated: C, 75.96; H, 5.60; N, 3.85. Found: C, 75.93; H, 5.50; N, 3.88. IR (KBr) cm "1: 3344, 3045, 1664, 1628, 1531, 1412, 1338, 1248, 1176, 968, 793, 658 aH NMR (200MHz, CDC13) d: 2.41 (3H, S), 4.58 (2H , s), 6.61 (1H, d, J = 15.6Hz), 7.25-7.31 (2H, m), 7.33-7.53 (7H, m), 7.55-7.67 (3H, m), 7.74 (1H, s), 7.83 (1H, d, J = 15.6Hz).

Reference Examples 42 To a solution cooled to -78 ° C of 2-bromopyridine (10.0 g) in diethyl ether (200 ml) was added dropwise a solution of 1.6M hexane butyllithium (39.6 ml) for 10 minutes. The mixture was stirred at -78 ° C for 1 hour, and a solution of 4-nitrobenzaldehyde in THF (50 ml) was added dropwise to the mixture. The reaction mixture was stirred at -78 ° C for 3 hours, and water (100 ml) was added to the mixture. The mixture was extracted with ethyl acetate, and the organic layer was washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was separated and purified by column chromatography (ethyl acetate / toluene = 1/2) and recrystallized from diisopropyl ether to give (4-nitro-phenyl) - (2-pyridyl) methanol (4.50 g) as crystals orange color. p.f. 114-115 ° C Elemental Analysis for C? 2H? 0N203 Calculated: C, 62. 61; H, 4 38; N, 12 17 Found: C, 62.61; H, 4.27; N, 12.16. IR (KBr) cm "1: 3113, 2852, 1595, 1506, 1437, 1336, 1267, 1068, 1047, 1007, 847, 814, 777, 756, 743, 706 aH NMR (200MHz, CDC13) d: 5.44 (1H, broad s), 5.86 (1H, s), 7.14-7.29 (2H, m), 7.55-7.73 (3H, m), 8.20 (2H, d, J = 8.8Hz), 8.59 (1H, d, J = 5.0Hz).

Reference Example 43 In ethanol (50 ml) was dissolved (4-nitrophenyl) - (2-pyridyl) ethanol (2.30 g) and 10% dry palladium on carbon (0.12 g) was added to the mixture. Under a hydrogen atmosphere, the mixture was stirred at room temperature under atmospheric pressure for 19 hours. The palladium was filtered, and the filtrate was concentrated. The residue was recrystallized from ethyl acetate-hexane to give (4-aminophenyl) (2-pyridyl) methanol (1.90 g) as pale yellow colqr crystals. p. f. 139- 140 ° C Elemental Analysis for C? 2H? 2N20 Calculated: C, 71. 98; H, 6 04; N, 13 99 Found: C, 71.76; H, 6.01; N, 13.82. IR (KBr) cm "1: 3292, 1612, 1589, 1512, 1473, 1439, 1263, 1055, 816, 752, 569 XH NMR (200MHz, CDC13) d: 3.65 (2H, broad s), 5.14 (1H, broad, 5.65 (1H, s), 6.65 (2H, d, J = 8.8Hz) , 7.10- 7.22 (4H, m), 7.61 (1H, dt, J = 1.8, 7.6Hz) 8.55 (1H, d, J = 4.8Hz).

Reference Example 44 Under an atmosphere of argon, ethyl 3-hydroxycinnamate (mp 88-89 ° C, 20.0 g) and triethylamine (34.5 ml) were dissolved in dichloromethane (200 ml), and the mixture was added dropwise Trifluoromethanesulfonic acid anhydride (31.6 g) at -5 ° C for 40 minutes. The reaction mixture was stirred at -5 ° C to 0 ° C for 20 minutes, and water (200 ml) was added to the mixture. The organic layer was separated, washed with a saturated sodium chloride solution, dried with anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by column chromatography (ethyl acetate / hexane = 1/4) and crystallized from hexane to give ethyl 3- (trifluoromethane-sulfoxy) cinnamate (33.5 g). p.f. 52-53 ° C NMR (200MHz, CDC13) d: 3.83 (3H, s), 6.48 (1H, d, J = 16.0Hz), 7.30 (1H, m), 7.41 (1H, t, J = 1.6Hz), 7.51 (2H, m), 7.67 (1H, d, J = 16.0Hz).

Reference Example 45 Under an atmosphere of argon, a mixture of ethyl 3- (trifluoromethanesulfoxy) cinnamate (3.10 g), 4-methyl-phenyl borate (1.63 g), potassium carbonate (2.76 g), toluene (100 ml), ethanol (10 ml) and water (10 ml) was stirred at room temperature for 30 minutes.

To the mixture was added tetracis (triphenylphosphine) palladium (0.46 g), and the mixture was heated to reflux for 18 hours. The reaction mixture was cooled to room temperature. The organic layer was separated, washed with a saturated sodium chloride solution, dried with anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by column chromatography (ethyl acetate / hexane = 1/6) to give the ethyl 3- (4-methylphenyl) -cinnamate (2.21 g) as a colorless oil. The oil (2.20 g) was dissolved in tetrahydrofuran (20 ml). To the mixture was added 2N sodium hydroxide (8.7 ml), and the mixture was stirred at 50 ° C for 2 hours. The reaction mixture was cooled, acidified with potassium acid sulfate and extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was washed with isopropyl ether to give 3- (4-methylphenyl) -cinnamic acid (1.54 g) as colorless crystals, m.p. 186-187 ° C tR NMR (200MHz, CDC13) d: 2.41 (3H, s), 6.53 (1H, d, J = 16.0Hz), 7.28 (2H, d, J = 7.4Hz), 7.46-7.52 (4H , m), 7.50 (1H, s), 7.63 (1H, m), 7.86 (1H, d, J = 16.0Hz).

Reference Example 46 Under an atmosphere of argon, a mixture of ethyl 3- (trifluoromethanesulfoxy) cinnamate (3.10 g), 2-methylphenyl borate (mp 165-166 ° C, 1.63 g), potassium carbonate (2.76 g) , toluene (100 ml), ethanol (10 ml) and water (10 ml) was stirred at room temperature for 30 minutes. To the mixture was added tetracis (triphenylphosphine) palladium (0.46 g), and the mixture was heated to reflux for 18 hours. The reaction mixture was cooled to room temperature, and the organic layer was separated, washed with a saturated sodium chloride solution, dried with anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by column chromatography (ethyl acetate / hexane = 1/6) to give the ethyl 3- (4-methylphenyl) -cinnamate (2.51 g) as a pale yellow oil. The oil (2.50 g) was dissolved in tetrahydrofuran (20 ml). To the mixture was added 2N sodium hydroxide (10.0 ml), and the mixture was stirred at 50 ° C for 2 hours. The reaction mixture was cooled, acidified with potassium acid sulfate and extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was washed with isopropyl ether to give 3- (2-methylphenyl) -cinnamic acid (1.96 g) as colorless crystals, m.p. 124-125 ° C NMR aH (200MHz, CDCl 3) d: 2.27 (3H, s), 6.49 (1H, d, J = 16.0Hz), 7.23-7.30 (4H, m), 7.36-7.57 (4H, m) , d, J = 7.4Hz), 7.84 (1H, d, J = 16.0Hz).

Reference Example 47 Under an atmosphere of argon, a mixture of ethyl 3- (trifluoromethanesulfoxy) cinnamate (3.10 g), 2,5-dimethylphenyl borate (mp 184-186 ° C, 1.80 g), potassium carbonate (2.76 g). g), toluene (100 ml), ethanol (10 ml) and water (10 ml) was stirred at room temperature for 30 minutes. To the mixture was added tetracis (triphenylphosphine) palladium (0.46 g), and the mixture was heated to reflux for 27 hours. The reaction mixture was cooled to room temperature, and the organic layer was separated, washed with a saturated sodium chloride solution, dried with anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by column chromatography (ethyl acetate / hexane = 1/6) to give ethyl 3- (2, 5-dimethylphenyl) -cinamate (2.66 g) as a pale yellow oil. The oil (2.50 g) was dissolved in tetrahydrofuran (20 ml), and to the mixture was added 2N sodium hydroxide (10.0 ml). The mixture was stirred at 50 ° C for 2 hours, cooled, acidified with potassium acid sulfate and extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was washed with isopropyl ether to give 3- (2, 5-dimethylphenyl) -cinnamic acid (1.96 g) as colorless crystals, m.p. 156-157 ° C NMR aH (200MHz, CDC13) d: 2.23 (3H, s), 2.60 (3H, s), 6.49 (1H, d, J = 16.0Hz), 7.06 (1H, s), 7.14 (2H , ABq, J = 7.8Hz), 7.35-7.55 (4H, m), 7.36-7.57 (4H, m), 7.84 (1H, d, J = 16, OHz).

Reference Example 48 Under an atmosphere of argon, a mixture of ethyl 3- (trifluoromethanesulfoxy) cinnamate (3.10 g), 3-nitrophenyl borate (2.00 g), potassium carbonate (2.76 g), toluene (100 ml), ethanol (10 ml) and water (10 ml) was stirred at room temperature for 30 minutes. TO . The mixture was added with tetracis (triphenylphosphine) aladium (0.46 g), and the mixture was heated to reflux for 24 hours. The reaction mixture was cooled to room temperature. The organic layer was separated, washed with a saturated sodium chloride solution, dried with anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified with column chromatography (ethyl acetate / hexane = 1/6) to give ethyl 3- (3-nitrophenyl) -cinnamate (2.40 g) as pale yellow crystals. The crystals (2.40 g) were dissolved in tetrahydrofuran (20 ml), and 2N sodium hydroxide (8.5 ml) was added to the mixture. The mixture was stirred at 50 ° C for 2 hours, cooled, acidified with potassium acid sulfate and extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was washed with isopropyl ether to give 3- (3-nitrophenyl) cinnamic acid (1.88 g) as pale yellow crystals, m.p. 247-248 ° C NMR aH (200MHz, DMSO-d6) d: 6.59 (1H, d, J = 16.0Hz), 7.51-7.76 (4H, m), 7.70 (1H, d, J = 16.0Hz), 7.96 (1H, d, J = 9.0Hz), 8.09 (1H, m), 8.22 (1H,), 8.49 (1H, d, J = 1.8Hz).

Working Example 1 (Production of Compound 1) In THF (5 ml), 7-cyclohexyl-3,4-dihydro-naphthalene-2-carboxylic acid (200 mg) was dissolved, and oxalyl chloride (82 μl) was added to the solution. ) and one drop of DMF. The mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The residue was dissolved in THF (5 ml), and 1- (4-aminobenzyl) piperidine (164 mg) and triethylamine (484 μl) were added to the solution at room temperature. The reaction mixture was stirred at room temperature for 3 hours, and water (100 ml) was added to the mixture. The mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-diisopropyl ether to give 7-cyclohexyl-N- [4- (piperidinomethyl) -phenyl] -3,4-dihydronaphthalene-2-carboxamide (Compound 1) (223 mg) as colorless crystals. , pf 180-181 ° C Elemental Analysis for C29H36N2? 2 Calculated: C, 81.27; H, 8.47; N, 6.54. Found: C, 81.03; H, 8.42; N, 6.53. IR (KBr) cm "1: 3430, 2931, 1645, 1597, 1514, 1412, 1317, 824 XH NMR (200MHz, CDC13) d: 1.20-1.90 (16H, m), 2.30-2.57 (5H, m), 2.60-2.72 (2H, m), 2.85-2.97 (2H, m), 3.46 (2H, s), 7.05-7.15 (3H, m), 7.25-7.34 (3H, m), 7.50-7.60 (3H, m ).

Working Example 2 (Production of Compound 2) In DMF (2 ml) was dissolved 7-cyclohexyl-N- [4- (piperidinomethyl) phenyl] -3,4-dihydronaphthalene-2-carboxamide (120 mg), and to the mixture methyl iodide (45 μl) was added. The mixture was stirred at room temperature for 24 hours and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to give the 1- [4- (7-cyclohexyl-3,4-dihydro-naphthalene-2-carboxamido) benzyl] -1-methylpiperidinium iodide (Compound 2) (148 mg) as colorless crystals. p.f. 188-191 ° C Elemental Analysis for Calculated C30H39N2OI: C, 63.15; H, 6.89; N, 4.91; I, 22.24. Found: C, 63.03; H, 6.93; N, 5.03; I, 22.22. IR (KBr) cm "1: 3430, 2929, 1649, 1599, 1520, 1417, 1321, 1248 aH NMR (200MHz, DMSO-d6) d: 1.20-1.90 (16H, m), 2.40-2.65 (3H, m ), 2.75-2.95 (5H, m), 3.20-3.45 (4H, m), 4.53 (2H, s), 7.14 (3H, s), 7.38 (1H, s), 7.49 (2H, d, J = 8.6 Hz), 7.88 (2H, d, J = 8.6Hz), 10.12 (1H, s).

Working Example 3 (Production of Compound 3) In THF (3 m) 7-cyclohexyl-3,4-dihydronaphthalene-2-carboxylic acid (100 mg) was dissolved, and to the solution oxalyl chloride (41 μl) was added and a drop of DMF. The mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The residue was dissolved in THF (3 ml), and p- (4-aminobenzyl) -N, N '-diethylphosphon-amide was added to the solution. (104 mg) and triethylamine (60 μl) at room temperature.

The reaction mixture was stirred at room temperature for 72 hours, and water (100 ml) was added to the mixture. The mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by column chromatography (ethyl acetate / methanol = 10/1) and recrystallized from diisopropyl ether to give 7-cyclohexyl-N- [4- [bis (ethylamino) phosphorylmethyl] -phenyl ] -3,4-dihydronaphthalene-2-carboxamide (Compound 3) (140 mg) as colorless crystals. p.f. 163-165 ° C Analysis Elemental for C28H38N3O2P Calculated: C, 70. 12; H, 7 99; N, 8 76 Found: C, 70.01; H, 7.99; N, 8.93. IR (KBr) c "1: 3250, 2926, 1645, 1599, 1514, 1414, 1321, 1250, 1182, 1126 aH NMR (200MHz, CDC13) d: 1.10 (6H, t, J = 7.1Hz), 1.20- 1.90 (10H, m), 1.95-2.20 (2H, m), 2.40-2.57 (1H, m), 2.60-2.72 (2H, m), 2.80-3.05 (7H,), 3.12 (1H, s), 7.05 -7.15 (3H, m), 7.22-7.32 (3H, m), 7.59 (2H, d, J = 8.2Hz), 7.83 (1H, s).

Working Example 4 (Production of Compound 4) In THF (20 ml) 7-phenyl-3,4-dihydro-naphthalene-2-carboxylic acid (1.00 g) was dissolved, and oxalyl chloride (523 μl) was added to the solution. ) and one drop of DMF. The mixture was added at room temperature for 1 hour and concentrated under reduced pressure. The residue was dissolved in THF (20 ml), and 1- (4-aminobenzyl) piperidine (837 mg) and triethylamine (673 μl) were added to the solution at room temperature. The reaction mixture was stirred at room temperature for 2 hours, and water (150 ml) was added to the mixture. The mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-diisopropyl ether to give 7-phenyl-N- [4- (piperidinomethyl) phenyl] -3,4-dihydro-naphthalene-2-carboxamide (Compound 4) (1.15 g) as crystals pale brown. p.f. 163-164 ° C Elemental Analysis for C29H30N2O • 0.1H20 Calculated: C, 82.08; H, 7.17; N, 6.60. Found: C, 81.94; H, 7.22; N, 6.49. IR (KBr) cm "1: 3336, 2935, 1651, 1527, 1412, 1317, 762, 698 aH NMR (200MHz, CDC13) d: 1.35-1.70 (6H, m), 2.30-2.45 (4H, m), 2.65-2.80 (2H, m), 2.92-3.04 (2H, m), 3.46 (2H, s), 7.23-7.62 (14H, m).

Working Example 5 (Production of Compound 5) In DMF (3 ml) 7-phenyl-N- [4- (piperidino-methyl) phenyl] -3,4-dihydronaphthalene-2-carboxamide (240 mg) was dissolved, the mixture was added with methyl iodide (106 μl). The mixture was stirred at room temperature for 60 hours and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to give 1-methyl-1- [4- (7-phenyl-3,4-dihydro-naphthalene-2-carboxamido) benzyl] peridinium iodide (Compound 5) (247 mg) as colorless crystals, mp 183-186 ° C Elemental Analysis for Calculated C30H33N2OI: C, 63.83; H, 5.89; N, 4.96. Found: C, 63.54; H, 5.82; N, 5.05. IR (KBr) cm "1: 3450, 1649, 1599, 1520, 1417, 1319 aH NMR (200MHz, DMS0-d6) d: 1.40-2.00 (6H, m), 2.55-2.70 (2H, m), 2.80- 3.00 (5H, m), 3.20-3.45 (4H, m), 4.53 (2H, s), 7.30-7.70 (11H, m), 7.89 (2H, d, J = 8.6Hz), 10.18 (1H, s) .

Working Example 6 (Production of Compound 6) In THF (10 m) 7-phenyl-3,4-dihydronaphthalene-2-carboxylic acid (500 mg) was dissolved, and to the solution oxalyl chloride (262 μl) was added and a drop of DMF. The mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The residue was dissolved in THF (10 ml), and to the solution were added 4-aminobenzyldimethylamine (330 mg) and triethylamine (337 μl) at room temperature. The reaction mixture was stirred at room temperature for 3 hours, and water (100 ml) was added to the mixture. The mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by column chromatography (ethyl acetate / triethylamine = 20 / L) and recrystallized from ethyl acetate-hexane to give N- [4- (dimethylaminomethyl) phenyl] -7-phenyl- 3,4-dihydronaphthalene-2-carboxamide (Compound 6) (131 mg) as colorless crystals. p.f. 182-184 ° C Elemental Analysis for C26H26 20 • 0.2H2O Calculated: C, 80.88; H, 6.89; N, 7.26. Found: C, 81.00; H, 6.90; N, 7.19. IR (KBr) cm "1: 3328, 1649, 1529, 1410, 1317, 762, 698 aH NMR (200MHz, CDC13) d: 2.24 (6H, s), 2.65-2.80 (2H, m), 2.94-3.03 ( 2H, m), 3.41 (2H, s), 7.25-7.63 (14H, m).

Working Example 7 (Production of Compound 7) In THF (10 ml) 7-phenyl-3,4-dihydronaphthalene-2-carboxylic acid (500 mg) was dissolved, and to the solution oxalyl chloride (262 μl) was added and a drop of DMF. The mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The residue was dissolved in THF (10 ml), and 1- (4-aminobenzyl) pyrrolidine (388 mg) and triethylamine (337 μl) were added to the solution at room temperature. The reaction mixture was stirred at room temperature for 3 hours, and water (100 ml) was added to the mixture. The mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by column chromatography (ethyl acetate / triethylamine = 20 / L) and recrystallized from ethyl acetate-diisopropyl ether to give 7-phenyl-N- [4- (1-pyrrolidinylmethyl) phenyl] -3,4-dihydronaphthalene-2-carboxamide (Compound 7) (107 mg) as colorless crystals. p.f. 186-187 ° C Elemental Analysis for C28H28N20 • 0.1H20 Calculated: C, 81.96; H, 6.93; N, 6.83. Found: C, 81.78; H, 6.84; N, 6.89.

IR (KBr) cm "1: 3329, 2962, 1649, 1529, 1410, 1319, 762, 698 aH NMR (200MHz, CDC13) d: 1.75-1.85 (4H, m), 2.45-2.55 (4H,), 2.65 -2.80 (2H, m), 2.90-3.05 (2H, m), 3.60 (2H, s), 7.25-7.60 (14H, m).

Working Example 8 (Production of Compound 8) In THF (10 ml) 7-phenyl-3,4-dihydronaphthalene-2-carboxylic acid (500 mg) was dissolved, and to the solution oxalyl chloride (262 μl) was added and a drop of DMF. The mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The residue was dissolved in THF (10 ml), and 1- (4-aminobenzyl) morpholine (423 mg) and triethylamine (337 μl) were added to the solution at room temperature. The reaction mixture was stirred at room temperature for 2 hours, and water (100 ml) was added to the mixture. The mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by column chromatography (ethyl acetate) and recrystallized from ethyl acetate-hexane to give N- [4- (morpholinomethyl) phenyl] -7-phenyl-3,4-dihydronaphthalene. 2-carboxamide (659 mg) as colorless crystals. p.f. 186-187 ° C Elemental Analysis for C28H28N202 Calculated: C, 79.22; H, 6.65; N, 6.60. Found: C, 78.89; H, 6.50; N, 6.66. IR (KBr) cm "1: 3450, 1651, 1620, 1597, 1527, 1412, 1319, 1113, 764, 700 tR NMR (200MHz, CDC13) d: 2.38-2.47 (4H, m), 2.66-2.78 (2H , m), 2.92-3.03 (2H, m), 3.48 (2H, s), 3.67-3.75 (4H, m), 7.25-7.60 (14H, m).

Working Example 9 (Production of Compound 9) In THF (10 m) 7-phenyl-3,4-dihydronaphthalene-2-carboxylic acid (500 mg) was dissolved, and to the solution oxalyl chloride (262 μl) was added and a drop of DMF. The mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The residue was dissolved in THF (10 ml), and 1- [2- (4-aminophenyl) ethyl] piperidine (450 mg) and triethylamine (337 μl) were added to the solution at room temperature. The reaction mixture was stirred at room temperature for 1 hour, and water (100 ml) was added to the mixture. The mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-diisopropyl ether to give 7-phenyl-N- [4- (2-piperidinoethyl) phenyl]] -3,4-dihydro-naphthalene-2-carboxamide (Compound 9) (576 mg) as light brown crystals, mp 157-159 ° C Elemental Analysis for C30H32N20 Calculated: C, 82.53; H, 7.39; N, 6.42. Found: C, 82.29; H, 7.24; N, 6.32. IR (KBr) cm "1: 3332, 2933, 1651, 1524, 1412, 1317, 1257, 1117, 762, 698 aH NMR (200MHz, CDC13) d: 1.40-1.80 (6H, m), 2.40-2.60 (6H , m), 2.65-2.85 (4H, m), 2.90-3.00 (2H, m), 7.15-7.60 (14H, m).

Working Example 10 (Production of Compound 10) In DMF (2 ml) was dissolved N- [4- (dimethylamino-methyl) phenyl] -7-phenyl-3,4-dihydronaphthalene-2-carboxamide (80 mg) and the The mixture was added with methyl iodide (39 μl). The mixture was stirred at room temperature for 17 hours and concentrated under reduced pressure. The residue was recrystallized from methanol-ethyl acetate to give trimethyl [4- (7-phenyl-3,4-dihydro-naphthalene-2-carboxamido) benzyl] ammonium iodide (Compound 10) (92 mg) as colorless crystals. , pf 190-192 ° C Elemental Analysis for C27H29N2OI • 0.5H20 Calculated: C, 60.79; H, 5.67; N, 5.25. Found: C, 60.81; H, 5.59; N, 5.30. IR (KBr) cm "1: 3450, 1662, 1595, 1520, 1483, 1416, 1319, 1250, 764, 700 NMR aH (200MHz, CDC13) d: 2.65-2.80 (2H, m), 2.80-2.95 (2H, m), 3.23 (9H, 4.98 (2H, 7.18 (1H, d, J = 8.0Hz), 7.30-7.60 (9H, m), 7.69 (1H, s), 7.82-7.90 (2H, m), 8.71 (1H, s).

Working Example 11 (Production of Compound 11) In DMF (2 ml) was dissolved 7-phenyl-N- [4- (1-pyrrolidinylmethyl) phenyl] -3,4-dihydronaphthalene-2-carboxamide (70 mg) and the To the mixture was added methyl iodide (32 μl). The mixture was stirred at room temperature for 17 hours and concentrated under reduced pressure. The residue was recrystallized from methanol-ethyl acetate to give 1-methyl-1- [4- (7-phenyl-3,4-dihydronaphthalene-2-carboxamido) benzyl] pyrrolidinium iodide.

(Compound 11) (78 mg) as pale yellow crystals. p.f. 156-160 ° C Elemental Analysis for C29H3? N2OI • 1.0H2O Calculated: C, 61.27; H, 5.85; N, 4.93. Found: C, 61.23; H, 5.89; N, 5.04.

IR (KBr) cm "1: 3442, 1655, 1593, 1520, 1416, 1317, 1248, 766, 700 NMR XH (200MHz, CDC13) d: 2.05-2.40 (4H, m), 2.65-2.76 (2H, m), 2.82-2.95 (2, H, m), 3.05 (3H, s), 3.43-3.57 (2H, m), 3.80-4.00 (2H, m), 4.98 (2H, s), 7.18 (1H, d, J = 8.0Hz), 7.30-7.56 (9H, m), 7.70 (1H, s), 7.80-7.90 (2H, m), 8.74 (1H, s).

Working Example 12 (Production of Compound 12) In DMF (4 ml) was dissolved N- [4- (morpholinomethyl) phenyl] -7-phenyl-3,4-dihydronaphthalene-2-carboxamide (450) and the mixture was added Methyl iodide (198 μl). The mixture was stirred at room temperature for 18 hours and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to give 4-methyl-4- [4- (7-phenyl-3,4-dihydro-naphthalene-2-carboxamido) benzyl] morpholinium iodide (Compound 12) (575 mg) as Pale yellow crystals. p.f. 166-170 ° Elemental Analysis for C29H31N202I • 0. 5H20 Calculated: C, 60. 53; H, 5 60; N, 4 87 Found: C, 60.41; H, 5.61; N, 4.74. IR (KBr) cm "1: 3450, 1653, 1593, 1520, 1481, 1416, 1317, 1246, 1122, 887, 764, 698 tR NMR (200MHz, CDC13) d: 2.60-2.75 (2H, m), 2.75 -2.90 (2H, m), 3.22 (3H, s), 3.35-3.50 (2H, m), 3.55-3.75 (2H, m), 3.80-4.05 (4H, m), 5.13 (2H, s), 7.12 (1H , d, J = 7.6Hz), 7.25-7.55 (9H, m), 7.71 (1H, s), 7.80-7.87 (2H, m), 8.95 (1H, s).

Working Example 13 (Production of Compound 13) In DMF (4 ml) was dissolved 7-phenyl-N- [4- (2-piperidinoethyl) phenyl] -3,4-dihydronaphthalene-2-carboxamide (350 mg) and the Methyl iodide (150 μl) was added to the mixture. The mixture was stirred at room temperature during 14 hours and concentrated under reduced pressure. The residue was recrystallized from methanol-ethyl acetate to give 1-methyl-1- [2- [4- (7-phenyl-3,4-dihydronaphthalene-2-carboxamide) phenyl] ethyl] -piperidinium iodide.

(Compound 13) (410 mg) as pale brown crystals. p.f. 219-220 ° C Elemental Analysis for C3? H35N2OI • 0.2H20 Calculated: C, 63.96; H, 6.13; N, 4.81. Found: C, 63.91; H, 6.06; N, 4.89. IR (KBr) cm "1: 2941, 1666, 1595, 1520, 1313, 1240, 1205, 837, 768, 702 aH NMR (200MHz, DMSO-d6) d: 1.45-1.90 (6H, m), 2.55-2.70 (2H, m), 2.80-3.17 (7H, m), 3.25-3.60 (6H, m ), 7.25-7.80 (13H, m), 9.95 (1H, s).

Working Example 14 (Production of Compound 14) In THF (10 m), 7- (4-methylphenyl) -3,4-dihydronaphthalene-2-carboxylic acid (500 mg) was dissolved, and to the solution were added oxalyl chloride ( 248 μl) and one drop of DMF. The mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The residue was dissolved in THF (10 ml), and to the solution were added 1- (4-aminobenzyl) piperidine (396 mg) and triethylamine (318 μl) at room temperature. The reaction mixture was stirred at room temperature for 14 hours, and water (100 ml) was added to the mixture. The mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-diisopropyl ether to give 7- (4-methylphenyl) -N- [4- (piperidinomethyl) phenyl] -3,4-dihydronaphthalene-2-carboxamide (Compound 14) (616 mg) as pale brown crystals. p.f. 187-189 ° C Elemental Analysis for C30H32N2O Calculated: C, 82.53; H, 7.39; N, 6.42. Found: C, 82.26; H, 7.36; N, 6.37. IR (KBr) cm "1: 3310, 2931, 1643, 1599, 1527, 1412, 1315, 1255, 806 aH NMR (200MHz, CDC13) d: 1.38-1.65 (6H, m), 2.32-2.42 (7H,) , 2.65-2.77 (2H, m), 2.92-3.02 (2H,), 3.46 (2H, s), 7.20-7.34 (6H, m), 7.40-7.58 (7H, m).

Working Example 15 (Production of Compound 15) In THF (10 m), 7- (4-fluorophenyl) -3,4-dihydronaphthalene-2-carboxylic acid (500 mg) was dissolved, and to the solution oxalyl chloride was added ( 243 μl) and one drop of DMF. The mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The residue was dissolved in THF (10 ml), and 1- (4-aminobenzyl) piperidine (389 mg) and triethylamine (313 μl) were added to the solution at room temperature. The reaction mixture was stirred at room temperature for 14 hours, and water (100 ml) was added to the mixture. The mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-diisopropyl ether to give 7- (4-fluorophenyl) -N- [4- (piperidinomethyl) phenyl] -3,4-dihydronaphthalene-2-carboxamide (Compound 15) (736 mg) as pale yellow crystals. p.f. 175-176 ° C Elemental Analysis for C29H29N2OF • 0. 2H2O Calculated: C, 78. 42; H, 6 67; N, 6 31 Found: C, 78.36; H, 6.68; N, 6.23. IR (KBr) cm "1: 3329, 2935, 1649, 1595, 1518, 1319, 1244, 824 tR NMR (200MHz, CDC13) d: 1.35-1.65 (6H, m), 2.34-2.41 (4H, m), 2.67-2.77 (2H, m), 2.92-3.02 (2H, m), 3.46 (2H, s), 7.07-7.58 (13H, m).

Working Example 16 (Production of Compound 16) In DMF (3 ml) was dissolved 7- (4-methylphenyl) -N- [4- (piperidinoethyl) phenyl] -3,4-dihydronaphthalene-2-carboxamide (400 mg ) and to the mixture was added methyl iodide (171 μl). The mixture was stirred at room temperature for 18 hours and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to give the 1-methyl-1- [4- [7- (4-methylphenyl) -3,4-dihydronaphthalene-2-carboxamido] benzyl] -piperidinium iodide (Compound 16) ( 490 mg) as colorless crystals. p.f. 202-204 ° C Elemental Analysis for C31H35N2OI • 0.5H20 Calculated: C, 63.37; H, 6.18; N, 4.77. Found: C, 63.69; H, 5.98; N, 4.87. IR (KBr) cm "1: 3450, 3294, 2941, 1649, 1622, 1599, 1520, 1417, 1319, 1248, 812 aH NMR (200MHz, DMS0-d6) d: 1.40-2.00 (6H, m), 2.35 (3H, s), 2.55-2.67 (2H, m), 2.82-2.95 (5H, m ), 3.22-3.35 (4H, m), 4.53 (2H, s), 7.24-7.35 (3H, m), 7.46-7.60 (7H,), 7. 89 (2H, d, J = 8.8Hz), 10.15 (1H, s).

Working Example 17 (Production of Compound 17) In DMF (3 ml) was dissolved 7- (4-fluorophenyl) -N- [4- (piperidinoethyl) phenyl] -3,4-dihydronaphthalene-2-carboxamide (450 mg ), and methyl iodide (212 μl) was added to the mixture. The mixture was stirred at room temperature for 18 hours and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to give the l- [4- [7- (4-fluoro-phenyl) -3,4-dihydronaphthalene-2-carboxamido] benzyl] -1-methylpiperidinium iodide (Compound 17) ( 610 mg) as colorless crystals. p.f. 177-180 ° C Elemental Analysis for C3oH32N2OFI • 0.2H20 Calculated: C, 61.48; H, 5.57; N, 4.78.

Found: C, 61.38; H, 5.50; N, 4.81. IR (KBr) cm "1: 3450, 3310, 2947, 1651, 1597, 1518, 1416, 1319, 1246, 1225, 824 aH NMR (200MHz, DMSO-d6) d: 1.40-2.00 (6H, m), 2.55 -2.67 (2H, m), 2.85-2.96 (5H, m), 3.20-3.38 (4H, m), 4.53 (2H, s), 7.25-7.38 (3H, m), 7.46-7.60 (5H, m) , 7.67-7.76 (2H, m), 7.89 (2H, d, J = 8.6Hz), 10.17 (1H, s).

Working Example 18 (Production of Compound 18) To the mixture of N- [4- (hydroxymethyl) phenyl] -7-phenyl-3,4-dihydronaphthalene-2-carboxamide (200 mg), triethylamine (158 μl) and THF (10 ml) was added methane-sulfonic acid anhydride (118 mg) at 0 ° C, and the mixture was stirred at room temperature for 3 hours. Dilute hydrochloric acid was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in DMF (3 ml), and pyridine (137 μl) was added to the mixture. The mixture was stirred at room temperature for 96 hours and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-methanol to give 1- [4- (7-phenyl-3,4-dihydronaphthalene-2-carboxamido) -benzyl] iridinium chloride (Compound 18) (95 mg) as colorless crystals. p.f. 162-164 ° C Elemental Analysis for C23H25 20C1 • 1. 0H2O Calculated: C, 73. 95; H, 5 78; N, 5 95; Cl, 7 53 Found: C, 74.25; H, 5.94; N, 5.92; Cl, 7.12. IR (KBr) cm "1: 3450, 3030, 1653, 1595, 1520, 1416, 1323, 1254, 1213, 762 NMR * H (200MHz, CDC13) d: 2.50-2.75 (4H, m), 5.92 (2H, broad s), 7.00 (1H, d, J = 8.0Hz), 7.15-7.40 (9H, m), 7.60- 7.85 (5H, m), 8.08-8.25 (1H, broad), 9.21 (2H, broad s), 9.73 (1H, broad s).

Working Example 19 (Production of Compound 19) To the mixture of N- [4- (hydroxymethyl) phenyl] -7-phenyl-3,4-dihydronaphthalene-2-carboxamide (200 mg), lithium chloride (95 mg) , triethylamine (182 μl) and dichloromethane (20 ml) were added methanesulfonyl chloride (174 μl), and the mixture was stirred at room temperature for 2 hours. Dilute hydrochloric acid was added to the reaction mixture. The organic layer was separated, washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in DMF (3 ml), and 3-picoline (167 μl) was added to the mixture. The reaction mixture was stirred at room temperature for 17 hours and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-methanol to give 3-methyl-1- [4- (7-phenyl-3,4-dihydro-naphthalene-2-carboxamido) benzyl] pyridinium chloride (90 mg) as crystals. colorless p.f. 136-140 ° C Elemental Analysis for C3oH27N2OCl • 1.5H20 Calculated: C, 72.94; H, 6.12; N, 5.67. Found: C, 73.19; H, 6.37; N, 5.61. IR (KBr) cm "1: 3450, 3030, 1653, 1597, 1520, 1416, 1319, 1250, 1213, 764 tR NMR (200MHz, CDC13) d: 2.48 (3H, s), 2.65-2.90 (4H, m ), 6.03 (2H, broad s), 7.12-7.20 (1H,), 7.25-7.55 (9H, m), 7.70-7.82 (4H, m), 7.95-8.07 (1H, m), 9.29 (2H, s) broad), 9.35-9.50 (1H, broad).

Working Example 20 (Production of Compound 20) To a mixture of N- [4- (hydroxymethyl) phenyl] -7-phenyl-3,4-dihydronaphthalene-2-carboxamide (200 mg), lithium chloride (48 mg) , triethylamine (158 μl) and dichloromethane (30 ml) were added methanesulfonyl chloride (61 μl), and the mixture was stirred at room temperature for 2 hours. Dilute hydrochloric acid was added to the reaction mixture. The organic layer was separated, washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in DMF (3 ml), and 3,5-lutidine (193 μl) was added to the mixture. The reaction mixture was stirred at room temperature for 65 hours and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-methanol to give the 3,5-dimethyl-1- [4- (7-phenyl-3,4-dihydronaphthalene-2-carboxamido) benzyl] iridinium chloride (Compound 20) (186 mg) as colorless crystals. p.f. 163-165 ° C Elemental Analysis for C31H29N2OCI • 1.3H20 Calculated: C, 73.81; H, 6.31; N, 5.55. Found: C, 73.85; H, 6.29; N, 5.49. IR (KBr) cm "1: 3450, 3030, 1655, 1597, 1520, 1483, 1416, 1319, 1252, 766 aH NMR (200MHz, CDC13) d: 2.44 (6H, s), 2.67-2.92 (4H, m ), 5.99 (2H, s), 7.16 (1H, d, J = 7.6Hz), 7.25-7.55 (9H, m), 7.77-7.90 (4H, m), 9.20 (1H, s), 9.72 (1H, s broad).

Working Example 21 (Production of Compound 21) In DMF (3 ml) was dissolved N- [4- (chloromethyl) -phenyl] -7-phenyl-3,4-dihydronaphthalene-2-carboxamide (140 mg), and the 4-cyanopyridine (117 mg) was added to the mixture. The mixture was stirred at 70 ° C for 24 hours and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-methanol to give the 4-cyano-l- [4- (7-phenyl-3,4-dihydro-naphthalene-2-carboxamido) benzyl] pyridinium chloride (Compound 21) (141 mg) as pale brown crystals. p.f. 163-165 ° C Elemental Analysis for C3oH24N3 • Cl • 0.5H20 Calculated: C, 73.99; H, 5.17; N, 8.63. Found: C, 73.71; H, 5.29; N, 8.47. IR (KBr) cm "1: 3430, 3024, 1653, 1597, 1524, 1416, 1319, 1252, 829, 764 aH NMR (200MHz, DMSO-d6) d: 2.50-2.65 (2H, m), 2.82-2.93 (2H, m), 5.92 (2H, s), 7.29-7.67 (11H, m), 7.85 (2H, d, J = 8.6Hz), 8.73 (2H, d, J = 6.8Hz), 9.54 (2H, d, J = 6.8Hz), . 19 (1H, s).

Working Example 22 (Production of Compound 22) In DMF (3 ml) the N- [4- (chloromethyl) -phenyl] -7-phenyl-3,4-dihydronaphthalene-2-carboxamide (160 mg) was dissolved, the mixture was added 3-cyanopyridine (133 mg). The mixture was stirred at 70 ° C for 24 hours and concentrated under reduced pressure.

The residue was recrystallized from ethyl acetate-methanol to give 3-cyano-l- [4- (7-phenyl-3,4-dihydro-naphthalene-2-carboxamido) benzyl] pyridinium chloride (Compound 22) (58 mg) as pale orange crystals. p.f. 158-161 ° C Elemental Analysis for C3oH24N3OCl • 1.5H20 Calculated: C, 71.35; H, 5.39; N, 8.32. Found: C, 71.28; H, 5.49; N, 8.40. IR (KBr) cm "1: 3450, 3028, 1653, 1597, 1520, 1416, 1319, 1252, 766 RMN R (200MHz, DMS0-d6) d: 2.55-2.68 (2H, m), 2.82-2.95 (2H, m), 5.88 (2H, s), 7.30-7.90 (13H, m), 8.32- 8.42 (1H,), 9.13 (1H, d, J = 8.0Hz), 9.47 (1H, d, J = 5.8Hz), . 05 (1H, s), 10.21 (1H, s).

Working Example 23 (Production of Compound 23) In DMF (3 ml) the N- [4- (chloromethyl) -phenyl] -7-phenyl-3,4-dihydronaphthalene-2-carboxy-ida (160 mg) was dissolved, 3-chloropyridine (122 μl) was added to the mixture. The mixture was stirred at 70 ° C for 24 hours and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-methanol to give 3-chloro-l- [4- (7-phenyl-3,4-dihydro-naphthalene-2-carboxamido) benzyl] pyridinium chloride (Compound 23) (110 mg) as pale yellow crystals. p.f. 136-139 ° C Elemental Analysis for C29H24N20C1 • 0. 5H20 Calculated: C, 70. 1 6; H, 5 08; N, 5 64 Found: C, 70.13; H, 5.03; N, 5.68. IR (KBr) cm "1: 3450, 3028, 1653, 1597, 1520, 1483, 1416, 1317, 1252, 1213, 1165, 766, 700 tR NMR (200MHz, DMSO-d6) d: 2.55-2.68 (2H, m), 2.82-2.95 (2H, m), 5.85 (2H, s), 7.30-7.70 (11H,), 7.86 (2H, d, J = 8.4Hz), 8.16-8.26 (1H, m), 8.81 (1H, d, J = 7.6Hz), 9.24 (1H, d, J = 6.0Hz), 9.72 (1H, s), 10.21 (1H, s).

Working Example 24 (Production of Compound 24) In DMF (3 ml) the N- [4- (chloromethyl) -phenyl] -7-phenyl-3,4-dihydronaphthalene-2-carboxamide (140 mg) was dissolved, the mixture was added 1-ethylpiperidine (154 μl). The mixture was stirred at room temperature for 14 hours and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-methanol to give 1-ethyl-1- [4- (7-phenyl-3,4-dihydro-naphthalene-2-carboxamido) -cyclic] pyridinium chloride (Compound 24) (125 mg) as colorless crystals. p. f. 153-156 ° C Elemental Analysis for C3? H35N2OCl • 1. 5H20 Calculated: C, 72. 42; H, 7 Four. Five; N, 5 Four. Five . Found: C, 72.14; H, 7.41; N, 5.32. IR (KBr) cm "1: 3450, 2943, 1655, 1595, 1520, 1483, 1416, 1319, 1255, 1217, 766, 700 1R NMR (200MHz, CDC13) d: 1.30-1.42 (3H, m), 1.60-1.90 (6H,), 2.68-2.95 (4H, m), 3.27-3.45 (4H, m), 3.55-3.70 (2H, m), 4.75 (2H, s), 7.17 (1H, d, J = 7.8Hz), 7.25-7.60 (9H,), 7.90 (1H, s), 8.03 (2H, d, J = 8.6Hz), 10.00 (1H, S).

Working Example 25 (Production of Compound 25) In DMF (3 ml) the N- [4- (chloromethyl) -phenyl] -7-phenyl-3,4-dihydronaphthalene-2-carboxamide (160 mg) was dissolved, the mixture was added triethylamine (180 μl). The mixture was stirred at room temperature for 14 hours and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to give triethyl [4- (7-phenyl-3,4-dihydronaphthalene-2-carboxamido) benzyl] ammonium chloride (Compound 25) (176 mg) as colorless crystals, m.p. 205-206 ° C Elemental Analysis for C3oH3sN2OCl • 0.2H20 Calculated: C, 75.28; H, 7.45; N, 5.85.

Found: C, 75.10; H, 7.38; N, 5.91. IR (KBr) cm "1: 3450, 3007, 1655, 1599, 1519, 1483, 1416, 1319, 1252, 1215, 768, 704 tR NMR (200MHz, CDC13) d: 1.37 (9H, t, J = 6.9Hz), 2.72- 2.96 (4H, m), 3.22 (6H, q, J = 6.9Hz) , 4.62 (2H, s), 7.15-7.45 (7H, m), 7.50-7.60 (3H, m), 7.99 (1H, s), 8.12 (2H, d, J = 8.6Hz), 10.19 (1H, s ).

Working Example 26 (Production of Compound 26) In DMF (3 ml) the N- [4- (chloromethyl) -phenyl] -7-phenyl-3,4-dihydronaphthalene-2-carboxamide (160 mg) was dissolved, the mixture was added tripropylamine (244 μl). The mixture was stirred at room temperature for 14 hours and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to give [4- (7-phenyl-3,4-dihydronaphthalene-2-carboxamido) benzyl] tripropylammonium chloride (Compound 26) (205 mg) as colorless crystals, m.p. 206-207 ° C Elemental Analysis for C33H4? N2OCl • 0.5H20 Calculated: C, 75.33; H, 8.05; N, 5.32. Found: C, 75.59; H, 7.88; N, 5.63. IR (KBr) cm "1: 3450, 2970, 1649, 1595, 1524, 1481, 1417, 1317, 1252, 1217, 770, 708 NMR aH (200MHz, CDC13) d: 0.94 (9H, t, J = 7.2Hz ), 1.60-1.90 (6H, m), 2.79-3.10 (10H, m), 4.64 (2H, s), 7.07 (2H, d, J = 8.4Hz), 7.20 (1H, d, J = 7.8Hz), 7.31-7.45 (4H,), 7.54-7.60 (3H, m), 8.10 (1H, s), 8.19 (2H) , d, J = 8.6Hz), 10.43 (1H, s).

Working Example 27 (Production of Compound 27) In DMF (3 ml) the N- [4- (chloromethyl) -phenyl] -7-phenyl-3,4-dihydronaphthalene-2-carboxamide (160 mg) was dissolved, the mixture was added 3-ethylpyridine (146 μl). The mixture was stirred at 70 ° C for 72 hours and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-methanol to give 3-ethyl-1- [4- (7-phenyl-3,4-dihydro-naphthalene-2-carboxamido) benzyl] pyridinium chloride (Compound 27) (185 mg) as colorless crystals. p.f. 142-145 ° C Elemental Analysis for C3? H29N20Cl • 0.5H20 Calculated: C, 75.98; H, 6.17; N, 5.72. Found: C, 75.96; H, 6.13; N, 5.99. IR (KBr) cm "1: 3381, 1657, 1597, 1520, 1416, 1317, 1252, 762 NMR aH (200MHz, CDC13) d: 1.25 (3H, t, J = 7.6Hz), 2.64- 2.88 (6H, m), 6.09 (2H, s), 7.14 (1H, d, J = 7.8Hz), 7.25-7.52 (9H, m), 7.71-7.88 (4H, m), 8.04 (1H, d, J = 8.0Hz), 9.37 (1H, d, J = 6.0Hz), 9.43 (1H, s), 9.81 (1H, s).

Working Example 28 (Production of Compound 28) In DMF (3 ml) the N- [4- (chloromethyl) -phenyl] -7-phenyl-3,4-dihydronaphthalene-2-carboxamide (160 mg) was dissolved, the mixture was added 2-picoline (126 μl). The mixture was stirred at 70 ° C for 63 hours and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-methanol to give 2-methyl-1- [4- (7-phenyl-3,4-dihydronaphthalene-2-carboxamido) benzyl] pyridinium chloride (Compound 28) (140 mg) as pale brown crystals. p. f. 152- 155 ° C Elemental Analysis for C30H27N2OCI • 1. 0H2O Calculated: C, 74. 29; H, 6 03; N, 5 78 Found: C, 74.56; H, 5.93; N, 5.80. IR (KBr) cm "1: 3402, 1630, 1597, 1520, 1414, 1319, 1250, 764, 700 NMR aH (200MHz, CDC13) d: 2.60-2.90 (7H, m), 6.07 (2H, s), 7.04-7.15 (3H, m), 7.25-7.50 (7H, m), 7.65 (1H, d, J = 7.8Hz), 7.72-7.92 (4H, m), 8.12-8.22 (1H, m), 9.63 (1H, d, J = 6.2Hz), 9.86 (1H, s).

Working Example 29 (Production of Compound 29) In DMF (3 ml) the N- [4- (chloromethyl) -phenyl] -7-phenyl-3,4-dihydronaphthalene-2-carboxamide (160 mg) was dissolved, Thiazole (91 μl) was added to the mixture. The mixture was stirred at 100 ° C for 48 hours and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-methanol to give 3- [4- (7-phenyl-3,4-dihydronaphthalene-2-carboxamido) benzyl] thiazolium chloride (Compound 29) (133 mg) as brown crystals. pale, mp 149-152 ° C Elemental Analysis for C27H23N20SC1 • 0.5H20 Calculated: C, 69.29; H, 5.17; N, 5.99. Found: C, 69.43; H, 4.88; N, 6.12. IR (KBr) cm "1: 3419, 3026, 1649, 1597, 1520, 1414, 1317, 1252, 764, 698 aH NMR (200MHz, DMSO-d6) d: 2.55-2.67 (2H, m), 2.82-2.96 (2H,), 5.78 (2H, s), 7.29-7.71 (11H, m), 7.84 (2H, d, J = 8.2Hz), 8.33-8.40 (1H, m), 8.58-8.66 (1H,), 10.18 (1H, s), 10.42 (1H, s).

Working Example 30 (Production of Compound 30) In DMF (3 ml) the N- [4- (chloromethyl) -phenyl] -7-phenyl-3,4-dihydronaphthalene-2-carboxamide (160 mg) was dissolved, the mixture was added quinuclidine (285 mg). The mixture was stirred at 100 ° C for 24 hours and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-methanol to give the 1- [4- (7-phenyl-3,4-dihydronaphthalene-2-carboxamide) benzyl] quinuclide chloride (Compound 30) (62 mg) as colorless crystals, pf 250-252 ° C Elemental Analysis for C3? H33N20Cl • 0.9H20 Calculated: C, 74.28; H, 7.00; N, 5.59. Found: C, 74.48; H, 7.01; N, 5.56. IR (KBr) c "1: 3425, 2945, 1655, 1595, 1520, 1416, 1319, 1255, 833, 766, 700 tR NMR (200MHz, CDC13) d: 1.75-2.15 (7H,), 2.68-2.90 (4H, m), 3.40-3.70 (6H, m), 4.73 (2H, s), 7.15 (1H, d, J = 7.8Hz), 7.25-7.56 (9H, m), 7.88 (1H, s), 7.96 (2H, d, J = 8.0Hz), 9.93 (1H, s).

Working Example 31 (Production of Compound 31) In DMF (3 ml) the N- [4- (chloromethyl) -phenyl] -7-phenyl-3,4-dihydronaphthalene-2-carboxamide (150 mg) was dissolved., and ethyl 1-methyl-piperidine-4-carboxylate (206 mg) was added to the mixture. The mixture was stirred at room temperature for 15 hours and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-methanol to give 4-ethoxycarbonyl-1-methyl-1- [4- (7-phenyl-3,4-dihydronaphthalene-2-carboxamido) benzyl] -peridinium chloride (Compound 31) ( 185 mg, ratio of isomers = 37: 63) as colorless crystals. p.f. 153-156 ° C Elemental Analysis for C33H37N203C1 • 0. 5H20 Calculated: C, 71. 53; H, 6 91; N, 5 06 Found: C, 71.69; H, 6.76; N, 5.11. IR (KBr) cm "1: 3388, 1726, 1655, 1595, 1520, 1483, 1416, 1319, 1254, 1214, 766, 700 tR NMR (200MHz, CDC13) d: 1.15-1.30 (3H, m), 2.05-2.22 (3H, m), 2.65-2.92 (6H, m), 3.02 (1.11H, s), 3.13 (1.89H, s), 3.38-3.75 (3.26H, m), 3.88-4.22 (2.74H, m), 4.76 (1.26H, s), 5.09 (0.74H, s), 7.15 (1H, dd, J = 4.4, 7.6Hz), 7.25-7.55 (9H, m), 7.83 (1H, s), 7.94 (1H, d, J = 8.4Hz), 8.00 (1H, d, J = 8.4Hz), 9.74 (0.63) H, s), 9.84 (0.37H, s).

Working Example 32 (Production of Compound 32) In THF (10 ml) the N- [4- (chloromethyl) -phenyl] -7-phenyl-3,4-dihydronaphthalene-2-carboxamide (300 mg) was dissolved, the mixture was added hexamethyleneimine (270 μl). The mixture was refluxed for 3.5 hours. The reaction mixture was cooled to room temperature, and water (30 ml) was added to the mixture. The mixture was extracted with ethyl acetate.

The organic layer was washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by column chromatography (ethyl acetate / triethylamine = 20 / L) and recrystallized from ethyl acetate-hexane to give N- [4- (1-perhydroazepinyl ethyl) -phenyl] - 7-phenyl-3,4-dihydronaphthalene-2-carboxamide (Compound 32) (257 mg) as colorless crystals. p.f. 168-170 ° C Elemental Analysis for C3oH32N20 Calculated: C, 82. 53; H, 7 39; N, 6 42 Found: C, 82.28; H, 7.26; "N, 6.37, IR (KBr) cm" 1: 3304, 2924, 1645, 1601, 1520, 1410, 1317, 1254, 831, 762, 698 tR NMR (200MHz, CDCl3) d: 1.61 (8H, s), 2.56-2.76 (6H, m), 2.92-3.03 (2H, m), 3.61 (2H, s), 7.23- 7.61 (14H, m).

Working Example 33 (Production of Compound 33) In DMF (3 ml) the N- [4- (l-perhydroazepinylmethyl) phenyl] -7-phenyl-3,4-dihydronaphthalene-2-carboxamide (150 mg) was dissolved, and to the mixture was added methyl iodide (64 μl). The mixture was stirred at room temperature for 12 hours and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-methanol to give 1-methyl-1- [4- (7-phenyl-3,4-dihydronaphthalene-2-carboxamido) benzyl] perhydro-azepinio iodide (180 mg) as crystals. colorless p.f. 197-199 ° C Elemental Analysis for C3? H25N2OI • 0. 5H20 Calculated: C, 63. 37; H, 6 18; N, 4 77 Found: C, 63.39; H, 6.31; N, 4.71. IR (KBr) cm "1: 3427, 3267, 2937, 1660, 1593, 1520, 1481, 1417, 1313, 1250, 694 aH NMR (200MHz, DMSO-d6) d: 1.50-1.70 (4H, m), 1.80-1.96 (4H, m), 2.55-2.68 (2H, m), 2.83-2.97 (5H , m), 3.22-3.36 (2H, m), 3.40-3.60 (2H, m), 4.50 (2H, s), 7.30-7.70 (11H, m), 7.89 (2H, d, J = 8.4Hz), 10.19 (1H, s).

Working Example 34 (Production of Compound 34) In DMF (3 ml) was dissolved N- [4- (chloromethyl) -phenyl] -7- (4-methylphenyl) -3,4-dihydronaphthalene-2-carboxamide (150 mg), and 1-ethylpiperidine (159 μl) was added to the mixture. The mixture was stirred at room temperature for 20 hours. To the reaction mixture was added ethyl acetate (100 ml), and the resulting precipitate was filtered to give 1-ethyl-1- [4- [7- (4-methylphenyl) -3,4-dihydronaphthalene-2-chloride] -carboxamido] benzyl] piperidinium (Compound 34) (156 mg) as colorless crystals, mp 207-209 ° C Elemental Analysis for C32H37N20C1 Calculated: C, 76.70; H, 7.44; N, 5.59. Found: C, 76.33; H, 7.22; N, 5.67. IR (KBr) cm "1: 3440, 2945, 1651, 1595, 1520, 1416, 1321, 1248, 808 1R NMR (200MHz, CDC13) d: 1.36 (3H, t, J = 6.0Hz), 1.60-1.90 ( 6H, m), 2.37 (3H, s), 2.68-2.92 (4H, m), 3.26-3.42 (4H, m), 3.52-3.70 (2H, m), 4.76 (2H, s), 7.11-7.23 ( 3H, m), 7.31-7.52 (6H, m), 7.90 (1H, s), 8.04 (2H, d, J = 8.4Hz), 10.07 (1H, s).

Working Example 35 (Production of Compound 35) In THF (15 ml) N- [4- (chloromethyl) -phenyl] -7- (4-methylphenyl-3,4-dihydronaphthalene-2-carboxamide (300 mg) was dissolved. ), 4-benzylpiperidine (408 μl) was added to the mixture, the mixture was refluxed for 19 hours, the reaction mixture was cooled to room temperature, and water (100 ml) was added to the mixture. extracted with ethyl acetate.The organic layer was washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by column chromatography (ethyl acetate) and recrystallized from ethyl acetate-hexane to give N- [4- (4-benzyl-piperidinomethyl) phenyl] -7- (4-methylphenyl) ) -3,4-dihydronaphthalene-2-carboxamide (Compound 35) (259 mg) as colorless crystals. p.f. 199-201 ° C Analysis Elemental for C3 H38N20 Calculated: C, 84. 37; H, 7 27; N, 5 32 Found: C, 84.34; H, 7.18; N, 5.39. IR (KBr) cm "1: 3439, 2920, 1647, 1520, 1412, 1315, 808, 700 NMR XH (200MHz, CDC13) d: 1.20-1.70 (5H, m), 1.80-1.97 (2H,), 2.40 (3H, s), 2.53 (2H, d, J = 6.2Hz), 2.65-2.78 ( 2H, m), 2.80-3.02 (4H, m), 3.45 (2H, s), 7.09-7.36 (11H, m), 7.40-7.63 (7H, m).

Working Example 36 (Production of Compound 36) In DMF (3 ml), N- [4- (4-benzyl-piperidino-methyl) phenyl] -7- (4-methylphenyl) -3,4-dihydroxycarbamate was dissolved. Naphthalene-2-carboxamide (150 mg), and to the mixture was added methyl iodide (53 μl). The mixture was stirred at room temperature for 23 hours. To the reaction mixture was added ethyl acetate (100 ml), and the resulting precipitate was filtered to give 4-benzyl-1-methyl-1- [4- (7- (4-methyl-phenyl) -iodide) 3,4-dihydronaphthalen-2-carboamido] benzyl] -peridinium (Compound 36) (141 mg, ratio of isomers = 19: 81) as colorless crystals, mp 209-212 ° C Elemental Analysis for C38H1 2? I • 0.5 H20 Calculated: C, 67.35; H, 6.25; N, 4.13, Found: C, 67.28; H, 6.33; N, 4.08, IR (KBr) cm "1: 3439, 1659, 1593, 1520, 1416, 1317, 1250 , 812 - NMR aH (200MHz, DMSO-d6) d: 1.55-2.00 (5H, m), 2.35 (3H, s), 2.52-2.75 (4H, m), 2.80-3.00 (5H, m), 3.20- 3.40 (4H, m), 4.49 (1.62H, s), 4.60 (0.38H, s), 7.13-7.60 (15H, m), 7.80-7.90 (2H, m), 10.15 (1H, s).

Working Example 37 (Production of Compound 37) In DMF (3 ml) the N- [4- (chloromethyl) -phenyl] -7- (4-methylphenyl) -3,4-dihydronaphthalene-2-carboxamide was dissolved (150 mg), and 1-ethylperhydroazepine (98 mg) was added to the mixture. The mixture was stirred at room temperature for 15 hours. To the reaction mixture was added ethyl acetate (100 ml), and the resulting precipitate was filtered and recrystallized from ethyl acetate-methanol to give the 1-ethyl-1- [4- [7- (4- methyl-phenyl) -3,4-dihydronaphthalene-2-carboxamido] benzyl] erhydroazepinio (Compound 37) (137 mg) as colorless crystals. p.f. 207-210 ° C Analisys is Elemental for C33H39N20C1 • 0. 5H20 Calculated: C, 75. 62; H, 7 69; N, 5 3. 4 . Found: C, 75.82; H, 7.69; N, 5.42. IR (KBr) cm "1: 3431, 2931, 1653, 1597, 1520, 1325, 1255, 808 1 H NMR (200MHz, DMSO-d6) d: 1.40 (3H, t, J = 7.1Hz), 1.50- 1.65 (4H, m), 1.70-1.90 (4H, m), 2.35 (3H, s), 2.55 -2.67 (2H, m), 2.80-2.93 (2H,), 3.12-3.35 (4H, m), 3.40-3.57 (2H, m), 4.47 (2H, s), 7.23-7.35 (3H, m), 7.50-7.60 (7H, m), 7.91 (2H, d, J = 8.4Hz), 10.26 (1H, s).

Working Example 38 (Production of Compound 38) In DMF (3 ml) was dissolved N- [4- (chloromethyl) -phenyl] -7- (4-methylphenyl) -3,4-dihydronaphthalene-2-carboxamide (150 mg ), and 1-propylperhydroazepine (109 mg) was added to the mixture. The mixture was stirred at room temperature for 15 hours. To the reaction mixture was added ethyl acetate (100 ml), and the resulting precipitate was filtered to give the chloride of 1- [4- [7- (4-methylphenyl) -3,4-dihydronaphthalene-2-carboxamide] benzyl] -1-propyl-perhydroazepinium (Compound 38) (163 mg) as colorless crystals. p.f. 195-199 ° C Elemental Analysis for C34H4? N2OCl • 0.5H20 Calculated: C, 75.88; H, 7.87; N, 5.21. Found: C, 76.07; H, 7.83; N, 5.21. IR (KBr) cm "1: 3423, 2937, 1651, 1595, 1520, 1317, 1250, 814 tR NMR (200MHz, DMS0-d6) d: 0.93 (3H, t, J = 7.2Hz), 1.52-1.65 ( 4H, m), 1.75-1.93 (6H, m), 2.35 (3H, s), 2.55-2.68 (2H, m), 2.80-2.95 (2H, m), 3.00-3.13 (2H, m), 3.22- 3.40 (2H, m), 3.40-3.58 (2H,), 4.49 (2H, s), 7.23-7.35 (3H, m), 7.46-7.60 (7H, m), 7.90 (2H, d, J = 8.0Hz ), 10.22 (1H, s).

Working Example 39 (Production of Compound 39) In DMF (3 ml) was dissolved N- [4- (chloromethyl) -phenyl] -7- (4-methylphenyl) -3,4-dihydronaphthalene-2-carboxamide (150 mg), and 1-ethylperhydroazocin (109 mg) was added to the mixture. The mixture was stirred at room temperature for 14 hours. To the reaction mixture was added ethyl acetate (100 ml), and the resulting precipitate was filtered and recrystallized from ethyl acetate-methanol to give the 1-ethyl-1- [4- [7- (4- methyl-phenyl) -3,4-dihydronaphthalene-2-carboxamido] benzyl] perhydroazocinium (Compound 39) (142 mg) as colorless crystals. p. f. 197- 199 ° C Elemental Analysis for C34H4? N20Cl • 0. 5H20 Calculated: C, 75, 88; H, 7 87; N, 5 twenty-one . Found: C, 75.67; H, 7.88; N, 5.30. IR (KBr) cm "1: 3437, 2926, 1655, 1595, 1520, 1489, 1416, 1321, 1252, 812 NMR aH (200MHz, DMSO-d6) d: 1.30-2.00 (13H, m), 2.35 (3H, s), 2.55-2.70 (2H, m), 2.85-3.00 (2H, m), 3.05-3.50 (6H,), 4.44 (2H, s), 7.20-7.37 (3H, m), 7.40-7.60 (7H, m), 7.92 (2H, d, J = 8.6Hz), 10.28 (1H, s) ).

Working Example 40 (Production of Compound 40) In THF (7 ml) N- [4- (chloromethyl) -phenyl] -7- (4-methylphenyl) -3,4-dihydro-naphthalene-2-carboxamide was dissolved. (150 mg), and 1-methylpiperazine (129 μl) was added to the mixture. The mixture was heated to reflux for 24 hours. The reaction mixture was cooled to room temperature, and 5% sodium hydrogen carbonate solution (50 ml) was added to the mixture. The mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by column chromatography (ethyl acetate / triethylamine = 20 / L) and recrystallized from ethyl acetate-hexane to give 7- (4-methylphenyl) -N- [4- (4 methyl-1-piperazinylmethyl) phenyl] -3,4-dihydronaphthalene-2-carboxamide (Compound 40) (105 mg) as colorless crystals. p.f. 174-175 ° C Analysis Elemental for C3oH33N30 Calculated: C, 79. 79; H, 7 37; N, 9 30 Found: C, 79.43; H, 7.41; N, 9.28. IR (KBr) cm "1: 3327, 2941, 2794, 1643, 1524, 1315, 1163, 1011, 808 aH NMR (200MHz, CDC13) d: 2.29 (3H, s), 2.35-2.60 (8H, m), 2.40 (3H, s), 2.65-2.78 (2H, m), 2.90-3.02 (2H, m), 3. 48 (2H, s), 7.20-7.35 (6H,), 7.39-7.63 (7H, m).

Working Example 41 (Production of Compound 41) In DMF (3 ml) the N- [4- (chloromethyl) -phenyl] -7- (4-methylphenyl) -3,4-dihydronaphthalene-2-carboxamide was dissolved (150 mg), and to the solution were added 1- (2-methoxyphenyl) piperazine (97 mg) and potassium carbonate (268 mg). The mixture was stirred at room temperature for 13 hours, and water (50 ml) was added to the mixture. The mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-diisopropyl ether to give N- [4- [1- (2-methoxyphenyl) -4-piperazinylmethyl] phenyL] -7- (4-methylphenyl) -3,4-dihydronaphthalene-2 -carboxamide (Compound 41) (142 mg) as colorless crystals. p.f. 202-205 ° C Elemental Analysis for C36H37N302 Calculated: C, 79. 53; H, 6 8 6; N, 7 73 Found: C, 79.28; H, 6.68; N, 7.66. IR (KBr) cm "1: 3350, 2933, 2812, 1649, 1595, 1520, 1500, 1313, 1240, 812, 746 tR NMR (200MHz, CDC13) d: 2.40 (3H, s), 2.60-2.75 (6H, m), 2.90-3.12 (6H, m), 3.57 (2H, s), 3.86 ( 3H, s), 6.80- 7.03 (4H, m), 7.20-7.28 (3H, m), 7.30-7.38 (3H, m), 7. 40-7.51 (4H,), 7.53-7.63 (3H, m).

Working Example 42 (Production of Compound 42) In THF (7 ml) N- [4- (chloromethyl) -phenyl] -7- (4-methylphenyl-3,4-dihydronaphthalene-2-carboxamide (150 mg) was dissolved. ), and l- (2-pyrimidyl) piperazine (190 mg) was added to the mixture, the mixture was refluxed for 24 hours, the reaction mixture was cooled to room temperature, and an acid carbonate solution was added to the mixture. sodium acetate 5% (50 ml) The mixture was extracted with ethyl acetate.The organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. separated and purified with column chromatography (ethyl acetate) and recrystallized from ethyl acetate-hexane to give 7- (4-methylphenyl) -N- [4- [1- (2-pyrimidyl) -4- piperazinylmethyl] -phenyl] -3,4-dihydronaphthalene-2-carboxamide (Compound 42) (166 mg) as colorless crystals, mp 203-204 ° C Elemental Analysis for C33H33N5O Calculated : C, 7.6.87; H, 6. Four. Five; N, 13 58 Found: C, 76.77; H, 6.40; N, 13.60. IR (KBr) cm "1: 3367, 2935, 1649, 1585, 1516, 1448, 1358, 1313, 1255, 984, 808 2H NMR (200MHz, CDC13) d: 2.40 (3H, s), 2.47-2.54 (4H , m), 2.65-2.78 (2H, m), 2.93-3.03 (2H, m), 3.53 (2H, s), 3.79-3.87 (4H, m), 6.47 (1H, t, J = 4.8Hz), 7.23-7.28 (3H, m), 7.30-7.38 (3H, m), 7.42-7.52 (4H, m), 7.54-7.62 (3H, m), 8.30 (2H, d J = 4.8Hz).

Working Example 43 (Production of Compound 43) In DMF (3 mL) N- [4- (chloromethyl) -phenyl] -7- (4-methylphenyl) -3,4-dihydronaphthalene-2-carboxamide was dissolved (150 mg), and 1-benzhydrylpiperazine (127 mg) and potassium carbonate (268 mg) were added to the solution. The mixture was stirred at room temperature for 24 hours, and water (50 ml) was added to the mixture. The mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized with acetone-diisopropyl ether to give N- [4- (4-benzhydryl-l-piperazinyl-methyl) phenyl] -7- (4-methylphenyl) -3,4-dihydronaphthalene-2-carboxamide (Compound 43) (140 mg) as colorless crystals. p.f. 217-218 ° C Elemental Analysis for C42H4iN30 Calculated: C, 83.55; H, 6.84; N, 6.96. Found: C, 83.25; H, 6.86; N, 7.06. IR (KBr) cm "1: 3417, 2954, 2812, 1659, 1618, 1520, 1410, 1313, 1007, 810, 706 NMR * H (200MHz, DMS0-d6) d: 2.20-2.65 (13H, m), 2.80-2.93 (2H, m), 3.42 (s, 2H), 4.26 (1H, s), 7.10-7.70 (22H,), 9.90 (1H, s).

Working Example 44 (Production of Compound 44) In DMF (3 ml) was dissolved N- [4- (chloromethyl) -phenyl] -7- (4-methylphenyl) -3,4-dihydronaphthalene-2-carboxamide (150 mg), and to the mixture were added 1- (2-furoyl) piperazine hydrochloride (109 mg) and potassium carbonate (268 mg). The mixture was stirred at room temperature for 18 hours, and water (50 ml) was added to the mixture. The mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified with ethyl acetate-diisopropyl ether to give N- [4- [1- (2-furoyl) -4-piperazinylmethyl] phenyl] -7- (4-methylphenyl) -3,4-dihydronaphthalene-2 -carboxamide (Compound 44) (112 mg) as an amorphous, colorless product. IR (KBr) c "1: 3309, 2920, 1618, 1518, 1489, 1437, 1313, 1184, 1001, 812, 754 Elemental Analysis for C34H33N303 Calculated: C, 76.81; H, 6.26; N, 7.90. Found: C , 76.60; H, 6.02; N, 7.61, aH NMR (200MHz, CDC13) d: 2.40 (3H, s), 2.43-2.55 (4H, m), 2.65-2.78 (2H, m), 2.90-3.03 (2H) , m), 3.52 (2H, s), 3.73-3.87 (4H, m), 6.44-6.49 (1H, m), 6.98 (1H, d, J = 3.2Hz), 7.20-7.68 (14H, m).

Working Example 45 (Production of Compound 45) In DMF (3 mL) was dissolved N- [4- (chloromethyl) -phenyl] -7- (4-methylphenyl) -3,4-dihydronaphthalene-2-carboxamide (150 mg), and to the solution were added 1- (3, 4, 5-trimethoxybenzyl) piperazine (138 mg) and potassium carbonate (268 mg) .The mixture was stirred at room temperature for 48 hours, and water was added to the mixture. (50 ml) The mixture was extracted with ethyl acetate, the organic layer was washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure.The residue was recrystallized with ethyl acetate. Ethyl-diisopropyl ether to give N- [4- [1- (3, 4, 5-trimethoxyphenyl) -4-piperazinylmethyl] phenyl] -7- (4-methylphenyl) -3,4-dihydronaphthalene-2-carboxamide ( Compound 45) (155 mg) as pale yellow crystals, mp 143-144 ° C Elemental Analysis for C39H43N30 Calculated: C, 75.82; H, 7.02; N, 6.80 Found: C, 75.74; H, 6.85; N, 6.75 IR (KB r) cm "1: 3425, 2935, 2806, 1649, 1593, 1520, 1458, 1421, 1313, 1236, 1128, 1009, 810 aH NMR (200MHz, CDC13) d: 2.40 (3H, s), 2.40-2.55 (8H, m), 2.65-2.77 (2H, m), 2.90-3.03 (2H, m), 3.45 (2H, s), 3.51 (2H, s), 3.84 (3H, s), 3.86 (6H, s) ), 6.56 (2H, s), 7.20-7.36 (6H, m), 7.40-7.62 (7H, m).

Working Example 46 (Production of Compound 46) In THF (7 ml) N- [4- (chloromethyl) -phenyl] -7- (4-methylphenyl) -3,4-dihydronaphthalene-2-carboxamide was dissolved (150 mg), and 1- (2-hydroxyethyl) piperazine (142 μl) was added to the mixture. The mixture was refluxed for 22 hours. The reaction mixture was cooled to room temperature, and a 5% sodium hydrogen carbonate solution (50 ml) was added to the mixture. The mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give N- [4- [1- (2-hydroxyethyl) -4-piperazinylmethyl] phenyl] -7- (4-methylphenyl) -3,4-dihydronaphthalene-2 carboxamide (Compound 46) (158 mg) as colorless crystals, m.p. 185-187 ° C Elemental Analysis for C3? H35N302 • 0.3H20 Calculated: C, 76.45; H, 7.37; N, 8.63. Found: C, 76.64; H, 7.13; N, 8.35. IR (KBr) cm "1: 3319, 2937, 2816, 1649, 1597, 1520, 1412, 1317, 812 XH NMR (200MHz, CDCl3) d: 2.40 (3H, s), 2.43-2.61 (10H, m), 2.65-2.78 (2H, m), 2.92-3.03 (2H, m), 3.50 (2H, s), 3.61 (2H, t, J = 5.5Hz), 7.21-7.36 (6H, m), 7.40-7.63 ( 7H, m) Working Example 47 (Production of Compound 47) In THF (7 ml) the N- [4- (chloromethyl) -phenyl] -7- (4-methylphenyl) -3,4-dihydronaphthalene-2-carboxamide was dissolved (150 mg), and 3-aminopyridine (109 mg) was added to the mixture. The mixture was refluxed for 45 hours. The reaction mixture was cooled to room temperature, and a 5% sodium hydrogen carbonate solution (50 ml) was added to the mixture. The mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by column chromatography (ethyl acetate / hexane = 3/1) and recrystallized from ethyl acetate-hexane to give 7- (4-methylphenyl) -N- [4- [N-] (3-pyridyl) minomethyl] phenyl] -3,4-dihydronaphthalene-2-carboxamide (Compound 47) (14 mg) as colorless crystals. p.f. 212-214 ° C IR (KBr) cm "1: 3383, 3022, 1655, 1591, 1516, 1412, 1315, 1254, 808, 708 1H NMR (200MHz, CDC13) d: 2.40 (3H, s), 2.66- 2.78 (2H, m), 2.92-3.03 (2H, m), 4.05-4.18 (1H, broad), 4.30-4.37 (2H, m), 6.88 (1H, ddd, J = 1.4, 2.8, 8.0Hz), 7.08 (1H, dd, J = 4.8, 8.0Hz), 7.23-7.30 (3H, m), 7.32-7.39 (3H, m), 7.41-7.51 (4H, m), 7.58-7.65 (3H, m), 7.98 (1H, dd, J = 1.4, 4.8Hz), 8.09 (1H, d, J = 2.8Hz).

Working Example 48 (Production of Compound 48) In DMF (3 ml) N- [4- (chloromethyl) -phenyl] -7- (4-methylphenyl) -3,4-dihydronaphthalene-2-carboxamide was dissolved (150 mg), and to the mixture was added 2-amino-1,3-propanediol (106 mg). The mixture was stirred at room temperature for 72 hours, and water (50 ml) was added to the mixture. The mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-diisopropyl ether to give N- [4 - [(1,3-dihydroxy-2-propyl) aminomethyl] phenyl] -7- (4-methyl-phenyl) -3-4- dihydronaphthalene-2-carboxamide (Compound 48) (60 mg) as colorless crystals, m.p. 189-193 ° C Elemental Analysis for C28H30N2O3 Calculated: C, 75.99; H, 6.83; N, 6.33.

Found: C, 75.64; H, 6.86; N, 6.11. IR (KBr) cm-1: 3332, 2931, 1649, 1620, 1597, 1520, 1412, 1319, 1255, 1045, 812 aH NMR (200MHz, DMS0-d6) d: 2.35 (3H, s), 2.53-2.65 (2H,), 2.80-2.93 (2H, m), 3.28-3.45 (5H,), 3.73 (2H, s), 4.43 (2H, s), 7.20-7.35 (5H, m), 7.43-7.59 (5H , m), 7.67 (2H, d, J = 8.4Hz), 9.90 (1H, s).

Working Example 49 (Production of Compound 49) In THF (10 mL) N- [4- (chloromethyl) -phenyl] -7- (4-methylphenyl) -3,4-dihydronaphthalene-2-carboxamide was dissolved (300 mg), and 4-hydroxypiperidine (235 mg) was added to the mixture. The mixture was heated to reflux for 24 hours. The reaction mixture was cooled to room temperature, and a 5% sodium hydrogen carbonate solution (50 ml) was added to the mixture. The mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give N- [4- (4-hydroxypiperidinomethyl) phenyl] -7- (4-methylphenyl) -3,4-dihydronaphthalene-2-carboxamide (Compound 49) (271 mg ) as colorless crystals. p.f. 223-224 ° C Elemental Analysis for C30H32N202 Calculated: C, 79.61; H, 7.13; N, 6.19. Found: C, 79.54; H, 7.00; N, 6.15. IR (KBr) cm "1: 3321, 2937, 1651, 1622, 1597, 1520, 1412, 1319, 1070, 812 tR NMR (200MHz, DMS0-d6) d: 1.28-1.47 (2H, m), 1.63-1.78 (2H, m), 1.88-2.08 (2H, m), 2.25-2.70 (7H, m), 2.80-2.92 (2H, m), 3.23-3.50 (2H, m), 4.50-4.58 (1H, m) , 7.17-7.33 (5H,), 7.45 (1H, s), 7.48-7.60 (4H, m), 7.67 (2H, d, J = 8.0Hz), 9.92 (1H, s).

Working Example 50 (Production of Compound 50) In THF (10 ml) the N- [4- (chloromethyl) -phenyl] -7- (4-methylphenyl) -3,4-dihydronaphthalene-2-carboxamide was dissolved (300 mg), and thiomorpholine (233 μl) was added to the mixture. The mixture was refluxed for 20 hours. The reaction mixture was cooled to room temperature, and a solution of 5% sodium hydrogen carbonate (50 ml) was added to the mixture. The mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give 7- (4-methylphenyl) -N- [4- (thiomorpholinomethyl) phenyl] -3,4-dihydro-naphthalene-2-carboxamide (Compound 50) (309 mg ) as colorless crystals. p.f. 178-180 ° C Elemental Analysis for C29H3oN2OS Calculated: C, 76. 61; H, 6 65; N, 6 1 6 Found: C, 76.39; H, 6.71; N, 5.94. IR (KBr) cm "1: 3307, 2910, 2810, 1648, 1599, 1520, 1412, 1315, 1257, 806 NMR aH (200MHz, CDC13) d: 2.40 (3H, s), 2.57-2.75 (10H, m), 2.90-3.03 (2H, m), 3.50 (2H, s), 7.22-7.62 ( 13H, m).

Working Example 51 (Production of Compound 51) In THF (10 ml) the N- [4- (chloromethyl) -phenyl] -7- (4-methylphenyl) -3,4-dihydronaphthalene-2-carboxamide was dissolved (300 mg), and diethanolamine (222 μl) was added to the mixture. The mixture was refluxed for 34 hours. The reaction mixture was cooled to room temperature, and a 5% sodium hydrogen carbonate solution (50 ml) was added to the mixture. The mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was separated and purified by column chromatography (ethyl acetate / triethylamine = 10 / L) and recrystallized from ethyl acetate-hexane to give N- [4- [N, N-bis (2-hydroxyethyl ) aminomethyl] phenyl] -7- (4-methylphenyl) -3,4-dihydro-naphthalene-2-carboxamide (Compound 51) (148 mg) as colorless crystals. p.f. 150-151 ° C Elemental Analysis for C29H32N203 Calculated: C, 76.29; H, 7.06; N, 6.14. Found: C, 75.90; H, 7.10; N, 6.18. IR (KBr) cm "1: 3307, 2943, 1645, 1599, 1524, 1412, 1321, 1255, 1036, 804 R NMR (200MHz, CDC13) d: 2.40 (3H, s), 2.64-2.75 (6H, m ), 2.90-3.00 (2H, m), 3.58-3.70 (6H, m), 7.20-7.37 (6H, m), 7.40-7.51 (4H, m), 7.58 (2H, d, J = 8.4Hz), 7.67-7.77 (1H, m).

Working Example 52 (Production of Compound 52) In DMF (5 ml) N- [4- (chloromethyl) -phenyl] -7- (4-methylphenyl) -3,4-dihydronaphthalene-2-carboxamide was dissolved (150 mg), and pyridine (94 μl) was added to the mixture. The mixture was stirred at 70 ° C for 24 hours, and water (50 ml) was added to the mixture. The mixture was washed with ethyl acetate. The aqueous layer was allowed to stand at room temperature for 3 hours. The resulting precipitate was filtered and purified with ethyl acetate-methanol to give 1- [7- (4-methylphenyl) -3,4-dihydronaphthalene-2-carboxamido) -cyclic] pyridinium chloride (Compound 52) (74 mg ) as an amorphous, colorless product. Elemental Analysis for C3QH27N2OC1 • 0. 5H20 Calculated: C, 75. 70; H, 5 93; N, 5 88 Found: C, 75.83; H, 6.02; N, 5.63. IR (KBr) cm "1: 3413, 1655, 1595, 1518, 1414, 1317, 1248, 810 NMR aH (200MHz, DMS0-d6) d: 2.35 (3H, s), 2.55-2.67 (2H, m), 2.80-2.93 (2H, m), 5.85 (2H, s), 7.24-7.34 (3H, m), 7.50-7.60 (7H, m), 7.85 (2H, d, J = 8.6Hz ), 8.14-8.25 (2H, m), 8.64 (1H, t, J = 7.7Hz), 9.20-9.30 (2H, m), 10.18 (1H, s).

Working Example 53 (Production of Compound 53) A solution of N- (4-chloromethylphenyl) -7- (4-methyl-1-phenyl) -2,3-dihydro-1-benzoxepin-4-carboxamide (0.2 g) and cyclohexyl sulfide Sodium (0.08 g) in dimethylformamide (10 ml) was stirred at room temperature for 2.5 hours. The solvent was evaporated, and water was added to the residue. The mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give crude crystals, which were recrystallized with ethyl acetate-hexane to give N- (4- (cyclohexylthiomethyl) -phenyl) -7- (4-methylphenyl) -2, 3- dihydro-l-benzoxepin-4-carboxamide (Compound 53) (0.19 g) as colorless crystals. p.f. 161-162 ° C tR NMR (d ppm, CDC13): 1.23-1.42 (6H, m), 1.63-1.75 (2H,), 1.92-2.05 (2H, m), 2.39 (3H, s), 2.49-2.59 (1H, m), 3.07 (2H, t, J = 4.5Hz), 3.73 (2H, s), 4.36 (2H, t, J = 4.5Hz), 7.06 (1H, d, J = 8.2Hz), 7.22 -7.34 (5H, m), 7.44-7.59 (7H, m). IR (KBr) v: 2928, 2851, 1 651 cm_1. Analysis for C3? H33N02S: Calculated C, 76.98; H, 6.88; N, 2.90. Found C, 76.65; H, 6.59; N, 3.09.

Working Example 54 (Production of Compound 54) In DMF (3 ml) was dissolved 3,4-dihydro-N- [4- (4-hydroxypiperidinomethyl) phenyl] -7- (4-methylphenyl) -naphthalene-2 carboxamide (130 mg), and to the mixture was added methyl iodide (54 μl). The mixture was stirred at room temperature for 17 hours, and ethyl acetate (100 ml) was added to the mixture. The resulting precipitate was filtered and recrystallized from ethyl acetate-methanol to give the iodide of 4-hydroxy-1-methyl-1- [4- [7- (4-methylphenyl) -3,4-dihydronaphthalene-2-carboxamide. ] benzyl] -piperidinium (Compound 54) (138 mg, ratio of isomers = 58:42) as colorless crystals. p.f. 157-161 ° C Analysis is The emental for C3? H35N202I • 0. 5H20 Calculated: C, 61. 69; H, 6 01; N, 4 64 Found: C, 61.75; H, 5.84; N, 4.64. IR (KBr) cm "1: 3396, 1655, 1595, 1520, 1416, 1319, 1250, 812 NMR aH (200MHz, DMS0-d6) d: 1.65-1.90 (2H, m 1.96-2.20 (2H, m), 2.35 (3H, s), 2.55-2.68 (2H, m), 2.82-3.00 (5H, m), 3.10-3.57 (4H, m), 3.70-3.90 (1H, m), 4.50-4.60 (2H, m), 5.05 (0.42H, d, J = 2.8Hz), 5.12 (0.58H, d, J = 3.6Hz), 7.22-7.35 (3H, m), 7.42-7.60 (7H, m), 7.83-7.93 (2H,), 10.18 (1H, s).

Working Example 55 (Production of Compound 55) In DMF (3 ml), 7- (4-methylphenyl) -N- [4- (thiomorpholinomethyl) phenyl] -3,4-dihydro-naphthalene-2-carboxamide was dissolved ( 160 mg), and methyl iodide (66 μl) was added to the mixture. The mixture was stirred at room temperature for 17 hours, and ethyl acetate (100 ml) was added to the mixture. The resulting precipitate was filtered and recrystallized from ethyl acetate-methanol to give 4-methyl-4- [4- [7- (4-methyl-phenyl) -3,4-dihydro-naphthalene-2-carboxamide iodide. ] benzyl] -thiomorpholinium (Compound 55) (165 mg) as colorless crystals, mp 183-185 ° C Elemental Analysis for C30H33N2OSI • 0.2H20 Calculated: C, 60.04; H, 5.61; N, 4.67. Found: C, 59.91; H, 5.52; N, 4.66. IR (KBr) cm "1: 3423, 1651, 1597, 1520, 1416, 1319, 1250, 812 tR NMR (200MHz, DMSO-d6) d: 2.35 (3H, s), 2.55-2.68 (2H, m), 2.83-3.30 (9H, m), 3.40-3.65 (4H, m), 4.62 (2H, s), 7.25-7.35 (3H, m), 7.45-7.61 (7H,), 7.90 (2H, d, J = 8.6Hz), 10.19 (1H, s).

Working Example 56 (Production of Compound 56) In DMF (3 ml) the N- [4- [N, N-bis (2-hydroxy-ethyl) aminomethyl] phenyl] -7- (4-methylphenyl) - was dissolved. 3,4-dihydronaphthalene-2-carboxamide (100 mg), and methyl iodide (41 μl) was added to the mixture. The mixture was stirred at room temperature for 22 hours. The solvent was evaporated and the residue was purified with ethyl acetate-methanol to give the bis (2-hydroxyethyl) methyl [4- [7- (4-methylphenyl) -3,4-naphthalene-2-carboxamido] iodide. benzyl] ammonium (Compound 56) (101 mg) as an amorphous, colorless product. Elemental Analysis for C30H35N2O3I • 0.5H20 Calculated: C, 59.31; H, 5.97; N, 4.61. Found: C, 59.19; H, 5.74; N, 4.68. IR (KBr) cm "1: 3365, 1651, 1593, 1520, 1416, 1319, 1250, 810 RMN tR (200MHz, DMS0-d6) d: 2.35 (3H, s), 2.55-2.67 (2H,), 2.84-3.01 (5H, m), 3.27-3.55 (4H, m), 3.88-3.98 (4H , m), 4.62 (2H, s), 5.33 (2H, t, J = 4.8Hz), 7.25-7.35 (3H,), 7.47-7.60 (7H, m), 7.88 (2H, d, J = 8.4Hz ), 10.18 (1H, s).

Working Example 57 (Production of Compound 57) In DMF (3 ml) the (E) -N- [4- (chloromethyl) -phenyl] -3- (4-methylphenyl) cinnamamide (200 mg) was dissolved and the solution was added l- (3,4-methylenedioxybenzyl) -piperazine (158 mg) and potassium carbonate (382 mg). The mixture was stirred at room temperature for 16 hours, and water (50 ml) was added to the mixture. The mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-diisopropyl ether to give (E) -N- [4- [1- (3,4-methylenedioxybenzyl) -4-piperazinylmethyl] phenyl] -3- (4-methylphenyl) cinnamamide ( Compound 57) (266 mg) as colorless crystals p. f. 204 -207 ° C Elemental Analysis for C35H35N3? 3 • 0. 5H20 Calculated: C, 75. 79; H, 6 54; N, 7 58 Found: C, 76.19; H, 6.48; N, 7.83. IR (KBr) cm "1: 2939, 2806, 1664, 1626, 1524, 1491, 1246, 1041, 1007, 970, 824, 795 aH NMR (200MHz, CDC13) d: 2.30-2.60 (8H, m), 2.41 (3H, s), 3.41 (2H, s), 3.48 (2H, s), 5.93 ( 2H, s), 6.61 (1H, d, J = 15.6Hz), 6.73 (2H, s), 6.84 (1H, s), 7.23-7.32 (4H, m), 7.35-7.60 (8H, m), 7.72 (1H, s), 7.81 (1H, d, J = 15.6Hz).

Working Example 58 (Production of Compound 58) In THF (10 ml) 7-phenylnaphthalene-2-carboxylic acid (350 mg) was dissolved, and to the solution were added oxalyl chloride (184 μl) and one drop of DMF. The mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The residue was dissolved in THF (10 ml) and 1- (4-aminobenzyl) -piperidine (295 mg) and triethylamine were added to the solution. (237 μl) at room temperature. The reaction mixture was stirred at room temperature for 2 hours, and water (100 ml) was added to the mixture. The mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-diisopropyl ether to give N- [4- (piperidinomethyl) phenyl] -7-phenylnaphthalene-2-carboxamide (Compound 58) (491 mg) as pale yellow crystals. p.f. 177-178 ° C Elemental Analysis for C29H28N20 • 0.2H2O Calculated: C, 82.12; H, 6.75; N, 6.60. Found: C, 82.26; H, 6.80; N, 6.62. IR (KBr) cm "1: 3313, 2933, 1649, 1527, 1317, 849, 754, 692 aH NMR (200MHz, CDC13) d: 1.37-1.65 (6H, m), 2.35-2.45 (4H, m), 3.48 (2H, s), 7.33-7.57 (5H, m), 7.62-7.77 (4H, m), 7.83-8.01 (5H, m), 8.15 (1H, s), 8.44 (1H, s).

Working Example 59 (Production of Compound 59) In DMF (3 ml) the N- [4- (piperidinomethyl) -phenyl] -7-phenylnaphthalene-2-carboxamide (300 mg) was dissolved, and the mixture was added with iodide of methyl (133 μl). The mixture was stirred at room temperature for 16 hours and concentrated under reduced pressure.

The residue was recrystallized from ethyl acetate to give the 1- [4- (7-phenylnaphthalene-2-carboxamido) benzyl] -1-methylpiperidinium iodide (Compound 59) (374 mg) as pale yellow crystals. p.f. 203-207 ° C Elemental Analysis for C3oH3? N2OI • 1. 0H2O Calculated: C, 62. 07; H, 5 73; N, 4 83 Found: C, 61.82; H, 5.43; N, 4.87. IR (KBr) cm "1: 3450, 1655, 1597, 1520, 1417, 1317, 1250, 700 NMR XH (200MHz, DMSO-d6) d: 1.40-2.00 (6H, m), 2.94 (3H, s), 3.25-3.40 (4H, m), 4.56 (2H, s), 7.40-7.60 (5H, m), 7.84-7.89 (2H, m), 7.95-8.17 (6H, m), 8.40 (1H, s), 8. 66 (1H, s), 10.68 (1H, s).

Working Example 60 (Production of Compound 60) In THF (15 ml), 5- (4-methylphenyl) -inden-2-carboxylic acid (500 mg) was dissolved, and to the solution oxalyl chloride (262 μl) was added and a drop of DMF. The mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The residue was dissolved in THF (15 ml), and 1- (4-aminobenzyl) piperidine (419 mg) and triethylamine (336 μl) were added to the solution at room temperature. The reaction mixture was stirred at room temperature for 16 hours, and water (100 ml) was added to the mixture. The mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give N- [4- (piperidinomethyl) phenyl] -5- (4-methylphenyl) -inden-2-carboxamide (Compound 60) (549 mg) as colorless crystals. p.f. 219-220 ° C Analysis Elemental for C29H30N20 Calculated: C, 82. 43; H, 7 1 6; N, 6 63 Found: C, 82.17; H, 7.13; N, 6.56. IR (KBr) cm "1: 3346, 2935, 1645, 1597, 1516, 1408, 1315, 1250, 808 tR NMR (200MHz, DMSO-d6) d: 1.34-1.57 (6H, m), 2.25-2.40 (7H, m), 3.30-3.43 (2H, m), 3.80-3.90 (2H, m), 7. 20-7.32 (4H, m), 7.56-7.68 (4H, m), 7.72 (2H, d, J = 8.4Hz), 7.83 (2H, s), 9.96 (1H, s).

Working Example 61 (Production of Compound 61) In DMF (10 ml) the N- [4- (piperidinomethyl) -phenyl] -5- (4-methylphenyl) -indene-2-carboxamide (400 mg) was dissolved, the mixture was added with methyl iodide (177 μl). The mixture was stirred at room temperature for 86 hours and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to give 1- [4- [5- (4-methylphenyl) indene-2-carboxamido] -benzyl] -1-methyl-piperidinium iodide (Compound 61) (516 mg) as crystals. pale yellow color, mp 199-201 ° C Elemental Analysis for C30H33N20I • 0.5H20 Calculated: C, 62.83; H, 5.98; N, 4.88. Found: C, 62.56; H, 5.87; N, 4.97. IR (KBr) cm "1: 3450, 2947, 1651, 1595, 1520, 1416, 1322, 1246, 808 tR NMR (200MHz, DMSO-d6) d: 1.40-2.00 (6H, m), 2.36 (3H, s), 2.92 (3H, s), 3.20-3.40 (4H, m), 3.80-3.90 (2H, m), 4.54 (2H, s), 7.30 (2H, d, J = 8.0Hz), 7.52 (2H, d, J = 8.0Hz), 7.55-7.70 (4H, m), 7.85-7.97 (4H, m), 10.20- 10.25 (1H, m).

Working Example 62 (Production of Compound 62) In DMF (3 ml) the (E) -N- [4- (chloromethyl) -phenyl] -3- (4-methylphenyl) cinnamamide (200 mg) was dissolved and the solution was added l- (4-methoxyphenyl) piperazine hydrochloride (190 mg) and potassium carbonate (382 mg). The mixture was stirred at room temperature for 14 hours, and water (50 ml) was added to the mixture. The mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-diisopropyl ether to give (E) -N- [4- [1- (4-methoxy-phenyl) -4-piperazinylmethyl] phenyl] -3- (4-methylphenyl) cinnamamide ( Compound 62) (224 mg) as colorless crystals, mp 207-208 ° C Elemental Analysis for C34H35N302 Calculated: C, 78.89; H, 6.81; N, 8.12. Found: C, 78.59; H, 6.65; N, 8.13. IR (KBr) cm "1: 2937, 2812, 1662, 1626, 1512, 1248, 820, 795 tR NMR (200MHz, CDC13) d: 2.41 (3H, s), 2.56-2.65 (4H, m), 3.04- 3.13 (4H, m), 3.54 (2H, s), 3.76 (3H, s), 6.61 (1H, d, J = 15.6Hz), 6.78-6.94 (4H, m), 7.23-7.63 (12H, m), 7.73 (1H, s), 7.82 (1H, d, J = 15.6Hz).

Working Example 63 (Production of Compound 63) In DMF (3 ml) the (E) -N- [4- (chloromethyl) -phenyl] -3- (4-methylphenyl) cinnamamide (200 mg) was dissolved and the solution was added 2- (3,4-dimethoxyphenyl) ethylmethyl-amine (132 μl) and potassium carbonate (382 mg). The mixture was stirred at room temperature for 12 hours, and water (50 ml) was added to the mixture. The mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by column chromatography (ethyl acetate) to give a colorless, amorphous product, which was dissolved in ethyl acetate (50 ml) and a 4N-hydrochloric acid solution was added to the mixture. ethyl (0.5 ml). The resulting precipitate was filtered and recrystallized from ethyl acetate-methanol to give the hydrochloride of (E) -N- [4- [N- [2- (3, 4-dimethoxyphenyl) ethyl] -N-methyl-aminomethyl] phenyl] -3- (4-methylphenyl) cinnamamide (Compound 63) (245 mg) as colorless crystals, m.p. 214-217 ° C Elemental Analysis for C3H36N203 • 1.0HC1 Calculated: C, 73.30; H, 6.69; N, 5.03; Cl, 6.36. Found: C, 73.00; H, 6.66; N, 4.99; Cl, 6.20. IR (KBr) cm "1: 3427, 2941, 1682, 1601, 1518, 1417, 1344, 1259, 1174, 1026, 793 t NMR (200MHz, DMSO-d6) d: 2.37 (3H, s), 2.66-2.75 (3H,), 2.95-3.40 (4H,), 3.73 (3H, s), 3.75 (3H, s), 4.15-4.28 (1H, m), 4.32-4.46 (1H,), 6.77 (1H, dd, J = 1.8, 8.2Hz), 6.84-6.94 (2H, m), 7.02 (1H, d, J = 16.0Hz), 7.31 (2H, d, J = 7.8Hz), 7.48-7.75 (8H,), 7.79 -7.93 (3H, m), 10.56 (2H, s).

Working Example 64 (Production of Compound 64) In DMF (3 ml) the (E) -N- [4- (chloromethyl) -phenyl] -3- (4-methylphenyl) cinnamamide (200 mg) was dissolved and the solution was added methylaminoacetonitrile hydrochloride (77 mg) and potassium carbonate (382 mg). The mixture was stirred at room temperature for 14 hours, and water (50 ml) was added to the mixture. The mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-diisopropyl ether to give (E) -N- [4- [N- (cyanomethyl) -N-methylaminomethyl] phenyl] -3- (4-methylphenyl) cinnamamide (Compound 64) ( 129 mg) as colorless crystals, m.p. 163-165 ° C Elemental Analysis for C26H25 30 • 0.1H20 Calculated: C, 78.60; H, 6.39; N, 10.58. Found: C, 78.44; H, 6.32; N, 10.35. IR (KBr) cm "1: 3250, 3055, 1662, 1626, 1599, 1535, 1516, 1412, 1344, 1184, 982, 822, 791 aH NMR (200MHz, CDC13) d: 2.42 (3H, s), 2.44 (3H, s), 3.46 (2H, s), 3.59 (2H, s), 6.61 (1H, d, J = 15.4Hz), 7.23-7.65 (12H, m), 7.74 (1H, s), 7.83 ( 1H, d, J = 15.4Hz).

Working Example 65 (Production of Compound 65) In DMF (3 ml) the (E) -N- [4- (chloromethyl) -phenyl] -3- (4-methylphenyl) cinnamamide (200 mg) was dissolved and the solution was added imidazole (49 mg) and potassium carbonate (382 mg). The mixture was stirred at room temperature for 18 hours, and water was added to the mixture. The mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-diisopropyl ether to give (E) -N- [4- [(imidazol-1-yl) methyl] phenyl] -3- (4-methylphenyl) -cinnamamide (Compound 53) ( 90 mg) as colorless crystals, mp 198-200 ° C Elemental Analysis for C26H23N30 • 0.3H20 Calculated: C, 78.29; H, 5.96; N, 10.53. Found: C, 78.26; H, 5.92; N, 10.17. IR (KBr) cm "1: 3026, 1674, 1628, 1601, 1539, 1518, 1416, 1342, 1182, 1080, 787 tR NMR (200MHz, CDCl3) d: 2.41 (3H, s), 5.08 (2H, s ), 6.67 (1H, d, J = 15.4Hz), 6.91 (1H, s), 7.09-7.16 (3H, m), 7.23-7.30 (2H, m), 7.35-7.66 (8H, m), 7.72 ( 1H, s), 7.82 (1H, d, J = 15.4Hz), 8.00 (1H, broad s).

Working Example 66 (Production of Compound 66) In DMF (3 ml), (E) -N- [4- (chloromethyl) -phenyl] -3- (4-methylphenyl) cinnamamide (200 mg) was dissolved and the solution was added 3- (hydroxymethyl) piperidine (191 mg). The mixture was stirred at room temperature for 72 hours, and water (50 ml) was added to the mixture. The mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-diisopropyl ether to give (E) -N- [4- [3- (hydroxymethyl) piperidinomethyl] phenyl] -3- (4-methylphenyl) -cinamamide (Compound 66) (160 mg ) as colorless crystals. p.f. 153-154 ° C Elemental Analysis for C29H32N202 • 0.1H20 Calculated: C, 78.74; H, 7.34; N, 6.33. Found: C, 78.51; H, 7.32; N, 6.25. IR (KBr) cm-1: 3290, 2924, 1664, 1626, 1603, 1543, 1514, 1412, 1346, 1186, 789 tR NMR (200MHz, CDC13) d: 1.50-1.90 (3H, m), 2.05-2.35 (4H, m), 2.41 (3H, s), 2.50-2.63 (1H, m), 2.70-2.80 (1H, m), 3.46 (2H, s), 3.50-3.71 (2H, m), 6.65 (1H , d, J = 15.6Hz), 7.23-7.31 (4H, m), 7.36-7.61 (7H, m), 7.70-7.87 (3H, m).

Working Example 67 (Production of Compound 67) In DMF (3 ml) the (E) -N- [4- (chloromethyl) -phenyl] -3- (4-methylphenyl) cinnamamide (200 mg) was dissolved and the solution was added 3-hydroxypiperidine (168 mg). The mixture was stirred at room temperature for 13 hours, and water (50 ml) was added to the mixture. The mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-diisopropyl ether to give (E) -N- [4- (3-hydroxypiperidino-methyl) phenyl] -3- (4-methylphenyl) cinnamamide (Compound 67) (174 mg) as colorless crystals. p.f. 132-134 ° C Anal is is Elemental for C28H3oN2? 2 Calculated: C, 78. 84; H, 7 09; N, 6 57 Found: C, 78.58; H, 7.08; N, 6.54. IR (KBr) cm "1: 3427, 2937, 1660, 1628, 1601, 1539, 1412, 1344, 1184, 791 XH NMR (200MHz, DMS0-d6) d: 1.28-1.90 (6H, m), 2.36 (3H , s), 2.59-2.68 (1H, m), 2.72-2.85 (1H, m), 3.33 (2H, s), 4.56 (1H, d, J = 4.8Hz), 6.93 (1H, d, J = 15.8 Hz), 7.20-7.35 (4H, m), 7.46-7.71 (8H, m), 7.89 (1H, s), 10.19 (1H, s).

Working Example 68 (Production of Compound 68) In DMF (3 ml) the (E) -N- [4- (chloromethyl) -phenyl] -3- (4-methylphenyl) cinnamamide (200 mg) was dissolved and the 2-piperidinemethanol (191 mg) was added to the mixture. The mixture was stirred at room temperature for 13 hours, and water (50 ml) was added to the mixture. The mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized with ethyl acetate-diisopropyl ether to give (E) -N- [4- [2- (hydroxy-methyl) iperidinomethyl] phenyl] -3- (4-methylphenyl) -cinnamamide (Compound 68) ( 120 mg) as colorless crystals. p.f. 137-139 ° C Elemental Analysis for C29H32N202_ Calculated: C, 79.06; H, 7.32; N, 6.36. Found: C, 78.73; H, 7.38; N, 6.37. IR (KBr) cm "1: 3325, 2922, 1664, 1630, 1601, 1531, 1412, Í338, 1174, 974, 793 tR NMR (200MHz, CDC13) d: 1.30-1.80 (6H, m), 2.10-2.25 (1H, m), 2.40-2.57 (1H, m), 2.41 (3H, s), 2.82-2.93 (1H, m), 3.33 (1H, d, J = 13.5Hz), 3.53 (1H, dd, J = 4.0, 10.8Hz), 3.88 (1H, dd, J = 4.0, 10.8Hz), 4.04 (1H, d, J = 13.5Hz), 6.61 (1H, d, J = 15.4Hz), 7.23-7.33 (4H , m), 7.37-7.62 (8H,), 7.74 (1H, s), 7.82 (1H, d, J = 15.4Hz).

Working Example 69 (Production of Compound 69) In DMF (3 ml) the (E) -N- [4- (chloromethyl) -phenyl] -3- (4-methylphenyl) cinnamamide (200 mg) was dissolved and the 2- (2-hydroxyethyl) piperidine was added to the mixture (214 mg) The mixture was stirred at room temperature for 18 hours, and water (50 ml) was added to the mixture. The mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-diisopropyl ether to give (E) -N- [4- [2- (2-hydroxyethyl) piperidinomethyl] phenyl] -3- (4-methylphenyl) -cinnamamide (Compound 69) ( 202 mg) as colorless crystals. p.f. 142-143 ° C Elemental Analysis for C3oH34N2? 2 Caiculated: C, 79.26; H, 7.54; N, 6.16. Found: C, 79.00; H, 7.27; N, 6.19. IR (KBr) cm "1: 3300, 2935, 1666, 1628, 1603, 1541, 1516, 1412, 1344, 1182, 789 NMR aH (200MHz, CDCl3) d: 1.30-2.13 (8H, m), 2.20-2.35 (1H, m), 2.41 (3H, s), 2.73-2.87 (1H, m), 2.92-3.07 (1H,), 3.48 (1H, d, J = 13.0Hz), 3.70-3.83 (1H, m) , 3.90-4.02 (1H, m), 4.14 (1H, d, J = 13.0Hz), 6.65 (1H, d, J = 15.4Hz), 7. 23-7.33 (4H, m), 7.38-7.64 (7H, m), 7.72-7.87 (3H, m).

Working Example 70 (Production of Compound 70) In THF (10 ml) the 3- (4-ethylphenyl) -cinnamic acid (0.48 g) was dissolved, and to the solution were added oxalyl chloride (0.35 ml) and a drop of DMF. The mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The residue was dissolved in THF (20 ml) and 1- (4-aminobenzyl) -piperidine (0.38 mg) and triethylamine (0.34 ml) were added to the solution at room temperature. The reaction mixture was stirred at room temperature for 2 hours, and water (150 ml) was added to the mixture. The mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-diisopropyl ether to give (E) -N- [4- (piperidinomethyl) -phenyl] -3- (4-methylphenyl) -cinamamide (Compound 70) (0.60 g) as pale yellow crystals. p.f. 154-156 ° C Elemental Analysis for C28H3oN20 • O.4H20 Calculated: C, 80.50; H, 7.43; N, 6.71. Found: C, 80.60; H, 7.28; N, 6.52. 1R NMR (200MHz, CDCl 3) d: 1.44 (2H, m), 1.58 (4H, m), 2. 39 (4H, m), 2.41 (3H, s), 3.47 (2H, s), 6.61 (1H, d, J = 15.6Hz), 7.25-7.60 (12H, m), 7.73 (1H, s), 7.82 (1H, d, J = 15.6Hz).

Working Example 71 (Production of Compound 71) In THF (10 ml), 3- (2-methylphenyl) -cinnamic acid (0.48 g) was dissolved, and to the solution were added oxalyl chloride (0.35 mg) and one drop of DMF. . The mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The residue was dissolved in THF (20 ml) and 1- (4-aminobenzyl) piperidine (0.38 mg) and triethylamine (0.34 ml) were added to the solution at room temperature. The reaction mixture was stirred at room temperature for 2 hours, and water (50 ml) was added to the mixture. The mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was washed with ethyl acetate-diisopropyl ether to give (E) -N- [4- (piperidinomethyl) phenyl] -3- (2-methyl-phenyl) -cinamamide (Compound 71) (0.75 g) as crystals pale yellow color. Elemental Analysis for C28H30N20 • 0.5H20 Calculated: C, 80.16; H, 7.45; N, 6.68. Found: C, 80.15; H, 7.38; N, 6.64. XR NMR (200MHz, CDC13) d: 1.45 (2H, m), 1.58 (4H, m), 2. 27 (3H, s), 2.39 (2H, m), 3.47 (2H, s), 6.58 (1H, d, J = 15.4Hz), 7.24-7.35 (7H, m), 7.39-7.58 (6H, m), 7.80 (1H, d, J = 15.6Hz).

Working Example 72 (Production of Compound 72) In DMF (4 mL) was dissolved (E) -N- [4- (piperidino-methyl) phenyl] -3- (4-methylphenyl) cinnamamide (0.41 g), and the mixture was added methyl iodide (0.43 mg). The mixture was stirred at room temperature for 20 hours and concentrated under reduced pressure.

The residue was crystallized from ethyl acetate to give the (E) -1-methyl-1- [4- (3- (4-methyl-phenyl) cinnamamido) benzyl] -piperidinium iodide (Compound 72) (0.51 mg) as pale yellow crystals. p.f. 176-178 ° C Elemental Analysis for C29H33N2OI • 1.5H¿0 Calculated: C, 60.10; H, 6.26; N, 4.83. Found: C, 60.19; H, 6.25; N, 4.95.

NMR aH (200MHz, DMSO-d6) d: 1.62 (2H, m), 1.88 (4H, m), 2. 37 (3H, s), 2.93 (3H, s), 3.36 (4H, m), 4.55 (2H, s), 6. 97 (1H, d, J = 15.8Hz), 7.31 (2H, d, J = 7.6Hz), 7.50-7.90 (11H, m), 10.44 (1H, s).

Working Example 73 (Production of Compound 73) In DMF (6 ml) the (E) -N- [4- (piperidino-methyl) phenyl] -3- (2-methylphenyl) cinnamamide was dissolved. (0.62 g), and to the mixture was added methyl iodide (0.64 mg). The mixture was stirred at room temperature for 20 hours and concentrated under reduced pressure.

The residue was solidified with ethyl acetate to give the (E) -1-methyl-1- [4- (3- (2-methyl-phenyl) cinnamamido) benzyl] -piperidinium iodide (Compound 73) (0.79 g) as a pale yellow amorphous product.

Elemental Analysis for C29H33N2OI • 1.5H20 Calculated: C, 60.10; H, 6.26; N, 4.83. Found: C, 60.00; H, 6.11; N, 5.00. NMR aH (200MHz, DMSO-d6) d: 1.62 (2H, m), 1.88 (4H, m), 2.27 (3H, s), 2.93 (3H, s), 3.32 (4H, m), 4.56 (2H, s), 6. 94 (1H, d, J = 15.6Hz), 7.27-7.73 (11H, m), 7.84 (2H, d, J = 8.4Hz), 10.40 (1H, s).

Working Example 74 (Production of Compound 74) In THF (10 ml), 3- (2,5-dimethylphenyl) cinnamic acid (0.50 mg) was dissolved, and to the solution were added oxalyl chloride (0.35 ml) and a drop of DMF. The mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The residue was dissolved in THF (20 ml), and 1- (4-aminobenzyl) piperidine (0.38 mg) and triethylamine (0.34 ml) were added to the solution at room temperature. The reaction mixture was stirred at room temperature for 2 hours, and water (50 ml) was added to the mixture. The mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was washed with ethyl acetate-diisopropyl ether to give (E) -N- [4- (piperidinomethyl) phenyl] -3- (2,5-dimethylphenyl) cinnamamide (Compound 74) (0.75 mg) as a product amorphous pale yellow color. Elemental Analysis for C29H32N20 • 0.5H20 Calculated: C, 80.33; H, 7.67; N, 6.46. Found: C, 80.25; H, 7.34; N, 6.68. NMR aH (200MHz, CDC13) d: 1.44 (2H, m), 1.61 (4H, m), 2.22 (3H, s), 2.36 (3H, s), 2.47 (4H, m), 3.55 (2H, s) , 6.61 (1H, d, J = 15.4Hz), 7.05-7.20 (3H, m), 7.28-7.60 (8H, m), 7.71 (1H, s), 7.79 (1H, d, J = 15.4Hz).

Working Example 75 (Production of Compound 75) In THF (10 ml), 3- (3-nitrophenyl) cinnamic acid (0.54 mg) was dissolved, and to the solution were added oxalyl chloride (0.35 ml) and one drop of DMF. The mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The residue was dissolved in THF (20 ml) and 1- (4-aminobenzyl) piperidine (0.38 mg) and triethylamine (0.34 ml) were added to the solution at room temperature. The reaction mixture was stirred at room temperature for 2 hours, and water (50 ml) was added to the mixture. The mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to give (E) -N- [4- (piperidinomethyl) -phenyl] -3- (3-nitrophenyl) cinnamamide (Compound 75) (0.65 mg) as pale yellow crystals, m.p. 178-179 ° C Elemental Analysis for C2H27N303 • 0.5H20 Calculated: C, 71.98; H, 6.26; N, 9.33. Found: C, 71.69; H, 6.38; N, 9.44. 1R NMR (200MHz, DMS0-d6) d: 1.51 (6H, m), 2.33 (4H, m), 3.39 (2H, s), 6.96 (1H, d, J = 15.8Hz), 7.24 (2H, d, J = 8.0Hz), 7.59-7.83 (7H, m), 8.02 (1H, s), 8.18-8.30 (2H, m), 8.52 (1H, s), 10.18 (1H, s).

Working Example 76 (Production of Compound 76) In DMF (6 ml) was dissolved (E) -N- [4- (piperidino-methyl) phenyl] -3- (2,5-dimethylphenyl) cinnamamide (0.60 g) , and to the mixture was added methyl iodide (0.60 mg). The mixture was stirred at room temperature for 20 hours and concentrated under reduced pressure. The residue was crystallized from ethyl acetate to give the (E) -1-methyl-l- [4- (3- (2,5-dimethylphenyl) cinnamamido) benzyl] -piperidinium iodide (Compound 76) (0.66 g) as' pale yellow crystals, mp 145-147 ° C Elemental Analysis for C3oH35N2OI • 1.5H20 Calculated: C, 60.71; H, 6.45; N, 4.72. Found: C, 61.06; H, 6.10; N, 4.74. NMR aH (200MHz, DMSO-d6) d: 1.62 (2H, m), 1.88 (4H,), 2.22 (3H, s), 2.33 (3H, s), 2.93 (3H, s), 3.33 (4H, m) ), 4.55 (2H, s), 6.92 (1H, d, J = 15.8Hz), 7.07 (1H, s), 7.15 (2H, ABq, J = 7.6Hz), 7.37 (1H, d, J = 7.4Hz ), 7.48-7.60 (5H, m), 7.67 (1H, d, J = 15.6Hz), 7.84 (2H, d, J = 8.4Hz), 10.39 (1H, 's).

Working Example 77 (Production of Compound 77) In DMF (6 mL) was dissolved (E) -N- [4- (piperidino-methyl) phenyl] -3- (3-nitrophenyl) cinnamamide (0.59 g), and the mixture was added methyl iodide (0.57 mg). The mixture was stirred at room temperature for 20 hours and concentrated under reduced pressure. The residue was crystallized from ethyl acetate to give the (E) -1-methyl-1- [4- (3- (3-nitro-phenyl) cinnamamido) benzyl] -piperidinium iodide (Compound 77) (0.75 g) as pale yellow crystals, mp 188-190 ° C Elemental Analysis for C28H3oN303I • 1.5H20 Calculated: C, 55.09; H, 5.45; N, 6.88. Found: C, 54.91; H, 5.40; N, 7.23. 2 H NMR (200MHz, DMSO-d 6) d: 1.65 (2H, m), 1.90 (4H, m), 2.94 (3H, s), 3.35 (4H, m), 4.56 (2H, s), 6.99 (1H, d, J = 15.8Hz), 7.49-7.88 (9H, m), 8.04 (1H, s), 8.18-8.29 (2H, m), 8.53 (1H, s), 10.45 (1H, s).

Working Example 78 (Production of Compound 78) In toluene (10 ml) the (E) -N- [4- (chloro-methyl) phenyl] -3- (4-methylphenyl) cinnamamide (300 mg) was dissolved, the mixture was added tributylphosphine (248 μl). The mixture was stirred at 80 ° C for 3 days and cooled to room temperature. The resulting precipitate was filtered and recrystallized from ethyl acetate-methanol to give the (E) -tributyl [4- [3- (4-methylphenyl) cinnamamido] benzyl] -phosphonium chloride (Compound 78) (389 mg) as colorless crystals. p.f. 216-217 ° C Elemental Analysis for C35H47N0C1P Calculated: C, 74.51; H, 8.40; N, 2.48. Found: C, 74.40; H, 8.33; N, 2.63. IR (KBr) cm "1: 3429, 2966, 1674, 1630, 1601, 1537, 1516, 1344, 1180, 789 2H NMR (200MHz, DMS0-d6) d: 0.85-1.00 (9H, m), 1.30-1.60 (12H, m), 2.05-2.25 (6H, m), 2.37 (3H, s), 3.79 (2H, d, J = 15.2Hz), 7.05 (1H, d, J = 15.8Hz), 7.25-7.35 ( 4H, m), 7.48-7.90 (9H, m), 10.61 (1H, s).

Working Example 79 (Production of Compound 79) In THF (10 ml), (E) -3- (4-methylphenyl) -cinnamic acid (400 mg) was dissolved, and oxalyl chloride (220 μl) was added to the solution and a drop of DMF. The mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The residue was dissolved in THF (10 ml) and a solution of (4-aminophenyl) - (2-pyridyl) ethanol was added dropwise to the solution. (370 mg) and triethylamine (471 μl) in THF (15 ml) at 0 ° C. The reaction mixture was stirred at room temperature for 20 hours, and water (50 ml) was added to the mixture. The mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give (E) -N- [4- [hydroxy (2-pyridyl) methyl] phenyl] -3- (4-methylphenyl) cinnamamide (Compound 79) (517 mg) as colorless crystals. p.f. 162-165 ° C Elemental Analysis for C28H24N202 • 0.1H20 Calculated: C, 79.63; H, 5.78; N, 6.63. Found: C, 79.53; H, 5.73; N, 6.58. IR (KBr) c "1: 3257, 1659, 1626, 1597, 1531, 1410, 1342, 1250, 1182, 787, 758 1R NMR (200MHz, CDC13) d: 2.41 (3H, s), 5.27-5.36 (1H , m), 5.70-5.77 (1H, m), 6.60 (1H, d, J = 15.4Hz), 7.12-7.86 (17H, m), 8.57 (1H, d, J = 4.4Hz).

Working Example 80 (Production of Compound 80) In THF (10 ml) the (E) -N- [4- [hydroxy (2-pyridyl) methyl] phenyl] -3 (4-ethylphenyl) cinnamamide (200 mg) was dissolved. ), 70% mCPBA (152 mg) was added to the mixture. The mixture was stirred at room temperature for 6 hours, and a solution of saturated sodium thiosulfate was added to the solution. (10 ml) and saturated potassium carbonate (10 ml). The mixture was stirred at room temperature for 30 minutes and extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized with ethyl acetate-methanol to give the (E) -N- [4- [Hydroxy (l-oxido-2-pyridyl) methyl] phenyl] -3- (4-methylphenyl) cinnamamide (Compound 80) (123 mg) as colorless crystals, m.p. 165-167 ° C Elemental Analysis for C28H24 2? 3 Calculated: C, 77.04; H, 5.54; N, 6.42. Found: C, 76.85; H, 5.55; N, 6.42. IR (KBr) cm "1: 3288, 1668, 1628, 1601, 1539, 1516, 1433, 1412, 1340, 1184, 791, 768 tR NMR (200MHz, CDC13) d: 2.40 (3H, s), 6.05 (1H , d, J = 4.4Hz), 6.37 (1H, d, J = 4.4Hz), 6.65 (1H, d, J = 15.8Hz) 6.99-7.06 (1H, m), 7.20-7.31 (4H, m) , 7.36-7.87 (12H, m), 8.20-8.26 (1H, m).

Working Example 81 (Production of Compound 81) To 3-phenyl cinnamic acid (0.62 g) were added thionyl chloride (5 ml) and dimethylformamide (catalytic amount), and the mixture was heated to reflux for 4 hours. The solvent was evaporated and the residue was dissolved in tetrahydrofuran. The mixture was added dropwise to a suspension of 1- (4-aminobenzyl) iperidine (0.5 g) and diisopropylethylamine (1.2 ml) in tetrahydrofuran (5 ml) under ice-cooling. Under a nitrogen atmosphere, the mixture was stirred at room temperature overnight. The solvent was evaporated, and water was added to the residue. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated and the residue was purified with a column of silica gel (methanol / triethylamine / ethyl acetate). The resulting crude crystals were recrystallized with ethyl acetate-hexane to give 1- (4- (3-phenylcinnamoylamino) -benzyl) piperidine (Compound 81) (0.45 g) as pale yellow crystals. p.f. 159-160 ° CR N-1H (d ppm, CDC13): 1.37-1.48 (2H, m), 1.49-1.63 (4H, m), 2.34-2.42 (4H, m), 3.45 (2H, s), 6.62 (1H, d, J = 15.4Hz), 7.23-7.63 (13H,), 7.76 (1H, s), 7.83 (1H, d, J = 15.4Hz). IR (KBr) v: 2934, 1659, 1624cm ~ 1.

Analysis for C27H28N20 • 0.5H2O: Calculated C, 79.97; H, 7.21; N, 6.91 Found C, 81.09; H, 7.02; N, 6.94 Working Example 82 (Production of Compound 82) A solution of N- (4-chloromethylphenyl) -7- (4-methyl-phenyl) -2,3-dihydro-l-benzaxepine-4-carboxamide (0.15 g) and Sodium phenyl sulfide (0.05 g) in dimethylformamide (10 ml) was stirred at room temperature overnight. The solvent was evaporated, and water was added to the residue. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give crude crystals, which were recrystallized with ethyl acetate-hexane to give 7- (4-methylphenyl) -N- (4- (phenyl-thiomethyl) phenyl) -2, 3 -dihydro-l-benzoxepin-4-carboxamide (Compound 82) (0.13 g) as colorless crystals. p.f. 176-177 ° C NMR-aH (d ppm, CDC13): 2.39 (3H, s), 3.07 (2H, t, J = 4.5Hz), 4.10 (2H, s), 4.35 (2H, t, J = 4.5 Hz), 7.06 (1H, d, J = 8.2Hz), 7.18-7.33 (9H, m), 7.43-7.53 (6H, m), 7.58 (1H, s). IR (KBr) v: 1652, 1515cm_1.

Analysis for C31H2-7NO2S: Calculated C, 77.96; H, 5.70; N, 2.93 Found C, 77.72; H, 5.57; N, 3.07 Working Example 83 (Production of Compound 83) A suspension of 1- (4- (3-bromocinamoylamino) -benzyl) piperidine (0.4 g), 4-fluorophenyl borate (0.14 g)1M potassium carbonate (2 ml) and ethanol (1 ml) in toluene (5 ml) was stirred under an argon atmosphere at room temperature for 30 minutes. To the suspension was added tetracistriphenylphosphine palladium (0.05 g), and the mixture was heated to reflux overnight. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated sodium chloride solution and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated and the residue was purified with a column of silica gel (methanol / triethylamine / ethyl acetate) to give crude crystals, which were recrystallized with ethyl acetate-hexane to give 1- (4- (3- (4-fluorophenyl) -cinnamoylamino) benzyl) piperidine (Compound 83) s (0.35 g) as colorless crystals, m.p. 166-167 ° C. NMR-1H (d ppm, CDC13): 1.38-1.50 (2H, m), 1.52-1.65 (4H, m), 2.34-2.39 (4H, m), 3.45 (2H, s), 6.61 (1H, d, J = 15.4Hz), 7.10-7.19 (2H, m), 7.30 (2H, d, J = 8.0Hz), 7.40-7.58 (8H, m), 7.68 (1H, s), 7.81 (1H, d, J = 15.4Hz). IR (KBr) v: 3262, 2936, readsScm1. Analysis for C27H27FN20 • 0.2H2O: Calculated C, 77.56; H, 6.61; N, 6.70. Found C, 77.72; H, 6.49; N, 6.79.

Working Example 84 (Production of Compound 84) A suspension of 1- (4- (3-bromocinamoylamino) -benzyl) piperidine (0.4 g), 4-methoxyphenyl borate (0.14 g), 1M potassium carbonate (2 ml) and ethanol (1 ml) in toluene (5 ml) was stirred under an argon atmosphere at room temperature for 30 minutes. To the suspension was added tetracistriphenylphosphine palladium (0.05 g), and the mixture was heated to reflux overnight. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated sodium chloride solution and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated and the residue was purified with a column of silica gel (methanol / triethylamine / ethyl acetate) to give the crude crystals, which were recrystallized with ethyl acetate-hexane to give l- (4- (3- (4-methoxyphenyl) -cinnamoylamino) benzyl) iperidine (Compound 84 ) (0.38 g) as colorless crystals. p.f. 150-151 ° C. NMR-aH (d ppm, CDC13): 1.38-1.50 (2H, m), 1.51-1.62 (4H, m), 2.35-2.40 (4H, m), 3.46 (2H, s), 3.87 (3H, s) , 6.61 (1H, d, J = 15.4Hz), 7.00 (2H, d, J = 9.0Hz), 7.29-7.36 (3H, m), 7.43-7.58 (7H, m), 7.71 (1H, s), 7.82 (1H, d, J = 15.4Hz). IR (KBr) V: 3264, 2936. 1663CX1. Analysis for C28H3oN202: Calculated C, 78.84; H, 7.09; N, 6.57. Found C, 79.07; H, 7.12; N, 6.69.

Working Example 85 (Production of Compound 85) A solution of 1- (4- (3-phenylcinthylamino) -benzyl) piperidine (0.32 g) and methyl iodide (0.15 ml) in dimethylformamide (5 ml) was stirred during the overnight, under a nitrogen atmosphere, at room temperature.

The solvent was evaporated, and ethyl acetate was added to the residue. The crude, precipitated crystal was filtered, which was recrystallized with ethanol to give the 1-methyl-1- (4- (3-phenylcinnamoylamino) -benzyl) piperidinium iodide (Compound 85) (0.26 g) as colorless crystals. p.f. 194-195 ° C. NMR-XH (d ppm, DMSO-de): 1.45-1.65 (2H, m), 1.75-1.95 (4H,), 2.92 (3H, s), 3.24-3.28 (4H, m), 4.54 (2H, s), 6.97 (1H, d, J = 15.8Hz), 7.41-7.93 (14H, m), 10.44 (1H, s). IR (KBr) v: 3241, 1682cm_1. Analysis for C28H31IN20: Calculated C, 62.46; H, 5.80; N, 5.20. Found C, 62.19; H, 5.74; N, 5.10.

Working Example 86 (Production of Compound 86) A solution of N- (4-chloromethylphenyl) -7- (4-methyl-phenyl) -2,3-dihydro-l-benzoxepin-4-carboxamide (0.15 g) and sodium benzyl sulfide (0.055 g) in dimethylformamide (10 ml) was stirred at room temperature overnight. The solvent was evaporated, and water was added to the residue. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give crude crystals, which were recrystallized with ethyl acetate-hexane to give N- (4- (benzylthiomethyl) phenyl) -7- (4-methylphenyl) -2, 3-dihydroxycarbonate. l-benzoxepin-4-carboxamide (Compound 86) (0.17 g) as colorless crystals. p.f. 145-146 ° C. NMR-XH (d ppm, CDC13): 2.39 (3H, s), 3.07 (2H, t, J = 4.7Hz), 3.59 (2H, s), 3.60 (2H, s), 4.35 (2H, t, J = 4.7Hz). 7.06 (1H, d, J = 8.0Hz), 7.22-7.32 (9H, m), 7. 43-7.57 (6H, m), 7.61 (1H, s). IR (KBr) v: 3028, 1646, 1515CI - "1. Analysis for C32H29N02S • 0.5H20: Calculated C, 76.77; H, 6.04; N, 2.80, Found C, 77.07; H, 5.96; N, 2.95.

Working Example 87 (Production of Compound 87) A solution of Compound 83 (0.25 g) and methyl iodide (0.2 ml) in dimethylformamide (5 ml) was stirred at room temperature overnight. The solvent was evaporated, and ethyl acetate was added to the residue. The crude, precipitated crystal was filtered, which was recrystallized with ethanol to give the 1-methyl-1- (4- (3- (4-fluorophenyl) cinnamoylamino) benzyl) -piperidinium iodide (Compound 87) (0.27 g) as pale brown crystals. p.f. 204-205 ° C. NMR-1H (d ppm, DMS0-d6): 1.42-1.75 (2H, m), 1.78-1.95 (4H, m), 2.91 (3H, s), 3.22-3.32 (4H, m), 4.52 (2H, s), 6. 95 (1H, d, J = 15.8 Hz), 7.29-7.38 (2H, m), 7.48-7.91 (11H, m), 10.44 (1H, s). IR (KBr) v: 3237, 1682cm ~ 1. Analysis for C2? H30FIN2O • 0.5H20: Calculated C, 59.47; H, 5.53; N, 4.95.

Found C, 59.49; H, 5.35; N, 4.9í Working Example 88 (Production of Compound 88) A solution of l- (4- (3- (4-methoxyphenyl) cinnamoylamino) benzyl) piperidine (0.32 g) and methyl iodide (0.2 g) in dimethylformamide (5 g) ml) was stirred at room temperature overnight. The solvent was evaporated, and ethyl acetate was added to the residue. The crude, precipitated crystal was filtered, which was recrystallized with ethanol-hexane to give the 1-methyl-1- (4- (3- (4-methoxyphenyl) cinnamoylamino) -benzyl) iperidinium iodide (Compound 88) (0.33 g) as pale brown crystals, mp 208-209 ° C. NMR-aH (d ppm, DMSO-d6): 1.45-1.68 (2H, m), 1.78-1.95 (4H,), 2.91 (3H, s), 3.24-3.34 (4H, m), 3.82 (3H, s) ), 4.53 (2H, s), 6.95 (1H, d, J = 15.8Hz), 7.06 (2H, d, J = 8.6Hz), 7.43-7.57 (4H, m), 7.61-7.74 (4H, m) , 7.84 (2H, d, J = 8.6Hz), 7.88 (1H, s), 10.45 (1H, s). IR (KBr) v: 3243, 1682cm "1. Analysis for C29H33IN202: Calculated C, 61.27; H, 5.85; N, 4.93, Found C, 60.87; H, 5.83; N, 4.88.

Working Example 89 (Production of Compound 89) To the 3, 4-dihydro-7-phenylnaphthalene-2-carboxylic acid (0.25 g) were added thionyl chloride (5 ml) and dimethylformamide (catalytic amount), and the mixture was heated reflux for 3 hours. The solvent was evaporated, and the residue was dissolved in tetrahydrofuran. The mixture was added dropwise to a suspension of 2- (4-aminobenzyl) -1,3-dimethyl-1,3,2-diazaphosphorin-2-oxide (0.25 g) and diisopropylethylamine (0.5 ml) in tetrahydrofuran (10 g). ml), under cooling with ice. Under a nitrogen atmosphere, the mixture was stirred at room temperature overnight. The solvent was evaporated, and water was added to the residue. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated. The crude, precipitated crystal was recrystallized with ethanol-hexane to give 2- (4- (3,4-dihydro-7-phenyl-naphthalene-2-carbonyl-amino) benzyl) -1,3-dimethyl-1,3 , 2-diazaphosphorin-2-oxide (Compound 89) (0.35 g) as colorless crystals. p.f. 249-250 ° C. NMR ^ H (d ppm, CDC13): 1.10-1.30 (1H, m), 1.65-1.85 (1H, m), 2.65 (3H, s), 2.69 (3H, s), 2.73-3.07 (8H, m) , 3.17 (2H, d, J = 17.4Hz), 7.18 (2H, dd, J = 2.6, 8.8Hz), 7. 29-7.60 (11H, m), 7.70 (1H, s). IR (KBr) V: 3283, 2940, 2886, 2832, ldSScm "1. L Analysis for C29H32N302P • 0.2H2O: Calculated C, 71.21; H, 6.68; N, 8.59, Found C, 71.12; H, 6.57; N, 8.52.

Working Example 90 (Production of Compound 90) To 3, 4-dihydro-7-phenylnaphthalene-2-carboxylic acid (0.35 g) were added thionyl chloride (10 ml) and dimethylformamide (catalytic amount), and the mixture was heated to reflux for 2.5 hours. The solvent was evaporated, and the residue was dissolved in tetrahydrofuran. The mixture was added dropwise to a suspension of 2- (4-aminobenzyl) -1,3-dimethyl-1,3,2-diazaphosphorane-2-oxide (0.33 g) and diisopropylethylamine (0.75 ml) in tetrahydrofuran (10 g). ml), under cooling with ice. Under a nitrogen atmosphere, the mixture was stirred at room temperature overnight. The solvent was evaporated, and water was added to the residue. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated. The crude, precipitated crystal was recrystallized with ethanol-hexane to give 2- (4- (3,4-dihydro-7-phenyl-naphthalene-2-carbonyl-amino) benzyl) -1,3-dimethyl-1,3 , 2-diaza-phosphorane-2-oxide (Compound 90) (0.24 g) as colorless crystals. p.f. 212-213 ° C. NMR-1H (d ppm, CDC13): 2.61 (3H, s), 2.65-2.76 (2H, m), 2. 66 (3H, s), 2.94-3.07 (2H, m), 3.22 (2H, d, J = 18.6Hz), 7. 19 (2H, dd, J = 2.6, 8.6Hz), 7.29-7.60 (11H, m), 7.72 (1H, s). IR (KBr) v: 3254, 2928, 2897, 1655cm-1. Analysis for C28H30N3O2P • 0. 5H20: Calculated C, 69. 98; H, 6 fifty; N, 8 74 Found C, 70.27; H, 6.32; N, 8.53.

Working Example 91 (Production of Compound 91) To a solution of 2- (4-methylphenyl) -6,7-dihydro-5H-benzocyclohepten-8-carboxylic acid (0.25 g) in dichloromethane (5 ml) were added sodium chloride. oxalyl (0.4 ml) and dimethylformamide (catalytic amount) under cooling with ice, and the mixture was stirred at 40 ° C for 1 hour. The solvent was evaporated and the residue was dissolved in tetrahydrofuran. The mixture was added dropwise to a solution of 1- (4-aminobenzyl) piperidine (0.17 g) and diisopropylethylamine (0.5 ml) in tetrahydrofuran (10 ml), under ice-cooling.

Under a nitrogen atmosphere, the mixture was stirred at room temperature overnight. The solvent was evaporated, and water was added to the residue. The mixture was extracted with dichloromethane and the organic layer was washed with water and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated and the crude crystal, precipitated, was recrystallized from dichloromethane-hexane to give 2- (4-methylphenyl) -N- (4-piperidinomethylphenyl) -6,7-dihydro-5H-benzocyclohepten-8 -carboxamide (Compound 91) (0.36 g) as colorless crystals. p.f. 192-193 ° C. R N-1H (d ppm, CDC13): 1.38-1.50 (2H,), 1.50-1.63 (4H, m), 2.13-2.22 (2H, m), 2.35-2.39 (4H, m), 2.40 (3H, s), 2.72 (2H, t, J = 6.4Hz), 2.85-2.91 (2H, m), 3.46 (2H, s), 7.21-7.33 (5H, m), 7.41-7.57 (6H,), 7.63 ( 1H, s). IR (KBr) v: 3352, 2932, 1647cm "1. Analysis for C3? H34N20 • 0.2H20: Calculated C, 81.97; H, 7.63; N, 6.17. Found C, 81.88; H, 7.52; N, 6.22.

Working Example 92 (Production of Compound 92) A solution of 2- (4-methylphenyl) -N- (4-piperidino-methylphenyl) -6,7-dihydro-5H-benzocyclohepten-8-carboxamide (0.26 g) and iodide of methyl (0.15 ml) in dimethylformamide (15 ml) was stirred at room temperature overnight. The solvent was evaporated, and ethyl acetate was added to the residue. The crude, precipitated crystal was filtered, which was recrystallized with ethanol-ethyl acetate to give the l- (N- (2- (4-methylphenyl) -6,7-dihydro-5H-benzocyclohepten-8-carbonyl iodide. ) -4-aminobenzyl) -1-methylpiperidinium (Compound 92) (0.3 g) as colorless crystals. p.f. 220-221 ° C (dec.). NMR-aH (d ppm, DMSO-d6): 1.45-1.65 (2H, m), 1.80-1.94 (4H, m), 1.99-2.09 (2H, m), 2.35 (3H, s), 2.64 (2H, t, J = 6.1Hz), 2.83-2.88 (2H, m), 2.91 (3H, s), 3.23-3.29 (4H, m), 4.53 (2H, s), 7.26-7.38 (4H, m), 7.48-7.68 (6H, m), 7.87 (2H, d, J = 8.6Hz), 10.23 (1H, s). IR (KBr) v: 3285, 2946, lßSlcrn "1. Analysis for C32H37IN20 • 0.5H20: Calculated C, 63.89; H, 6.37; N, 4.66, Found C, 63.94; H, 6.33; N, 4.60.

Working Example 93 (Production of Compound 93) To a solution of 7- (4-methylphenyl) -N- (4-hydroxy-methylphenyl) -2,3-dihydro-1-benzothiepin-4-carboxamide (0.2 g), triethylamine (0.21 ml) and dimethylaminopyridine (catalytic amount) in tetrahydrofuran (10 ml) was added dropwise methanol-sulfonyl chloride (0.06 ml) under ice-cooling, and the mixture was stirred for 10 minutes. To the mixture was added pyridine (0.15 ml), and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated, and water was added to the residue. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated and the residue was purified with a column of silica gel (methanol / triethylamine / ethyl acetate) to give crude crystals, which were recrystallized with ethyl acetate-hexane to give 7- ( 4-methylphenyl) -N- (4-piperidinomethylphenyl) -2,3-dihydro-l-benzothiepin-4-carboxamide (Compound 93) (0.19 g) as colorless crystals. p.f. 203-204 ° C. NMR-1H (d ppm, CDC13): 1.35-1.50 (2H, m), 1.55-1.63 (4H, m), 2.38-2.40 (4H,), 2.40 (3H, s), 3.08 (2H, t, J = 5.7Hz), 3.29 (2H, t, J = 5.7Hz), 3.47 (2H, s), 7.24-7.46 (7H, m), 7.50-7.58 (5H, m), 7.68 (1H, s). IR (KBr) V: 2934, ldSlcm "1. Analysis for C30H32N2OS • 0.2H2O: Calculated C, 76.30; H, 6.92; N, 5.93, Found C, 76.27; H, 6.77; N, 6.06.

Working Example 94 (Production of Compound 94) A solution of 7- (4-methylphenyl) -N- (4-piperidino-methyl-phenyl) -2,3-dihydro-1-benzothiepin-4-carboxamide (0.08 g ) and methyl iodide (0.13 ml) in dimethylformamide (20 ml) was stirred at room temperature overnight. The solvent was evaporated, and ethyl acetate was added to the residue. The crude, precipitated crystal was filtered, which was recrystallized with ethanol-hexane to give the l- (N- (7- (4-methylphenyl) -2,3-dihydro-l-benzo-tiepin-4-carbonyl iodide. ) -4-aminobenzyl) -1-methyl-piperidinium (Compound 94) (0.077 g) as colorless crystals. p.f. 196-197 ° C. NMR-aH (d ppm, DMSO-d6): 1.45-1.65 (2H,), 1.80-1.95 (4H, m), 2.35 (3H, s), 2.91 (3H, s), 2.99-3.05 (2H, m ), 3. 15-3.29 (6H, m), 4.53 (2H, s), 7.29 (2H, d, J = 8.2Hz), 7. 46-7.63 (7H, m), 7.82-7.89 (3H,), 10.34 (1H, s). I (KBr) V: 3284, 2947, 1652cm_1. Analysis for C3? H35IN20S • 0.5H2O: Calculated C, 60.09; H, 5.86; N, 4.52. Found C, 60.03; H, 5.57; N, 4.44.

Working Example 95 (Production of Compound 95) To a suspension of 7- (4-methylphenyl-2,3-dihydro-l-benzoxepin-4-carboxylic acid (1.0 g) in dichloromethane (30 ml) were added oxalyl chloride (0.93 ml) and dimethylformamide (catalytic amount), under cooling with ice, and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated, and the residue was dissolved in tetrahydrofuran.

The mixture was added dropwise to a solution of 1- (4-amino-benzyl) piperidine (0.75 g) and triethylamine (1.5 ml) in tetrahydrofuran (50 ml), under cooling with ice. Under a nitrogen atmosphere, the mixture was stirred at room temperature overnight. The solvent was evaporated, and water was added to the residue. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give crude crystals which were recrystallized with ethyl acetate-hexane to give 7- (4-methyl-phenyl) -N- (4- ((piperidinomethyl) phenyl) -2, 3 -dihydro-l-benzoxepin-4-carboxamide (Compound 95) (1.45 g) as colorless crystals, mp 188-189 ° C. RMN-1 H (d ppm, CDCl 3): 1.40-1.47 (2H, m), 1.52- 1.60 (4H,), 2.34-2.39 (4H, m), 2.39 (3H, s), 3.07 (2H, t, J = 4.4Hz), 3.46 (2H, s), 4.36 (2H, t, J = 4.4 Hz), 7.06 (1H, d, J = 8.4Hz), 7.22-7.33 (5H, m), 7.43-7.58 (6H, m).

IR (KBr) V: 2935, 1652cm "1. Analysis for C30H32N2O2: Calculated 0.79.61; H, 7. 13; N, 6. 19, Found C, 79.53; H, 6.91; N, 6.22.

Working Example 96 (Production of Compound 96) A solution of 7- (4-methylphenyl) -N- (4-piperidino-methyl) phenyl) -2,3-dihydro-l-benzoxepin-4-carboxamide (1.4 g) and methyl iodide (0.58 ml) in dimethylformamide (50 ml) was stirred at room temperature overnight. The solvent was evaporated, and ethyl acetate was added to the residue. The crude, precipitated crystal was filtered, which was recrystallized with ethanol-ethyl acetate to give the l- (N- (7- (4-methylphenyl) -2,3-dihydro-l-benzoxepin-4-carbonyl iodide. ) -4-aminobenzyl) -1-methylpiperidinium (Compound 96) (1.6 g) as colorless crystals. p.f. 227-228 ° C (dec.). R N-1H (d ppm, DMS0-d6): 1.45-1.70 (2H,), 1.70-1.95 (4H, m), 2.34 (3H, s), 2.91 (3H, s), 3.00 (2H, broad) , 3.24-3.34 (4H, m), 4.31 (2H, broad), 4.53 (2H, s), 7.06 (1H, d, J = 8.4Hz), 7.27 (2H, d, J = 8.0Hz), 7.36 ( 1H, s), 7.48-7.59 (5H, m), 7.75 (1H, s), 7.86 (2H, d, J = 8.8Hz), 10.19 (1H, s). IR (KBr) v: 3289, 2938, 1649cm ~ 1.

Analysis for C3? H35lN202: Calculated C, 62.63; H, 5.93; N, 4.71 Found C, 62.43; H, 5.91; N, 4.52 Working Example 97 (Production of Compound 97) A solution of N- (4-chloromethylphenyl) -7- (4-methyl-phenyl) -2,3-dihydro-l-benzoxepin-4-carboxamide (0.15 g) and 1 Methylpiperidine (0.14 ml) in dimethylformamide (15 ml) was stirred at room temperature overnight. The solvent was evaporated, and ethyl acetate was added to the residue. The raw crystal, precipitate was filtered, which was recrystallized with ethanol-diethyl ether to give the l- (N- (7- (4-ethylphenyl) -2,3-dihydro-l-benzoxepin-4-carbonyl) -4- chloride. aminobenzyl) -1-methylpiperidinium (Compound 97) (0.15 g) as colorless crystals, m.p. 231-232 ° C. NMR-aH (d ppm, DMSO-d6): 1.45-1.65 (2H, m), 1.80-1.95 (4H, m), 2.34 (3H, s), 2.91 (3H, s), 2.97-3.05 (2H, m), 3.23-3.30 (4H, m), 4.25-4.35 (2H,), 4.53 (2H, s), 7.06 (1H, d, J = 8.4Hz), 7.27 (2H, d, J = 8.4Hz) , 7.38 (1H, s), 7.48-7.59 (5H, m), 7.75 (1H, s), 7.86 (2H, d, J = 8.8Hz), 10.23 (1H, s). IR (KBr) v: 3227, 2969, 1665C? QT1. Analysis for C3? H35ClN202 • 0.5H20: Calculated C, 72.71; H, 7.09; N, 5.47 Found C, 72.85; H, 6.93; N, 5.48 Working Example 98 (Production of Compound 98) A solution of N- (4-chloromethylphenyl) -7- (4-methyl-phenyl) -2,3-dihydro-l-benzoxepin-4-carboxamide (0.18 g) and 1 Ethylpiperidine (0.31 ml) in dimethylformamide (5 ml) was stirred at 50 ° C overnight. The solvent was evaporated, and ethyl acetate was added to the residue. The crude, precipitated crystal was filtered, which was recrystallized-with ethanol-ethyl acetate to give the chloride of 1- (N- (7- (4-methylphenyl) -2,3-dihydro-l-benzoxepin-4- carbonyl) -4-amino-benzyl) -1-ethylpiperidinium (Compound 98) (0.17 g) as colorless crystals. p.f. 209-210 ° C. NMR ^ H (d ppm, DMSO-d6): 1.34 (3H, t, J = 6.9Hz), 1.38-1.66 (2H, m), 1.80-1.99 (4H, m), 2.34 (3H, s), 3.00 (2H, t, J = 4.2Hz), 3.13-3.31 (6H, m), 4.30 (2H, t, J = 4.2Hz), 4.50 (2H, s), 7.06 (1H, d, J = 8.4Hz) , 7.27 (2H, d, J = 8.0Hz), 7.39 (1H, s), 7.46-7.59 (5H, m), 7.76 (1H, d, J = 2.2Hz), 7.87 (2H, d, J = 8.8 Hz), 10.24 (1H, s). IR (KBr) v: 3202, 2946, 1645cm_1. Analysis for C32H37C1N202 • 0.3H20: Calculated C, 73.56; H, 7.25; N, 5.36.

Found C, 73.59; H, 7.26; N, 5.32 Working Example 99 (Production of Compound 99) To a suspension of 7- (4-methylphenyl) -2,3-dihydro-l-benzoxepin-4-carboxylic acid (0.15 g) in dichloromethane (5 ml) were added sodium chloride. oxalyl (0.41 ml) and dimethylformamide (catalytic amount), under ice-cooling, and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated, and the residue was dissolved in tetrahydrofuran.

The mixture was added dropwise to a solution of 1- (2- (4-aminophenyl) ethyl) piperidine (0.11 g) and triethylamine (0.23 ml) in tetrahydrofuran (10 ml), under cooling with ice. Under a nitrogen atmosphere, the mixture was stirred at room temperature overnight. The solvent was evaporated, and water was added to the residue. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give crude crystals which were recrystallized with ethyl acetate-hexane to give N- (4- (2-piperidinoethyl) phenyl) -7- (4-methylphenyl) -2, 3- dihydro-l-benzoxepin-4-carboxamide (Compound 99) (0.19 g) as colorless crystals. p.f. 201-202 ° C.

RMN-1H. (d ppm, CDC13): 1.45-1.48 (2H, m), 1.50-1.65 (4H,), 2.39 (3H, s), 2.47-2.58 (6H, m), 2.76-2.84 (2H, m), 3.07 (2H, t, J = 4.4Hz), 4.36 (2H, t, J = 4.4Hz), 7.05 (1H, d, J = 8.0Hz), 7.17-7.26 (4H, m), 7.43-7.51 (7H, m).

IR (KBr) V: 2933, 1652cm_1. Analysis for C3? H3 N202: Calculated C, 79.79; H, 7.34; N, 6.00. Found C, 79.63; H, 7.42; N, 6.07.

Working Example 100 (Production of Compound 100) A solution of N- (4- (2-piperidinoethyl) phenyl) -7- (4-methylphenyl) -2,3-dihydro-l-benzoxepin-4-carboxamide (0.09 g ) and methyl iodide (0.06 ml) in dimethylformamide (10 ml) was stirred at room temperature overnight. The solvent was evaporated, and ethyl acetate was added to the residue. The crude, precipitated crystal was filtered, which was recrystallized with ethanol-hexane to give the N - ((7- (4-phenylphenyl) -2,3-dihydro-l-benzoxepin-4-carbonyl) iodide. (4-aminophenyl) ethyl) -N-methylpiperidinium (Compound 100) (0.12 g) as pale yellow crystals, mp. 168-169 ° C. N ^ H (d ppm, CDC13): 1.65-1.95 (6H,), 2.35 (3H, s), 2.95-3.05 (4H, m), 3.25 (3H, s), 3.61-3.85 (6H,), 4.29 (2H, t, J = 4.2Hz), 7.01 (1H, d, J = 8.4Hz), 7.17-7.26 (4H, m), 7.40-7.50 (4H, m), 7.58 (2H, d, J = 4Hz ), 7.70 (1H, d, J = 2.2Hz), 8.49 (1H, broad). IR (KBr) V: 2949, 1656cm_1. Analysis for C32H37IN202- 0.5H2O: Calculated C, 62.24; H, 6.20; N, 4.54. Found C, 61.92; H, 6.17; N, 4.57.

Working Example 101 (Production of Compound 101) To a suspension of 7- (4-methylphenyl) -2-phenyl-2, 3-dihydro-1-benzoxepin-4-carboxylic acid (0.1 g) in dichloromethane (10 ml) oxalyl chloride (0.1 ml) and dimethylformamide (catalytic amount) were added under cooling with ice, and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated, and the residue was dissolved in tetrahydrofuran.

The mixture was added dropwise to a solution of 4- (N-methyl-N- (tetrahydropyran-4-yl) amino-methyl) aniline. (0.06 g) and triethylamine (0.12 ml) in tetrahydrofuran (5 ml), under ice-cooling. Under a nitrogen atmosphere, the mixture was stirred at room temperature overnight. The solvent was evaporated, and water was added to the residue. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated and the residue was purified with a column of silica gel (ethyl acetate) to give crude crystals which were recrystallized from ethyl acetate-hexane to give 7- (4-methylphenyl) - 2-phenyl-N- (4- ((N-tetrahydropyran-4-yl-N-methylamino) methyl) phenyl) -2, 3-dihydro-l-benzoxepin-4-carboxamide (Compound 101) (0.11 g) as colorless crystals. p.f. 178-179 ° C. NMR - ^ - H (d ppm, CDCl 3): 1.63-1.74 (4H, m), 2.20 (3H, s), 2. 40 (3H, s), 2.56-2.66 (1H, m), 3.15-3.43 (4H, m), 3.56 (2H, s), 4.01-4.05 (2H, m), 5.09 (1H, dd, J = 2.2, 8.4Hz), 7. 10 (1H, d, J = 8.4Hz), 7.17-7.57 (16H, m). IR (KBr) V: 2949, 2844, 1652cm "1. Analysis for C37H38N203: Calculated C, 79.54; H, 6.86; N, 5.01, Found C, 79.28; H, 6.96; N, 4.97.

Working Example 102 (Production of Compound 102) To a suspension of 7- (4-methylphenyl) -2-phenyl-2,3-dihydro-l-benzoxepin-4-carboxylic acid (0.1 g) in dichloromethane (10 ml) oxalyl chloride (0.1 ml) and dimethylformamide (catalytic amount) were added, under cooling with ice, and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated, and the residue was dissolved in tetrahydrofuran.

The mixture was added dropwise to a solution of 1- (4-amino-benzyl) piperidine (0.06 g) and triethylamine (0.12 ml) in tetrahydrofuran (5 ml), under cooling with ice. Under a nitrogen atmosphere, the mixture was stirred at room temperature overnight. The solvent was evaporated, and water was added to the residue. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated and the residue was purified with a column of silica gel (ethyl acetate) to give crude crystals which were recrystallized from ethyl acetate-hexane to give 7- (4-methylphenyl) - 2-phenyl-N- (4- (piperidinomethyl) phenyl) -2,3-dihydro-l-benzoxepin-4-carboxamide (Compound 102) (0.12 g) as colorless crystals, mp. 210-211 ° C. NMR-1H (d ppm, CDC13): 1.40-1.47 (2H, m), 1.52-1.62 (4H, m), 2.34-2.40 (4H, m), 2.40 (3H, s), 3.23-3.31 (2H, m), 3.45 (2H, s), 5.09 (1H, dd, J = 2.0, 8.8Hz), 7.10 (1H, d, J = 8.4Hz), 7.23-7.56 (16H, m). IR (KBr) v: 2935, 1652cm "1. Analysis for C36H36N202: Calculated C, 81.79; H, 6.86; N, 5.30, Found C, 81.45; H, 6.82; N, 5.28.

Working Example 103 (Production of Compound 103) A solution of 7- (4-methylphenyl) -2-phenyl-N- (4- (piperidinomethyl) phenyl) -2,3-dihydro-l-benzoxepin-4-carboxamide (0.08 g) and methyl iodide (0.05 ml) in dimethylformamide (15 ml) was stirred at room temperature overnight. The solvent was evaporated, and ethyl acetate was added to the residue. The crude, precipitated crystal was filtered, which was recrystallized with ethanol-ethyl acetate to give the l- (N- (7- (4-methylphenyl) -2-phenyl-2,3-dihydro-l-benzoxepin iodide. -4-carbonyl) -4-aminobenzyl) -1-methyl-piperidinium (Compound 103) (0.057 g) as colorless crystals. p.f. 232-233 ° C (dec.). NMR-1H (d ppm, DMSO-d6): 1.45-1.70 (2H, m), 1.75-1.95 (4H, m), 2.35 (3H, s), 2.91 (3H, s), 3.25-3.44 (6H, m), 4. 53 (2H, s), 5.12 (1H, t, J = 5.0Hz), 7.09 (1H, d, J = 8.4Hz), 7.28 (2H, d, J = 8.2Hz), 7.37-7.61 (11H, m), 7. 81-7.87 (3H, m), 10.20 (1H, s). IR (KBr) v: 2949, 1650cm-1. Analysis for C37H39IN202 • 0.2H20: Calculated C, 65.91; H, 5.89; N, 4.15. Found C, 65.80; H, 5.84; N, 4.17.

Working Example 104 (Production of Compound 104) To a suspension of 7- (4-methylphenyl) -2-methyl-2,3-dihydro-1-benzoxepin-4-carboxylic acid (0.1 g) in dichloromethane (5) ml) oxalyl chloride (0.1 ml) and dimethylformamide (catalytic amount) were added under cooling with ice, and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated, and the residue was dissolved in tetrahydrofuran. The mixture was added dropwise to a solution of 4- (N-methyl-N- (tetrahydropyran-4-yl) amino-methyl) aniline. (0.08 g) and triethylamine (0.14 ml) in tetrahydrofuran (5 ml), under ice-cooling. Under a nitrogen atmosphere, the mixture was stirred at room temperature overnight. The solvent was evaporated, and water was added to the residue. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give crude crystals, which were recrystallized with ethyl acetate-hexane to give 7- (4-methylphenyl) -2-phenyl-N- (4- ((N-tetrahydropyran-4 -yl-N-methylamino) methyl) phenyl) -2,3-dihydro-l-benzoxepin-4-carboxamide (Compound 104) (0.12 g) as colorless crystals. p.f. 170-171 ° C. 1 H NMR (d ppm, CDCl 3): 1.54 (3H, d, J = 6.4Hz), 1.60-1.78 (4H, m), 2.22 (3H, s), 2.39 (3H, s), 2.63-2.68 (1H , m), 2.85 (1H, ddd, J = 2.6, 9.2, 17.6Hz), 3.14 (1H, d, J = 17.6Hz), 3.37 (2H, dt, J = 2.8, 11.3Hz), 3.58 (2H, s), 4.01-4.07 (2H, m), 4.24-4.30 (1H, m), 7.05 (1H, d, J = 8.4Hz), 7.22-7.34 (4H, m), 7.43-7.56 (7H, m) . IR (KBr) v: 2951, 2845, 1651cm "x Analysis for C32H36N203: Calculated C, 77.39; H, 7.31; N, 5.64, Found C, 77.21; H, 7.43; N, 5.51.

Working Example 105 (Production of Compound 105) To a suspension of 7- (4-methylphenyl) -2-methyl-2,3-dihydro-l-benzoxepin-4-carboxylic acid (0.1 g) in dichloromethane (5) ml) oxalyl chloride (0.1 ml) and dimethylformamide (catalytic amount) were added under cooling with ice, and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated, and the residue was dissolved in tetrahydrofuran. The mixture was added dropwise to a solution of 1- (4-aminobenzyl) piperidine (0.07 g) and triethylamine (0.14 ml) in tetrahydrofuran (5 ml), under cooling with ice. Under a nitrogen atmosphere, the mixture was stirred at room temperature overnight. The solvent was evaporated, and water was added to the residue. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give crude crystals, which were recrystallized with ethyl acetate-hexane to give 7- (4-methylphenyl) -2-methyl-N- (4- (piperidinomethyl) -phenyl) - 2,3-dihydro-l-benzoxepin-4-carboxamide (Compound 105) (0.12 g) as colorless crystals. p.f. 175-176 ° C. NMR - ^ - H (d ppm, CDC13): 1.40-1.45 (2H, m), 1.54 (3H, d, J = 6.2Hz), 1.53-1.61 (4H, m), 2.30-2.40 (4H, m) , 2.39 (3H, s), 2.85 (1H, ddd, J = 2.6, 8.8, 18.0Hz), 3.14 (1H, d, J = 18.0Hz), 3.47 (2H, s), 4.23-4.30 (1H, m ), 7.05 (1H, d, J = 8.8Hz), 7.16-7.36 (4H, m), 7.43-7.55 (7H, m). IR (KBr) v: 2936, ldSlcm "1. Analysis for C31H34N202: Calculated C, 79.79; H, 7.34; N, 6.00, Found C, 79.53; H, 7.35; N, 5.82.

Working Example 106 (Production of Compound 106) To a solution of N- (4- (cyclohexylthiomethyl) phenyl) -7- (4-methylphenyl) -2,3-dihydro-l-benzoxepin-4-carboxamide (0.19 g) in dichloromethane (5 ml) 70% m-chloroperbenzoic acid (0.097 g) was added under cooling with ice, and the mixture was stirred for 10 minutes. To the mixture was added a solution of sodium thiosulfate, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with a column of silica gel (methanol / dichloromethane) to give crude crystals, which were recrystallized with ethanol to give N- (4- (cyclohexylsulfinylmethyl) phenyl) -7- (4-methylphenyl) -2, 3-dihydro-l-benzoxepin-4-carboxamide (Compound 106) (0.048 g) as colorless crystals, m.p. 257-258 ° C (dec.). NMR ^ H (d ppm, CDC13): 1.19-1.69 (6H, m), 1.81-1.85 (3H, m), 2.01-2.08 (1H, m), 2.40 (3H, s), 2.40-2.49 (1H, m 3.08, 2H, t, J = 4.6Hz, 3.90 (2H, dd, J = 13.2, 24. 2Hz), 4.35 (2H, t, J = 4.6Hz), 7.06 (1H, d, J = 8.6Hz), 7. 23-7.28 (4H, m), 7.44-7.54 (4H, m), 7.60 (2H, d, J = 8.4Hz), 8.07 (1H, s). IR (KBr) v: 2930, 2853, 1659cm_1. Analysis for C31H33N03S • 0.3H20: Calculated C, 73.72; H, 6.71; N, 2.77. Found C, 73.66; H, 6.70; N, 2.80.

Working Example 107 (Production of Compound 107) To a solution of N- (4- (cyclohexylsulfinylmethyl) phenyl) -7- (4-methylphenyl) -2,3-dihydro-l-benzoxepin-4-carboxamide (0.13 g) in chloroform (45 ml) 70% m-chloroperbenzoic acid (mCPBA) (0.097 g) was added under cooling with ice, and the mixture was stirred at room temperature for 30 minutes. A solution of sodium thiosulfate was added to the mixture, and the mixture was washed with a solution of sodium hydrogen carbonate and water, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give crude crystals, which were recrystallized with ethanol-hexane to give N- (4- (cyclohexylsulfonylmethyl) phenyl) -7- (4-methylphenyl) -2,3-dihydrole -benzoxepin-4-carboxamide (Compound 107) (0.11 g) as colorless crystals, m.p. 250-251 ° C. NMR-aH (d ppm, CDC13): 1.18-1.26 (4H, m), 1.52-1.71 (2H, m), 1.87-1.94 (2H, m), 2.09-2.17 (2H, m), 2.40 (3H, s), 2.65-283 (1H, m), 3.08 (2H, t, J = 4.6Hz), 4.18 (2H, s), 4.37 (2H, t, J = 4.6Hz), 7.07 (1H, d, J = 8.4Hz), 7.23-7.27 (2H, m), 7.38-7.53 (6H, m), 7.65 (2H, d, J = 8.6Hz), 7.70 (1H, s). IR (KBr) v: 2932, 2857, 1667cm_1. Analysis for C31H33N04S • 0.2H20: Calculated C, 71.70; H, 6.48; N, 2.70 Found C, 71.70; H, 6.54; N, 2.79 Working Example 108 (Production of Compound 108) To a solution of 7- (4-methylphenyl) -N- (4- (phenyl-thiomethyl) phenyl) -2,3-dihydro-l-benzoxepin-4-carboxamide (0.1 g) in dichloromethane (30 ml) was added 70% m-chloroperbenzoic acid (0.046 g) at the temperature ranging from -20 to -10 ° C, and the mixture was stirred for 30 minutes. To the mixture was added a solution of sodium thiosulfate, and the mixture was concentrated and extracted with ethyl acetate. The organic layer was washed with sodium hydrogen carbon solution, water and saturated sodium chloride solution and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give crude crystals, which were recrystallized with ethyl acetate-hexane to give 7- (4-methylphenyl) -N- (4- (phenylsulfinylmethyl) phenyl) -2, 3-dihydro -l-benzoxepin-4-carboxamide (Compound 108) (0.11 g) as colorless crystals, mp. 127-128 ° C. NMR-1H (d ppm, CDC13): 2.39 (3H, s), 3.06 (2H, t, J = 4.6Hz), 4.01 (2H, s), 4.34 (2H, t, J = 4.6Hz), 6.95 ( 2H, d, J = 8.8Hz), 7.05 (1H, d, J = 8.0Hz), 7.22-7.26 (3H, m), 7.37-7.53 (10H, m), 7.85 (1H, s).

IR (KBr) v: 3026, 2925, 1652cm. Analysis for C3? H27N03S: Calculated C, 75.43; H, 5.51; N, 2.84 Found C, 75.14; H, 5.55; N, 2.99 Working Example 109 (Production of Compound 109) To a solution of N- (4- (benzylthiomethyl) phenyl) -7- (4-methylphenyl) -2,3-dihydro-l-benzoxepin-4-carboxamide (0.12 g) in dichloromethane (25 ml) was added m-chloroperbenzoic acid 70% (0.06 g) at the temperature ranging from -20 to -10 ° C, and the mixture was stirred for 10 minutes. To the mixture was added a solution of sodium thiosulfate, and the mixture was concentrated and extracted with ethyl acetate. The organic layer was washed with a sodium hydrogen carbonate solution, water and saturated sodium chloride solution and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give crude crystals, which were recrystallized with ethyl acetate-hexane to give N- (4- (benzylsulfinylmethyl) phenyl) -7- (4-methylphenyl) -2,3-dihydro -l-benzoxepin-4-carboxamide (Compound 109) (0.08 g) as colorless crystals. p.f. 208-209 ° C. NMR- ^ H (d ppm, CDC13): 2.39 (3H, s), 3.07 (2H, t, J = 4.5Hz), 3.76-3.94 (4H,), 4.35 (2H, t, J = 4.5Hz), 7.06 (1H, d, J = 8.2Hz), 7.23-7.27 (6H, m), 7.35-7.53 (7H, m), 7. 61 (2H, d, J = 8.4Hz), 7.93 (1H, s). IR (KBr) v: 3030, 1662cm "1. Analysis for C32H29N03S • 0.2H20: Calculated C, 75.18; H, 5.80; N, 2.74, Found C, 75.35; H, 5.81; N, 2.87.

Working Example 110 (Production of Compound 110) To a solution of 7- (4-methylphenyl) -2,3-dihydro-1-benzoxepin-4-carboxylic acid (0.1 g) in dichloromethane (5 ml) were added sodium chloride. oxalyl (0.1 ml) and dimethylformamide (catalytic amount) under cooling with ice, and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated, and the residue was dissolved in tetrahydrofuran.

The mixture was added dropwise to a solution of 4-aminobenzyl 4-methylphenyl sulfone (0.11 g) and triethylamine. (0.15 ml) in tetrahydrofuran (10 ml), under cooling with ice. Under a nitrogen atmosphere, the mixture was stirred at room temperature overnight. The solvent was evaporated, and water was added to the residue. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give crude crystals, which were recrystallized with ethyl acetate-hexane to give the N- (4 - ((4-methylphenyl) sulfonyl) -methylphenyl) -7- (4-methylphenyl) -2, 3-dihydro-l-benzoxepin-4-carboxamide (Compound 110) (0.13 g) as colorless crystals, m.p. 230-231 ° C. NMR-1H (d ppm, CDC13): 2.40 (3H, s), 2.43 (3H, s), 3.07 (2H, t, J = 4.5Hz), 4.27 (2H, s), 4.36 (2H, t, J = 4.5Hz), 7.04-7.10 (3H, m), 7.23-7.26 (5H, m), 7.43-7.55 (8H, m), 7.63 (1H, s). IR (KBr) v: 3027, 2884, 1663cm_1. Analysis for C32H29N04S • 0.2H20: Calculated C, 72.90; H, 5.62; ", 2.66, Found C, 72.74; H, 5.73; N, 2.76.

Working Example 111 (Production of Compound 111) A solution of N- (4-chloromethylphenyl) -7- (4-methylphenyl) -2,3-dihydro-1-benzoxepin-4-carboxamide (0.1 g) and N- Methylcyclopentylamine (0.07 g) in dimethylformamide (10 ml) was stirred at room temperature overnight. The solvent was evaporated, and water was added to the residue. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give crude crystals, which were recrystallized with ethanol-hexane to give the N- (4 - ((N-cyclopentyl-N-methyl) amino-methyl) phenyl) -7- (4 -methylphenyl) -2, 3-dihydro-l-benzoxepin-4-carboxamide (Compound 111) (0.1 g) as colorless crystals, m.p. 171-172 ° C. RM -1H (d ppm, CDC13): 1.45-1.75 (6H, m), 1.80-1.95 (2H, m), 2.13 (3H, s), 2.39 (3H, s), 2.70-2.80 (1H, m), 3. 08 (2H, t, J = 4.6Hz), 3.50 (2H, s), 4.35 (2H, t, J = 4.6Hz), 7.06 (1H, d, J = 8.0Hz), 7.22-7.33 (4H, m), 7. 43-7.58 (7H, m). IR (KBr) v: 3340, 2958, 1646cm "1. Analysis for C3? H34N202 • 0 .2H20: Calculated C, 79.18; H, 7.37; N, 5. 96. Found C, 79.15; H, 7.18; N, 5.96.

Working Example 112 (Production of Compound 112) To a solution of N- (4-hydroxymethylphenyl) -7- (4-methylphenyl) -2,3-dihydro-l-benzoxepin-4-carboxamide (0.15 g), triethylamine ( 0.14 ml) and 4-dimethylaminopyridine (catalytic amount) in dichloromethane was added dropwise methanesulfonyl chloride (0.04 ml) under ice-cooling, and the mixture was stirred for 15 minutes. To the mixture was added N-methylcyclohexylamine (0.15 ml), and the mixture was stirred at room temperature overnight. The solvent was evaporated, and the residue was purified with a column% silica gel (ethyl acetate / methanol / triethylamine) to give crude crystals, which were recrystallized with ethyl acetate-hexane to give the N- (4- ((N-cyclohexyl-N-methyl) -aminoethyl) phenyl) -7- (4-methylphenyl) -2,3-dihydro-l-benzoxepin-4-carboxamide (Compound 112) (0.03 g) as colorless crystals. p.f. 176-177 ° C. NMR-aH (d ppm, CDC13): 1.15-1.35 (6H, m), 1.70-1.95 (4H, m), 2.23 (3H, s), 2.39 (3H, s), 2.39-2.55 (1H, m) , 3.08 (2H, t, J = 4.6Hz), 3.59 (2H, s), 4.37 (2H, t, J = 4.6Hz), 7.06 (1H, d, J = 8.0Hz), 7.23-7.35 (5H, m), 7.44-7.58 (7H, m). IR (KBr) v: 2930, 2853, ldSlcm "1. Analysis for C32H36N202 • 0.4H20: Calculated C, 78.78; H, 7.60; N, 5.74, Found C, 78.97; H, 7.49; N, 5.94.

Working Example 113 (Production of Compound 113) A solution of N- (4-chloromethylphenyl) -7- (4-methyl-phenyl) -2,3-dihydro-l-benzoxepin-4-carboxamide (0.09 g), N-methylcycloheptylamine (0.04 g) and potassium carbonate (0.1 g) in dimethylformamide (10 ml) was stirred at room temperature overnight. The solvent was evaporated, and water was added to the residue. The mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give crude crystals, which were recrystallized with ethyl acetate-hexane to give the N- (4- ((N-cycloheptyl-N-methyl) aminomethyl) phenyl) -7- (4 -methylphenyl) -2, 3-dihydro-l-benzoxepin-4-carboxamide (Compound 113) (0.08 g) as colorless crystals, m.p. 167-168 ° C. NMR ^ H (d ppm, CDC13): 1.35-1.55 (8H, m), 1.55-1.80 (2H,), 1.80-1.95 (2H,), 2.16 (3H, s), 2.39 (3H, s), 2.55 -2.70 (1H, m), 3.08 (2H, t, J = 4.6Hz), 3.49 (2H, s), 4.35 (2H, t, J = 4.6Hz), 7.05 (1H, d, J = 8.4Hz) , 7.22-7.33 (4H, m), 7.43-7.58 (7H, m). IR (KBr) v: 2927, ldSOcm "1. Analysis for C33H38N202 • 0.1H20: Calculated C, 79.83; H, 7.76; N, 5.64, Found C, 79.62; H, 7.43; N, 5.53.

Working Example 114 (Production of Compound 114) A solution of N- (4-chloromethylphenyl) -7- (4-methyl-phenyl) -2,3-dihydro-l-benzoxepin-4-carboxamide (0.15 g) and Cyclohexylamine (0.17 ml) in dimethylformamide (10 ml) was stirred at room temperature for 2.5 hours. The solvent was evaporated and the residue was purified with a column of silica gel (ethyl acetate / methanol / triethylamine) to give crude crystals, which were recrystallized with ethanol-hexane to give the N- (4- ((cyclohexylamino) methyl) phenyl) -7- (4-methylphenyl) -2,3-dihydro-l-benzoxepin-4-carboxamide (Compound 114) (0.09 g) as colorless crystals. p.f. 183-184 ° C. NMR-aH (d ppm, CDC13): 1.17-1.30 (6H, m), 1.58-1.82 (4H, m), 2.39 (3H, s), 2.45-2.60 (1H, m), 3.08 (2H, t, J = 4.6Hz), 3.81 (2H, s), 4.35 (2H, t, J = 4.6Hz), 7.05 (1H, d, J = 8.4Hz), 7.22-7.34 (5H, m), 7.43-7.55 ( 6H, m), 7.72 (1H, s). IR (KBr) V: 2928, 2853, 1647cm-l. Analysis for C31H34N202 • 0.5H20: Calculated C, 78.28; H, 7.42; N, 5.89. Found C, 78.56; H, 7.12; N, 6.01.

Working Example 115 (Production of Compound 115) A solution of N- (4-chloromethylphenyl) -7- (4-methyl-phenyl) -2,3-dihydro-l-benzoxepin-4-carboxamide (0.15 g) and Aniline (0.1 ml) in dimethylformamide (10 ml) was stirred at room temperature overnight. The solvent was evaporated, and water was added to the residue. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated with sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with a column of silica gel (ethyl acetate / hexane) to give crude crystals, which were recrystallized with ethanol-hexane to give the N- (4- ( (phenylamino) methyl) -phenyl) -7- (4-methyl-phenyl) -2,3-dihydro-l-benzoxepin-4-carboxamide (Compound 115) (0.1 g) as colorless crystals, m.p. 157-158 ° C. NMR-1H (d ppm, CDC13): 2.39 (3H, s), 3.07 (2H, t, J = 4.8Hz), 4.31 (2H, s), 4.35 (2H, t, J = 4.8Hz), 6.62- 6.76 (3H, m), 7.06 (1H, d, J = 8.4Hz), 7.18-7.22 (5H, m), 7.36 (2H, d, J = 8.4Hz), 7.43-7.60 (6H, m). IR (KBr) v: 1652, 1602cm "1. Analysis for C31H28N202: Calculated C, 80.84; H, 6.13; N, 6.08, Found C, 80.57; H, 6.09; N, 6.06.

Working Example 116 (Production of Compound 116) A suspension of N- (4-chloromethylphenyl) -7- (4-methylphenyl) -2,3-dihydro-l-benzoxepin-4-carboxamide (0.15 g), N- Methylaniline (0.06 ml) and potassium carbonate (0.15 g) in dimethylformamide (10 ml) was stirred at room temperature overnight. The solvent was evaporated, and water was added to the residue. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give crude crystals, which were recrystallized with ethyl acetate-hexane to give the N- (4- ((N-methyl-N-phenyl) aminomethyl) phenyl) -7- (4-methyl- phenyl) -2,3-dihydro-l-benzoxepin-4-carboxamide (Compound 116) (0.15 g) as colorless crystals, m.p. 164-165 ° C. RM ^ H (d ppm, CDC13): 2.39 (3H, s), 3.00 (3H, s), 3.06 (2H, t, J = 4.6Hz), 4.34 (2H, t, J = 4.6Hz), 4.51 ( 2H, s), 6.68-6.77 (3H, m), 7.05 (1H, d, J = 8.4Hz), 7.19-7.26 (6H, m), 7.43-7.54 (6H, m), 7.60 (1H, s) . IR (KBr) v: 3344, 3020, 1644cm "1. Analysis for C32H30N202: Calculated C, 80.98; H, 6.37; N, 5.90. Found C, 80.64; H, 6.32; N, 5.85.

Working Example 117 (Production of Compound 117) A suspension of N- (4-chloromethylphenyl) -7- (4-methylphenyl) -2,3-dihydro-l-benzoxepin-4-carboxamide (0.1 g), hydrochloride Benzylamine (0.5 g) and potassium carbonate (0.6 g) in dimethylformamide (10 ml) was stirred at room temperature overnight. The solvent was evaporated, and water was added to the residue. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with a column of silica gel (ethyl acetate / methanol / triethylamine) to give crude crystals, which were recrystallized with ethyl acetate-hexane to give the N- (4- ((benzylamino) methyl) phenyl) -7- (4-methylphenyl) -2,3-dihydro-l-benzoxepin-4-carboxamide (Compound 117) (0.08 g) as colorless crystals. p.f. 147-148 ° C. NMR-aH (d ppm, CDC13): 2.39 (3H, s), 3.08 (2H, t, J = 4.6Hz), 3.80 (2H, s), 3.81 (2H, s), 4.35 (2H, t, J = 4.6Hz), 7.06 (1H, d, J = 8.4Hz), 7.22-7.36 (9H, m), 7.43-7.61 (7H, m). IR (KBr) v: 3028, 1652cm ~ 1. Analysis for C32H30N202 • 0.1H20: Calculated C, 80.68; H, 6.39; N, 5.88. Found C, 80.43; H, 6.23; N, 5.95.

Working Example 118 (Production of Compound 118) A suspension of N- (4-chloromethylphenyl) -7- (4-methylphenyl) -2,3-dihydro-l-benzoxepin-4-carboxamide (0.1 g), N- Methylbenzylamine (0.05 ml) and potassium carbonate (0.1 g) in dimethylformamide (5 ml) was stirred at room temperature for 2 hours. The solvent was evaporated, and water was added to the residue. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give crude crystals, which were recrystallized with ethyl acetate-hexane to give the N- (4- ((N-benzyl-N-methyl) aminomethyl) phenyl) -7- (4 -methylphenyl) -2,3-dihydro-l-benzoxepin-4-carboxamide (Compound 118) (0.09 g) as colorless crystals, m.p. 157-158 ° C. NMR- ^? (d ppm, CDC13): 2.18 (3H, s), 2.39 (3H, s), 3.06 (2H, t, J = 4.6Hz), 3.50 (2H, s), 3.52 (2H, s), 4.34 (2H , t, J = 4.6Hz), 7.05 (1H, d, J = 8.0Hz), 7.22-7.30 (3H, m), 7.33-7.37 (5H, m), 7.43-7.57 (7H, m), 7.63 ( 1H, s). IR (KBr) v: 3336, 1643cm "1. Analysis for C33H32N202 • 0.2H20: Calculated C, 80.52; H, 6.63; N, 5.69, Found C, 80.61; H, 6.49; N, 5.54.

Working Example 119 (Production of Compound 119) A solution of N- (4-chloromethylphenyl) -7- (4-methyl-phenyl) -2,3-dihydro-1-benzoxepin-4-carboxamide (0.1 g) and Diisopropylamine (0.1 ml) in dimethylformamide (10 ml) was stirred at room temperature overnight. The solvent was evaporated, and water was added to the residue. The mixture was extracted cop. ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give crude crystals, which were recrystallized with ethyl acetate-hexane to give N- (4- ((diisopropylamino) methyl) -phenyl) -7- (4-methyl-phenyl) -2, 3-dihydro-1-benzoxepin-4-carboxamide (Compound 119) (0.11 g) as colorless crystals, mp. 152-153 ° C. NMR-1H (d ppm, CDC13): 1.02 (12H, d, J = 6.6Hz), 2.39 (3H, s), 2.98-3.10 (4H,), 3.62 (2H, s), 4.35 (2H, t, J = 4.8Hz), 7.05 (1H, d, J = 8.6Hz), 7.24 (2H, d, J = 8.0Hz), 7. 35-7.55 (9H, m). IR (KBr) v: 2964, 1646cm "1. Analysis for C3? H36N202: Calculated C, 79.45; H, 7.74; N, 5.98, Found C, 79.18; H, 7.66; N, 5.93.

Working Example 120 (Production of Compound 120) A solution of N- (4-chloromethylphenyl) -7- (4-methyl-1-phenyl) -2,3-dihydro-1-benzoxepin-4-carboxamide (0.1 g) and N-Ethylcyclohexylamine (0.11 ml) in dimethylformamide (10 ml) was stirred at room temperature overnight. The solvent was evaporated, and water was added to the residue. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give crude crystals, which were recrystallized with ethyl acetate-hexane to give N- (4 - ((N-cyclohexyl-N-ethyl) -aminomethyl) phenyl) -7- (4 -methylphenyl) -2,3-dihydro-l-benzoxepin-4-carboxamide (Compound 120) (0.1 g) as colorless crystals, mp 166-167 ° C. NMR ^ H (d ppm, CDC13): 0.98 (3H, t, J = 7.2Hz), 1.02-1.26 (6H, m), 1.60-1.80 (4H, m), 2.39 (3H, s), 2.48-2.59 (3H, m), 3.08 (2H, t, J = 4.5Hz), 3.59 (2H, s), 4.36 (2H, t, J = 4.5Hz), 7.05 (1H, d, J = 8.4Hz), 7.24 (2H, d, J = 7.6Hz), 7.35 (2H, d, J = 8.4Hz), 7.43- 7.56 (7H, m). IR (KBr) v: 2929, 1648cm "1. Analysis for C33H38N202 • 0.2H20: Calculated C, 79.55; H, 7.77; N, 5.62, Found C, 79.65; H, 7.63; N, 5.66.

Working Example 121 (Production of Compound 121) A suspension of N- (4-chloromethylphenyl) -1- (4-methylphenyl) -2,3-dihydro-l-benzoxepin-4-carboxamide (0.1 g), 4-ethyl-amino-1-benzylpiperidine (0.11 g) and potassium carbonate (0.05 g) in dimethylformamide (10 ml) was stirred at room temperature overnight. The solvent was evaporated, and water was added to the residue. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give crude crystals, which were recrystallized with diethyl ether-hexane to give N- (4- ((N- (1-benzylpiperidin-4-yl) -N-ethyl) amino-methyl ) phenyl) -7- (4-methylphenyl) -2,3-dihydro-l-benzoxepin-4-carboxamide (Compound 121) (0.13 g) as colorless crystals, mp. 121-122 ° C. NMR-1H (d ppm, CDC13): 0.98 (3H, t, J = 7.1Hz), 1.55-1.75 (4H, m), 1.87-2.00 (2H, m), 2.39 (3H, s), 2.49-2.60 (3H, m), 2.90-2.96 (2H, m), 3.08 (2H, t, J = 4.4Hz), 3.48 (2H, s), 3.60 (2H, s), 4.36 (2H, t, J = 4.4 Hz), 7.06 (1H, d, J = 8.2Hz), 7.23-7.35 (9H, m), 7.44-7.55 (7H,). IR (KBr) v: 2939, 1652cm "1. Analysis for C39H 3N302: Calculated C, 79.97; H, 7.40; N, 7.17.

Found C, 79.95; H, 7.50; N, 7.21 Working Example 122 (Production of Compound 122) A suspension of N- (4-chloromethylphenyl) -7- (4-methylphenyl) -2,3-dihydro-l-benzoxepin-4-carboxamide (0.1 g), amino-methylcyclohexane (0.05 g) and potassium carbonate (0.1 g) in dimethylformamide (10 ml) was stirred at room temperature overnight. The solvent was evaporated, and water was added to the residue. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with a column of silica gel (ethyl acetate / methanol / triethylamine) to give crude crystals, which were recrystallized with ethyl acetate-hexane to give the N- (4- ((cyclohexylmethyl) aminomethyl) phenyl) -7- (4-methyl-phenyl) -2,3-dihydro-l-benzoxepin-4-carboxamide (Compound 122) (0.06"g) as colorless crystals, mp 154 -155 ° C. RMN- ^ H (d ppm, CDC13): 0.88-0.99 (2H, m), 1.17-1.26 (4H, m), 1.43-1.56 (1H, m), 1.65-1.78 (4H, m ), 2.39 (3H, s), 2.45 (2H, d, J = 6.6Hz), 3.07 (2H, t, J = 4.5Hz), 3.76 (2H, s), 4.35 (2H, t, J = 4.5Hz) ), 7.05 (1H, d, J = 4Hz) 7.22-7.33 (5H, m), 7.43-7.61 (6H, m). IR (KBr) v: 3357, 2918, 1648cm "1. Analysis for C32H36N202 • 0.2H20: Calculated C, 79.37; H, 7.58; N, 5.78. Found C, 79.58; H, 7.50; N, 5.80.

Working Example 123 (Production of Compound 123) A solution of N- (4-chloromethylphenyl) -7- (4-methyl-phenyl) -2,3-dihydro-l-benzoxepin-4-carboxamide (0.1 g) and L-methyl-4-methylaminopiperidine (0.1 ml) in dimethylformamide (5 ml) was stirred at room temperature overnight. The solvent was evaporated, and water was added to the residue. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give crude crystals, which were recrystallized with ethyl acetate-hexane to give the N- (4- ((N-methyl-N- (l-methyl-piperidin-4-yl)) aminomethyl ) phenyl) -7- (4-methylphenyl) -2,3-dihydro-l-benzoxepin-4-carboxamide (Compound 123) (0.03 g) as colorless crystals, mp 183-184 ° C.

NMR-1H (d ppm, CDC13): 1.67-2.05 (6H, m), 2.20 (3H, s), 2.28 (3H, s), 2.39 (3H, s), 2.38-2.45 (1H, m), 2.91 -2.96 (1H, m), 3.08 (2H, t, J = 4.6Hz), 3.56 (2H, s), 4.36 (2H, t, J = 4.5Hz), 7.06 (1H, d, J = 8.0Hz) , 7.22-7.33 (4H, m), 7.44-7.59 (7H,). IR (KBr) v: 2939, 2785, 1652cm "1. Analysis for C32H37N302: Calculated C, 77.54; H, 7.52; N, 8.48, Found C, 77.34; H, 7.57; N, 8.56.

Working Example 124 (Production of Compound 124) To a solution of 7- (4- (4-methyl-piperazin-1-yl) -phenyl) -2,3-dihydro-l-benzoxepin-4-carboxylic acid (0.12 g) , 4- (N-methyl-N- (tetrahydropyran-4-yl) amino-methyl) aniline (0.08 ml) and 1-hydroxybenzotriazole (0.05 g) in dimethylformamide (15 ml) was added hydrochloride - of l-ethyl-3 - (3-dimethylaminopropyl) carbodiimide (0.1 g), under cooling with ice. Under a nitrogen atmosphere, the mixture was cooled to room temperature. To the mixture were added 4-dimethylaminopyridine (catalytic amount) and triethylamine (0.14 ml), and the mixture was stirred overnight. The solvent was evaporated, and water was added to the residue. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated and the residue was purified with a column of silica gel (ethyl acetate / methanol / triethylamine) to give crude crystals, which were recrystallized from ethyl acetate-hexane to give 7- ( 4- (4-methyl-piperazin-1-yl) -phenyl) -N- (4- ((N-tetrahydropyran-4-yl-N-methylamino) methyl) phenyl) -2, 3-dihydro-l-benzoxepin- 4-carboxainidamide (Compound 124) (0.15 g) as colorless crystals, m.p. 220-221 ° C. NMR ^ H (d ppm, CDC13): 1.64-1.75 (4H, m), 2.22 (3H, s), 2.37 (3H, s), 2.58-2.71 (5H, m), 3.08 (2H, t, J = 4.6Hz), 3.25-3.32 (4H,), 3.37 (2H, dt, J = 2.8, 11.4Hz), 3.58 (2H, s), 4.01-4.07 (2H, m), 4.35 (2H, t, J = 4.6Hz), 6.97-7.06 (3H, m), 7.32 (2H, d, J = 8.4Hz), 7.41-7.58 (7H, m). IR (KBr) V: 2946, 2841, 1663cm-: L. Analysis for C35H42N403- 0.5H2O: Calculated C, 73.01; H, 7.53; N, 9.73. Found C, 73.25; H, 7.46; N, 9.72.

Working Example 125 (Production of Compound 125) A solution of N- (4- ((N- (1-t-butoxycarbonyl-piperidin-4-yl) -N-methylamino) methyl) phenyl) -7- (4 methylphenyl) -2,3-dihydro-l-benzoxepin-4-carboxamide (0.14 g) and trifluoroacetic acid (5 ml) in dichloromethane (20 ml) was stirred at room temperature for 1.5 hours. The reaction mixture was neutralized with a sodium acid carbonate solution, and the solvent was evaporated. Water was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give crude crystals, which were recrystallized with ethanol-hexane to give the N- (4- ((N-methyl-N- (piperidin-4-yl)) aminomethyl) phenyl) - 7- (4-methyl-phenyl) -2,3-dihydro-l-benzoxepin-4-carboxamide (Compound 125) (0.08 g) as colorless crystals. p.f. 129-130 ° C. RM ^ H (d ppm, CDC13): 1.68-1.95 (4H, m), 2.22 (3H, s), 2.39 (3H, s), 2.61-2.79 (3H, m), 3.08 (2H, t, J = 4.5Hz), 3.25-3.33 (2H, m), 3.58 (2H, s), 4.36 (2H, t, J = 4.5Hz), 7.06 (1H, d, J = 8.4Hz), 7.23-7.33 (4H, m), 7.44-7.60 (7H, m). GO . { KBr) v: 2929. 1 6 Q 3 ctT'L.

Working Example 126 (Production of Compound 126) and Working Example 127 (Production of Compound 127) A suspension of N- (4-chloromethylphenyl) -7- (4-methylphenyl) -2,3-dihydro-l-benzoxepin -4-carboxamide (0.1 g), N, 4-dimethylcyclohexylamine hydrochloride (0.08 ml) and potassium carbonate (0.17 g) in dimethylformamide (10 ml) was stirred at room temperature overnight. The solvent was evaporated, and water was added to the residue. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated and the residue was purified with a column of silica gel (ethyl acetate) to give each of the crude crystals, which were recrystallized with ethyl acetate-hexane to give each N-isomer. - (4- ((N-methyl-N- (4-methylcyclohexyl)) amino-methyl) phenyl) -7- (4-methylphenyl) -2,3-dihydro-l-benzoxepin-4-carboxamide (Compound 126 ( 0.05 g), Compound 127 (0.03 g)) as colorless crystals. (Compound 126): p.f. 144-145 ° C. NMR-aH (d ppm, CDC13) d: 0.96 (3H, d, J = 6.8Hz), 1.40-1.80 (9H, m), 2.17 (3H, s), 2.20-2.40 (1H, m), 2.39 ( 3H, s), 3.08 (2H, t, J = 4.5Hz), 3.55 (2H, s), 4.36 (2H, t, J = 4.5Hz), 7.05 (1H, d, J = 8.4Hz), 7.22- 7.34 (4H, m), 7.43-7.58 (7H, m).

IR (KBr) v: 2927, 1650CI - 1. "Analysis for C33H38N202- 0.2H20: Calculated C, 79.55; H, 7.77; N, 5.62, Found C, 79.59; H, 7.68; N, 5.84. (Compound 127 ): mp 183-184 ° C. RMN ^ H (d ppm, CDC13): 0.87 (3H, d, J = 6.6Hz), 0.89-1.02 (2H, m), 1.26-1.89 (7H, m), 2.20 (3H, s), 2.20-2.40 (1H, m), 2.39 (3H, s), 3.08 (2H, t, J = 4.6Hz), 3.56 (2H, s), 4.36 (2H, t, J = 4.6Hz), 7.06 (1H, d, J = 8.4Hz), 7.22-7.34 (5H, m), 7.44-7.55 (6H, m). IR (KBr) v: 2925, 1654cm ~ x. Analysis for C33H38N202 • 0.2H20: Calculated C, 79.55; H, 7.77; N, 5.62. Found C, 79.48; H, 7.70; N, 5.83.

Working Example 128 (Production of Compound 128) To a suspension of 7- (4-methylphenyl) -2,3-dihydro-1-benzoxepin-4-carboxylic acid (0.15 g) in dichloromethane (7 ml) were added sodium chloride. oxalyl (0.14 ml) and dimethylformamide (catalytic amount) under cooling with ice, and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated and the residue was dissolved in tetrahydrofuran. The mixture was added dropwise to a solution of 4- (N-methyl-N- (tetrahydropyran-4-yl) amino-methyl) aniline (0.12 g) and triethylamine (0.23 g) in tetrahydrofuran (10 ml), under cooling with ice. Under a nitrogen atmosphere, the mixture was stirred at room temperature overnight. The solvent was evaporated, and water was added to the residue. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give crude crystals, which were recrystallized with ethyl acetate-hexane to give the N- (4- (N-methyl- (N-tetrahydropyran-4-yl) aminomethyl) phenyl) - 7- (4-methylphenyl) -2, 3-dihydro-l-benzoxepin-4-carboxamide (Compound 128) (0.19 g) as colorless crystals, m.p. 162-163 ° C. NMR ^ H (d ppm, CDC13): 1.59-1.74 (4H,), 2.20 (3H, s), 2.39 (3H, s), 2.58-2.66 (1H, m), 3.07 (2H, t, J = 4.5 Hz), 3.37 (2H, dt, J = 2.8, 11. OHz), 3.56 (2H, s), 4.01-4.06 (2H, m), 4.35 (2H, t, J = 4.5Hz), 7.05 (1H, d, J = 8.4Hz), 7.22-7.33 (4H, m), 7.43-7.56 (6H, m), 7.62 ( 1H, s). IR (KBr) v: 3296, 2950, 1654cm ~ 1. Analysis for C3? H34N203- 0.2H2O: Calculated C, 76.58; H, 7.13; N, 5.76. Found C, 76.51; H, 7.07; N, 5.53.

Working Example 129 (Production of Compound 129) To a suspension of 7- (4-methylphenyl) -2,3-dihydro-l-benzoxepin-4-carboxylic acid (0.15 g) in dichloromethane (5 ml) were added oxalyl (0.14 ml) and dimethylformamide (catalytic amount) under cooling with ice, and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated and the residue was dissolved in tetrahydrofuran. The mixture was added dropwise to a solution of 4- (N-methyl-N- (tetrahydropyran-3-yl) amino-methyl) aniline (0.13 g) and triethylamine (0.23 ml) in tetrahydrofuran (10 ml), under cooling with ice, and the mixture was stirred under a nitrogen atmosphere at room temperature overnight. The solvent was evaporated, and water was added to the residue. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with a column of silica gel (ethyl acetate) to give crude crystals, which were recrystallized with ethyl acetate-hexane to give N- (4- (( N-tetrahydropyran-3-yl-N-methyl) aminomethyl) -phenyl) -7- (4-methylphenyl) -2,3-dihydro-l-benzoxepin-4-carboxamide (Compound 129) (0.18 g) as colorless crystals . p.f. 158-159 ° C. RMMT-1H (d ppm, CDC13): 1.57-1.75 (3H, m), 2.00-2.05 (1H, m), 2.21 (3H, s), 2.39 (3H, s), 2.55-2.68 (1H, m) , 3.08 (2H, t, J = 4.7Hz), 3.22-3.39 (2H, m), 3.59 (2H, s), 3.84-3.90 (1H, m), 4.04-4.07 (1H, m), 4.37 (2H , t, J = 4.7Hz), 7.06 (1H, d, J = 8.0Hz), 7.23-7.32 (4H, m), 7.44-7.55 (7H, m). IR (KBr) V: 2941, 1652cm "1. Analysis for C3? H34N203: Calculated C, 77.15; H, 7.10; N, 5.80, Found C, 77.12; H, 7.02; N, 5.88.

Working Example 130 (Production of Compound 130) To a suspension of 7- (4-methylphenyl) -2,3-dihydro-l-benzoxepin-4-carboxylic acid (0.15 g) in dichloromethane (7 ml) were added sodium chloride. oxalyl (0.14 ml) and dimethylformamide (catalytic amount), under cooling with ice, and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated, and the residue was dissolved in tetrahydrofuran.

The mixture was added dropwise to a solution of 4- ((N-indan-2-yl-N-methyl) aminomethyl) aniline (0.14 g) and triethylamine (0.23 ml) in tetrahydrofuran (15 ml), under cooling with ice. Under a nitrogen atmosphere, the mixture was stirred at room temperature overnight. The solvent was evaporated, and water was added to the residue. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give crude crystals, which were recrystallized with ethyl acetate-ethanol-hexane to give the N- (4 - ((N-indan-2-yl-N-methyl) amino-methyl) ) phenyl) -7- (4-methylphenyl) -2,3-dihydro-l-benzoxepin-4-carboxamide (Compound 130) (0.23 g) as colorless crystals, m.p. 204-205 ° C. NMR-H d ppm, CDC13): 2.19 (3H, s), 2.39 (3H, s) 2. 94-3.18 (6H, m), 3.41-3.48 (1H, m), 3.57 (2H, s), 4.36 (2H, t, J = 4..7Hz), 7.06 (1H, d, J = 8.4Hz) , 7.16-7.22 (6H, m), 7.33-7.57 (9H, m). IR (KBr) v: 1654cm_1. Analysis for C35H34N202 • 0.2H20: Calculated C, 81.11; H, 6.69; N, 5.41. Found C, 81.06; H, 6.57; N, 5.49.

Working Example 131 (Production of Compound 131) To a suspension of 7- (4-methylphenyl) -2,3-dihydro-l-benzoxepin-4-carboxylic acid (0.15 g) in dichloromethane (6 ml) were added sodium chloride. oxalyl (0.14 ml) and dimethylformamide (catalytic amount) under cooling with ice, and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated, and the residue was dissolved in tetrahydrofuran. The mixture was added dropwise to a solution of (E) -4- ((N-4-t-butylcyclohexyl-N-methyl) aminomethyl) aniline (0.15 g) and triethylamine (0.23 ml) in tetrahydrofuran (10 ml), under cooling with ice. Under a nitrogen atmosphere, the mixture was stirred at room temperature overnight. The solvent was evaporated, and water was added to the residue. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give crude crystals, which were recrystallized with ethyl acetate-hexane to give (E) -N- (4- ((N- (4-t-butylcyclohexyl) -N-methyl) aminomethyl) -phenyl) -7- (4-methylphenyl) -2,3-dihydro-l-benzoxepin-4-carboxamide (Compound 131) (0.22 g) as colorless crystals. p.f. 225-226 ° C. NMR- ^? (d ppm, CDC13): 0.84 (9H, s), 0.95-1.05 (2H, m), 1.22-1.33 (2H, m), 1.82-1.95 (5H, m) 2.20 (3H, s), 2.30-2.45 (1H, m), 2.39 (3H, s), 3.08 (2H, t, J = 4.6Hz), 3.55 (2H, s), 4.36 (2H, t, J = 4.6Hz), 7.06 (1H, d, J = 8.0Hz), 7.22-7.34 (4H, m), 7.44-7.55 (7H, m).

IR (KBr) v: 2943, 1 652cm "1. Analysis for C36H44N202: Calculated C, 80.56; H, 8.26; N, 5.22 Found C, 80.30; H, 8.42; N, 5.32 Working Example 132 (Production of Compound 132) To a suspension of 7- (4-methylphenyl) -2,3-dihydro-1-benzoxepin-4-carboxylic acid (0.15 g) in dichloromethane (6 ml) were added sodium chloride. oxalyl (0.14 ml) and dimethylformamide (catalytic amount), under cooling with ice, and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated and the residue was dissolved in tetrahydrofuran. The mixture was added dropwise to a solution of (Z) -4- ((N-4-t-butylcyclohexyl-N-methyl) -aminomethyl) aniline (0.15 g) and triethylamine (0.23 ml) in tetrahydrofuran (10 ml), under cooling with ice. Under a nitrogen atmosphere, the mixture was stirred at room temperature overnight. The solvent evaporated, and water was added to the residue. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give crude crystals, which were recrystallized with diethyl ether-hexane to give (Z) -N- (4- ((N- (4-t-butylcyclohexyl) -N-methyl) aminomethyl) -phenyl) -7- (4-methylphenyl) -2,3-dihydro-l-benzoxepin-4-carboxamide (Compound 132) (0.2 g) as colorless crystals. p.f. 169-170 ° C. NMR - ^ - H (d ppm, CDC13): 0.89 (9H, s), 1.05-1.20 (1H, m), 1.36-1.50 (6H, m), 2.06 (3H, s), 2.06-2.14 (2H, m), 2.30-2.32 (1H, m), 2.39 (3H, s), 3.09 (2H, t, J = 4.8Hz), 3.50 (2H, s), 4.37 (2H, t, J = 4.8Hz), 7.06 (1H, d, J = 8.4Hz), 7.23-7.35 (4H, m), 7.44-7.54 (7H,). IR (KBr) v: 2941, 1648cm "1. Analysis for C36H44N202 • 0.2H2O: Calculated C, 80.02; H, 8.28; N, 5.18. Found C, 80.23; H, 8.30; N, 5.22.

Working Example 133 (Production of Compound 133) To a suspension of 7- (4-methylphenyl) -2,3-dihydro-1-benzoxepin-4-carboxylic acid (0.15 g) in dichloromethane (6 ml) were added sodium chloride. oxalyl (0.14 ml) and dimethylformamide (catalytic amount) under cooling with ice, and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated and the residue was dissolved in tetrahydrofuran. The mixture was added dropwise to a solution of 4- ((N- (3,5-dimethylcyclohexyl) -N-methyl) -aminomethyl) aniline (0.13 g) and triethylamine (0.23 ml) in tetrahydrofuran. (10 ml), under cooling with ice. Under a nitrogen atmosphere, the mixture was stirred at room temperature overnight. The solvent was evaporated, and water was added to the residue. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give crude crystals, which were recrystallized with diethyl ether-hexane to give the N- (4- ((N-methyl-N- (3,5-dimethylcyclohexyl) aminomethyl) phenyl) - 7- (4-methylphenyl) -2, 3-dihydro-l-benzoxepin-4-carboxamide (Compound 133) (0.22 g) as colorless crystals, m.p. 135-136 ° C. NMR-aH (d ppm, CDC13): 0.45-0.68 (1H, m), 0.84 (3H, s), 0.87 (3H, s), 0.96-1.03 (2H, m), 1.65-2.05 (5H, m) 2.06 (3H, s), 2.39 (3H, s), 2.39-2.42 (1H, m), 3.08 (2H, t, J = 4.7Hz), 3.50 (2H, s), 4.36 (2H, t, J = 4.7 Hz), 7.06 (1H, d, J = 8.4Hz), 7.16-7.32 (4H, m), 7.44-7.54 (7H, m). IR (KBr) v: 2947, 1652cm "1. Analysis for C34H40N2O2: Calculated C, 80.28; H, 7.93; N, 5.51, Found C, 80.19; H, 7.95; N, 5.54.

Working Example 134 (Production of Compound 134) To a suspension of 7- (4-methylphenyl) -2,3-dihydro-l-benzoxepin-4-carboxylic acid (0.15 g) in dichloromethane (6 ml) were added sodium chloride. oxalyl (0.14 ml) and dimethylformamide (catalytic amount) under cooling with ice, and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated and the residue was dissolved in tetrahydrofuran. The mixture was added dropwise to a solution of 4- ((N-4- (3,5-dimethylcyclohexyl) -N-methyl) -aminomethyl) aniline (0.13 g) and triethylamine (0.23 ml) in tetrahydrofuran (10 ml), under cooling with ice. Under a nitrogen atmosphere, the mixture was stirred at room temperature overnight. The solvent was evaporated, and water was added to the residue. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give crude crystals, which were recrystallized with ethyl acetate-hexane to give the N- (4- ((N-methyl-N- (3,5-dimethylcyclohexyl)) aminomethyl) phenyl ) -7- (4-methylphenyl) -2,3-dihydro-l-benzoxepin-4-carboxamide (Compound 134) (0.2 g) as colorless crystals. p.f. 173-174 ° C.

NMR-aH (d ppm, CDC13): 0.43-0.60 (1H, m), 0.81-0.99 (2H, m), 0.91 (3H, s), 0.95 (3H, s), 1.30-1.58 (3H, m) , 1.79- 1.84 (2H,), 2.19 (3H, s), 2.39 (3H, s), 2.48-2.60 (1H, m), 3.08 (2H, t, J = 4.6Hz), 3.55 (2H, s) , 4.36 (2H, t, J = 4.6Hz), 7.06 (1H, d, J = 8.4Hz) 7.22-7.33 (4H, m), 7. 44-7.55 (7H, m). IR (KBr) v: 2950, 1652cm "1. Analysis for C34H4oN2? 2- 0.2H2O: Calculated C, 79.71; H, 7.95; N, 5.47. Found C, 79.83; H, 7.83; N, 5.54.

Working Example 135 (Production of Compound 135) To a suspension of 7- (4-methylphenyl) -2,3-dihydro-l-benzoxepin-4-carboxylic acid (0.12 g) in dichloromethane (5 ml) were added sodium chloride. oxalyl (0.11 ml) and dimethylformamide (catalytic amount) under cooling with ice, and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated and the residue was dissolved in tetrahydrofuran. The mixture was added dropwise to a solution of 4- ((N- (3,5-dimethylcyclohexyl) -N-methyl) -aminomethyl) aniline (0.1 g) and triethylamine (0.17 ml) in tetrahydrofuran (10 ml), under cooling with ice. Under a nitrogen atmosphere, the mixture was stirred at room temperature overnight. The solvent was evaporated, and water was added to the residue. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated and the residue was purified with a column of silica gel (ethyl acetate) to give crude crystals, which were recrystallized with diethyl ether-hexane to give the N- (4- ((N -methyl-N- (3,5-dimethylcyclohexyl)) aminomethyl) -phenyl) -7- (4-methylphenyl) -2,3-dihydro-l-benzoxepin-4-carboxamide (Compound 135) (0.08 g) as crystals colorless, pf 99-100 ° C. NMR- ^ H (d ppm, CDC13): 0.82-1.13 (8H, m), 1.40-1.53 (2H, m), 1.64-1.85 (3H, m), 2.08-2.18 (1H,), 2.18 (3H, s), 2.39 (3H, s), 2.69-2.81 (1H, m), 3.08 (2H, t, J = 4.8Hz), 3.54 (2H, s), 4.35 (2H, t, J = 4.8Hz), 7.05 (1H, d, J = 8.2Hz), 7.22-7.33 (4H, m), 7.43-7.58 (7H, m). IR (KBr) v: 2923, 1652cm "1. Analysis for C34H40N202 • 0.5H2O: Calculated C, 78.88; H, 7.98; N, 5.41. Found C, 78.88; H, 7.74; N, 5.50.

Working Example 136 (Production of Compound 136) To a suspension of 7- (4-methylphenyl) -2,3-dihydro-l-benzoxepin-4-carboxylic acid (0.15 g) in dichloromethane (5 ml) were added sodium chloride. oxalyl (0.14 ml) and dimethylformamide (catalytic amount) under cooling with ice, and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated and the residue was dissolved in tetrahydrofuran. The mixture was added dropwise to a solution of 4- ((N-methyl-N-n-propyl) aminomethyl) aniline (0.1 g) and triethylamine (0.23 ml) in tetrahydrofuran (10 ml), under cooling with ice. Under a nitrogen atmosphere, the mixture was stirred at room temperature overnight. The solvent was evaporated, and water was added to the residue. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated and the residue was purified with a column of silica gel (ethyl acetate / methanol / triethylamine) to give crude crystals, which were recrystallized from diethyl ether-hexane to give the N- (4 - ((N-methyl-Nn-propyl) aminomethyl) phenyl) -7- (4-methyl-phenyl) -2,3-dihydro-l-benzoxepin-4-carboxamide (Compound 136) (0.1 g) as colorless crystals , pf 142-143 ° C. NMR-aH (d ppm, CDC13): 0.90 (3H, t, J = 7.3Hz), 1.48-1.59 (2H, m), 2.19 (3H, s), 2.29-2.37 (2H, m), 2.39 (3H , s), 3.08 (2H, t, J = 4.4Hz), 3.47 (2H, s), 4.36 (2H, t, J = 4.4Hz), 7.06 (2H, d, J = 8.4Hz), 7.22-7.33 (4H, m), 7. 43-7.57 (7H, m). GO . { KBr) v: 2962, 1652, 1517cm "a .. Analysis for C29H32N202-0.2H2O: Calculated C, 78.42; H, 7.35; N, 6. 31. Found C, 78.41; H, 7.21; N, 6.26.

Working Example 137 (Production of Compound 137) A solution of N- (4-chloromethylphenyl) -7- (4-methyl-1-phenyl) -2,3-dihydro-1-benzoxepin-4-carboxamide (0.1 g) and N -methyl-n-butylamine (0.06 g) in dimethylformamide (10 ml) was stirred at room temperature overnight. The solvent was evaporated, and water was added to the residue. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give crude crystals, which were recrystallized with ethyl acetate-hexane to give the N- (4 - ((Nn-butyl-N-methyl) amino-methyl) phenyl) -7- (4-methylphenyl) -2,3-dihydro-l-benzoxepin-4-carboxamide (Compound 137) (0.09 g) as colorless crystals, m.p. 138-139 ° C. 1H-NMR (d ppm, CDC13): 0.91 (3H, t, J = 1.2Hz), 1.27-1.55 (4H, m), 2.19 (3H, s), 2.33-2.39 (2H, m), 2.39 (3H , s), 3.08 (2H, t, J = 4.5Hz), 3.47 (2H, s), 4.36 (2H, t, J = 4.5Hz), 7.06 (1H, d, J = 8.2Hz), 7.22-7.33 (4H, m), 7.44-7.58 (7H,). IR (KBr) v: 2956, 2931, 1652cm "1. Analysis for C30H34N2O2- 0.2H2O: Calculated C, 78.64; H, 7.57; N, 6.11, Found C, 78.83; H, 7.44; N, 6.19.

Working Example 138 (Production of Compound 138) To a suspension of 7- (4-methylphenyl) -2,3-dihydro-1-benzoxepin-4-carboxylic acid (0.15 g) in dichloromethane (5 ml) were added sodium chloride. oxalyl (0.14 ml) and dimethylformamide (catalytic amount) under cooling with ice, and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated and the residue was dissolved in tetrahydrofuran. The mixture was added dropwise to a solution of 4- ((N-isopropyl-N-methyl) aminomethyl) aniline (0.1 g) and triethylamine (0.23 ml) in tetrahydrofuran (10 ml), under ice-cooling. Under a nitrogen atmosphere, the mixture was stirred at room temperature overnight. The solvent was evaporated, and water was added to the residue. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give crude crystals, which were recrystallized with ethyl acetate-hexane to give the N- (4 - ((N-isopropyl-N-methyl) -aminomethyl) phenyl) -7- ( 4-methylphenyl) -2,3-dihydro-l-benzoxepin-4-carboxamide (Compound 138) (0.18 g) as colorless crystals, m.p. 181-182 ° C. NMR-aH (d ppm, CDC13): 1.07 (6H, d, J = 6.6Hz), 2.15 (3H, s), 2.39 (3H, s), 2.83-2.96 (1H, m), 3.08 (2H, t , J = 4.7Hz), 3.49 (2H, s), 4.36 (2H, t, J = 4.7Hz). 7.06 (1H, d, J = 8.4Hz), 7.22-7.34 (4H, m), 7.44-7.55 (7H, m). IR (KBr) V: 2968, 1652cm "1. Analysis for C29H32N202: Calculated C, 79.06; H, 7.32; N, 6.36. Found C, 78.87; H, 7.30; N, 6.33.

Working Example 139 (Production of Compound 139) To a suspension of 7- (4-methylphenyl) -2,3-dihydro-l-benzoxepin-4-carboxylic acid (0.15 g) in dichloromethane (15 ml) were added sodium chloride. oxalyl (0.14 ml) and dimethylformamide (catalytic amount) under cooling with ice, and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated and the residue was dissolved in tetrahydrofuran. The mixture was added dropwise to a solution of 4- ((N-sec-butyl-N-methyl) aminomethyl) aniline (0.12 g) and triethylamine (0.23 ml) in tetrahydrofuran (10 ml), under ice-cooling. Under a nitrogen atmosphere, the mixture was stirred at room temperature overnight. The solvent was evaporated, and water was added to the residue. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with a column of silica gel (ethyl acetate) to give crude crystals, which were recrystallized with ethyl acetate-hexane to give N- (4- (( N-sec-butyl-N-methyl) -aminomethyl) phenyl) -7- (4-methylphenyl) -2,3-dihydro-l-benzoxepin-4-carboxamide (Compound 139) (0.12 g) as colorless crystals, m.p. 152-153 ° C. NMR-1H (d ppm, CDC13): 0.89-1.01 (6H, m), 1.22-1.39 (1H, m), 1.50-1.67 (1H, m), 2.13 (3H, s), 2.39 (3H, s) , 2.54-2.65 (1H, m), 3.08 (2H, t, J = 4.7Hz), 3.44 (1H, d, J = 13.2Hz), 3.56 (1H, d, J = 13.2Hz), 4.36 (2H, t, J = 4.7Hz), 7.06 (2H, d, J = 8.0Hz), 7.22-7.35 (4H, m), 7.44-7.54 (7H, m). IR (pure) v: 2964, 1652cm_1.

Analysis for C30H34N202 • 0.2H2O: Calculated C, 78.64; H, 7.57; N, 6.11 Found C, 78.88; H, 7.39; N, 6.16 Working Example 140 (Production of Compound 140) A solution of N- (4-chloromethylphenyl) -7- (4-ethyl-phenyl) -2,3-dihydro-1-benzoxepin-4-carboxamide (0.1 g) and N -methylisobutylamine (0.06 g) in dimethylformamide (10 ml) was stirred at room temperature overnight. The solvent was evaporated, and water was added to the residue. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give crude crystals, which were recrystallized with ethyl acetate-hexane to give the N ~ (4 - ((N-isobutyl-N-methyl) amino-methyl) phenyl) -7- (4-methyl-phenyl) -2,3-dihydro-l-benzoxepin-4-carboxamide (Compound 140) (0.08 g) as colorless crystals. p.f. 137-138 ° C. NMR-aH (d ppm, CDC13): 0.90 (6H, d, J = 6.6Hz), 1.78-1.88 (1H, m), 2.10 (2H, d, J = 7.4Hz), 2.16 (3H, s), 2.39 (3H, s), 3.08 (2H, t, J = 4.6Hz), 3.44 (2H, s), 4.36 (2H, t, J = 4.6Hz), 7.06 (1H, d, J = 8.0Hz), 7.23-7.34 (4H, m), 7.44-7.57 (7H, m).

IR (KBr) v: 2954, 1 652cm "1. Analysis for C30H3 N2O2: Calculated C, 79.26; H, 7.54; N, 6.1.6, Found C, 78.99; H, 7.38; N, 6.21 Working Example 141 (Production of Compound 141) To a suspension of 7- (4-methylphenyl) -2,3-dihydro-l-benzoxepin-4-carboxylic acid (0.1 g) in dichloromethane (5 ml) were added sodium chloride. oxalyl (0.1 ml) and dimethylformamide (catalytic amount) under cooling with ice, and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated and the residue was dissolved in tetrahydrofuran. The mixture was added dropwise to a solution of 4- ((N-t-butyl-N-methyl) amino-methyl) aniline (0.08 g) and triethylamine (0.12 ml) in tetrahydrofuran (10 ml), under ice-cooling. Under a nitrogen atmosphere, the mixture was stirred at room temperature overnight. The solvent was evaporated, and water was added to the residue. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give crude crystals, which were recrystallized with ethyl acetate-hexane to give the N- (4 - ((Nt-butyl-N-methyl) amino-methyl) phenyl) -7- (4-methylphenyl) -2,3-dihydro-l-benzoxepin-4-carboxamide (Compound 141) (0.12 g) as colorless crystals, m.p. 122-123 ° C. NMR-1H (d ppm, CDC13): 1.16 (9H, s). 2.09 (3H, s), 2.39 (3H, s), 3.08 (2H, t, J = 4.7Hz), 3.49 (2H, s), 4.36 (2H, t, J = 4.7Hz), 7.06 (1H, d) , J = 8.4Hz), 7.23-7.36 (4H, m), 7.44-7.54 (7H, m). IR (KBr) v: 2971, 1 651, 1599, 1516cm-1. Anal is is for C3oH34N202: Calculated C, 79.26; H, 7.54; N, 6.16. Found C, 79.16; H, 7.55; N, 5.98.

Working Example 142 (Production of Compound 142) To a suspension of 7- (4-methylphenyl) -2,3-dihydro-1-benzoxepin-4-carboxylic acid (0.1 g) in dichloromethane (5 ml) were added sodium chloride. oxalyl (0.1 ml) and dimethylformamide (catalytic amount) under cooling with ice, and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated and the residue was dissolved in tetrahydrofuran. The mixture was added dropwise to a solution of 4- ((N-methyl-N- (pentan-3-yl)) aminomethyl) aniline (0.08 g) and triethylamine (0.12 ml) in tetrahydrofuran (10 ml), under cooling with ice. Under a nitrogen atmosphere, the mixture was stirred at room temperature overnight. The solvent was evaporated, and water was added to the residue. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give crude crystals, which were recrystallized with ethyl acetate-hexane to give the N- (4- ((N-methyl-N- (pentan-3-yl)) aminomethyl) phenyl ) -7- (4-methyl-phenyl) -2,3-dihydro-l-benzoxepin-4-carboxamide (Compound 142) (0.12 g) as colorless crystals, mp. 133-134 ° C. NMR- ^ H (d ppm, CDC13): 0.94 (6H, t, J = 7.5Hz), 1.26-1.53 (4H, m), 2.13 (3H, s), 2.24-2.31 (1H, m), 2.40 ( 3H, s), 3.09 (2H, t, J = 4.4Hz), 3.55 (2H, s), 4.37 (2H, t, J = 4.4Hz), 7.06 (1H, d, J = 8.4Hz), 7.17- 7.36 (4H, m), 7.44-7.54 (7H, m). IR (KBr) v: 2930, 1649, 1597, lSldcm "1. Analysis for C3? H36N202: Calculated C, 79.45; H, 7.74; N, 5.98, Found C, 79.06; H, 7.56; N, 5.98.

Working Example 143 (Production of Compound 143) To a suspension of 7- (4-methylphenyl) -2,3-dihydro-1-benzoxepin-4-carboxylic acid (0.1 g) in dichloromethane (5 ml) were added sodium chloride. oxalyl (0.1 ml) and dimethylformamide (catalytic amount) under cooling with ice, and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated and the residue was dissolved in tetrahydrofuran. The mixture was added dropwise to a solution of 4- ((N-methyl-N- (norbornyan-2-yl)) aminomethyl) aniline (0.09 g) and triethylamine (0.12 ml) in tetrahydrofuran (10 ml), under cooling with ice. Under a nitrogen atmosphere, the mixture was stirred at room temperature overnight. The solvent was evaporated, and water was added to the residue. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated and the residue was purified with a column of silica gel (ethyl acetate / hexane). The purified product was dissolved in ethyl acetate (10 ml), and a solution of 4N-hydrochloric acid-ethyl acetate (0.2 ml) was added to the mixture under cooling with ice. The solvent was evaporated to give crude crystals, which were recrystallized with ethanol-hexane to give the N- (4- ((N-methyl-N- (norbornan-2-yl)) aminomethyl) -phenyl hydrochloride) -7 - (4-methylphenyl) -2,3-dihydro-l-benzoxepin-4-carboxamide (Compound 143) (0.16 g) as colorless crystals. p.f. 268-269 ° C (dec.). NMR-aH (d ppm, DMSO-d6): 1.24-1.55 (6H, m), 1.99-2.15 (3H, m), 2.28 (1H, broad), 2.34 (3H, s), 2.51-2.63 (3H, ), 2.82 (1H, broad), 3.00 (2H, broad), 4.04-4.45 (4H, m), 7.06 (1H, d, J = 8.4Hz), 7.33 (2H, d, J = 7.8Hz), 7.38 (1H, s), 7.48-7.59 (5H, m), 7.75-7.85 (3H, m), 9.52 (0.5H, broad), 9.83 (0.5H, broad), 10.18 (1H, s). IR (KBr) v: 2957, 2492, 1661cm_1. Analysis for C33H37C1N202- 0.2H20: Calculated C, 74.40; H, 7.08; N, 5.26. Found C, 74.34; H, 7.05; N, 5.19.

Working Example 144 (Production of Compound 144) To a suspension of 7- (4-methylphenyl) -2,3-dihydro-l-benzoxepin-4-carboxylic acid (0.15 g) in dichloromethane (5 ml) were added sodium chloride. oxalyl (0.14 ml) and dimethylformamide (catalytic amount) under cooling with ice, and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated and the residue was dissolved in tetrahydrofuran. The mixture was added dropwise to a solution of 4- (2- (N-cyclohexyl-N-methyl) aminoethyl) aniline (0.15 g) and triethylamine (0.23 ml) in tetrahydrofuran (15 ml), under cooling with ice. Under a nitrogen atmosphere, the mixture was stirred at room temperature overnight. The solvent was evaporated, and water was added to the residue. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give crude crystals, which were recrystallized with ethyl acetate-hexane to give the N- (4- (2 - ((N-cyclohexyl-N-methyl) amino) ethyl) phenyl) -7- (4-methylphenyl) -2,3-dihydro-l-benzoxepin-4-carboxamide (Compound 144) (0.23 g) as colorless crystals, m.p. 154-155 ° C. NMR-aH (d ppm, CDC13): 1.18-1.30 (6H, m), 1.65-1.80 (4H, m), 2.35 (3H, s), 2.39 (3H, s), 2.39-2.50 (1H,), 2.66-2.73 (4H, m), 3.08 (2H, t, J = 4.6Hz), 4.36 (2H, t, J = 4.6Hz), 7.06 (1H, d, J = 8.4Hz), 7.18-7.26 (4H , m), 7.44-7.55 (7H, m). IR (KBr) v: 2929, 2854, 1648cm_1. Analysis for C33H38N202"0.3H2O: Calculated C, 79.26; H, 7.78; N, 5.60. Found C, 79.26; H, 7.48; N, 5.62.

Working Example 145 (Production of Compound 145] To a suspension of 7- (4-methylphenyl) -2,3-dihydro-l-benzoxepin-4-carboxylic acid (0.1 g) in dichloromethane (5 ml) were added sodium chloride. oxalyl (0.1 ml) and dimethylformamide (catalytic amount) under ice-cooling, and the mixture was stirred at room temperature for 2 hours.The solvent was evaporated, and the residue was dissolved in tetrahydrofuran.The mixture was added dropwise to a solution of 4- (l-hydroxy-2-piperidino-ethyl) aniline (0.09 g) and triethylamine (0.12 ml) in tetrahydrofuran (10 ml), under cooling with ice Under a nitrogen atmosphere, the mixture was stirred at room temperature The solvent was evaporated, and water was added to the residue The mixture was extracted with ethyl acetate The organic layer was washed with water and saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give crystals c crude, which were recrystallized with ethyl acetate-hexane to give the N- (4- (1-hydroxy-2-piperidinoethyl) phenyl) -7- (4-methyl-phenyl) -2,3-dihydro-l- benzoxepin-4-carboxamide (Compound 145) (0.14 g) as colorless crystals, m.p. 212-213 ° C. NMR ^ H (d ppm, CDC13): 1.44-1.52 (2H, m), 1.56-1.69 (4H, m), 2.32-2.47 (4H, m), 2.40 (3H, s), 2.65-2.74 (2H, m), 3.08 (2H, t, J = 4.5Hz), 4.37 (2H, t, J = 4.5Hz), 4.72 (1H, dd, J = 3.8, 10. OHz), 7.06 (1H, d, J = 8.4Hz), 7.25 (2H, d, J = 7.4Hz), 7.35-7.59 (9H, m). IR (KBr) v: 2936, 1651, 1520cm "1. Analysis for C3? H34N203: Calculated C, 77.15; H, 7.10; N, 5.80, Found C, 76.95; H, 7.34; N, 5.69.

Working Example 146 (Production of Compound 146) To a suspension of 7- (3-pyridyl) -2,3-dihydro-l-benzoxepin-4-carboxylic acid (0.15 g), 4- (N-methyl-N- (tetra-hydropyran-4-yl) aminomethyl) aniline (0.12 g) and triethylamine (0.16 ml) in dimethylformamide (50 ml) were added diethyl cyanophosphate (0.1 ml) under ice-cooling, and the mixture was stirred under one atmosphere of nitrogen at room temperature overnight. The solvent was evaporated, and the residue was purified with a column of silica gel (methanol / ethyl acetate / triethylamine) to give crude crystals, which were recrystallized with ethanol-hexane to give 7- (3-pyridyl) - N- (4- ((N-tetrahydropyran-4-yl-N-methylamino) -methyl) phenyl) -2,3-dihydro-l-benzoxepin-4-carboxamide (Compound 146) (0.06 g) as colorless crystals. p.f. 158-159 ° C.

NMR-aH (d ppm, CDC13): 1.64-1.71 (4H, m), 2.23 (3H, s), 2.65-2.75 (1H, m), 3.11 (2H, t, J = 4.8Hz), 3.37 (2H , dt, J = 2.4, 11. OHz), 3.60 (2H, s), 4.01-4.07 (2H, m), 4.38 (2H, t, J = 4.8Hz), 7.12 (1H, d, J = 8.4Hz ), 7.31-7.40 (3H, m), 7.44-7.58 (4H, m), 7.66 (1H, broad), 7.84 (1H, d, J = 7.6Hz), 8.58 (1H, d, J = 4.8Hz) , 8.82 (1H, d, J = 2.2Hz). IR (KBr) v: 2949, 2845, 1661cm_1. Analysis for C2gH31N303"0.5H20: Calculated C, 72.78; H, 6.74; N, 8.78, Found C, 72.72; H, 6.72; N, 8.95.

Working Example 147 (Production of Compound 147) To a solution of 7- (4-pyridyl) -2,3-dihydro-l-benzoxepin-4-carboxylic acid (0.15 g), 4- (N-methyl-N- (tetrahydropyran-4-yl) aminomethyl) aniline (0.12 g) and triethylamine (0.16 ml) in dimethylformamide (50 ml) were added diethyl cyanophosphate (0.1 ml) under cooling with ice and the mixture was stirred under a nitrogen atmosphere at room temperature. Room temperature during the night. The solvent was evaporated and the residue was purified with a column of silica gel (methanol / ethyl acetate / triethylamine) to give crude crystals, which were recrystallized with ethanol-hexane to give 7- (4-pyridyl) -N - (4- ((N-tetrahydropyran-4-yl-N-methylamino) methyl) phenyl) -2,3-dihydro-l-benzoxepin-4-carboxamide (Compound 147) (0.07 g) as colorless crystals. p.f. 186-187 ° C. NMR-1H (d ppm, CDC13): 1.67-1.73 (4H, m), 2.23 (3H, s), 2. 60-2.75 (1H, m), 3.11 (2H, t, J = 4.6Hz), 3.37 (2H, dt, J = 3.0, 11. OHz), 3.60 (2H, s), 4.01-4.07 (2H, m), 4.38 (2H, t, J = 4.6Hz), 7.12 (1H, d, J = 8.0Hz), 7.34 (2H, d, J = 8.4Hz), 7.45-7.51 (3H, m), 7.55-7.59 (3H, m), 7.82 (1H, broad), 8.64 (2H, d, J = 5.8Hz). IR (KBr) v: 2948, IdS? Cm "1. Analysis for C29H3? N303- 0.5H2O: Calculated C, 72.78; H, 6.74; N, 8.78. Found C, 72.64; H, 6.51; N, 8.85.

Working Example 148 (Production of Compound 148) To a solution of 7- (2-furyl) -2,3-dihydro-l-benzoxepin-4-carboxylic acid (0.15 g), 4- (N-methyl-N- (tetrahydropyran-4-yl) aminomethyl) aniline (0.15 g) and triethylamine (0.25 ml) in dimethylformamide (10 ml) were added diethyl cyanophosphate (0.13 ml) under cooling with ice and the mixture was stirred under a nitrogen atmosphere at room temperature. Room temperature during the night. The solvent was evaporated and the residue was purified with a column of silica gel (methanol / ethyl acetate / triethylamine) to give crude crystals, which were recrystallized with ethyl acetate-hexane to give 7- (2-furyl) -N- (4- ((N-tetrahydropyran-4-yl-N-methylamino) ethyl) phenyl) -2, 3-dihydro-l-benzoxepin-4-carboxamide (Compound 148) (0.1 g) as chlorine crystals coffee. p.f. 166-167 ° C (dec.). NMR-1H (d ppm, CDC13): 1.64-1.78 (4H, m), 2.22 (3H, s), 2.60-2.75 (1H, m), 3.06 (2H, t, J = 4.6Hz), 3.37 (2H , dt, J = 3.0, 11.1Hz), 3.59 (2H, s), 4.02-4.07 (2H, m), 4.33 (2H, t, J = 4.6Hz), 6.46 (1H, dd, J = 1.8, 3.3 Hz), 6.56 (1H, d, J = 3.3Hz), 7.01 (2H, d, J = 8.4Hz), 7.21 (1H, s), 7.32 (2H, d, J = 8.6Hz), 7.44 (1H, d, J = 1.8Hz), 7.50-7.62 (4H, m), 7.73 (1H, s). IR (KBr) v: 2951, 1659CK. "1. Analysis for C28H3oN2? 4 • 0.5H2O: Calculated C, 71.93; H, 6.68; N, 5.99, Found C, 71.97; H, 6.52; N, 6.08.

Working Example 149 (Production of Compound 149) To a solution of 7- (4-dimethylaminophenyl) -2,3-dihydro-l-benzoxepin-4-carboxylic acid (0.15 g), 4- (N-methyl-N- (tetrahydropyran-4-yl) aminomethyl) aniline (0.11 g) and triethylamine (0.2 ml) in dimethylformamide (15 ml) was added diethyl cyanophosphate (0.11 ml) under ice-cooling and the mixture was stirred under a nitrogen atmosphere at room temperature. Room temperature during the night. The solvent was evaporated, and the residue was purified with a column of silica gel (methanol / ethyl acetate / triethylamine) to give crude crystals, which were recrystallized with ethyl acetate-hexane to give 7- (4-dimethylaminophenyl) ) -N- (4- ((N-tetrahydropyran-4-yl-N-methylamino) methyl) phenyl) -2, 3-dihydro-l-benzoxepin-4-carboxamide (Compound 149) (0.07 g) as color crystals pale coffee p.f. 208-209 ° C (dec.). NMR-aH (d ppm, CDC13): 1.63-1.78 (4H, m), 2.20 (3H, s), 2.59-2.70 (1H, m), 2.98 (6H, s), 3.04 (2H, t, J = 4.5Hz), 3.36 (2H, dt, J = 2.6, 11. OHz), 3.56 (2H, s), 4.00-4.06 (2H, m), 4.31 (2H, t, J = 4.5Hz), 6.78 (2H , d, J = 8.8Hz). 7.01 (1H, d, J = 8.0Hz), 7.24-7.31 (3H, m), 7.39-7.46 (4H, m), 7.55 (2H, d, J = 8.4Hz), 7.79 (1H, s). IR (KBr) v: 2949, 2845, 1659cm_1. Analysis for C 32 H 37 N 30 - 0.3 H 20: Calculated C, 74.33; H, 7.33; N, 8.13. Found C, 74.11; H, 7.22; N, 8.21.

Working Example 150 (Production of Compound 150) To a solution of 7- (4- (pyrrolidin-1-yl) phenyl) -2,3-dihydro-l-benzoxepin-4-carboxylic acid (0.15 g), 4- (N-methyl-N- (tetrahydropyran-4-yl) aminomethyl) -aniline (0.1 g) and 1-hydroxybenzotriazole (0.07 ml) in dimethylformamide (10 ml) were added 1-ethyl-3- (3-dimethylamino) hydrochloride -propyl) carbodiimide (0.13 g) under cooling with ice and the mixture was stirred under a nitrogen atmosphere at room temperature for 3 hours. To the mixture was added 4-dimethylaminopyridine (catalytic amount) and 1,8-diazabicyclo [5.4.0] -7-undecene (0.2 ml), and the mixture was stirred overnight. The solvent was evaporated and the residue was purified with a column of silica gel (methanol / ethyl acetate / triethylamine) to give crude crystals, which were recrystallized with ethanol-hexane to give 7- (4- (pyrrolidin-1) -yl) phenyl) -N- (4- ((N-tetrahydropyran-4-yl-N-methylamino) -methyl) phenyl) -2,3-dihydro-l-benzoxepin-4-carboxamide (Compound 150) (0.08 g) as colorless crystals. p.f. 210-211 ° C. NMR-1H (d ppm, CDC13): 1.69-1.78 (8H, m), 1.99-2.06 (4H, m), 2.21 (3H, s), 2.55-2.70 (1H, m), 3.07 (2H, t, J = 4.5Hz), 3.30-3.38 (4H, m), 3.38-3.57 (2H, m), 3.57 (2H, s), 4.01-4.06 (2H, m), 4.35 (2H, t, J = 4.5Hz ), 6.63 (2H, d, J = 8.8Hz), 7.02 (1H, d, J = 8.4Hz), 7.31 (2H, d, J = 8.4Hz), 7.40-7.48 (4H, m), 7.54 (2H) , d, J = 8.4Hz), 7.61 (1H, s).

IR (KBr) V: 2951, 2841, 1 653CTCT1. Analysis for C 34 H 39 N 3 O 3: Calculated C, 75. 95; H, 7 31; N, 7 81 Found C, 75. 70; H, 7 10; N, 7 83 Working Example 151 (Production of Compound 151) To a solution of 7- (4-piperidinophenyl) -2,3-dihydro-l-benzoxepin-4-carboxylic acid (0.15 g), 4- (N-methyl-N- (tetrahydropyran-4-yl) aminomethyl) aniline (0.1 g) and 1-hydroxy-benzotriazole (0.07 ml) in dimethylformamide (10 ml) was added l-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (0.13 g) ) under cooling with ice. Under a nitrogen atmosphere, the mixture was heated to room temperature. To the mixture was added 4-dimethylaminopyridine (catalytic amount) and triethylamine (0.18 ml), and the mixture was stirred overnight. The solvent was evaporated, and water was added to the residue. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give crude crystals, which were recrystallized with ethyl acetate-hexane to give 7- (4-piperidino-phenyl) -N- (4- ((N-methyl-N-tetrahydro- pyran-4-yl) amino) -methyl) phenyl) -2,3-dihydro-l-benzoxepin-4-carboxamide (Compound 151) (0.18 g) as colorless crystals, m.p. 197-198 ° C. NMR-1H (d ppm, CDC13): 1.58-1.70 (2H, m), 1.70-1.73 (4H, m), 2.21 (3H, s), 2.55-2.70 (1H, m), 3.08 (2H, t, J = 4.6Hz), 3.18-3.23 (4H, m), 3.37 (2H, dt, J = 2.4, 11. OHz), 3.57 (2H, s), 4.01-4.07 (2H, m), 4.35 (2H, t, J = 4.6Hz), 6.63 (2H, d, J = 8.8Hz), 6.97-7.05 (3H, m), 7.31 (2H, d, J = 8.4Hz), 7.43-7.57 (7H, m). IR (KBr) V: 2938, 2847, ldSlcm "1. Analysis for C35H4? N303 • 0.5H20: Calculated C, 74.97; H, 7.55; N, 7.49, Found C, 75.26; H, 7.53; N, 7.63.

Working Example 152 (Production of Compound 152) To a solution of 7- (4-morpholinophenyl) -2,3-dihydro-l-benzoxepin-4-carboxylic acid (0.15 g), 4- (N-methyl-N- (tetrahydropyran-4-yl) aminomethyl) aniline (0.1 g) and 1-hydroxybenzotriazole (0.06 ml) in dimethylformamide (15 ml) was added l-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (0.12 g) under cooling with ice. Under a nitrogen atmosphere, the mixture was heated to room temperature. To the mixture was added 4-dimethylaminopyridine (catalytic amount) and triethylamine (0.18 ml), and the mixture was stirred overnight. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give crude crystals, which were recrystallized with ethyl acetate-hexane to give N- (4- ((N-methyl-N- (tetrahydropyran-4-yl) aminomethyl) -phenyl) -7- (4-morpholinophenyl) -2,3-dihydro-l-benzoxepin-4-carboxamide (Compound 152) (0.17 g) as pale brown crystals, mp 238-239 ° C (dec.). NMR ^ H (d ppm, CDC13): 1.58-1.77 (4H, m), 2.21 (3H, s), 2.55-2.75 (1H, m), 3.08 (2H, t, J = 4.6Hz), 3.19-3.24 (4H, m), 3.37 (2H, dt, J = 3.0, 11.3Hz), 3.57 (2H, s), 3.87-3.91 (4H, m), 4.01-4.11 (2H, m), 4.36 (2H, t, J = 4.6Hz), 6.98 (2H, d, J = 9.0Hz), 7.05 (1H, d, J = 8.4Hz), 7.27-7.34 (3H, m), 7.42-7.57 (6H, m), IR (KBr) v: 2961, 2847, 1660CIT. "1. Analysis for C34H39N304 • 0.5H2O: Calculated C, 72.57; H, 7.16; N, 7.47, Found C, 72.79; H, 7.08; N, 7.35.

Working Example 153 (Production of Compound 153) To a solution of 7- (4- (l-imidazolyl) phenyl) -2,3-dihydro-l-benzoxepin-4-carboxylic acid (0.13 g), 4- (N -methyl-N- (tetxahydropyran-4-yl) aminomethyl) aniline (0.11 g) and 1-hydroxybenzotriazole (0.07 ml) in dimethylformamide (20 ml) was added l-ethyl-3- (3-dimethylamino-propyl) hydrochloride -carbodiimide (0.13 g) under cooling with ice. Under a nitrogen atmosphere, the mixture was heated to room temperature. To the mixture was added 4-dimethylaminopyridine (catalytic amount) and triethylamine (0.2 ml), and the mixture was stirred overnight. The solvent evaporated, and the residue extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated and the residue was purified with a column of silica gel (ethyl acetate / methanol / triethylamine) to give crude crystals, which were recrystallized with ethanol-hexane to give 7- (4- (1-imidazolyl) phenyl) -N- (4- ((N-tetrahydropyran-4-yl-N-methylamino) methyl) phenyl) -2,3-dihydro-l-benzoxepin-4-carboxamide (Compound 153 ) (0.11 g) as pale yellow crystals, mp 194-195 ° C. NMR-1H (d ppm, CDC13): 1.63-1.80 (4H, m), 2.21 (3H, s), 2.59-2.70 (1H, m), 3.10 (2H, t, J = 4.6Hz), 3.37 (2H , dt, J = 2.6, 11.8Hz), 3.58 (2H, s), 4.00-4.08 (2H, m), 4.39 (2H, t, J = 4.6Hz), 7.11 (1H, d, J = 8.2Hz) , 7.23-7.24 (1H, m), 7.30-7.34 (4H, m), 7.42-7.46 (3H, m), 7.51 (1H, s), 7.57 (2H, d, J = 8.6Hz), 7.65 (2H , d, J = 8.6Hz), 7.84 (1H, broad), 7.91 (1H, s). IR (KBr) V: 2949, 2843, ldSlcm "1. Analysis for C33H34N403- 0.2H2O: Calculated C, 73.64; H, 6.44; N, 10.41. Found C, 73.63; H, 6.23; N, 10.46.

Working Example 154 (Production of Compound 154) To a solution of 7- (4-dimethylaminophenyl) -2,3-dihydro-l-benzoxepin-4-carboxylic acid (0.1 g), 1- (4-aminobenzyl) phosphinan- 1-Oxide (0.08 g) and 1-hydroxybenzotriazole (0.05 g) in dimethylformamide (7 ml) were added 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.1 g) under ice-cooling. Under a nitrogen atmosphere, the mixture was heated to room temperature. To the mixture was added 4-dimethylaminopyridine (catalytic amount) and triethylamine (0.15 ml), and the mixture was stirred overnight. The solvent was evaporated and the residue was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated and the residue was purified with a column of silica gel (ethyl acetate / methanol / triethylamine) to give crude crystals, which were recrystallized with ethanol-hexane to give 7- (4- dimethylaminophenyl) -N- (4- ((1-oxophosphorinan-1-yl) methyl) -phenyl) -2,3-dihydro-1-benzoxepin-4-carboxamide (Compound 154) (0.12 g) as colorless crystals, m.p. 293-294 ° C (dec.). R N-1H (d ppm, CDC13): 1.35-1.55 (2H, m), 1.60-1.75 (6H, m), 1.75-2.05 (2H, m), 3.00 (6H, s), 3.09 (2H, t , J = 4.7Hz), 3.13 (2H, d, J = 13.6Hz), 4.35 (2H, t, J = 4.7Hz), 6.80 (2H, d, J = 8.8Hz), 7.03 (1H, dt J = 8.4Hz), 7.21-7.27 (3H, m), 7.41-7.51 (4H, m), 7.60 (2H, d, J = 8.2Hz), 8.24 (1H, broad). IR (KBr) V: 2940, 1665cm-1. Analysis for C31H35N203P: Calculated C, 72. 35; H, 6 86; N, 5 44 Found C, 72.00; H, 6.84; N, 5.45.

Working Example 155 (Production of Compound 155) To a solution of 7- (4-dimethylaminophenyl) -N- (4- ((1-oxophosphorinan-1-yl) methyl) phenyl) -2, 3-dihydro-l- Benzoxepin-4-carboxamide (0.1 g) in ethanol was added 4N hydrochloric acid-ethyl acetate (0.2 ml) under ice-cooling. The solvent was evaporated and the residue crystallized with ethanol and diethyl ether to give 7- (4-dimethylamino-phenyl) -N- (4- ((1-oxophosphorinan-1-yl) ethyl) phenyl) -2 hydrochloride, 3-dihydro-1-benzoxepin-4-carboxamide (Compound 155) (0.1 g) as colorless crystals. p.f. 162-163 ° C. NMR ^ H (d ppm, DMSO-d6): 1.40-1.50 (2H, m), 1.50-1.90 (8H, m), 2.99 (2H, broad), 3.04 (6H, s), 3.16 (2H, d, J = 13.6Hz), 4.30 (2H, broad), 7.05 (1H, d, J = 8.8Hz), 7.20-7.25 (4H, m), 7.35 (1H, s), 7.54 (1H, dd, J = 2.2 , 8.2, 8.8Hz), 7.63-7.69 (4H, m), 7.74 (1H, d, J = 2.2Hz), 9.97 (1H, s). Analysis for C3? H35N202P -HC1 • 2H20: Calculated C, 63.42; H, 6.87; N, 4.77. Found C, 63.45; H, 6.99; N, 4.39.

Working Example 156 (Production of Compound 156) In methanol (100 ml) and ethyl acetate (150 ml) was dissolved N- (4- (1-tert-butoxycarbonyl) piperidin-2-ylcarbonyl) phenyl) -7- ( 4-methylphenyl) -2,3-dihydro-l-benzoxepin-4-carboxamide (1.0 g) and hydrochloric acid (17 ml) was added to the mixture. The mixture was stirred at room temperature for 2 hours, concentrated and neutralized with a sodium acid carbonate solution. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give crude crystals, which were recrystallized with ethanol-ethyl acetate-hexane to give the N- (4- (piperidin-2-ylcarbonyl) phenyl) -7- (4-methyl- phenyl) -2,3-dihydro-l-benzoxepin-4-carboxamide (Compound 156) (0.6 g) as colorless crystals, mp 195-196 ° C (dec.). NMR-1H (d ppm, CDC13): 1.26-1.49 (2H, m), 1.50-1.70 (2H, m), 1.87-1.94 (2H, m), 2.39 (3H, s), 2.79 (1H, t, J = 12.0Hz), 3.08 (2H, t, J = 4.4Hz), 3.26 (1H, d, J = 12.0Hz), 4.26-4.37 (3H, m), 7.06 (1H, d, J = 8.4Hz) , 7.24 (2H, d, J = 8.4Hz), 7.30 (1H, s), 7.43-7.53 (4H, m), 7.71 (2H, d, J = 8.8Hz), 7.90-7.95 (3H, m). IR (KBr) v: 2934, 1674cm "x Analysis for C30H30N203- 0.3H2O: Calculated C, 76.34; H, 6.53; N, 5.94, Found C, 76.35; H, 6.44; N, 5.88.

Working Example 157 (Production of Compound 157) In dichloromethane (35 ml) was dissolved N- (4- (piperidin-2-ylcarbonyl) phenyl) -7- (4-methylphenyl) -2, 3-dihydro-l- benzoxepin-4-carboxamide (1.3 g) and to the solution were added methyl iodide (0.08 ml) and diisopropylethylamine (0.17 ml). The mixture was stirred at room temperature overnight. The solvent was evaporated, and water was added to the residue. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated and the residue was purified with a column of silica gel (ethyl acetate / methanol / triethylamine) to give crude crystals, which were recrystallized with ethyl acetate-hexane to give the N- ( 4- (L-methylpiperidin-2-ylcarbonyl) phenyl) -7- (4-methylphenyl) -2,3-dihydro-l-benzoxepin-4-carboxamide (Compound 157) (0.17 g) as colorless crystals, m.p. 162-163. NMR ^ H (d ppm, CDC13): 1.27-1.45 (2H, m), 1.50-1.90 (4H, m), 2.04-2.20 (1H, m), 2.21 (3H, s), 2.39 (3H, s) , 3.00-3.05 (1H, m), 3.08 (2H, t, J = 4.6Hz), 3.48 (1H, d, J = 7.6Hz), 4.36 (2H, t, J = 4.6Hz), 7.06 (1H, d, J = 8.0Hz), 7.25 (2H, d, J = 12.4Hz), 7.43-7.51 (4H, m), 7.69 (2H, d, J = 8.8Hz), 7.81 (1H, s), 8.18 ( 2H, d, J = 8.4Hz). IR (KBr) v: 2940, 1667cm "a.Analysis for C3? H32N203: Calculated C, 77.47; H, 6.71; N, 5.83, Found C, 77.22; H, 6.71; N, 5.63.

Working Example 158 (Production of Compound 158) In methanol (40 ml) was dissolved N- (4- (l-methyl-piperidin-2-ylcarbonyl) phenyl) -7- (4-methylphenyl) -2, 3- dihydro-l-benzoxepin-4-carboxamide (1.0 g) under cooling with ice and sodium borohydride (10 mg) was added to the mixture. The mixture was stirred for 15 hours, and water was added to the mixture. The mixture was concentrated and extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, and dried with anhydrous magnesium sulfate.

Under reduced pressure, the solvent was evaporated and the residue was purified with a column of silica gel (ethyl acetate / methanol / triethylamine) to give crude crystals, which were recrystallized with ethanol-ethyl acetate-hexane to give the N- (4- (hydroxy (l-methylpiperidin-2-yl) methyl) phenyl) - 7- (4-methylphenyl) -2,3-dihydro-l-benzoxepin-4-carboxamide (Compound 158) (0.07 g) as colorless crystals, m.p. 195-196. NMR-aH (d ppm, CDC13): 0.95-1.05 (2H, m), 1.25-1.40 (2H,), 2.04-2.30 (4H, m), 2.39 (3H, s), 2.50 (3H, s), 2.95-3.01 (1H, m), 3.08 (2H, t, J = 4.6Hz), 4.36 (2H, t, J = 4.6Hz), 5.16 (1H, d, J = 3.0Hz), 7.06 (1H, d , J = 8.4Hz), 7.24 (2H, d, J = 8.0Hz), 7.33 (2H, d, J = 8.4Hz), 7.43-7.52 (4H, m), 7.56 (2H, d, J = 8.4Hz ), 7.61 (1H, s).

IR (KBr) v: 3287, 2938, 1647cm "1. Analysis for C3? H34N2? 3 'O .6H20: Calculated C, 75.46; H, 7.19; N, 5.68. Found C, 75.36; H, 7.33; N, 5.76.

Working Example 159 (Production of Compound 159) Under a nitrogen atmosphere, oxalyl chloride (0.31 ml) was added to a solution of 7- (4-methylphenyl) -2,3-dihydro-benzoxepin-4-carboxylic acid ( 0.65 g) in tetrahydrofuran (10 ml) at room temperature. To the mixture was added a drop of DMF, and the mixture was stirred for 1 hour. Under reduced pressure, the solvent was evaporated and the residue was dissolved in tetrahydrofuran (15 ml). To the solution were added triethylamine (0.65 ml) and 2- (4-aminophenyl) pyridine (J. Chem. Soc., P.1511, 1960) (0.44 g) at 0 ° C, and the mixture was stirred at room temperature. for 2 hours. The reaction mixture was added to water stirred vigorously to stop the reaction. The mixture was extracted with ethyl acetate. The precipitated crystal was collected by filtration to give N- [4- (2-pyridyl) phenyl] -7- (4-methylphenyl) -2,3-dihydro-l-benzoxepin-4-carboxamide (Compound 159) (185.9 mg) as colorless crystals. The mother liquor was concentrated and recrystallized from ethyl acetate-tetrahydrofuran to give N- [4- (2-pyridyl) phenyl] -7- (4-methylphenyl) -2,3-dihydro-l-benzoxepin-4- carboxamide (Compound 159) (0.58 g) as pale yellow crystals, mp 228-229 ° C NMR-aH (200MHz, CDC13) d 2.39 (3H, s), 3.09 (2H, t, J = 4.4 Hz), 4.36 (2H, t, J = 4.4Hz), 7.06 (1H, d , J = 8.2Hz), 7.16-7.32 (4H, m), 7.42-7.56 (4H, m), 7.68-7.82 (5H, m), 8.02 (2H, dd, J = 8.8, 2.0 Hz), 8.65 -8.73 (1H, dt, J = 4.8, 1.4 Hz). IR (KBr) 3338, 1645, 1593, 1516, 1493, 1466, 1435, 1323, 1248, 810, 777 cm "1 Elemental Analysis for C29H24N202 Calculated C, 80.53; H, 5.59; N, 6.48: Found C, 80.46; H, 5.62; N, 6.46.

Working Example 160 (Production of Compound 160) To a suspension of N- [4- (2-pyridyl) phenyl] -7- (4-methylphenyl) -2,3-dihydro-l-benzoxepin-4-carboxamide (400 mg) in dichloromethane (10 ml) was added 3-chloroperbenzoic acid (70%, 0.25 g) at 0 ° C, and the mixture was stirred at room temperature for 70 hours. To the mixture was added a solution of sodium thiosulfate, and the mixture was stirred for minutes. The mixture was extracted with dichloromethane. The organic layer was washed with a saturated sodium bicarbonate solution and a saturated sodium chloride solution, and dried with magnesium sulfate. The mixture was concentrated, purified by column chromatography (ethanol / ethyl acetate = 1: 1) to give crystals, which were dissolved in chloroform. The mixture was concentrated, and ethanol was added to the residue. The precipitated crystal was collected by filtration to give crystals, which were washed with ethanol to give N- [4- (l-oxidopyridin-2-yl) phenyl] -7- (4-methylphenyl) -2, 3-dihydro -l-benzoxepin-4-carboxamide (Compound 160) (60 mg) as colorless crystals, m.p. 254 ° C (dec.) NMR-1H (200MHz, CDC13) d 2.40 (3H, s), 3.06 (2H, t, J = 4.4 Hz), 4.36 (2H, t, J = 4.4 Hz), 7.00-7.14 (2H, m), 7.16-7.30 (4H, m), 7.38-7.51 (5H, m), 7.67 (2H, d, J = 8.6 Hz), 7.78 (2H, d, J = 8.8 Hz), 8.19 ' (1H, d, J = 7.0 Hz), 8.38-8.48 (1H, m). IR (KBr) 3334, 3039, 1653, 1487, 1240, 814, 760 cm "1 Elemental Analysis for C29H24N203 '0.5H20 Calculated C, 76.13; H, 5.51; N, 6.12: Found C, 75.82; H, 5.27; N , 6.18.

Working Example 161 (Production of Compound 161) Under a nitrogen atmosphere, oxalyl chloride (0.19 ml) was added to a solution of 7- (4-methylphenyl) -2,3-dihydro-l-benzoxepin-4-acid. carboxylic acid (0.40 g) in tetrahydrofuran (10 ml) at room temperature. To the mixture was added a drop of DMF, and the mixture was stirred for 1 hour. Under reduced pressure, the solvent was evaporated and the residue was dissolved in tetrahydrofuran (6 ml). To the solution were added triethylamine (0.40 ml) and a solution of 2- (4-aminobenzyl) pyridine (0.29 g) in tetrahydrofuran (5 ml) at 0 ° C, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was added to water stirred vigorously to stop the reaction. The mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with magnesium sulfate, concentrated and recrystallized from ethyl acetate to give N- [4- (2-pyridylmethyl) phenyl] -7- (4 -methylphenyl) -2,3-dihydro-l-benzoxepin-4-carboxamide (Compound 161) (303 mg) as colorless crystals. p.f. 189-190 ° C NMR-aH (200MHz, CDCl 3) d 2.39 (3H, s), 3.06 (2H, t, J = 4.6 Hz), 4.14 (2H, s), 4.35 (2H, t, J = 4.6 Hz ), 7.03-7.16 (3H, m), 7.18-7.31 (5H,), 7.40-7.64 (8H, m), 8.52-8.58 (1H, m). IR (KBr) 3338, 1645, 1510, 1493, 1414, 1313, 1252, 1234, 816, 750 cm "1. Elemental Analysis for C30H24N2O2 Calculated C, 80.69; H, 5.87; N, 6.27 Found C, 80.63; H, 5.80; N, 6.37 Working Example 162 (Production of Compound 162) To a solution of N- [4- (2-pyridylmethyl) phenyl] -7- (4-methylphenyl) -2,3-dihydro-l-benzoxepin-4-carboxamide (200 mg) in tetrahydrofuran (10 ml) was added 3-chloroperbenzoic acid (70%, 0.18 g) at 0 ° C, and the mixture was stirred at room temperature for 17 hours. To the reaction mixture was added a solution of sodium thiosulfate, and the mixture was stirred for a few minutes. The mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium bicarbonate solution and a saturated sodium chloride solution, and dried with magnesium sulfate and concentrated to give crystals, which were collected by filtration and recrystallized with ethanol to give the N- [4- (l-Oxidopyridin-2-ylmethyl) phenyl] -7- (4-methylphenyl) -2,3-dihydro-l-benzoxepin-4-carboxamide (Compound 162) (124 mg) as colorless crystals, pf 188-190 ° C NMR-aH (200MHz, CDC13) d 2.39 (3H, s), 3.09 (2H, t, J = 4.6 Hz), 4.24 (2H, s), 4.36 (2H, t, J = 4.6 Hz ), 6.90-7.01 (1H, m), 7.06 (1H, d, J = 8.4 Hz), 7.11-7.16 (2H, m), 7.22-7.29 (5H, m), 7.43-7.51 (4H, m), 7.54-7.76 (3H, m), 8. 24-8.31 (1H, m). IR (KBr) 3319, 1666, 1601, 1517, 1491, 1412, 1319, 1246, 813 cm "1 Elemental Analysis for C30H26N2O3 • 0 .3H20 Calculated C, 77.00; H, 5.73; N, 5.99: Found C, 76.98; H, 5.59; N, 6.10.

Working Example 163 (Production of Compound 163) Under a nitrogen atmosphere, oxalyl chloride (0.07 ml) was added to a solution of 7- (4-methylphenyl) -2,3-dihydro-l-benzoxepin-4-acid. carboxylic acid (144.8 mg) in tetrahydrofuran (10 ml) at room temperature. To the mixture was added a drop of DMF, and the mixture was stirred for 1 hour. Under reduced pressure, the solvent was evaporated and the residue was dissolved in tetrahydrofuran (10 ml). To the solution was added triethylamine (0.14 ml) and a solution of 4-aminobenzyldiethylphosphine oxide (120 mg) in tetrahydrofuran (5 ml) at 0 ° C, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was added to water stirred vigorously to stop the reaction. The mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with magnesium sulfate, concentrated and recrystallized with ethanol-tetrahydrofuran to give N- (4-diethylphosphoryl-methylphenyl) -7- (4-methylphenyl) -2, 3-dihydro-l-benzoxepin-4-carboxamide (Compound 163) (157 mg) as colorless crystals, mp. 240-241 ° C NMR-'H (200MHz, CDC13) d 1.13 (6H, dt, J = 16.4, 8.0 Hz), 1.53-1.72 (4H, m), 2.39 (3H, s), 3.06-3.13 (4H , m), 4.36 (2H, t, J = 4.8 Hz), 7.06 (1H, d, J = 8.4 Hz), 7.22-7.27 (5H, m), 7.44-7.52 (4H, m), 7.58 (2H, d, J = 8.4 Hz), 7.98 (1H, s). IR (KBr) 3263, 1653, 1599, 1516, 1491, 1410, 1319, 1250, 1173, 1132, 843, 808 cm "1 Elemental Analysis for C29H32N03P Calculated C, 73.55; H, 6.81; N, 2.96; P, 6.54 : Found C, 73.23; H, 6.64; N, 3.01; P, 6.63.

Working Example 164 (Production of Compound 164) Under a nitrogen atmosphere, oxalyl chloride (0.28 ml) was added to a solution of 7- (4-methylphenyl) -2,3-dihydro-l-benzoxepin-4-acid. carboxylic (0.60 g) in tetrahydrofuran (10 ml) at room temperature. To the mixture was added a drop of DMF, and the mixture was stirred for 1 hour. Under reduced pressure, the solvent was evaporated and the residue was dissolved in tetrahydrofuran (10 ml). To the solution were added triethylamine (0.60 ml) and 3- (4-aminophenyl) pyridine (J. Cbem. Soc., P.1511, 1960) (0.40 g) at 0 ° C, and the mixture was stirred at room temperature. for 2 hours. The reaction mixture was added to water stirred vigorously to stop the reaction. The mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with magnesium sulfate, concentrated and recrystallized from ethanol to give N- [4- (3-pyridyl) phenyl] -7- (4-methyl) phenyl) -2,3-dihydro-l-benzoxepin-4-carboxamide (Compound 164) (750 mg) as yellow crystals, mp 214-216 ° C NMR-aH (200MHz, CDC13) d 2.39 (3H, s), 3.07-3.11 (2H, m), 4.34-4.39 (2H, m), 7.06 (1H, d, J = 8.2 Hz) , 7.18-7.63 (10H, m), 7.71-7.90 (4H, m), 8.57-8.59 (1H, m), 8.85 (1H, d, J = 1.8 Hz). IR (KBr) 3313, 1666, 1524, 1493, 1321, 1244, 808 cm "1 Elemental Analysis for C29H24N202-0.2H20 Calculated 'C, 79.87; H, 5.64; N, 6.42: Found C, 80.00; H, 5.59; N, 6.00.

Working Example 165 (Production of Compound 165) To a solution of N- [4- (3-pyridyl) phenyl] -7- (4-methylphenyl) -2,3-dihydro-l-benzoxepin-4-carboxamide (400 mg) in dichloromethane (50 ml) was added 3-chloroperbenzoic acid (70%, 0.34 g) at 0 ° C, and the mixture was stirred at room temperature for 68 hours. To the reaction mixture was added a solution of sodium thiosulfate, and the mixture was stirred for a few minutes and extracted with dichloromethane. The organic layer was washed with a saturated sodium bicarbonate solution and a saturated sodium chloride solution, and dried with magnesium sulfate and concentrated. The residue was separated and purified by column chromatography (ethanol / ethyl acetate = 1: 1) and crystallized with ethanol-chloroform to give N- [4- (1-oxypyridin-3-yl) phenyl] - 7- (4-methylphenyl) -2, 3-dihydro-l-benzoxepin-4-carboxamide (Compound 165) (216 mg) as pale yellow crystals. p.f. 262 ° C (dec.) RMN- ^ H (200MHz, CDC13) d 2.40 (3H, s), 3.10 (2H, t, J = 4.4 Hz), 4.38 (2H, t, J = 4.4 Hz), 7.07 ( 1H, d, J = 8.4Hz), 7.23-7.36 (4H, m), 7.42-7.58 (7H, m), 7.76 (2H, dd, J = 8.8, 2.0 Hz), 7.88 (1H, broad s), 8.16-8.20 (1H, m), 8.43-8.47 (1H, m). IR (KBr) 3313, 1655, 1599, 1525, 1491, 1244, 1203, 814 cm "1 Elemental Analysis for C29H24N203 - 0. 1H20 Calculated C, 77.35; H, 5.42; N, 6.22: Found C, 77.13; H, 5.28; N, 6.21.

Working Example 166 (Production of Compound 166) Under a nitrogen atmosphere, oxalyl chloride (0.19 ml) was added to a solution of 7- (4-methylphenyl) -2,3-dihydro-l-benzoxepin-4-acid. carboxylic acid (0.40 g) in tetrahydrofuran (10 ml) at room temperature. To the mixture was added a drop of DMF, and the mixture was stirred for 1 hour. Under reduced pressure, the solvent was evaporated and the residue was dissolved in tetrahydrofuran (10 ml). To the solution, triethylamine (0.40 ml) and (4-aminophenyl) - (2-pyridyl) methanol (0.31 g) were added at 0 ° C and the mixture was stirred at room temperature for 18 hours. The reaction mixture was added to water stirred vigorously to stop the reaction. The mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with magnesium sulfate, concentrated and recrystallized from ethanol-ethyl acetate to give N- [4- [hydroxy (2-pyridyl) -methyl] phenyl] -7- (4-methylphenyl) -2,3-dihydro-l-benzoxepin-4-carboxamide (Compound 166) (549 mg) as pale yellow crystals, mp. 215-217 ° C NMR-aH (200MHz, CDC13) d 2.39 (3H, s), 3.06 (2H, t, J = 4.4 Hz), 4.34 (2H, t, J = 4.4 Hz), 5.26-5.38 (1H , m), 5.70-5.78 (1H, m), 7.03-7.27 (6H, m), 7.33-7.79 (10H, m), 8.57 (1H, d, J = 4.8 Hz). IR (KBr) 3392, 1651, 1537, 1514, 1493, 1319, 1248 c "1 Elemental Analysis for C3oH2e-N2? 3 '0. 2H20 Calculated C, 77.30; H, 5.71; N, 6.01: Found C, 77.21; H, 5.75; N, 5.86.

Working Example 167 (Production of Compound 167) To a solution of N- [4- [hydroxy (2-pyridyl) methyl] -phenyl] -7- (4-methylphenyl) -2,3-dihydro-1-benzoxepin- 4-carboxamide (351.3 mg) in tetrahydrofuran (20 ml) was added 3-chloroperbenzoic acid (70%, 0.28 g) at 0 ° C, and the mixture was stirred at room temperature for 16 hours. To the reaction mixture was added a solution of sodium thiosulfate, and the mixture was stirred for a few minutes. The mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium bicarbonate solution and a saturated sodium chloride solution, and dried with magnesium sulfate and concentrated. The residue was separated and purified by column chromatography (ethanol-diethyl ether = 1: 1) and recrystallized from ethanol to give N- [4- [hydroxy (l-oxidopyridin-2-yl) methyl] phenyl] -7- (4-methylphenyl) -2,3-dihydro-l-benzoxepin-4-carboxamide (Compound 167) (184 mg) as colorless crystals. p.f. 208-210 ° C NMR-1H (200MHz, CDC13) d 2.40 (3H, s), 3.09 (2H, t, J = 4.4 Hz), 4.37 (2H, t, J = 4.5 Hz), 6.07 (1H, d , J = 4.5 Hz), 6.41 (1H, d, J = 4.6 Hz), 6.93-6.98 (1H, m), 7.06 (1H, d, J = 8.4 Hz), 7.20-7.31 (5H, m), 7.41 -7.55 (6H, m), 7.65 (2H, d, J = 8.8 Hz), 7.73 (1H, broad s), 8.24-8.28 (1H, m). IR (KBr) 3427, 1645, 1599, 1531, 1514, 1491, 1317, 1263 cm "1 Elemental Analysis for C30H26N2? 4 • 0.1H20 Calculated C, 75.01; H, 5.50; N, 5.83: Found C, 74.96; H 5.36; N, 5.73.

Working Example 168 (Production of Compound 168) Under a nitrogen atmosphere, oxalyl chloride (0.2 ml) was added to a solution of 7- (4-methylphenyl) -2,3-dihydro-l-benzoxepin-4-acid. carboxylic acid (400 mg) in tetrahydrofuran (10 ml) at room temperature. To the mixture was added a drop of DMF, and the mixture was stirred for 1 hour. Under reduced pressure, the solvent was evaporated and the residue was dissolved in tetrahydrofuran (10 ml). To the solution was added triethylamine (0.4 ml) and 4-amino-benzyldipropylphosphine oxide (0.38 mg) at 0 ° C, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was added to water stirred vigorously to stop the reaction. The mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with magnesium sulfate and concentrated. The residue was separated and purified with column chromatography (Ethanol / ethyl acetate = 1: 5), and recrystallized with ethanol to give the N- (4-dipropylphosphorylmethylphenyl) -7- (4-methylphenyl) -2, 3-dihydro-1-benzoxepin-4-carboxamide ( Compound 168) (456 mg) as colorless crystals, mp 219-220 ° C NMR-aH (200MHz, CDC13) d 0.84-0.98 (6H, m), 1.41-1.63 (8H, m), 2.39 (3H, s), 3.02 (2H, d, J = 13.2 Hz), 3.09 (2H, t, J = 4.4 Hz), 4.35 (2H, t, J = 4.4Hz), 7.06 (1H, d, J = 8.0Hz), 7.13-7.29 (5H, m), 7.44-7.48 (3H, m), 7.53 (1H, d, J = 2.2 Hz), 7.61 (2H, d, J = 8.0 Hz), 8.64 (1H, s). IR (KBr) 3386, 2960, 1653, 1518, 1491, 1319, 1248, 1185, 1128, 849 cm "1 Elemental Analysis for C31H36N03P • 0.3H20 Calculated C, 73.44; H, 7.28; N, 2.76; P, 6.11: Found C, 73.35; H, 7.40; N, 2.62; P, 6.35.

Working Example 169 (Production of Compound 169) Under a nitrogen atmosphere, oxalyl chloride (0.17 ml) was added to a solution of 7- (4-methylphenyl) -2,3-dihydro-l-benzoxepin-4-acid. carboxylic acid (350 mg) in tetrahydrofuran (10 ml) at room temperature. To the mixture was added a drop of DMF, and the mixture was stirred for 1 hour. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in tetrahydrofuran (10 ml). To the solution was added triethylamine (0.35 ml) and (4-aminophenyl) (3-methoxy-pyridin-2-yl) methanol (316 mg) at 0 ° C, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was added to water stirred vigorously to stop the reaction. The mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with magnesium sulfate and concentrated. The residue was separated and purified by column chromatography (ethyl acetate), and recrystallized with tetrahydrofuran-hexane to give N- [4- [hydroxy (3-methoxy-pyridin-2-yl) methyl] -phenyl ] -7- (4-methylphenyl) -2,3-dihydro-l-benzoxepin-4-carboxamide (Compound 169) (509 mg) as colorless crystals. p.f. 232-233 ° C RM ^ H (200MHz, CDC13) d 2.39 (3H, s), 3.05 (2H, t, J = 4.8 Hz), 3.77 (3H, s), 4.34 (2H, t, J = 4.8 Hz ), 5.51 (1H, d, J = 6.8 Hz), 5.93 (1H, d, J = 6.8Hz), 7.05 (1H, d, J = 8.0 Hz), 7.10-7.26 (5H, m), 7.34-7.54 (9H, m), 8.18 (1H, d, J = 5.2 Hz). IR (KBr) 3354, 1651, 1518, 1491, 1412, 1311, 1279, 1240, 1211, 1022, 816 cm "1 Elemental Analysis for C3? H28N204 Calculated C, 75.59; H, 5.73; N, 5.69: Found C, 75.47; H, 5.61; N, 5.70.

Working Example 170 (Production of Compound 170) To a solution of N- [4- [hydroxy (3-methoxypyridin-2-yl) methyl] phenyl] -7- (4-methylphenyl) -2,3-dihydrole -benzoxepin-4-carboxamide (350 mg) in tetrahydrofuran (30 ml) was added 3-chloroperbenzoic acid (70%, 0.26 g) at 0 ° C, and the mixture was stirred at room temperature for 64 hours. To the mixture was added sodium thiosulfate, and the mixture was stirred for a few minutes and extracted with ethyl acetate. The organic layer was washed with a saturated sodium bicarbonate solution and a saturated sodium chloride solution, and dried with magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified with column chromatography (ethyl acetate-> ethanol / ethyl acetate = 1: 4) was recrystallized with tetrahydrofuran-hexane to give N- [4- [hydroxy (3-methoxy) L-Oxidopyridin-2-yl) methyl] phenyl] -7- (4-methylphenyl) -2,3-dihydro-l-benzoxepin-4-carboxamide (Compound 170) (168 mg) as colorless crystals, mp 242 ° C (dec.) NMR-1H (200MHz, CDC13) d 2.39 (3H, s), 3.06 (2H, t, J = 4.4 Hz), 3.97 (3H, s), 4.35 (2H, t, J = 4.4Hz), 6.34 (1H, d, J = 11.4 Hz), 6.97 (1H, d, J = 7.8Hz), 7.05 (1H, d, J = 8.2 Hz), 7.14-7.27 (4H, m), 7.42 -7.53 (8H, m), 7.61 (1H, broad s), 7.84 (1H, d, J = 6.6 Hz), 7.87 (1H, d, J = 11.2 Hz). IR (KBr) 3493, 3294, 2953, 1657, 1601, 1516, 1493, 1323, 1207, 1184, 1088, 1043, 817 cm "1 Elemental Analysis for C31H28N202 • 0.2H20 Calculated C, 72.70; H, 5.59; N, 5.47: Found C, 72.53; H, 5.64; N, 5.36.

Working Example 171 (Production of Compound 171) Under a nitrogen atmosphere, oxalyl chloride (0.12 ml) was added to a solution of 7- (4-methylphenyl) -2,3-dihydro-l-benzoxepin-4-acid. carboxylic acid (250 mg) in tetrahydrofuran (10 ml) at room temperature. To the mixture was added a drop of DMF, and the mixture was stirred for 1 hour. Under reduced pressure, the solvent was evaporated and the residue was dissolved in tetrahydrofuran (10 ml). To the solution were added triethylamine (0.25 ml) and 1- (4-aminobenzyl) -phosphorane-1-oxide (204.8 mg) at 0 ° C, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was added to water stirred vigorously to stop the reaction. The mixture was extracted with ethyl acetate and the organic layer was washed with a saturated sodium chloride solution, concentrated and recrystallized from ethanol to give N- (4- (tetramethylene) phosphoryl-methylphenyl) -7- (4 -methylphenyl) -2,3-dihydro-benzoxepin-4-carboxamide (Compound 171) (316 mg) as colorless crystals, m.p. 273-275 ° C NMR-aH (200MHz, CDC13) d 1.43-1.97 (8H, m), 2.40 (3H, s), 3.09 (2H, t, J = 4.4 Hz), 3.20 (2H, d, J = 14.4 Hz), 4.40 (2H, t, J = 4.4 Hz), 7.06 (1H, d, J = 8.4 Hz), 7.18-7.29 (5H, m), 7.44-7.54 (4H,), 7.60 (2H, d , J = 8.0 Hz), 8.12-8.23 (1H, m). IR (KBr) 3223, 2952, 1653, 1518, 1491, 1321, 1254, 1186, 810 c "1. Elemental Analysis for Calculated C29H30NO3P C, 73.87; H, 6.41; N, 2.97; P, 6.57: Found C, 73.79; H, 6.33; N, 3.00; P, 6.59.

Working Example 172 (Production of Compound 172) Under a nitrogen atmosphere, oxalyl chloride (0.47 ml) was added to a solution of 7- (4-methylphenyl) -2,3-dihydro-l-benzoxepin-4-acid. carboxylic acid (1.0 g) in tetrahydrofuran (20 ml) at room temperature. To the mixture was added a drop of DMF, and the mixture was stirred for 1 hour. Under reduced pressure, the solvent was evaporated and the residue was dissolved in tetrahydrofuran (20 ml) at 0 ° C. To the solution was added triethylamine (1.0 ml) and 2- (4-aminobenzyl) -3-methoxymethoxypyridine (0.96 g), and the mixture was stirred at room temperature for 4 hours. The reaction mixture was added to water stirred vigorously to stop the reaction. The mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with magnesium sulfate and concentrated. The residue was separated and purified by column chromatography (ethyl acetate / hexane = 2: 1) to give N- [4- (3-methoxymethoxy-pyridin-2-ylmethyl) phenyl] -7- (4- methylphenyl) -2,3-dihydro-l-benzoxepin-4-carboxamide (Compound 172) (1.63 mg) as orange crystals. NMR-aH (200MHz, CDC13) d 2.39 (3H, s), 3.03 (2H, t, J = 4.4 Hz), 3.37 (3H, s), 4.18 (2H, s), 4.32 (2H, t, J = 4.4 Hz), 5.17 (2H, s), 7.03 (1H, d, J = 8.0 Hz), 7.10 (1H, dd, J = 8.4, 4.8 Hz), 7.19-7.51 (12H, m), 7.62 (1H, s broad), 8.20 (lH, dd, J = 4.8, 1.2 Hz).

IR (KBr) 3275, 2945, 1659, 1516, 1444, 1406, 1491, 1313, 1240, 1153, 982, 814 cm " Working Example 173 (Production of Compound 173) To a solution of N- [4- (3-methoxymethoxypyridin-2-ylmethyl) phenyl] -7- (4-methylphenyl) -2,3-dihydro-l-benzoxepin-4 -carboxamide (300 mg) in tetrahydrofuran (10 ml) was added 3-chloroperbenzoic acid (70%, 0.22 g) at 0 ° C, and the mixture was stirred at room temperature for 18 hours. Sodium thiosulfate was added to the mixture, and the mixture was stirred for a few minutes. The mixture was extracted with ethyl acetate, and the organic layer was washed with a saturated sodium bicarbonate solution and a saturated sodium chloride solution, and dried with magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by column chromatography (ethanol / ethyl acetate = 1: 15-> 1: 10) and recrystallized from ethanol to give N- [4- (l-oxide-3-methoxymethoxypyridine. -2-ylmethyl) phenyl] -7- (4-methyl-phenyl) -2,3-dihydro-l-benzoxepin-4-carboxamide (Compound 173) (203 mg) as colorless crystals, m.p. 206-208 ° C NMR-1H (200MHz, CDC13) d 2.39 (3H, s), 3.06 (2H, t, J = 4.6 Hz), 3.44 (3H, s), 4.35 (2H, t, J = 4.6 Hz ), 4.37 (2H, s), 5.24 (2H, s), 6.96-7.08 (3H, m), 7.19-7.27 (4H, m), 7.38-7.52 (7H, m), 7.62 (1H, s broad) 7.99 (1H, dd, J = 5.0, 2.2 Hz). IR (KBr) 3305, 1653, 1601, 1516, 1491, 1321, 1244, 1053, 818 cm "1 Elemental Analysis for C32H3o 3? 5 • 0.2H20 Calculated C, 73.04; H, 5.82; N, 5.32: Found C, 72.96; H, 5.72; N, 5.30.

Working Example 174 (Production of Compound 174) To a solution of N- [4- (3-methoxymethoxypyridin-2-ylmethyl) phenyl] -7- (4-methylphenyl) -2,3-dihydro-l-benzoxepin-4 -carboxamide (1.00 mg) in ethanol (20 ml) was added concentrated hydrochloric acid (5.0 ml), and the mixture was stirred at room temperature for 4 days. To the mixture was added a solution of saturated sodium bicarbonate at 0 ° C to make the solution pH 6-7, and the precipitated crystal was collected by filtration to give the N- [4- (3-hydroxy-pyridin-2- ylmethyl) phenyl] -7- (4-methylphenyl) -2,3-dihydro-l-benzoxepin-4-carboxamide (Compound 174) (693 mg) as pale yellow crystals. p.f. 285-288 ° C NMR-aH (200MHz, DMS0-d6) d 2.34 (3H, s), 2.97 (2H, t, J = 4.4 Hz), 4.00 (2H, s), 4.28 (2H, t, J = 4.4 Hz), 7.02-7.32 (8H, m), 7.49-7.64 (5H, m), 7.73 (1H, d, J = 2.2 Hz), 7. 95 (1H, dd, J = 4.4, 1.4 Hz), 9.86 (1H, broad s). IR (KBr) 3390, 3028, 1651, 1510, 1408, 1284, 1236, 808 cm "1 Elemental Analysis for C3oH26N2? 3 - 0, 2H20 Calculated C, 77.30; H, 5.71; N, 6.01: Found C, 77.20; H, 5.63; N, 5.89.

Working Example 175 (Production of Compound 175) To a suspension of N- [4- (3-hydroxypyridin-2-ylmethyl) phenyl] -7- (4-methylphenyl) -2,3-dihydro-l-benzoxepin- acid 4-carboxamide (400 mg) in tetrahydrofuran (30 ml) was added 3-chloroperbenzoic acid (70%, 0.32 g) at 0 ° C, and the mixture was stirred at room temperature for 15 hours. To the mixture was added sodium thiosulfate and the mixture was stirred for a few minutes and extracted with ethyl acetate. The organic layer was washed with a saturated sodium bicarbonate solution and a saturated sodium chloride solution, dried with magnesium sulfate, concentrated under reduced pressure and recrystallized from ethanol to give the N- [4- (1-) Oxide-3-hydroxypyridin-2-ylmethyl) phenyl] -7- (4-methylphenyl) -2,3-dihydro-l-benzoxepin-4-carboxamide (Compound 175) (262 mg) as pale yellow crystals. p.f. 254 ° C (dec.) 1 H-NMR (200MHz, DMSO-d 6) d 2.34 (3H, s), 2.92-3.02 (2H, m), 4.14 (2H, s), 4.23-4.34 (2H, m), 6.87 (1H, d, J = 7.4 Hz), 7.04 (1H, d, J = 8.6 Hz), 7.11 (1H, dd, J = 8.4.66) Hz), 7.18-7.36 (5H, m), 7.48-7.61 (5H, m), 7.73 (1H, d, J = 2.2 Hz), 7.83 (1H, dd, J = 6.4, 1.0 Hz), 9.88 (1H, s).

IR (KBr) 3180, 3102, 1651, 1601, 1537, 1516, 1493, 1437, 1227, 1036, 816 cm "1 Elemental Analysis for C3oH26N2? 4 • 0 .2H20 Calculated C, 74.73; H, 5.52; N, 5.81: Found C, 74.63; H, 5.35; N, 5.55.

Working Example 176 (Production of Compound 176) Under a nitrogen atmosphere, oxalyl chloride (0.12 ml) was added to a solution of 7- (4-methylphenyl) -2,3-dihydro-benzoxepin-4-carboxylic acid ( 250 mg) in tetrahydrofuran (10 ml) at room temperature.

To the mixture was added a drop of DMF, and the mixture was stirred for 1 hour. Under reduced pressure, the solvent was evaporated. The residue was dissolved in tetrahydrofuran (15 ml) and triethylamine (0.25 ml) and 1- (4-aminobenzyl) phosphorine-1-oxide (219.0 mg) were added to the solution. 0 ° C. The mixture was stirred at room temperature for 4 hours, added to vigorously stirred water to stop the reaction and extracted with chloroform. The organic layer was washed with a saturated sodium chloride solution, dried with magnesium sulfate, concentrated and recrystallized from ethanol to give N- (4- (pentamethylene) phosphorylmethyl-phenyl) -7- (4-methylphenyl). ) -2, 3-dihydro-l-benzoxepin-4-carboxamide (Compound 176) (253 mg) as colorless crystals, m.p. 283-286 ° C. NMR-aH (200MHz, CDC13) d 1.32-2.09 (10H, m), 2.39 (3H, s), 3.04-3.18 (4H, m), 4.36 (2H, t, J = 4.6 Hz), 7.06 (1H, d, J = 8.4 Hz), 7.19-7.29 (5H, m), 7.44-7.48 (3H, m), 7.53 (1H, d, J = 2.6 Hz), 7.59 (2H, d, J = 8.4 Hz), 8.09 (1H, broad s). IR (KBr) 3217, 2927, 1655, 1599, 1516, 1493, 1321, 1255, 1236, 1167, 1134, 847, 810 cm "1 Elemental Analysis for C3oH32N03P Calculated C, 74.21; H, 6.64; N, 2.88; P , 6.38: Found C, 73.96; H, 6.53; N, 3.11; P, 6.56.

Working Example 177 (Production of Compound 177) Under a nitrogen atmosphere, oxalyl chloride (0.06 ml) was added to a solution of 7- (4-methylphenyl) -2,3-dihydro-l-benzoxepin-4-acid. carboxylic (120 mg) in tetrahydrofuran (10 ml) at room temperature. To the mixture was added a drop of DMF, and the mixture was stirred for 1 hour. Under reduced pressure, the solvent was evaporated and the residue was dissolved in tetrahydrofuran (10 ml). To the solution were added triethylamine (0.12 ml) and 4- [N-methyl-N- (tetrahydro-pyran-4-yl) aminomethyl] -aniline (99 mg) at 0 ° C, and the mixture was stirred at room temperature during 3 hours. The reaction mixture was added to water stirred vigorously to stop the reaction. The mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with magnesium sulfate and concentrated. The residue was purified with column chromatography (ethanol / ethyl acetate = 1: 5) and recrystallized from ethyl acetate to give N- [4- [N-methyl-N- (tetrahydropyran-4-yl) aminomethyl) ] -phenyl] -7- (4-ethylphenyl) -2, 3-dihydro-l-benzoxepin-4-carboxamide (Compound 177) (99 mg) as colorless crystals, m.p. 181-182 ° C NMR-1H (200MHz, CDC13) d 1.28 (3H, t, J = 7.6 Hz), 1.60-1.82 (4H, m), 2.21 (3H, s), 2.57-2.61 (1H, m) , 2.69 (2H, q, J = 7.6 Hz), 3.09 (2H, t, J = 4.6 Hz), 3.37 (2H, dt, J = 3.3, 11.1Hz), 3.58 (2H, s), 3.98-4.09 ( 2H, m), 4.37 (2H, t, J = 4.6 Hz), 7.06 (1H, d, J = 8.4 Hz), 7.23-7.36 (5H, m), 7.44-7.58 (7H, m). IR (KBr) 3305, 2960, 1647, 1539, 1514, 1491, 1321, 820 cm -1 Elemental Analysis for C32H36N203 Calculated C, 77.39; H, 7.31; N, 5.64 Found C, 77.38; H, 7.24; N, 5.66 Working Example 178 (Production of Compound 178) Under a nitrogen atmosphere, oxalyl chloride (0.06 ml) was added to a solution of 7- (4-ethylphenyl) -2,3-dihydro-l-benzoxepin-4-acid. carboxylic acid (120 mg) in tetrahydrofuran (10 ml) at room temperature. To the mixture was added a drop of DMF, and the mixture was stirred for 1 hour. Under reduced pressure, the solvent was evaporated. The residue was dissolved in tetrahydrofuran (20 ml), and to the solution were added triethylamine (0.12 ml) and 1- (4-aminobenzyl) phosphorin-1-oxide (100 mg) at 0 ° C, and the mixture was stirred at room temperature. environment for 5 hours. The reaction mixture was added to vigorously stirred water to stop the reaction, and the mixture was extracted with chloroform. The organic layer was washed with a saturated sodium chloride solution, dried with magnesium sulfate and concentrated. The residue was purified with column chromatography (ethanol / ethyl acetate = 1: 5-1: 4) and recrystallized from ethanol to give N- (4- (pentamethylene) phosphorylmethylphenyl) -7- (4-ethylphenyl) -2, 3-dihydro-l-benzoxepin-4-carboxamide (Compound 178) (88 mg) as colorless crystals. p.f. 287-288 ° C NMR-1H (200MHz, CDC13) d 1.28 (3H, t, J = 7.4 Hz), 1.42- 2.16 (10H, m), 2.70 (2H, q, J = 7.4 Hz), 3.05-3.19 (4H, m), 4.37 (2H, t, J = 4.6 Hz), 7.06 (1H, d, J = 8.4 Hz), 7. 21-7.31 (5H, m), 7.43-7.62 (6H, m), 7.84 (1H, broad s) IR (KBr) 3392, 1655, 1599, 1533, 1516, 1493, 1321, 1255, 1167, 847, 824 cm "1 Elemental Analysis for C3? H34N03P Calculated C, 74.53; H, 6.86; N, 2.80; P, 6.20: Found C, 74.23; H, 6.78; N, 2.89; P, 6.07.

Working Example 179 (Production of Compound 179) Under a nitrogen atmosphere, oxalyl chloride (0.06 ml) was added to a solution of 7- (4-tert-butylphenyl) -2,3-dihydro-1-benzoxepin- 4-carboxylic acid (130 mg) in tetrahydrofuran (10 ml) at room temperature. To the mixture was added a drop of DMF, and the mixture was stirred for 1 hour. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in tetrahydrofuran (10 ml). To the solution were added triethylamine (0.12 ml) and 4- [N-methyl-N- (tetrahydro-pyran-4-yl) aminomethyl] -aniline (98 mg) at 0 ° C, and the mixture was stirred at room temperature during 3 hours. The reaction mixture was added to water stirred vigorously to stop the reaction. The mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with magnesium sulfate and concentrated. The residue was purified with column chromatography (ethanol / ethyl acetate = 1: 4) and recrystallized from ethyl acetate to give N- [4- [N-methyl-N- (tetrahydropyran-4-yl) aminomethyl) ] -phenyl] -7- (4-tert-butylphenyl) -2,3-dihydro-l-benzoxepin-4-carboxamide (Compound 179) (126 mg) as colorless crystals, mp. 193-194 ° C NMR-aH (200MHz, CDC13) d 1.37 (9H, s), 1.60-1.82 (4H, m), 2.21 (3H, s), 2.56-2.75 (1H, m), 3.09 (2H, t, J = 4.6 Hz), 3.29-3.45 (2H, m), 3.58 (2H, s), 3.97-4.09 (2H, m), 4.37 (2H, t, J = 4.6 Hz), 7.06 (1H, d , J = 8.0 Hz), 7.23-7.35 (3H, m), 7.41-7.58 (9H, m). IR (KBr) 3342, 2949, 1647, 1512, 1406, 1313, 1240, 1136, 822 cm "1 Elemental Analysis for C34H4oN203 Calculated C, 77.83; H, 7.68; N, 5.34: Found C, 77.69; H, 7.71; N, 5.39.

Working Example 180 (Production of Compound 180) Under a nitrogen atmosphere, oxalyl chloride (0.06 ml) was added to a solution of 7- (4-tert-butylphenyl) -2,3-dihydro-1-benzoxepin- 4-carboxylic acid (130 mg) in tetrahydrofuran (10 ml) at room temperature. To the mixture was added a drop of DMF, and the mixture was stirred for 1 hour. Under reduced pressure, the solvent was evaporated. The residue was dissolved in dichloromethane (10 ml), and to the solution were added triethylamine (0.12 ml) and l- (4-aminobenzyl) phosphorin-1-oxide (99 mg) at 0 ° C, and the mixture was stirred at room temperature. environment for 4 hours. The reaction mixture was added to water stirred vigorously to stop the reaction, and the mixture was extracted with dichloromethane. The organic layer was washed with a saturated sodium chloride solution, dried with magnesium sulfate and concentrated. The residue was purified with column chromatography (ethanol / ethyl acetate = 1: 4) and recrystallized from ethanol to give N- (4- (pentamethylene) phosphorylmethyl-phenyl) -7- (4-tert-butylphenyl) -2, 3-dihydro-l-benzoxepin-4-carboxamide (Compound 180) (106 mg) as colorless crystals, m.p. 292-294 ° C NMR ^ H (200MHz, CDC13) d 1.36 (9H, s), 1.39-2.10 (10H, m), 3.04-3.19 (4H, m), 4.36 (2H, t, J = 4.6 Hz) , 7.06 (1H, d, J = 8.2 Hz), 7.19-7.30 (3H, m), 7.41-7.63 (8H,), 8.24 (1H, broad s). IR (KBr) 3236, 1664, 1516, 1491, 1311, 1252, 1232, 1163, 1132, 845, 824 cm "1 Elemental Analysis for C33H38N03P Calculated C, 75.12; H, 7.26; N, 2.65; P, 5.87: Found C, 74.82; H, 7.25; N, 2.73; P, 5.99.

Working Example 181 (Production of Compound 181) Under a nitrogen atmosphere, oxalyl chloride (0.06 ml) was added to a solution of 7- (4-chlorophenyl) -2,3-dihydro-l-benzoxepin-4-acid. carboxylic acid (120 mg) in tetrahydrofuran (10 ml) at room temperature. To the mixture was added a drop of DMF, and the mixture was stirred for 1 hour. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in tetrahydrofuran (10 ml). To the solution were added triethylamine (0.12 ml) and 4- [N-methyl-N- (tetrahydro-pyran-4-yl) aminomethyl] -aniline (97 mg) at 0 ° C, and the mixture was stirred at room temperature during 3 hours. The reaction mixture was added to water stirred vigorously to stop the reaction. The mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with magnesium sulfate and concentrated. The residue was purified with column chromatography (ethanol / ethyl acetate = 1: 4) and recrystallized from ethyl acetate-diethyl ether to give N- [4- [N-methyl-N- (tetrahydropyran-1- il) aminomethyl] -phenyl] -7- (4-chlorophenyl) -2,3-dihydro-l-benzoxepin-4-carboxamide (Compound 181) (67 mg) as colorless crystals, mp. 191-192 ° C NMR-aH (200MHz, CDC13) d 1.61-1.83 (4H, m), 2.21 (3H, s), 2.54-2.74 (1H, m), 3.09 (2H, t, J = 4.7 Hz) , 3.31-3.44 (2H, m), 3.58 (2H, s), 3.97-4.09 (2H,), 4.37 (2H, t, J = 4.7 Hz), 7.08 (1H, d, J = 8.2 Hz), 7.23 -7.58 (12H, m). IR (KBr) 3309, 1643, 1520, 1485, 1319, 1246, 816 cm "1 Elemental Analysis for C30H3? N2O3Cl Calculated C, 71.63; H, 6.21; N, 5.57; Cl, 7.05: Found C, 71.32; H, 6.21; N, 5.60; Cl, 6.81.

Working Example 182 (Production of Compound 182) Under a nitrogen atmosphere, oxalyl chloride (0.06 ml) was added to a solution of 7- (4-chlorophenyl) -2,3-dihydro-l-benzoxepin-4- acid. carboxylic (120 mg) in tetrahydrofuran (10 ml) at room temperature. To the mixture was added a drop of DMF, and the mixture was stirred for 1 hour. Under reduced pressure, the solvent was evaporated. The residue was dissolved in dichloromethane (10 ml). To the solution were added triethylamine (0.12 ml) and 1- (4-aminobenzyl) phosphorin-1-oxide (98 mg) at 0 ° C, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was added to vigorously stirred water to stop the reaction, and the mixture was extracted with dichloromethane. The organic layer was washed with a saturated sodium chloride solution, dried with magnesium sulfate and concentrated. The residue was purified by column chromatography (ethanol / ethyl acetate = 1: 4) and recrystallized from ethanol to give N- (4-pentamethylene) phosphorylmethylphenyl) -7- (4-chlorophenyl) -2, 3- dihydro-l-benzoxepin-4-carboxamide (Compound 182) (69 mg) as colorless crystals, m.p. 270-272 ° C NMR-aH (200MHz, CDC13) d 1.31-2.10 (10H, m), 3.04-3.18 (4H, m), 4.37 (2H, t, J = 4.6 Hz), 7.07 (1H, d, J = 8.4 Hz), 7. 19-7.29 (3H, m), 7.38-7.52 (6H, m), 7.58 (2H, d, J = 8.4 Hz), 8.07 (1H, broad s). IR (KBr) 3230, 2935, 1655, 1599, 1516, 1483, 1317, 1254, 1230, 1157, 824 cm "1 Elemental Analysis for C29H29N03C1P • 0.5H20 Calculated C, 67.64; H, 5.87; N, 2.72; Cl, 6.88; P, 6.01: Found C, 67.55; H, 5.81; N, 2.79; Cl, 6.67; P, 6.11.

Working Example 183 (Production of Compound 183) Under a nitrogen atmosphere, oxalyl chloride (0.05 ml) was added to a solution of 7- (4-trifluoromethylphenyl) -2-, 3-dihydro-1-benzoxepin-4 acid. -carboxylic acid (130 mg) in tetrahydrofuran (10 ml) at room temperature. To the mixture was added a drop of DMF, and the mixture was stirred for 1 hour. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in tetrahydrofuran (10 ml). To the solution were added triethylamine (0.1 ml) and 4- [N-methyl-N- (tetrahydrofuran-4-yl) amino-methyl] aniline (95 mg) at 0 ° C., and the mixture was stirred at room temperature for 3 hours. The reaction mixture was added to water stirred vigorously to stop the reaction. The mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with magnesium sulfate and concentrated. The residue was purified with column chromatography (ethanol / ethyl acetate = 1: 4) and recrystallized from ethyl acetate-hexane to give N- [4- [N-methyl-N- (tetrahydropyran-4-yl. ) aminomethyl] phenyl] -7- (4-trifluoromethylphenyl) -2,3-dihydro-l-benzoxepin-4-carboxamide (Compound 183) (91 mg) as colorless crystals. p.f. 205-209 ° CR N- ^ H (200MHz, CDC13) d 1.69-1.82 (4H, m), 2.21 (3H, s), 2.55-2.74 (1H, m), 3.10 (2H, t, J = 4.7 Hz ), 3.31-3.44 (2H,), 3.58 (2H, s), 3.99-4.11 (2H, m), 4.39 (2H, t, J = 4.7 Hz), 7.11 (1H, d, J = 8.4 Hz), 7.25-7.34 (3H, m), 7. 46-7.58 (5H, m), 7.62-7.71 (4H, m). IR (KBr) 3315, 2958, 2846, 1643, 1522, 1327, 1165, 1115, 1072, 835, 822 cm "1 Analysis Elemental for C3? H31N203F3 Calculated C, 69.39; H, 5.82; N, 5.22; F, 10.62: Found C, 69.21; H, 5.79; N, 5.24; F, 10.60.

Working Example 184 (Production of Compound 184) Under a nitrogen atmosphere, oxalyl chloride (0.05 ml) was added to a solution of 7- (4-trifluoromethylphenyl) -2,3-dihydro-l-benzoxepin-4-acid. carboxylic acid (130 mg) in tetrahydrofuran (10 ml) at room temperature. To the mixture was added a drop of DMF, and the mixture was stirred for 1 hour. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in tetrahydrofuran (10 ml). To the solution were added triethylamine (0.1 ml) and l- (4-aminobenzyl) phosphorin-1-oxide (94.5 mg) at 0 ° C, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was added to water stirred vigorously to stop the reaction. The mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with magnesium sulfate and concentrated. The residue was purified by column chromatography (ethanol / ethyl acetate = 1: 4) and recrystallized from ethyl acetate-hexane to give N- (4- (pentamethylene) phosphorylmethyl-phenyl) -7- (4- trifluoromethylphenyl) -2,3-dihydro-l-benzoxepin-4-carboxamide (Compound 184) (111 mg) as colorless crystals. p.f. 269 ° C (dec.) RMN- ^ H (200MHz, CDC13) d 1.19-2.08 (10H, m), 3.03-3.16 (4H, m), 4.38 (2H, t, J = 4.6Hz), 7.10 (1H , d, J = 8.4 Hz), 7.15-7.30 (3H, m), 7.48 (1H, dd, J = 8.4, 2.2 Hz), 7.52-7.73 (7H, m), 8.39-8.46 (1H, m). IR (KBr) 3221, 2937, 1657, 1533, 1516, 1327, 1257, 1167, 1128, 1072, 849, 825 cm "1 Elemental Analysis for C30H29NO3F3P • 0.2H20 Calculated C, 66.34; H, 5.46; N, 2.58: Found C, 66.21; H, 5.62; N, 2.61.

Working Example 185 (Production of Compound 185) Under a nitrogen atmosphere, oxalyl chloride (0.08 ml) was added to a solution of 7- (4-ethoxyphenyl) -2,3-dihydro-l-benzoxepin-4-acid. carboxylic (154.8 mg) in tetrahydrofuran (10 ml) at room temperature. To the mixture was added a drop of DMF, and the mixture was stirred for 1 hour. Under reduced pressure, the solvent was evaporated. The residue was dissolved in tetrahydrofuran (20 ml), and to the solution were added triethylamine (0.2 ml) and 4- [N-methyl-N- (tetrahydropyran-4-yl) aminomethyl] aniline (121 mg) at 0 ° C, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was added to water stirred vigorously to stop the reaction. The mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with magnesium sulfate and concentrated. The residue was purified with column chromatography (ethanol / ethyl acetate = 1: 4) and recrystallized from ethanol to give 7- (4-ethoxyphenyl) -N- [4- [N-methyl-N- (tetrahydropyran -4-yl) aminomethyl] phenyl] -2,3-dihydro-l-benzoxepin-4-carboxamide (Compound 185) (202 mg) as colorless crystals. p.f. 174-176 ° C NMR ^ H (200MHz, CDC13) d 1.44 (3H, t, J = 7.0 Hz), 1.62-1.82 (4H, m), 2.21 (3H, s), 2.55-2.72 (1H, m) , 3.08 (2H, t, J = 4.8 Hz), 3.31-3.44 (2H, m), 3.57 (2H, s), 3.97-4.10 (2H, m), 4.08 (2H, q, J = 7.0 Hz), 4.36 (2H, t, J = 4.8 Hz), 6.96 (2H, d, J = 8.8 Hz), 7.05 (1H, d, J = 8.4 Hz), 7.24-7.58 (10H, m).

IR (KBr) 3327, 2947, 1645, 1608, 1514, 1495, 1240, 1180, 1051, 822 cm "1 Elemental Analysis for C32H36N204 Calculated C, 74.97; H, 7.08; N, 5.46: Found C, 74.88; H, 7.27; N, 5.50.

Working Example 186 (Production of Compound 186) Under a nitrogen atmosphere, oxalyl chloride (0.06 ml) was added to a solution of 7- (4-trifluoromethoxyphenyl) -2,3-dihydro-l-benzoxepin-4- acid. carboxylic (150 mg) in tetrahydrofuran (10 ml) at room temperature. A drop of DMF was added to the mixture., and the mixture was stirred for 1 hour. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in tetrahydrofuran (10 ml). To the solution were added triethylamine (0.12 ml) and 4- [N-methyl-N- (tetrahydropyran-4-yl) aminomethyl] aniline (104 mg) at 0 ° C, and the mixture was stirred at room temperature for 3 hours . The reaction mixture was added to water stirred vigorously to stop the reaction. The mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with magnesium sulfate and concentrated. The residue was separated and purified by column chromatography (ethanol / ethyl acetate = 1: 4) and recrystallized from ethyl acetate-hexane to give N- [4- [N-methyl-N- (tetrahydro- pyran-4-yl) aminomethyl] phenyl] -7- (4-trifluoromethoxy-phenyl) -2,3-dihydro-l-benzoxepin-4-carboxamide (Compound 186) (143 mg) as colorless crystals. p.f. 187-188 ° C NMR ^ H (200MHz, CDC13) d 1.62-1.82 (4H, m), 2.21 (3H, s), 2.55-2.74 (1H, m), 3.10 (2H, t, J = 4.7 Hz) , 3.29-3.45 (2H, m), 3.57 (2H, s), 3.99-4.10 (2H, m), 4.38 (2H, t, J = 4.7 Hz), 7.09 (1H, d, J = 8.4 Hz), 7.22-7.35 (3H, m), 7.40-7.60 (9H, m). IR (KBr) 3319, 2960, 2845, 1643, 1520, 1493, 1319, 1261, 1205, 1163, 835, 810 cm "1 Elemental Analysis for C3? H3? N204F3 Calculated C, 67.38; H, 5.65; N, 5.07; F, 10.31: Found C, 67.39; H, 5.38; N, 5.07; F, 10.18.

Working Example 187 (Production of Compound 187) Under a nitrogen atmosphere, oxalyl chloride (0.07 ml) was added to an acid solution (E) -3- (4-methylphenyl) cinnamic (125 mg) in tetrahydrofuran (10 ml) at room temperature. To the mixture was added a drop of DMF, and the mixture was stirred for 1 hour. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in tetrahydrofuran (10 ml). To the solution were added triethylamine (0.14 ml) and (4-aminobenzyl) diethylphosphine oxide (120 mg) in tetrahydrofuran (5 ml) at 0 ° C, and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was added to water stirred vigorously to stop the reaction. The mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with magnesium sulfate and concentrated and recrystallized from ethanol-ethyl acetate to give (E) -N- (4-diethylphosphorylmethylphenyl) -3- ( 4-methylphenyl) -cinamamide (Compound 187) (125 mg) as pale yellow crystals. p.f. 197-198 ° C NMR-aH (200MHz, CDCl 3) d 1.13 (6H, dt, J = 16.6, 8.0 Hz), 1.55-1.71 (4H, m), 2.41 (3H, m), 3.08 (2H, d, J = 13.2 Hz), 6.81 (1H, d, J = 15.4 Hz), 7.15-7.30 (4H,), 7.41-7.62 (7H, m), 7.74-7.84 (2H, m), 8.93-9.02 (1H, m). IR (KBr) 3242, 1678, 1630, 1603, 1541, 1514, 1409, 1344, 1250, 1165, 1130, 985, 847, 791 cm "1 Elemental Analysis for C27H30NO2P • 0.3H20 Calculated C, 74.22; H, 7.06; N, 3.21; P, 7.09: Found C, 73.96; H, 6.77; N, 3.34; P, 7.01.

Working Example 188 (Production of Compound 188) Under a nitrogen atmosphere, oxalyl chloride (0.27 ml) was added to an acid solution (E) -3- (4-methylphenyl) cinnamic (0.50 mg) in tetrahydrofuran (10 ml) at room temperature. To the mixture was added a drop of DMF, and the mixture was stirred for 1 hour. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in tetrahydrofuran (10 ml). To the solution were added triethylamine (0.60 ml) and 2- (4-aminophenyl) pyridine (0.39 mg) and the mixture was stirred at room temperature for 2 hours. The reaction mixture was added to water stirred vigorously to stop the reaction. The mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with magnesium sulfate, concentrated under reduced pressure and recrystallized with tetrahydrofuran-hexane (1: 1) to give the (E) -N- [4- (2-pyridyl) phenyl] -3- (4-methylphenyl) cinnamamide (Compound 188) (561 mg) as pale yellow crystals, mp. 220-222 ° C NMR-aH (200MHz, CDC13) d 2.42 (3H, s), 6.63 (1H, d, J = 15.4 Hz), 7.18-7.31 (3H,), 7.44-7.63 (6H, m), 7.70-7.83 (5H, m), 7.85 (1H, d, J = 15.4Hz), 8.02 (2H, d, J = 8.8Hz), 8.66-8.72 (1H, m).

IR (KBr) 3286, 1657, 1622, 1597, 1524, 1462, 1333, 1180, 970, 787 cm "1 Elemental Analysis for C27H22N20 • 0.1H20 Calculated C, 82.67; H, 5.70; N, 7.14: Found C, 82.45; H, 5.70; N, 7.13.

Working Example 189 (Production of Compound 189) To a solution of (E) -N- [4- (2-pyridyl) phenyl] -3- (4-methylphenyl) cinnamamide (350 mg) in tetrahydrofuran (10 ml) and dichloromethane (30 ml) was added 3-chloroperbenzoic acid (70%, 0.27 g) at 0 ° C, and the mixture was stirred at room temperature for 2 days. To the reaction mixture was added a solution of sodium thiosulfate, and the mixture was stirred for a few minutes and extracted with dichloromethane. The organic layer was washed with a saturated sodium bicarbonate solution and a saturated sodium chloride solution, dried with magnesium sulfate and concentrated. The residue was purified by column chromatography (ethanol / ethyl acetate = 1: 1), concentrated to give crystals, which were recrystallized with ethanol-chloroform to give (E) -N- [4- (1-oxidopyridin -2-yl) phenyl] -3- (4-methylphenyl) cinnamamide (Compound 189) (188 mg) as pale yellow crystals. p.f. 240-241 ° C NMR-aH (200MHz, CDC13) d 2.43 (3H, s), 6.63 (1H, d, J = 15.4 Hz), 6.98-7.07 (1H, m), 7.24-7.35 (4H, m), 7.37- 7.68 (10H, m), 7.78 (1H, d, J = 15.4 Hz), 8.33-8.36 (1H , m), 8.58-8.66 (1H, m). IR (KBr) 3300, 1680, 1630, 1595, 1529, 1475, 1342, 1225, 970, 837, 766 cm "1 Elemental Analysis for C27H22N202 Calculated C, 79.78; H, 5.46; N, 6.89: Found C, 79.71; H, 5.39; N, 6.93.

Working Example 190 (Production of Compound 190) Under a nitrogen atmosphere, oxalyl chloride (0.22 ml) was added to an acid solution (E) -3- (4-methylphenyl) cinnamic (0.40 mg) in tetrahydrofuran (10 ml) at room temperature. To the mixture was added a drop of DMF, and the mixture was stirred for 1 hour. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in tetrahydrofuran (10 ml). To the solution were added triethylamine (0.50 ml) and 2- (4-amino-benzyl) pyridine (0.34 mg) in tetrahydrofuran (5 ml) at 0 ° C, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was added to water stirred vigorously to stop the reaction. The mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with magnesium sulfate, concentrated and recrystallized from ethyl acetate-hexane to give (E) -N- [4- (2-pyridylmethyl) - phenyl] -3- (4-methylphenyl) -cinamamide (Compound 190) (490 mg) as colorless crystals. p.f. 169-171 ° C NMR ^ H (200MHz, CDC13) d 2.41 (3H, s), 4.14 (2H, s), 6. 60 (1H, d, J = 15.4 Hz), 7.10-7.15 (2H, m), 7.22-7.28 (4H, m), 7.42-7.63 (9H, m), 7.71 (1H, broad s), 7.80 (1H, d, J = 15.4 Hz), 8.53-8.58 (1H, m). IR (KBr) 3238, 1673, 1630, 1601, 1539, 1512, 1348, 1248, 1174, 976, 791, 760 cm "1 Elemental Analysis for C28H2 N20 • 0. 1H20 Calculated C, 82.77; H, 6.00; N, 6.89: Found C, 82.73; H, 5.89; N, 6.97.

Working Example 191 (Production of Compound 191) To a solution of (E) -N- [4- (2-pyridylmethyl) phenyl] -3- (4-methylphenyl) cinnamamide (302 mg) in tetrahydrofuran (10 ml) was added 3-chloroperbenzoic acid (70%, 0.27 g) at 0 ° C, and the mixture was stirred at room temperature for 18 days. To the reaction mixture was added a solution of sodium thiosulfate, and the mixture was stirred for a few minutes. The mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium bicarbonate solution and a saturated sodium chloride solution, dried with magnesium sulfate and concentrated. The residue was recrystallized from ethanol to give (E) -N- [4- (l-oxidopyridin-2-ylmethyl) -phenyl] -3- (4-ethylphenyl) cinnamamide (Compound 191) (180 mg) as color crystals. pale yellow, mp 183-185 ° C NMR-aH (200MHz, CDC13) d 2.41 (3H, s), 4.24 (2H, s), 6.64 (1H, d, J = 15.4 Hz), 6.96-7.01 (1H, m), 7.12 -7.17 (2H, m), 7.22-7.30 (4H, m), 7.40-7.51 (4H, m), 7.54-7.63 (3H, m), 7.66-7.74 (2H, m), 7.82 (1H, d, J = 15.4 Hz), 8.29-8.31 (1H, m). IR (KBr) 3255, 1684, 1605, 1541, 1514, 1412, 1346, 1244, 8 39, 785 cm "1 Elemental Analysis for C28H24N202 Calculated C, 79.98; H, 5.75; N, 6.66: Found C, 80.18; H 5.63; N, 6.69.

Working Example 192 (Production of Compound 192) Under a nitrogen atmosphere, oxalyl chloride (0.27 ml) was added to a solution of (E) -3- (4-methylphenyl) cinnamic acid (0.50 g) in tetrahydrofuran (10 mg). ml) at room temperature. To the mixture was added a drop of DMF, and the mixture was stirred for 1 hour. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in tetrahydrofuran (10 ml). To the solution were added triethylamine (0.60 ml) and 3- (4-aminophenyl) pyridine (0.39 mg) at 0 ° C, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was added to water stirred vigorously to stop the reaction. The mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with magnesium sulfate, and concentrated. The residue was purified with column chromatography (ethyl acetate) to give yellow crystals, which were recrystallized with tetrahydrofuran-ethanol to give the (E) -N- [4- (3-pyridyl) phenyl] -3- (4-methylphenyl) cinnamamide (Compound 192) (447 mg) as pale yellow crystals. p.f. 213-214 ° C NMR-1H (200MHz, CDC13) d 2.15 (3H, s), 6.65 (1H, d, J = 15.4 Hz), 7.26-7.64 (11H, m), 7.75-7.90 (5H, m) , 8.59 (1H, dd, J = 4.8, 1.8 Hz), 8.85 (1H, d, J = 1.8 Hz). IR (KBr) 3344, 1660, 1626, 1525, 1481, 1335, 1171, 978, 795 cm "1 Elemental Analysis for C27H22N20 Calculated C, 83.05; H, 5.68; N, 7.17: Found C, 83.01; H, 5.82; N, 7.23.

Working Example 193 (Production of Compound 193) To a solution of (E) -N- [4- (3-pyridyl) phenyl] -3- (4-methylphenyl) cinnamamide (250 mg) in tetrahydrofuran (20 ml) was added 3-chloroperbenzoic acid (70%, 0.24 g) at 0 ° C, and the mixture was stirred at room temperature for 18 hours. To the reaction mixture was added a solution of sodium thiosulfate, and the mixture was stirred for a few minutes and extracted with dichloromethane. The organic layer was washed with a saturated sodium bicarbonate solution and a saturated sodium chloride solution, dried with magnesium sulfate and concentrated. The residue was recrystallized from ethanol-tetrahydrofuran-acetone to give (E) -N- [4- (l-oxidopyridin-3-yl) -phenyl] -3- (4-methylphenyl) cinnamamide (Compound 193) (208 mg ) as pale yellow crystals. NMR-aH (200MHz, CDC13) d 2.38 (3H, s), 6.95 (1H, d, J = 15.7 Hz), 7.31 (2H, d, J = 8.1 Hz), 7.45-7.57 (2H, m), 7.59 -7.94 (12H, m), 8.19 (1H, d, J = 6.5 Hz), 8.58 (1H, s). IR (KBr) 3423, 1672, 1597, 1531, 1477, 1340, 1201, 901, 835, 793 c "1 Working Example 194 (Production of Compound 194) Under a nitrogen atmosphere, oxalyl chloride (0.19 ml) was added to an acid solution (E) -3- (4-methylphenyl) cinnamic acid (340 mg) in tetrahydrofuran (10 ml) at room temperature. To the mixture was added a drop of DMF, and the mixture was stirred for 1 hour. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in tetrahydrofuran (10 ml). To the solution were added triethylamine (0.4 ml) and 4-aminobenzyl dipropylphosphine oxide (0.38 mg) at 0 ° C, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was added to water stirred vigorously to stop the reaction. The mixture was extracted with ethyl acetate. The organic layer was concentrated. The residue was recrystallized with ethanol to give (E) -N- (4-dipropyl-phosphorylmethyl-phenyl) -3- (4-methylphenyl) cinnamamide (Compound 194) (489 mg) as colorless crystals, m.p. 225-227 ° CR N-1H (200MHz, DMSO-d6) d 0.87-1.00 (6H, m), 1.37-1.63 (8H, m), 2.37 (3H, s), 3.07 (2H, d, J = 15.0 Hz), 6.93 (1H, d, J = 16.0 Hz), 7.16-7.25 (2H, m), 7.30 (2H, d, J = 8.0 Hz), 7.50-7.71 (9H, m), 7.89 (1H, s) large). IR (KBr) 3232, 1676, 1624, 1605, 1545, 1512, 1338, 1151 cm "1 - Elemental Analysis for C29H3N02P Calculated C, 75.79; H, 7.46; N, 3.05; P, 6.74 Found C, 75.60; H, 7.68; N, 2.99; P, 6.83 Working Example 195 (Production of Compound 195) Under a nitrogen atmosphere, oxalyl chloride (0.11 ml) was added to a solution of (E) -3- (4-methylphenyl) cinnamic acid (200 mg) in tetrahydrofuran (10 mg). ml) at room temperature. To the mixture was added a drop of DMF, and the mixture was stirred for 1 hour. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in tetrahydrofuran (10 ml). To the solution were added triethylamine (0.25 ml) 1- (4-aminobenzyl) phosphorane-1-oxide (193 mg) at 0 ° C, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was added to water stirred vigorously to stop the reaction. The mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution and concentrated. The residue was recrystallized from ethanol to give (E) -N- (4- (tetramethylene) phosphoryl-methylphenyl) -3- (4-methylphenyl) -cinnamamide (Compound 195) (221 mg) as colorless crystals, m.p. 273-275 ° C NMR ^ H (200MHz, CDC13) d 1.48-2.04 (8H, m), 2.41 (3H, s), 3.19 (2H, d, J = 13.6 Hz), 6.78 (1H, d, J = 15.8 Hz), 7.14-7.31 (4H, m), 7.43-7.59 (7H, m), 7.73-7.76 (1H, m), 7. 79 (1H, d, J = 15.8 Hz), 8.75-8.84 (1H, m). IR (KBr) 3232, 1676, 1628, 1603, 1543, 1512, 1410, 1341, 1171, 985, 868, 793 cm "1 Elemental Analysis for C27H28N02P • 0 .3H20 Calculated C, 74.56; H, 6.62; N, 3.22; P, 7.12: Found C, 74.36; H, 6 64; N, 3.20; P, 7.06.

Working Example 196 (Production of Compound 196) Under a nitrogen atmosphere, oxalyl chloride (0.12 ml) was added to an acid solution (E) -3- (4-methylphenyl) cinnamic acid (220 mg) in tetrahydrofuran (10 ml) at room temperature. To the mixture was added a drop of DMF, and the mixture was stirred for 1 hour. Under reduced pressure, the solvent was evaporated. The residue was dissolved in tetrahydrofuran (20 ml) and triethylamine (0.26 ml) and 1- (4-amino-benzyl) phosphorin-1-oxide (226 mg) were added to the solution at 0 ° C. The mixture was stirred at room temperature for 2 hours. The reaction mixture was added to vigorously stirred water to stop the reaction, and the mixture was extracted with chloroform. The organic layer was washed with a saturated sodium chloride solution, dried with magnesium sulfate, and concentrated. The residue was recrystallized from ethanol to give (E) -N- (4- (pentamethylene) phosphorylmethylphenyl) -3- (4-methylphenyl) -cinamamide (Compound 196) (271 mg) as colorless crystals. p.f. 273-276 ° C NMR-aH (200MHz, CDC13) d 1.43-2.08 (10H, m), 2.41 (3H, s), 3.13 (2H, d, J = 12.8 Hz), 6.81 (1H, d, J = 15.8 Hz), 7. 14-7.30 (4H, m), 7.41-7.61 (7H, m), 7.76 (1H, s), 7.80 (1H, d, J = 15.8 Hz), 8.72-8.87 (1H, m). IR (KBr) 3242, 1676, 1628, 1603, 1539, 1514, 1344, 1174, 1155, 1126, 991, 789 cm "1 Elemental Analysis for C2? H30N02P • 1 .5H20 Calculated C, 71.47; H, 7.06; N, 2.98; P, 6.58: Found C, 71.53; H, 6.99; N, 2.87; P, 6.76.

Working Example 197 (Production of Compound 197) Under a nitrogen atmosphere, oxalyl chloride (0.20 ml) was added to a solution of 6- (4-methylphenyl) -2H-1-benzo-pyran-3-carboxylic acid ( 300 mg) in tetrahydrofuran (10 ml) at room temperature. To the mixture was added a drop of DMF, and the mixture was stirred for 1 hour. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in tetrahydrofuran (10 ml). To the solution were added triethylamine (0.31 ml) and 1- (4-aminobenzyl) -pyridine (0.24 g) at 0 ° C, and the mixture was stirred at room temperature for 3 hours.

The reaction mixture was added to water stirred vigorously to stop the reaction. The mixture was extracted with ethyl acetate. The organic layer was concentrated. The residue was separated and purified by column chromatography (ethanol / ethyl acetate = 1: 5) to give N- [4- (1-piperidinylmethyl) phenyl] -6- (4-methyl-phenyl) -2H -l-benzopyran-3-carboxamide (Compound 197) (324 mg) as yellow crystals, m.p. 196-197 ° C NMR-1H (200MHz, CDC13) d 1.41-1.71 (6H, m), 2.34-2.43 (7H, m), 3.46 (2H, s), 5.12 (2H, d, J = 1. 4 Hz), 6.95 (1H, d, J = 8.0 Hz), 7.14 (1H, broad s), 7.23-7.29 (3H, m), 7.31-7.38 (2H, m), 7.40-7.46 (6H, m). GO . { KBr) 3361, 1643, 1601, 1529, 1485, 1317, 1254, 810 Elemental Analysis for C29H30N202 '0.1H20 Calculated C, 79.10; H, 6.91; N, 6.36: Found C, 78.85; H, 6.90; N, 6.26.

Working Example 198 (Production of Compound 198) To a solution of N- [4- (l-piperidinylmethyl) phenyl] -6- (4-methylphenyl) -2H-1-benzopyran-3-carboxamide (200 mg) in DMF (3 ml) was added methyl iodide (0.1 ml) at room temperature, and the mixture was stirred for 20 minutes. To the mixture was added ethyl acetate. The precipitated crystal was collected by filtration and recrystallized with chloroform-ethanol to give the l- [4- [N- [6- (4-methylphenyl) -2H-l-benzopyran-3-carbonyl] -amino] benzyl. ] -1-methyl-piperidinium (Compound 198) (188 mg) as yellow crystals, mp 210 ° C (dec.) NMR - ^ - H (200MHz, CDC13) d 1.62-2.01 (6H, m), 2.36 (3H, s), 3.06 (3H, broad s), 3.34-3.49 (2H, m) , 3.60-3.76 (2H, m), 4.97 (2H, broad s), 5.04 (2H, broad s), 6.85 (1H, d, J = 8.4 Hz), 7.17 (2H, d, J = 8.2 Hz), 7.37-7.42 (3H, m), 7.47-7.52 (3H, m), 7.83-7.91 (3H, m), 9.00 (1H, broad s). IR (KBr) 3246, 1668, 1527, 1483, 1319, 1248, 808 cm "1 Elemental Analysis for C3oH33N202I • 0.2H2O Calculated C, 61.69; H, 5.76; N, 4.80: Found C, 61.53; H, 5.72; N , 4.85.

Working Example 199 (Production of Compound 199) Under a nitrogen atmosphere, oxalyl chloride (0.26 ml) was added to a solution of 6- (4-methylphenyl) -2H-1-benzo-pyran-3-carboxylic acid ( 0.52 g) in tetrahydrofuran (10 ml) at room temperature. To the mixture was added a drop of DMF, and the mixture was stirred for 1 hour. Under reduced pressure, the solvent was evaporated. The residue was dissolved in tetrahydrofuran (6 ml) and to the solution were added triethylamine (0.60 ml) and 2- (4-aminobenzyl) pyridine (0.40 g) in tetrahydrofuran (5 ml), and the mixture was stirred at room temperature for 3 hours. hours. The reaction mixture was added to water stirred vigorously to stop the reaction. The mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by column chromatography (ethyl acetate / hexane = 2: 1) and concentrated to give crystals, which were recrystallized with ethanol-ethyl acetate) to give the N- [4- ( 2-pyridylmethyl) phenyl] -6- (4-methyl-phenyl) -2H-l-benzopyran-3-carboxamide (Compound 199) (353.2 mg) as yellow crystals, which were recrystallized in a similar manner to give the latter crystals (208 mg). p.f. 184-187 ° C NMR-aH (200MHz, CDC13) d 2.39 (3H, m), 4.14 (2H, s), 5.10 (2H, d, J = 1.4 Hz), 6.93 (1H, d, J = 8.4 Hz ), 7.09-7.15 (3H, m), 7.19-7.32 (5H, m), 7.37-7.66 (7H, m), 8.53-8.57 (1H, m). IR (KBr) 3296, 1639, 1599, 1531, 1514, 1473, 1325, 1259 c "1 Elemental Analysis, for C29H24N202 Calculated C, 80.53; H, 5.59; N, 6.48 Found C, 80.24; H, 5.75; N, 6.43 Working Example 200 (Production of Compound 200) To a solution of N- [4- (2-pyridylmethyl) phenyl] -6- (4-methylphenyl) -2H-1-benzopyran-3-carboxamide (250 mg) in tetrahydrofuran (10 ml) was added 3-chloroperbenzoic acid (70%, 0.21 g) at 0 ° C, and the mixture was stirred at room temperature for 14 hours. To the reaction mixture was added a solution of sodium thiosulfate, and the mixture was stirred for a few minutes. The mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium bicarbonate solution and a saturated sodium chloride solution, dried with magnesium sulfate and concentrated. The residue was separated and purified by column chromatography (ethanol / ethyl acetate = 1: 3), concentrated to give crystals, which were recrystallized with chloroform-ethanol to give the N- [4- (l-oxidopyridin- 2-ylmethyl) phenyl] -6- (4-methyl-phenyl) -2H-1-benzopyran-3-carboxamide (Compound 200) (191 mg) as pale yellow crystals, mp. 261-263 ° C NMR-aH (200MHz, CDC13) d 2.40 (3H, s), 4.25 (2H, s), . 11 (2H, s), 6.92-7.01 (2H, m), 7.13-7.67 (14H, m), 8. 29 (1H, t, J = 4.2 Hz). IR (KBr) 3302, 1660, 1605, 1537, 1520, 1250 cm "1 Elemental Analysis for C29H2 N203 Calculated C, 77.66; H, 5.39; N, 6.25: Found C, 77.90; H, 5.37; N, 6.21.

Working Example 201 (Production of Compound 201) Under a nitrogen atmosphere, oxalyl chloride (0.19 ml) was added to a solution of 6- (4-methylphenyl) -2H-1-benzo-pyran-3-carboxylic acid ( 380 mg) in tetrahydrofuran (10 ml) at room temperature. To the mixture was added a drop of DMF, and the mixture was stirred for 1 hour. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in tetrahydrofuran (10 ml). To the solution were added triethylamine (0.4 ml) and 4-aminobenzyldipropyl-phosphine oxide (0.38 g) to 0 ° C, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was added to water stirred vigorously to stop the reaction. The mixture was extracted with ethyl acetate. The organic layer was concentrated, and the residue was recrystallized with ethanol to give the N- (4-dipropylphosphoryl-methyl-phenyl) -6- (4-methylphenyl) -2H-1-benzopyran-3-carboxamide (Compound 201) ( 460 mg) as pale yellow crystals, mp 192-194 ° C NMR-1H (200MHz, CDC13) d 0.83-0.97 (6H, m), 1.39-1.68 (8H, m), 2.39 (3H, s), 3.05 (2H, d, J = 13.2 Hz) , 5.12 (2H, d, J = 0.8 Hz), 6.94 (1H, d, J = 8.4 Hz), 7.11-7.28 (4H, m), 7.31-7.50 (5H, m), 7.61 (2H, d, J = 8.4 Hz), 9.13-9.24 (1H, m). IR (KBr) 3265, 1664, 1628, 1603, 1539, 1514, 1487, 1325, 1252, 1167, 851 cm "1 Elemental Analysis for C30H34NO3P Calculated C, 73.90; H, 7.03; N, 2.87; P, 6.35: Found C, 73.95; H, 6.87; N, 2.84; P, 6.41.

Working Example 202 (Production of Compound 202) Under a nitrogen atmosphere, oxalyl chloride (0.19 ml) was added to a solution of 6- (4-methylphenyl) -2-methyl-2H-1-benzopyran-3-acid. carboxylic acid (400 mg) in tetrahydrofuran (10 ml) at room temperature. To the mixture was added a drop of DMF, and the mixture was stirred for 1 hour. Under reduced pressure, the solvent was evaporated and the residue was dissolved in tetrahydrofuran (10 ml). To the solution were added triethylamine (0.4 ml) and (4-amino-phenyl) - (2-pyridyl) methanol (310 mg) at 0 ° C, and the mixture was stirred at room temperature for 20 hours. The reaction mixture was added to water stirred vigorously to stop the reaction, extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with magnesium sulfate and concentrated. The precipitated crystal was recrystallized from tetrahydrofuran-hexane to give N- [4- [hydroxy (2-pyridyl) methyl] -phenyl] -6- (4-methylphenyl) -2-methyl-2H-1-benzopyran-3. carboxamide (Compound 202) (470 mg) as yellow crystals, mp 202-205 ° C NMR-aH (200MHz, CDC13) d 1.47 (3H, d, J = 6.6 Hz), 2.39 (3H, s), 5.29-5.38 (1H, m), 5.48 (1H, q, J = 6.6 Hz), 5.74 (1H, broad s), 6.94 (1H, d, J = 8.0 Hz), 7.08-7.26 (5H, m), 7.33-7.67 (10H, m), 8.57 (1H, d, J = 4.6 Hz). IR (KBr) 3255, 1647, 1597, 1518, 1485, 1412, 1317, 1255, 812, 756 cm "1 Elemental Analysis for C3oH26N203 • 0.2H20 Calculated C, 77.30; H, 5.70; N, 6.01: Found C, 77.31; H, 5.60; N, 6.21.

Working Example 203 (Production of Compound 203) To a solution of N- [4- [hydroxy (2-pyridyl) methyl] -phenyl] -6- (4-methylphenyl) -2-methyl-2H-l-benzopyran- 3-carboxamide (300 mg) in tetrahydrofuran (10 ml) was added 3-chloroperbenzoic acid (70%, 0.24 g) at 0 ° C, and the mixture was stirred at room temperature for 24 hours. To the mixture was added sodium thiosulfate, and the mixture was stirred for a few minutes, extracted with ethyl acetate. The organic layer was washed with a saturated sodium bicarbonate solution and a saturated sodium chloride solution, dried with magnesium sulfate and concentrated. The residue was separated and purified with column chromatography (ethanol / ethyl acetate = 1: 2) to give crystals, which were recrystallized with ethanol-ethyl acetate to give the N- [4- [hydroxy (1- Oxidopyridin-2-yl) -methyl] phenyl] -6- (4-methylphenyl) -2-methyl-2H-l-benzopyran-3-carboxamide (Compound 203) (129 mg) as pale yellow crystals, mp 230-232 ° C RM ^ H (200MHz, CDC13) d 1.49 (3H, d, J = 6.6 Hz), 2.40 (3H, s), 5.50 (1H, q, J = 6.6 Hz), 6.07 (1H, d , J = 4.5 Hz), 6.40 (1H, d, J = 4.5 Hz), 6.93-6.97 (2H, m), 7.12 (1H, s), 7.22-7.29 (4H, m), 7.35 (1H, d, J = 2.2 Hz), 7.42-7.50 (5H, m), 7.64 (2H, d, J = 8.4 Hz), 7.73 (1H, broad s), 8.24-8.28 (1H, m). IR (KBr) 3311, 1664, 1603, 1535, 1485, 1321, 1252, 812 cm Elemental Analysis for C30H26N2O4 • 0. 3H20 Calculated C, 74.46; H, 5.54; N, 5.79 Found C, 74.41; H, 5.46; N, 5.78 Working Example 204 (Production of Compound 204) Under a nitrogen atmosphere, oxalyl chloride (0.11 ml) was added to a solution of 6- (4-methylphenyl) -2H-1-benzopyran-3-carboxylic acid (230 mg. ) in tetrahydrofuran (10 ml) at room temperature. To the mixture was added a drop of DMF, and the mixture was stirred for 1 hour. Under reduced pressure, the solvent was evaporated. The residue was dissolved in tetrahydrofuran (20 ml) and to the solution were added triethylamine (0.25 ml) and 1- (4-aminobenzyl) phosphorane-1-oxide (200 mg) at 0 ° C, and the mixture was stirred at room temperature for 20 hours. The reaction mixture was added to water stirred vigorously to stop the reaction. The precipitated crystal was collected by filtration to give N- (4-tetramethylenephosphorylmethyl-phenyl) -6- (4-methylphenyl) -2H-1-benzopyran-3-carboxamide (Compound 204) (181 mg) as colorless crystals, m.p. > 300 ° C NMR-1H (200MHz, CDC13) d 1.49-2.04 (8H, m), 2.40 (3H, s), 3.22 (2H, d, J = 14.4 Hz), 5.12 (2H, s), 6.94 (1H , d, J = 8.4 Hz), 7.21-7.29 (4H, m), 7.34-7.50 (5H, m), 7.58 (2H, d, J = 8.4 Hz), 8.04-8.07 (1H, m).

IR (KBr) 3236, 1657, 1601, 1535, 1518, 1487, 1323, 1255, 1180, 810 cm "1 Elemental Analysis for C28H28N03P • 0 .3H20 Calculated C, 72.65; H, 6.23; N, 3.03; P, 6.69: Found C, 72.30; H, 5.90; N, 3.00; P, 6.98.

Working Example 205 (Production of Compound 205) Under a nitrogen atmosphere, oxalyl chloride (0.12 ml) was added to a solution of 6- (4-methylphenyl) -2H-1-benzopyran-3-carboxylic acid (240 mg ) in tetrahydrofuran (10 ml) at room temperature. To the mixture was added a drop of DMF, and the mixture was stirred for 1 hour. Under reduced pressure, the solvent was evaporated. The residue was dissolved in tetrahydrofuran (20 ml) and to the solution were added triethylamine (0.25 ml) and 1- (4-aminobenzyl) -phosphorin-1-oxide (221 mg) at 0 ° C, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was added to water stirred vigorously to stop the reaction. The mixture was extracted with chloroform. The organic layer was washed with a saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethanol to give N- (4- (pentamethylene) phosphorylmethylphenyl) -6- (4-methylphenyl) -2H-1-benzopyran-3-carboxamide (Compound 205) (257 mg) as yellow crystals. p.f. 268 ° C (dec.) NMR- ^ H (200MHz, CDC13) d 1.39-2.15 (10H, m), 2.40 (3H, s), 3.14 (2H, d, J = 12.8 Hz), 5.12 (2H, s ), 6.94 (1H, d, J = 8.0 Hz), 7.18-7.49 (9H, m), 7.59 (2H, d, J = 8.4 Hz), 8. 54 (1H, broad s). IR (KBr) 3296, 1660, 1533, 1514, 1323, 1255, 1163, 845, 812 cm "1 Elemental Analysis for C29H30N03P Calculated C, 73.87; H, 6.41; N, 2.97; P, 6.57: Found C, 74.20; H, 6.39; N, 2.78; P, 6.45.

Working Example 206 (Production of Compound 206) Under a nitrogen atmosphere, oxalyl chloride (0.06 ml) was added to a solution of 6- (4-methylphenyl) -2H-1-benzo-pyran-3-carboxylic acid ( 120 mg) in tetrahydrofuran (10 ml) at room temperature. To the mixture was added a drop of DMF, and the mixture was stirred for 1 hour. Under reduced pressure, the solvent was evaporated. The residue was dissolved in tetrahydrofuran (20 ml). To the solution were added triethylamine (0.2 ml) and 4- [N-methyl-N- (tetrahydropyran-4-yl) aminomethyl] -aniline (109 mg) at 0 ° C, and the mixture was stirred at room temperature During 4 hours. The reaction mixture was added to water stirred vigorously to stop the reaction. The mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by column chromatography (ethanol / ethyl acetate = 1: 4), and recrystallized from ethyl acetate-hexane to give the N- [4- [N-methyl-N- (tetrahydro -piran-4-yl) aminomethyl] -phenyl] -6- (4-methylphenyl) -2H-l-benzopyran-3-carboxamide (Compound 206) (117 mg) as pale yellow crystals, mp. 143-145 ° C NMR-aH (200MHz, CDC13) d 1.62-1.84 (4H, m), 2.21 (3H, s), 2.40 (3H, s), 2.56-2.74 (1H, m), 3.28-3.45 ( 2H, m), 3.57 (2H, s), 3.98-4.11 (2H, m), 5.12 (2H, d, J = l .0 Hz), 6.94 (1H, d, J = 8.4 Hz), 7.15 (1H , s broad), 7.21-7.37 (5H, m), 7.39-7.59 (6H,). IR (KBr) 3280, 2937, 2848, 1649, 1597, 1539, 1489, 1336, 1257, 1138, 1007, 810 cm "1 Elemental Analysis for C30H32N203 Calculated C, 76.90; H, 6.88; N, 5.98: Found C, 76.56; H, 6.87 N, 6.00 Working Example 207 (Production of Compound 207) Under a nitrogen atmosphere, oxalyl chloride (0.06 ml) was added to a solution of 6- (4-methylphenyl) -2H-1-benzo-pyran-3-carboxylic acid ( 120 mg) in tetrahydrofuran (10 ml) at room temperature. To the mixture was added a drop of DMF, and the mixture was stirred for 1 hour. Under reduced pressure, the solvent was evaporated and the residue was dissolved in tetrahydrofuran (20 ml). To the solution were added triethylamine (0.13 ml) and 4- [N-methyl-N- (tetrahydropyran-4-yl) amino-methyl] aniline (117 mg) at 0 ° C., and the mixture was stirred at room temperature for 4 hours. The reaction mixture was added to water stirred vigorously to stop the reaction. The mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by column chromatography (ethanol / ethyl acetate = 1: 4), and recrystallized from ethyl acetate-hexane to give N- [4- [N-methyl-N- (tetrahydrothio -piran-4-yl) aminomethyl] phenyl] -6- (4-methylphenyl) -2H-l-benzopyran-3-carboxamide (Compound 207) (125 mg) as pale yellow crystals, mp. 169-171 ° C NMR-1H (200MHz, CDC13) d 1.63-1.80 (2H, m), 2.09-2.24 (2H, m), 2.21 (3H, s), 2.40 (3H, s), 2.42-2.56 ( 1H, m), 2.64-2.74 (4H, m), 3.57 (2H, s), 5.12 (2H, d, J = 1.0 Hz), 6. 94 (1H, d, J = 8.8 Hz), 7.15 (1H, broad s), 7.23-7.36 (5H, m), 7.39-7.57 (6H, m). IR (KBr) 3286, 2922, 1649, 1597, 1539, 1336, 1319, 1261, 808 cm-1 C3oH32N203S Calculated C, 74.35; H, 6.65; N, 5.78; S, 6.62: Found C, 74.25; H, 6.47; N, 5.91; S, 6.52.

Working Example 208 (Production of Compound 208) To a solution of (E) -3- [5- (4-methylphenyl) thiophen-2-yl] acrylic acid (400 mg) in tetrahydrofuran (10 ml) was added oxalyl (0.22 mg) at room temperature. To the mixture was added a drop of DMF, and the mixture was stirred for 1 hour. Under reduced pressure, the solvent was evaporated and the residue was dissolved in tetrahydrofuran (20 ml). To the solution were added triethylamine (0.46 ml) and 4- [N-methyl-N- (tetrahydropyran-4-yl) amino-methyl] aniline (0.40 g) at 0 ° C, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was added to water stirred vigorously to stop the reaction. The mixture was extracted with chloroform. The organic layer was washed with a saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethanol to give the amide (E) -N- [4- [N-methyl-N- (tetrahydropyran-4-yl) amino-methyl] phenyl] -3- [5- (4-methylphenyl) thiophen-2-yl] acrylic (Compound 208) (293 mg) as a yellow crystal, mp 199-201 ° C NMR-XH (200MHz, CD3OD) d 1.57-1.95 (4H, m), 2.32 (3H, s), 2.36 (3H, s), 2.74-2.96 (1H, m), 3.32-3.47 ( 2H, m), 3.76 (2H, s), 3.96-4.09 (2H, m), 6.55 (1H, d, J = 15.2 Hz), 7.23 (2H, d, J = 8.4 Hz), 7.29-7.36 (4H , m), 7.56 (2H, d, J = 8.0 Hz), 7.66 (2H, d, J = 8.4 Hz), 7.75 (1H, d, J = 15.2Hz). IR (KBr) 3359, 1668, 1608, 1554, 1512, 1363, 802 cm "1 Elemental Analysis for C27H30N2O2S • 1.2H20 Calculated C, 69.26; H, 6.97; N, 5.98: Found C, 69.28; H, 6.90; N , 6.06.

Working Example 209 (Production of Compound 209) To a solution of (E) -3- [5- (4-methylphenyl) thiophen-2-yl] acrylic acid (150 mg) in tetrahydrofuran (10 ml) was added oxalyl (0.1 mg) at room temperature. To the mixture was added a drop of DMF, and the mixture was stirred for 1 hour.

Under reduced pressure, the solvent was evaporated and the residue was dissolved in tetrahydrofuran (30 ml). To the solution were added triethylamine (0.2 ml) and l- (4-aminobenzyl) phosphorin-1-oxide (150 mg) at 0 ° C, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was added to water stirred vigorously to stop the reaction. The mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethanol to give the amide (E) -N- (4-penta-methylenephosphorylmethylphenyl) -3- [5- (4-methylphenyl) -thiophen-2-yl] acrylic (Compound 209) (172 mg) as yellow crystals, pf 294-297 ° C NMR-aH (200MHz, CDC13) d 1.35-2.13 (10H, m), 2.29 (3H, s), 3.06 (2H, d, J = 13.0 Hz), 6.36-6.48 (1H, m) , 7.06-7.17 (6H, m), 7.38-7.49 (4H, m), 7.73 (1H, d, J = 15.0 Hz). IR (KBr) 3048, 1672, 1606, 1541, 1512, 1348, 1151, 804 cm-1 Elemental Analysis for C26H28N02SP Calculated C, 69.47; H, 6.28; N, 3.12; P, 6.89: Found C, 69.48; H, 6.23; N, 3.20; P, 7.17.

Working Example 210 (Production of Compound 210) To a solution of (E) -3- [5- (4-methylphenyl) furan-2-yl] acrylic acid (200 mg), 4- [N-methyl-N- (tetrahydropyran-4-yl) aminomethyl] aniline (212 mg) and triethylamine (0.15 ml) in DMF (10 ml) were added diethyl cyanophosphate (0.16 ml) at 0 ° C, and the mixture was stirred at room temperature for 3 hours. hours. To the mixture was added ethyl acetate, and the mixture was washed with water, and a saturated sodium chloride solution, dried with magnesium sulfate and concentrated. The residue was separated and purified by column chromatography (ethanol / ethyl acetate = 1: 5-1: 25-1: 10) to give the amide (E) -N- [4- [N-methyl-N] - (tetrahydropyran-4-yl) aminomethyl] phenyl] -3- [5- (4-methylphenyl) furan-2-yl] acrylic (Compound 210) (87 mg) as an amorphous, brown product. NMR-aH (200MHz, CDC13) d 1.53-1.85 (4H, m), 2.21 (3H, s), 2.38 (3H, s), 2.54-2.72 (1H, m), 3.31-3.44 (2H, m), 3.56 (2H, s), 3.98-4.11 (2H, m), 6.52 (1H, d, J = 15.4 Hz), 6.67-6.69 (2H, m), 7.22 (2H, d, J = 8.0 Hz), 7.29 (2H, d, J = 8.4 Hz), 7.41 (1H, s), 7.48-7.64 (5H, m).

Working Example 211 (Production of Compound 211) To a solution of (E) -3- [5- (4-methylphenyl) furan-2-yl] acrylic acid (150 mg), 1- (4-aminobenzyl) -phosphorin -1-Oxide (161 mg) and triethylamine (0.11 ml) in DMF (10 ml) was added diethyl cyanophosphate (0.12 ml) at 0 ° C, and the mixture was stirred at room temperature for 3 hours. To the mixture was added ethyl acetate, and the mixture was washed with water and saturated sodium chloride solution, dried with magnesium sulfate and concentrated. The residue was separated and purified with column chromatography (Ethanol / ethyl acetate = 1: 10-> 1: 5-1: 4) to give the amide (E) -N- (4- (pentamethylene) phosphorylmethylphenyl) -3- [5- (4-methylphenyl) furan-2-yl] acrylic (Compound 211) (53 mg) as brown crystals. NMR-aH (200MHz, CDC13) d 1.43-2.09 (10H, m), 2.39 (3H, s), 3.15 (2H, d, J = 13.2 Hz), 6.58-6.70 (3H, m), 7.16-7.29 ( 4H, m), 7.48-7.65 (5H, m), 8.24-8.35 (1H, m). IR (KBr) 3292, 1672, 1614, 1541, 1512, 1489, 1412, 1335, 1244, 1120, 787 cm "1 Working Example 212 (Production of Compound 212) Under a nitrogen atmosphere, oxalyl chloride (0.16 ml) was added to an acid solution (E) -3- [4- (4-Methylphenyl) -thiophen-2-yl] acrylic acid (300 mg) in tetrahydrofuran (10 ml) at room temperature. To the mixture was added a drop of DMF, and the mixture was stirred for 1 hour. Under reduced pressure, the solvent was evaporated and the residue was dissolved in tetrahydrofuran (10 ml). To the solution were added triethylamine (0.4 ml) and 4- [N-methyl-N- (tetrahydro-pyran-4-yl) aminomethyl] -aniline (298 mg) at 0 ° C, and the mixture was stirred at room temperature during 3 hours. The reaction mixture was added to water stirred vigorously to stop the reaction. The mixture was extracted with chloroform. The organic layer was washed with a saturated sodium chloride solution, dried with magnesium sulfate, concentrated under reduced pressure. The residue was separated and purified with column chromatography (ethanol / ethyl acetate 1: 4), and recrystallized with ethanol to give pale yellow crystals, which were recrystallized with tetrahydrofuran-hexane to give the (E) - N- [4- [N-methyl-N- (tetrahydropyran-4-yl) aminomethyl] -phenyl] -3- [4- (4-methylphenyl) thiophen-2-yl] acrylamide (Compound 212) (261 mg) as pale yellow crystals, mp 188-190 ° C NMR-aH (200MHz, CDC13) d 1.45-1.83 (4H, m), 2.20 (3H, s), 2.38 (3H, s), 2.55-2.73 (1H, m), 3.31-3.44 ( 2H, m), 3.56 (2H, s), 3.99-4.10 (2H, m), 6.38 (1H, d, J = 15.2 Hz), 7.20-7.32 (5H, m), 7.41-7.58 (6H,), 7.89 (1H, d, J = 15.2 Hz).

IR (KBr) 3329, 2954, 1668, 1608, 1554, 1512, 1412, 1360, 1342, 1254, 1174, 1159, 984, 816 cm "1 Elemental Analysis for C27H30N202S1.0H2O Calculated C, 69.80; H, 6.94; N , 6.03: Found C, 69.94; H, 6.85; N, 5.98.

Working Example 213 (Production of Compound 213) Under a nitrogen atmosphere, oxalyl chloride (0.08 ml) was added to a solution of (E) -3- [4- (4-methylphenyl) -thiophen-2-yl) acid. ] acrylic (150 mg) in tetrahydrofuran (10 ml) at room temperature. To the mixture was added a drop of DMF, and the mixture was stirred for 1 hour. Under reduced pressure, the solvent was evaporated and the residue was dissolved in tetrahydrofuran (20 ml). To the solution were added triethylamine (0.2 ml) and 1- (4-aminobenzyl) -phosphorin-1-oxide (150 mg) at 0 ° C, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was added to water stirred vigorously to stop the reaction. The mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethanol to give the amide (E) -N- (4- (penta-methylene) phosphorylmethylphenyl) -3- [4- (4-methyl-phenyl) thiophen-2-yl] acrylic (Compound 213) (138 mg) as pale yellow crystals, mp 279 ° C (dec.) NMR-aH (200MHz, CDC13) d 1.49-2.23 (10H, m), 2.38 (3H, s), 3.15 (2H, d, J = 12.8 Hz), 6.61 (1H, d, J = 15.2 Hz), 7.13-7.28 (4H, m), 7.38-7.57 (6H, m), 7.86 (1H, d, J = 15.2 Hz), 9.09-9.20 (1H, m). IR (KBr) 3392, 2935, 1672, 1618, 1543, 1512, 1336, 1250, 1161, 818 cm "1 Elemental Analysis for C26H28NO2SP - 0.3H20 Calculated C, 68.64; H, 6.34; N, 3.08; P, 6.81: Found: C, 68.44; H, 6.30; N, 3.06 '; P, 6.65.

Working Example 214 (Production of Compound 214) Under a nitrogen atmosphere, oxalyl chloride (0.12 ml) was added to a soon of 2- (4-methylphenyl) -7,8-dihydro-6H-cyclohepta [b] Thiophene-5-carboxylic acid (250 mg) in tetrahydrofuran (10 ml) at room temperature. A drop of DMF was added to the mixture, and the mixture was stirred for 2 hours. Under reduced pressure, the solvent was evaporated and the residue was dissolved in tetrahydrofuran (20 ml). To the soon were added triethylamine (0.25 ml) and 4- [N-methyl-N- (tetrahydropyran-4-yl) aminomethyl] aniline (215 mg) at 0 ° C, and the mixture was stirred at room temperature for 4 hours . The reaction mixture was added to water stirred vigorously to stop the reaction. The mixture was extracted with chloroform. The organic layer was washed with a saturated sodium chloride soon, dried with magnesium sulfate and concentrated. The residue was purified by column chromatography (ethanol / ethyl acetate = 1: 4) and recrystallized from ethanol to give N- [4- [N-methyl-N- (tetrahydropyran-4-yl) aminomethyl] - phenyl] -2- (4-methyl phenyl) -7,8-dihydro-6H-cyclohepta [b] thiophene-5-carboxamide (Compound 214) (319 mg) as colorless crystals, m.p. 201-203 ° C NMR-aH (200MHz, CDC13) d 1.62-1.84 (4H, m), 2.06-2.18 (2H, m), 2.21 (3H, s), 2.36 (3H, s), 2.53-2.71 ( 1H,), 2.79-2.87 (2H, m), 3.06-3.15 (2H, m), 3.31-3.44 (2H, m), 3.57 (2H, s), 3.97-4.08 (2H, m), 7.08 (1H , s), 7.14-7.22 (3H, m), 7.30 (2H, d, J = 8.8 Hz), 7.43 (2H, d, J = 8.0 Hz), 7.50-7.56 (3H, m). IR (KBr) 3311, 2943, 1649, 1518, 1408, 1311, 810 cm "1 Elemental Analysis for C30H34N2O2S Calculated C, 74.04; H, 7.04; N, 5.76; S, 6.59: Found C, 73.92; H, 6.85; N, 5.70; S, 6.53.

Working Example 215 (Production of Compound 215) To a soon of (E) -3- [5- (4-methylphenyl) pyridin-3-yl] acrylic acid (150 mg), 4- [N-methyl-N- (tetrahydropyran-4-yl) aminomethyl] aniline (168 mg) and triethylamine (0.10 ml) in DMF (10 ml) was added diethyl cyanophosphate (0.12 ml) at 0 ° C, and the mixture was stirred at room temperature for 3 hours. hours and concentrated under reduced pressure. Water was added to the residue, the mixture was extracted with chloroform. The organic layer was washed with a saturated sodium chloride soon, dried with magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by column chromatography (ethanol / ethyl acetate = 1: 2) to give the amide (E) -N- [4- (N- (methyl-N- (tetrahydropyran-4-yl) ) aminomethyl] -phenyl [-3- [5- (4-methylphenyl) pyridin-3-yl] acrylic (Compound 215) (24 mg) as yellow crystals, NMR-aH (200MHz, CDC13) d 1.66-1.83 ( 4H,), 2.21 (3H, s), 2.43 (3H, s), 2.53-2.74 (1H, m), 3.30-3.45 (2H, m), 3.57 (2H, s), 3.99-4.10 (2H, m ), 6.69 (1H, d, J = 15.5 Hz), 7.24-7.37 (4H, m), 7.41-7.63 (5H, m), 7.82 (1H, d, J = 15.5 Hz), 7.95-8.01 (1H, m), 8.74 (1H, d, J = 1.8 Hz), 8.81 (1H, d, J = 2.2 Hz). IR (KBr) 3242, 3190, 1678, 1606, 1545, 1514, 1348, 976, 816 cm "1 Working Example 216 (Production of Compound 216) To a soon of 6- (4-methylphenyl) -2-methyl-quinoline-3-carboxylic acid (120 mg) and 1-hydroxy-benzotriazole (88 mg) in DMF (5 ml) was added l-ethyl-3- (3'-dimethylaminopropyl) carbodiimide hydrochloride (125 mg) at room temperature, and the mixture was stirred for 2 hours. To the mixture was added a soon of 4- [N-methyl-N- (tetrahydropyran-4-yl) aminomethyl] aniline (105 mg) and triethylamine (0.2 ml) in DMF (5 ml), and the mixture was stirred for 18 hours and concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with chloroform. The organic layer was washed with a saturated sodium chloride soon, dried with magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by column chromatography (ethanol / ethyl acetate = 1: 2), and recrystallized from ethyl acetate-hexane to give the N- [4- [N-methyl-N- (tetrahydropyran -4-yl) aminomethyl] phenyl] -6- (4-methylphenyl) -2-methylquinoline-3-carboxamide (Compound 216) (82 mg) as pale yellow crystals, mp. 157-160 ° C NMR-1H (200MHz, CDC13) d 1.49-1.85 (4H, m), 2.23 (3H, s), 2.43 (3H, s), 2.54-2.76 (1H, m), 2.89 (3H, s), 3.31-3.47 (2H, m), 3.60 (2H, s), 4.00-4.11 (2H, m), 7. 25-7.41 (4H, m), 7.55-7.71 (4H, m), 7.83 (1H, broad s), 7.88 (1H, d, J = 1.8 Hz), 8.01 (1H, dd, J = 8.8, 1. 8 Hz), 8.09 (1H, d, J = 8.8 Hz), 8.21 (1H, s). IR (KBr) 3311, 2958, 1657, 1520, 1313, 110, 847, 812 cm "1 Elemental Analysis for C3? H33N302 • 0.3H20 Calculated C, 76.76; H, 6.98; N, 8.66: Found C, 76.68; H 7.07; N, 8.80.

Working Example 217 (Production of Compound 217) In THF (20 ml), 7-phenyl-3,4-dihydro-naphthalene-2-carboxylic acid (1.00 g) was dissolved, and oxalyl chloride (523 μl) was added to the solution. ) and one drop of DMF. The mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The residue was dissolved in THF (20 ml), and 1- (3-aminobenzyl) piperidine (837 mg) and triethylamine (673 μl) were added to the solution at room temperature. The reaction mixture was stirred at room temperature for 2 hours and water (100 ml) was added to the mixture. The mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-diisopropyl ether to give 7-phenyl-N- [3- (piperidinomethyl) phenyl] -3,4-dihydro-naphthalene-2-carboxamide (Compound 217) (1.29 g) as crystals pale yellow color. p.f. 152-153 ° C Elemental Analysis for C29H30N20 • 0.1H20 Calculated: C, 82.08; H, 7.17; N, 6.60. Found: C, 81.97; H, 7.27; N, 6.47. IR (KBr) cm "1: 3373, 2933, 1645, 1543, 1487, 1439, 770, 696 1 H NMR (200MHz, CDCl 3) d: 1.35-1.70 (6H, m), 2.32-2.45 (4H, m), 2.65-2.80 (2H, m), 2.92-3.03 (2H, m), 3.48 (2H, s), 7.08 (1H, d, J = 7.6Hz), 7.25-7.50 (10H, m), 7.52-7.67 ( 3H, m).

Working Example 218 (Production of Compound 218) In DMF (3 ml) was dissolved 7-phenyl-N- [3- (piperidino-methyl) phenyl] -3,4-dihydronaphthalene-2-carboxamide (200 mg), and the mixture was added methyl iodide (88 μl). The mixture was stirred at room temperature for 15 hours and concentrated under reduced pressure. The residue was recrystallized from methanol-ethyl acetate to give 1-methyl-1- [3- (7-phenyl-3,4-dihydronaphthalene-2-carboxamido) benzyl] -piperidinium iodide (Compound 218) (211 mg ) as colorless crystals. p.f. 208-209 ° C Elemental Analysis for C20H33N2OI Calculated: C, 63.83; H, 5.89; N, 4.96. Found: C, 63.58; H, 5.89; N, 4.95. IR (KBr) cm "1: 3450, 1657, 1520, 1483, 1439, 1250, 1215, 766, 702 1H NMR (200MHz, 'DMS0-d6) d: 1.40-2.00 (6H, m), 2.55-2.70 ( 2H, m), 2.80-3.00 (5H, m), 3.20-3.40 (4H, m), 4.57 (2H, s), 7.20-7.82 (12H, m), 8.03 (1H, s), 10.14 (1H, s).

Working Example 219 (Production of Compound 219) To a solution of 2- (4-methylphenyl) -6,7-dihydro-5H-benzocyclohepten-8-carboxylic acid (0.2 g) in dichloromethane (5 ml) were added sodium chloride. oxalyl (0.19 ml) and dimethylformamide (catalytic amount) under cooling with ice, the mixture was stirred at room temperature for 2 hours. The solvent was evaporated, and the residue was dissolved in tetrahydrofuran. The mixture was added to a solution of 4- (N-methyl-N- (tetrahydropyran-4-yl) aminomethyl] aniline (0.17 g) and triethylamine (0.3 ml) in tetrahydrofuran (10 ml), under cooling with ice. a nitrogen atmosphere, the mixture was stirred at room temperature overnight The solvent was evaporated, and water was added to the residue The mixture was extracted with ethyl acetate The organic layer was washed with water and sodium chloride solution The solvent was evaporated and the crude crystal, precipitated, was recrystallized from ethyl acetate-hexane to give the 2- (4-methylphenyl) -N- (4- (( N-tetrahydropyran-4-yl-N-methyl-amino) methyl) phenyl) -6,7-dihydro-5H-benzo-cyclohepten-8-carboxamide (Compound 219) (0.29 g) as colorless crystals, mp 161-162 ° C. NMR-1H (d ppm, CDC13): 1.59-1.77 (4H, m), 2.13-2.21 (2H, m), 2.21 (3H, s), 2.40 (3H, s), 2.55-2.75 (3H , m), 2. 86-2.92 (2H, m), 3.37 (2H, dt, J = 2.8, 10.9Hz), 3.57 (2H, s), 4.01-4.07 (2H, m), 7.21-7.33 (4H, m), 7.41-7.58 (7H, m), 7.63 (1H, s). IR (KBr) v: 2938, 1651cm_1. Analysis for C32H36N202: Calculated C, 79.97; H, 7.55; N, 5.83. Found C, 79.63; H, 7.43; N, 5.64.

Working Example 220 (Production of Compound 220) A solution of 2- (4-methylphenyl) -N- (4- ((N-tetrahydropyran-4-yl-N-methylamino) methyl) phenyl) -6,7 Dihydro-5H-benzocyclohepten-8-carboxamide (0.11 g) and methyl iodide (0.02 ml) in dimethylformamide (4 ml) was stirred at room temperature overnight. The solvent was evaporated, and the residue was dissolved in ethyl acetate. The crude, precipitated crystal was filtered, which was recrystallized from ethanol-ethyl acetate to give the N, N-dimethyl-N- (4- ((2- (4-methylphenyl) -6,7-dihydro-) iodide. 5H-benzocyclohepten-8-yl) carbonyl) aminobenzyl) -N- (4-tetrahydropyranyl) ammonium (Compound 220) (0.13 g) as pale yellow crystals. p.f. 157-158 ° C. NMR- ^ H (d ppm, DMSO-d6): 1.80-2.20 (6H, m), 2.35 (3H, s), 2.64 (2H, t, J = 6.6Hz), 2.80-2.88 (2H, m), 2.88 (6H, s), 3.33-3.40 (2H, m), 3.50-3.65 (1H, m), 4.02-4.09 (2H, m), 4.47 (2H, s), 7.26-7.37 (4H, m), 7.50-7.60 (5H, m), 7.66 (1H, s), 7.88 (2H, d, J = 8.8Hz), 10.22 (1H, s). IR (KBr) v: 1659cm_1. Analysis for C33H39IN202 • 0.5H20: Calculated C, 62.76; H, 6.38; N, 4.44. Found C, 62.69; H, 6.38; N, 4.21.

Working Example 221 (Production of Compound 221) A solution of 7- (4-piperidinophenyl) -N-4- ((N-tetrahydropyran-4-yl-N-methylamino) methyl) phenyl) -2, 3-dihydro acid -l-benzoxepin-4-carboxamide (0.2 g) and methyl iodide (0.025 ml) in dimethylformamide (5 ml) was stirred at room temperature overnight. The solvent was evaporated, and ethyl acetate was added to the residue. The crude, precipitated crystal was filtered, which was recrystallized from ethanol-ethyl acetate to give dimethyl (N- (7- (4-piperidinophenyl) -2,3-dihydro-l-benzoxepin-4-carbonyl iodide) -4-aminobenzyl) -4-tetrahydropyranylammonium (Compound 221) (0.1 g) as colorless crystals, mp 189-190 ° C. NMR-1H (d ppm, DMSO-d6): 1.50-1.70 (6H, m), 1.75-2.00 (2H, m), 2.05-2.25 (2H, m), 2.88 (6H, s), 2.99 (2H, broad), 3.16-3.19 (4H, m), 3.26-3.33 (2H, m), 3.50-1.70 (1H, m), 4.01-4.15 (2H, m), 4.29 (2H, broad), 4.47 (2H, s), 7.00 (2H, d, J = 8.8Hz), 7.03 (1H, d, J = 8.4Hz), 7.35 (1H, s), 7.50-7.57 (5H, m), 7.68 (1H, d, J = 2.6Hz), 7.86 (2H, d, J = 8.4Hz), 10.19 (1H, s). IR (KBr) v: 2936, 1659cm_1. Analysis for C36H44IN303 • H20: Calculated C, 60.76; H, 6.51; N, 5.90. Found C, 60.57; H, 6.60; N, 5.85.

Working Example 222 (Production of Compound 222) To a suspension of 7- (4-methylphenyl) -2,3-dihydro-1-benzoxepin-4-carboxylic acid (0.3 g) in dichloromethane (10 ml) were added sodium chloride. oxalyl (0.28 ml) and dimethylformamide (catalytic amount) under cooling with ice, and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated, and the residue was dissolved in tetrahydrofuran. The mixture was added dropwise to a solution of 4- (N-methyl-N- (tetrahydrothiopyran-4-yl) -aminomethyl) aniline. (0.26 g) and triethylamine (0.5 ml) in tetrahydrofuran (20 ml), under ice-cooling. Under a nitrogen atmosphere, the mixture was stirred at room temperature for 7 hours. The solvent was evaporated, and water was added to the residue. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated and the residue was purified with a column of silica gel (ethyl acetate) to give crude crystals, which were recrystallized with ethyl acetate-hexane to give the N- (4- (( N-tetrahydrothiopyran-4-yl-N-methyl) amino-methyl) -phenyl) -7- (4-methylphenyl) -2,3-dihydro-l-benzoxepin-4-carboxamide (Compound 222) (0.47 g) as colorless crystals. p.f. 180-181 ° C. NMR-aH (d ppm, CDC13): 1.60-1.85 (2H, m), 2.10-2.15 (2H, m), 2.21 (3H, s), 2.39 (3H, s), 2.40-2.50 (1H, m) , 2.66-2.72 (4H, m), 3.08 (2H, t, J = 4.6Hz), 3.57 (2H, s), 4.36 (2H, t, J = 4.6Hz), 7.06 (1H, d, J = 8.4 Hz), 7.24 (2H, d, J = 8.0Hz), 7.31 (2H, d, J = 8.4Hz), 7.43-7.57 (7H, m).

IR (KBr) v: 2934, IdSScm "1. Analysis for C3? H34N2? 2S: Calculated C, 74.66; H, 6.87; N, 5.62, Found C, 74.46; H, 6.72; N, 5.42.

Working Example 223 (Production of Compound 223) A solution of N- (4- ((N-tetrahydrothiopyran-4-yl-N-methyl) aminomethyl) phenyl) -7- (4-methylphenyl) -2,3-dihydro -l-benzoxepin-4-carboxamide (0.11 g) and methyl iodide (0.025 ml) in dimethylformamide (5 ml) was stirred at room temperature overnight. The solvent was evaporated, and the residue was purified with a column of silica gel (chloroform / methanol) to give dimethyl- (N- (7- (4-methyl-phenyl) -2,3-dihydroyl) iodide. -benzoxepin-4-carboxynyl) -4-amino-benzyl) -4-tetrahydrothiopyranylammonium (Compound 223) (0.09 g) as colorless crystals. p.f. 185-186 ° C (dec.). NMR-aH (d ppm, DMSO-d6): 1.75-2.00 (2H, m), 2.34 (3H, s), 2.55-2.75 (4H, m), 2.75-2.85 (2H,), 2.90 (6H, s) ), 3.00 (2H, broad), 3.14-3.25 (1H, m), 4.31 (2H, broad), 4.47 (2H, s), 7.07 (1H, d, J = 8.4Hz), 7.27 (2H, d, J = 7.8Hz), 7.36 (1H, s), 7.50-7.59 (5H,), 7.74 (1H, d, J = 2.2Hz), 7.86 (2H, d, J = 8.8Hz), 10.19 (1H, s). IR (KBr) v: 2901, 1659cm_1. Analysis for C32H37N202SI • H20: Calculated C, 58.36; H, 5.97; N, 4.25. Found C, 58.62; H, 6.04; N, 4.29.

Working Example 224 (Production of Compound 224) To a solution of 2- (4-piperidinophenyl) -6,7-dihydro-5H-benzocycloheptene-8-carboxylic acid (0.45 g), 4- (N-methyl-N- (tetrahydropyran-4-yl) aminomethyl) aniline (0.31 g) and 1-hydroxybenzotriazole (0.18 g) in dimethylformamide (20 ml) was added 1-ethyl-3- (3-dimethylamino-propyl) carbodiimide hydrochloride (0.37 g) under cooling with ice. Under a nitrogen atmosphere, the mixture was heated to room temperature. To the mixture were added 4-dimethyl-aminopyridine (catalytic amount) and triethylamine (0.54 ml), and the mixture was stirred overnight. The solvent was evaporated, and water was added to the residue. The mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated and the residue was purified with a column of silica gel (ethyl acetate / methanol / triethylamine) to give crude crystals, which were recrystallized with ethyl acetate-hexane to give 2- ( 4-piperidinophenyl) -N- (4- ((N-tetrahydropyran-4-yl-N-methylamino) methyl) phenyl) -6,7-dihydro-5H-benzocyclohepten-8-carboxamide (Compound 224) (0.44 g) as pale orange crystals, mp 170-171 ° C. NMR ^ H (d ppm, CDC13): 1.59-1.65 (2H,), 1.65-1.80 (8H, m), 2.05-2.21 (2H, m), 2.21 (3H, s), 2.55-2.68 (1H, m ), 2.71 (2H, t, J = 6.3Hz), 2.84-2.90 (2H,), 3.19-3.24 (4H, m), 3.37 (2H, dt, J = 2.8, 11.2Hz), 4.01-4.11 (2H) , m), 7.00 (2H, d, J = 8.8Hz), 7.20 (1H, d, J = 7.6Hz), 7.31 (2H, d, J = 8.4Hz), 7.41-7.51 (4H,), 7.56 ( 2H, d, J = 8.4Hz), 7.63 (1H, s). IR (KBr) v: 2936, ld? Lcm "1. Analysis for C36H43N302- 0.2H2O: Calculated C, 78.14; H, 7.91; N, 7.59, Found C, 78.09; H, 7.93; N, 7.55.

Working Example 225 (Production of Compound 225) A solution of 2- (4-piperidinophenyl) -N- (4- ((N-tetrahydropyran-4-yl-N-methylamino) methyl) phenyl) -6,7-dihydro -5H-benzocyclohepten-8-carboxamide (0.2 g) and methyl iodide (0.025 ml) in dimethylformamide (10 ml) was stirred at room temperature overnight. The solvent was evaporated, and the residue was purified with a column of silica gel (chloroform / methanol) to give crude crystals, which were recrystallized with ethanol-hexane to give the dimethyl- (N- (2- (4)) iodide. -piperidinophenyl) -6,7-dihydro-5H-benzocyclohepten-8-carbonyl) -4-aminobenzyl) -4-tetrahydropyranyl-ammonium (Compound 225) (0.15 g) as pale brown crystals. p.f. 177-178 ° C. NMR ^ H (d ppm, DMSO-d6): 1.50-1.70 (6H, m), 1.80-1.95 (2H, m), 2.00-2.10 (2H,), 2.10-2.20 (2H, m), 2.60-2.70 (2H, m), 2.75-2.87 (2H, m), 2.88 (6H, s), 3.14-3.24 (6H, m), 3.53-3.65 (1H, m), 4.00-4.15 (2H,), 4.46 ( 2H, s), 7. 00 (2H, d, J = 8.8Hz), 7.26 (1H, d, J = 8.0Hz), 7.36 (1H, s), 7.46-7.62 (6H, m), 7.87 (2H, d, J = 8.8Hz ), 10.22 (1H, s). IR (KBr) v: 2934, l dSScm "1. Analysis for C37H46IN302 • H20: Calculated C, 62. 62; H, 6. 82; N, 5. 92. Found C, 62. 32; H, 6. 71; N, 5 .92.

Working Example 226 (Production of Compound 226) Under a nitrogen atmosphere, oxalyl chloride (0.05 ml) was added to a solution of 7- (4-methylthiophenyl) -2,3-dihydro-l-benzoxepin-4-acid. carboxylic acid (80.6 mg) in tetrahydrofuran (10 ml) at room temperature. To the mixture was added a drop of DMF, and the mixture was stirred for 1 hour. Under reduced pressure, the solvent was evaporated. The residue was dissolved in tetrahydrofuran (20 ml). To the solution were added triethylamine (0.1 ml) and 4- [N-methyl-N- (tetrahydropyran-4-yl) aminomethyl] aniline (62.5 mg) at 0 ° C, and the mixture was stirred at room temperature for 3 hours . The reaction mixture was added to water stirred vigorously to stop the reaction. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with magnesium sulfate and concentrated. The residue was purified by column chromatography (ethanol / ethyl acetate = 1: 4), and recrystallized from ethanol to give N- [4- [N-methyl-N- (tetrahydropyran-4-yl) aminomethyl] phenyl] -7- (4-methylthiophenyl) -2,3-dihydro-l-benzoxepin-4-carboxamide (Compound 226) (85 mg) as colorless crystals, mp. 180-186 ° C NMR-aH (200MHz, CDC13) d 1.53-1.81 (4H,), 2.21 (3H, s), 2.52 (3H, s), 2.54-2.73 (1H, m), 3.08 (2H, t , J = 4.6 Hz), 3.31-3.43 (2H, m), 3.57 (2H, s), 3.98-4.10 (2H, m), 4.36 (2H, t, J = 4.6 Hz), 7.06 (1H, d, J = 8.4 Hz), 7.23-7'.36 (4H, m), 7.41-7.63 (8H, m).

IR (KBr) 3319, 2947, 1645, 1516, 1485, 1315, 1248, 1140, 1086, 812 cm "1 Elemental Analysis for C3? H34N203S • 0 .2H20 Calculated C, 71.84; H, 6.69; N, 5.40; S, 6.19: Found C, 71.75; H, 6.70; N, 5.38; S, 6.24.

Reference Example 49 To 3-bromo-cinnamic acid (2.0 g) were added thionyl chloride (25 ml) and dimethylformamide (catalytic amount), and the mixture was refluxed for 1.5 hours. The solvent was evaporated, and the residue was dissolved in tetrahydrofuran. The mixture was added dropwise to a suspension of 1- (4-aminobenzyl) iperidine (1.7 g) and diisopropylethylamine (4 ml) in tetrahydrofuran (5 ml) under ice-cooling. Under a nitrogen atmosphere, the mixture was stirred at room temperature overnight. The solvent was evaporated and water was added to the residue. The mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated and the residue was purified with a column of silica gel (methanol / triethylamine / ethyl acetate) to give crude crystals, which were recrystallized with ethyl acetate-hexane to give the l- (4- (3-bromocinamoylamino) -benzyl) piperidine (1.8 g) as colorless crystals, m.p. 144-145 ° C. NMR-1H (d ppm, CDC13): 1.37-1.49 (2H, m), 1.52-1.63 (4H, m), 2.34-2.39 (4H, m), 3.45 (2H, s), 6.54 (1H, d, J = 15.5Hz), 7.21-7.33 (3H, m), 7.41-7.57 (5H, m), 7.67 (1H, d, J = 15.5Hz), 7.69 (1H, s). IR (KBr) V: 3270, 2934, 1663cm_1. r Analysis for C2? H23BrN20 • 0.2H2O: Calculated C, 62.60; H, 5.85; N, 6.95. Found C, 62.67; H, 5.79; N, 6.93.

Reference Example 50 To the 3-phenyl cinnamic acid (0.24 g) were added thionyl chloride (10 ml) and dimethylformamide (catalytic amount), and the mixture was heated to reflux for 2 hours. The solvent was evaporated, and the residue was dissolved in tetrahydrofuran. The mixture was added dropwise to a suspension of 2- (4-aminobenzyl) -1, 3, 2-dioxaphosphorin-2-oxide (0.2 g) and diisopropylethylamine (0.8 ml) in tetrahydrofuran (20 ml), under cooling with ice. Under a nitrogen atmosphere, the mixture was stirred at room temperature overnight. The solvent was evaporated and water was added to the residue. The mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated and the crude crystal, precipitated, was recrystallized from ethanol-hexane to give 2- (4- (3-phenylcinnamoylamino) -benzyl) -1,3,2-dioxaphosphoriane-2-oxide (0.32). g) as colorless crystals. p.f. 204-205 ° C NMR ^ H (d ppm, CDC13): 1.84-1.88 (2H, m), 3.24 (2H, d, J = 21.2Hz), 4.07-4.22 (2H, m), 4.34-4.44 (2H, m), 6.74 (1H, d, J = 15.8Hz), 7.23 (2H, dd, J = 2.6, 8.8Hz), 7.38- 7.63 (10H, m), 7.77 (1H, s), 7.81 (1H, d, J = 15.8 Hz), 8. 16 (1H, broad). IR (KBr) V: 3059, 1680CH- "1. Analysis for C25H24N04P: Calculated C, 69.28; H, 5.58; N, 3.23, Found C, 68.82; H, 5.58; N, 3.30.

Reference Example 51 To a suspension of 1- (4-methylphenyl) -2,3-dihydro-l-bezoxepin-4-carboxylic acid (0.15 g) in dichloromethane (7 ml) were added oxalyl chloride (0.14 ml) and dimethylformamide (catalytic amount) under cooling with ice, and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated and the residue was dissolved in tetrahydrofuran. The mixture was added dropwise to a solution of 2- (4-aminobenzyl) -1, 3, 2-dioxaphosphorin-2-oxide (0.13 g) and triethylamine (0.23 ml) in tetrahydrofuran (20 ml), under cooling with ice. Under a nitrogen atmosphere, the mixture was stirred at room temperature overnight. The solvent was evaporated and water was added to the residue. The mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give crude crystals, which were recrystallized with ethyl acetate-ethanol-hexane to give 2- (4- (7- (4-methylphenyl) -2,3-dihydro-l- benzoxepin-4-carbonylamino) benzyl) -1, 3, 2-dioxaphosphorin-2-oxide (0.23 g) as colorless crystals, m.p. 268-269 ° C. NMR-'H (d ppm, CDC13): 1.75-1.87 (2H, m), 2.40 (3H, s), 3.09 (2H, t, J = 4.5Hz), 3.24 (2H, d, J = 21.6Hz) , 4.02-4.19 (2H, m), 4.34-4.50 (4H, m), 7.06 (1H, d, J = 8.4Hz), 7.23-7.3.2 (4H, m), 7.44-7.60 (6H, m) 7.81 (1H, s). IR (KBr) v: 1652cm "1. Analysis for C28H28N05P: Calculated C, 68.70; H, 5.77; N, 2.86.

Found C, 68.54; H, 5.71; N, 2.86.

Reference Example 52 A suspension of N- (4-chloromethylphenyl) -7- (4-methylphenyl) -2,3-dihydro-l-benzoxepin-4-carboxamide (0.18 g), lt-butoxycarbonyl-4-methylaminopiperidine (0.19) g) and potassium carbonate (0.18 g) in dimethylformamide (10 ml) was stirred at room temperature overnight. The solvent was evaporated, and water was added to the residue. The mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give crude crystals, which were recrystallized with ethyl acetate-hexane to give the N- (4- (N- (1-t-butoxy-carbonylpiperidin-4-yl) -N- methyl) aminomethyl) phenyl) -7- (4-methylphenyl) -2,3-dihydro-1-benzoxepin-4-carboxamide (0.25 g) as colorless crystals, m.p. 203-204 ° C. RM ^ H (d ppm, CDC13): 1.37-1.70 (4H, m), 1.46 (9H, s), 1. 77-1.83 (2H, m), 2.19 (3H, s), 2.39 (3H, s), 2.52-2.74 (3H,), 3.08 (2H, t, J = 4.6Hz), 3.56 (2H, s), 4.18 (1H, broad), 4.36 (2H, t, J = 4.6Hz), 7.06 (1H, d, J = 8.4Hz), 7.22-7.33 (5H, m), 7.43-7.61 (6H, m). IR (KBr) v: 2977, 2933, 1695, 1668CIT. "1.

Analysis for C36H43N3? 4: Calculated C, 74. 33; H, 7 Four. Five; N, 7 22 Found C, 74.00; H, 7.41; N, 7.26 Reference Example 53 To a suspension of 7- (4-methylphenyl) -2,3-dihydro-l-bezoxepin-4-carboxylic acid (0.6 g) in dichloromethane (25 ml) were added oxalyl chloride (0.56 ml) and dimethylformamide (catalytic amount) under cooling with ice, and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated and the residue was dissolved in tetrahydrofuran. The mixture was added dropwise to a solution of (4-aminophenyl) [1- (tert-butoxycarbonyl-piperidin-2-ylmetanone (0.72 g) and triethylamine (0.9 ml) in tetrahydrofuran (50 ml), under ice-cooling Under a nitrogen atmosphere, the mixture was stirred at room temperature overnight The solvent was evaporated and water was added to the residue The mixture was extracted with ethyl acetate The organic layer was washed with water and a chloride solution saturated sodium, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give crude crystals, which were recrystallized with ethyl acetate-hexane to give N- (4- (1- (tert-butoxycarbonyl) piperidin-2-ylcarbonyl) -phenyl) -7 - (4-methylphenyl) -2,3-dihydro-1-benzoxepin-4-carboxamide (1.1 g) as colorless crystals. p.f. 223-224 ° C. NMR-2H (d ppm, CDC13): 1.44 (9H, broad), 1.44-1.65 (4H, m), 1.70-1.95 (1H, m), 2.00-2.20 (1H, m), 2.39 (3H, s) , 3. 08 (2H, t, J = 4.4Hz), 5.60 (1H, broad), 7.06 (1H, d, J = 8.4Hz), 7.25 (2H, d, J = 11.8Hz), 7.44-7.53 (4H, m), 7. 65 (1H, broad), 7.69 (1H, broad), 7.82 (1H, broad), 7. 94 (2H, d, J = 8.8Hz). IR (KBr) V: 2942, 1678cm "1. Analysis for C35H38N2O5 • 0.3H2O: Calculated C, 73.48; H, 6.80; N, 4.90, Found C, 73.51; H, 6.60; N, 4.68.

Reference Example 54 To a mixture of 3-bromobenzaldehyde (10 g) and methoxy-carbonylmethylenetriphenylphosphine (20 g) was added toluene (150 ml), and the mixture was heated to reflux under a nitrogen atmosphere for 2 hours. The solvent was evaporated, and the organic layer was washed with water and a saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated and the residue was purified with a column of silica gel (ethyl acetate / hexane) to give methyl 3-bromo-cinnamate (10.7 g) as colorless crystals. NMR-aH (d ppm, CDC13): 3.82 (3H, s), 6.44 (1H, d, J = 16.0Hz), 7.27 (1H, d, J = 15.6Hz), 7.43-7.54 (2H, m), 7. 62 (1H, d, J = 16.0Hz), 7.66-7.68 (1H, m). IR (KBr) v: 1734, 1717cm "1. Analysis for C? 0H9BrO2: Calculated C, 49.82; H, 3.76, Found C, 49.90; H, 3.90.

Reference Example 55 In a solution of methanol (200 ml) and 2N sodium hydroxide (50 ml), methyl 3-bromocyanamate (10.7 g) was dissolved, and the mixture was stirred at room temperature overnight, concentrated and neutralized with IN hydrochloric acid. The mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give the 3-bromophenyl cinnamic acid (9.2 g) as colorless crystals. NMR- ^ H (d ppm, CDC13): 6.45 (1H, d, J = 15.8Hz), 7.28 (1H, t, J = 7.7Hz), 7.45-7.56 (2H, m), 7.67-7.75 (2H, m). IR (KBr) v: ldSdcm "1. Analysis for C9H7Br02: Calculated C, 47.61; H, 3.11 Found C, 47.57; H, 3.10 Reference Example 56 A suspension of methyl 3-bromocyanamate (3.8 g), phenyl borate (2.0 g), 1M potassium carbonate (20 ml) and ethanol (10 ml) in toluene (100 ml) was stirred under an argon atmosphere at room temperature for 30 minutes. To the reaction mixture was added tetracistriphenyl-phosphine-palladium (0.9 g), and the mixture was heated to reflux overnight and extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with a column of silica gel (ethyl acetate / hexane) to give colorless crystals (3.6 g), 1.8 g of which were dissolved in a methanol solution ( 100 ml) and IN sodium hydroxide (20 ml). The mixture was stirred at room temperature overnight, concentrated, neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give 3-phenyl cinnamic acid (1.5 g) as colorless crystals. NMR-1H (d ppm, CDC13): 6.54 (1H, d, J = 16.0Hz), 7.39-7.67 (8H, m), 7.76-7.77 (1H, m), 7.87 (1H, d, J = 16.0Hz). IR (KBr) v 1709cm "1. Analysis for C? 5H? 202: Calculated C, 80.34; H, 5.39, Found C, 80.62; H, 5.40.

Reference Example 57 To 4-nitrobenzylphosphonic acid (0.5 g) were added thionyl chloride (5 ml) and dimethylformamide (catalytic amount), and the mixture was heated to reflux under a nitrogen atmosphere for 4 hours. The solvent was evaporated, and toluene was added to the residue. The solvent was evaporated. The residue was dissolved in tetrahydrofuran (15 ml), and the mixture was cooled to -78 ° C under a nitrogen atmosphere. To the mixture was added dropwise dimethylpropanediamine (0.3 ml) dissolved in tetrahydrofuran (2 ml) and then triethylamine (1.6 ml), and the mixture was gradually warmed to room temperature and stirred at room temperature overnight. The solvent was evaporated and the residue was purified with a column of silica gel (ethyl acetate / methanol / triethylamine) to give colorless crystals., which were dissolved in ethanol (15 ml). Palladium on carbon 10% (0.04 g) was added to the mixture, and the catalytic hydrogenation was carried out at room temperature for 3.5 hours. The catalyst was filtered and the solvent was evaporated to give 2- (4-a-benzene) -1,3-dimethyl-1,2,3-diazaphosphorin-2-oxide (0.6 g) as colorless crystals. NMR-1H (d ppm, CDC13): 1.09-1.27 (1H, m), 1.68-1.85 (1H, m), 2.65 (3H, s), 2.69 (3H, s), 2.72-3.01 (4H, m) , 3.08 (2H, d, J = 17.4Hz), 6.65 (2H, d, J = 8.1Hz), 6.96 (2H, dd, J = 2.4, 8.1Hz). IR (KBr) v: 3339, 2897, 1615cm_1. Analysis for C? 2H20N3OP • 0.3H2O: Calculated C, 55.72; H, 8.03; N, 16.24. Found C, 55.69; H, 7.98; N, 16.13.

Reference Example 58 To 4-nitrobenzylphosphonic acid (0.5 g) were added thionyl chloride (5 ml) and dimethylformamide (catalytic amount), and the mixture was refluxed for 3 hours under a nitrogen atmosphere. The solvent was evaporated, and toluene was added to the residue. The solvent was evaporated. The residue was dissolved in tetrahydrofuran (5 ml), and the mixture was cooled to -78 ° C under a nitrogen atmosphere. To the mixture was added dropwise dimethylethylenediamine (0.25 ml) dissolved in tetrahydrofuran (2 ml), and then triethylamine (1.5 ml), and the mixture was gradually warmed to room temperature and stirred at room temperature overnight. The solvent was evaporated and the residue was purified with a column of silica gel (ethyl acetate / methanol / triethylamine) to give colorless crystals, which were dissolved in ethanol (15 ml). Palladium on carbon 10% (0.05 g) was added to the mixture, and the catalytic hydrogenation was carried out at room temperature for 3 hours. The catalyst was filtered and the solvent was evaporated to give 2- (4-aminobenzyl) -1,3-dimethyl-1,2,3-diazaphosphorane-2-oxide (0.3 g) as colorless crystals. RM ^ H (d ppm, CDC13): 2.61 (3H, s), 2.63-2.71 (2H, m), 2.66 (3H, s), 3.00-3.07 (2H, m), 3.13 (2H, d, J = 18.2Hz), 6.63 (2H, d, J = 8.5Hz), 6.97 (2H, dd, J = 2.4, 8.5Hz). IR (KBr) v: 3341, 2895, 1632cm "1. Analysis for CnH? 8N3Op • 0.5H20: Calculated C, 53.22; H, 7.71; N, 16.93, Found C, 53.23; H, 7.53; N, 16.83.

Reference Example 59 A suspension of 3-bromo-6,7,8,9-tetrahydro-5H-benzocycloheptan-5-one (4.6 g, LAM Cornelius and DW Combs, Synth Commun, (1994), 24 (19) , 2777-2788), 4-methylphenyl borate (3.8 g), 2M potassium carbonate (30 ml) and ethanol (30 ml) in toluene (100 ml) was stirred under an argon atmosphere at room temperature for 30 minutes. To the reaction mixture was added tetracistriphenylphosphine palladium (1.5 g), and the mixture was heated to reflux overnight and extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with a column of silica gel (ethyl acetate / hexane) to give a pale brown oil (5.7 g), to which sodium methoxide (6.2 g) was added. ) and dimethyl carbonate (100 ml). The mixture was heated to reflux under a nitrogen atmosphere for 8 hours and emptied into IN hydrochloric acid under cooling with ice. The mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified with a column of silica gel (ethyl acetate / hexane) to give a brown oil (5.5 g), which was dissolved in dichloromethane (20 ml). To the mixture was added dropwise sodium hydride dissolved in methanol, under cooling with ice. After the starting materials disappeared, water was added to the reaction mixture and the mixture was concentrated and extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. The solvent was evaporated and IN sodium sodium hydroxide (40 ml), methanol (40 ml) and diethyl ether (100 ml) were added to the residue. The mixture was heated at 50 ° C for 30 minutes and concentrated. To the residue was added 1N sodium hydroxide, and the mixture was extracted with water, washed with ethyl acetate and acidified with hydrochloric acid. The mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. The solvent was evaporated, and the residue was dissolved in Diglyme (20 ml). Hydrochloric acid (5 ml) was added to the mixture and the mixture was heated at 100 ° C for 6 hours and emptied into water. The mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. The solvent was evaporated to give 2- (4-methylphenyl) -6,7-dihydro-5H-benzocyclohepten-8-carboxylic acid (0.3 g) as colorless crystals.

NMR-aH (d ppm, CDC13): 2.07-2.16 (2H, m), 2.40 (3H, s), 2. 70 (2H, t, J = 6.6Hz), 2.86-2.91 (2H, m), 7.21-7.28 (3H, m), 7.44-7.56 (4H, m), 7.91 (1H, s). IR (KBr) v: 2930, 1678cm ~ 1. Analysis for C? 9H? 802: Calculated C, 81.99; H, 6.52. Found C, 81.64; H, 6.41.

Reference Example 60 In dimethylformamide (100 ml) was added 4-bromo-thiophenol (25 g). To the solution were added ethyl 4-bromobutyrate (30 g) and potassium carbonate. (36 g) and the mixture was stirred at room temperature overnight. The solvent was evaporated and water was added to the residue. The mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. The solvent was evaporated, and to the residue were added 1N sodium hydroxide (240 ml) and methanol (120 ml). The mixture was stirred at room temperature overnight and concentrated. The residue was dissolved in water, and the mixture was washed with ethyl acetate. The aqueous layer was acidified with hydrochloric acid under cooling with ice. The mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. The solvent was evaporated to give colorless crystals (32 g), to which polyphosphoric acid (250 g) was added and the mixture was stirred at 100 ° C for 1 hour and emptied into ice water. The mixture was extracted with ethyl acetate. The organic layer was washed with water, a sodium acid carbonate solution, water and a saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. The solvent was evaporated to give brown crystals (13.6 g), to which was added sodium methoxide (14.2 g) and dimethyl carbonate (200 ml), and the mixture was heated under reflux under a nitrogen atmosphere for 8 hours . Under cooling with ice, the mixture was poured into 1N hydrochloric acid. The mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. The solvent was evaporated to give brown crystals (11.5 g), which were dissolved in dichloromethane (100 ml). Sodium borohydride dissolved in methane was added dropwise to the mixture under cooling with ice. After the starting materials disappeared, water was added to the reaction mixture, and the mixture was concentrated and extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. The solvent was evaporated and IN sodium sodium hydroxide (100 ml), methanol (100 ml) and diethyl ether (500 ml) were added to the residue. The mixture was stirred at room temperature for 1.5 hours and concentrated. To the residue was added sodium hydroxide IN, and the mixture was extracted with water, washed with diethyl ether and acidified with hydrochloric acid. The mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. The solvent was evaporated, and the residue was dissolved in Diglyme (100 ml). Hydrochloric acid (20 ml) was added to the mixture, and the mixture was heated at 110 ° C for 2.5 hours and emptied into water. The mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. The solvent was evaporated to give a colorless crystal (1.1 g), 1 g of which was suspended in dichloromethane (15 ml). To the suspension oxalyl chloride (1 ml) and dimethylformamide (catalytic amount) were added under cooling with ice, and the mixture was stirred at room temperature for 2.5 hours. The solvent was evaporated and the residue was dissolved in tetrahydrofuran. The mixture was added dropwise to a solution of 4- (tert-butyldimethylsilyloxy) aniline (0.76) and triethylamine (1.6 ml) in tetrahydrofuran (20 ml), under ice-cooling. Under a nitrogen atmosphere, the mixture was stirred at room temperature overnight. The solvent was evaporated and water was added to the residue. The mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give a brown oil (1.8 g), to which were added 4-methylphenyl borate (0.5 g), 1M potassium carbonate (15 ml), ethanol (15 ml) and toluene ( 500 ml) and the mixture was stirred under an argon atmosphere at room temperature for 30 minutes. To the mixture was added tetracistriphenylphosphine palladium (0.2 g) and the mixture was heated to reflux overnight. The mixture was extracted with ethyl acetate and the organic layer was washed with water and a saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated and the residue was purified with a column of silica gel (ethyl acetate / hexane) to give colorless crystals (1.3 g), which were dissolved in ethyl acetate (50 ml). Hydrochloric acid (5 ml) was added to the mixture, and the mixture was stirred at room temperature for 1.5 hours, washed with a sodium hydrogen carbonate solution, water, saturated sodium chloride solution and dried with magnesium sulfate. anhydrous. Under reduced pressure, the solvent was evaporated to give 7- (4-methylphenyl) -N- (4-hydroxy-methylphenyl) -2,3-dihydro-1-benzothiepin-4-carboxamide (1.0 g) as colorless crystals. NMR-aH (d ppm, CDC13): 2.40 (3H, s), 3.08 (2H, t, J = 5.8Hz), 3.29 (2H, t, J = 5.8Hz), 4.69 (2H, s), 7.24- 7.28 (2H, m), 7.35-7.62 (10H, m), 7.71 (1H, broad). IR (KBr) v: 3314, 2928, 1649cm ~ 1. Analysis for C25H23N02S • 0.2H20: Calculated C, 74.12; H, 5.82; N, 3.46. Found C, 74.10; H, 5.65; N, 3.47.

Reference Example 61 In dimethylformamide (100 ml) 4-bromo phenol (17.3 g) was dissolved. To the solution were added ethyl 4-bromobutyrate (21.1 g) and potassium carbonate (25 g) and the mixture was stirred at room temperature overnight. The solvent was evaporated and water was added to the residue. The mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. The solvent evaporated, and the residue tJSibttS were added 3N sodium hydroxide (100 ml) and methanol (60 ml). The mixture was stirred at 70 ° C for 30 minutes and concentrated. The residue was dissolved in water, and the mixture was washed with diethyl ether. The aqueous layer was acidified with hydrochloric acid under cooling with ice and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. The solvent was evaporated to give a colorless crystal (23.9 g), to 10 g of which polyphosphoric acid (120 g) was added. The mixture was stirred at 100 ° C for 45 minutes and emptied in ice water. The mixture was extracted with ethyl acetate. The organic layer was washed with water, a sodium hydrogen carbonate solution, water and a saturated sodium chloride solution and dried with anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified with a column of silica gel (ethyl acetate / hexane) to give 7-bromo-2,3,4,5-tetrahydrobenzoxepin-5-one as a yellow oil (6.5 g). NMR-aH (d ppm, CDC13): 2.15-2.29 (2H, m), 2.89 (2H, t, J = 7.0Hz), 4.24 (2H, t, J = 6.6Hz), 6.97 (1H, d, J = 8.8Hz), 7.50 (1H, dd, J = 2.6, 8.1Hz), 7.87 (1H, d, J = 2.6Hz). IR (pure) v: 2969, IdSdcm "1.

Reference Example 62 To the 7-bromo-2,3,4,5-tetrahydrobenzoxepin-5-one (6.5 g) were added 4-methylphenyl borate (4.1 g), 2M potassium carbonate (30 ml), ethanol ( 30 ml) and toluene (100 ml), and the mixture was stirred under an argon atmosphere at room temperature for 30 minutes. To the mixture was added tetracistriphenylphosphine palladium (1.3 g) and the mixture was heated to reflux overnight and extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with a column of silica gel (ethyl acetate / hexane) to give a pale yellow crystal (5.7 g), at 3.6 g of which sodium methoxide was dissolved (3.9 g) and dimethyl carbonate (50 ml). Under a nitrogen atmosphere, the mixture was refluxed for 8 hours and poured into IN hydrochloric acid under cooling with ice. The mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, and dried with anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified with a column of silica gel (ethyl acetate / hexane) to give a colorless crystal (3.5 g), 1.8 g of which was dissolved in dichloromethane (25 ml). To the mixture was added dropwise sodium hydride dissolved in methanol, under cooling with ice. After the starting materials disappeared, water was added to the reaction mixture and the mixture was concentrated and extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, and dried with anhydrous magnesium sulfate, and the solvent was evaporated. To the residue was added sodium hydroxide IN (50 ml), methanol (25 ml) and diethyl ether (25 ml), and the mixture was stirred at room temperature for 30 minutes and concentrated. To the mixture was added 1N sodium hydroxide, and the mixture was extracted with water, washed with diethyl ether and acidified with hydrochloric acid. The mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. The solvent was evaporated and the residue was dissolved in Diglyme (25 ml). Hydrochloric acid (5 ml) was added to the mixture and the mixture was heated at 100 ° C for 40 minutes and emptied into water. The mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution and dried with anhydrous magnesium sulfate. The solvent was evaporated to give 7- (4-methylphenyl) -2 acid, 3-dihydro-l-benzoxepin-4-carboxylic acid (1.2 g) as colorless crystals. p.f. 255-256 ° C. NMR-aH (d ppm, CDC13): 2.40 (3H, s), 3.02 (2H, t, J = 4.6Hz), 4.33 (2H, t, J = 4.6Hz), 7.05 (1H, d, J = 8.6Hz), 7. 24 (2H, d, J = 8.2Hz), 7.46 (2H, d, J = 8.2Hz), 7.47-7.56 (2H, m), 7.78 (1H, s). IR (KBr) v: 2996, 1694cm-1. Analysis for C? 8H? 603: Calculated C, 77.12; H, 5.75. Found C, 76.91; H, 5.75.

Reference Example 63 To dichloromethane (10 ml) was suspended 7- (4-methyl-phenyl) -2,3-dihydro-l-benzoxepin-4-carboxylic acid (1.0 g) and to the suspension were added oxalyl chloride (1 ml) and dimethylformamide (catalytic amount) under ice-cooling. The mixture was stirred at room temperature for 3 hours. The solvent was evaporated and the residue was dissolved in tetrahydrofuran.The mixture was added dropwise to a solution of 4- (tert-butyldimethylsilyloxy) aniline (0.93 g) and triethylamine. (1.5 ml) in tetrahydrofuran (15 ml), under cooling with ice. Under a nitrogen atmosphere, the mixture was stirred at room temperature overnight. The solvent was evaporated and water was added to the residue. The mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated and the residue was purified with a column of silica gel (ethyl acetate / hexane) to give a colorless oil (1.88 g), which was dissolved in ethyl acetate (20 ml), hydrochloric acid (5 ml) was added to the mixture, and the mixture was stirred at room temperature 1.5 hours.The mixture was washed with a carbonate solution Sodium acid, water and a saturated sodium chloride solution were dried with anhydrous magnesium sulfate.With reduced pressure, the solvent was evaporated and the residue was purified with a column of silica gel (ethyl acetate / hexane) give the colorless crystals (0.9 g), which were suspended in dichloromethane (60 ml), to the suspension were added lithium chloride (0.1 g) and triethylamine (1 ml), methanesulfonyl chloride was added dropwise to the mixture. (0.3 ml) under cooling with ice, and the mixture was stirred at room temperature overnight.The solvent was evaporated and water was added to the residue.The mixture was extracted with ethyl acetate.The organic layer was washed with water and a saturated sodium chloride solution, and dried or with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated and the residue was purified with a column of silica gel (ethyl acetate) to give N- (4-chloromethylphenyl) -7- (4-methyl-phenyl) -2, 3- dihydro-l-benzoxepin-4-carboxamide (0.4 g). NMR-aH (d ppm, CDC13): 2.39 (3H, s), 3.08 (2H, t, J = 4.6Hz), 4.36 (2H, t, J = 4.6Hz), 4.59 (2H, s), 7.06 ( 1H, d, J = 8.4Hz), 7.22-7.26 (2H, m), 7.36-7.53 (6H, m), 7.60 (2H, d, J = 8.4Hz), 7.65 (1H, s). IR (KBr) v: 3025, 1649cm "1.

Reference Example 64 In tetrahydrofuran (50 ml) p-nitro-phenethylbromide (2.3 g) and sodium iodide (1.5 g) were suspended. Pyridine (4 ml) was added to the suspension and the mixture was stirred at room temperature overnight. The solvent was evaporated and water was added to the residue. The mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give a yellow oil (2.3 g), which was dissolved in ethanol (50 ml). Palladium on carbon 10% (0.23 g) was added to the mixture, and the catalytic hydrogenation was carried out at room temperature overnight. The catalyst was filtered and the solvent was evaporated to give 1- (2- (4-aminophenyl) ethyl) -piperidine (2.0 g) as an oil. NMR-1H (d ppm, CDC13): 1.43-1.50 (2H, m), 1.56-1.67 (4H, m), 2.42-2.53 (6H, m), 2.67-2.75 (2H,), 3.55 (2H, broad ), 6.62 (2H, d, J = 8.4Hz), 6.99 (2H, d, J = 8.4Hz). IR (pure) v: 2935, 1623cm "1.

Reference Example 65 To 5 '-bromo-2' -hydroxyacetophenone (10 g) were added 4-methylphenyl borate (6.7 g), 2M potassium carbonate (70 ml), ethanol (70 ml) and toluene (200 ml), and the mixture was stirred under an argon atmosphere at room temperature for 30 minutes. To the mixture was added tetracistriphenylphosphine palladium (2.1 g), and the mixture was heated to reflux overnight. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and a saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated and the residue was purified with a column of silica gel(ethyl acetate / hexane) to give a pale yellow crystal (7.4 g), 2.3 g of which was dissolved in pyridine (15 ml). To the mixture was added benzoyl chloride (1.4 ml) and the mixture was stirred at room temperature for 30 minutes. The solvent was evaporated, and water was added to the residue. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and a saturated sodium chloride solution and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give colorless crystals (3.0 g), 2.9 g of which were dissolved in pyridine (25 ml). To the mixture potassium hydroxide (0.7 g) was added little by little at 50 ° C. The mixture was stirred at 50 ° C for 1 hour, and the solvent was evaporated. To the residue, 10% acetic acid was added under cooling with ice and the mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give a yellow crystal (2.3 g), to which was added sulfuric acid (0.37 ml) and acetic acid (15 ml). The mixture was refluxed for 1 hour and poured into ice water. The mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give a colorless crystal (2.1 g), which was dissolved in dimethyl sulfoxide (150 ml). To the mixture was added dropwise a solution which was prepared by adding a solution of trimethylsulfoxonium iodide (2.3 g) in dimethyl sulfoxide (60 ml) dropwise to a suspension of sodium hydride (60%, 0.44 g ) in dimethyl sulfoxide (10 ml) and the mixture was stirred under a nitrogen atmosphere at room temperature for 40 minutes. The mixture was stirred at room temperature for 3 hours and further stirred at 50 ° C for 2 hours. The mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with a column of silica gel (ethyl acetate / hexane) to give pale yellow crystals (1.7 g), to which tributyltin hydride (2.1 ml) was added. ), 2,2'-azobis (isobutyro-nitrile) (0.64 g) and toluene (50 ml). The mixture was stirred under a nitrogen atmosphere at 100 ° C for 1 hour, washed with water and a saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with a column of silica gel (ethyl acetate / hexane) to give colorless crystals (0.65 g), to which were added sodium methoxide (0.54 g) and dimethyl carbonate (25 ml). The mixture was refluxed under a nitrogen atmosphere for 8 hours and was emptied into IN hydrochloric acid under ice-cooling. The mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. The solvent was evaporated to give a pale brown oil (0.76 g), which was dissolved in dichloromethane (50 ml). To the mixture was added dropwise the solution of sodium borohydride in methanol at -10 ° C. After the starting materials disappeared, water was added to the reaction mixture, and the mixture was concentrated, extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, and dried with anhydrous magnesium sulfate, and the solvent was evaporated. To the residue were added 1N sodium hydroxide (20 ml) and methanol (200 ml) and the mixture was stirred at room temperature for 3 hours, concentrated and acidified with hydrochloric acid. The mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, and dried with anhydrous magnesium sulfate, and the solvent was evaporated. The residue was dissolved in Diglyme (50 ml), and hydrochloric acid (10 ml) was added to the mixture. The mixture was stirred at 100 ° C for 30 minutes and emptied in water. The mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. The solvent was evaporated to give 7- (4-methylphenyl) -2-phenyl-2,3-dihydro-l-benzoxepin-4-carboxylic acid (0.4 g) as colorless crystals. p.f. 296-297 ° C NMR- ^ H (d ppm, CDC13): 2.40 (3H, s), 3.10-3.39 (2H, m), . 02 (1H, dd, J = 1.8, 8.8Hz), 7.10 (1H, d, J = 8.4Hz), 7. 12-7.27 (2H, m), 7.35-7.53 (8H, m), 7.58 (1H, d, J = 2.2Hz), 7.86 (1H, d, J = 2.0Hz). IR (KBr) v: 1673cm "1. Analysis for C2H2o03 • 0.1H20: Calculated C, 80.47; H, 5.68, Found C, 80.41; H, 5.73.

Reference Example 66 In 1, 2-dichloroethane (100 ml), p-nitro-benzylamine hydrochloride (7.5 g), 4H-tetrahydropyran-4-one (4.0 g) and triethylamine (5.6 ml) were suspended and the suspension was added. triacetoxy boron sodium hydride (11.8 g) under ice-cooling. The mixture was stirred under a nitrogen atmosphere at room temperature for 5 hours. 37% formalin (3.6 ml) and triacetoxy boron sodium hydride (11.8 g) were added to the mixture under cooling with ice, and the mixture was stirred under a nitrogen atmosphere at room temperature for 4 hours. The solvent was evaporated, and the residue was neutralized with sodium hydroxide. The mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give a brown oil (10 g), to which were added reduced iron (9 g) and acetic acid (200 ml). The mixture was stirred at room temperature overnight. The solvent was evaporated, and ethyl acetate was added to the residue. The precipitate was filtered and the filtrate was washed with a sodium acid carbonate solution, water and a saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give 4- (N-methyl-N- (tetrahydropyran-4-yl) aminomethyl) aniline (7.3 g) as colorless crystals. p.f. 93-94 ° C. NMR-aH (d ppm, CDC13): 1.65-1.76 (4H, m), 2.19 (3H, s), 2.58-2.68 (1H,), 3.36 (2H, dt, J = 3.2, 11.3Hz), 3.48 ( 2H, s), 3.60 (2H, broad), 4.00-4.05 (2H, m), 6.65 (2H, d, J = 8.4Hz), 7.09 (2H, d, J = 8.4Hz). GO . { KBr) V: 2952, 2844, 2788, ldlScm "1.

Analysis for C? 3H20N2O • O.1H20: Calculated C, 70.30; H, 9.17; N, 12.61 Found C, 70.21; H, 8.85; N, 12.64 Reference Example 67 In methanol (20 ml), ethyl levulinate (10 g) was dissolved, and sodium boron hydride (0.7 g) was added to the mixture at -78 ° C. The mixture was heated to room temperature, and a solution of ammonium chloride was added to the mixture. The mixture was concentrated, extracted with diethyl ether and dried with anhydrous magnesium sulfate. The solvent was evaporated to give a colorless oil (9.3 g), which was dissolved in tetrahydrofuran (50 ml). Triethylamine (10.6 ml) was added to the mixture under cooling with ice, and methanol-sulfonyl chloride (4.9 ml) was added dropwise to the mixture. The mixture was warmed to room temperature, and the solvent was evaporated. To the residue was added sodium iodide (11.4 g) and acetone (50 ml), and the mixture was stirred at 50 ° C for 2 hours. The solvent was evaporated and ethyl acetate was added to the residue. The precipitate was filtered and the solvent was evaporated. The residue was purified with a column of silica gel (ethyl acetate / hexane) to give a colorless oil (7.0 g), which was dissolved in dimethylformamide (20 ml). The mixture was added dropwise to a solution of methyl 5-bromosalicylate (1.8 g) and sodium hydride (60%, 0.33 g) in dimethylformamide (20 ml), under ice-cooling, and the mixture was stirred at 50 ° C. ° C during the night. The solvent was evaporated, and water was added to the residue. The mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated and the residue was purified with a column of silica gel (ethyl acetate / hexane) to give a colorless oil (1.1 g), which was dissolved in tetrahydrofuran (20 ml). The mixture was added dropwise to a solution of lithium diisopropylamine, which was prepared by diisopropylamine (0.37 g) and a solution of n-butyl lithium in hexane (1.6M)., 2.1 ml), in tetrahydrofuran, at -78 ° C. The mixture was stirred at room temperature under an argon atmosphere overnight and was poured into water. The mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with a column of silica gel (ethyl acetate / hexane) to give a colorless oil (0.3 g), which was dissolved in dichloromethane (25 ml). The mixture was added dropwise to a solution of boron sodium hydride in methanol at -10 ° C. After the starting materials disappeared, water was added to the reaction mixture, and the mixture was concentrated and extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. The solvent was evaporated, and the residue was dissolved in dichloromethane (25 ml). To the mixture was added triethylamine (0.74 ml), and methanesulfonyl chloride (0.15 ml) was added dropwise to the mixture under cooling with ice. The mixture was stirred at room temperature under a nitrogen atmosphere overnight, washed with water and dried with anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified with a column of silica gel (ethyl acetate / hexane) to give colorless crystals (0.2 g), to which were added 4-methylphenyl borate (0.1 g), potassium carbonate. 1M (2.5 ml), ethanol (2.5 ml) and toluene (15 ml). The mixture was stirred under an argon atmosphere at room temperature for 30 minutes, and tetracistriphenylphosphine palladium was added to the mixture. (0.03 g). The mixture was refluxed overnight and extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with a column of silica gel (ethyl acetate / hexane) to give colorless crystals (0.2 g), to which 1N sodium hydroxide (5 ml) was added. and methanol (50 ml). The mixture was refluxed for 30 minutes, concentrated, acidified with hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. The solvent was evaporated to give 7- (4-methylphenyl) -2-methyl-2,3-dihydro-l-benzoxepin-4-carboxylic acid (0.2 g) as colorless crystals, m.p. 224-225 ° C. RM ^ H (d ppm, CDC13): 1.53 (3H, d, J = 6.2Hz), 2.40 (3H, s), 2.81 (1H, ddd, J = 2.2, 8.8, 18. OHz), 3.08 (1H, d, J = 18.0Hz), 4.17-4.27 (1H, m), 7.04 (1H, d, J = 8.2Hz), 7.24 (2H, d, J = 7.4Hz), 7.44-7.52 (4H, m), 7.77 (1H, d, J = 2.2Hz). IR (KBr) v: 2973, 1674cm_1. Analysis for C? 9H? 803: Calculated C, 77.53; H, 6.16. Found C, 77.60; H, 6.14.

Reference Example 68 In ethanol (10 ml) and ethyl acetate (60 ml) 4-methylphenyl 4-nitrobenzyl sulfone (0.5 g, G. Bram et al., Synthesis, 1987, 56-59) was dissolved. Palladium on carbon 10% (0.05 g) was added to the mixture and the catalytic hydrogenation was carried out at room temperature overnight. The catalyst was filtered and the solvent was evaporated to give the 4-aminobenzyl 4-methylphenyl sulfone (0.4 g) as colorless crystals. NMR -'- H (d ppm, CDC13): 2.42 (3H, s), 4.18 (2H, s), 6.56 (2H, d, J = 8.4Hz), 6.86 (2H, d, J = 8.4Hz), 7.24 (2H, d, J = 8.2Hz), 7.52 (2H, d, J = 8.2Hz). IR (KBr) v: 3443, 3370, 2926, 1612cm "1. Analysis for d4H? 5N02S • 0.2H20: Calculated C, 63.47; H, 5.86; N, 5.29, Found C, 63.63; H, 5.86; N, 5.09 .

Reference Example 69 In 1, 2-dichloroethane (50 ml), cyclopentanone (1 g), methylamine hydrochloride (1.6 g) and triethylamine (3.4 ml) were suspended and triacetoxy boron sodium hydride (3.5 g) was added to the suspension. cooling with ice. Under a nitrogen atmosphere, the mixture was stirred at room temperature overnight. The mixture was neutralized with sodium hydroxide, concentrated and water extracted. The aqueous layer was washed with ethyl acetate. The aqueous layer was saturated with sodium chloride and extracted with diethyl ether. The organic layer was dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give the N-methylcyclopentylamine (0.5 g) as a colorless oil. NMR - ^ - H (d ppm, CDC13): 1.21-1.86 (8H, m), 2.40 (3H, s), 2.94-3.01 (1H, m).

Reference Example 70 In 1, 2-dichloroethane (50 ml), cycloheptanone (2 g), methylamine hydrochloride (3 g) and triethylamine (6.2 ml) were suspended and triacetoxy boron sodium hydride (5.3 g) was added to the suspension. cooling with ice. Under a nitrogen atmosphere, the mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was neutralized with sodium hydroxide. The mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give the N-methylcycloheptylamine (1.8 g) as a colorless oil. 1 H NMR (d ppm, CDC13): 1.26-1.70 (10H, m), 1.77-1.89 (2H, m), 2.40 (3H, s), 2.47-2.58 (1H, m). IR (KBr) v: 2933, 2860cm "1.

Reference Example 71 In tetrahydrofuran (100 ml) were added 4-amino-1-benzyl-piperidine (10 g) and triethylamine (36 ml), and to the mixture was added dropwise acetyl chloride (4.1 ml) under cooling with ice. The mixture was stirred at room temperature for 1 hour, and the solvent was evaporated. Water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give a colorless crystal (2.6 g), which was dissolved in tetrahydrofuran (10 ml). Under cooling with ice, the borane methylsulfide (2.2 ml) was added dropwise to the solution. Under a nitrogen atmosphere, the mixture was heated to reflux for 5 hours. Under ice-cooling, methanol (10 ml) was added to the mixture, and the mixture was stirred at room temperature for 1 hour. To the mixture was added 4N hydrochloric acid-ethyl acetate, and the mixture was heated to reflux for 1 hour. The solvent was evaporated and sodium hydroxide IN was added to the residue. The mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give 4-ethylamino-1-benzylpiperidine (1.2 g) as a colorless oil. NMR-aH (d ppm, CDC13): 1.10 (3H, t, J = 7.2Hz), 1.28-1.47 (2H, m), 1.82-1.88 (2H, m), 1.95-2.07 (2H, m), 2.40 -2.51 (1H, m), 2.66 (2H, q, J = 7.2Hz), 2.82-2.88 (2H, m), 3.50 (2H, s), 7.20-7.33 (5H, m).

Reference Example 72 To a mixture of ethyl 7-bromo-2,3-dihydro-l-benzoxepin-4-carboxylate (0.5 g), 4- (4-methylpiperazin-1-yl) phenyl borate (0.44 g) , potassium carbonate 1M (6 ml) and ethanol (6 ml) was added toluene (50 ml), and the mixture was stirred under an argon atmosphere at room temperature for 30 minutes. To the mixture was added tetracistriphenylphosphine palladium (0.07 g), and the mixture was heated to reflux overnight and extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with a column of silica gel (ethyl acetate) to give colorless crystals (0.39 g), which were dissolved in sodium hydroxide. (15 ml) and methanol (100 ml). The mixture was refluxed for 2 hours, concentrated and neutralized with hydrochloric acid to precipitate 7- (4- (4-methyl-piperazin-1-yl) phenyl-2,3-dihydro-l-benzoxepin-4-acid. carboxylic acid (0.33 g) as colorless crystals, mp 278-279 ° C (dec.). RMN-aH (d ppm, DMS0-d6): 2.24 (3H, s), 2.45-2.52 (4H, m), 2.87 ( 2H, t, J = 4.0Hz), 3.15-3.20 (4H, m), 4.23 (2H, t, J = 4.8Hz), 6.97-7.01 (3H, m), 7.49-7.62 (4H,), 7.70 (1H, d, J = 2.2Hz). IR (KBr) v: 1692cm_1. Analysis for C22H24N203 • 0.5H2O: Calculated C, 70.76; H, 6.75; N, 7.50. Found C, 70.87; H, 6.50; N, 7.56.

Reference Example 73 In 1, 2-dichloroethane (35 ml), 4-methyl-cyclohexanone (2.5 g), methylamine hydrochloride (1.6 g) and triethylamine (3.3 ml) were suspended and triacetoxy boron sodium hydride was added to the suspension. (6.6 g) under cooling with ice. The mixture was stirred under a nitrogen atmosphere at room temperature overnight. The solvent was evaporated and the residue was neutralized with sodium hydroxide. The mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated. To the residue was added 4N hydrochloric acid-ethyl acetate, and the solvent was evaporated to give the N, 4-dimethyl-cyclohexylamine hydrochloride (2.6 g) as colorless crystals. NMR-1H (d ppm, CDC13): 0.90 (1.5H, d, J = 6.6Hz), 1.01 (1.5H, d, J = 6.6Hz), 1.45-2.10 (8H, m), 2.19-2.26 (1H , m), 2.61-2.68 (3H,), 3.03 (1H, broad). Analysis for C8H18C1N: Calculated C, 58.70; H, 11.08; N, 8.56. Found C, 58.42; H, 10.91; N, 8.48.

Reference Example 74 In 1, 2-dichloroethane (25 ml), p-nitro-benzylamine hydrochloride (1.2 g), tetrahydropyran-3-one (0.6 g, Nu ata et al., JP-A-63-170372) were suspended. ) and triethylamine (0.9 ml), and triacetoxy boron sodium hydride (1.8 g) was added to the suspension under cooling with ice. Under a nitrogen atmosphere, the mixture was stirred at room temperature overnight. Under cooling with ice, 37% formalin (0.6 ml) and triacetoxy boron sodium hydride (1.8 g) were added to the mixture. Under a nitrogen atmosphere, the mixture was stirred at room temperature overnight, and the solvent was evaporated. The residue was neutralized with sodium hydroxide, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated and the residue was purified with a column of silica gel (ethyl acetate / hexane) to give a pale yellow oil (1.0 g) to which reduced iron (0.6 g) and acid were added. acetic acid (50 ml). The mixture was stirred at room temperature overnight. The solvent was evaporated, and ethyl acetate was added to the residue. The precipitate was filtered and the filtrate was washed with a sodium acid carbonate solution, water and a saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give 4- (N-methyl-N- (tetrahydropyran-3-yl) -aminomethyl) aniline (0.3 g) as a brown oil.

NMR ^ H (d ppm, CDC13): 1.46-1.75 (3H, m), 1.95-2.01 (1H, m), 2.19 (3H, s), 2.55-2.68 (1H, m), 3.21-3.40 (2H, m), 3.49 (2H, s), 3.59 (2H, broad), 3.83-3.89 (1H, m), 4.00-4.08 (1H, m), 6.64 (2H, d, J = 8.4Hz), 7.07 (2H) , d, J = 8.4Hz).

IR (pure) v: 2941, 2846, 1615cm-i Reference Example 75 In 1, 2-dichloroethane (50 ml), 2-amino-indane hydrochloride (1.0 g), p-nitrobenzaldehyde (0.9 g) and triethylamine (0.9 ml) were suspended, and triacetoxy boron hydride was added to the mixture. of sodium (1.8 g) under cooling with ice. Under a nitrogen atmosphere, the mixture was stirred at room temperature overnight. Under cooling with ice, 37% formalin (0.6 ml) and triacetoxy boron sodium hydride (1.8 g) were added to the mixture. Under a nitrogen atmosphere, the mixture was stirred at room temperature overnight, and the solvent was evaporated. The residue was neutralized with sodium hydroxide, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give colorless crystals (1.7 g), which were dissolved in ethanol (50 ml) and ethyl acetate (50 ml). Palladium on carbon 10% (0.15 g) was added to the mixture, and the catalytic hydrogenation was carried out at room temperature for 1 hour. The catalyst was filtered and the solvent was evaporated. The residue was purified with a column of silica gel (ethyl acetate) to give 4- ((N-indan-2-yl-N-methyl) aminomethyl) aniline (0.6 g) as colorless crystals. p.f. 95-96 ° C. NMR-1 ^ (d ppm, CDC13): 2.17 (3H, s), 2.91-3.16 (4H, m), 3. 32-3.43 (1H,), 3.47 (2H, s), 3.61 (2H, broad), 6.66 (2H, d, J = 8.8Hz), 7.10-7.22 (6H,). IR (KBr) v: 2782, 1623cm_1. Analysis for C17H20N2 • 0. 2H20: Calculated C, 79. 77; H, 8 03; N, 10 94 Found C, 79.87; H, 8.04; N, 10.75.

Reference Example 76 In 1, 2-dichloroethane (50 ml), p-nitro-benzylamine hydrochloride (1.9 g), 4-t-butylcyclohexanone (1.5 g) and triethylamine (1.4 ml) were suspended and added to the suspension. triacetoxy boron sodium hydride (3 g) under cooling with ice. Under a nitrogen atmosphere, the mixture was stirred at room temperature overnight. Under cooling with ice, 37% formalin (0.9 ml) and triacetoxy boron sodium hydride (3 g) were added to the mixture. Under a nitrogen atmosphere, the mixture was stirred at room temperature overnight, and the solvent was evaporated. The residue was neutralized with sodium hydroxide, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated and the residue was purified with a column of silica gel (ethyl acetate / hexane) to give (E) -N- (4-t-butylcyclohexyl) -N-methyl-N- (4-nitro-benzyl) amine (0.3 g) as colorless crystals and (Z) -N- (4-t-butylcyclohexyl) -N-methyl-N- (4-nitrobenzyl) amine (2.4 g) as a yellow oil . (E) -N- (4-t-butylcyclohexyl) -N-methyl-N- (4-nitrobenzyl) amine: m.p. 96-97 ° C. NMR-1H (d ppm, CDC13): 0.85 (9H, s), 0.94-1.05 (3H, m), 1.20-1.40 (2H,), 1.80-2.00 (4H, m), 2.19 (3H, s), 2.29-2.44 (1H, m), 3.65 (2H, s), 7.51 (2H, d, J = 8.4Hz), 8.17 (2H, d, J = 8.4Hz). IR (KBr) v: 2941, 1604, 1513cm "a.Analysis for C? 8H28N202: Calculated C, 71.02; H, 9.27; N, 9.20, Found C, 70.77; H, 9.26; N, 9.32. (Z) - N- (4-t-butylcyclohexyl) -N-methyl-N- (4-nitrobenzyl) -amine: NMR ^ H (d ppm, CDC13): 0.89 (9H, s), 1.15-1.20 (1H, m), 1.30-1.54 (6H, m), 1.97-2.10 (2H,), 2.08 (3H, s), 2.38 (1H, broad), 3.61 (2H, s), 7.52 (2H, d, J = 8.4Hz), 8.18 (2H, d, J = 8.4Hz).

IR (pure) v: 2943, 1606, 1521cm_1 Reference Example 77 In ethanol (25 ml) and ethyl acetate (25 ml) was dissolved (E) -N- (4-t-butylcyclohexyl) -N-methyl-N- (4-nitrobenzyl) amine (0.3 g). Palladium on carbon 10% (0.03 g) was added to the mixture and the catalytic hydrogenation was carried out at room temperature for 1 hour. The catalyst was filtered and the solvent was evaporated. The residue was purified with a column of silica gel (ethyl acetate / methanol / triethylamine) to give (E) -4- ((N-4-t-butyl-cyclohexyl-N-methyl) aminomethyl) aniline (0.2 g) as colorless crystals. p.f. 87-88 ° C. NMR ^ H (d ppm, CDC13): 0.84 (9H, s), 0.93-1.03 (2H, m), 1.15-1.40 (2H, m), 1.81-1.96 (5H, m), 2.19 (3H, s), 2.30-2.45 (1H , m), 3.48 (2H, s), 3.60 (2H, broad), 6.65 (2H, d, J = 8.4Hz), 7.10 (2H, d, J = 8.4Hz). IR (KBr) v: 2927, 1614, 1517cm_1. Analysis for C? 8H30N2 • 0.2H20: Calculated C, 77.75; H, 11.02; N, 10.07. Found C, 77.87; H, 10.93; N, 10.16.

Reference Example 78 In acetic acid (70 ml), (Z) -N- (4-t-butyl-cyclohexyl) -N-methyl-N- (4-nitrobenzyl) amine was dissolved. (1.2 g), and reduced iron (1.1 g) was added to the mixture. The mixture was stirred at room temperature overnight. The solvent was evaporated and ethyl acetate was added to the residue. The precipitate was filtered and the filtrate was washed with a sodium acid carbonate solution, water and a saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with a column of silica gel (ethyl acetate to give (Z) -4- ((N-4-t-butyl-cyclohexyl-N-methyl) aminomethyl) aniline (0.7 g) as a yellow oil, NMR-aH (d ppm, CDC13): 0.87 (9H, s), 1.00-1.20 (1H, m), 1.25-1.56 (6H, m), 2.04 (3H , s), 2.04-2.13 (2H, m), 2.26-2.29 (1H, m), 3.40 (2H, s), 3.58 (2H, broad), 6.65 (2H, d, J = 8.4Hz), 7.10 ( 2H, d, J = 8.4Hz). IR (pure) v: 2941, 1623, 1515cm-1.

Reference Example 79 In 1, 2-dichloroethane (70 ml), p-nitro-benzylamine hydrochloride (3.8 g), 3,5-dimethylcyclohexanone (2.5 g) and triethylamine (2.8 ml) were suspended.

Under cooling with ice, triacetoxy boron sodium hydride (5.9 g) was added to the mixture. Under a nitrogen atmosphere, the mixture was stirred at room temperature overnight. Under cooling with ice, 37% formalin (1.8 ml) and triacetoxy boron sodium hydride (5.9 g) were added to the mixture. Under a nitrogen atmosphere, the mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was neutralized with sodium hydroxide. The mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated and the residue was purified with a column of silica gel (ethyl acetate / hexane) to give 3 isomers of N-methyl-N- (3,5-dimethylcyclohexyl) -N- (4 -nitrobenzyl) amine (4.3 g; (31-a), 0.7 g; (31-b), 0.2 g; (31-c)) as each yellow oil. 31-a: NMR- ^ H (d ppm, CDC13): 0.53-0.74 (1H, m), 0.84 (3H, s), 0.87 (3H, s), 0.93-1.07 (2H, m), 1.73-1.99 (5H, m), 2.06 (3H, s), 2.49 (1H, t, J = 2.8Hz), 3.60 (2H, s), 7.50 (2H, d, J = 8.8Hz) 8.17 (2H, d, J = 8.8Hz). IR (pure) v: 2949, 1606, 1521cm "1. 31-b: RMN- ^ H (d ppm, CDC13): 0.51 (1H, q, J = 12.0Hz), 0.80-1.02 (2H, m), 0.92 (3H, s), 0.95 (3H, s), 1.34-1.53 (2H, m), 1.58-1.66 (1H, m), 1.78-1.84 (2H, m), 2.19 (3H, S), 2.53 (1H, tt, J = 3.3, 11.7Hz), 3.65 (2H, s), 7.51 (2H, d, J = 8.8Hz), 8.17 (2H, d, J = 8.8Hz). IR (pure) v: 2949, 1606, 1519cm_1. 31-c: NMR-aH (d ppm, CDC13): 0.80-1.13 (8H, m), 1.38-1.52 (2H, m), 1.62-1.68 (2H, m), 1.80-1.86 (1H, m), 2. 08-2.17 (1H, m), 2.18 (3H, s), 2.74 (1H, tt, J = 3.5, 11. 9Hz), 3.64 (2H, s), 7.51 (2H, d, J = 8.4Hz), 8.17 (2H, d, J = 8.4Hz). IR (pure) v: 2920, 1606, 1521cm "1.

Reference Example 80 In ethanol (50 ml) and ethyl acetate (50 ml) was dissolved N-methyl-N- (3,5-dimethylcyclohexyl) -N- (4-nitrobenzyl) amine (2.0 g; )). Palladium on carbon 10% (0.2 g) was added to the mixture and the catalytic hydrogenation was carried out at room temperature for 1 hour. The catalyst was filtered and the solvent was evaporated. The residue was purified with a column of silica gel (ethyl acetate / methanol / triethylamine) to give 4 - ((N- (3,5-dimethylcyclohexyl) -N-methyl) aminomethyl) aniline (0.2 g) as a pale yellow oil. NMR-XH (d ppm, CDC13): 0.58 (1H, q, J = 11.7Hz), 0.83 (3H, s), 0.86 (3H, s), 0.93-1.00 (2H, m), 1.69-2.04 (5H , m), 2.04 (3H, s), 2.24-2.40 (1H, m), 3.41 (2H, s), 3.50 (2H, broad), 6.64 (2H, d, J = 8.6Hz), 7.08 (2H, d, J = 8.6Hz). IR (pure) v: 2947, 1623cm ~ 1.

Reference Example 81 In acetic acid (30 ml) was dissolved N-methyl-N- (3,5-dimethylcyclohexyl) -N- (4-nitrobenzyl) amine (0.7 g; (31-b)), and to the mixture Reduced iron (0.7 g) was added. The mixture was stirred at room temperature overnight. The solvent was evaporated and ethyl acetate was added to the residue. The precipitate was filtered and the filtrate was washed with a sodium acid carbonate solution, water and a saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with a column of silica gel (ethyl acetate / methanol / triethylamine) to give 4- ((N- (3,5-dimethylcyclohexyl) -N -methyl) aminomethyl) aniline (0.4 g) as a yellow oil. NMR-aH (d ppm, CDC13): 0.50 (1H, q, J = 12.0Hz), 0.80-1.03 (1H, m), 0.91 (3H, s), 0.94 (3H, s), 1.22-1.50 (3H , m), 1.55-1.64 (1H, m), 1.78-1.84 (2H, m), 2.17 (3H, s), 2.53 (1H, tt, J = 3.3, 11.8Hz), 3.46 (2H, s), 3.58 (2H, broad), 6.64 (2H, d, J = 8.6Hz), 7.09 (2H, d, J = 8.6Hz).

IR (pure) v: 2949, 1621cm "1.

Reference Example 82 In acetic acid (15 ml) the N-methyl-N- (3,5-dimethylcyclohexyl) -N- (4-nitrobenzyl) amine was dissolved (0.2 g; (31-c)), and reduced iron (0.2 g) was added to the mixture. The mixture was stirred at room temperature overnight. The solvent was evaporated and ethyl acetate was added to the residue. The precipitate was filtered and the filtrate was washed with a sodium acid carbonate solution, water and a saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with a column of silica gel (ethyl acetate / methanol / triethylamine) to give 4- ((N- (3,5-dimethylcyclohexyl) -N -methyl) aminomethyl) aniline (0.1 g) as a brown oil. NMR ^ H (d ppm, CDC13): 0.87-1.15 (7H, m), 1.35-1.55 (2H, m), 1.60-1.70 (2H, m), 1.75-1.90 (1H, m), 2.05-2.19 ( 2H, m), 2.17 (3H, s), 2.75 (1H, tt, J = 3.3, 12.1Hz), 3.45 (2H, s), 3.60 (2H, broad), 6.64 (2H, d, J = 8.3Hz ), 7.09 (2H, d, J = 8.3Hz).

Reference Example 83 In 1,2-dichloroethane (50 ml), n-propylamine (1.1 g) and p-nitrobenzaldehyde (2.3 g) were dissolved. Under cooling with ice, triacetoxy boron sodium hydride (4.5 g) was added to the mixture. Under a nitrogen atmosphere, the mixture was stirred at room temperature overnight. Under cooling with ice, 37% formalin (1.7 ml) and triacetoxy boron sodium hydride (4.5 g) were added to the mixture. Under a nitrogen atmosphere, the mixture was stirred at room temperature overnight and the solvent was evaporated. The residue was neutralized with sodium hydroxide, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated and the residue was purified with a column of silica gel (ethyl acetate / hexane) to give a pale yellow oil (2.3 g) which was dissolved in tetrahydrofuran (10 ml). The mixture was added dropwise to a solution, which was prepared by adding dropwise lithium aluminum hydride (0.5 g) to a solution of titanium tetrachloride (2 ml) in tetrahydrofuran (50), under cooling with ice, and stirring the mixture at room temperature for 15 minutes, under cooling with ice. The mixture was stirred at room temperature for 30 minutes, and water (50 ml) and an ammonia solution were added to the mixture. (fifty) . The mixture was concentrated and extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated and the residue was purified with a column of silica gel (ethyl acetate / methanol / triethylamine) to give 4- ((N-methyl-Nn-propyl) aminomethyl) aniline (0.25 g. ) as a yellow oil. NMR-aH (d ppm, CDC13): 0.88 (3H, t, J = 7.3Hz), 1.43-1.61 (2H, m), 2.16 (3H, s), 2.30 (2H, t, J = 7.7Hz), 3.37 (2H, s), 3.59 (2H, broad), 6.64 (2H, d, J = 8.0Hz) , 7.08 (2H, d, J = 8, OHz). IR (pure) v: 2960, 1623, 1517cm "1.

Reference Example 84 In 1, 2-dichloroethane (50 ml), isopropylamine (1 g) and p-nitrobenzaldehyde (2.3 g) were dissolved, and triacetoxy boron sodium hydride was added to the mixture. (4.5 g) under cooling. Under a nitrogen atmosphere, the mixture was stirred at room temperature overnight. Under cooling with ice, 37% formalin (1.5 ml) and triacetoxy boron sodium hydride (4.5 g) were added to the mixture. Under a nitrogen atmosphere, the mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was neutralized with sodium hydroxide. The mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated and the residue was purified with a column of silica gel (ethyl acetate / hexane) to give a yellow oil (2.8 g), 1.5 g of which was dissolved in ethanol (25 ml) and ethyl acetate (25 ml). Palladium on carbon 10% (0.15 g) was added to the mixture, and the catalytic hydrogenation was carried out at room temperature for 1 hour. The catalyst was filtered and the solvent was evaporated. The residue was purified with a column of silica gel (ethyl acetate / methanol / triethylamine) to give 4- ((N-isopropyl-N-methyl) aminomethyl) aniline (0.17 g) as a pale yellow oil. NMR-aH (d ppm, CDC13): 1.05 (6H, d, J = 6.6Hz), 2.13 (3H, s), 2.81-2.95 (1H, m), 3.40 (2H, s), 3.60 (2H, broad) ), 6.65 (2H, d, J = 8.4Hz), 7.10 (2H, d, J = 8.4Hz). IR (pure) v: 2966, 1623, 1517cm "1.

Reference Example 85 In 1, 2-dichloroethane (50 ml) was dissolved 1-methyl-propylamine (1.3 g) and p-nitrobenzaldehyde (2.3 g) and triacetoxy boron sodium hydride (4.5 g) was added to the mixture under cooling with ice. Under a nitrogen atmosphere, the mixture was stirred at room temperature overnight. Under cooling with ice, 37% formalin (1.7 ml) and triacetoxy boron sodium hydride (4.5 g) were added to the mixture. Under a nitrogen atmosphere, the mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was neutralized with sodium hydroxide. The mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give a brown oil (3.4 g), 2.0 g of which was dissolved in tetrahydrofuran (20 ml). The mixture was added dropwise to a solution, which was prepared by adding dropwise lithium aluminum hydride (0.7 g) to a solution of titanium tetrachloride (3 ml) in tetrahydrofuran (50 ml) under cooling with ice and stirring the mixture at room temperature for 15 minutes, under cooling with ice. The mixture was stirred at room temperature overnight, and water (75 ml) and ammonia solution (75 ml) were added to the mixture. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated and the residue was purified with a column of silica gel (ethyl acetate / methanol / triethylamine) to give 4- ((N-sec-butyl-N-methyl) aminomethyl) aniline ( 0.8 g) as a yellow oil. NMR-1H (d ppm, CDC13): 0.87-0.99 (6H, m), 1.22-1.37 (1H, m), 1.53-1.63 (1H, m), 2.11 (3H, s), 2.53-2.63 (1H, m), 3.34 (1H, d, J = 12.8Hz), 3.46 (1H, d, J = 12.8Hz), 3.57 (2H, broad), 6.64 (2H, d, J = 8.4Hz), 7.11 (2H, d, J = 8.4Hz). IR (pure) v: 2962, 2933, 2873, 1617, 1517cm_1.

Reference Example 86 In 1, 2-dichloroethane (70 ml) t-butylamine (1.6 g) and p-nitrobenzaldehyde (3.0 g) were dissolved and triacetoxy boron sodium hydride (5.9 g) was added to the mixture under cooling with ice. Under a nitrogen atmosphere, the mixture was stirred at room temperature overnight. Under cooling with ice, 37% formalin (2 ml) and triacetoxy boron sodium hydride (5.9 g) were added to the mixture. Under a nitrogen atmosphere, the mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was neutralized with sodium hydroxide. The mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give a brown oil (4.4 g), which was dissolved in acetic acid (50 ml). To the mixture was added reduced iron (3.2 g) and the mixture was stirred at room temperature overnight. The solvent was evaporated and ethyl acetate was added to the residue. The precipitate was filtered and the filtrate was washed with a sodium acid carbonate solution, water and a saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give 4- ((N-t-butyl-N-methyl) aminomethyl) -aniline (2.2 g) as a brown oil. NMR-aH (d ppm, CDC13): 1.14 (9H, s), 2.07 (3H, s), 3.38 (2H, s), 3.57 (2H, broad), 6.64 (2H, d, J = 8.4Hz), 7.11 (2H, d, J = 8.4Hz). IR (pure) v: 2971, 1622, ISldc "1.

Reference Example 87 In 1, 2-dichloroethane (70 ml) were suspended p-nitro-benzylamine hydrochloride (3.8 g) and 3-pentanone (1.7 g), and triethylamine (2.8 ml) was added to the suspension. Under cooling with ice, triacetoxy boron sodium hydride (5.9 g) was added to the mixture. Under a nitrogen atmosphere, the mixture was stirred at room temperature overnight. Under cooling with ice, 37% formalin (1.8 ml) and triacetoxy boron sodium hydride (5.9 g) were added to the mixture. Under a nitrogen atmosphere, the mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was neutralized with sodium hydroxide. The mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give a pale yellow oil (4.6 g), which was dissolved in acetic acid (100 ml). To the mixture, reduced iron (4.7 g) was added, and the mixture was stirred at room temperature overnight. The solvent was evaporated and ethyl acetate was added to the residue. The precipitate was filtered and the filtrate was washed with a sodium acid carbonate solution, water and a saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give 4- ((N-methyl-N- (pentan-3-yl)) -amino-methyl) aniline (3.3 g) as a pale brown oil. NMR-aH (d ppm, CDC13): 0.92 (6H, t, J = 7.3Hz), 1.20-1.59 (4H, m), 2.10 (3H, s), 2.18-2.29 (1H, m), 3.44 (2H , s), 3.57 (2H, broad), 6.64 (2H, d, J = 8.4Hz), 7.11 (2H, d, J = 8.4Hz). IR (pure) v: 2959, 1622, lSldcm "1.

Reference Example 88 In 1, 2-dichloroethane (70 ml), p-nitro-benzylamine hydrochloride (3.8 g) and norcamfor (2.2 g) were suspended, and triethylamine (2.8 ml) was added to the suspension. Under cooling with ice, triacetoxy boron sodium hydride (5.9 g) was added to the mixture. Under a nitrogen atmosphere, the mixture was stirred at room temperature overnight. Under cooling with ice, 37% formalin (1.8 ml) and triacetoxy boron sodium hydride (5.9 g) were added to the mixture. Under a nitrogen atmosphere, the mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was neutralized with sodium hydroxide. The mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give a pale yellow oil (5.2 g), which was dissolved in acetic acid (100 ml). Reduced iron (5 g) was added to the mixture, and the mixture was stirred at room temperature overnight. The solvent was evaporated and ethyl acetate was added to the residue. The precipitate was filtered and the filtrate was washed with a sodium acid carbonate solution, water and a saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give 4- ((N-methyl-N- (norbornan-2-yl)) amino-methyl) aniline (4.0 g) as a pale brown oil. NMR-aH (d ppm, CDC13): 0.94-1.04 (1H,), 1.22-1.55 (5H, m), 1.68-1.97 (2H, m), 2.00 (3H, s), 2.16 (1H, broad), 2.37 (2H, broad), 3.22 (1H, d, J = 12.8Hz), 3.42 (1H, d, J = 12.5Hz), 3.58 (2H, broad), 6.64 (2H, d, J = 8.4Hz), 7.09 (2H, d, J = 8.4Hz). IR (pure) v: 2949, 1622, lSldcm "1.

Reference Example 89 To the mixture of p-nitrophenethyl bromide (2.3 g), N-methylcyclohexylamine (2.8 g), potassium carbonate (6.6 g) and sodium iodide (1.5 g) was added dimethylformamide (50 ml), and the The mixture was stirred at 50 ° C overnight. The solvent was evaporated, and water was added to the residue. The mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated and the residue was purified with a column of silica gel (ethyl acetate / methanol / triethylamine) to give a yellow oil (2.2 g), which was dissolved in ethanol (50 ml. ). Palladium on carbon 10% (0.2 g) was added to the mixture, and the catalytic hydrogenation was carried out at room temperature overnight. The catalyst was filtered and the solvent was evaporated to give 4- (2- (N-cyclohexyl-N-methyl) aminoethyl) aniline (1.9 g) as a pale yellow oil. NMR-aH (d ppm, CDC13): 1.05-1.30 (6H, m), 1.60-1.79 (4H, m), 2.33 (3H, s), 2.33-2.45 (1H, m), 2.61-2.63 (4H, m), 3.55 (2H, broad), 6.63 (2H, d, J = 8.4Hz), 6.99 (2H, d, J = 8.4Hz). IR (pure) v: 2929, 1625, 1517cm_1.

Reference Example 90 In ethanol (15 ml), p-nitrostyrene oxide (0.5 g, E. Borredon et al., J.

Org. Che., 1990, 55, 501-504) and piperidine (0.36 ml), and the mixture was heated to reflux for 1 hour. The solvent was evaporated to give yellow crystals (0.53 g), which were dissolved in ethanol (50 ml). To the mixture was added palladium on carbon 5% (0.05 g) and the catalytic hydrogenation was carried out at room temperature 1.5 hours. The catalyst was filtered and the solvent was evaporated, 4- (1-hydroxy-2-piperidino-ethyl) aniline (0.4 g) as colorless crystals. p.f. 75-76 ° C. NMR- ^ H (d ppm, CDC13): 1.40-1.50 (2H, m), 1.55-1.70 (4H, m), 2.31-2.41 (4H, m), 2.62-2.75 (2H, m), 3.61 (2H , broad), 4.61 (1H, dd, J = 6.2, 8.0Hz), 6.66 (2H, d, J = 8.4Hz), 7.15 (2H, d, J = 8.4Hz). IR (KBr) v: 2936, 1622, 1518cm-1. Analysis for C? 3H20N20: Calculated C, 70.87; H, 9.15; N, 12.72. Found C, 71.02; H, 9.10; N, 13.01.

Reference Example 91 In dimethylformamide (50 ml), methyl 5-bromosalicylate (5 g) was dissolved, Ethyl 4-bromobutyrate (4.2 g) and potassium carbonate (7.5 g), and the mixture was stirred at room temperature overnight. The solvent was evaporated and water was added to the residue. The mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated and the residue was purified with a column of silica gel (ethyl acetate / hexane) to give a colorless oil (6.5 g), which was dissolved in tetrahydrofuran (20 ml). The mixture was added dropwise to a solution of lithium diisopropylamine in tetrahydrofuran prepared by diisopropylamine (3.2 ml) and n-butyllithium in hexane (1.6M, 13 ml) at -78 ° C. The mixture was stirred at room temperature under an argon atmosphere overnight and was poured into water. The mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give an oil, which was dissolved in dichloromethane (100 ml). The mixture was added dropwise to a solution of boron sodium hydride in methanol at -15 ° C. After the starting materials disappeared, water was added to the reaction mixture, and the mixture was concentrated and extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. The solvent was evaporated and the residue was dissolved in dichloromethane (100 ml). To the mixture was added triethylamine (7.9 ml), and methanesulfonyl chloride (2.2 ml) was added dropwise to the mixture under cooling with ice. The mixture was stirred at room temperature under a nitrogen atmosphere overnight, and water was added to the mixture. The mixture was concentrated and extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified with a column of silica gel (ethyl acetate / hexane) to give ethyl 7-bromo-2,3-dihydro-l-benzoxepin-4-carboxylate (2.3 g) as colorless crystals. p.f. 86-87 ° C. NMR- ^ H (d ppm, CDC13): 1.35 (3H, t, J = 7.2Hz), 2.98 (2H, t, J = 4.7Hz), 4.23-4.33 (4H, m), 6.86 (1H, d, J = 8.8Hz), 7.32 (1H, dd, J = 2.6, 8.8Hz), 7.46-7.47 (2H, m).

Reference Example 92 To a mixture of ethyl 7-bromo-2,3-dihydro-l-benzoxepin-4-carboxylate (0.5 g), diethyl (3-pyridyl) -borane (0.26 g), 1M potassium carbonate ( 6 ml) and ethanol (6 ml) was added toluene (50 ml), and the mixture was stirred under an argon atmosphere at room temperature for 30 minutes. To the mixture was added tetracistriphenyl-phosphinepalladium (0.07 g), and the mixture was heated to reflux overnight. The mixture was extracted with ethyl acetate and the organic layer was washed with water and a saturated sodium chloride solution and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated and the residue was purified with a column of silica gel (ethyl acetate / hexane) to give colorless crystals (0.28 g), which were dissolved in 1N sodium hydroxide (10 ml) and methanol (50 ml). The mixture was stirred at room temperature overnight, concentrated and neutralized with hydrochloric acid to precipitate 7- (3-pyridyl) -2,3-dihydro-1-benzoxepin-4-carboxylic acid (0.3 g) as crystals. colorless 1 H NMR (d ppm, DMSO-d 6): 2.89 (2H, t, J = 4.6Hz), 4.27 (2H, t, J = 4.6Hz), 7.09 (1H, d, J = 8.4Hz), 7.46 ( 1H, dd, J = 4.6, 7.8Hz), 7.64-7.69 (2H, m), 7.90 (1H, d, J = 2.2Hz), 8.10 (1H, dt, J = 7.8, 1.5Hz), 8.54 (1H , dd, J = 1.5, 4.6Hz), 8.92 (1H, d, J = 2.2Hz). IR (KBr) v: Idggcm "1. Analysis for C? 6H13N03 • 0.2H20: Calculated C, 70.94; H, 4.99; N, 5.17, Found C, 70.71; H, 5.00; N, 5.17.

Reference Example 93 To a mixture of 7-bromo-2,3-dihydro-l-benzoxepin-4-carboxylic acid ethyl ester (1.0 g), 4-pyridyl borate (0.46 g), 1M potassium carbonate (11 ml) and ethanol (11 ml) was added toluene (80 ml), and the mixture was stirred under an argon atmosphere at room temperature for 30 minutes. To the mixture was added tetracistriphenylphosphine palladium (0.16 g), and the mixture was heated to reflux overnight and extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated and the residue was purified with a column of silica gel (ethyl acetate / hexane) to give a colorless oil (0.52 g), which was dissolved in IN sodium hydroxide (18 ml) and methanol (100 ml). The mixture was stirred at room temperature overnight, concentrated and neutralized with hydrochloric acid to precipitate 7- (4-pyridyl) -2,3-dihydro-l-benzoxepin-4-carboxylic acid (0.34 g) as crystals. colorless, pf 277-278 ° C (dec.). NMR-aH (d ppm, DMS0-d6): 2.89 (2H, t, J = 4.8Hz), 4.28 (2H, t, J = 4.8Hz), 7.10 (1H, d, J = 8.6Hz), 7.68 ( 1H, s), 7.74-7.79 (3H, m), 8.02 (1H, d, J = 2.2Hz), 61 (2H, d, J = 5.6Hz). Analysis for C? 6H13N03 • 0.1H2O: Calculated C, 71.42; H, 4.94; N, 5.21. Found C, 71.30; H, 4.80; N, 5.05.

Reference Example 94 To a mixture of ethyl 7-bromo-2,3-dihydro-l-benzoxepin-4-carboxylate (0.5 g), 2-furyl borate (0.22 g), 1M potassium carbonate (6 ml) and ethanol (6 ml) was added toluene (50 ml) and the mixture was stirred under an argon atmosphere at room temperature for 30 minutes. To the mixture was added tetracistriphenylphosphine palladium (0.07 g), and the mixture was heated to reflux overnight and extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated and the residue was purified with a column of silica gel (ethyl acetate / hexane) to give colorless crystals (0.37 g), which were dissolved in IN sodium hydroxide (10 ml) and methanol (50 ml). The mixture was stirred at room temperature overnight, concentrated and acidified with hydrochloric acid. The mixture was extracted with ethyl acetate.

The organic layer was washed with water and a saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give 7- (2-furyl) -2,3-dihydro-1-benzoxepin-4-carboxylic acid (0.3 g) as colorless crystals. p.f. 234-235 ° C (dec.). NMR-aH (d ppm, CDC13): 3.02 (2H, t, J = 4.7Hz), 4.32 (2H, t, J = 4.7Hz), 6.47 (1H, dd, J = 1.5, 3.2Hz), 6.58 ( 1H, dd, J = 0.7, 3.2Hz), 7.02 (1H, d, J = 8.6Hz), 7.46 (1H, dd, J = 0.7, 1.5Hz), 7.57 (1H, dd, J = 2.2, 8.6Hz), 7.68 (1H, d, J = 2.2Hz), 7.77 (1H, s). IR (KBr) v: esescm "1. Analysis for C? 5H120: Calculated C, 70.31; H, 4.72, Found C, 70.31; H, 4.73.

Reference Example 95 To a mixture of ethyl 7-bromo-2,3-dihydro-l-benzoxepin-4-carboxylate (0.5 g), 4-dimethylaminophenyl borate (0.3 g), 1M potassium carbonate (6 ml) and ethanol (6 ml) was added toluene (50 ml), and the mixture was stirred under an argon atmosphere at room temperature for 30 minutes. To the mixture was added tetracistriphenylphosphine palladium (0.07 g), and the mixture was heated to reflux overnight and extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated and the residue was purified with a column of silica gel (ethyl acetate / hexane) to give pale yellow crystals (0.45 g), which were dissolved in IN sodium hydroxide (15 ml. ), methanol (100 ml) and tetrahydrofuran (25 ml). The mixture was stirred at room temperature overnight, concentrated and neutralized with hydrochloric acid to precipitate 7- (4-dimethylamino-phenyl) -2,3-dihydro-1-benzoxepin-4-carboxylic acid (0.4 g). as pale yellow crystals. p.f. 281-282 ° C (dec.). NMR-1H (d ppm, DMSO-d6): 2.87 (2H, t, J = 4.6Hz), 2.93 (6H, s), 4.23 (2H, t, J = 4.6Hz), 6.78 (2H, d, J = 8.8Hz), 6.99 (1H, d, J = 8.4Hz), 7.47-7.54 (3H, m), 7.62 (1H, s), 7.67 (1H, d, J = 2.2Hz); IR (KBr) v: 1676cm-1. Analysis for C? 9H? 9N03: Calculated C, 73.77; H, 6.19; N, 4.53. Found C, 73.57; H, 6.22; N, 4.64.

Reference Example 96 To a mixture of ethyl 7-bromo-2,3-dihydro-l-benzoxepin-4-carboxylate (0.5 g), 4- (pyrrolidin-1-yl) phenyl borate (0.35 g), carbonate of potassium 1M (6 ml) and ethanol (6 ml) was added toluene (50 ml), and the mixture was stirred under an argon atmosphere at room temperature for 30 minutes. To the mixture was added tetracistriphenylphosphine palladium (0.07 g), and the mixture was heated to reflux overnight and extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated and the residue was purified with a column of silica gel (ethyl acetate / hexane) to give pale yellow crystals. (0.55 g), which were dissolved in 1N sodium hydroxide (15 ml), methanol (25 ml) and tetrahydrofuran (25 ml). The mixture was stirred at room temperature overnight, concentrated and neutralized with hydrochloric acid to precipitate 7- (4- (pyrrolidin-1-yl) phenyl) -2,3-dihydro-l-benzoxepin-4 acid. carboxylic (0.5 g) as pale yellow crystals, mp 266-267 ° C (dec.). R -1 H (d ppm, DMSO-d 6): 1.94-2.00 (4H, m), 2.87 (2H, t, J = 4.4Hz), 3.25-3.30 (4H, m), 4.22 (2H, t, J = 4.4Hz), 6.59 (2H, d, J = 8.8Hz), 6.98 (1H, d, J = 8.4Hz), 7.45-7.52 (3H, m), 7.61 (1H, s), 7.65 (1H, d, J = 2.2Hz). GO . { KBr) v: 1678cm_1. Analysis for C2? H2? N03- 0.2H2O: Calculated C, 74.40; H, 6.36; N, 4.13. Found C, 74.49; H, 6.39; N, 4.47.

Reference Example 97 To a mixture of ethyl 7-bromo-2,3-dihydro-l-benzoxepin-4-carboxylate (0.5 g), 4-piperidinophenyl borate (0.38 g), 1M potassium carbonate (6 ml) and ethanol (6 ml) was added toluene (50 ml), and the mixture was stirred under an argon atmosphere at room temperature for 30 minutes. To the mixture was added tetracistriphenylphosphine palladium (0.07 g), and the mixture was heated to reflux overnight and extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated and the residue was purified with a column of silica gel (ethyl acetate / hexane) to give colorless crystals (0.62 g), which were dissolved in IN sodium hydroxide (10 ml), methanol (25 ml) and tetrahydrofuran (25 ml). The mixture was stirred at room temperature overnight, concentrated and neutralized with hydrochloric acid to precipitate 7- (4-piperidino-phenyl) -2,3-dihydro-l-benzoxepin-4-carboxylic acid (0.6 g). as pale yellow crystals. p.f. 262-263 ° C (dec.). NMR- ^ H (d ppm, DMS0-d6): 1.50-1.75 (6H,), 2.87 (2H, t, J = 4.8Hz), 3.15-3.19 (4H, m), 4.23 (2H, t, J = 4.8Hz), 6.96 (2H, d, J = 8.8Hz), 7.00 (1H, d, J = 8.4Hz), 7.51 (1H, dd, J = 2.4, 8.4Hz), 7.52 (2H, d, J = 8.8Hz), 7.62 (1H, s), 7.68 (1H, d, J = 2.4Hz) IR (KBr) v: 2932, 1690cm_1 Reference Example 98 To a mixture of ethyl 7-bromo-2,3-dihydro-l-benzoxepin-4-carboxylate (0.5 g), 4-morpholinophenyl borate (0.39 g), 1M potassium carbonate (6 ml) and ethanol (6 ml) was added toluene (50 ml), and the mixture was stirred under an argon atmosphere at room temperature for 30 minutes. To the mixture was added tetracistriphenylphosphine palladium (0.07 g), and the mixture was heated to reflux for 4 hours and extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated and the residue was purified with a column of silica gel (ethyl acetate / hexane) to give colorless crystals (0.54 g), which were dissolved in IN sodium hydroxide (15 ml), methanol (100 ml) and tetrahydrofuran (100 ml). The mixture was stirred at room temperature overnight, concentrated and neutralized with hydrochloric acid to precipitate 7- (4-morpholino-phenyl) -2,3-dihydro-l-benzoxepin-4-carboxylic acid (0.44 g). as colorless crystals, mp 291-292 ° C (dec.). NMR-1H (d ppm, DMSO-dβ): 2.87 (2H, t, J = 4.8Hz), 3.12-3.17 (4H, m), 3.73-3.78 (4H, m), 4.23 (2H, t, J = 4.8Hz), 7.00 (3H, d, J = 8.4Hz), 7.51 (1H, dd, J = 2.4, 8.4Hz), 7.56 (2H, d, J = 8.8Hz), 7.60 (1H, s), 7.69 (1H, d, J = 2.4Hz). Analysis for C2? H2? N04: Calculated C, 71.78; H, 6.02; N, 3.99. Found C, 71.42; H, 6.19; N, 4.16.

Reference Example 99 To a mixture of 7-bromo-2,3-dihydro-l-benzoxepin-4-carboxylic acid ethyl ester (0.5 g), 4- (1-imidazole) phenyl borate (0.38 g), potassium carbonate 1M (7 ml) and ethanol (7 ml) were added toluene (50 ml), and the mixture was stirred under an atmosphere of argon at room temperature for 30 minutes. To the mixture was added tetracistriphenylphosphine palladium (0.07 g), and the mixture was heated to reflux for 4 hours and extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated and the residue was purified with a column of silica gel (ethyl acetate) to give colorless crystals (0.53 g), which were dissolved in IN sodium hydroxide (10 ml) and methanol ( 50 ml). The mixture was stirred at room temperature overnight, concentrated and neutralized with hydrochloric acid to precipitate 7- (4- (1-imidazolyl) phenyl) -2,3-dihydro-l-benzoxepin-4-carboxylic acid ( 0.44 g) as colorless crystals, mp > 300 ° C. R N-1H (d ppm, DMS0-d6): 2.89 (2H, t, J = 4.5Hz), 4.26 (2H, t, J = 4.5Hz), 7.07 (1H, d, J = 8.4Hz), 7.13 (1H, s), 7.55-7.68 (3H, m), 7.73 (2H, d, J = 8.8Hz), 7.81 (1H, s), 7.85 (2H, d, J = 8.8Hz), 8.33 (1H, s). Analysis for C20H? 6N203- 0.3H2O: Calculated C, 71.12; H, 4.95; N, 8.29. Found C, 71.15; H, 4.84; N, 8.21.

Reference Example 100 In 1, 2-dichloroethane (100 ml) was suspended the hydrochloride of p-nitro-benzylamine (8.1 g), 4H-tetrahydrothio-pyran-4-one (5.0 g) and triethylamine (6 ml) and the suspension, triacetoxy boron sodium hydride (12.8 g) was added under cooling with ice. Under a nitrogen atmosphere, the mixture was stirred at room temperature for 9 hours. Under cooling with ice, 37% formalin (3.9 ml) and triacetoxy boron sodium hydride (12.8 g) were added to the mixture. Under a nitrogen atmosphere, the mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was neutralized with sodium hydroxide. The mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give a yellow oil (11.5 g), to which reduced iron (12 g) and acetic acid (200 ml) were added. The mixture was stirred at room temperature overnight. The solvent was evaporated and ethyl acetate was added to the residue. The precipitate was filtered and the filtrate was washed with a sodium acid carbonate solution, water and a saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated and the residue was purified with a column of silica gel (ethyl acetate / methanol / triethylamine) to give 4- (N-methyl-N- (tetrahydrothiopyran-4-yl) amino- methyl) aniline (8.8 g) as pale yellow crystals. p.f. 88-89 ° C. NMR-1H (d ppm, CDC13): 1.65-1.84 (2H, m), 2.10-2.18 (2H, m), 2.19 (3H, s), 2.45 (1H, tt, J = 3.2, 13. OHz), 2.65- 2.71 (4H, m), 3.47 (2H, s), 3.61 (2H, broad), 6.64 (2H, d, J = 8.4Hz), 7.08 (2H, d, J = 8.4Hz). IR (KBr) v: 2932, 1620cm_1. Analysis for C? 3H20N2S: Calculated C, 66.06; H, 8.53; N, 11.85. Found C, 66.03; H, 8.35; N, 11.78.

Reference Example 101 A mixture of sodium methoxide (12.5 g) and dimethyl carbonate (150 ml) was added to 3-bromo-6,7,8,9-tetrahydro-5H-benzocycloheptan-5-one (10.8 g), and the mixture was heated to reflux for 8 hours under a nitrogen atmosphere. Under cooling with ice, the mixture was poured into IN hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution and dried with anhydrous magnesium sulfate. The solvent was evaporated to give a brown oil (13.1 g), which was dissolved in dichloromethane (150 ml). To the mixture was added dropwise sodium hydride dissolved in methanol, under cooling with ice. After the starting materials disappeared, water was added to the reaction mixture, and the mixture was concentrated and extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution and dried with anhydrous magnesium sulfate. The solvent was evaporated and the residue was dissolved in dichloromethane (150 ml). Triethylamine (29 ml) was added to the mixture, and methanol-sulfonyl chloride (5.3 ml) was added dropwise to the mixture under cooling with ice. The mixture was stirred at room temperature under a nitrogen atmosphere overnight, and water was added to the mixture. The mixture was concentrated and extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified with a column of silica gel (ethyl acetate / hexane) to give methyl 2-bromo-6,7-dihydro-5H-benzo-cyclohepten-8-carboxylate (1.7 g) as colorless crystals, mp 83-84 ° C. 1 H NMR (d ppm, CDCl 3): 1.97-2.10 (2H, m), 2.62 (2H, t, J = 6.6Hz), 2.72-2.78 (2H, m), 3.82 (3H, s), 7.02 (1H , d, J = 8.0Hz), 7.32 (1H, dd, J = 2.2, 8.0Hz), 7.45 (1H, d, J = 2.2Hz), 7.60 (1H, s).

GO . { KBr) v: 2946, 1713cm "1. Analysis for C? 3H? 3Br02: Calculated C, 55.54; H, 4.66. Found C, 55.56; H, 4.75.

Reference Example 102 To a mixture of methyl 2-bromo-6,7-dihydro-5H-benzocyclohepten-8-carboxylate (0.5 g), 4-piperidinophenyl borate (0.4 g), 1M potassium carbonate (6 ml) and ethanol (6 ml) was added toluene (50 ml), and the mixture was stirred under an argon atmosphere at room temperature for 30 minutes. To the mixture was added tetracistriphenylphosphine palladium (0.08 g), and the mixture was heated to reflux overnight and extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated and the residue was purified with a column of silica gel (ethyl acetate / hexane) to give colorless crystals (0.45 g), which were dissolved in IN sodium hydroxide (15 ml), methanol (50 ml) and tetrahydrofuran (50 ml). The mixture was refluxed at room temperature for 2 hours, concentrated and neutralized with hydrochloric acid to precipitate 2- (4-piperidino-phenyl) -6,7-dihydro-5H-benzocyclohepten-8-carboxylic acid. (0.46 g) as colorless crystals, m.p. 219-220 ° C (dec.). NMR-1H (d ppm, DMSO-d6): 1.50-1.70 (6H,), 1.85-2.05 (2H, m), 2.56 (2H, t, J = 6.4Hz), 2.80-2.82 (2H, s), 3.13-3.25 (4H, m), 6.99 (2H, d, J = 8.7Hz), 7.23 ( 1H, d, J = 8.0Hz). 7.47 (1H, dd, J = 1.8, 8.0Hz), 7.54 (2H, d, J = 8.7Hz), 7.60 (1H, d, J = 1.8Hz); 7.70 (1H, s). Analysis for C23H25 02 • 0.2H20: Calculated C, 78.69; H, 7.29; N, 3.99. Found C, 78.82; H, 7.38; N, 3.89.

Reference Example 103 To a mixture of Nt-butoxycarbonylpiperidin-4-one (3 g, MS Ashwood et al., J. Chem. Soc. Perkin Trans. 1, 1995, 641-644) and methylamine hydrochloride (1 g) were they added triethylamine (2.1 ml) and 1,2-dichloroethane (50 ml). Under cooling with ice, triacetoxy boron sodium hydride (4.5 g) was added to the mixture, and the mixture was stirred under a nitrogen atmosphere at room temperature for 4 hours. The mixture was neutralized with sodium hydroxide, concentrated and extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give 1-t-butoxy-carbonyl-4-methylaminopiperidino (3.1 g) as a colorless oil. NMR-aH (d ppm, CDC13): 1.13-1.33 (3H, m), 1.33-1.54 (3H, m), 1.45 (9H, s), 1.83-1.88 (2H, m), 2.44 (3H, s) , 2.44-2.56 (1H, m), 2.73-2.87 (2H, m), 4.01 (1H, broad).

Reference Example 104 In dichloromethane (100 ml) 2-bromo-4'-acetophenone (25.1 g) was dissolved, and the mixture was added dropwise to a suspension of hexamethylenetetramine (15.9 g) in chlorobenzene (100 ml). The mixture was stirred under a nitrogen atmosphere at 60 ° C for 4 hours and cooled to precipitate the crystals, which were filtered and washed with ethanol and diethyl ether. The resulting crystals were added little by little to a mixture of 95% ethanol (100 ml) and hydrochloric acid (50 ml), and the mixture was stirred at room temperature overnight. The precipitated crystal was filtered and washed with diethyl ether. To the crystal was added di-t-butyl bicarbonate (32 g), triethylamine (29 ml) and dichloromethane (500 ml) and the mixture was stirred at room temperature for 2 hours, washed with water, citric acid 10% and water , and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated and the residue was purified with a column of silica gel (ethyl acetate / hexane) to give a yellow solid (24.9 g), 12 g of which were dissolved in ethanol (200 ml) and ethyl acetate (50 ml). Palladium on carbon 10% (1.2 g) was added to the mixture and the catalytic hydrogenation was carried out at room temperature for 6 hours. The catalyst was filtered and the solvent was evaporated to give colorless crystals (6.5 g), 4 g of which were dissolved in dimethylformamide (50 ml). To the mixture was added sodium hydride (60%, 1.4 g) at -3 ° C, and the mixture was stirred for 20 minutes. To the mixture was added dropwise 1,4-dibromobutane (2.1 ml) and the mixture was stirred under ice-cooling for 1.5 hours. To the mixture was added a solution of ammonium chloride, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated, (4-aminophenyl) [1- (tert-butoxycarbonyl) piperidin-2-yl] methanone (2.1 g) as pale yellow crystals, m.p. 187-188 ° C. NMR-aH (d ppm, CDC13): 1.42 (9H, broad), 1.43 (2H, broad), 1.80 (1H, broad), 2.05 (1H, broad), 3.22 (1H, broad), 3.95 (1H, broad) ), 4.09 (2H, broad), 5.55 (1H, broad), 6.63 (2H, d, J = 8.4Hz), 7.79 (2H, d, J = 8.4Hz). IR (KBr) v: 3362, 2942, 1682cm ~ 1. Analysis for C? 7H24N203- 0.1H2O: Calculated C, 66.69; H, 7.97; N, 9.15. Found C, 66.60; H, 7.91; N, 8.87.

Reference Example 105 A mixture of 2- (4-nitrobenzyl) pyridine (J. Chem. Soc, p549, 1929) (1.50 g) and Pd-C 5% (0.15 g) in ethanol (30 ml) was stirred vigorously under a nitrogen atmosphere for 8 hours, and the Pd-C was filtered. The filtrate was concentrated under reduced pressure and the residue was separated and purified by column chromatography (ethyl acetate / hexane = 1: 1-> 2: 1) to give 2- (4-aminobenzyl) -pyridine ( 1.9 g) as a yellow oil. NMR ^ H (200MHz, CDCl 3) d 3.41-3.75 (2H,), 4.05 (2H, s), 6.50-6.69 (2H, m), 6.97-7.16 (4H, m), 7.51-7.60 (1H, m) , 8.48-8.57 (1H, m). IR (pure) 3338, 3213, 3008, 1622, 1593, 1516, 1471, 1433, 1281, 754 cm "1.

Reference Example 106 Under a nitrogen atmosphere, to a solution of ethyl magnesium chloride in tetrahydrofuran (1.58M, 95 ml) was added diethyl phosphite (6.91 g) under ice-cooling, and the mixture was stirred at room temperature during 1 hour. To the mixture was added benzyl bromide (7.2 ml), and the mixture was heated to reflux for 4 hours. The reaction mixture was stirred vigorously and concentrated hydrochloric acid-ice was added to the mixture to stop the reaction. The mixture was extracted with diethyl ether and concentrated. To the residue chloroform was added and the mixture was washed with water and concentrated under reduced pressure. The residue was separated and purified by column chromatography (ethyl acetate / ethanol = 3: 1-> 2: 1) to give benzyldiethyphosphine oxide (1.45 g) as colorless crystals. NMR- ^ H (200MHz, CDC13) d 1.17 (6H, dt, J = 16.6, 8.0 Hz), 1.57-1.75 (4H, m), 3.14 (2H, d, J = 14.4 Hz), 7.19-7.40 (4H ,). IR (KBr) 3396, 2974, 16445, 1495, 1458, 1410, 1242, 1159, 1124, 1034, 829, 789, 702 cm -i RefereExample 107 To the mixture of nitric acid (0.4 g) and cotrated sulfuric acid (3 ml) was added benzyldiethylphosphine oxide (1.05 g) at 0 ° C, and the mixture was stirred at 50 ° C for 1 hour. The reaction mixture was added to ice water and ammonia solution was added to the solution to neutralize the solution, which was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with magnesium sulfate and cotrated. The residue was separated and purified by column chromatography (ethyl acetate / ethanol = 3: 2-> 1: 1) to give the 4-nitrobenzyldiethylphosphine oxide (518 g) as pale yellow crystals. NMR-1H (200MHz, CDCl 3) d 1.18 (6H, dt, J = 17.0, 8.0 Hz), 1.64-1.86 (4H, m), 3.23 (2H, d, J = 13.6 Hz), 7.49 (2H, dd, J = 8.8, 1.6 Hz), 8.20 (2H, d, J = 8.8 Hz). IR (KBr) 1599, 1506, 1340, 1169, 864, 773, 694, 501 cm -i RefereExample 108 A mixture of 4-nitrobenzyldiethylphosphine oxide (0.4 g) and 10% Pd-C (0.06 g) in ethanol (10 ml) was stirred vigorously under a nitrogen atmosphere for 16 hours, and the Pd-C was filtered . The filtrate was cotrated under reduced pressure to give the 4-aminobenzyldiethylphosphine oxide (349 mg) as a brown oil. NMR-1H (200MHz, CDC13) d 1.16 (6H, dt, J = 16.6, 7.8 Hz), 1.56-1.76 (4H, m), 3.02 (2H, d, J = 14.4 Hz), 6.64 (2H, d, J = 8.4 Hz), 7.03 (2H, dd, J = 8.4, 1.8 Hz). IR (pure) 3336, 1630, 1614, 1516, 1460, 1408, 1284, 1157, 1126, 841, 791, 768, 540 cm "1 RefereExample 109 Under a nitrogen atmosphere, to a solution of propyl magnesium bromide in tetrahydrofuran (2M, 250 g) was added diethyl phosphite (18.0 g) under ice-cooling, and the mixture was stirred at room temperature for 3 hours. hours.

Benzyl chloride was added to the reaction mixture (24.7 ml), and the mixture was heated to reflux for 5 hours. The reaction mixture was stirred vigorously and was added to cotrated hydrochloric acid-ice to stop the reaction. The mixture was extracted with ethyl acetate and cotrated. The residue was separated and purified by column chromatography (ethyl acetate - ethyl acetate / ethanol = 3: 1) to give the benzyldipropylphosphine oxide (25.33 g) as colorless crystals. NMR- ^ H (200MHz, CDC13) d 0.94-1.09 (6H, m), 1.49-1.75 (8H, m), 3.15 (2H, d, J = 14.6 Hz), 7.19-7.39 (5H, m). IR (KBr) 3425, 2964, 1645, 1603, 1497, 1456, 1242, 1161, 1126, 1080, 1030, 843 cm "1 RefereExample 110 To a mixture of nitric acid (3.6 g) and cotrated sulfuric acid (22) ml) benzyldipropylphosphine oxide (10.75 g) was added at 0 ° C, and the mixture was stirred at 60 ° C for 1.5 hours.The reaction mixture was added to ice water, and a solution of ammonia was added to the mixture to remove the mixture. The solution was neutralized, which was extracted with ethyl acetate.The organic layer was washed with a saturated sodium chloride solution, dried with magnesium sulfate and cotrated.The residue was separated and purified by column chromatography ( ethyl acetate / ethanol = 9: 1-4: 1) to give the 4-nitrobenzyldipropylphosphine oxide (3.77 g) as pale yellow crystals, NMR ^ H (200MHz, CDC13) d 0.96-1.09 (6H, m), 1.51-1.75 (8H, m), 3.20 (2H, d, J = 13.6 Hz), 7.47 (2H, dd, J = 8.8, 2.0 Hz), 8.21 (2H, d, J = 8.8 Hz). ) 1527, 1431, 1352, 1028 cm "1 RefereExample 111 A mixture of 4-nitrobenzyldipropylphosphine oxide (3.0 g) and 5% Pd-C (0.3 g) in ethanol (50 ml) was stirred vigorously under a nitrogen atmosphere for 16 hours, and the Pd-C was filtered . The filtrate was cotrated under reduced pressure. The residue was separated and purified by column chromatography (ethanol / ethyl acetate = 1: 5-> 1: 4) and recrystallized from ethanol-ethyl acetate to give the 4-aminobenzyldipropylphosphine oxide (1.78 g) as colorless crystals, mp 104-106 ° C NMR- ^ H (200MHz, CDC13) d 0.88-1.12 (6H, m), 1.43-1.72 (8H, m), 3.01 (2H, d, J = 14.8 Hz), 3.52-3.76 (2H , m), 6.65 (2H, d, J = 8.6 Hz), 7.01 (2H, dd, J = 8.6, 2.0 Hz). IR (KBr) 3348, 3209, 2058, 1608, 1512, 1155, 1126, 852 cm "1 Elemental Analysis for C? 3 H22 NOP Calculated C, 65.25; H, 9.27; N, 5.85; P, 12.94: Found C, 65.16; H, 9.04; N, 5.91; p, 12.94.

Reference Example 112 Under a nitrogen atmosphere, to a solution of 2-bromo-3-hydroxypyridine (10.00 g) in DMF (100 ml) was added sodium hydride (60% oil, 2.5 g) at 0 ° C, and the mixture was stirred for 30 minutes. To the reaction mixture was added methyl iodide (4.0 ml) and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with magnesium sulfate and concentrated. Under reduced pressure, the residue was separated and purified by column chromatography (ethyl acetate / hexane = 1: 2) to give 2-bromo-3-methoxypyridine (9.24 g) as colorless crystals, m.p. 41-43 ° C NMR-1H (200MHz, CDC13) d 3.92 (3H, s), 7.15 (1H, dd, J = 8.0, 1.4 Hz), 7.24 (1H, dd, J = 8.0, 4.4 Hz), 7.99 (1H, dd, J = 4.4, 1.4 Hz). IR (KBr) 3055, 1562, 1468, 1414, 1298, 1205, 1078, 1049, 791, 667 cm "1 Elemental Analysis for C6H6NO Calculated C, 38.33; H, 3.22; N, 7.45: Found C, 38.35; H, 3.07; N, 7.28.

Reference Example 113 To a solution of 2-bromo-3-methoxypyridine (1.00 g) in diethyl ether (20 ml) was added a solution of n-butyllithium in hexane (1.6M, 3.7 ml) at -78 ° C, and The mixture was stirred for 1 hour to prepare the lithium salt, which was added dropwise to a solution of 4-nitrobenzaldehyde (0.81 g) in tetrahydrofuran (10 ml) cooled to -78 ° C. The mixture was stirred at -78 ° C. Water was added to the reaction mixture to stop the reaction and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with magnesium sulfate and concentrated. Under reduced pressure, the residue was separated and purified by column chromatography (ethyl acetate / hexane = 1: 3-1: 1) to give 3-methoxypyridin-2-yl) - (4-nitrophenyl) methanol ( 742 mg) as pale yellow crystals. p.f. 137-138 ° C NMR-aH (200MHz, CDC13) d 3.81 (3H, s), 5.64 (1H, d, J = 6.8 Hz), 6.02 (1H, d, J = 6.8 Hz), 7.17 (1H, dd, J = 8.4, 1. 4 Hz), 7.27 (1H, dd, J = 8.4, 4.6Hz), 7.58 (2H, dd, J = 7.0, 2.0 Hz), 8.15 (2H, dd, J = 7.0, 2.0Hz), 8.21 (1H, dd, J = 4.6, 1.4 Hz). IR (KBr) 3348, 1524, 1464, 1344, 1284, 1053, 1020, 837, 797, 744, 689 cm "1 Elemental Analysis for C? 3H? 2N204 Calculated C, 60.00; H, 4.65; N, 10.76: Found C, 59.97; H, 4.57; N, 10.82.

Reference Example 114 A mixture of (3-methoxypyridin-2-yl) - (4-nitro-phenyl) methanol (600 mg) and 5% Pd-C (0.06 g) in ethanol (20 ml) was vigorously stirred under a nitrogen atmosphere for 3 hours, and Pd-C was filtered. The filtrate was concentrated under reduced pressure to give (4-aminophenyl) - (3-methoxypyridin-2-yl) -methanol (483 mg) as pale yellow crystals. NMR-aH (200MHz, CDC13) d 3.51-3.65 (2H, m), 3.75 (3H, s), 5.33 (1H, d, J = 7.1 Hz), 5.85 (1H, d, J = 7.1 Hz), 6.60 (2H, dd, J = 6.6, 1.8Hz), 7.08-7.23 (4H, m), 8.17 (1H, dd, J = 4.6, 1.4 Hz). IR (KBr) 3458, 3463, 3323, 1626, 1614, 1518, 1454, 1427, 1279, 1178, 1038, 835, 804 c "1 Reference Example 115 A solution of diethyl benzylphosphonate (25 g) in methanol (10 ml) and a concentrated hydrochloric acid solution (500 ml) was heated to reflux for 4 days. The mixture was cooled to room temperature, and the precipitated crystal was collected by filtration to give the benzylphosphonic acid (11.17 g) as colorless crystals, m.p. 171-173 ° C NMR- ^ H (200MHz, DMS0-d6) d 2.96 (2H, d, J = 21.6 Hz), 7.13-7.34 (5H, m). IR (KBr) 2779, 2330, 1497, 1458, 1263, 1074, 993, 943, 781, 694, 527, 428 cm "1 Elemental Analysis for C7H903P Calculated C, 48.85; H, 5.27; P, 18.00: Found C, 48.75 H, 5.01 P, 17.7! Reference Example 116 Under a nitrogen atmosphere, a solution of 1,4-dibromobutane (5.55 ml) was added dropwise to a mixture of magnesium (3.39 g) and a piece of iodine in diethyl ether (16 ml). , 2-dibromoethane (2 ml) in diethyl ether (80 ml) at 40 ° C for 1 hour. The mixture was refluxed for 1 hour, it was cooled to room temperature and allowed to stand for 2 hours. The top layer of diethyl ether was removed through a cannula, to obtain the di-Grignard reagent, which was dissolved in dichloromethane (210 ml). The resulting di-Grignard reagent as it was was used for the next reaction. To the benzyl phosphonate (8.0 g) was added thionyl chloride (40 ml) and then 2 drops of DMF, and the mixture was refluxed for 4 hours and concentrated under reduced pressure. The residue was dissolved in dichloromethane (210 ml), and the mixture was cooled to 0 ° C. To the mixture was added dropwise a solution of the above di-Grignard reagent in dichloromethane, which was cooled at 0 ° C, through the cannula for 1 hour, and the mixture was stirred at room temperature for 16 hours. To the reaction mixture was added a 10% solution of ammonium chloride (100 ml) and a saturated sodium chloride solution, and the mixture was extracted with dichloromethane. The organic layer was washed with a saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by column chromatography (ethanol / ethyl acetate = 1: 4) to give 1-benzyl-phosphorane-1-oxide (4.83 g) as colorless crystals. R N-1H (200MHz, CDC13) d 1.40-2.08 (8H, m), 3.27 (2H, d, J = 15.0 Hz), 7.11-7.42 (5H, m). IR (KBr) 2951, 1643, 1495, 1454, 1406, 1265, 1236, 1165, 1120, 702 cm "1 Reference Example 117 To 1-benzylphosphorane-1-oxide (4.17 g) nitric acid (1.7 ml) and sulfuric acid (11 ml) were added at 0 ° C, and the mixture was stirred at 50-60 ° C for 2 hours . The reaction mixture was added to crushed ice and neutralized with an ammonia solution. The mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with magnesium sulfate and concentrated. Under reduced pressure, the residue was separated and purified by column chromatography (ethanol / ethyl acetate = 1: 4-1: 1) to give the 1- (4-nitro-benzyl) phosphorane-1-oxide ( 2.22 g) as yellow crystals. NMR-aH (200MHz, CDC13) d 1.55-2.13 (8H,), 3.32 (2H, d, J = 13.8 Hz), 7.50 (2H, dd, J = 8.8, 1.8 Hz), 8.22 (2H, d, J = 8.8 Hz). IR (KBr) 3402, 2954, 1514, 1346, 1171, 860, 700 cm "1 Reference Example 118 A mixture of 1- (4-nitrobenzyl) phosphorane-1-oxide (1.80 g) and 10% Pd-C (0.2 g) in ethanol (30 ml) was stirred vigorously under a nitrogen atmosphere for 24 hours , and the catalyst was filtered. The filtrate was concentrated and purified by column chromatography (ethanol / ethyl acetate = 1: 2) and recrystallized from ethanol-diethyl ether to give 1- (4-aminobenzyl) phosphorane-1-oxide (0.90 g ) as colorless crystals. NMR-aH (200MHz, CDC13) d 1.32-2.02 (8H, m), 3.16 (2H, d, J = 14.6 Hz), 3.52-3.74 (2H,), 6.65 (2H, d, J = 8.4 Hz), 7.04 (2H, dd, J = 8.4, 2.2 Hz). IR (KBr) 3386, 3338, 3228, 1641, 1612, 1516, 1296, 1263, 1174, 1124, 833 cm "1 Reference Example 119 Under a nitrogen atmosphere, to a solution of 2-bromo-3-methoxymethoxypyridine ( 10.00 g) in diethyl ether (150 ml) was added a solution of n-butyllithium in hexane (1.6M, 31.4 ml) at -78 ° C, and the mixture was stirred for 1 hour to prepare the lithium salt. The resulting lithium was added dropwise to a solution of 4-nitrobenzaldehyde (6.93 g) in tetrahydrofuran (100 ml) cooled to -78 ° C, and the mixture was stirred at the same temperature for 3 hours. water was added to stop the reaction, and the mixture was extracted with ethyl acetate.The organic layer was washed with a saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure. it was purified with column chromatography (ethyl acetate / hexane = 1: 3-> 1: 2) to give the (3-methoxymethoxypyridi n-2-yl) - (4-nitrophenyl) -methanol (11.78 g) as a yellow oil. NMR-aH (200MHz, CDC13) d 3.27 (3H, s), 5.12 (1H, d, J = 7.0 Hz), 5.20 (1H, d, J = 7.0 Hz), 5.70 (1H, d, J = 7.0 Hz) ), 6.02 (1H, d, J = 7.0 Hz), 7.25 (1H, dd, J = 8.4, 4.4 Hz), 7.42 (1H, dd, J = 8.4, 1.4 Hz), 7.58 (2H, d, J = 8.8 Hz), 8.15 (2H, d, J = 8.8 Hz), 8.27 (1H, dd, J = 4.4, 1.4 Hz).

IR (pure) 3390, 1522, 1448, 1348, 1155, 1084, 1055, 980, 824, 849, 800, 744, 700 cm " Reference Example 120 A mixture of (3-methoxymethoxypyridin-2-yl) - (4-nitrophenyl) methanol (11.78) and 10% Pd-C (1.2 g) in ethanol (100 ml) was stirred vigorously under a nitrogen atmosphere for 24 hours. The catalyst was filtered and the filtrate was concentrated under reduced pressure. The residue was separated and purified by column chromatography (ethyl acetate / hexane = 1: 1-2: 1) to give 2- (4-aminobenzyl) -3-methoxymethoxypyridine (2.92 g) as an orange oil . R N-1H (200MHz, CDC13) d 3.37 (3H, s), 4.08 (2H, s), 5.16 (2H, s), 6.59 (2H, dd, J = 8.4, 2.0 Hz), 7.04-7.19 (3H , m), 7.33 (1H, dd, J = 8.4, 1.2 Hz), 8.18 (1H, dd, J = 4.8, 1. 2Hz). IR (pure) 3433, 3352, 3219, 1620, 1514, 1446, 1265, 1153, 1082, 985, 922, 798 cm "1 Reference Example 121 Under a nitrogen atmosphere, a mixture of magnesium (3.2 g) and a piece of iodine in diethyl ether (20 ml) was added dropwise to a solution of 1,5-dibromopentane (13.21 g) and 1,2-dibromoethane (1.21 ml) in diethyl ether (80 ml) at 40 ° C for 1 hour. The mixture was refluxed for 1 hour, cooled to room temperature and allowed to stand for 2 hours. The top layer of diethyl ether was removed through a cannula, to obtain the di-Grignard reagent, which was dissolved in dichloromethane (250 ml). The resulting di-Grignard reagent as it was was used for the next reaction. To benzylphosphonic acid (10.0 g) was added thionyl chloride (30 ml) and then a drop of DMF, and the mixture was heated to reflux for 3 hours and concentrated under reduced pressure. The residue was dissolved in dichloromethane (210 ml) and the mixture was cooled to 0 ° C. To the mixture was added dropwise a solution of the above di-Grignard reagent in -dichloromethane, which was cooled to 0 ° C, through a cannula for 1 hour and the mixture was stirred at room temperature for 20 hours. To the reaction mixture were added 10% ammonium chloride solution (100 ml) and a saturated sodium chloride solution, and the mixture was extracted with dichloromethane. The organic layer was washed with a saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by column chromatography (ethanol / ethyl acetate = 1: 3-1: 2) to give 1-benzylphosphorin-1-oxide (5.39 g) as colorless crystals. 1 H-NMR (200MHz, CDCl 3) d 1.36-2.18 (10H, m), 3.17 (2H, d, J = 14.0 Hz), 7.23-7.42 (5H, m). IR (KBr) 2939, 2912, 2886, 1493, 1452, 1404, 1232, 1161, 827, 700 cm "1 Reference Example 122 To a solution of diethyl benzylphosphe (2.5 g) in tetrahydrofuran (500 ml) was added Red-Al (70% toluene solution) (3.8 g) at room temperature and the mixture was stirred until gas production stopped. To the reaction mixture was added 1,5-dibromopentane (25.18 g), and the mixture was stirred at 50-60 ° C for 16 hours. Water (200 ml) was added to the reaction mixture, and the precipitate was removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was separated and purified by column chromatography (ethyl acetate-ethanol ethyl acetate = 1: 2) to give 1-benzylphosphorin-1-oxide (8.41 g) as colorless crystals. NMR-H (200MHz, CDCl 3) d 1.36-2.18 (10H, m), 3.17 (2H, d, J = 14.0 Hz), 7.23-7.42 (5H,).

IR (KBr) 2939, 2912, 2886, 1493, 1452, 1404, 1232, 1161, 827, 700 cm "1 Reference Example 123 To 1-benzylphosphorin-1-oxide (5.39 g) were added nitric acid (1.94 ml) and sulfuric acid (15 ml) at 0 ° C, and the mixture was stirred at 50-60 ° C for 2 hours. The reaction mixture was added to crushed ice-water, neutralized with ammonium solution and extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by column chromatography (ethanol / ethyl acetate = 1: 3-1: 2) to give 1- (4-nitrobenzyl) -phosphorin-1-oxide (2.47 g) as color crystals. pale yellow. NMR-aH (200MHz, CDC13) d 1.46-2.18 (10H, m), 3.28 (2H, d, J = 13.6 Hz), 7.48 (2H, dd, J = 8.8, 2.2 Hz), 8.21 (2H, d, J = 8.8 Hz). IR (KBr) 2926, 1599, 1516, 1348, 1230, 1159, 1132, 864, 822, 696 cm "1 Reference Example 124 A mixture of 1- (4-nitrobenzyl) phosphorin-1-oxide (2.25 g) and 10% Pd-C (0.2 g) in ethanol (30 ml) was stirred vigorously under a nitrogen atmosphere for 24 hours . The catalyst was filtered and the filtrate was concentrated, recrystallized from ethanol-diethyl ether to give 1- (4-aminobenzyl) -phosphorin-1-oxide (1.5 g) as pale yellow crystals NMR- ^ H (200MHz, CDC13) d 1.27-2.16 (10H, m), 3.06 (2H, d, J = 13.8Hz), 3.53-3.80 (2H, m), 6.65 (2H, d, J = 8.3Hz), 7.05 (2H, dd , J = 8.3, 2.0 Hz). IR (KBr) 3386, 3334, 3224, 2939, 1639, 1612, 1514, 1296, 1225, 1153, 1120, 841 c "1 Reference Example 125 Under an atmosphere of argon, to a solution of 4-ethylbromobenzene (10.0 g) in tetrahydrofuran (60 ml) was added n-butyllithium (1.6M hexane solution) (37.2 ml) at -78 ° C, and the mixture was stirred for 1 hour. To the reaction mixture was added dropwise a solution of tributyl borate (13.68 g) in tetrahydrofuran (30 ml), and the reaction mixture was warmed to room temperature and stirred at room temperature for 2 hours. To the reaction mixture was added 10% sulfuric acid (100 ml) and the mixture was stirred for 1 hour. The mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in acetone (30 ml) and 10% sulfuric acid (50 ml) was added to the mixture. The mixture was stirred at room temperature for 16 hours and under reduced pressure the acetone was evaporated. The mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by column chromatography (ethyl acetate / hexane = 1: 2) to give crude 4-ethylphenyl borate (0.91 g) as a colorless solid. Under an argon atmosphere, a solution of ethyl 7-bromo-2,3-dihydro-l-benzoxepin-4-carboxylate (500 mg), crude 4-ethylphenyl borate, above (0.32 g) and potassium carbe ( 0.49 g) in toluene-ethanol-water (20-2-2 ml) was stirred at room temperature for 1 hour. Tetracistriphenyl-phosphaladium was added to the reaction mixture (0.06 g), and the mixture was heated to reflux for 18 hours and cooled to room temperature. The organic layer was washed with a saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by column chromatography (ethyl acetate / hexane = 1: 15) to give ethyl 7- (4-ethylphenyl) -2,3-dihydro-l-benzoxepin-4-carboxylate ( 464 mg) as colorless crystals, mp 81-83 ° C NMR-aH (200MHz, CDC13) d 1.28 (3H, t, J = 7.6 Hz), 1.36 (3H, t, J = 7.2 Hz), 2.69 (2H, q, J = 7.6 Hz), 3.00 (2H, t, J = 5.2 Hz), 4.29 (2H, q, J = 7.2 Hz), 4.30 (2H, t, J = 5.2 Hz), 7.04 (1H, d, J = 8.4 Hz), 7.27 ( 2H, d, J = 8.6 Hz), 7.44-7.51 (3H, m), 7.55 (1H, d, J = 2.6 Hz), 7.65 (1H, broad s) IR (KBr) 1699, 1493, 1302, 1254, 1213, 1012, 822 cm "1 Elemental Analysis for C2? H2203 Calculated C, 78.23; H, 6.88: Found C, 78.05; H, 6.61.

Reference Example 126 To a solution of ethyl 7- (4-ethylphenyl) -2,3-dihydro-l-benzoxepin-4-carboxylate (430 mg) in ethanol (20 ml) was added 1N sodium hydroxide (4.0 ml. ) at room temperature, and the mixture was stirred for 24 hours and concentrated under reduced pressure. To the residue was added IN hydrochloric acid (15 ml), and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with magnesium sulfate and concentrated to give crystals, which were collected by filtration to give 7- (4-ethylphenyl) -2,3-dihydro acid. -l-benzoxepin-4-carboxylic acid (328 mg) as colorless crystals, m.p. 241-2436 ° C NMR-XH (200MHz, CDC13) d 1.28 (3H, t, J = 7.8 Hz), 2.70 (2H, q, J = 7.8 Hz), 3.02 (2H, t, J = 4.8 Hz), 4.33 (2H, t, J = 4.8 Hz), 7.05 (1H, d, J = 8.4 Hz), 7.27 (2H, d, J = 8.0), 7.46-7.56 (4H, m), 7.78 (1H, broad s ) IR (KBr) 2966, 1689, 1491, 1437, 1263, 1230, 822 cm "1 Elemental Analysis for C19H? 803 Calculated C, 77.53; H, 6.16: Found C, 77.52; H, 6.27.

Reference Example 127 Under an atmosphere of argon, to a solution of 4-tert-butyl-bromobenzene (10.0 g) in diethyl ether (50 ml) was added n-butyllithium (1.6M, hexane solution). (32.3 ml) at -78 ° C, and the mixture was stirred for 1 hour.

Trimethyl boronic acid (16 ml) in diethyl ether (30 ml) was added dropwise to the reaction mixture and the mixture was warmed to room temperature and stirred at room temperature for 16 hours. INN hydrochloric acid (50 ml) and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by column chromatography (ethyl acetate / hexane = 1: 9) to give crude 4-ter-phenyl borate (0.84 g) as a yellow oil. Under an argon atmosphere, a solution of ethyl 7-bromo-2, 3-dihydro-l-benzoxepin-4-carboxylate (500 mg), crude 4-tert-butylphenyl borate (0.59 g) and potassium carbonate (0.47 g) in toluene-ethanol-water (20-2-2ml) was stirred at room temperature for 1 hour. Tetracistriphenylphosphine palladium was added to the reaction mixture (0.06 g), and the mixture was heated to reflux for 20 hours and cooled to room temperature. The organic layer was washed with a saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by column chromatography (ethyl acetate / hexane = 1: 19) to give 7- (4-tert-butyl-phenyl) -2,3-dihydro-l-benzoxepin-4- ethyl carboxylate (504 mg) as a colorless oil. NMR-aH (200MHz, CDC13) d 1.36 (9H, s), 1.36 (3H, t, J = 7.2 Hz), 3.00 (2H, t, J = 4.7 Hz), 4.29 (2H, q, J = 7.2 Hz) ), 4.30 (2H, t, J = 4.7 Hz), 7.04 (1H, d, J = 8.2 Hz), 7.42-7.56 (6H, m), 7.65 (1H, broad s) IR (pure) 1731, 1491, 1298, 1246, 1211, 1184, 1090, 1018, 824 cm "1 Reference Example 128 To a solution of ethyl 7- (4-tert-butylphenyl) -2,3-dihydro-l-benzoxepin-4-carboxylate ( 503.8 mg) in ethanol (10 ml) was added 1N sodium hydroxide (2.0 m) at room temperature and the mixture was stirred for 64 hours and concentrated under reduced pressure, to the residue was added 1N hydrochloric acid (15 ml)., and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with magnesium sulfate and concentrated. The resulting crystal was collected by ration to give 7- (4-tert-butyl-phenyl) -2,3-dihydro-l-benzoxepin-4-carboxylic acid (396 mg) as colorless crystals, m.p. 259-261 ° C NMR-aH (200MHz, CDC13) d 1.37 (9H, S), 3.03 (2H, t, J-4.4 Hz), 4.34 (2H, t, J = 4.4Hz), 7.06 (1H, d , J = 8.4 Hz), 7.41-7.58 (6H, m), 7.79 (1H, broad s). IR (KBr) 2951, 1678, 1489, 1263, 829, 820 cm "1 Elemental Analysis for C2? H2203 Calculated C, 78.23; H, 6.88: Found C, 78.10; H, 6.81.

Reference Example 129 Under an argon atmosphere, a solution of ethyl 7-bromo-2,3-dihydro-l-benzoxepin-4-carboxylate (500 mg), 4-chloro-phenyl borate (289 g) and carbonate of potassium (464 mg) in toluene-ethanol-water (20-2-2 ml) was stirred at room temperature for 1 hour. To the reaction mixture was added tetracistriphenyl-phosphine palladium (0.06 g) and the mixture was heated to reflux for 24 hours and cooled to room temperature. The organic layer was washed with a saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by column chromatography (ethyl acetate / hexane = 1: 19) to give ethyl 7- (4-chlorophenyl) -2,3-dihydro-l-benzoxepin-4-carboxylate ( 459 mg) as colorless crystals, mp 131-134 ° C. NMR-aH (200MHz, CDC13) d 1.36 (3H, t, J = 7.2 Hz), 3.01 (2H, t, J = 5.0 Hz), 4.23-4.34 (4H, m), 7.05 (1H, d, J = 8.4 Hz), 7.37-7.52 (6H, m), 7.64 (1H, s). IR (KBr) 1705, 1485, 1302, 1255, 1213, 820 cm "1 Elemental Analysis for C19H? 703Cl Calculated C, 69.41; H, 5.21; Cl, 10.78: Found C, 69.16; H, 5.12; Cl, 10.85.

Reference Example 130 To a solution of ethyl 7- (4-chlorophenyl) -2,3-dihydro-l-benzoxepin-4-carboxylate (400 mg) in tetrahydrofuran-ethanol (10-10 ml) was added sodium hydroxide IN (2.0 ml) at room temperature and the mixture was stirred for 42 hours and concentrated under reduced pressure. To the residue was added IN hydrochloric acid (15 ml), and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with magnesium sulfate and concentrated. The resulting crystal was collected by filtration to give 7- (4-chlorophenyl) -2,3-dihydro-1-benzoxepin-4-carboxylic acid (342 mg) as colorless crystals, m.p. 263-264 ° C NMR-1H (200MHz, CDC13) d 3.03 (2H, t, J = 4.7 Hz), 4.34 (2H, t, J = 4.7 Hz), 7.07 (1H, d, J = 8.4 Hz), 7.35-7.55 (6H, m), 7.76 (1H, broad s) IR (KBr) 2959, 1 680, 1483, 12 67, 1230, 818 cm "1 Elemental Analysis for C17H13O3CI Calculated C, 69.89; H, 4 36; Cl, 11. 79: Found C, 67.55; H, 4.19; Cl, 11.46.

Reference Example 131 Under an argon atmosphere, a solution of ethyl 7-bromo-2,3-dihydro-l-benzoxepin-4-carboxylate (500 mg), 4-tri-fluoromethylphenyl borate (351.5 mg) and carbonate of potassium (0.47 mg) in toluene-ethanol-water (20-2-2 ml) was stirred at room temperature for 1 hour. Tetracistriphenylphosphine palladium (0.06 g) was added to the reaction mixture and the mixture was heated to reflux for 20 hours and cooled to room temperature. The organic layer was washed with a saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by column chromatography (ethyl acetate / hexane = 1: 10) to give ethyl 7- (4-trifluoromethylphenyl) -2,3-dihydro-l-benzoxepin-4-carboxylate ( 489 mg) as colorless crystals, mp 107-110 ° C NMR-1H (200MHz, CDC13) d 1.37 (3H, t, J = 7.2 Hz), 2.99-3.05 (2H, m), 4.29 (2H, q, J = 7.2 Hz), 4.33 (2H , t, J = 4.8 Hz), 7.09 (1H, d, J = 8.4 Hz), 7.49 (1H, dd, J = 8.4, 2.4 Hz), 7.58 (1H, d, J = 2.4 Hz), 7.62-7.73 (5H, m). IR (KBr) 1701, 1329, 1257, 1126, 1107, 1068, 1012, 822 cm "1 Elemental Analysis for C2oH? 703F3 Calculated C, 66.30; H, 4.73; F, 15.73: Found C, 66.40; H, 4.63; F, 15.44.

Reference Example 132 To a solution of ethyl 7- (4-trifluoromethylphenyl) -2,3-dihydro-l-benzoxepin-4-carboxylate (440 mg) in tetrahydrofuran-ethanol (10-10 ml) was added sodium hydroxide 1N (4.0 ml) at room temperature and the mixture was stirred for 20 hours and concentrated under reduced pressure. To the residue was added IN hydrochloric acid (5 ml) and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with magnesium sulfate and concentrated. The resulting crystal was collected by filtration to give 7- (4-trifluoromethylphenyl) -2,3-dihydro-1-benzoxepin-4-carboxylic acid (392 mg) as colorless crystals. p.f. 273-276 ° C NMR-aH (200MHz, DMSO-d6) d 2.89 (2H, t, J = 4.4 Hz), 4.28 (2H, t, J = 4.4 Hz), 7.09 (1H, d, J = 8.4 Hz ), 7.61-7.70 (2H, m), 7.78 (2H, d, J = 8.4 Hz), 7.92-7.96 (3H, m). IR (KBr) 2979, 1689, 1329, 1263, 1134, 1072, 831 cm "1 Elemental Analysis for C? 8H? 303F3 Calculated C, 64.67; H, 3.92: Found C, 64.62; H, 3.89.

Reference Example 133 Under an atmosphere of argon, to a solution of 4-bromo-phenethol (26.4 g) in tetrahydrofuran (200 ml) was added dropwise n-butyl lithium (1.6M, hexane solution) (90.3 ml) at -78 ° C for 50 minutes, and the mixture was stirred for 30 minutes. To the reaction mixture was added dropwise a solution of trimethyl borate (40.8 g) in tetrahydrofuran (40 ml) for 30 minutes, and the mixture was stirred for 30 minutes, warmed to room temperature and further stirred for 1.5 hours. To the reaction mixture was added 10% sulfuric acid (182 ml) for 40 minutes or more, and the mixture was stirred for 1.5 hours, extracted with ethyl acetate, washed with a saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized with diisopropyl ether-hexane to give 4-ethoxyphenyl borate (15.5 g) as colorless crystals. Under an argon atmosphere, a solution of ethyl 7-bromo-2, 3-dihydro-l-benzoxepin-4-carboxylate (504.5 mg), the above 4-ethoxyphenyl borate (310 mg) and potassium carbonate (0.47) g) in toluene-ethanol-water (20-2-2 ml) was stirred at room temperature for 1 hour. Tetracistriphenylphosphine palladium (0.06 g) was added to the reaction mixture and the mixture was heated to reflux for 20 hours and collected at room temperature. The organic layer was washed with a saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by column chromatography (ethyl acetate / hexane = 1: 9-15) to give 7- (4-ethoxy-phenyl) -2, 3-dihydro-1-benzoxepin-4. ethyl carboxylate (468 mg) as colorless crystals. p.f. 124-127 ° C RM - ^ H (200MHz, CDC13) d 1.36 (3H, t, J = 7.2 Hz), 1.44 (3H, t, J = 7.0 Hz), 3.00 (2H, t, J = 4.0 Hz) , 4.08 (2H, q, J = 7.0 Hz), 4.28 (2H, q, J = 7.2 Hz), 4.30 (2H, t, J = 4.0 Hz), 6.96 (2H, dd, J = 6.6, 2.2 Hz) , 7.02 (1H, d, J = 8.4Hz), 7.41 (1H, d, J = 2.6 Hz), 7.44-7.51 (3H, m), 7.65 (1H, broad s). IR (KBr) 1701, 1493, 1254, 1215, 1014, 824 cm "1 Elemental Analysis for C2? H22? 4 Calculated C, 74.54; H, 6.55: Found C, 74.42; H, 6.47.

Reference Example 134 To a solution of ethyl 7- (4-ethoxyphenyl) -2,3-dihydro-l-benzoxepin-4-carboxylate (447.8 mg) in ethanol (20 ml) was added 2N sodium hydroxide (2.0 ml. ) at room temperature, and the mixture was stirred for hours and concentrated under reduced pressure. To the residue was added 1N hydrochloric acid (5 ml) and the mixture was extracted with ethyl acetate and concentrated. The resulting crystal was collected by filtration to give 7- (4-ethoxy-phenyl) -2,3-dihydro-1-benzoxepin-4-carboxylic acid (380 mg) as colorless crystals. p.f. 269-271 ° C NMR-1H (200MHz, DMS0-d6) d 1.35 (3H, t, J = 7.0 Hz), 2.81-2.94 (2H, m), 4.06 (2H, q, J = 7.0 Hz), 4.18 -4.31 (2H, m), 6. 94-7.00 (3H, m), 7.49-7.79 (5H, m). IR (KBr) 2980, 1678, 1610, 1493, 1431, 1265, 1232, 1182, 1049, 926, 829, 810 cm "1 Elemental Analysis for C? 9H? 8? 4 Calculated C, 73.53; H, 5.85: Found C, 73.44; H, 5.77.

Reference Example 135 Under an atmosphere of argon, to a solution of 4-trifluoromethoxybromobenzene (10.0 g) in I tetrahydrofuran (75 ml) was added dropwise n-butyllithium (hexane solution, 1.6M) (28.5 ml) to - 78 ° C for 20 minutes, and the mixture was stirred for 40 minutes. To the reaction mixture was added dropwise a solution of trimethyl borate (12.9 g) in tetrahydrofuran (12 ml) for 15 minutes, and the mixture was stirred at -78 ° C for 30 minutes and at room temperature for 1 hour. . To the reaction mixture, 10% sulfuric acid (57.6 ml) was added dropwise over 15 minutes and the mixture was stirred for 2 hours, extracted with ethyl acetate, washed with a saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from hexane to give 4-trifluoromethoxyphenyl borate (2.7 g) as colorless crystals. Under an argon atmosphere, a solution of ethyl 7-bromo-2,3-dihydro-l-benzoxepin-4-carboxylate (500 mg), the above 4-trifluoromethoxyphenyl borate (380 mg) and potassium carbonate (0.46) g) in toluene-ethanol-water (20-2-2 ml) was stirred at room temperature for 1 hour. Tetracistriphenylphosphine palladium was added to the reaction mixture (0.06 g) and the mixture was heated to reflux for 18 hours and collected at room temperature. The organic layer was washed with a saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by column chromatography (ethyl acetate / hexane = 1: 10) to give ethyl 7- (4-trifluoromethoxyphenyl) -2,3-dihydro-l-benzoxepin-4-carboxylate ( 379 mg) as colorless crystals, m.p. 59-63 ° C NMR-aH (200MHz, CDC13) d 1.36 (3H, t, J = 7.1 Hz), 3.01 (2H, t, J = 4.8 Hz), 4.24-4.34 (4H, m), 7.06 (1H , d, J = 8.4 Hz), 7.22-7.31 (2H, m), 7.44 (1H, dd, J = 8.4, 2.2 Hz), 7.52 (1H, d, J = 2.2 Hz), 7.57 (2H, d, J = 8.8 Hz), 7.64 (1H, broad s). IR (KBr) 1701, 1489, 1304, 1257, 1227, 1211, 1182, 1134, 1014, 833, 808 cm "1 Elemental Analysis for C2oHi7? F3 Calculated C, 63.49; H, 4.53: Found C, 63.68; H, 4.47.

Reference Example 136 To a solution of ethyl 7- (4-trifluoromethyloxy-phenyl) -2,3-dihydro-l-benzoxepin-4-carboxylate (323.9 mg) in tetrahydrofuran-ethanol (5-5 ml) was added hydroxide NH sodium (2.0 ml) at room temperature, and the mixture was stirred for 5 days and concentrated under reduced pressure. To the residue, IN hydrochloric acid (5 ml) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with magnesium sulfate and concentrated. The resulting crystal was collected by filtration to give the acid 7- (4-trifluoromethoxyphenyl) -2,3-dihydro-l-benzoxepin-4-carboxylic acid (282 mg) as colorless crystals. p.f. 252-254 ° C NMR-1H (200MHz, CDC13) d 3.03 (2H, t, J = 4.6 Hz), 4.34 (2H, t, J = 4.6 Hz), 7.08 (1H, d, J = 8.4 Hz), 7.28 (2H, d, J = 8.8 Hz), 7.47 (1H, dd, J = 8.4, 2.2 Hz), 7.54 (1H, d, J = 2.2 Hz), 7.59 (2H, d, J = 8.8 Hz), 7.78 (1H, broad s) IR (KBr) 2981, 1691, 1493, 1290, 1261, 1213, 1169, 835 cm Anál is is Elemental for C? 8Hi3 ? F3 Calculated C, 61.72; H, 3.74; F, 16.27 Found C, 61.61; H, 3.72; F, 16.06.

Reference Example 137 To a solution of 5-bromosalicylaldehyde (10.0 g) and tert-butyl acrylate (17.5 ml) in tert-butanol (100 ml) was added potassium tert-butoxide (1.67 g) at room temperature, and The mixture was refluxed for 66 hours and cooled to room temperature. To the mixture was added ethyl acetate, and the mixture was washed with water, 1N sodium hydroxide and a saturated sodium chloride solution, dried with magnesium sulfate and concentrated. The residue was separated and purified by column chromatography (ethyl acetate / hexane = 1: 19) to give tert-butyl 6-bromo-2H-l-benzopyran-3-carboxylate (10.86 g) as color crystals. pale yellow pf 96-97 ° C NMR ^ H (200MHz, CDC13) d 1.53 (9H, s), 4.95 (2H, d, J = 0.8 Hz), 6.72 (1H, d, J = 8.4 Hz), 7.21-7.30 (3H, m). IR (KBr) 1699, 1479, 1331, 1288, 1159, 1088, 816 cm "1 Elemental Analysis for C14H? S03Br Calculated C, 54.04; H, 4.86; Br, 25.68: Found C, 53.98; H, 4.86; Br, 25.90.

Reference Example 138 Under an argon atmosphere, a solution of tert-butyl 6-bromo-2H-l-benzopyran-3-carboxylate (5.00 g), 4-methyl-phenyl borate (2.62 g) and potassium carbonate (4.44 g) in toluene-ethanol-water (160-16-16 ml) was stirred at room temperature for 1 hour. Tetracistriphenylphosphine palladium (0.56) was added to the reaction mixture, and the mixture was heated to reflux for 14 hours and cooled to room temperature. The organic layer was washed with a saturated sodium chloride solution, dried with magnesium sulfate and concentrated. The residue was separated and purified by column chromatography (ethyl acetate / hexane = 1: 19) to give pale yellow crystals, which is recrystallized with ethanol to give 6- (4-methylphenyl) -2H-1. -benzopyran-3-carboxylic acid tert-butyl ester (3.84 g) as pale yellow crystals. p.f. 80-82 ° C NMR-1H (200MHz, CDC13) d 1.54 (9H, s), 2.39 (3H, s), 4.98 (2H, d, J = 1.4 Hz), 6.94 (1H, d, J = 8.2 Hz ), 7.23 (2H, d, J = 8.0 Hz), 7.33 (1H, d, J = 2.2 Hz), 7.36-7.45 (4H, m). IR (KBr) 1705, 1367, 1340, 1311, 1251, 1159, 1133, 1003, 808 cm "1 Elemental Analysis for C2? H2203 Calculated C, 78.23; H, 6.88: Found C, 78.07; H, 6.89.

Reference Example 139 To 6- (4-methylphenyl) -2H-l-benzopyran-3-carboxylic acid tert-butyl ester (3.00 g) was added 4N hydrochloric acid-ethyl acetate (10 ml) at room temperature, and the mixture it was stirred for 16 hours. To the reaction mixture was added hexane, and the crystal was collected by filtration and washed with hexane to give 6- (4-methylphenyl) -2H-1-benzopyran-3-carboxylic acid (2.14 g) as yellow crystals. pale, mp 236-237 ° C NMR ^ H (200MHz, CDC13) d 2.40 (3H, s), 5.05 (2H, d, J = 1 .4 Hz), 6.94 (1H, d, J = 8.2 Hz), 7.23-7.27 (2H, m), 7.37 (1H, d, J = 2.2 Hz), 7.41-7.52 (3H, m), 7.63 (1H, broad s). IR (KBr) 3022, 1689, 1633, 1485, 1442, 1306, 1242, 812 cm "1 Elemental Analysis for C? 7H? 403 Calculated C, 76.68; H, 5.30: Found C, 76.51; H, 5.03.

Reference Example 140 To a solution of 5-bromo-salicylaldehyde (10.0 g) and ethyl crotonate (11.36 g) in tert-butanol (50 ml) was added potassium tert-butoxide (1.12 g) at room temperature, and The mixture was heated to reflux for 3 days. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with magnesium sulfate and concentrated. The residue was separated and purified by column chromatography (ethyl acetate / hexane = 1: 10- »1: 5) to give a pale yellow liquid (5.75 g). The resulting compound was used for the next reaction without being subjected to further purification. Under a nitrogen atmosphere, to a solution of the above crude product (5.5 g) and triethylamine (7.3 ml) in dichloromethane (50 ml) was added methanol-sulfonyl chloride (2.0 ml) at 0 ° C, and the mixture it was stirred at 0 ° C for 10 minutes and then at room temperature for 18 hours. Water was added to the reaction mixture and the mixture was extracted with diethyl ether. The organic layer was washed with a saturated sodium chloride solution, dried with magnesium sulfate and concentrated. The residue was separated and purified by column chromatography (ethyl acetate / hexane = 1: 15) to give a crude product (4.85 g) as a pale yellow oil. The resulting compound was used for the next reaction without being subjected to further purification. Under a nitrogen atmosphere, a solution of the above crude product (4.7 g), 4-methylphenyl borate (2.58 g) and potassium carbonate (4.4 g) in toluene-ethanol-water (160-16-16 ml) was stirred at room temperature for 1 hour. Tetracistriphenylphosphine palladium (0.54 g) was added to the reaction mixture, and the mixture was heated to reflux for 20 hours and cooled to room temperature. The organic layer was washed with a saturated sodium chloride solution, dried with magnesium sulfate and concentrated. The residue was separated and purified by column chromatography (ethyl acetate / hexane = 1: 15) to give 6- (4-methylphenyl) -2-methyl-2H-l-benzopyran-3-carboxylic acid ethyl ester ( 3.63 g) as pale yellow crystals, mp 82-84 ° C NMR-aH (200MHz, CDC13) d 1.35 (3H, t, J = 7.2 Hz), 1.40 (3H, d, J = 6.6 Hz), 2.39 (3H, s), 4.29 (2H, q , J = 7.2 Hz), 5.40 (1H, q, J = 6.6Hz), 6.92 (1H, d, J = 8.4 Hz), 7.24 (2H, d, J = 8.2 Hz), 7.36 (1H, d, J = 2.2 Hz), 7.40-7.49 (4H, m). IR (KBr) 1699, 1485, 1296, 1244, 1217, 1190, 1136, 1047, 804, 764, 511 cm "1 Elemental Analysis for C20H20O Calculated C, 77.90; H, 6.54: Found C, 77.79; H, 6.46.

Reference Example 141 To a solution of ethyl 6- (4-methylphenyl) -2-methyl-2H-l-benzopyran-3-carboxylate (3.0 g) in ethanol-tetrahydrofuran (30-30 ml) was added sodium hydroxide IN (12 ml) at room temperature, and the mixture was stirred for 16 hours. Under reduced pressure, the solvent was evaporated and acidified with IN hydrochloric acid. The mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated to give 6- (4-methylphenyl) -2-methyl-2H-1-benzopyran-3-carboxylic acid (2.15 g) as yellow crystals. p.f. 190-192 ° C NMR ^ H (200MHz, CDC13) d 1.43 (3H, d, J = 6.6 Hz), 2.39 (3H, s), 5.40 (1H, q, J = 6.6 Hz), 6.94 (1H, d , J = 8.4 Hz), 7. 24 (2H, d, J = 8.0 Hz), 7.38 (1H, d, J = 2.2Hz), 7.44 (2H, d, J = 8.0 Hz), 7.50 (1H, dd, J = 8.4, 2.2 Hz), 7.60 (1H, s). IR (KBr) 2983, 1680, 1635, 1485, 1421, 1298, 1261, 1190, 808 cm "1 Elemental Analysis for C? 8Hi6? 3 Calculated C, 77.12; H, 5.75: Found C, 77.25; H, 5.63.

Reference Example 142 To a solution of 5-bromo-2-thiophenecarboxyaldehyde (6.08 g) and methyl (triphenylphosphoranylidene) acetate (11.12 g) in toluene (60 ml) was heated to reflux under a nitrogen atmosphere for 2 hours and cooled. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by column chromatography (ethyl acetate / hexane = 1: 15- 1: 9) and recrystallized from ethyl acetate to give (E) -3- (5-bromothiophene-2) il) -acrylate (7.44 g) as pale yellow crystals. NMR-XH (200MHz, CDC13) d 3.79 (3H, s) 6.13 (1H, d, J = 15.8 Hz), 6.96-7.05 (2H, m), 7.66 (1H, d, J = 15.8 Hz). IR (KBr) 1724, 1624, 1417, 1257, 1203, 1165, 968, 802, 486 cm "1 Elemental Analysis for C8H702SBr Calculated C, 38.88; H, 2.86; S, 12.98; Br, 32.34: Found C, 38.95; H, 2.83; S, 13.13; Br, 32.36.

Reference Example 143 Under an atmosphere of argon, a solution of methyl (E) -3- (5-bromothiophen-2-yl) acrylate (4.0 g), 4-methylphenyl borate (2.64 g) and potassium carbonate (4.48 g) in toluene-ethanol-water (160-16-16 ml) was stirred at room temperature for 1 hour. Tetracistriphenylphosphine palladium (0.56) was added to the reaction mixture, and the mixture was heated to reflux for 16 hours and cooled to room temperature. The organic layer was washed with a saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure to give the crude product (5.24 g). To a solution of the resulting carboxylic acid ester (5.24 g) in tetrahydrofuran (100 ml) was added IN sodium hydroxide (20 ml) at room temperature and the mixture was stirred for 5 days. Water was added to the reaction mixture, and the mixture was washed with ethyl acetate. The aqueous layer was acidified with concentrated hydrochloric acid, and the mixture was extracted with ethyl acetate, washed with a saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure to give the acid (E) -3- [5- (4-methylphenyl) -thiophen-2-yl] acrylic (1.9 g) as yellow crystals. p.f. 223-225 ° C NMR-1H (200MHz, CDC13) d 2.38 (3H, s), 6.21 (1H, d, J = 15.8 Hz), 7.16-7.27 (4H, m), 7.52 (2H, d, J = 8.0 Hz), 7.84 (1H, d, J-15.8 Hz). IR (KBr) 2968, 1666, 1606, 1413, 1261, 1230, 804 cm "1 Elemental Analysis for C? 4H? 202S Calculated C, 38.83; H, 4.95; S, 13.12: Found C, 68.76; H, 5.07; S, 13.28.

Reference Example 144 To a suspension of 5-bromo-2-furancarboxylic acid (5.00 g) and N-hydroxysuccinimide (3.31 g) in acetonitrile (50 ml) was added 1-ethyl-3- (3'-dimethylaminopropyl) hydrochloride Carbodiimide (5.52 g) at room temperature, and the mixture was stirred for 2 hours. To the reaction mixture was added a suspension of N, O-dimethylhydroxylamine hydrochloride (2.81 g) and triethylamine (10 ml) in acetonitrile (20 ml), and the mixture was stirred for 1 hour. To the reaction mixture was added 1,8-diazabicyclo [5.4.0] -7-undecene (4.3 ml) and DMF (50 ml) and the mixture was stirred for 3 hours and concentrated under reduced pressure. The residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by column chromatography (ethyl acetate / hexane = 1: 4-> 1: 3-1: 2) to give N-methyl-N-methoxy-5-bromofuran-2. carboxamide (2.77 g) as a pale yellow oil. NMR -'- H (200MHz, CDC13) d 3.34 (3H, s), 3.77 (3H, s), 6.45 (1H, d, J = 3.6 Hz), 7.09 (1H, d, J = 3.6 Hz). IR (pure) 2974, 2937, 1647, 1475, 1416, 1385, 1211, 1024, 985, 926, 796, 739 cm "1 Reference Example 145 Under an atmosphere of argon, a solution of N-methyl-N-methoxy-5-bromofuran-2-carboxamide (2.77 g), 4-methyl-phenyl borate (1.93 g) and potassium carbonate (3.27) g) in toluene-ethanol-water (110-11-11 ml) was stirred at room temperature for 1 hour. Tetracistriphenylphosphine palladium (0.41) was added to the reaction mixture, and the mixture was heated to reflux for 20 hours and cooled to room temperature. The organic layer was washed with a saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by column chromatography (ethyl acetate / hexane = 1: 5-1: 2-1: 1) to give the N-methyl-N-methoxy-5- (4-methylphenyl) furan. -2-carboxamide (2.65 g) as colorless crystals, mp 54-58 ° C NMR- ^ H (200MHz, CDC13) d 2.38 (3H, s), 3.38 (3H, s), 3.82 (3H, s), 6.69 (1H, d, J = 3.8 Hz), 7.20- 7.26 (3H, m), 7.68 (2H, d, J = 8.6 Hz). IR (pure) 1632, 1487, 1381, 1032, 987, 798, 739, 557, 494 cm "1 Elemental Analysis for C? 4H15N03 Calculated C, 68.56; H, 6.16; N, 5.71: Found C, 68.22; H, 6.02; N, 5.47.

Reference Example 146 Under a nitrogen atmosphere, a solution of N-methyl-N-methoxy-5- (4-methylphenyl) furan-2-carboxamide (2.5 g) in tetrahydrofuran (20 ml) was added aluminum diisobutyl hydride aluminum (toluene solution 1.01M) (15 ml) at -78 ° C and the mixture was stirred at -78 ° C for 10 minutes and then at 0 ° C for 15 minutes. To the reaction mixture was added IN hydrochloric acid to stop the reaction, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with magnesium sulfate and concentrated. The residue was separated and purified by column chromatography (ethyl acetate / hexane = 1: 5-41: 4) to give the crude product (1.49 g). A solution of crude aldehyde (1.49 g) and methyl (triphenylphosphoranylidene) acetate (2.67 g) in toluene (30 ml) was heated to reflux under a nitrogen atmosphere for 1 hour and cooled. Water was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by column chromatography (ethyl acetate / hexane = 1: 9 → 1: 5) to give (E) -3- [5- (4-methylphenyl) furan-2-yl] Methyl acrylate (1.63 g) as pale yellow crystals. p.f. 113-115 ° C NMR ^ H (200MHz, CDC13) d 2.38 (3H, s), 3.80 (3H, s), 6. 39 (1H, d, J = 15.5 Hz), 6.68 (2H, s), 7.22 (2H, d, J = 8.4 Hz), 7.44 (1H, d, J = 15.5 Hz), 7.62 (2H, d, J = 8.4 Hz). IR (KBr) 1716, 1632, 1304, 1201, 1161, 798 c "1 Elemental Analysis for C? 5H? 403 Calculated C, 74.36; H, 5.82: Found C, 74.36; H, 5.75.

Reference Example 147 To a solution of methyl (E) -3- [5- (4-methylphenyl) -furan-2-yl] acrylate (1.49 g) in tetrahydrofuran-ethanol (10-10 ml) was added sodium hydroxide. 2N sodium (4 ml) at room temperature and the mixture was stirred for 24 hours. The reaction mixture was acidified with IN hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure to give the acid (E) -3- [5- (4-methylphenyl) -furan-2-yl. ] acrylic (0.93 g) as colorless crystals. p.f. 183-184 ° C NMR-1H (200MHz, CDC13) d 2.39 (3H, s), 6.39 (1H, d, J = 15.4 Hz), 6.70 (1H, d, J = 3.4 Hz), 6.75 (1H, d , J = 3.4 Hz), 7.23 (2H, d, J = 8.2 Hz), 7.52 (1H, d, J = 15.4 Hz), 7.64 (1H, d, J = 8.2 Hz). IR (KBr) 2964, 1678, 1624, 1419, 1308, 1261, 785 cm "1 Elemental Analysis for C? 4H? 203 Calculated C, 73.67; H, 5.30: Found C, 73.42; H, 5.15.

Reference Example 148 A solution of 4-bromo-2-thiophenecarboxyaldehyde (4.77 g) and methyl (triphenylphosphoranylidene) acetate (8.44 g) in toluene (50 ml) was heated to reflux under a nitrogen atmosphere for 3 hours and cooled. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by column chromatography (ethyl acetate / hexane = 1: 15) to give methyl (E) -3- (4-bromothiophen-2-yl) acrylate (5.55 g) as crystals pale yellow color, mp 63-67 ° C NMR-aH (200MHz, CDC13) d 3.80 (3H, s), 6.25 (1H, d, J = 15.8 Hz), 7.16 (1H, d, J = 0.8 Hz), 7.26 (1H, d, J = 0.8 Hz), 7.68 (1H, d, J = 15.8 Hz). IR (KBr) 1713, 1630, 1304, 1257, 1165, 958, 828 cm "1 Elemental Analysis for Calculated C8H02SBr C, 38.88; H, 2.86; S, 12.98; Br, 32.34: Found C, 38.78; H, 2.83; S, 12.98; Br, 32.27.

Reference Example 149 Under an atmosphere of argon, a solution of methyl (E) -3- (4-bromothiophen-2-yl) acrylic acid (3.0 g), 4-methyl-phenyl borate (1.82 g) and carbonate of potassium (3.36 g) in toluene-ethanol-water (120-12-12 ml) was stirred at room temperature for 1 hour. Tetracistriphenylphosphine palladium (0.42 g) was added to the reaction mixture and the mixture was heated to reflux for 24 hours and cooled to room temperature. The organic layer was washed with a saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by column chromatography (ethyl acetate / hexane = 1: 9-l: 5-l: 2) to give (E) -3- [4- (4-methylphenyl) thiophene- 2-yl) methyl acrylate (2.40 g) as pale yellow crystals. p.f. 116-118 ° C NMR- ^ H (200MHz, CDC13) d 2.38 (3H, s), 3.80 (3H, s), 6. 27 (1H, d, J = 15.8 Hz), 7.21 (2H, d, J = 7.8 Hz), 7.43-7.50 (4H, m), 7.80 (1H, d, J = 15.8 Hz). IR (KBr) 1713, 1622, 1506, 1423, 1302, 1240, 1192, 1159, 966, 847, 916, 760 cm "1 Elemental Analysis for C? 5H? 402S Calculated C, 69.74; H, 5.46; S, 12.41: Found C, 69.54; H, 5.47; S, 12.24.

Reference Example 150 To a solution of methyl (E) -3- [4- (4-methylphenyl) -thiophen-2-yl) acrylate (2.40 g) in tetrahydrofuran (50 ml) was added 2N sodium hydroxide (6.0 ml) at room temperature, and the mixture was stirred for 6 days. The precipitated crystal was collected by filtration and washed with tetrahydrofuran. INN hydrochloric acid (20 ml) was added to the crystals, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure to give (E) -3- [4- (4-methylphenyl) thiophen-2-yl] acid] acrylic (1.24 g) as pale yellow crystals, mp 206-207 ° C NMR-aH (200MHz, CDC13) d 2.38 (3H, s), 6.28 (1H, d, J = 15.6 Hz), 7.23 (2H, d, J = 8.0 Hz), 7.47 (2H, d, J = 8.0 Hz), 7.49 (1H, s), 7.55 (1H, d, J = 1 .4 Hz), 7.90 (1H, d, J = 15.6 Hz). IR (KBr) 2970, 2918, 1682, 1622, 1306, 1196, 966, 818, 764 cm "1 Elemental Analysis for C? 4H? 202S Calculated C, 68.83; H, 4.95; S, 13.12: Found C, 68.66; H, 4.77; S, 13.08.

Reference Example 151 Under a nitrogen atmosphere, to a solution of ethyl chloroformylbutyrate (25.0 g) in 1,2-dichloroethane (150 ml) was added dropwise a solution of tin tetrachloride (76.6 g) in 1.2 Dichloroethane (50 ml) at 0 ° C and then a solution of 2-bromothiophene (22.8 g) in 1,2-dichloroethane (20 ml), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was stirred vigorously and was added to concentrated hydrochloric acid-ice to stop the reaction. The mixture was stirred for 30 minutes and extracted with dichloromethane. The organic layer was washed with a saturated sodium bicarbonate solution and a saturated sodium chloride solution, dried with magnesium sulfate and concentrated. The residue was separated and purified by column chromatography (ethyl acetate / hexane = 1: 5) to give ethyl 5- (5-bromothiophen-2-yl) -5-oxovalerate (28.1 g) as colorless crystals. , pf 53-54 ° C NMR-1H (200MHz, CDC13) d 1.26 (3H, t, J = 7.2 Hz), 1.97-2.12 (2H, m), 2.41 (2H, t, J = 7.2 Hz), 2.92 (2H , t, J = 7.3 Hz), 4.14 (2H, q, J = 7.2 Hz), 7.10 (1H, d, J = 4.0 Hz), 7.47 (1H, d, J = 4.0 Hz). IR (KBr) 1726, 1664, 1419, 1281, 1184, 980, 812 cm "1 Elemental Analysis for CnHi? 3SBr Calculated C, 43.29; H, 4.29; S, 10.51; Br, 26.18: Found C, 43.54; H, 4.20; S, 10.64; Br, 26.24.

Reference Example 152 Under an argon atmosphere, a solution of - (5-Bromothiophen-2-yl) -5-oxovalerate ethyl (10.09 g), 4-methyl-phenyl borate (5.39 g) and potassium carbonate (9.14 g) in toluene-ethanol-water (320-32-32 ml) was stirred at room temperature for 1 hour. Tetracistriphenylphosphine palladium (1.14 g) was added to the reaction mixture, and the mixture was heated to reflux for 8 hours and cooled to room temperature. The organic layer was washed with a saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by column chromatography (ethyl acetate / hexane = 1: 4- »1: 3 → 1: 2-1: 1) to give 5- [5- (4-methylphenyl) ethyl thiophen-2-yl] -5-oxovalerate (10.23 g) as colorless crystals, m.p. 120-121 ° C NMR-aH (200MHz, CDC13) d 1.26 (3H, t, J = 7.2 Hz), 2.01-2.15 (2H, m), 2.38 (3H, s), 2.44 (2H, t, J = 7.4 Hz), 2.97 (2H, t, J = 7.2 Hz), 4.15 (2H, q, J = 7.2 Hz), 7.22 (2H, d, J = 7.9 Hz), 7.27 (1H, d, J = 4.1 Hz ), 7.55 (2H, d, J = 7.9 Hz), 7.68 (1H, d, J = 4.1 Hz). IR (KBr) 1722, 1647, 1448, 1286, 1173, 816 cm "1 Elemental Analysis for C? 8H20O3S Calculated C, 68.33; H, 6.37; S, 10.13: Found C, 68.40; H, 6.26; S, 10.11.

Reference Example 153 To a solution of ethyl 5- [5- (4-methylphenyl) thiophen-2-yl] -5-oxovalerate (4.50 g) in trifluoroacetic acid (7.66 ml) was added triethylsilane (5.7 ml) at room temperature, and the mixture was stirred for 4 days. To the reaction mixture was added ethyl acetate, and the mixture was made alkaline with a saturated sodium bicarbonate solution. The organic layer was washed with a saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by column chromatography (ethyl acetate / hexane = 1: 9) to give crude ethyl 5- [5- (4-methyl-phenyl) thiophen-2-yl] valerate. To a solution of crude ethyl 5- [5- (4-methylphenyl) thiophen-2-yl] valerate in tetrahydrofuran (50 ml) was added IN sodium hydroxide (20 ml) at room temperature, and the mixture was stirred for 24 hours. Water was added to the reaction mixture and the mixture was washed with diethyl ether. The aqueous layer was acidified with IN hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure to precipitate crystals, which were collected by filtration and washed with hexane to give the acid 5- [5- (4-methylphenyl) -thiophen-2-yl] valeric acid (2.88 g) as colorless crystals. p.f. 124-127 ° C NMR-1H (200MHz, CDC13) d 1.67-1.82 (4H, m), 2.35 (3H, s), 2.36-2.45 (2H, m), 2.78-2.90 (2H, m), 6.73 ( 1H, d, J = 3.6 Hz), 7.07 (1H, d, J = 3.6 Hz), 7.15 (2H, d, J = 8.4 Hz), 7.44 (2H, d, J = 8.4 Hz).

IR (KBr) 2941, 1693, 1512, 1429, 1408, 1317, 1267, 1203, 945, 797, 771 c "1 Elemental Analysis for C? 6H? 8? 2S Calculated C, 70.04; H, 6.61; S, 11.69: Found C, 69.79; H, 6.37; N, 11.62.

Reference Example 154 Under a nitrogen atmosphere, oxalyl chloride (1.24 ml) was added to a solution of 5- [5- (4-methylphenyl) thiophen-2-yl] valeric acid (2.60 g) in tetrahydrofuran (30 ml). ) at room temperature and then one drop of DMF, and the mixture was stirred 1 hour. Under reduced pressure, the solvent was evaporated and the residue was dissolved in dichloromethane (30 ml). To the mixture was added tin tetrachloride (1.5 ml) at 0 ° C, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was added to water to stop the reaction, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by column chromatography (ethyl acetate / hexane = 1: 9-1: 5) to give 2- (4-methylphenyl) -4-oxo-5, 6, 7, 8- tetrahydro-4H-cyclohepta [b] -thiofen (2.07 'g) as pale yellow crystals. p.f. 82-84 ° C NMR ^ H (200MHz, CDC13) d 1.82-2.06 (4H, m), 2.35 (3H, s), 2.71-2.78 (2H, m), 3.06-3.12 (2H, m), 7.17 ( 2H, d, J = 8.2 Hz), 7.44 (2H, d, J = 8.2 Hz), 7.57 (1H, s). IR (KBr) 2927, 1662, 1390, 1176, 810CIU "1 Elemental Analysis for C? 6H? 6OS Calculated C, 74.96; H, 6.29; S, 12.51: Found C, 74.89; H, 6.20; S, 12.53.

Reference Example 155 To a solution of 2- (4-methylphenyl) -4-oxo-5,6,7,8-tetrahydro-4H-cyclohepta [b] thiophene (2.62 g) and dimethyl carbonate (2.6 ml) in tetrahydrofuran (50 ml) was added potassium tert-butoxide (1.38 g) at room temperature, and the mixture was heated to reflux for 1 hour. To the reaction mixture was added potassium tert-butoxide (1.4 g) and dimethyl carbonate (5 ml), and the mixture was added. heated to reflux for 2 hours and cooled to room temperature. INN hydrochloric acid (150 ml) was added to the mixture at 0 ° C and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure to give the crude products (3.30 g). To crude products (3.30 g) in dichloromethane (50 ml) was added boron sodium hydride (0.77 g) at room temperature and then methanol (8 ml) at -15 ° C for 30 minutes and the mixture was stirred for 2 hours . Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure to give the crude product (2.95 g). To a solution of crude product (2.95 g) and triethylamine (7 ml) in dichloromethane (20 ml) was added methanesulfonyl chloride (1.2 ml) at 0 ° C, and the mixture was stirred at room temperature for 17 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure. The concentrated product was purified by column chromatography (ethyl acetate / hexane = 1: 9) to give 2- (4-methyl-phenyl) -7,8-dihydro-6H-cyclohepta [b] thiophen-5 Methyl carboxylate (884 mg) as yellow crystals.

NMR ^ H (200MHz, CDC13) d 1.98-2.11 (2H, m), 2.36 (3H, s), 2.79 (2H, t, J = 5.5 Hz), 3.09 (2H, t, J = 5.6 Hz), 3. 79 (3H, s), 7.08 (1H, s), 7.17 (2H, d, J = 8.1 Hz), 7.42 (2H, d, J = 8.1 Hz), 7.60 (1H, s) Reference Example 156 To a solution of methyl 2- (4-methylphenyl) -7,8-dihydro-6H-cyclohepta [b] thiophene-5-carboxylate (803 mg) in ethanol-tetrahydrofuran (5-10 ml) was 2N sodium hydroxide (2 ml) was added at room temperature, and the mixture was stirred for 5 days, and concentrated under reduced pressure. To the residue was added IN hydrochloric acid (10 ml), and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure to precipitate the crystals, which were collected by filtration and washed with diisopropyl ether to give the acid 2- ( 4-methylphenyl) -7,8-dihydro-6H-cyclohepta [b] thiophene-5-carboxylic acid (650 ml) as pale yellow crystals, mp .250-251 ° C NMR-1H (200MHz, CDC13) d 2.00- 2.14 (2H, m), 2.36 (3H, s), 2.75-2.85 (2H, m), 3.07-3.16 (2H, m), 7.10 (1H, s), 7.18 (2H, d, J = 8.0 Hz) 7.43 (2H, d, J = 8. O Hz), 7.72 (1H, s). IR (KBr) 2910, 2831, 1670, 1614, 1423, 1287, 1242, 810c "1 Elemental Analysis for C? 7H? 602S Calculated C, 71.80; H, 5.67; S, 11.28: Found C, 71.74; H, 5.64; S, 11.06.

Reference Example 157 To a suspension of 5-bromonicotinic acid (5.0 g) and N-hydroxysuccinimide (4.27 g) in acetonitrile (60 ml) were added l-ethyl-3- (3'-dimethylaminopropyl) carbodiimide hydrochloride (7.12 g) at room temperature, and the mixture was stirred for 30 minutes. minutes To the reaction mixture were added N, O-dimethyl-hydroxylamine hydrochloride (2.66 g) and triethylamine (10 ml), and the mixture was stirred for 64 hours and concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by column chromatography (ethyl acetate / hexane = 2: 1) to give the N-methyl-N-methoxy-5-bromo-pyridine-3-carboxamide (3.71 g) as an oil. pale yellow color. NMR-1H (200MHz, CDC13) d 3.40 (3H, s), 3.58 (3H, s), 8. 19 (1H, dd, J = 2.2, 1.8 Hz), 8.76 (1H, d, J = 2.2 Hz), 8. 88 (1H, d, J = 1 .8 Hz). IR (pure) 1647, 1412, 1381, 1221, 1099, 1020, 982, 897, 773, 739, 969, 667, 575, 461 cm "1 Reference Example 158 Under an argon atmosphere, a solution of N-methyl-N-methoxy-5-bromopyridine-3-carboxamide (3.70 g), 4-methyl-phenyl borate (2.26 g) and potassium carbonate (4.17 g) in toluene-ethanol-water (100-10-10 ml) was stirred at room temperature for 1 hour. Tetracistriphenylphosphine palladium was added to the reaction mixture (0.52 g), and the mixture was heated to reflux for 16 hours and cooled to room temperature. The organic layer was washed with a saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by column chromatography (ethyl acetate / hexane = 1: 2-> 1: 1) to give N-methyl-N-methoxy-5- (4-methylphenyl) pyridin-3. -carboxamide (3.97 g) as a pale yellow oil.

RM ^ H (200MHz, CDC13) d 2.42 (3H, s), 3.42 (3H, s), 3. 60 (3H, s), 7.30 (2H, d, J = 8.3 Hz), 7.51 (2H, d, J = 8.3 Hz), 8.20 (1H, t, J = 2.1 Hz), 8.89-8.81 (2H, m). IR (pure) 1647, 1431, 1379, 1203, 982, 818, 743, 540, 426 c "1 Reference Example 159 Under a nitrogen atmosphere, hydride was added dropwise to a solution of N-methyl-N-methoxy-5- (4-methylphenyl) pyridine-3-carboxamide (3.95 g) in tetrahydrofuran (30 ml). diisobutylaluminium (1.01M toluene solution) (30 ml) at -78 ° C, and the mixture was stirred at the same temperature for 2 hours. IN hydrochloric acid was added to the reaction mixture to stop the reaction. To the mixture was added ethyl acetate, and the mixture was made alkaline with 1N sodium hydroxide. The organic layer was washed with a saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by column chromatography (ethyl acetate / hexane = 1: 2-> 1: 1) to give 5- (4-methylphenyl) pyridine-3-carboxaldehyde (1.82 g) as crystals colorless, pf 60-61 ° C NMR-aH (200MHz, CDC13) d 2.43 (3H, s), 7.33 (2H, d, J = 7.8 Hz), 7.54 (2H, d, J = 7.8 Hz), 8.33 (1H, dd, J = 2.2, 2. 0 Hz), 9.03 (1H, d, J = 2.0 Hz), 9.07 (1H, d, J = 2.2 Hz), . 19 (1H, s) IR (KBr) 1701, 1186, 818, 725, 806 cm "1 Elemental Analysis for CpHpNO Calculated C, 79.17; H, 5.62; N, 7.10: Found C, 79.24; H, 5.64; N, 7.01.

Reference Example 160 A solution of 5- (4-methylphenyl) pyridine-3-carboxyaldehyde (1.82 g) and methyl (triphenylphosphoranylidene) -acetate (3.46 g) in toluene (20 ml) was heated to reflux under a nitrogen atmosphere for 4 hours and cooled. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by column chromatography (ethyl acetate / hexane = 1: 2-1: 1) to give (E) -3- [5- (4-methylphenyl) pyridin-3-yl] Methyl acrylate (2.34 g) as colorless crystals, mp 141-144 ° C NMR - ^ - H (200MHz, CDC13) d 2.43 (3H, s), 3.84 (3H, s), 6.59 (1H, d, J = 16.0 Hz), 7.32 (2H, d, J = 7.9 Hz), 7.50 (2H, d, J = 7.9 Hz), 7.76 (1H, d, J = 16.0 Hz), 7.98 (1H, dd, J = 2.2, 2.0 Hz), 8.70 (1H, d, J = 2.0 Hz), 8.82 (1H, d, J = 2.2 Hz). IR (KBr) 1718, 1639, 1431, 1335, 1196, 1176, 995, 816 cm "1 Elemental Analysis for C? 6H? 5 02 Calculated C, 75.87; H, 5.97; N, 5.53: Found C, 75.82; H 5.86; N, 5.47.

Reference Example 161 To a solution of methyl (E) -3- [5- (4-methylphenyl) -pyridin-3-yl] acrylate (2.25 g) in tetrahydrofuran (20 ml) was added sodium hydroxide (11). ml) at room temperature, and mixture was stirred for 5 days. To the reaction mixture was added IN hydrochloric acid (12 ml), and the mixture was concentrated under reduced pressure to precipitate crystals, which were collected by filtration and washed with water and diethyl ether to give the acid (E) -3- [5- (4-methylphenyl) pyridin-3-yl] acrylic (1.92 g) as colorless crystals. p.f. 208-211 ° C NMR-aH (200MHz, DMSO-d6) d 2.37 (3H, s), 6.85 (1H, d, J = 16.2 Hz), 7.33 (2H, d, J = 8.6 Hz), 7.66-7.74 (3H,), 8.40-8.45 (1H, m), 8.81 (1H, d, J = 1. 8 Hz), 8.89 (1H, d, J = 2.2 Hz). IR (KBr) 3030, 1672, 1635, 1435, 1331, 1302, 987, 820 cm "1 Elemental Analysis for C? 5H? 3N02 Calculated C, 75.30; H, 5.48; N, 5.85: Found C, 74.99; H, 5.39; N, 5.94.

Reference Example 162 To DMF (7.18 ml) phosphoryl chloride (8.64 ml) was added dropwise at 0 ° C, and the mixture was stirred at room temperature for 30 minutes. To the mixture was added methyl acetoacetate (10 ml) at 0 ° C, and the mixture was stirred at room temperature for 2 hours. The mixture was cooled to 0 ° C and 4-bromoaniline (16.78 g) was added to the mixture, and the mixture was stirred at 90 ° C for 4 hours. Chloroform was added to the reaction mixture and the mixture was neutralized with 8N sodium hydroxide. The organic layer was washed with water and a saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by column chromatography (ethyl acetate / hexane = 1: 2) and recrystallized from ethyl acetate-hexane to give the Methyl 6-bromo-2-methylquinoline-3-carboxylate (6.02 g) as pale yellow crystals. p.f. 150-151 ° C NMR-aH (200MHz, CDC13) d 2.97 (3H, s), 3.99 (3H, s), 7. 84 (1H, dd, J = 9.0, 2.0 Hz), 7.92 (1H, d, J = 9.0 Hz), 8. 02 (1H, d, J = 2.0 Hz), 8.65 (1H, s) IR (KBr) 1726, 1423, 1396, 1277, 1238, 1219, 1134, 1074, 829 cm "1 Elemental Analysis for C? 2H? 0N02Br Calculated C, 51.45; H, 3.60; N, 5.00: Found C, 51.57; H, 3.55; N, 5.17.

Reference Example 163 Under an argon atmosphere, a solution of Methyl 6-bromo-2-methylquinoline-3-carboxylate (1.22 g), 4-methylphenyl borate (0.65 g) and potassium carbonate (1.18 g) in toluene-ethanol-water (40-4-4 ml) were added. stirred at room temperature for 1 hour. Tetracistriphenylphosphine palladium was added to the reaction mixture (0.15 g), and the mixture was heated to reflux for 18 hours and cooled to room temperature. The organic layer was washed with a saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by column chromatography (ethyl acetate / hexane = 1: 1) to give methyl 6- (4-methylphenyl) -2-methylquinoline-3-carboxylate (1.27 g) as colorless crystals. . p.f. 84-87 ° C NMR-aH (200MHz, CDC13) d 2.43 (3H, s), 3.01 (3H, s), 4. 00 (3H, s), 7.32 (2H, d, J = 8.0 Hz), 7.61 (2H, d, J = 8.0 Hz), 8.01-8.12 (3H, m), 8.79 (1H, s). IR (KBr) 1732, 1440, 1277, 1213, 1068, 814 cm "1 Elemental Analysis for C? 9H? 7N02 Calculated C, 78.33; H, 5.88; N, 4.81: Found C, 77.98; H, 6.02; N, 4.75.

Reference Example 164 To a solution of methyl 6- (4-methylphenyl) -2-methyl-quinoline-3-carboxylate (0.99 g) in tetrahydrofuran-ethanol (5-5 ml) was added 2N sodium hydroxide (2 ml. ) at room temperature, and the mixture was stirred for 2 days. To the reaction mixture was added 1N hydrochloric acid (4 ml) and the mixture was concentrated under reduced pressure to precipitate crystals, which were collected by filtration and washed with ethanol and diethyl ether to give 6- (4-methylphenyl) acid. -2-methylquinoline-3-carboxylic acid (648 mg) as colorless crystals. p. f. 273 ° C (dec.) 1 H-NMR (200 MHz, DMSO-d 6) d 2.38 (3 H, s), 2.89 (3 H, s), 7. 34 (2H, d, J = 8.3Hz), 7.74 (2H, d, J = 8.3 Hz), 8.02 (1H, d, J = 8.8 Hz), 8.15 (1H, dd, J = 8.8, 2.1 Hz), 8.37 (1H, d, J = 2.1 Hz), 8.90 (1H, s). IR (KBr) 2918, .1703, 1570, 1495, 1257, 1227, 1180, 1151, 1065, 812, 770 cm "1 Elemental Analysis for C? 0H? 5NO2 Calculated C, 77.96; H, 5.45; N, 5.05: Found C, 77.74; H, 5.34; N, 5.12.

Reference Example 165 Under an argon atmosphere, a solution of ethyl 7-bromo-2,3-dihydro-l-benzoxepin-4-carboxylate (1.0 g), 4-methylthiophenyl borate (622 mg) and potassium carbonate (0.93 g) in toluene-ethanol-water (30-3-3 ml) was stirred at room temperature for 1 hour. To the reaction mixture was added tetracistriphenylphosphinepalladium (117 mg), and the mixture was heated to reflux for 16 hours. Tetracistriphenyl-phosphine palladium was added to the reaction mixture (0.13 g), and the mixture was heated to reflux for 24 hours and cooled to room temperature. The organic layer was washed with a saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by column chromatography (ethyl acetate / hexane = 1: 10) to give ethyl 7- (4-methylthiophenyl) -2,3-dihydroxy-l-benzoxepin-4-carboxylate ( 442 mg) as colorless crystals. NMR ^ H (200MHz, CDC13) d 1.36 (3H, t, J = 7.0 Hz), 2.52 (3H, s), 3.00 (2H, t, J = 4.8 Hz), 4.29 (2H, q, J = 7.0 Hz ), 4.30 (2H, t, J = 4.8 Hz), 7.04 (1H, d, J = 8.4 Hz), 7.32 (2H, d, J = 8.8 Hz), 7.42-7.54 (4H, m), 7.65 (1H , s broad). IR (KBr) 1705, 1489, 1302, 1250, 1230, 1200, 1090, 1063, 1011, 813 cm "1 Reference Example 166 To a solution of ethyl 7- (4-methylthiophenyl) -2,3-dihydro-l-benzoxepin-4-carboxylate (132 mg) in ethanol-tetrahydrofuran (5 ml-5 ml) was added sodium hydroxide. NH sodium (1.0 ml) at room temperature, and the mixture was stirred for 20 hours and concentrated under reduced pressure. To the residue was added 1N hydrochloric acid (2 ml) and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure. The resulting crystal was collected by filtration to give 7- (4-methylthiophenyl) -2,3-dihydro-1-benzoxepin-4-carboxylic acid (113 mg) as colorless crystals. NMR- ^ H (200MHz, DMSO-d6) d 2.51 (3H, s), 2.89 (2H, t, J = 4.4 Hz), 4.25 (2H, t, J = .4 Hz), 7.04 (1H, d, J = 8.4 Hz), 7.33 (2H, d, J = 8.4 Hz), 7.58 (1H, dd, J = 8.4, 2.4 Hz), 7.61-7.70 (3H,), 7.80 (1H, d, J = 2.4 Hz). IR (KBr) 2974, 1689, 1493, 1263, 1213, 1169, 1020, 833 Reference Example 167 To a solution of 4-nitrobenzyl alcohol (50 g, 0.326 mole) in ethyl acetate (EtOAc) (20 ml) were added 3,4-dihydropyran (35.7 ml, 0.392 mole) and CSA (camphor sulfonic acid) ) (379 mg, 1.63 mmol) under stirring at room temperature, and the mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was neutralized with a saturated solution of NaHCO 3 and the separated ethyl acetate layer was dried with MgSO 4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give 4- (2-tetrahydropyranyloxymethyl) nitrobenzene (74.5 g, 96%) as a syrup. R N- ^ H (200MHz, CDC13) d 1.55-2.05 (6H, m), 3.51-3.62 (1H, m), 3.83-3.94 (1H, m), 4.61 (1H, d, J = 13.6Hz), 4.74 (1H, t, J = 3.2Hz), 4.93 (1H, d, J = 13.4 Hz), 7.51-7.56 (2H, d, J = 8.8Hz), 8.18-8.24 (2H, m).

Reference Example 168 To a solution of 4- (2-tetrahydropyranyloxymethyl) -nitrobenzene (59.7 g, 0.256 mol) in ethanol (EtOH) (300 ml) was added under an atmosphere of nitrogen at room temperature Pd / C 10% (5.97) g), and the catalytic hydrogenation was carried out. The mixture was stirred at room temperature for 24 hours. After the reaction was completed, the catalyst was filtered and the organic layer was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give 4- (2-tetrahydropyranyloxymethyl) -aniline (39.7 g, 76%) as a syrup. NMR-1H (200MHz, CDC13) d 1.45-1.95 (6H, m), 3.00-3.60 (3H, broad m), 3.87-4.14 (1H, m), 4.39 (1H, d, J = 11.4Hz), 4.68 (1H, d, J = 11.4Hz), 4.71 (1H, m), 6.65-6.69 (2H, m), 7.15-7.19 (2H, m).

Reference Example 169 To a solution of 2- (4-methylphenyl) -6,7-dihydro-5H-benzocycloheptene-8-carboxylic acid (35.0 g, 0.126 mol) in tetrahydrofuran (THF) (280 mL) were added (C0C1 ) 2 (21.9 ml, 0.251 moles) and DMF (0.7 ml) at 0 ° C. Under a nitrogen atmosphere, the mixture was stirred at room temperature for 4 hours. After the reaction was completed, the solvent was evaporated and THF (315 ml) was added to the residue. To a solution of the acid chloride was added a solution of 4- (2-tetrahydropyranoloxymethyl) aniline (28.1 g, 0.138 mol) and triethylamine (Et3N) (26.3 ml, 0.189 mol) in THF (105 ml) at 0 ° C, and the mixture was stirred under a nitrogen atmosphere, at room temperature for 2 hours. After the reaction was complete, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated solution of NaCl and dried with MgSO.sub.0. The solvent was evaporated and the residue was dissolved in methanol (MeOH) (470 ml). To the mixture was added dropwise 6N HCl (5.9 ml) at room temperature, and the mixture was stirred for 1 hour. After the reaction was completed, the mixture was neutralized with a saturated solution of NaHCO 3 and the solvent was removed. The residue was washed with water and then acetone / isopropyl ether (10: 1; 60), and the resulting precipitated product was filtered, which was dissolved in THF. The mixture was dried with MgSO, and the solvent was evaporated. The resulting powder was washed twice with hexane: ethyl acetate (10: 1, 50 ml) to give N- (4-hydroxymethylphenyl) -3- (4-methylphenyl) -6,7-dihydro-5H-benzocyclohepten- 6-carboxamide (26.8 g, 56%) as a white powder. NMR-aH (200MHz, CDC13) d: 2.10-2.22 (2H, m), 2.39 (3H, s), 2.71 (2H, broad t, J = 6.4), 2.84-2.91 (2H, m), 4.67 (2H, s), 7.20-7.26 (2H,), 7.33-7.51 (7H, m), 7.61 (2H, d, J = 8.4), 7.71 (1H, broad s).

Reference Example 170 To a solution of N- (4-hydroxymethylphenyl) -2- (4-methylphenyl) -6,7-dihydro-5H-benzocyclohepten-8-carboxamide (10.0 g, 26.1 mmol) and pyridine (0.1 ml) in chloroform (150 ml) a solution of thionyl chloride (3.4 ml, 39.2 mmol) in chloroform (90 ml) was added dropwise, and the mixture was stirred under a nitrogen atmosphere at room temperature for 17 hours. After the reaction was completed, water was added to the mixture, and the mixture was extracted with chloroform. The organic layer was washed with a saturated sodium chloride solution and dried with anhydrous magnesium sulfate. The solvent was evaporated, and the resulting powder was washed with hexane to give the N- (4-chloromethylphenyl) -2- (4-methylphenyl) -6,7-dihydro-5H-benzocyclohepten-8-carboxamide (10.2 g, 97 %) as a colorless powder.

NMR-1H (200MHz, CDC13) d: 2.05-2.21 (2H,), 2.40 (3H, s), 2.71 (2H, broad t, J = 6.4), 2.84-2.91 (2H, m), 4.58 (2H, s), 7.20-7.27 (2H, m), 7.35-7.52 (7H, m), 7.59-7.65 (2H, m), 7.71 (1H, broad s). Analysis for C26H24N0C1 • 0.25H20: Calculated: C; 76.83, H; 6.08, N; 3.45. Found: C; 76.55, H; 6.00, N; 3.53.

Reference Example 171 To a solution of tetrahydro-4H-pyran-4-one (60 g, 0.6 moles) and water (5 ml) in DMF (70 ml, 0.90 moles) were added formic acid (46 ml, 1.2 moles), and the mixture was stirred at 140 ° C for 23 hours. After the reaction was completed, the reflux apparatus was charged to the evaporation apparatus, a crude amine (74.6 g) was obtained by evaporation. e.g. 117 - 123 ° C (27 mm). To an aqueous solution (100 ml) of the crude amine (30 g) was added dropwise 6N HCl (5 drops), and the mixture was washed twice with dichloromethane. The aqueous layer was adjusted to pH 11 with sodium hydroxide. To the mixture was added NaCl and the mixture was extracted with dichloromethane three times. The organic layer was dried with potassium carbonate, and the solvent was evaporated. The residue was purified with evaporation to give N, N-dimethyl-N-tetrahydropyran-4-ylamine (10.4 g, 29%) as a colorless oil. e.g. 75-82 ° C (29 mm). NMR ^ H (200MHz, CDC13) d 1.40-1.82 (4H, m), 2.28 (6H, s), 2.25-2.40 (1H, m), 3.37 (2H, ddd, J = 11.8, 11.8 and 2. 2), 3.97-4.05 (2H, m).

Reference Example 172 To a suspension of 7- (4-methylphenyl) -2,3-dihydro-1-benzoxepin-4-carboxylic acid (0.6 g, 2.1 mmol) in tetrahydrofuran (10 ml) were added oxalyl chloride (0.33). ml, 4.3 mmol) and N, N-dimethylformamide (1 drop) at 0 ° C, and the mixture was stirred at room temperature for 2.5 hours. The solvent was evaporated, and the residue was dissolved in tetrahydrofuran (6 ml). To the mixture, 4- (tert-butyldimethylsilyloxymethyl) aniline (0.56 g, 2.4 mmol) and triethylamine (0.36 ml, 3.6 mmol) in tetrahydrofuran were added dropwise. (2 ml) at 0 ° C, and the mixture was stirred at room temperature for 16 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with a saturated sodium chloride solution and dried with magnesium sulfate. The solvent was evaporated, and the residue was subjected to column chromatography on silica gel. The crude amide (1.1 g) was obtained from the hexane: ethyl acetate = 5: 1 fractions. This product was dissolved in acetone (8 ml), and 6N hydrochloric acid was added dropwise to the mixture. The mixture was stirred for 1 hour. To the mixture were added 1% sodium hydrogen carbonate (100 ml) and diisopropyl ether (100 ml), and the precipitated product was filtered, which was dissolved in acetone. The mixture was dried with magnesium sulfate, and the solvent was evaporated. The resulting powder was recrystallized with acetone-diisopropyl ether to give N- (4-hydroxymethylphenyl) -7- (4-methylphenyl) -2,3-dihydro-l-benzoxepin-4-carboxamide (0.87 g) as colorless crystals. NMR -'- H (CDC13) d 2.39 (3H, s), 3.08 (2H, broad t, J = 4.4), 4.36 (2H, t, J = 4.4), 4.68 (2H, s), 7.06 (2H, d, J = 8.4), 7.18-7.61 (10H, m), 7.24 (2H, d, J = 8.4). Analysis for C25H23N03: Calculated: C; 77.90, H; 6.01, N; 3.63. Found: C; 77.91, H; 6.10, N; 3.55.

Reference Example 173 To a solution of N- (4-hydroxymethylphenyl) -7- (4-methylphenyl) -2, 3-dihydro-l-benzoxepin-4-carboxamide (412 mg, 1.07 mmol) and pyridine (1 drop) in chloroform (5 ml) thionyl chloride (0.14 ml, 1.61 mmol) was added dropwise and the mixture was stirred for 2 hours. The mixture was diluted with water and extracted with chloroform. The extract was washed with a saturated sodium chloride solution and dried with magnesium sulfate. The solvent was evaporated and the resulting powder was washed with hexane-ethyl acetate (1: 1) to give the N- (4-chloromethyl-phenyl) -7- (4-methylphenyl) -2,3-dihydro-l- benzoxepin-4-carboxamide (380 gm, 88%) as a colorless powder. p.f. 164 ° C NMR ^ H (CDC13) d 3.29 (3H, s), 3.07 (2H, t, J = 4.8), 4.36 (2H, t, J = 4.8), 4.59 (2H, s), 7.05 (1H, d, J = 8.2), 7.22-7.26 (2H, m), 7.36-7.52 (6H, m), 7.57-7.62 ( 3H, m). Analysis for C25H22N02C1: Calculated: C; 74.34, H; 5.49, N; 3.47. Found: C; 74.00, H; 5.42, N; 3.29.

Reference Example 174 To a suspension of 1,4-cyclohexanedione monoethylene ketal (3.82 g, 24.6 mmole) and dimethylamine hydrochloride (2.00 g, 24.6 mmole) in 1,2-dichloroethane (50 ml) were added dropwise triethylamine (4.2 ml, 29. 6 mmole) and DBU (1,8-diazabicyclo- [5.4.0] -7-undecene) (4.4 ml), and the mixture was stirred for 10 minutes. To the mixture was added triacetoxyborohydride (7.68 g, 34.4 mmol) and the mixture was stirred for 4.5 hours. The precipitated product was filtered, and the filtrate was concentrated to give a crude product (6.34 g), which was dissolved in water (10 ml). Concentrated hydrochloric acid (6 ml) was added dropwise to the mixture, and the mixture was stirred for 48 hours. The reaction mixture was diluted with water and washed twice with ether. The aqueous layer was made basic with sodium hydroxide and extracted with ether twice. The extract was washed with a saturated sodium chloride solution, dried with potassium carbonate and purified by evaporation to give 4-dimethylaminocyclohexanone (0.59 g, 17%). e.g. 142-5 ° C NMR-aH (CDC13) d 1.69-2.13 (4H, m), 2.32 (6H, s), 2.20-2.41 (2H, m), 2.44-2.64 (3H, m).

Reference Example 175 To a solution of 7- (4-ethoxyphenyl) -2,3-dihydro-l-benzoxepin-4-carboxylic acid (2.38 g) in THF (50 ml) were added oxalyl chloride (1.4 ml) and DMF (2 drops) at room temperature, and the mixture was stirred for 1 hour. Under reduced pressure, the solvent was evaporated and the residue was dissolved in THF (50 ml). To the mixture was added dropwise a solution of triethylamine (2.1 ml) and 4-aminobenzyloxy-tert-butyldimethylsilane (2.00 g) in THF (10 ml) at 0 ° C, and the mixture was stirred at room temperature for 18 hours . Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by column chromatography (ethyl acetate / hexane = 1: 4) to give pale yellow crystals (3.99 g), which were dissolved in acetone (50 ml). To the mixture was added 6N hydrochloric acid (1.3 ml) at room temperature, and the mixture was stirred for 1 hour. To the reaction mixture were added a solution of 5% sodium hydrogen carbonate (15 ml) and diisopropyl ether (100 ml). The precipitate was collected by filtration and washed with water and diisopropyl ether. The resulting solid was dissolved in THF, dried with magnesium sulfate and concentrated under reduced pressure to give crystals, which were recrystallized with THF to give 7- (4-ethoxyphenyl) -N- (4-hydroxymethylphenyl) -2 , 3-dihydro-l-benzoxepin-4-carboxamide (2.65 g) as colorless crystals, m.p. 208-210 ° C NMR-aH (200MHz, DMS0-d6) d: 1.35 (3H, t, J = 7.0 Hz), 2. 93-3.03 (2H,), 4.06 (2H, q, J = 7.0 Hz), 4.45 (2H, broad s), 5.01-5.18 (1H, m), 6.98-7.05 (3H, m), 7.25-7.34 (3H ,,), 7.49-7.71 (6H, m), 9.92 (1H, s). IR (KBr) v: 3363, 3290, 1659, 1612, 1525, 1493, 1242, 1227, 825 cm "1 Analysis for C26H25N04 Calculated: C, 75.16; H, 6.06; N, 3.37 Found: C, 75.16; H, 6.08; N, 3.31.

Reference Example 176 To a suspension of 7- (4-ethoxyphenyl) -N- (4-hydroxy-methylphenyl) -2, 3-dihydro-1-benzoxepin-4-carboxamide (2.55 g) and pyridine (2 drops) in Chloroform (50 ml) was added thionyl chloride (0.8 ml) at room temperature, and the mixture was stirred for 20 hours. To the reaction mixture was added water and then THF, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure to give a solid, which was dissolved in THF and ethyl acetate. The mixture was concentrated under reduced pressure to give crystals, which were collected by filtration and washed with diisopropyl ether to give the N- (4-chloromethylphenyl) -7- (4-ethoxyphenyl) -2,3-dihydro-l- benzoxepin-4-carboxamide (2.42 g) as colorless crystals, m.p. 187-189 ° C NMR-aH (200MHz, DMSO-d6) d: 1.35 (3H, t, J = 7.0 Hz), 2.93-3.04 (2H,), 4.06 (2H, q, J = 7.0 Hz), 4.23 -4.34 (2H, m), 4.74 (2H, s), 6.98-7.06 (3H,), 7.35-7.42 (3H, m), 7.52 (1H, dd, J = 8.4, 2.2 Hz), 7.59 (2H, d, J = 8.8 Hz), 7.70-7.74 (3H, m), 10.04 (1H, s). IR (KBr) v: 3400, 1659, 1610, 1525, 1493, 1242, 1047, 822 cm "1 Analysis for C26H24N03C1 Calculated: C, 71.97; H, 5.57; N, 3.23 Found: C, 71.96; H, 5.54; N, 3.04.

Working Example 227 (Production of Compound 227) To a solution of 7- (4-ethoxyphenyl) -N- [4- [N-methyl-N- (tetrahydropyran-4-yl) aminomethyl] phenyl] -2, 3- Dihydro-l-benzoxepin-4-carboxamide (111 mg) in DMF (5 ml) was added methyl iodide (0.04 ml) at room temperature, and the mixture was stirred for 8 hours. Under reduced pressure, the mixture was concentrated, and ethyl acetate was added to the residue to precipitate a solid, which was collected by filtration and recrystallized with ethanol-ethyl acetate to give dimethyl- [4-N- [ 7- (4-Ethoxyphenyl) -2,3-dihydro-l-benzoxepin-4-carbonyl] aminobenzyl] -4-tetrahydro-pyranylammonium (97 mg) as pale yellow crystals, m.p. 152-158 ° C NMR-aH (200MHz, CDC13) d: 1.41 (3H, t, J = 7.0 Hz), 1.68-1.98 (2H, m), 2.10-2.26 (2H, m), 2.94 (6H, s ), 2.98-3.08 (2H, m), 3.35-3.59 (3H, m), 3.96-4.16 (2H, m), 4.03 (2H, q, J = 7.0 Hz), 4.19-4.31 (2H, m), 4.84 (2H, s), 6.91 (2H, d, J = 8.8 Hz), 6.97 (1H, d, J = 8.4 Hz), 7.38 (1H, dd, J = 8.4, 2.2 Hz), 7.44-7.57 (5H , m), 7.69 (1H, d, J = 2.2 Hz), 7.80 (2H, d, J = 8.4 Hz), 8.01 (1H, s). IR (KBr) v: 3440, 1657, 1605, 1520, 1491, 1317, 1240 cm "1 Analysis for C33H39N204I • 1.0H2O Calculated: C, 58.93; H, 6.14; N, 4.16 Found: C, 58.86; H, 6.18; N, 4.19.

Working Example 228 (Production of Compound 228) To a solution of 7- (4-ethylphenyl) -N- [4- [N-methyl-N- (tetrahydropyran-4-yl) aminomethyl] phenyl] -2, 3- Dihydro-1-benzoxepin-4-carboxamide (125 mg) in DMF (5 ml) was added methyl iodide (0.04 ml) at room temperature, and the mixture was stirred for 20 hours. Under reduced pressure, the mixture was concentrated and ethyl acetate was added to the residue to precipitate the solid, which was collected by filtration and recrystallized with acetone-diethyl ether-ethanol-diethyl ether) to give dimethyl-4-iodide. N- [7- (4-Ethylphenyl) -2,3-dihydro-l-benzoxepin-4-carbonyl] aminobenzyl] -4-tetrahydro-pyranylammonium (68 mg) as pale yellow crystals. p.f. 156-160 ° C NMR-1H (200MHz, CDC13) d: 1.25 (3H, t, J = 7.6 Hz), 1.69- 1.93 (2H, m), 2.13-2.28 (2H,), 2.66 (2H, q, J = 7.6 Hz), 2. 95 (6H, s), 3.00-3.09 (2H,), 3.39-3.56 (2H, m), 4. 02-4.34 (5H, m), 4.86 (2H, s), 6.99 (1H, d, J = 8.4 Hz), 7. 18-7.28 (3H, m), 7.39-7.56 (5H, m), 7.69-7.73 (1H, m), 7. 79 (2H, d, J = 8.8 Hz), 8.78 (1H, s). IR (KBr) v: 3429, 1657, 1301, 1520, 1491, 1412, 1319, 1244, 827 cm "1 Analysis for C33H39N203I • 1 .OH2O Calculated: C, 60.37; H, 6.29; N, 4.27 Found: C, 60.40; H, 6.24; N, 4.10.

Working Example 229 (Production of Compound 229) To a solution of N- [4- [N-methyl-N- (tetrahydropyran-4-yl) aminomethyl] phenyl] -7- (4-trifluoromethylphenyl) -2, 3-dihydro-l-benzoxepin-4-carboxamide (113.6 mg) in DMF (5 ml) was added methyl iodide (0.04 ml) at room temperature, and the mixture was stirred for 24 hours. Under reduced pressure, the mixture was concentrated and ethyl acetate was added to the residue to precipitate a solid, which was collected by filtration and recrystallized with acetone-diethyl ether-ethanol-diethyl ether) to give the dimethyl iodide- [ 4-N- [7- (4-trifluoromethylphenyl) -2,3-dihydro-l-benzoxepin-4-carbonyl] aminobenzyl] -4-tetrahydro-pyranylammonium (99 mg) as pale yellow crystals. p.f. 213 ° C (dec.) NMR ^ H (200MHz, DMSO-d6) d: 1.42-1.66 (2H, m), 1.75-1.88 (2H, m), 2.55 (6H, s), 2.62-2.72 (2H, m), 2.94-3.35 (3H, m), 3.68-3.81 (2H, m), 3.96-4.08 (2H, m), 4.13 (2H, s), 6.80 (1H, d, J = 8.8 Hz), 7.05 (1H, s), 7.21 (2H, d, J = 8.4 Hz), 7.34-7.40 (1H, m), 7.44-7.63 (7H,), 9.89 (1H, s). IR (KBr) v: 3277, 1649, 1510, 1520, 1491, 1325, 1255, 1120, 843 cm "1 Analis is for C32H34N203F3I • 0 .2H20 Calculated: C, 56.35; H, 5.08; N, 4.11 Found: C, 56.21; H, 5.16; N, 4.11.

Reference Example 177 In 1, 2-dichloroethane (400 ml) was suspended p-nitro-benzylamine hydrochloride (30.8 g), 1,4-dichlohexanedione monoethylene ketal (25.4 g) and triethylamine (23 ml), and suspension sodium triacetoxy boron hydride (50.9 g) was added under cooling with ice. Under a nitrogen atmosphere, the mixture was stirred at room temperature for 2.5 hours. Under ice-cooling, 37% formalin (14.6 ml) and triacetoxy boron sodium hydride (50.9 g) were added to the mixture. Under a nitrogen atmosphere, the mixture was stirred at room temperature overnight. The mixture was neutralized with sodium hydrogen carbonate and extracted with 1,2-dichloroethanol. The organic layer was washed with a sodium chloride solution and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give a yellow solid (47.5 g), 44 g of which was dissolved in (660 ml). To the mixture reduced iron (32 g) was added little by little, and the mixture was stirred at room temperature overnight. The solvent was evaporated and ethyl acetate was added to the residue. The precipitate was filtered and the filtrate was made alkaline with potassium carbonate and extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated and the residue was purified by column chromatography on silica gel (ethyl acetate / triethylamine / methanol) to give 4 - ((N- (4,4-ethylenedioxycyclohexyl) -N- methyl) aminomethyl) aniline (34.1 g) as a brown oil. 1 H-NMR (CDCl 3) d: 1.36-1.93 (8H,), 2.17 (3H, s), 2.43-2.57 (1H, m), 3.46 (2H, s), 3.60 (2H, broad), 3.94 (4H, s), 6.64 (2H, d, J = 8.4Hz), 7.09 (2H, d, J = 8.4Hz). IR (pure) v: 2946, 1615CT. "1.

Working Example 230 (Production of Compound 230) In dichloromethane (400 ml) was suspended 7- (4-methylphenyl) -2,3-dihydro-l-benzoxepin-4-carboxylic acid (17.0 g), and the suspension was oxalyl chloride (10.3 ml) and dimethylformamide (catalytic amount) were added under cooling with ice. The mixture was stirred at room temperature for 2 hours, and the solvent was evaporated. The residue was dissolved in tetrahydrofuran (300 ml) and the mixture was added dropwise to a solution of 4 - ((N- (4,4-ethylenedioxycyclohexyl) -N-methyl) aminomethyl) -aniline (16.75 g) and triethylamine (25 ml) in tetrahydrofuran (200 ml), under cooling with ice. Under an argon atmosphere, the mixture was stirred at room temperature overnight, and the solvent was evaporated. Water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give crude crystals, which were recrystallized with ethyl acetate to give N- (4- ((N- (4,4-ethylenedioxy-cyclohexyl) -N-methyl) aminomethyl) phenyl ) -7- (4-methyl-phenyl) -2,3-dihydro-l-benzoxepin-4-carboxamide (17.1 g) as colorless crystals. p.f. 192-193 ° C. NMR-2H (CDC13) d: 1.48-1.86 (8H, m), 2.20 (3H, s), 2.39 (3H, s), 2.45-2.60 (1H,), 3.08 (2H, t, J = 4.5Hz) , 3.56 (2H, s), 3.95 (4H, s), 4.36 (2H, tr J = 4.5Hz), 7.06 (1H, d, J = 8.4Hz) 7.23-7.33 (4H, m), 7.44-7.56 ( 7H, m). IR (KBr) v: 2948, 1651er - "1. Analysis for C3H38N2? 4: Calculated: C, 75.81; H, 7.11; N, 5.20, Found: C, 75.51; H, 6.99; N, 5.29.

Working Example 231 (Production of Compound 231) In acetic acid (100 ml) and hydrochloric acid IN (200 ml) was dissolved N- (4- ((N- (4,4-ethylenedioxycyclohexyl) -N-methyl) aminomethyl) phenyl) -7- (4-methylphenyl) -2,3-dihydrole -benzoxepin-4-carboxamide (17.1 g), and the mixture was stirred at 100 ° C for 1.5 hours and concentrated. The residue was neutralized with IN sodium hydroxide and extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give crude crystals, which were recrystallized with ethyl acetate-methanol to give the N- (4- ((N- (4-oxocyclohexyl) -N-methyl) aminomethyl) phenyl-7- (4 -methylphenyl) -2, 3-dihydro-l-benzoxepin-4-carboxamide (12 g) as colorless crystals, mp 149-150 ° C. NMR-aH (CDC13) d: 1.78-2.13 (4H, m) 2.23 ( 3H, s), 2.25-2.35 (2H, m), 2.39 (3H, s), 2.45-2.57 (2H, m), 2.84-2.94 (1H, m), 3.08 (2H, t, J = 4.4Hz) , 3.59 (2H, s), 4.35 (2H, t, J = 4.4Hz), 7.06 (1H, d, J = 8.0Hz), 7.22-7.34 (4H, m), 7.43-7.57 (6H,), 7.65 (1H, s) .R { KBr) v: 2946, 1713cm "1. Analysis for C32H34N203 Calculated: C, 77.70; H, 6.93; N, 5.66. Found: C, 77.45; H, 6.78; N, 5.65.

Reference Example 178 To a mixture of methyl 2-bromo-6,7-dihydro-5H-benzocyclohepten-8-carboxylate (0.5 g), 4- (l-pyrrolidinyl) phenyl borate (0.37 g), potassium carbonate 1M (6 ml) and ethanol (6 ml) were added toluene (50 ml), and the mixture was stirred under an atmosphere of argon at room temperature for 30 minutes. To the mixture was added tetracistriphenylphosphine palladium (0.08 g), and the mixture was heated to reflux for 6 hours and extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with a column of silica gel (ethyl acetate / hexane) to give colorless crystals (0.48 g), which were dissolved in IN sodium hydroxide (15 ml) , methanol (50 ml) and tetrahydrofuran (50 ml). The mixture was stirred at room temperature overnight, concentrated and neutralized with hydrochloric acid to precipitate 2- (4- (l-pyrrolidinyl) phenyl) -6,7-dihydro-5H-benzocyclohepten-8-carboxylic acid ( 0.46 g) as pale yellow crystals, mp 242-243 ° C (dec.). NMR-aH (DMSO-d6) d: 1.93-2.00 (6H, m), 2.56 (2H, t, J = 5.8Hz), 2.76-2.82 (2H, m), 3.23-3.35 (4H, m), 6.60 (2H, d, J = 8.8Hz), 7.20 (1H, d, J = 8.2Hz), 7.44 (1H, dd, J = 1.0, 8.2Hz), 7.53 (2H, d, J = 8.8Hz), 7.56 (1H, "d, J = 1.0Hz), 7.69 (1H, s) Analysis for C22H23N02 • 0.1H20: Calculated: C, 78.82; H, 6.98; N, 4.18.

Found C, 78.92; H, 6.95; N, 4.15 Working Example 232 (Production of Compound 232) To a solution of 2- (4- (l-pyrrolidinyl) phenyl) -6,7-dihydro-5H-benzocyclohepten-8-carboxylic acid (0.45 g), 4- (N -methyl-N- (tetrahydropyran-4-yl) aminomethyl) aniline (0.33 g) and 1-hydroxybenzotriazole (0.18 g) in dimethylformamide (20 ml) were added l-ethyl-3- (3-dimethylamino-propyl) hydrochloride carbodiimide (0.39 g) under cooling with ice. Under a nitrogen atmosphere, the reaction mixture was cooled to room temperature, and 4-dimethylaminopyridine (catalytic amount) and tri-ethylamine (0.56 ml) were added to the mixture. The mixture was stirred overnight, emptied in water and extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with a column of silica gel (ethyl acetate / methanol / triethylamine) to give crude crystals, which were recrystallized with ethyl acetate-hexane to give 2- ( 4- (1-pyrrolidinyl) phenyl) -N- (4- ((N-tetrahydropyran-4-yl-N-methyl) aminomethyl) phenyl) -6,7-dihydro-5H-benzocyclohepten-8-carboxamide (0.28 g ) as colorless crystals. p.f. 124-125 ° C. NMR-aH (CDC13) d: 1.66-1.77 (4H, m), 1.99-2.06 (4H, m), 2. 11-2.18 (2H, m), 2.21 (3H, s), 2.55-2.75 (3H, m), 2. 84-2.90 (2H, m), 3.30-3.44 (6H,), 3.58 (2H, s), 4. 00-4.14 (2H, m), 6.64 (2H, d, J = 9.0Hz), 7.19 (1H, d, J = 8.0Hz), 7.31 (2H, d, J = 8.5Hz), 7.39-7.51 (4H, m), 7.57 (2H, d, J = 8.5Hz), 7.64 (1H, s). IR (KBr) v: 2946, 2843, 1651, ldllcm "1. Analysis for C35H4? N302 • 0.2H20 Calculated: C, 77.95; H, 7.74; N, 7.79. Found: C, 77.76; H, 7.59; N, 7.79.

Reference Example 179 In 1, 2-dichloroethane (50 ml), p-nitro-benzaldehyde (5 g) and 3-amino-1-propanol (2.5 g) were dissolved and triacetoxy boron sodium hydride was added to the mixture. (9.8 g) under cooling with ice. Under a nitrogen atmosphere, the mixture was stirred at room temperature for 5 hours. Under cooling with ice, 37% formalin (3 ml) and triacetoxy boron sodium hydride (9.8 g) were added to the mixture. Under a nitrogen atmosphere, the mixture was stirred at room temperature overnight. Water was added to the mixture and the mixture was concentrated, neutralized with aqueous sodium hydroxide and extracted with ethyl acetate. The organic layer was washed with water and a sodium chloride solution and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with a column of silica gel (ethyl acetate / methanol / triethylamine) to give a yellow oil (5.0 g), 2.5 g of which was dissolved in ethanol ( 50 ml) and the catalytic hydrogenation was carried out with palladium on carbon 5% (0.2 g) for 1.5 hours.

The catalyst was filtered, and the solvent was evaporated. The residue was purified with a column of silica gel (ethyl acetate / methanol / triethylamine) to give 4- ((N-3-hydroxypropyl-N-methyl) aminomethyl) -aniline (1.5 g) as a pale yellow oil. NMR ^ H (CDC13) d: 1.67-1.78 (2H, m), 2.21 (3H, s), 2.62 (2H, t, J = 5.5Hz), 3.41 (2H, s), 3.65 (2H, broad), 3.77 (2H, t, J = 5.1Hz), 6.65 (2H, d, J = 8.4Hz), 7.07 (2H, d, J = 8.4Hz). IR (pure) v: 3347, 2948, 2799, ldlScm "1.

Working Example 233 (Production of Compound 233) In dichloromethane (5 ml) was suspended 2- (4-methyl-phenyl) -6,7-dihydro-5H-benzocyclohepten-8-carboxylic acid (0.3 g), and to suspension Oxalyl chloride (0.28 ml) and dimethylformamide (catalytic amount) were added under cooling with ice. The mixture was stirred at room temperature for 1.5 hours, and the solvent was evaporated. The residue was dissolved in tetrahydrofuran (15 ml) and the mixture was added dropwise to a solution of 4- ((N- (3-hydroxypropyl-N-methyl) aminomethyl) aniline (0.23 g) and triethylamine (0.45 ml) in tetrahydrofuran (15 ml), under ice cooling Under a nitrogen atmosphere, the mixture was stirred at room temperature overnight, and the solvent was evaporated, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution and dried with anhydrous magnesium sulfate.With reduced pressure, the solvent was evaporated, and the residue was purified with a column of silica gel (ethyl acetate methanol / triethylamine) to give crude crystals, which were recrystallized with ethyl acetate-hexane to give the N- (4- ((N-3-hydroxypropyl-N-methyl) aminomethyl) phenyl) -2- (4- methylphenyl) -6,7-dihydro-5H-benzocyclohepten-8-carboxamide (0.32 g) as colorless crystals, mp 139-140 ° C. NMR-1H (CDC13) d: 1.72-1.81 (2H, m), 2.13-2.19 (2H, m), 2.25 (3H, s), 2.40 (3H, s), 2.63-2.75 (4H, m) , 2.86-2.92 (2H, m), 3.53 (2H, s), 3.79 (2H, t, J = 5.4Hz), 7.21-7.32 (3H, m), 7.42-7.52 (6H, m), 7.58 (2H , d, J = 8.4Hz), 7.66 (1H, s). IR (KBr) v: 2936, ldSlcm "1. Analysis for C3oH34 202 • O.5H20: Calculated: C, 77.72; H, 7.61; N, 6.04 Found: C, 77.94; H, 7.62; N, 6.15.

Working Example 234 (Production of Compound 234) In dichloromethane (12 ml) the acid was suspended 7- (4-methyl-phenyl) -2,3-dihydro-l-benzoxepin-4-carboxylic acid (0.4 g), and to the suspension were added oxalyl chloride (0.37 ml) and dimethylformamide (catalytic amount) under ice-cooling . The mixture was stirred at room temperature for 2 hours, and the solvent was evaporated. The residue was dissolved in tetrahydrofuran (15 ml) and the mixture was added dropwise to a solution of 4- ((N-3-hydroxy-propyl-N-methyl) aminomethyl) aniline (0.33 g) and triethylamine (0.6 ml). ) in tetrahydrofuran (15 ml), under cooling with ice. Under a nitrogen atmosphere, the mixture was stirred at room temperature overnight, and the solvent was evaporated. Water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with a column of silica gel (ethyl acetate / methanol / triethylamine) to give crude crystals, which were recrystallized with ethyl acetate-hexane to give the N- (4- ((N-3-hydroxypropyl-N-methyl) aminomethyl) phenyl) -7- (4-methylphenyl) -2,3-dihydro-l-bezoxepin-4-carboxamide (0.39 g) as colorless crystals. p.f. 119-120 ° C. NMR-aH (CDC13) d: 1.68-1.80 (2H, m), 2.24 (3H, s), 2.39 (3H, s), 2.65 (2H, t, J = 5.8Hz), 3.07 (2H, t, J = 4.6Hz), 3.52 (2H, s), 3.77 (2H, t, J = 5.2Hz), 4.35 (2H, t, J = 4.6Hz), 7.05 (1H, d, J = 8.4Hz), 7.22- 7.31 (3H,), 7.43-7.52 (5H, m), 7.57 (2H, d, J = 8.4Hz), 7.78 (1H, s). IR (KBr) v: 3287, 2948, 1649 cm "1. Analysis for C29H32N203 • 0.2H20: Calculated: C, 75.69; H, 7.10; N, 6.09. Found: C, 75.58; H, 6.93; N, 6.08.

Working Example 235 (Production of Compound 235) In dichloromethane (10 ml) was suspended 7- (4-methyl-phenyl) -2,3-dihydro-l-benzoxepin-4-carboxylic acid (0.3 g), and the oxalyl chloride (0.27 ml) and dimethylformamide (catalytic amount) were added under cooling with ice. The mixture was stirred at room temperature for 2 hours, and the solvent was evaporated. The residue was dissolved in tetrahydrofuran (15 ml) and the mixture was added dropwise to a solution of 4- (N-methyl-N- (tetrahydropyran-4-yl) aminomethyl) aniline (0.25 g) and triethylamine (0.42 ml). ) en-tetrahydrofuran (15 ml), under cooling with ice. Under a nitrogen atmosphere, the mixture was stirred at room temperature overnight, and the solvent was evaporated. Water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give crude crystals, which were recrystallized with ethyl acetate-hexane to give 7- (4-methylphenyl) -N- (4- ((N-tetrahydropyran-4-yl-N) methyl) aminomethyl) phenyl) -2,3-dihydro-l-benzothiepin-4-carboxamide (0.45 g) as colorless crystals. p.f. 177-178 ° C. NMR ^ H (CDC13) d: 1.63-1.77 (4H, m), 2.21 (3H, s), 2.40 (3H, s), 2.57-2.70 (1H, m), 3.08 (2H, t, J = 5.8 Hz ), 3.26-3.44 (4H, m), 3.57 (2H, s), 4.01-4.11 (2H, m), 7.24-7.34 (3H, m), 7.40-7.57 (8H,), 7.70 (1H, s) . IR (KBr) V: 2949, 1651cm_1.

Analysis for C3? H34N202S • O.3H20: Calculated: C, 73.86; H, 6.92; N, 5.56 Found: C, 73.93; H, 6.73; N, 5.82 Working Example 236 (Production of Compound 236) In dichloromethane (6 ml), 2- (4-methylphenyl) -6,7-dihydro-5H-benzocyclohepten-8-carboxylic acid (0.25 g) was suspended and the suspension was suspended. oxalyl chloride (0.24 ml) and dimethylformamide (catalytic amount) were added under cooling with ice. The mixture was stirred at room temperature for 1.5 hours, and the solvent was evaporated. The residue was dissolved in tetrahydrofuran (15 ml, and the mixture was added dropwise to a solution of 4- ((N-methyl-N- (pentan-3-yl)) aminomethyl) aniline (0.2 g) and triethylamine ( 0.38 ml) in tetrahydrofuran (15 ml), under ice cooling Under a nitrogen atmosphere, the mixture was stirred at room temperature for 5 hours, and the solvent was evaporated, water was added to the residue, and the mixture was extracted with water. Ethyl acetate The organic layer was washed with water and a saturated sodium chloride solution and dried with anhydrous magnesium sulfate.With reduced pressure, the solvent was evaporated to give crude crystals, which were recrystallized with ethyl acetate. hexane to give the N- (4- ((N-methyl-N- (pentan-3-yl)) aminomethyl) phenyl) -2- (4-methylphenyl) -6,7-dihydro-5H-bezocyclohepten-8- carboxamide (0.23 g) as colorless crystals, mp 112-113 ° C. NMR ^ H (CDC13) d: 0.94 (6H, t, J = 7.3Hz), 1.26-1.54 (4H, m), 2.14 (3H, s) ), 2.14-2.32 (3H,), 2.40 (3 H, s), 2.72 (2H, t, J = 6.4Hz), 2.86-2.91 (2H, m), 3.55 (2H, s), 7.21- 7.27 (3H, m), 7.31-7.56 (8H, m), 7.62 (1H, s) ). IR (KBr) v: 2930, 1651cm_1. Analysis for C32H38N20: Calculated: C, 82. 36; H, 8 twenty-one; N, 6 00 Found: C, 82.30; H, 8.05; N, 5.90.

Reference Example 180 To the mixture of 3- (4-methylphenyl) -6, 7, 8, 9-tetrahydro-5H-benzocycloheptan-5-one (0.5 g), potassium carbonate (1.65 g) and 18- crown-6 (1.5 g) was added dimethyl sulfoxide (10 ml). Under a carbon dioxide atmosphere, the mixture was stirred at room temperature for 20 hours, poured into water, acidified with hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and subjected again to extraction with sodium hydroxide and water. The aqueous layer was collected, acidified with hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution and dried with anhydrous magnesium sulfate. The solvent was evaporated to precipitate colorless crystals (0.42 g), which were filtered with hexane and dissolved in ethanol (40 ml). To the mixture was added boron sodium hydride (0.54 g), and the mixture was stirred at room temperature for 1 hour. To the mixture was added water, and the mixture was concentrated, acidified with hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution and dried with anhydrous magnesium sulfate. The solvent was evaporated to give colorless crystals (0.41 g), which were dissolved in 80% formic acid (40 ml). The mixture was stirred at 100 ° C for 2.5 hours and concentrated. Water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution and dried with anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified with a column of silica gel (ethyl acetate / hexane) to give 2- (4-methylphenyl) -6,7-dihydro-5H-benzocyclohepten-8-carboxylic acid (0.14. g) as colorless crystals.

NMR ^ H (CDCl 3) d: 2.04-2.18 (2H, m), 2.40 (3H, s), 2.70 (2H, t, J = 6.8Hz), 2.86-2.91 (2H, m), 7.21-7.28 (3H ,), 7.44-7.56 (4H, m), 7.91 (1H, s).

Reference Example 181 In dimethyl sulfoxide (15 ml), 3- (4-methylphenyl) -6,7,8,9-tetrahydro-5H-benzocycloheptan-5-one (0.5 g) and 18-crown-6 were dissolved. (1.05 g). Under cooling with ice, potassium t-butoxide (1.65 g) was added to the solution. Under a carbon dioxide atmosphere, the mixture was stirred at room temperature for 3 hours, poured into water, acidified with hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and subjected again to extraction with sodium hydroxide and water. The aqueous layer was collected, acidified with hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution and dried with anhydrous magnesium sulfate. The solvent was evaporated to precipitate the colorless crystals (0.47 g), which were filtered with hexane and dissolved in ethanol (40 ml). To the mixture was added boron sodium hydride (0.58 g), and the mixture was stirred at room temperature for 1 hour. To the mixture was added water, and the mixture was concentrated, acidified with hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution and dried with anhydrous magnesium sulfate. The solvent was evaporated to precipitate the colorless crystals (0.46 g), which were filtered with hexane. To the crystals 80% formic acid (10 ml) was added, and the mixture was heated to reflux for 1.5 hours. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and subjected again to extraction with sodium hydroxide and water. The aqueous layer was collected, acidified with hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution and dried with anhydrous magnesium sulfate. The solvent was evaporated to precipitate 2- (4-methyl-phenyl) -6,7-dihydro-5H-benzocyclohepten-8-carboxylic acid (0.22 g) as colorless crystals. NMR-1H (CDC13) d: 2.04-2.16 (2H, m), 2.40 (3H, s), 2.69 (2H, t, J = 6.7Hz), 2.86-2.91 (2H, m), 7.21-7.278 (3H , m), 7.44-7.56 (4H, m), 7.89 (1H, s).

Working Example 237 (Production of Compound 237) In dimethylformamide (100 ml) was dissolved 7- (4-methylphenyl) -N- (4- ((N- (4-oxocyclohexyl) -N-methyl) -aminomethyl) -phenyl 2, 3-dihydro-1-benzoxepin-4-carboxamide (7.5 g), and methyl iodide (4.7 ml) was added to the mixture. Under a nitrogen atmosphere, the mixture was stirred at room temperature overnight. The solvent was evaporated, and acetone was added to the residue to give the dimethyl-N- (7- (4-methylphenyl) -2,3-dihydro-l-benzoxepin-4-carbonyl) -4-aminobenzyl) iodide. - (4-oxocyclohexyl) ammonium (8.9 g) as colorless crystals. NMR ^ H (DMSO-de) d: 2.09-2.24 (2H, m), 2.34 (3H, s), 2.41-2.61 (6H, m), 2.97 (6H, s), 2.97-3.00 (2H, m) , 3.79-3.90 (1H, m), 4.31 (2H, t, J = 4.4Hz), 4.56 (2H, s), 7.07 (1H, d, J = 8.4Hz), 7.27 (2H, d, J = 8.2 Hz), 7.37 (1H, s), 7.55-7.60 (5H, m), 7.75 (1H, d, J = 2.2Hz), 7.88 (2H, d, J = 8.8Hz), 10.20 (1H, s).

Working Example 238 (Production of Compound 238) In dimethylformamide (5 ml) was dissolved in 2- (4- (l-pyrrolidinyl) phenyl) -N- (4- ((N-tetrahydropyran-4-yl-N-methyl) ) aminomethyl) phenyl) -6,7-dihydro-5H-benzo-cyclohepten-8-carboxamide (0.15 g), and methyl iodide (0.02 ml) was added to the mixture. Under a nitrogen atmosphere, the mixture was stirred at room temperature overnight. To the mixture was added ethyl acetate and the crude crystal was filtered. The crude crystal was recrystallized from ethanol-ethyl acetate to give dimethyl- (N- (2- (4- (l-pyrrolidinyl) phenyl) -6,7-dihydro-5H-benzocyclohepten-8-carbonyl iodide. -aminobenzyl) -4-tetrahydropyranylammonium (0.05 g) as a pale brown powder. NMR-aH (DMSO-de) d: 1.80-2.20 (10H, m), 2.63 (2H, t, J = 5.6Hz), 2.81-2.84 (2H, m), 2.88 (6H, s), 3.24-3.44 (6H, m), 3.54-3.65 (1H, m), 4.02-4.11 (2H, m), 4.46 (2H, s), 6.62 (2H, d, J = 9.0Hz), 7.25 (1H, d, J = 7.8Hz), 7.36-7.60 (7H, m), 7.88 (2H, d, J = 8.4Hz), 10.22 (1H, s). IR (KBr) v: 2967, 1663, 1609cm_1. Analysis for C36H44IN302 • H20: Calculated: C, 62.15; H, 6.66; N, 6.04. Found: C, 61.89; H, 6.30; N, 5.97.

Working Example 239 (Production of Compound 239) In dimethylformamide (5 ml) was dissolved N- (4- ((N-3-hydroxypropyl-N-methyl) aminomethyl) phenyl) -2- (4-methyl-phenyl) - 6,7-dihydro-5H-benzocyclohepten-8-carboxamide (0.2 g) and methyl iodide (0.04 ml) was added to the mixture. Under a nitrogen atmosphere, the mixture was stirred at room temperature overnight. The solvent was evaporated, and ethyl acetate was added to the residue to give crude crystals, which were filtered and recrystallized with ethanol-ethyl acetate to give the N- (3-hydroxypropyl) -N, N-dimethyl-iodide ( N- (2- (4-methylphenyl) -6,7-dihydro-5H-benzo-cyclohepten-8-carbonyl) -4-aminobenzyl) ammonium (0.05 g) as colorless crystals. p.f. 210-213 ° C. NMR-aH (CDCI3 + CD3OD) d: 2.00-2.20 (4H, m), 2.40 (3H, s), 2. 71 (2H, t, J = 6.6Hz), 2.87-2.92 (2H, m), 3.10 (6H, s), 3. 54-3.65 (2H, m), 3.73 (2H, t, J = 5.3Hz), 4.63 (2H, s), 7. 22-7.27 (3H, m), 7.43-7.58 (7H, m), 7.80 (2H, d, J = 8.4Hz), 9.21 (1H, s). IR (KBr) V: 3337, 2934, ldSScm "1. Analysis for C3? H37IN202 • 0 .5H20: Calculated: C, 61. 49; H, 6. 33; N, 4. 63. Found: C, 61.55; H, 6.22; N, 4.74.

Working Example 240 (Production of Compound 240) In dimethylformamide (5 ml) was dissolved N- (4- ((N-3-hydroxypropyl-N-methyl) aminomethyl) phenyl) -7- (4-methyl-phenyl) - 2,3-dihydro-l-benzoxepin-4-carboxamide (0.14 g), and methyl iodide (0.04 ml) was added to the mixture. Under a nitrogen atmosphere, the mixture was stirred at room temperature overnight. The solvent was evaporated and ethyl acetate was added to the residue to give crude crystals, which were filtered and recrystallized with ethanol-ethyl acetate to give dimethyl-3-hydroxypropyl- (N- (7- (4-methylphenyl) iodide. ) -2, 3-dihydro-l-benzoxepin-4-carbonyl) -4-aminobenzyl) ammonium (0.15 g) as colorless crystals, mp 216-219 ° C. NMR-1H (CDC13 + CD30D) d: 2.00-2.20 (2H, m), 2.40 (3H, s), 3.06-3.10 (2H,), 3.10 (6H, s), 3.51-3.61 (2H, m), 3.73 (2H, t, J = 5.4Hz), 4.37 (2H, t, J = 4.6Hz), 4.61 (2H, s), 7.07 (1H, d, J = 8.4Hz), 7.25 (2H, d, J = 8.2Hz), 7.46-7.59 (7H, m), 7.81 (2H, d, J = 8.2Hz), 9.54 (1H, s). IR (KBr) v: 3306, ldSlcm "1. Analysis for C3oH35l 203 • 0.5H20: Calculated: C, 59.31; H, 5.97; N, 4.61, Found: C, 59.36; H, 5.95; N, 4.75.

Working Example 241 (Production of Compound 241) In dimethylformamide (5 ml) was dissolved 7- (4-methylphenyl) -N- (4- ((N-tetrahydropyran-4-yl-N-methyl) -aminomethyl) - phenyl) -2,3-dihydro-l-benzothiepin-4-carboxamide (0.19 g), and methyl iodide (0.03 ml) was added to the mixture. Under a nitrogen atmosphere, the mixture was stirred at room temperature overnight. The solvent was evaporated, and ethyl acetate was added to the residue to give crude crystals, which were filtered and recrystallized with ethanol-hexane to give dimethyl- (N- (7- (4-methyl-phenyl) -2-iodide. , 3-dihydro-l-benzothiepin-4-carbonyl) -4-aminobenzyl) -N- (4-tetrahydropyranyl) ammonium (0.2 g) as colorless crystals. p.f. 220-222 ° C (dec.). NMR-1H (DMSO-d6) d: 1.78-1.95 (2H, m), 2.05-2.20 (2H, m), 2.35 (3H, s), 2.88 (6H, s), 2.95-3.05 (2H, m) , 3.21- 3.32 (4H, m), 3.50-3.65 (1H, m), 4.05-4.15 (2H, m), 4.46 (2H, s), 7.29 (2H, d, J = 8.0Hz), 7.46-7.63 (7H, m), 7.81-7.90 (3H, m), 10.34 (1H, s). IR (KBr) v: 2924, 1657cm_1.

Working Example 242 (Production of Compound 242) In dimethylformamide (5 ml) was dissolved N- (4- ((N-methyl-N- (pentan-3-yl)) aminomethyl) phenyl) -2- (4- methylphenyl) -6,7-dihydro-5H-benzocyclohepten-8-carboxamide (0.17 g), and methyl iodide (0.08 ml) was added to the mixture. Under a nitrogen atmosphere, the mixture was stirred at 45 ° C overnight. The solvent was evaporated, and ethyl acetate was added to the residue to give crude crystals, which were filtered and recrystallized with ethanol-ethyl acetate to give the dimethyl- (N- (2- (4-methyl-phenyl) iodide ) -6,7-dihydro-5H-benzocyclohepten-8-carbonyl) -4-aminobenzyl) -N- (pentan-3-yl) ammonium (0.15 g) as colorless crystals, mp 190-194 ° C (dec.).

RM ^ H (CDCl 3) d: 1.15 (6H, t, J = 7.4Hz), 1.67-1.82 (2H, m 2.05-2.25 (4H, m), 2.39 (3H, s), 2.73 (2H, t, J = 6.6Hz), 2.80-2.90 (2H, m), 3.11 (6H, s), 3.40-3.51 (1H, m), 4.91 (2H, s), 7.18-7.26 (3H, m), 7.44 (1H , dd, J = 1.8, 8.4Hz), 7.49 (2H, d, J = 8.4Hz), 7.57-7.62 (4H, m), 7.80 (2H, d, J = 8.4Hz), 8.35 (1H, s) . IR (KBr) V 2936, ldSgcm "1. Analysis for C33H4" IN20 - 0.5H20: Calculated: C, 64.18; H, 6.85; N, 4.54 Found: C, 63.84; H, 6.73; N, 4.47.

Reference Example 182 In DMF (50 ml) N-cyclohexyl-N-methylamine (12.5 g, 0.11 mole) was dissolved, and to the solution were added potassium carbonate (27.6 g, 0.20 mole) and 4-nitrobenzyl bromide (21.6 g). g, 0.10 moles). The mixture was stirred at room temperature for 5 hours. Under reduced pressure, the reaction mixture was concentrated. Ethyl acetate was added to the residue, and the mixture was extracted with water. The ethyl acetate layer was washed with a saturated sodium chloride solution, dried with MgSO 4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate / hexane) to give N-cyclohexyl-N-methyl-N- (4-nitrobenzyl) amine (24.8 g).

NMR ^ H (200MHz, CDC13) d: 1.0-1.95 (10H, m), 2.19 (3H, s), 3.66 (2H, s), 7.51 (2H, d, J = 8.8Hz), 8.17 (2H, d) , J = 8.8Hz).

Reference Example 183 To a solution of N-cyclohexyl-N-methyl-N- (4-nitrobenzyl) amine (12.4 g, 50.0 mmol) in methanol (250 ml) were added nickel bromide (1.09 g, 5.0 mmol) and then sodium borohydride (7.57 g, 200 mmol) at 0 ° C, and the mixture was stirred at room temperature for 30 minutes. To the mixture were added nickel bromide (0.55 g, 2.5 mmol) and then boron sodium hydride (3.78 g, 100 mmol) at 0 ° C, and the mixture was stirred at room temperature for 30 hours. Water (100 ml) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. Ethyl acetate was added to the residue, and the insoluble material was filtered with Celite. The filtrate was washed with ethyl acetate and the ethyl acetate layer was dried with MgSO, and concentrated under reduced pressure. The residue was washed with hexane to give 4- (N-cyclohexyl-N-methylaminoethyl) aniline (3.99 g, 37%). NMR- ^ H (200 MHz, CDC13) d: 1.0-1.95 (10H, m), 2.17 (3H, s), 2.3-2.55 (1H, m), 3.46 (2H, s), 3.59 (2H, broad s ), 6.65 (2H, d, J = 8.5Hz), 7.10 (2H, d, J = 8.5Hz).

Working Example 243 (Production of Compound 243) To a solution of 7- (4-methylphenyl) -2,3-dihydro-l-benzoxepin-4-carboxylic acid (0.28 g), 4- (N-cyclohexyl-N- methylaminomethyl) aniline (0.24 g) and 1-hydroxybenzo-triazole (0.15 g) in dimethylformamide (10 ml) was added l-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.29 g) under ice-cooling. Under a nitrogen atmosphere, the mixture was cooled to room temperature and 4-dimethylaminopyridine (3 mg) and triethylamine (0.42 ml) were added to the mixture. The mixture was stirred for 20 hours, poured into water and extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated and the residue was washed with ethyl acetate and dried to give N- (4- (N-cyclohexyl-N-methylamomethyl) phenyl) -7- (4-methylphenyl) -2 , 3-dihydro-l-benzoxepin-4-carboxamide (0.40 g). NMR-aH (CDC13) d: 1.0-1.95 (10H, m), 2.20 (3H, s), 2.35-2.55 (1H, m), 2.40 (3H, s), 3.0-3.15 (2H, m), 3.56 (2H, s), 4.3-4.45 (2H, m), 7.06 (1H, d, J = 8.4Hz), 7.2-7.6 (11H, m).

Working Example 244 (Production of Compound 244) In dimethylformamide (7 ml) was dissolved N- (4- (N-cyclohexyl-N-methylaminomethyl) phenyl) -7- (4-methyl-phenyl) -2, 3-dihydro -l-benzoxepin-4-carboxamide (0.15 g), and to the mixture was added methyl iodide (0.06 ml). Under a nitrogen atmosphere, the mixture was stirred at room temperature for 20 hours. The solvent was evaporated and ethyl acetate was added to the residue to give the crude crystals, which were filtered and recrystallized with ethanol to give the iodide of N-cyclohexyl-N, N-dimethyl-N- ((7- (4 -methylphenyl) -2,3-dihydro-l-benzoxepin-4-carbonyl) -4-aminobenzyl) ammonium (0.15 g). NMR-H (CDC13) d: 1.0-1.8 (6H, m), 1.9-2.05 (2H, m), 2.45 (2H, m), 2.36 (3H, s), 2.95-3.15 (8H, m), 3.45-3.7 (1H, m), 4.2-4.35 (2H, m), 4.83 (2H, s), 6.99 (1H, d, J = 8.4Hz), 7.21 (2H, d, J = 7.6Hz), 7.35-7.6 ( 6H, m), 7.74 (1H, d, J = 2.2Hz), 7.85 (2H, d, J = 8.6Hz), 8.79 (1H, s). IR (KBr) v: 1659, 1609, 1593, 1518, 1493 cm "1.

Working Example 245 (Production of Compound 245) In dimethylformamide (5 ml) was dissolved N- (4- (N-methyl-N- (tetrahydropyran-4-yl) aminomethyl) phenyl) -7- (4-morpholino-phenyl) ) -2, 3-dihydro-l-benzoxepin-4-carboxamide (0.20 g), and to the mixture was added methyl iodide (0.03 ml). Under a nitrogen atmosphere, the mixture was stirred at room temperature for 32 hours. The solvent was evaporated, and the residue was purified by column chromatography on silica gel (dichloromethane / methanol). The desired fraction was concentrated, and ethyl acetate was added to the residue. The iuble material was filtered and recrystallized from ethanol to give the dimethyl-N- (7- (4-morpholinophenyl) -2,3-dihydro-l-benzoxepin-4-carbonyl) -4-aminobenzyl-N- iodide ( 4-tetrahydropyranyl) ammonium (0.18 g). NMR-1H (CDC13) d: 1.6-2.0 (2H, m), 2.1-2.3 (2H, m), 2.92 (6H, s), 2.95-3.2 (6H, m), 3.35-3.55 (2H,), 3.8-3.9 (4H, m), 4.0-4.35 (5H, m), 4.84 (2H, s), 6.85-7.05 (3H, m), 7.35-7.85 (9H, m), 8.92 (1H, s). IR (KBr) v: 1659, 1609, 1520, 1495cm "1.

Reference Example 184 In tetrahydrofuran (100 ml), 1,2-methylenedioxy-4-bromobenzene (24.0 g) was dissolved, and n-butyllithium (1.6M hexane solution, 82 ml) was added dropwise to -55 to the mixture. ° C or less. The mixture was stirred at -70 ° C or less for 30 minutes. The resulting solution was added dropwise to a solution of trimethyl borate (18.6 g) in tetrahydrofuran (50 ml) at -60 ° C or less through a cannula, and the mixture was stirred at -70 ° C or less for 1 hour and then for 2 hours while the mixture is heated to room temperature. To the reaction mixture were added IN hydrochloric acid (130 ml) and diethyl ether (150 ml), and the organic layer was separated. The organic layer was washed with water and a saturated sodium chloride solution and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated. The residue was washed with diisopropyl ether to give 3,4-methylenedioxyphenyl borate (6.79 g) NMR-aH (DMSO-de) d: 5.99 (2H, s), 6.8-6.95 (1H, m), 7.25-7.45 ( 2H, m).

Reference Example 185 To a mixture of methyl 7-bromo-2,3-dihydro-l-benzoxepin-4-carboxylate (0.57 g), 3,4-methylenedioxy-phenyl borate (0.47 g) and sodium carbonate ( 0.42 g) water (2 ml) and 1,2-dimethoxyethane (12 ml) were added. Under an argon atmosphere, the mixture was stirred at room temperature for 30 minutes, and tetracistriphenylphosphinepalladium (0.16 g) was added to the mixture. The mixture was stirred at 80 ° C for 14 hours and extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with a column of silica gel (ethyl acetate / hexane) to give 7- (3,4-methylenedioxyphenyl) -2,3-dihydro-l-benzoxepin. Methyl-4-carboxylate (0.43 g). NMR-aH (CDC13) d: 2.95-3.10 (2H,), 3.83 (3H, s), 4.25-4.35 (2H, m), 6.01 (2H, s), 6.87 (1H, d, J = 8.6Hz) , 6.95-7.10 (3H, m), 7.40 (1H, dd, J = 8.4, 2.4Hz), 7.47 (1H, d, J = 2.2Hz), 7.65 (1H, s).

Reference Example 186 To methyl 7- (3, 4-methylenedioxyphenyl) -2,3-dihydro-l-benzoxepin-4-carboxylate (0.40 g) were added methanol (5 m) and 1N sodium hydroxide (3.7 ml) , and the mixture was stirred at room temperature for 20 hours. INN hydrochloric acid (3.7 ml) was added to the mixture and the mixture was concentrated under reduced pressure. The precipitate was washed with water and diethyl ether and dried under reduced pressure to give 7- (3,4-methylene-dioxyphenyl) -2,3-dihydro-l-benzoxepin-4-carboxylic acid (0.32 g). NMR-1H (DMSO-de) d: 2.80-2.95 (2H, m), 4.15-4.35 (2H, m), 6.05 (2H, s), 6.97 (1H, d, J = 8.1Hz), 7.01 (1H , d, J = 8.4Hz), 7.16 (1H, dd, J = 8.1, 1.7Hz), 7.29 (1H, d, J = 1.7Hz), 7.53 (2H, dd, J = 8.4, 2.3Hz), 7.63 (1H, s), 7.74 (1H, d, J = 2.3Hz).

Working Example 246 (Production of Compound 246) To a solution of 7- (3,4-methylenedioxyphenyl) -2,3-dihydro-1-benzoxepin-4-carboxylic acid (0.14 g), 4- (N-methyl- N- (tetrahydropyran-4-yl) aminomethyl) aniline (0.11 g) and 1-hydroxy-benzotriazole (0.15 g) in dimethylformamide (10 ml) were added l-ethyl-3- (3-dimethyl-aminopropyl) carbodiimide hydrochloride (0.13 g) under cooling with ice. Under a nitrogen atmosphere, the reaction mixture was warmed to room temperature. To the mixture were added 4-dimethylaminopyridine (3 mg) and triethylamine (0.19 ml), and the mixture was stirred for 18 hours, poured into water and extracted with ethyl acetate. The organic layer was washed with water and a chloride solution of. saturated sodium and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated and the residue was purified with a column of silica gel (ethyl acetate) to give 7- (3,4-methylenedioxyphenyl) -4- (N-methyl-N- (tetrahydropyran- 4-yl) aminomethyl) phenyl) -2,3-dihydro-l-benzoxepin-4-carboxamide (0.19 g). NMR ^ H (CDC13) d: 1.55-1.85 (4H, m), 2.21 (3H, s), 2.55-2.80 (1H, m), 3.00-3.15 (2H, m), 3.30-3.45 (2H, m) , 3.58 (2H, s), 3.95-4.15 (2H, m), 4.30-4.45 (2H, m), 6.01 (2H, s), 6.88 (1H, d, J = 8.6Hz), 6.95-7.10 (3H , m), 7.20-7.65 (7H, m). GO . { KBr) V: 1653, 1597, 1514, 1483cm "1.

Working Example 247 (Production of Compound 247) In dimethylformamide (5 ml) was dissolved 7- (3,4-methylenedioxyphenyl) -4- (N-methyl-N- (tetrahydropyran-4-yl) aminomethyl) phenyl) -2 , 3-dihydro-l-benzoxepin-4-carboxamide (95 mg), and to the mixture was added methyl iodide (0.012 ml). Under a nitrogen atmosphere, the mixture was stirred at room temperature for 18 hours. The solvent was evaporated, and ethyl acetate was added to the residue. The insoluble material was filtered and recrystallized from ethanol to give dimethyl-N- (7- (3,4-methylenedioxy-phenyl) -2,3-dihydro-l-benzoxepin-4-carbonyl) -4-amino iodide -benzyl-N- (4-tetrahydropyranyl) ammonium (101 mg). NMR-aH (CDC13) d: 1.7-2.0 (2H, m), 2.15-2.3 (2H, m), 2.85-3.1 (8H, m), 3.4-3.55 (2H, m), 4.0-4.35 (5H, m), 4.85 (2H, s), 5.96 (2H, s), 6.81 (1H, d, J = 7.8Hz), 6.9-7.1 (3H, m), 7.25-7.7 (5H, m), 7.83 (2H , d, J = 8.2 Hz), 8.89 (1H, s). IR (KBr) v: 1659, 1609, 1520, 1495cm_1.

Working Example 248 (Production of Compound 248) In aqueous methanol, N, N-dimethyl-N- (4- (((2- (4-methylphenyl) -6,7-dihydro-5H-benzocyclohepten-8-iodide was dissolved. -yl) carbonyl) amino) benzyl) -N- (4-tetrahydropyranyl) ammonium (1.9 g), and the mixture was subjected to a column of ion exchange resin (DOWEX1-x8, 100-200 mesh, Cl type) , which was eluted with aqueous methanol, the solvent of the desired fractions was evaporated and acetone was added to the residue to give the crude crystals, which were recrystallized with ethanol to give the N, N-dimethyl-N- (4) chloride. - (((2- (4-methylphenyl) -6,7-dihydro-5H-benzocyclohepten-8-yl) carbonyl) amino) benzyl) -N- (4-tetrahydropyranyl) ammonium (10.1 g) as colorless crystals, m.p. 226-232 ° C (dec.). RMN-1H (CDCl 3 + CD 3 OH) d: 1.80-2.00 (2H, m), 2.07-2.26 (4H, m), 2.39 (3H, s), 2.72 (2H, t , J = 6.6Hz), 2.85-2.91 (2H, m), 3.00 (6H, s), 3.54 (2H, t, J = 11.3Hz), 4.00-4.21 (3H, m), 4.70 (2H, s) , 7.21-7.29 (3H, m), 7.42-7.56 (7H, m), 7.81 (2H, d, J = 8.4Hz), 9.06 (1H, s). IR (KBr) v: 2934, ldSScm "1. Analysis for C33H39C1N202: Calculated: C, 74.62; H, 7.40; N, 5.27; Cl, 6.67. Found: C, 74.35; H, 7.33; N, 5.20; Cl, 6.80.

Working Example 248a (Production of Compound 248) To a solution of N- (4-chloromethylphenyl) -2- (4-methylphenyl) -6,7-dihydro-5H-benzocyclohepten-8-carboxamide (9.38 g, 23.3 mmol) in DMF (50 ml) a solution of N, N-dimethyl-N-tetrahydropyran-4-ylamine (4.5 g, 35.0 mmol) in DMF (50 ml) was added dropwise. Under a nitrogen atmosphere, the mixture was stirred for 23 hours. The solvent was evaporated to a powder, which was washed with acetone and dried. The resulting colorless powder was recrystallized from ethanol to give the N, N-dimethyl-N- (4- (((2- (4-methylphenyl) -6,7-dihydro-5H-benzocyclohepten-8-yl chloride) carbonyl) amino) benzyl) -N- (4-tetrahydropyranyl) ammonium (Compound 248) (10.6 g, 86%) as a colorless powder.

Working Example 249 (Production of Compound 249) In aqueous acetonitrile, N, N-dimethyl-N- (4- (((7- (4-methylphenyl) -2,3-dihydro-1-benzoxepin-4-iodide was dissolved. -yl) carbonyl) amino) benzyl) -N- (4-oxocyclohexyl) ammonium (22.8 g), and the mixture was subjected to an ion exchange resin column (DOWEX-SBR, Cl type), which was eluted with aqueous acetonitrile The solvent of the desired fractions was evaporated and the residue dissolved in water The mixture was subjected to freeze drying to give N, N-dimethyl-N- (4- (((7- (4 methylphenyl) -2,3-dihydro-l-benzoxepin-4-yl) carbonyl) amino) benzyl) -N- (4-oxocyclohexyl) ammonium (Compound 249) (16.1 g) as a colorless powder. aH (DMSO-de) d: 2.05-2.25 (2H, m), 2.34 (3H, s), 2.41-2.61 (6H, m), 2.97 (6H, s), 2.97-3.00 (2H, m), 3.75 -3.90 (1H, m), 4.30 (2H, t, J = 4.4Hz), 4.57 (2H, s), 7.06 (1H, d, J = 8.4Hz), 7.27 (2H, d, J = 7.8Hz) , 7.45 (1H, s), 7.53-7.60 (5H, m), 7.78 (1H, d, J = 2.2Hz), 7.92 (2H, d, J = 8.4Hz), 10.34 (1H, s). IR (KBr) v: 3025, 2967, 1717, iSScm "1. Analysis for C33H37C1N203 • 0.5H20: Calculated: C, 71.53; H, 6.91; N, 5.06; Cl, 6.40 Found: C, 71.21; H, 6.94; N, 4.94; Cl, 6.24.

Working Example 249a (Production of Compound 249) To a solution of N- (4-chloromethylphenyl) -7- (4-methylphenyl) -2,3-dihydro-l-benzoxepin-4-carboxamide (214 mg, 0.530 mmol) in N, N-dimethylformamide (1 ml) was added dropwise a solution of 4-dimethylaminocyclohexanone (112 mg, 0.795 mmole), in N, -dimethylformamide (1 ml). Under a nitrogen atmosphere, the mixture was stirred for 14 hours. The solvent was evaporated to give a crude product, which was washed with ether to give the N, N-dimethyl-N- (4- (((7- (4-methylphenyl) -2,3-dihydroyl) chloride. -benzoxepin-4-yl) carbonyl) -amino) benzyl) -N- (4-oxocydohexyl) ammonium (Compound 249) (305 mg) as a colorless powder.

Working Example 250 (Production of Compound 250) To a solution of N- (4-chloromethylphenyl) -7- (4-ethoxyphenyl) -2,3-dihydro-l-benzoxepin-4-carboxamide (2.38 g) in DMF ( 20 ml) was added N, N-dimethyl-N-tetrahydropyran-4-ylamine (1.42 g) at room temperature, and the mixture was stirred for 14 hours. To the reaction mixture was added ethyl acetate (100 ml) to precipitate the crystals, which were collected by filtration. The crystal was washed with ethyl acetate to give the crude product as the pale yellow crystals, which were recrystallized with ethanol to give the N- (4- (((7- (4-ethoxyphenyl) -2, 3-chloride. -dihydro-l-benzoxepin-4-yl) carbonyl) amino) benzyl) -N, N-dimethyl-N- (4-tetrahydropyranyl) ammonium (Compound 250) (1.29 g) as colorless crystals, m.p. 200-204 '° C NMR-1H (200MHz, DMSO-d6) d: 1.35 (3H, t, J = 7.0 Hz), 1.75-1.98 (2H, m), 2.06-2.24 (2H, m), 2.88 ( 6H, s), 2.94-3.05 (2H, m), 3.28-3.43 (2H, m), 3.49-3.69 (1H, m), 3.99-4.13 (2H, m), 4.07 (2H, q, J = 7.0 Hz), 4.23-4.35 (2H, m), 4.47 (2H, s), 6.98-7.07 (3H, m), 7.37 (1H, s), 7.50-7.61 (5H,), 7.72 (1H, d, J = 2.2 Hz), 7.87 (2H, d, J = 8.4 Hz), 10.22 (1H, s). IR (KBr) V 3425, 1647, 1603, 1520, 1489, 1407, 1317, 1294, 1240, 831 cm "1 Analysis for C33H39N204C1 Calculated: C, 70.38; H, 6.98; N, 4.97; Cl, 6.30 Found: C , 70.49; H, 7.08; N, 4.94; Cl. 6.19.

Working Example 250a (Production of Compound 250) In nonaqueous methanol, N- (4- (((7- (4-ethoxyphenyl) -2,3-dihydro-l-benzoxepin-4-yl) carbonyl) amino was dissolved. benzyl) -N, N-dimethyl-N- (4-tetrahydropyranyl) ammonium (26.6 g), and the mixture was subjected to a column of ion exchange resin (DOWEX-SBR, Cl type "), which was eluted with Aqueous methanol The solvent of the desired fractions was evaporated, and acetone was added to the residue to give crude crystals, which were recrystallized with ethanol to give the N- (4- (((7- (4-ethoxyphenyl) - 2, 3-dihydro-l-benzoxepin-4-yl) carbonyl) amino) benzyl) -N, N-dimethyl-N- (4-tetrahydropyranyl) ammonium (Compound 250) (16.6 g) as colorless crystals.

Working Example 251 (Production of Compound 251) To a solution of N- (4- ((N-tetrahydrothiopyran-4-yl-N-methyl) aminomethyl) phenyl-7- (4-methylphenyl) -2,3-dihydro -l-benzoxepin-4-carboxamide (0.2 g) in dichloromethane (10 ml) was added mCPBA (0.1 g) at -10 to -20 ° C, and the mixture was stirred for 30 minutes. of sodium thiosulfate, and the mixture was concentrated and extracted with acetate.The organic layer was washed with a solution of sodium hydrogen carbonate, water and saturated brine and dried with anhydrous magnesium sulfate. Evaporated and the residue was purified with a column of silica gel (methanol / triphenylamine / ethyl acetate) to give the N- (4- ((N- (1-oxotetrahydrothiopyran-4-yl) -N-methyl) -aminomethyl) ) phenyl) 7- (4-methylphenyl) -2,3-dihydro-l-benzoxepin-4-carboxamide (Compound 251) (mixture E, Z: 0.12 g) as a colorless powder: RMN-XH d ppm, CDC13 0-1.97 (2H, 2.17 (1.4H, s), 2.28 (1.6H, s), 2.37-2.51 (3H, m), 2.39 (3H, s), 2. 56-2.73 (2H, m), 3.08 (2H, t, J = 4.7Hz), 3.15-3.28 (2H, m), 3.54 (0.9H, s), 3.63 (1.1H, s), 4.36 (2H, t, J = 4.7Hz), 7.06 (1H, d, J = 8.4Hz), 7.23-7.34 (4H, m), 7. 44-7.57 (6H, m), 7.64 (1H, s). IR (KBr) v: 3279, 2946, 1651cm_1. Analysis Calculated for C3? H34N203S: C72.34; H, 6.66; N, 5.44 Found C72.31; H, 6.66; N, 5.35 Working Example 252 (Production of Compound 252) To a suspension of 2- (4-methylphenyl) -6,7-dihydro-5H-benzocyclohepten-8-carboxylic acid (0.15 g) in dichloromethane (5 ml) were added, under ice cooling, oxalyl chloride (0.15 ml) and dimethylformamide (catalytic amount) and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated and the residue was dissolved in tetrahydrofuran (15 ml). The mixture was added dropwise, under ice-cooling, to a mixture of l- (4-aminobenzyl) phosphorin-1-oxide (0.13 g) and triethylamine (0.23 ml) in tetrahydrofuran (15 ml). Under a nitrogen atmosphere, the mixture was stirred at room temperature overnight. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give crude crystals, which were recrystallized with ethanol / hexane to give 2- (4-methyl-phenyl) -N- (4- ((1-oxophospholin-1-yl) methyl) ) -phenyl) -6,7-dihydro-5H-benzocyclohepten-8-carboxamide (Compound 252) (0.16 g) as colorless crystals. p.f. 282-283 ° C (dec.). NMR ^ H (d ppm, CDC13) 1.40-1.60 (2H, m), 1.70-1.80 (6H, m), 1.80-2.20 (4H, m), 2.40 (3H, s), 2.72 (2H, t, J = 6.6Hz), 2.86-2.95 (2H ~, m), 3.16 (2H, d, J = 13.6Hz), 7. 15-7.26 (4H, m), 7.42-7.52 (5H, m), 7.60 (2H, d, J = 8.0Hz), 7.80 (1H, s). GO . { KBr) V: 2932, 1659cm_1. Analysis Calculated for C3? H3 N02P • 0.2H20: C, 76.43; H, 7.12; N, 2.87. Found C, 76.20; H, 7.31; N, 3.00.

Working Example 253 (Production of Compound 253) To a suspension of 2- (4-methylphenyl) -6,7-dihydro-5H-benzocyclohepten-8-carboxylic acid (0.3 g) in dichloromethane (5 ml) were added, under ice cooling, oxalyl chloride (0.3 ml) and dimethylformamide (catalytic amount), and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated and the residue was dissolved in tetrahydrofuran (10 ml). The mixture was added dropwise, under cooling with ice, to a mixture of 4- (N-methyl-N- (tetrahydrothiopyran-4-yl) -aminomethyl) aniline. (0.27 g) and triethylamine (0.45 ml) in tetrahydrofuran (10 ml). Under a nitrogen atmosphere, the mixture was stirred at room temperature for 4 hours. The solvent was evaporated, and water was added to the residue. The mixture was extracted with ethyl acetate and the organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give crude crystals, which were recrystallized with ethyl acetate / hexane to give the N- (4- ((N-tetrahydrothiopyran-4-yl-N-methyl) aminomethyl) -phenyl) -2- (4-methylphenyl) -6, 7-dihydro-5H-benzocycloheten-8-carboxamide (Compound 253) (0.45 g) as colorless crystals, m.p. 177-178 ° C. NMR-1H (d ppm, CDC13) 1.65-1.85 (2H, m), 2.14-2.20 (2H, m), 2.22 (3H, s), 2.40 (3H, s), 2.47-2.53 (1H, m), 2.68-2.72 (6H, m), 2.86-2.92 (2H, m), 3.58 (2H, s), 7.21-7.27 (2H, m), 7.31 (2H, d, J = 8.4Hz), 7.42-7.52 ( 5H, m), 7.56 (2H, d, J = 8.4Hz), 7.63 (1H, s). GO . { KBr) v: 2932, 1651 r - "1. Analysis calculated for C32H3eN20S • 0.2H20: C76.82; H, 7.33; N, 5.60. Found C, 76.89; H, 7.35; N, 5.64.

Working Example 254 (Production of Compound 254a and 254b) To a solution of N- (4- ((N-tetrahydrothiopyran-4-yl-N-methyl) aminomethyl) phenyl) -2- (4-methylphenyl) -6, 7-dihydro-5H-benzocyclohepten- = 8-carboxamide (0.3 g) in dichloromethane (20 ml) was added mCPBA (0.18 g) at -10 to -20 ° C and the mixture was stirred for 1.5 hours. To the mixture was added a solution of sodium thiosulfate, and the mixture was concentrated and extracted with ethyl acetate. The organic layer was washed with a solution of sodium hydrogen carbonate, water and saturated brine, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with a column of silica gel (methanol / triethylamine / ethyl acetate) to give two kinds of crude crystals, each of which was recrystallized with ethyl acetate. ethanol / hexane to give (E) or (Z) -N- (4- ((N- (1-oxotetrahydrothiopyran-4-yl) -N-methyl) aminomethyl) phenyl) -2- (4-methylphenyl) -6 , 7-dihydro-5H-benzocyclohepten-8-carboxamide (Compound 254a) (76 mg) and (Z) or (E) -N- (4- ((N- (l-oxotetrahydro-thiopyran-4-yl) - N-methyl) aminomethyl) phenyl) -2- (4-methylphenyl) -6,7-dihydro-5H-benzocyclohepten-8-carboxamide (Compound 254b) (O.llg) as colorless crystals, respectively. Compound 254a: p.f. 218-219 ° C. NMR-aH (d ppm, CDC13) 1.80-2.00 (2H, m), 2.10-2.20 (2H,), 2.19 (3H, s), 2.25-2.39 (2H, m), 2.40 (3H, s), 2.61 -2.76 (5H, m), 2.86-2.92 (2H, m), 3.23-3.33 (2H, m), 3.57 (2H, s), 7.22-7.31 (4H,), 7.42-7.52 (5H, m), 7.58 (2H, d, J = 8.4Hz), 7.66 (1H, s). Analysis Calculated for C32H3eN202S • 0.2H20: C, 74.44; H, 7.11; N, 5.43. Found C, 74.43; H, 7.18; N, 5.66. Compound 254b: p.f. 216-218 ° C. NMR-aH (d ppm, CDC13) 1.80-2.00 (3H, m), 2.10-2.25 (3H, m), 2.35 (3H, s), 2.40 (3H, s), 2.44-2.53 (2H, m), 2.69-2.76 (3H,), 2.86-2.92 (2H,), 3.07-3.17 (2H,), 3.71 (2H, s), 7.22-7.27 (2H, m), 7.35-7.52 (7H,), 7.60 (2H, d, J = 8.4Hz), 7.73 (1H, s).

Working Example 255 (Production of Compound 255) In dichloromethane (5 ml) the acid was suspended 2- (4-methyl-phenyl) -6,7-dihydro-5H-benzocyclohepten-8-carboxylic acid (0.3 g), and to the mixture, oxalyl chloride (0.3 ml) and dimethylformamide (amount) were added under cooling with ice. catalytic). The mixture was stirred at room temperature for 2 hours, and the solvent was evaporated. The residue was dissolved in tetrahydrofuran (15 ml), and the solution was added dropwise, under ice-cooling, to a solution of 4- (N-ethyl-N- (tetrahydropyran-4-yl) amino-methyl) aniline. (0.27 g) and triethylamine (0.45 ml) in tetrahydrofuran (10 ml). Under a nitrogen atmosphere, the mixture was stirred at room temperature overnight. The solvent was evaporated and water was added to the residue. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with a column of silica gel (ethyl acetate) to give the crude crystals, which were recrystallized with ethyl acetate / hexane to give the N- (4- ((N-Ethyl-N-tetrahydropyran-4-yl) aminomethyl) -phenyl) -2- (4-methylphenyl) -6,7-dihydro-5H-benzocyclohepten-8-carboxamide (Compound 255) (0.38 g) as colorless crystals. p.f. 122-123 ° C. NMR ^ H (d ppm, CDC13) 1.01 (3H, t, J = 7.1Hz), 1.62-1.72 (4H, m), 2.13-2.19 (2H, m), 2.40 (3H, s), 2.57 (2H, q, J = 7.1Hz), 2.69-2.76 (3H, m), 2.86-2.92 (2H,), 3.34 (2H, dt, J = 3.4, 10.9Hz); 3.62 (2H, s), 3.97-4.04 (2H, m), 7.21-7.28 (3H, m), 7.35 (2H, d, J = 8.6Hz), 7.42-7.57 (6H, m), 7.62 (1H, s). IR (KBr) v: 2936, 1651cm_1 Analysis Calculated for C33H38N2_02: C, 80.13; H, 7.74; N, 5.66. Found C, 79.96; H, 7.77; N, 5.38.

Working Example 256 (Production of Compound 256) To a suspension of 7- (4-methylphenyl) -2,3-dihydro-1-benzothiepin-4-carboxylic acid (0.3 g) in dichloromethane (6 ml) were added, under ice cooling, oxalyl chloride (0.25 ml) and dimethylformamide (catalytic amount), and the mixture was stirred at room temperature for 1.5 hours. The solvent was evaporated, and the residue was dissolved in tetrahydrofuran (15 ml). The mixture was added dropwise, under cooling with ice, to a solution of 4- ((N-methyl-N- (pentan-3-yl)) aminomethyl) -aniline (0.23 g) and triethylamine (0.42 ml) in tetrahydrofuran (15 ml). Under a nitrogen atmosphere, the mixture was stirred at room temperature overnight. The solvent was evaporated and water was added to the residue. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give crude crystals, which were recrystallized with ethyl acetate / hexane to give the N- (4- ((N-methyl-N- (pentan-3-yl) amino) methyl) phenyl) -7- (4-methylphenyl) -2,3-dihydro-l-benzothiepin-4-carboxamide (Compound 256) (0.34 g) as colorless crystals, m.p. 136-137 ° C.

NMR ^ H (d ppm, CDC13) 0.94 (6H, t, J = 7.3Hz), 1.26-1.54 (4H, m), 2.13 (3H, s), 2.17-2.32 (1H, m), 2.40 (3H, s), 3.08 (2H, t, J = 5.9Hz), 3.29 (2H, t, J = 5.9Hz), 3.55 (2H, s), 7.24-7.28 (2H, m), 7.31-7.40 (3H, m ), 7.44-7.57 (6H, m), 7.66 (1H, s). IR (KBr) v: 2959, 2928, 1651cm "a .. Calculated Analysis for C31H36N2OS: C, 76.82; H, 7.49; N, 5.78, Found C, 76.77; H, 7.21; N, 5.63.

Working Example 257 (Production of Compound 257) In dichloromethane (5 ml) was suspended 7- (4-methyl-phenyl) -2,3-dihydro-l-benzoxepin-4-carboxylic acid (0.25 g), and the The suspension was added, under cooling with ice, oxalyl chloride (0.23 ml) and dimethylformamide (catalytic amount). The mixture was stirred at room temperature for 2 hours, and the solvent was evaporated. The residue was dissolved in tetrahydrofuran (20 ml), and the mixture was added dropwise, under ice-cooling, to a solution of 2- (N- (4-aminobenzyl) -N-methylamino) -1,3-propanediol. (0.21 g) and triethylamine (0.37 ml) in tetrahydrofuran (10 ml). Under a nitrogen atmosphere, the mixture was stirred at room temperature overnight. The solvent was evaporated and water was added to the residue. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with a column of silica gel (methanol / triethylamine / ethyl acetate) to give crude crystals, which were recrystallized with ethyl acetate / ethanol / hexane to give the N- (4- ((N-bis (hydroxy-methyl) methyl-N-methyl) aminomethyl) phenyl) -7- (4-methylphenyl) -2,3-dihydro-l-bezoxepin-4-carboxamide (Compound 257 ) (0.22 g) as colorless crystals, mp 199-201 ° C. NMR ^ H (d ppm, CDC13) 2.30 (3H, s), 2.39 (3H, s), 2.96-3.03 (1H,), 3.08 (2H, t, J = 4.5Hz), 3.61-3.73 (4H, m ), 3.78 (2H, s), 4.36 (2H, t, J = 4.5Hz), 7.06 (1H, d, J = 8.4Hz), 7.23-7.32 (4H, m), 7.44-7.58 (6H, m) 7.62 (1H, s). IR (KBr) V: 3260, 2928, 1653c rt. Analysis Calculated for C29H32N204 • 0.2H20: C, 73.15; H, 6.86; N, 5.88. Found C, 73.20; H, 6.86; N, 5.91.

Working Example 258 (Production of Compound 258) In dichloromethane (5 ml) was suspended 7- (4-methyl-f-enyl) -2,3-dihydro-l-benzoxepin-4-carboxylic acid (0.3 g), Oxalyl chloride (0.28 ml) and trimethylformamide (catalytic amount) were added to the mixture under cooling with ice. The mixture was stirred at room temperature for 2 hours, and the solvent was evaporated. The residue was dissolved in tetrahydrofuran (20 ml), and the mixture was added dropwise, under cooling with ice, to a solution of N- (4-aminobenzyl) sarcosine methyl ester (0.25 g) and triethylamine (0.45 ml). in tetrahydrofuran (10 ml). Under a nitrogen atmosphere, the mixture was stirred at room temperature overnight. The solvent was evaporated and water was added to the residue. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with a column of silica gel (ethyl acetate / hexane) to give crude crystals, which were recrystallized with ethyl acetate / hexane to give the N- (4 - ((N-methoxycarbonylmethyl-N-methyl) aminomethyl) -phenyl) -7- (4-methylphenyl) -2,3-dihydro-l-benzoxepin-4-carboxamide (Compound 258) (0.38 g) as colorless crystals, pf 135-136 ° C. NMR ^ H (d ppm, CDC13) 2.39 (3H, s), 2.39 (3H, s), 3.08 (2H, t, J = 4.4Hz), 3.26 (2H, s), 3.65 (2H, s), 3.72 (3H, s), 4.36 (2H, t, J = 4.4Hz), 7.06 (1H, d, J = 8.4Hz) 7.22-7.36 (4H, m), 7.43-7.60 (7H, m). IR (KBr) V: 3262, 2951, 1740cm "1. Analysis Calculated for C29H3oN2? 4: C74.02; H, 6.43; N, 5.95, Found C, 74.07; H, 6.47; N, 5.94.

Working Example 259 (Production of Compound 259) In methanol (20 ml) and THF (10 ml) was dissolved N- (4- ((N-methoxycarbonylmethyl-N-methyl) aminomethyl-phenyl) -7- (4-methylphenyl) ) -2, 3-dihydro-l-benzoxepin-4-carboxamide (0.24 g), and a 1N sodium hydroxide solution (3.0 ml) was added to the mixture. The mixture was stirred at room temperature overnight and concentrated. The residue was neutralized with IN hydrochloric acid, and the precipitated materials were filtered and dissolved in methanol. The mixture was filtered and to the filtrate was added 4N hydrochloric acid-ethyl acetate. The solvent was evaporated, and the residue was purified with methanol / diethyl ether to give N- (4- ((N-carboxymethyl-N-methyl) -aminomethyl) phenyl) -7- (4-methyphenyl) -2 hydrochloride , 3-dihydro-l-benzoxepin-4-carboxamide (Compound 259) (0.21 g) as an amorphous, pale yellow product.

NMR-aH (d ppm, DMSO-d6) 2.34 (3H, s), 2.76 (3H, s), 2. 99 (2H, broad), 3.36 (2H, broad), 4.02 (2H, s), 4.30 (2H, broad), 7.06 (1H, d, J = 8.4Hz), 7.27 (2H, d, J = 7.8Hz), 7.38 (1H, s), 7.48 (2H, d, J = 8.6Hz), 7.55-7.59 (3H, m), 7.76 (1H, d, J = 2.2Hz), 7.82 (2H, d, J = 8.6Hz), . 18 (1H, s). IR (KBr) v: 1744cm "1. Analysis calculated for C28H29C1N204 • 0.5H20:] C, 66.99; H, 6.02; N, 5.58, Found C, 66.93; H, 5.87; N, 5.11.

Working Example 260 (Production of Compound 260) In dichloromethane (10 ml) was suspended 7- (4-methyl-phenyl) -2,3-dihydro-1-benzothiepin-4-carboxylic acid (0.3 g), and to the mixture Methyl chloride (0.25 mL) and dimethylformamide (catalytic amount) were added under cooling with ice. The mixture was stirred at room temperature for 2 hours, and the solvent was evaporated. The residue was dissolved in tetrahydrofuran (20 ml), and the mixture was added dropwise, under cooling with ice, to a solution of N- (4-aminobenzyl) sarcosine methyl ester (0.23 g) and triethylamine (0.42 ml) in tetrahydrofuran (10 ml). Under a nitrogen atmosphere, the mixture was stirred at room temperature overnight. The solvent was evaporated and water was added to the residue. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give crude crystals, which were recrystallized with ethyl acetate / hexane to give the N- (4- ((N-methoxycarbonylmethyl-N-methyl) aminomethyl) phenyl) -7- (4 -methylphenyl) -2, 3-dihydro-l-benzothiepin-4-carboxamide (Compound 260) (0.43 g) as colorless crystals, m.p. 148-150 ° C. RM ^ H (d ppm, CDC13) 2.39 (3H, s), 2.40 (3H, s), 3.08 (2H, t, J = 6.0Hz), 3.26 (2H, s), 3.29 (2H, t, J = 6.0Hz), 3.66 (2H, s), 3.72 (3H, s), 7.24-7.58 (11H, ), 7.67 (1H, s). GO . { KBr) v: 1738cm "1. Analyzes Calculated for C29H3oN203S: C, 71.58; H, 6.21; N, 5.76, Found C, 71.75; H, 5.95; N, 5.60.

Working Example 261 (Production of Compound 261) In methanol (20 ml) and THF (10 ml) was dissolved N- (4- ((N-methoxycarbonylmethyl-N-methyl) aminomethyl) -phenyl) -7- (4- methylphenyl) -2,3-dihydro-l-benzoxepin-4-carboxamide (0.23 g), and a solution of IN sodium hydroxide (2.4 ml) was added to the mixture. The mixture was stirred at room temperature overnight, concentrated and neutralized with 1N hydrochloric acid. The precipitated materials were filtered, washed with water and recrystallized with ethanol / hexane to give the N- (4 - ((N-carboxymethyl-N-methyl) aminomethyl) phenyl) -7- (4-methyl-phenyl) - 2,3-dihydro-l-benzothiepin-4-carboxamide (Compound 261) (0.16 g) as colorless crystals, m.p. 243-245 ° C. NMR-1H (d ppm, DMSO-d6), 2.34 (6H, broad), 3.00 (2H, broad), 3.16 (2H, broad), 3.22 (2H, broad), 3.80 (2H, broad), 7.20-7.35 (4H, m), 7.45-7.72 (7H, m), 7.82 (1H, s), 10.14 (1H, s). Analysis Calculated for C28H28N203S • 0.5H20: C, 69.83; H, 6.07; N, 5.82. Found C, 69.62; H, 5.92; N, 5.58.

Working Example 262 (Production of Compound 262) In dichloromethane (5 ml) was suspended 7- (4-methylphenyl) -2,3-dihydro-1-benzothiepin-4-carboxylic acid (0.2 g), and the mixture was added , under cooling with ice, methyl chloride (0.18 ml) and dimethylformamide (catalytic amount). The mixture was stirred at room temperature for 2 hours, and the solvent was evaporated. The residue was dissolved in tetrahydrofuran (20 ml), and the mixture was added dropwise, under ice-cooling, to a solution of 1- (N- (4-aminobenzyl) -N-methylamino) -3-propanol (0.15. g) and triethylamine (0.28 ml) in tetrahydrofuran (10 ml). Under a nitrogen atmosphere, the mixture was stirred at room temperature overnight. The solvent was evaporated and water was added to the residue. The mixture was extracted with ethyl acetate and the organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent evaporated, and the residue was purified with a column of silica gel (methanol / triethylamine / ethyl acetate) to give the crude crystals, which were recrystallized with ethyl acetate / hexane to give the N- (4 - ((N- 3-hydroxypropyl-N-methyl) aminomethyl) phenyl) -7- (4-methylphenyl) -2,3-dihydro-l-benzothiepin-4-carboxamide (Compound 262) (0.16 g) as colorless crystals, m.p. 147-148 ° C. RM ^ H (d ppm, CDC13) 1.69-1.80 (2H, m), 2.25 (3H, s), 2.40 (3H, s), 2.67 (2H, t, J = 5.6Hz), 3.08 (2H, t, J = 5.9Hz), 3.28 (2H, t, J = 5.9Hz), 3.53 (2H, s), 3.78 (2H, t, J = 5.3Hz), 7.24-7.32 (3H, m), 7.41-7.50 ( 4H, m), 7.53-7.60 (4H, m), 7.81 (1H, s). IR (KBr) V: 3266, 2948, 1649cm "1. Analysis Calculated for C29H32N202S - 0.3H20: C, 72.86; H, 6.87; N, 5.86.

Found C, 72.90; H, 6.70; N, 6.05 Working Example 263 (Production of Compound 263) In dichloromethane "(5 ml) was suspended 7- (4-methylphenyl) -2,3-dihydro-l-benzothiepin-4-carboxylic acid (0.2 g), and oxalyl chloride (0.19 mL) and dimethylformamide (catalytic amount) were added to the mixture under cooling with ice. The mixture was stirred at room temperature for 2 hours, and the solvent was evaporated. The residue was dissolved in tetrahydrofuran (20 ml), and the mixture was added dropwise, under ice-cooling, to a solution of 4- ((N-3-methoxypropyl-N-methyl) amino) ethyl) aniline (0.16). g) and triethylamine (0.3 ml) in tetrahydrofuran (10 ml). Under a nitrogen atmosphere, the mixture was stirred at room temperature overnight. The solvent was evaporated and water was added to the residue. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give the crude crystals, which were recrystallized with ethyl acetate / hexane to give the N- (4- ((N-3-methoxypropyl-N-methyl) aminomethyl) phenyl) -7 - (4-methyl-phenyl) -2,3-dihydro-l-benzoxepin-4-carboxamide (Compound 263) (0.28 g) as colorless crystals. p.f. 121-123 ° C. NMR-aH (d ppm, CDCl 3) 1.75-1.84 (2H, m), 2.19 (3H, s), 2.40 (3H, s), 2.45 (2H, t, J = 7.3Hz), 3.09 (2H, t, J = 4.6Hz), 3.33 (3H, s), 3.43 (2H, t, J = 6.6Hz), 3.47 (2H, s), 4.37 (2H, t, J = 4.6Hz), 7.06 (1H, d, J = 8.2Hz), 7.23-7.33 (4H, m), 7.44-7.56 (7H, m). IR (KBr) v: 2934, 1653cm_1. Analysis Calculated for C3oH34 203: C, 76.57; H, 7.28; N, 5.95. Found C, 76.41; H, 7.24; N, 6.02.

Working Example 264 (Production of Compound 264) In dichloromethane (5 ml) was suspended 7- (4-methylphenyl) -2,3-dihydro-1-benzothiepin-4-carboxylic acid (0.15 g), and the mixture was added , under cooling with ice, methyl chloride (0.15 mL) and dimethylformamide (catalytic amount). The mixture was stirred at room temperature for 2 hours, and the solvent was evaporated. The residue was dissolved in tetrahydrofuran (15 ml), and the mixture was added dropwise, under cooling with ice, to a solution of 4- ((N-3-methoxypropyl-N-methyl) amino-methyl) aniline (0.12 g). g) and triethylamine (0.21 ml) in tetrahydrofuran (10 ml). Under a nitrogen atmosphere, the mixture was stirred at room temperature overnight. The solvent was evaporated and water was added to the residue. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give the crude crystals, which were recrystallized with ethyl acetate / hexane to give the N- (4- ((N-3-methoxypropyl-N-methyl) aminomethyl) phenyl) -7 - (4-methylphenyl) -2,3-dihydro-l-benzothiepin-4-carboxamide (Compound 264) (0.18 g) as colorless crystals. p.f. 128-129 ° C. NMR-aH (d ppm, CDC13) 1.70-1.87 (2H, m), 2.19 (3H, s), 2.40 (3H, s), 2.45 (2H, t, J = 8.4Hz), 3.08 (2H, t, J = 5.6Hz), 3.29 (2H, t, J = 5.6Hz), 3.33 (3H, s), 3.43 (2H, t, J = 6.4Hz), 3.47 (2H, s), 7.24-7.33 (3H, m), 7.40-7.58 (8H, m), 7.68 (1H, s). IR (KBr) v; 2924, 1651cm_1. Analysis Calculated for C3oH34N202S: C74.04; H, 7.04; N, 5.76. Found C, 73.80; H, 6.95; N, 5.87.

Working Example 265 (Production of Compound 265) In dichloromethane (5 ml) was suspended 2- (4-methylphenyl) -6,7-dihydro-5H-benzocyclohepten-8-carboxylic acid (0.2 g), and the mixture was added , under cooling with ice, oxalyl chloride (0.19 ml) and dimethylformamide (catalytic amount). The mixture was stirred at room temperature for 2 hours, and the solvent was evaporated. The residue was dissolved in tetrahydrofuran (15 ml), and the mixture was added dropwise, under cooling with ice, to a solution of (4-aminophenyl) - (2-pyridyl) methanol (0.15 g) and triethylamine (0.3 ml. ) in tetrahydrofuran (15 ml). Under a nitrogen atmosphere, the mixture was stirred at room temperature overnight. The solvent was evaporated and water was added to the residue. The mixture was extracted with ethyl acetate and the organic layer was washed with water and saturated brine., and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give crude crystals, which were recrystallized with ethyl acetate / hexane to give 2- (4-methylphenyl) -N- (4-hydroxy (2-pyridyl) methylphenyl) -6, 7-dihydro-5H-benzocyclohepten-8-carboxamide (Compound 265) (0.30 g) as colorless crystals, m.p. 195-196 ° C. NMR-1H (d ppm, CDC13) 2.12-2.18 (2H, m), 2.39 (3H, s), 2.71 (2H, t, J = 6.2Hz), 2.85-2.91 (2H, m), 5.31 (1H, d, J = 3.8Hz), 5.75 (1H, d, J = 3.8Hz), 7.12-7.26 (4H, m), 7.35-7.67 (11H, m), 8.57 (1H, d, J = 5.4Hz). IR (KBr) v; 2930, 1651cm_1. Analysis Calculated for C3? H28N202 • 0.2H20: C, 80.21; H, 6.17; N, 6.04 Found C, 80.15; H, 6.05; N, 6.13 Working Example 266 (Production of Compound 266) In dichloromethane (25 ml) was dissolved 2- (4-eti1-phenyl) -N- (4-hydroxy (2-pyridyl) methylphenyl) -6,7-dihydro-5H- benzocyclohepten-8-carboxamide (0.2 g) and mCPBA (0.14 g) was added to the mixture under cooling with ice. The mixture was stirred at room temperature overnight, and a solution of sodium thiosulfate was added to the mixture. The mixture was concentrated and extracted with ethyl acetate. The organic layer was washed with a solution of sodium hydrogen carbonate, water and saturated brine, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated and the residue was purified with a column of silica gel (methanol / triethylamine / ethyl acetate) to give crude crystals, which were recrystallized with ethyl acetate / hexane to give 2- ( 4-methylphenyl) -N- (4-hydroxy (l-oxidepyridin-2-yl) eti1-phenyl) -6,7-dihydro-5H-benzocyclohepten-8-carboxamide (Compound 266) (0.12 g) as colorless crystals, pf 127-128 ° C. NMR ^ H (d ppm, CDC13) 2.14-2.20 (2H, m), 2.40 (3H, s), 2.73 (2H, t, J = 6.4Hz), 2.87-2.92 (2H, m), 6.07 (1H, s), 6.40 (1H, broad), 6.93-6.98 (1H, m), 7.22-7.28 (4H, m), 7.43-7.53 (7H,), 7.67 (2H, d, J = 8.8Hz), 7.75 ( 1H, s), 8.24-8.28 (1H,). IR (KBr) v; 2928, 1651cm_1. Analysis Calculated for C3? H28N203 • 0.5H20: C, 76.68; H, 6.02; N, 5.77 Found C, 76.59; H, 6.00; N, 5.65 Working Example 267 (Production of Compound 267) In dimethylformamide (5 ml) was dissolved N- (4- (piperidin-2-ylcarbonyl) phenyl) -7- (4-methylphenyl) -2, 3-dihydro-l-benzoxepin -4-carboxamide (0.2 g), and to the mixture was added sodium hydrogen carbonate (0.05 g) and methyl iodide (0.1 ml). Under a nitrogen atmosphere, the mixture was stirred at room temperature overnight. The solvent was evaporated, and ethyl acetate was added to the residue to give crude crystals, which were recrystallized with ethanol / ethyl acetate to give the N, N-dimethyl-2- (4- ((7- (4)) iodide -methylphenyl) -2,3-dihydro-l-benzoxepin-4-carbonyl) amino) benzoyl) piperidinium (Compound 267) (0.16 g) as a colorless powder. p.f. 236-237 ° C (dec.). NMR-aH (d ppm, CDC13) 1.75-2.10 (4H, m), 2.15-2.38 (2H, m), 2.38 (3H, s), 3.07 (2H, t, J = 4.6Hz), 3.43 (3H, s), 3.53 (3H, s), 3.62-3.68 (1H, m), 4.34 (2H, t, J = 4.6Hz), 4. 68 (1H, broad), 6.41-6.45 (1H, m), 7.03 (1H, d, J = 8.4Hz), 7.22 (2H, d, J = 8.0Hz), 7.43-7.52 (4H, m), 7.73 (1H, d, J = 2.2Hz), 7.95 (2H, d, J = 9.2Hz), 8.34 (2H, d, J = 8.8Hz), 8.59 (1H, s). IR (KBr) V: 2955, 1674cm "1. Analysis Calculated for C32H35IN2? 3 • 0.5H20: C, 60.86; H, 5.75; N, 4.44, Found C, 60.89; H, 5.49; N, 4.52.

Working Example 268 (Production of Compound 268) To a solution of 2-methyl-6- (4-methylphenyl) -quinolin-3-carboxylic acid (120 mg) and 1-hydroxy-benzotriazole (88 mg) in DMF (5%). ml) l-ethyl-3- (3'-dimethylaminopropyl) -carbodiimide hydrochloride (125 mg) was added at room temperature, and the mixture was stirred for 1 hour. To the mixture was added a solution of 1- (4-aminobenzyl) phosphorin-1-oxide (109 mg) and triethylamine (0.1 ml) in DMF (3 ml), and the mixture was stirred for 3 days. Under reduced pressure, the mixture was concentrated and water was added to the residue. The mixture was extracted with chloroform, and the organic layer was washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the mixture was concentrated, and the residue was separated and purified by column chromatography (ethanol / ethyl acetate = 1: 2) and recrystallized from (ethanol / ethyl acetate) to give pale yellow crystals. of 2-methyl-6- (4-methylphenyl) -N- (pentamethylenephosphorylmethylphenyl) quinoline-3-carboxamide (Compound 268) (116.1 mg). p.f. 273-275 ° C NMR-aH (200MHz, CDC13) d 1.01-1.84 (10H, m), 2.44 (3H, s), 2.90 (3H, s), 3.04 (2H, d, J = 12.6 Hz), 7.17 -7.25 (2H, m), 7.32 (2H, d, J = 7.9 Hz), 7.61 (2H, d, J = 7.9 Hz), 7. 69 (2H, d, J = 8.2 Hz), 7.99-8.13 (3H, m), 8.30 (1H, s), 9. 44 (1H, broad s). IR (KBr) 3024, 1664, 1601, 1539, 1516, 1319, 1159, 847, 816 cm "1 Calculated Analysis for C30H31N202P • 0.3H20 Calculated C, 73.84; H, 6.53; N, 5.74; P, 6.35.

Found C, 73.67; H, 6.58; N, 5.67; P, 6.27.

Working Example 269 (Production of Compound 269) Under a nitrogen atmosphere, to a solution of (E) -3- [5- (4-isopropylphenyl) thiophen-2-yl] acrylic acid (130 mg) in THF (10 mg) ml) oxalyl chloride (0.07 ml) was added at room temperature and then one drop of DMF, and the mixture was stirred for 1 hour. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in THF (20 ml). To the mixture were added 1- (4-aminobenzyl) -phosphorin-1-oxide (117 mg) and triethylamine (0.15 ml) at 0 ° C, and the mixture was stirred at room temperature for 4 hours. The mixture was added to vigorously stirred water to stop the reaction and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried with magnesium sulfate, concentrated and purified by column chromatography (ethanol / ethyl acetate = 1: 4) and recrystallized from ethanol / ethyl acetate to give color crystals. yellow of (E) -3- [5- (4-methylphenyl) thiophen-2-yl] -N- (pentaethylenephosphorylmethylphenyl) acrylamide (Compound 269) (60.5 g). p.f. 295 ° C (dec.) MN ^ H (200MHz, CDC13) d 1.28 (6H, d, J = 7.0 Hz), 1.51-2.10 (10H, m), 2.89-3.00 (1H, m), 3.15 (2H, d, J = 13.2 Hz), 6.48 (1H, d, J = 15.0 Hz), 7.15-7.33 (6H, m), 7.50-7.62 (4H, m), 7.82 (1H, d, J = 15.0 Hz), 8.37-8.59 (1H, m). IR (KBr) 3057, 1672, 1618, 1543, 1510, 1412, 1356, 1327, 1250, 1232, 1165, 960, 852, 829, 793 c "1 Calculated Analysis for C28H32N02SP Calculated C, 70.41; H, 6.75; N 2.93, Found C, 70.06, H, 6.82, N, 2.98.

Working Example 270 (Production of Compound 270) Under a nitrogen atmosphere, to a solution of (E) -3- [5- (4-tert-butylphenyl) thiophen-2-yl] acrylic acid (120 mg) in THF (10 ml) oxalyl chloride (0.06 ml) and one drop of DMF were added at room temperature, and the mixture was stirred for 1 hour. Under reduced pressure, the solvent was evaporated and the residue was dissolved in THF (20 ml). To the mixture were added at 0 ° C 1- (4-aminobenzyl) phosphorin-1-oxide (104 mg) and triethylamine (0.12 ml), and the mixture was stirred at room temperature for 18 hours. The mixture was added to vigorously stirred water to stop the reaction and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the mixture was concentrated and the residue was purified with column chromatography (ethanol / ethyl acetate = 1: 4) and recrystallized from ethanol to give yellow crystals of (E) -N- (4-pentamethylenephosphorylmethylphenyl) -3- [5- (4-tert-Butylphenyl) -thiophen-2-yl] acrylamide (Compound 270) (82.1 mg). p.f. > 300 ° C NMR ^ H (200MHz, CDC13) d 1.35 (9H, s), 1.50-2.22 (10H, m), 3.15 (2H, d, J = 13.2 Hz), 6.53 (1H, d, J = 15.4 Hz ), 7.12-7.30 (4H, m), 7.42 (2H, d, J = 8.4 Hz), 7.49-7.60 (4H, m), 7.82 (1H, d, J = 15.4 Hz), 8.79-8.98 (1H, m). IR (KBr) 3238, 1672, 1618, 1543, 1514, 1358, 1252. 1167, 852, 793 c "1 Analis is Calculated for C29H34N02SP Calculated C, 70.85; H, 6.97; N, 2.85; P, 6.30.

Found C, 70.61; H, 6.90; N, 2.89; P, 6.17.

Working Example 271 (Production of Compound 271) Under a nitrogen atmosphere, to a solution of 2- (4-methylphenyl) benzofuran-5-carboxylic acid (130 mg) in THF (10 ml) was added at room temperature oxalyl (0.07 ml) and one drop of DMF, and the mixture was stirred for 1 hour. Under reduced pressure, the solvent was evaporated and the residue was dissolved in THF (20 ml). To the mixture were added at 0 ° C 1- (4-aminobenzyl) phosphorin-1-oxide (126 mg) and triethylamine (0.15 ml), and the mixture was stirred at room temperature for 3 hours. The mixture was added to vigorously stirred water to stop the reaction and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried with magnesium sulfate and concentrated. The resulting crystals were recrystallized with ethanol to give colorless crystals of 2- (4-methylphenyl) -N- (4-pentamethylenephosphorylphenyl) benzofuran-5-carboxamide.

(Compound 271) (134.6 mg). p.f. 297-296 ° C NMR-1H (200MHz, CDC13) d 1.42-2.16 (10H, m), 2.42 (3H, s), 3.17 (2H, d, J = 13.2 Hz), 7.04 (1H, s), 7.24 -7.33 (4H, m), 7.58 (1H, d, J = 8.6 Hz), 7.67 (2H, d, J = 8.4 Hz), 7.76-7.85 (3H, m), 8.14 (1H, d, J = 1.8 Hz) , 8.15-8.19 (1H, m). IR (KBr) 3390, 2929, 1657, 1524, 1323, 1230, 1161, 1132, 849, 824, 800, 760 cm "1 Calculated Analysis for C28H28N03P Calculated C, 73.51; H, 6.17; N, 3.06 Found C, 73.45; H, 5.89; N, 2.83.

Working Example 272 (Production of Compound 272) To a solution of 2- (4-methylphenyl) benzofuran-6-carboxylic acid (130 mg) in THF (10 ml) were added oxalyl chloride (0.07 ml) and one drop of dimethylformamide at room temperature, and the mixture was stirred for 1 hour. Under reduced pressure, the solvent was evaporated and the residue was dissolved in THF (20 ml). To the mixture were added at 0 ° C l- (4-aminobenzyl) phosphorin-1-oxide (126 ml) and triethylamine (0.15 ml), and the mixture was stirred at room temperature for 20 hours. The mixture was added to vigorously stirred water to stop the reaction and extracted with dichloromethane, and the organic layer was washed with saturated brine. Under reduced pressure, the mixture was concentrated, and the residue was recrystallized from ethanol to give pale yellow crystals of 2- (4-methyl-phenyl) -N- (4-pentamethylenephosphorylmethylphenyl) benzofuran-6-carboxamide (Compound 272) ( 149.9 mg). p.f. > 300 ° C IR (KBr) 3224, 1651, 1535, 1512, 1323, 1165, 845, 820 Analysis is Calculated for C28H28N03P Calculated C, 73.51; H, 6.17; N, 3.06. Found C, 73.50, H, 6.17; N, 2.92.

Working Example 273 (Production of Compound 273) To a solution of 7- (4-methylsulfonylphenyl) -2,3-dihydro-l-benzoxepin-4-carboxylic acid (100 mg) in THF (10 ml) were added at room temperature oxalyl chloride environment (0.05 ml) and one drop of DMF, and the mixture was stirred for 1 hour. Under reduced pressure, the solvent was evaporated and the residue was dissolved in THF (20 ml). To the mixture were added at 0 ° C 4- [N-methyl-N- (tetrahydropyran-4-yl) aminomethyl] aniline (71 mg) and triethylamine (0.1 ml), and the mixture was stirred at room temperature for 16 hours . The mixture was added to vigorously stirred water to stop the reaction and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the mixture was concentrated, and the residue was purified by column chromatography (ethanol / ethyl acetate = 1: 3) and recrystallized from ethanol to give colorless crystals of 7- (4-methylsulfonylphenyl) -N- [4- [N-methyl-N- (tetrahydropyran-4-yl) aminomethyl] phenyl] -2,3-dihydro-l-benzoxepin-4-carboxamide (Compound 273) (123 mg). p.f. 233-235 ° C NMR ^ H (200MHz, CDC13) d 1.62-1.82 (4H, m), 2.21 (3H, s), 2.56-2.73 (1H, m), 3.04-3.15 (2H, m), 3.10 ( 3H, s), 3.31-3.43 (2H, m), 3.57 (2H, s), 3.99-4.09 (2H, m), 4.39 (2H, t, J = 4.5 Hz), 7.12 (1H, d, J = 8.4 Hz), 7.24-7.35 (3H, m), 7.46-7.60 (5H, m), 7.74 (2H, d, J = 8.6 Hz), 8.00 (2H, d, J = 8.6 Hz). IR (KBr) 3292, 1645, 1524, 1308, 1144 cm "1 Calculated Analysis for C3? H34N205S Calculated C, 68.11; H, 6.27; N, 5.12; S, 5.87, Found C, 67.94; H, 6.40; N, 5.09; S, 5.90.

Working Example 274 (Production of Compound 274) Under a nitrogen atmosphere, to a solution of (E) -3- [5- (4-isopropylphenyl) thiophen-2-yl] acrylic acid (130 mg) in THF (10%). ml) oxalyl chloride (0.07 ml) and one drop of DMF were added at room temperature, and the mixture was stirred for 1 hour. Under reduced pressure, the solvent was evaporated and the residue was dissolved in THF (20 ml). To the mixture were added at 0 ° C 4- [N-methyl-N- (tetrahydropyran-4-yl) aminomethyl] aniline (116 mg) and triethylamine (0.15 ml), and the mixture was stirred at room temperature for 4 hours . The mixture was added to vigorously stirred water to stop the reaction and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried with magnesium sulfatewas concentrated and purified by column chromatography (ethanol / ethyl acetate = 1: 4) and recrystallized from ethyl acetate / hexane to give yellow crystals of (E) -3- [5- (4-isopropylphenyl) ) thiophen-2-yl] -N- [4- [N-methyl-N- (tetrahydropyran-4-yl) aminomethyl] -phenyl] acrylamide (Compound 274) (162.9 mg). p.f. 187-189 ° C NMR ^ H (200MHz, CDC13) d 1.27 (6H, d, J = 6.8 Hz), 1.54-1.84 (4H, m), 2.21 (3H, s), 2.55-2.72 (1H, m) , 2.84-3.01 (1H, m), 3.30-3.44 (2H, m), 3.56 (2H, s), 3.97-4.10 (2H, m), 6.31 (1H, d, J = 15.4 Hz), 7.19-7.35 (7H,), 7.49-7.61 (4H,), 7.84 (1H, d, J = 15.4 Hz). IR (KBr) 3315, 1664, 1606, 1535, 1512, 1408, 1335, 1169, 829, 804 cm "1 Calculated Analysis for C29H3N202S Calculated C, 73.38; H, 7.22; N, 5.90; 5, 6.76. Found C, 73.12; H, 7.34; N, 5.88; 5, 6.83.

Working Example 275 (Production of Compound 275) A solution of 7- (4-methylthiophenyl) -N- [4- [N-methyl-N- (4-tetrahydropyran-4-yl) aminomethyl] phenyl] -2, 3 -dihydro-l-benzoxepin-4-carboxamide (110 mg) and sodium periodate (48 mg) in methanol / water (40/15 ml) was stirred at room temperature for 2 days. Under reduced pressure, the mixture was concentrated and water was added to the residue. The mixture was extracted with chloroform. The organic layer was washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the mixture was concentrated, and the residue was purified by column chromatography (ethanol / ethyl acetate = 1: 1) and recrystallized from ethanol / ethyl acetate to give colorless crystals of 7- (4-methylsulfonylphenyl) ) -N- [4- [N-methyl-N- (4-tetrahydropyran-4-yl) aminomethyl] phenyl] -2,3-dihydro-l-benzoxepin-4-carboxamide (Compound 275) (15.5 mg).

NMR-1H (200MHz, CDC13) d 1.52-1.83 (4H, m), 2.21 (3H, s), 2.52-2.74 (1H, m), 2.77 (3H, s), 3.10 (2H, t, J = 4.4 Hz), 3.29-3.43 (2H,), 3.57 (2H, s), 3.98-4.10 (2H,), 4.39 (2H, t, J = 4.4 Hz), 7.11 (1H, d, J = 8.0 Hz), 7.23-7.35 (3H, m), 7.44-7.63 (5H, m), 7.71 (4H, s). IR (KBr) 3327, 1649, 1515, 1410, 1315, 1240, 1038, 822 cm "1 Working Example 276 (Production of Compound 276) Under a nitrogen atmosphere, to a solution of (E) -3- [5- (4-tert-butylphenyl) thiophen-2-yl] acrylic acid (130 mg) in THF (10 ml) oxalyl chloride (0.06 ml) and one drop of DMF were added at room temperature, and the mixture was stirred for 1 hour. Under reduced pressure, the solvent was evaporated and the residue was dissolved in THF (20 ml). To the mixture were added at 0 ° C 4- [N-methyl-N- (tetrahydropyran-4-yl) aminomethyl] aniline (109 mg) and triethylamine (0.13 ml), and the mixture was stirred at room temperature for 6 days . The mixture was added to vigorously stirred water to stop the reaction and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried with magnesium sulfate, and concentrated. The residue was purified by column chromatography (ethanol / ethyl acetate = 1: 4) and recrystallized from ethyl acetate / hexane to give yellow crystals of (E) -3- [5- (4-tert-butylphenyl) ) thiophen-2-yl] -N- [4- [N-methyl-N- (tetrahydropyran-4-yl) aminomethyl] phenyl] acrylamide (Compound 276) (107.3 mg). p. f. 216-220 ° C NMR - ^ - H (200MHz, CDC13) d 1.35 (9H, s), 1.50-1.86 (4H, m), 2. 21 (3H, s), 2.51-2.76 (1H, m), 3.30-3.45 (2H, m), 3.57 (2H, s), 3.99-4.10 (2H, m), 6.32 (1H, d, J = 14.8 Hz), 7.21-7.35 (5H, m), 7.43 (2H, d, J = 8.4 Hz), 7.51- 7.61 (4H, m), 7.84 (1H, d, J = 14.8 Hz). IR (KBr) 3320, 1666, 1606, 1535, 1335, 831 cm "1 Calculated Analysis for C30H36N2O2S • 0.1H20 Calculated C, 73.46; H, 7.44; N, 5.71, Found C, 73.41; H, 7.41; N, 5.83 .

Working Example 277 (Production of Compound 277) Under a nitrogen atmosphere, to a solution of 2- (4-methylphenyl) benzofuran-5-carboxylic acid (200 mg) in THF (10 ml) was added at room temperature oxalyl (0.1 ml) and one drop of DMF, and the mixture was stirred for 1 hour. Under reduced pressure, the solvent was evaporated and the residue was dissolved in THF (20 ml). To the mixture were added at 0 ° C 4- [N-methyl-N- (tetrahydropyran-4-yl) amino-methyl] aniline (192 mg) and triethylamine (0.22 ml), and the mixture was stirred at room temperature for 18 hours. The mixture was added to vigorously stirred water to stop the reaction and extracted with chloroform. The organic layer was washed with saturated brine, dried with magnesium sulfate and concentrated. The resulting crystals were recrystallized with ethanol to give colorless crystals of 2- (4-methylphenyl) -N- [4- (N-methyl-N- (tetrahydropyran-4-yl) aminomethyl) phenyl] benzofuran-5-carboxamide (Compound 277) (295.8 mg). p.f. 233-236 ° C RJN-1H (200MHz, CDC13) d 1.62-1.83 (4H, m), 2.22 (3H, s), 2.42 (3H, s), 2.57-2.72 (1H, m), 3.32-3.44 ( 2H, m), 3.59 (2H, s), 3.99-4.09 (2H, m), 7.03 (1H, s), 7.31-7.36 (4H, m), 7.56-7.64 (3H, m), 7.76-7.82 ( 3H,), 7.87 (1H, s), 8.11 (1H, d, J = 1.4 Hz). IR (KBr) 3388, 2943, 1647, 1597, 1525, 1408, 1319, 1148, 794 cm "1 Calculated Analysis for C29H30N2O3 Calculated C, 76.63; H, 6.65; N, 6.16, Found C, 76.61; H, 6.47; N, 6.00.

Working Example 278 (Production of Compound 278) To a solution of 2- (4-methylphenyl) benzofuran-6-carboxylic acid (200 mg) in THF (10 ml) were added oxalyl chloride (0.1 ml) at room temperature and one drop of DMF, and the mixture was stirred for 1 hour. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in THF (20 ml). To the mixture was added at 0 ° C 4- [N-methyl-N- (tetrahydropyran-4-yl) aminomethyl] aniline (192 mg) and triethylamine (0.22 ml), and the mixture was stirred at room temperature for 4 hours . The mixture was added to vigorously stirred water to stop the reaction and extracted with dichloromethane. The organic layer was washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the mixture was concentrated and the residue was purified by column chromatography (ethanol / ethyl acetate = 1: 4-1: 2-> 2: 1) and recrystallized from ethanol to give pale yellow crystals. of 2- (4-methylphenyl) -N- [4- [N-methyl-N- (tetrahydropyran-4-yl) aminomethyl] phenyl] benzofuran-6-carboxamide (Compound 278) (280 mg). p.f. 224-227 ° C NMR-aH (200MHz, CDC13) d 1.41-1.82 (4H, m), 2.22 (3H, s), 2. 42 (3H, s), 2.56-2.74 (1H, m), 3.32-3.44 (2H,), 3.59 (2H, s), 3.98-4.12 (2H, m), 7.02 (1H, s), 7.25-7.37 (4H, m), 7.61-7.66 (3H, m), 7.72-7.81 (3H, m), 7.92 (1H, s), 8. 07 (1H, s). IR (KBr) 3304, 1647, 1520, 1313, 822 c "1 Analysis is Calculated for C29H3oN203 Calculated C, 76.63; H, 6.65; N, 6.16, Found C, 76.79; H, 6.39; N, 6.13.

Working Example 279 (Production of Compound 279) To a solution of (E) -3- [5- (4-methylphenyl) thiophen-2-yl] -N- [4- [N-methyl-N- (tetrahydropyran- 4-yl) amino-methyl] phenyl] acrylamide (100 mg) in DMF (3 ml) were added at room temperature methyl iodide (0.5 ml), and the mixture was stirred for 2 days. Under reduced pressure, the mixture was concentrated, and acetonitrile was added to the residue. The resulting crystals were collected by filtration to give yellow iodide crystals of N, N-dimethyl-N- [4- [[(E) -3- [5- (4-methylphenyl) thiophen-2-yl] -2] -propenoyl] amino] benzyl] -4-tetrahydropyranyl ammonium (Compound 279) (101.1 mg). p.f. 212-216 ° C NMR-aH (200MHz, DMS0-d6) d 1.74-1.99 (2H, m), 2.09-2.22 (2H, m), 2.34 (3H, s), 2.87 (6H, broad s), 3.24 -3.42 (2H, m), 3.48-3.66 (1H, m), 4.00-4.11 (2H, m), 4.46 (2H, s), 6.58 (1H, d, J = 15.4 Hz), 7.27 (2H, d) , J = 7.9 Hz), 7.44-7.58 (4H,), 7.61 (2H, d, J = 7.9 Hz), 7.76 (1H, d, J = 15.4 Hz), 7.82 (2H, d, J = 8.8 Hz) , 10.43 (1H, s). IR - (KBr) 3165, 1675, 1606, 1525, 1155, 814 cm "1 Calculated Analysis for C28H33N202SI • 0.5H20 Calculated C, 56.28; H, 5.74; N, 4.69 Found C, 56.04; H, 5.71; N, 4.71 .

Working Example 280 (Production of Compound 280) To a solution of (E) -N- [4- [N-methyl-N- (tetrahydropyran-4-yl) aminomethyl] phenyl] -3- [5- (4- isopropyl-phenyl) thiophen-2-yl] acrylamide (80 mg) in DMF (5 ml) was added at room temperature methyl iodide (0.04 ml), and the mixture was stirred for 3 days. Under reduced pressure, the solvent was evaporated and acetonitrile was added to the residue. The resulting crystals were collected by filtration to give yellow crystals of N, -dimethyl-N- [4- [[(E) -3- [5- (4-isopropylphenyl) thiophen-2-yl] -2-iodide crystals. -propenoyl] amino] benzyl] -4-tetrahydropyranyl ammonium (Compound 280) (76.9 mg). p.f. 217-220 ° C NMR ^ H (200MHz, DMS0-d6) d 1.23 (6H, d, J = 7.0 Hz), 1.72-2.01 (2H, m), 2.08-2.23 (2H, m), 2.79-3.01 ( 1H, m), 2.87 (6H, s), 3.25-3.44 (2H, m), 3.49-3.68 (1H, m), 3.99-4.12 (2H, m), 4.46 (2H, s), 6.58 (1H, d, J = 15.4 Hz), 7.33 (2H, d J = 8.5 Hz), 7.44-7.57 (4H, m), 7.63 (2H, d, J = 8.5 Hz), 7.76 (1H, d, J = 15.4 Hz), 7.82 (2H, d, J = 8.8 Hz), . 42 (1H, s).

IR (KBr) 3298, 1654, 1608, 1527, 1452, 1417, 1323, 1252, 1163, 843, 802 cm "1 Analyzes Calculated for C30H37N2O2S I Calculated C, 58.44; H, 6.05; N, 4.54, Found C, 58.24; H, 5.83; N, 4.27.

Working Example 281 (Production of Compound 281) To a solution of 2- (4-methylphenyl) -N- [4- (N-methyl-N- (tetrahydropyran-4-yl) aminomethyl) phenyl] -benzofuran-5- carboxamide (120 mg) in DMF (20 ml) was added at room temperature methyl iodide (0.04 ml), and the mixture was stirred for 24 hours. Under reduced pressure, the solvent was evaporated and ethanol was added to the residue. The resulting crystals were collected by filtration to give yellow crystals of N, -dimethyl-N- [4- [[2- (4-methyl-phenyl) benzofuran-5-carbonyl] amino] -benzyl] -4- iodide crystals. tetrahydropyranyl ammonium (Compound 281) (142.1 mg). p.f. 208-212 ° C RM ^ H (200MHz, DMS0-d6) d 1.71-2.01 (2H, m), 2.12-2.23 (2H, m), 2.39 (3H, s), 2.89 (6H, s), 3.10-3.43 (2H, m), 3. 48-3.69 (1H, m), 4.03-4.15 (2H, m), 4.48 (2H, s), 7.36 (2H, d, J = 8.0 Hz), 7.53-7.59 (3H, m), 7.77 (1H, d J = 8.4 Hz), 7.85-7.99 (5H, m), 8.29 (1H, d, J = 1.8 Hz), 10.52 (1H, s).

IR (KBr) 3277, 1643, 1595, 1525, 1468, 1416, 1325, 842, 820, 789, 762 cm "1 Calculated Analysis for C30H33N203I • 1.0H2O Calculated C, 58.64; H, 5.74; N, 4.56. 58.98; H, 5.62; N, 4.55.

Working Example 282 (Production of Compound 282) To a solution of 7- (4-methoxyphenyl) -2,3-dihydro-1-benzothiepin-4-carboxylic acid (150 mg) in THF (10 ml) were added at room temperature oxalyl chloride environment (0.13 ml), and one drop of DMF, and the mixture was stirred for 1 hour. Under reduced pressure, the solvent was evaporated and the residue was dissolved in THF (20 ml) To the mixture were added at 0 ° C 4- [N-methyl-N- (tetrahydropyran-4-yl) amino-methyl] aniline ( 116 mg) and triethylamine (0.2 ml), and the mixture was stirred at room temperature for 4 hours. The mixture was added to vigorously stirred water to stop the reaction and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the mixture was concentrated and the residue was purified by column chromatography (ethanol / ethyl acetate = 1: 4) and recrystallized from ethanol / diethyl ether to give pale yellow crystals of 7- (4-methoxyphenyl) ) -N- [4- [N-methyl-N- (tetrahydropyran-4-yl) aminomethyl] phenyl] -2,3-dihydro-l-benzothiepin-4-carboxamide (Compound 282) (128.5 mg). pf162-164 ° C NMR ^ H (200MHz, CDC13) d 1.61-1.83 (4H, m), 2.21 (3H, s), 2.55-2.72 (1H, m), 3.05-3.10 (2H, m), 3.26 -3.44 (4H, m), 3.57 (2H, s), 3.86 (3H, s), 3.96-4.09 (2H, m), 6.98 (2H, d, J = 8.8 Hz), 7.32 (2H, d, J = 8.4 Hz), 7.35-7.43 (2H, m), 7.48-7.57 (6H,), 7.68 (1H, broad s). IR (KBr) 3332, 1647, 1515, 1248, 818 cm "1 Calculated Analysis for C3? H3N2? 3S Calculated C, 72.34; H, 6.66; N, 5.44, Found C, 72.25; H, 6.67; N, 5.43.

Working Example 283 (Production of Compound 283) To a solution of 7- (4-methoxyphenyl) -2,3-dihydro-1-benzothiepin-4-carboxylic acid (200 mg) in THF (10 ml) were added at room temperature oxalyl chloride environment (0.30 ml), and one drop of DMF, and the mixture was stirred for 1 hour. Under reduced pressure, the solvent was evaporated and the residue was dissolved in THF (20 ml). To the mixture, 4- [N- (4,4-ethylenedioxycydohexyl) -N-methylaminomethyl] aniline (0.20 mg) and triethylamine (0.3 ml) were added at 0 ° C, and the mixture was stirred at room temperature for 4 hours. The mixture was added to vigorously stirred water to stop the reaction and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the mixture was concentrated and the solid residue was recrystallized with acetone / diethyl ether to give pale yellow crystals of N- [4- [N- (4,4-ethylenedioxy-cyclohexyl) -N-methylaminomethyl] phenyl] -7- (4-methoxy-phenyl) -2,3-dihydro-l-benzothiepin-4-carboxamide (Compound 283) (226.4 mg). p.f. 198-201 ° C NMR ^ H (200MHz, CDC13) d 1.45-1.91 (8H, m), 2.21 (3H, s), 2.44-2.65 (1H, m), 3.03-3.10 (2H, m), 3.26- 3.31 (2H, m), 3.57 (2H, s), 3.86 (3H, s), 3.95 (4H, s), 6.98 (2H, d, J = 8.8 Hz), 7.32 (2H, d, J = 8.4 Hz ), 7.37-7.43 (2H, m), 7.46-7.60 (6H, m), 7.68 (1H, broad s). IR (KBr) 3359, 1651, 1514, 1252, 1103, 1030, 926, 830 cm 1 Analysis is calculated for C34H38N204S • 0. 3H20 Calculated C, 70. 88; H, 6 75; N, 4 8 6. Found C, 70. 8 6; H, 6 70; N, 4 77 Working Example 284 (Production of Compound 284) To a solution of N- [4- [N- (4,4-ethylenedioxy-cyclohexyl) -N-methylaminomethyl] phenyl] -7- (4-methoxy-phenyl) -2 , 3-dihydro-l-benzothiepin-4-carboxamide (130 mg) in THF (15 ml) was added at room temperature 6N hydrochloric acid (1 ml), and the mixture was stirred for 66 hours. To the mixture was added a solution of sodium bicarbonate, and extracted with ethyl acetate. The organic layer was washed with saturated brine and magnesium sulfate. Under reduced pressure, the mixture was concentrated and the resulting solid was recrystallized from ethyl acetate / hexane to give pale yellow crystals of 7- (4-methoxyphenyl) -N- [4- [N-methyl-N- (4- oxocyclohexyl) aminomethyl] phenyl] -2,3-dihydro-l-benzothiepin-4-carboxamide (Compound 284) (78.3 mg). p.f. 133-139 ° C NMR-1H (200MHz, CDC13) d 1.74-2.19 (4H, m), 2.23 (3H, s), 2.30-2.59 (4H, m), 2.81-2.97 (1H, m), 3.04- 3.10 (2H, m), 3.26-3.32 (2H, m), 3.60 (2H, s), 3.86 (3H, s), 6.98 (2H, d, J = 9.2 Hz), 7.33 (2H, d, J = 8.4 Hz), 7.38-7.43 (2H, m), 7.48-7.58 (6H, m), 7.71 (1H, broad s). IR (KBr) 3273, 1711, 1651, 1605, 1515, 1408, 1317, 1248, 1180, 820 cm "1 Calculated Analysis for C32H34N203S • 0.2H20 Calculated C, 72.48; H, 6.54; N, 5.28. Found C, 72.33; H, 6.42; N, 5.13.

Working Example 285 (Production of Compound 285) To a solution of 7- (4-morpholinophenyl) -2,3-dihydro-1-benzothiepin-4-carboxylic acid (150 mg) and 1-hydroxy-benzotriazole (0.11 g) In DMF (5 ml), l-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.16 ml) was added at room temperature, and the mixture was stirred for 1 hour. To the mixture was added a solution of 4- [N-methyl-N- (tetrahydropyran-4-yl) aminomethyl] aniline (135 mg) and triethylamine (0.11 ml) in DMF (5 ml), and the mixture was stirred for 18 hours. Under reduced pressure, the mixture was concentrated and water was added to the mixture. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with column chromatography (ethanol / ethyl acetate = 1: 2) to give yellow crystals of N- [4- [N-methyl-N- (tetrahydropyran -4-yl) aminomethyl] phenyl] -7- (4-morpholinophenyl) -2,3-dihydro-l-benzothiepin-4-carboxamide (Compound 285) (113.9 mg). p.f. 255-259 ° C NMR ^ H (200MHz, CDCl 3) d 1.63-1.84 (4H, m), 2.21 (3H, s), 2.55-2.76 (1H,), 3.02-3.10 (2H, m), 3.19-3.46 (8H, m), 3.58 (2H, s), 3.85-3.93 (4H, m), 3.98-4.10 (2H, m), 6.99 (2H, d, J = 9.2 Hz), 7.32 (2H, d, J = 8.4 Hz), 7.37-7.45 (2H, m), 7.49-7.58 (6H, m), 7.67 (1H, broad s).

IR (KBr) 3288, 1653, 1606, 1522, 1232, 1119, 928, 816 cm "1 Calculated Analysis for C34H39N303S • 0.5H20 Calculated C, 70.56; H, 6.97; N, 7.26 Found C, 70.43; H, 6.83; N, 7.22.

Working Example 286 (Production of Compound 286) To a solution of 7- (3,4-methylenedioxyphenyl) -2,3-dihydro-1-benzothiepin-4-carboxylic acid (150 mg) in THF (10 ml) was added at room temperature oxalyl chloride (0.08 ml) and one drop of DMF, and the mixture was stirred for 1 hour. Under reduced pressure, the solvent was evaporated and the residue was dissolved in THF (20 ml). To the mixture was added at 0 ° C 4- [N-methyl-N- (tetrahydropyran-4-yl) aminomethyl] aniline (112 mg) and triethylamine (0.13 ml) and the mixture was stirred at room temperature for 18 hours. The mixture was added to vigorously stirred water to stop the reaction and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the mixture was concentrated and the residue was purified by column chromatography (ethanol / ethyl acetate = 1: 3) and recrystallized from ethanol to give colorless crystals of 7- (3,4-methylenedioxyphenyl) -N - [14- [N-Methyl-N- (tetrahydropyran-4-yl) aminomethyl] phenyl] -2,3-dihydro-l-benzothiepin-4-carboxamide (Compound 286) (183.2 mg). p.f. 193-194 ° C NMR ^ H (200MHz, CDC13) d 1.52-1.83 (4H, m), 2.21 (3H, s), 2.54-2.72 (1H, m), 3.04-3.10 (2H, m), 3.23- 3.44 (4H, m), 3. 57 (2H, s), 3.98-4.09 (2H, m), 6.01 (2H, s), 6.88 (1H, d, J = 8.8Hz), 7.01-7.07 (2H, m), 7.29-7.38 (4H, m), 7.46-7.58 (4H, m), 7.68 (1H, broad s). IR (KBr) 3334, 1647, 1506, 1475, 1408, 1313, 1232, 1041, 818 cm "1 Calculated Analysis for C31H32N2O4S Calculated C, 70.43; H, 6.10; N, 5.30, Found C, 70.28; H, 5.94; N, 5.14.

Work Example 287 (Production of Compound 287) To a solution of 7- (4-ethoxyphenyl) -2,3-dihydro-l-benzoxepin-4-carboxylic acid (200 mg) in THF (10 ml) were added to oxalyl chloride room temperature (0.11 ml) and one drop of DMF, and the mixture was stirred for 1 hour. Under reduced pressure, the mixture was concentrated and the residue was dissolved in THF (20 ml). To the mixture was added at 0 ° C a solution of 4- [N- (4,4-ethylenedioxy-cyclohexyl) -N-methylaminomethyl] aniline (0.19 mg) and triethylamine (0.18 ml) in THF (5 ml), and The mixture was stirred at room temperature for 16 hours. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated and the residue was purified with column chromatography (ethanol / ethyl acetate = 1: 3) and recrystallized with ethyl acetate / diisopropyl ether) to give colorless crystals of 7- (4- ethoxyphenyl) -N- [4- [N- (4, 4-ethylenedioxycyclohexyl) -N-methylaminomethyl] -phenyl] -2,3-dihydro-l-benzoxepin-4-carboxamide (Compound 287) (19.1 mg). The mother liquor was concentrated to give a crude product (91.5 mg). p.f. 172-174 ° C NMR-1H (200MHz, CDC13) d 1.44 (3H, t, J = 7.0 Hz), 1.51-1.88 (8H, m), 2.20 (3H, s), 2.44-2.64 (1H, m) , 3.08 (2H, t, J = 4.6 Hz), 3.56 (2H, s), 3.95 (4H, s), 4.08 (2H, q, J = 7.0 Hz), 4.36 (2H, t, J = 4.6 Hz) , 6.96 (2H, d, J = 9.0 Hz), 7.05 (1H, d, J = 8.4 Hz), 7.32 (2H, d, J = 8.4 Hz), 7.40-7.56 (8H, m). IR (KBr) 3350, 1651, 1515, 1493, 1242, 1101, 922, 829, 802 cm "1 Calculated Analysis for C35H4oN2? 5 Calculated C, 73.92; H, 7.09; N, 4.93, Found C, 73.82; H, 7.01; N, 4.90.

Working Example 288 (Production of Compound 288) To a solution of 7- (4-ethoxyphenyl) -N- [4- [N- (4,4-ethylenedioxycyclohexyl) -N-methylaminomethyl] phenyl] -2,3-dihydro -l-benzoxepin-4-carboxamide (151.5 mg) in THF (10 ml) was added at room temperature 3N hydrochloric acid (2 ml), and the mixture was stirred for 22 hours. To the mixture was added a saturated sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the mixture was concentrated to give a colorless solid, which was recrystallized with ethyl acetate / diisopropyl ether to give colorless crystals of 7- (4-ethoxyphenyl) -N- [4- [N-methyl-N- (4-oxocyclohexyl) aminomethyl] phenyl] -2,3-dihydro-l-benzoxepin-4-carboxamide (Compound 288) (103.5 mg). p.f. 146-148 ° C NMR ^ H (200MHz, CDC13) d 1.44 (3H, t, J = 7.0 Hz), 1.80-2.19 (4H,), 2.23 (3H, s), 2.29-2.59 (4H, m), 2.83-2.98 (1H, m), 3.04-3.12 (2H, m), 3.61 (2H, s), 4.08 (2H, q, J = 7.0 Hz), 4.34-4.39 (2H, m), 6.96 (2H, d, J = 8.8 Hz), 7.05 (1H, d, J = 8.4 Hz), 7.33 (2H, d, J = 8.0 Hz), 7.41-7.57 (8H, m). IR (KBr) 3329, 1709, 1645, 1518, 1495, 1242, 825 cm "1. Analysis Calculated for C33H36N2O • 0.25H20 Calculated C, 74.91; H, 6.95; N, 5.29 Found C, 74.68; H, 6.92; N , 5.28 Working Example 289 (Production of Compound 289) To a solution of 4- [l- (4-ethylphenylsulfonyl) piperidin-4-yl] -6,7-dihydro-5H-benzocyclohepten-8-carboxylic acid (200 mg) in THF (10 ml) oxalyl chloride (0.08 ml) and one drop of DMF were added at room temperature, and the mixture was stirred for 1 hour. Under reduced pressure, the mixture was concentrated, and the residue was dissolved in THF (20 ml). To the mixture was added at 0 ° C a solution of 4- [N-methyl-N- (tetrahydropyran-4-yl) aminomethyl] -aniline (114 mg) and triethylamine (0.2 ml) in THF (5 ml), and The mixture was stirred at room temperature for 3 hours. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the mixture was concentrated, and the residue was purified with column chromatography (ethanol / ethyl acetate = 1: 3) and recrystallized from ethanol to give colorless crystals of 4- [1- (4-methyl- phenylsulfonyl) piperidin-4-yl] -N- [4- [N-methyl-N- (tetrahydropyran-4-yl) aminomethyl] phenyl] -6,7-dihydro-5H-benzocyclohepten-8-carboxamide (Compound 289) (203.5 mg). p.f. 175-176 ° C NMR - ^ - H (200MHz, CDC13) d 1.66-1.81 (4H, m), 1.83-1.92 (4H, m), 2.04-2.17 (2H, m), 2.21 (3H, s), 2.26-2.43 (3H, m), 2.45 (3H, s), 2.65-2.71 (2H, m), 2.76-2.86 (2H, m), 3.30-3.45 (2H, m), 3.57 (2H, s), 3.87-4.10 (4H, m), 6.97-7.13 (3H,), 7.29-7.37 (5H, m), 7.55 (2H, d, J = 8.4 Hz), 7.58 (1H, s), 7.68 (2H, d , J = 8.2 Hz). IR (KBr) 3346, 1647, 1518, 1344, 1159, 926, 725, 546 cm "1 Calculated Analysis for C 37 H 45 N 3 4 4 S Calculated C, 70.78; H, 7.22; N, 6.69, Found C, 70.71; H, 7.14; N, 6.46.

Working Example 290 (Production of Compound 290) In THF (3.4 ml), 7- (5-methyl-2-thienyl) -2,3-dihydro-l-benzoxepin-4-carboxylic acid (340 mg) was dissolved and Oxalyl chloride (0.198 ml) and DMF (one drop) were added to the mixture while stirring at room temperature. The mixture was stirred at room temperature for 2 hours. Under reduced pressure, the solvent was removed, and the resulting residue was dissolved in THF (5.1 ml). The mixture was added dropwise to a solution of 4- [N-methyl-N- (tetrahydropyran-4-yl) aminomethyl] aniline (308 mg) and triethylamine (0.473 ml) in THF (5.1 ml), under cooling with ice, and the mixture was stirred at room temperature for 13 hours. The mixture was poured into water, extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was removed and the resulting residue was purified with silica gel column chromatography (ethyl acetate / ethanol = 2/1) and recrystallized with hexane / ethyl acetate to give the N- [4- [N -methyl-N- (tetrahydropyran-4-yl) amino-methyl] phenyl] -7- (5-methyl-2-thienyl) -2,3-dihydro-l-benzoxepin-4-carboxamide (Compound 290) (20 mg). p.f. 129-130 ° C NMR ^ H (200MHz, CDCl 3) d 1.50-1.82 (4H, m), 2.21 (3H, s), 2.31 (3H, s), 2.65 (1H,), 3.08 (2H, t, J = 4.6Hz), 3.37 (2H, dt, J = 11.2, 3.2Hz), 3.58 (2H, s), 4.04 (2H,), 4.37 (2H, t, J = 4.6Hz), 6.92 (1H, d, J = 5.2Hz), 7.04 (1H, d, J = 5.2Hz), 7.18-7.52 (7H, m), 7.51-7.56 (2H, m) IR (KBr) 3294, 1653, 1597, 1514, 1498, 1456 1406, 1315, 1248, 733 cm "1 Working Example 291 (Production of Compound 291) In THF (10 ml), 7- (3-thienyl) -2,3-dihydro-1-benzoxepin-4-carboxylic acid (240 mg) was dissolved and the mixture was added to the mixture. oxalyl chloride (0.15 ml) and DMF (one drop) while stirring at room temperature, and the mixture was stirred at room temperature for 1.5 hours. Under reduced pressure, the solvent was removed, and the resulting residue in THF (6 ml) was added dropwise to a solution of 4- [N-methyl-N- (tetrahydropyran-4-yl) aminomethyl] aniline (247 mg ) and triethylamine (0.35 ml) in THF (10 ml), under cooling with ice, and the mixture was stirred at room temperature for 14 hours. The mixture was poured into water, extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was removed and the resulting residue was purified by column chromatography on silica gel (ethyl acetate / ethanol = 2/1) and recrystallized from hexane / ethyl acetate to give the N- [4 - [N-Methyl-N- (tetrahydropyran-4-yl) aminomethyl] phenyl] -7- (3-thienyl) -2,3-dihydro-l-benzoxepin-4-carboxamide (Compound 291) (180 mg). p.f. 194-195 ° C NMR ^ H (200MHz, CDC13) d 1.60-1.84 (4H,), 2.22 (3H, s), 2.69 (1H, m), 3.09 (2H, t, J = 4.6Hz), 3.36 ( 2H, dt, J = 11.2, 2.6Hz), 3.60 (2H, s), 4.04 (2H, m), 4.34 (2H, t, J = 4.6Hz), 7.03 (1H, d, J = 8.4Hz), 7.25-7.42 (7H, m), 7.47 (1H, dd, J = 8.4, 2.2Hz), 7.54 (1H, s), 7.58 (1H, s), 7.67 (1H, s).

IR (KBr) 3306, 1645, 1604, 1514, 1496, 1456, 1408, 1321, 1230, 781 c "1 Calculated Analysis for C28H3oN2? 3S Calculated C, 70. 8 6; H, 6.37; N, 5. 90. Found C, 70.74; H, 6.16; N, 5.92 Working Example 292 (Production of Compound 292) In THF 10 ml was dissolved in 7- (4-methyl-2-thienyl) -2,3-dihydro-l-benzoxepin-4-carboxylic acid (250 mg), and the Oxalyl chloride was added to the mixture. (0.145 ml) and DMF (one drop) while stirring at room temperature, and the mixture was stirred at room temperature for 2 hours. Under reduced pressure, the solvent was removed, and the resulting residue in methylene chloride (10 ml) was added dropwise to a solution of 4- [N-methyl-N- (tetrahydropyran-4-yl) aminomethyl] aniline ( 250 mg) and triethylamine (0.35 ml) in THF (5 ml), under cooling with ice, and the mixture was stirred at room temperature for 13 hours. The mixture was poured into water, extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was removed and the resulting residue was purified by column chromatography on silica gel (ethyl acetate / ethanol = 2/1) and recrystallized from hexane / ethyl acetate to give the N- [4 - [N-Methyl-N- (tetrahydropyran-4-yl) aminomethyl] phenyl] -1 - (4-methyl-2-thienyl) -2,3-dihydro-l-benzoxepin-4-carboxamide (Compound 292 ) (185 mg). p.f. 147-148 ° C NMR ^ H (200MHz, CDC13) d 1.60-1.80 (4H, m), 2.21 (3H, s), 2.31 (3H, s), 2.64 (1H, m), 3.06 (2H, t, J = 4.2Hz), 3.37 (2H, dt, J = 11.4, 2.8Hz), 3.57 (2H, s), 4.04 (2H, m), 4.33 (2H, t, J = 4.2Hz), 6.82 (1H, d, J = 1.2Hz), 6.99 (1H, d, J = 8.4Hz), 7.04 (1H, d, J = 1.2Hz), 7.19 (1H, s), 7.41-7.57 (5H,), 7.67 (1H , s) IR (KBr) 3292, 1653, 1597, 1514, 1456, 1406, 1315, 1246, 733cm_1 Analysis Calculated for C29H32N203S • 0.5H20 Calculated C, 69.99; H, 6.68; N, 5.63. Found C, 69.85; H, 6.43; N, 5.68.

Working Example 293 (Production of Compound 293) In THF (5.0 ml), 7- (4-fluorophenyl) -2,3-dihydro-l-benzoxepin-4-carboxylic acid (137 mg) was dissolved and the mixture was added to the mixture. DMF (one drop) and oxalyl chloride (0.085 ml). The mixture was stirred at room temperature for 1 hour, and the solvent was removed under reduced pressure. The residue was dissolved in THF (5.0 ml), and to the mixture was added a solution of 4- [(N-methyl-N- (tetrahydropyran-4-yl) aminomethyl] aniline (117 mg) and triethylamine (0.135 ml) in THF (5.0 ml) The mixture was stirred at room temperature for 1 hour, and water was added to the mixture (50 ml) The mixture was extracted with ethyl acetate (100 ml and 50 ml), and the organic layer was dried with anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel and recrystallized to give 7- (4-fluoro-phenyl) -N- [4- [(N-methyl-N- tetrahydropyran-4-yl) amino-methyl] -phenyl] -2,3-dihydro-l-benzoxepin-4-carboxamide (Compound 293) (149 mg, 64%) as pale yellow needle-like crystals, m.p. 177-178 ° C. IR (KBr) 3351, 2938, 1649, 1632, 1595, 1518, 1491, 1412, 1316, 1219, 829cm "1. NMR-aH (200MHz, CDC13) d 1.69-1.77 (4H, m), 2.21 (3H, s), 2.60-2.70 (1H, m), 3.09 (2H, t, J = 4.2Hz), 3.37 (2H, td, J = ll.l, 2.9Hz), 3.58 (2H, s), 4.04 (2H) , d, J = 10.6Hz), 4.37 (2H, t, J = 4.7Hz), 7.04-7.16 (3H, m), 7.29-7.56 (8H, m.Analysis Calculated for C30H3? FN203; C, 74.05, H, 6.42, N, 5.76 Found; C, 73.90, H, 6.35, N, 5.53 Working Example 294 (Production of Compound 294) To a suspension of 6- (4-methylphenyl) -2H-thiochromen-3-carboxylic acid (0.36 g, 1.28 mmole) in dichloromethane (5 ml) oxalyl chloride (0.33 ml, 3.84 mmol) and N, N-dimethylformamide (one drop) were added at 0 ° C, and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated, and the residue was dissolved in tetrahydrofuran (3 ml). To the mixture was added dropwise a solution of aniline (0.31 g, 1.41 mmol) and triethylamine (0.54 ml, 3.84 mmol) in tetrahydrofuran (2 ml), and the mixture was stirred for 3 hours. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated and the resulting powder was washed with hexane to give 6- (4-methylphenyl) -N- (4- ((N-methyl-N-tetrahydropyran-4-yl) amino) -methyl) phenyl-2H -thiochromen-3-carboxamide (Compound 294) (0.45 g, 72%) as a pale yellow powder. p.f. 200 ° C. NMR ^ H (200MHz, DMSO-d6) d: 7.32-7.36 (3H, m), 7.21-7.28 (4H, m), 7.07 (1H, d, J = 8.2), 6.92-6.99 (4H,), 3.50- 3.66 (2H, m), 3.48 (2H, s), 3.20 (2H, s), 2.86- 3.00 (2H,), 2.20-2.37 (1H, m), 2.03 (3H, s), 1.78 (3H, s), 1.08-1.46 (4H, m).

Analysis Calculated for C30H32N2O2S • 0. 25H2O C; 73.66, H; 6.70, N; 5.73. Found C; 73.84, H; 6.60, N; 5.84.

Working Example 295 (Production of Compound 295) To a suspension of 6- (4-methylphenyl) -2H-thiochromen-3-carboxylic acid (226 g, 0.785 mmol) in tetrahydrofuran (7 ml) were added oxalyl chloride (0.21). ml, 2.35 mmol) and N, N-dimethylformamide (one drop), and the mixture was stirred at room temperature for 1 hour. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in tetrahydrofuran (5 ml). To the mixture was added dropwise a solution of (E) -4- ((N- (4-hydroxycyclohexyl) -N-methyl) aminomethyl) aniline (202 mg 0.864 mmol) and triethylamine (0.33 ml, 2.35 mmol) in tetrahydrofuran (2 ml), and the mixture was stirred for 15 hours. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated, and the residue was purified by column chromatography on silica gel [ethyl acetate: ethanol (2: 1)] to give (E) -N- (4- ((N- (4- hydroxycyclohexyl) -N-methyl) amino) methyl) phenyl-6- (4-methylphenyl) -2H-thiochromen-3-carboxamide (Compound 295) (160 mg, 41%), which was recrystallized from ethyl acetate / hexane to give yellow crystals, pf 149 ° C NMR-1H (CDC13) d 7.73 (1H, broad s), 7.42-7.58 (6H, m), 7.22-7.38 (5H, m), 3.81 (2H, d, J = 0.8), 3.59 (2H , s), 3.55-3.68 (1H, m), 2.42-2.61 (1H, m), 2.40 (3H, s), 2.21 (3H, s), 1.86-2.20 (4H, m), 1.23-1.57 (4H , m). Analysis Calculated for C3: LH34N204S • 1.25H20: C; 71.44, H; 7.06, N; 5.37. Found: C; 71.12, H; 6.53, N; 5.51.

Working Example 296 (Production of Compound 296) To a suspension of 6- (4-methylphenyl) -2H-thiochromen-3-carboxylic acid (204 mg, 0.708 mmol) in tetrahydrofuran (6 ml) were added oxalyl chloride (0.19). ml) and N, -dimethylformamide (one drop), and the mixture was stirred at room temperature for 1 hour. Under reduced pressure, the solvent was evaporated and the residue was dissolved in tetrahydrofuran (5 ml). To the mixture was added dropwise a solution of 4- ((N- (2-ethoxy-ethyl) -N-methyl) aminomethyl) aniline (153 mg, 0.802 mmol) and triethylamine (0.30 ml) in tetrahydrofuran (2 ml. ), and the mixture was stirred for 15 hours. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated and the residue was purified by column chromatography on silica gel [ethyl acetate ethanol (2: 1)] to give N- (4- (N- (4-methoxyethyl) -N-methyl) ) aminomethyl) -phenyl-6- (4-methylphenyl) -2H-thiochromen-3-carboxamide (Compound 296) (170 mg, 52%) which was recrystallized from ethyl acetate / hexane to give yellow crystals, mp. 101 ° C NMR-1H (CDC13) d: 7.67 (1H, broad s), 7.41-7.57 (6H, m), 7.20-7.38 (5H, m), 3.82 (2H, t, J = 0.8), 3.56 ( 2H, s), 3.53 (2H, t, J = 5.8), 3.35 (3H, s), 2.61 (2H, t, J = 5.8), 2.40 (3H, s), 2.28 (3H, s). Analysis Calculated for C28H3oN202S • 0.25H2O: C; 72.62, H; 6.64, N; 6.05. Found: C; 72:43, H; 6.39, N; 6.36.

Working Example 297 (Production of Compound 297) To a suspension of 7- (4-methylphenyl) -2,3-dihydro-1-benzothiepin-4-carboxylic acid (292 mg, 0.987 mmol) in tetrahydrofuran (10 ml) was oxalyl chloride (0.26 ml) and N, N-dimethylformamide (one drop) were added at 0 ° C, and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated and the residue was dissolved in tetrahydrofuran (8 ml). To the residue, a solution of 4 - ((N- (3-ethoxycarbonylethyl) -N-methyl) -aminomethyl) aniline (233 mg, 0.987 mmol) and triethylamine (0.42 ml) in tetrahydrofuran (2 ml) was added dropwise to the residue. 0 ° C, and the mixture was stirred at room temperature for 17 hours. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated, and the residue was purified by column chromatography on silica gel [ethyl acetate] to give N- (4- (N- (3-ethoxy-carbonylethyl) -N-methyl) aminomethyl) phenyl -7- (4-methyl-phenyl) -2,3-dihydro-l-benzothiepin-4-carboxamide (Compound 297) (408 mg, 80%), which was recrystallized from acetone / ethanol to give colorless crystals, mp. 124 ° c NMR-aH (CDC13) d: 7.89 (1H, broad s), 7.38-7.58 (7H, m), 7.22-7.30 (4H,), 4.14 (2H, q, J = 7.4), 3.48 (2H , s), 3.25 (2H, dt, J = 5.4, 1.4) 3.05 (2H, t, J = 5.4), 2.74 (2H, t, J = 6.8), 2.51 (2H, t, J = 6.8), 2.39 (3H, s), 2.19 (3H, s), 1.25 (3H, t, J = 7.4). Analysis is Calculated for C3? H34N203S: C; 72.34, H; 6.66, N; 5.44. Found: C; 72.32, H; 6.43, N; 5.45.

Working Example 298 (Production of Compound 29) To a suspension of 7- (4-methylphenyl) -2,3-dihydro-1-benzothiepin-4-carboxylic acid (222 mg, 0.750 'mmole) in tetrahydrofuran (7 ml) was oxalyl chloride (0.26 ml, 2.97 mmol) and N, N-dimethylformamide (one drop) were added at 0 ° C, and the mixture was stirred at room temperature for 2 hours.The solvent was evaporated, and the residue was dissolved in tetrahydrofuran. (5 ml) To the residue was added dropwise an aniline solution (149 mg, 0.825 mmol) and triethylamine (0.31 ml, 2.25 mmol) in tetrahydrofuran (2 ml) at 0 ° C, and the mixture was stirred at room temperature. After 3 days, water was added to the mixture, and the mixture was extracted with ethyl acetate.The extract was washed with saturated brine and dried with magnesium sulfate, the solvent was evaporated and the residue was purified by chromatography on silica gel column [ethyl acetate methanol: triethylamine (5: 1: 0.6)] to give the N- (4- (N- (2-hid) roxy-ethyl) -N-methyl) aminomethyl) phenyl-7- (4-methylphenyl) -2,3-dihydro-1-benzothiepin-4-carboxamide (Compound 298) (310 mg, 90%). p.f. 138 ° C. NMR-aH (CDC13) d: 7.74 (1H, broad s), 7.40-7.59 (7H, m), 7.23-7.32 (4H, m), 3.64 (2H, t, J = 5.2), 3.58 (2H, s) ), 3.28 (2H, t, J = 5.6), 3.07 (2H, t, J = 5.6), 2.62 (2H, t, J = 5.2).

Analysis Calculated for C3? H34N203S: C; 72.34, H; 6.66, N; 5.44 Found: C; 72.32, H; 6.43, N; 5.45 Working Example 299 (Production of Compound 299) To a suspension of 6- (4-methylphenyl) -2-pyridine-acrylic acid (160 mg, 0.67 mmole) in DMF (5 ml) were added at 0 ° C 1-hydroxybenzotriazole (99 mg, 0.73 mmol), 4- [N-methyl-N- (4-tetrahydropyranyl) aminomethyl] aniline (162 mg, 0.74 mmol), l-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (192 mg , 1.00 mmol), triethylamine (0.28 ml, 2.01 mmol) and 4-dimethylaminopyridine (10 mg) in this order, and the mixture was stirred at room temperature for 17 hours. The mixture was concentrated under reduced pressure and ethyl acetate was added to the residue (40 ml). The mixture was washed with water (5 ml, 3 ml x 2), a saturated sodium bicarbonate solution (3 ml x 3) and saturated brine (3 ml) in this order. The organic layer was dried with anhydrous sodium sulfate and concentrated under reduced pressure and the residue was purified by column chromatography (silica gel 15 g, ethyl acetate / methanol = 9/1). The desired fraction was concentrated under reduced pressure to give N- [4- [N-methyl-N- (4-tetrahydropyranyl) amino-methyl] phenyl] -6- (4-methylphenyl) -2-pyridine acrylamide (Compound 299) (259 mg, 0.59 mmol, 88%). IR (KBr): 1667, 1634, 1601, 1537, 1514 cm "1. NMR-aH (CDC13) d: 1.55-1.85 (4H, m), 2.21 (3H, s), 2.43 (3H, s), 2.55 -2.75 (1H, m), 3.30-3.45 (2H, m), 3.58 (2H, s), 3.95-4.10 (2H, m), 7.20-7.50 (5H, m), 7.45-7.85 (6H, m) , 7.98 (2H, d, J = 8.2Hz).

Working Example 300 (Production of Compound 300) In DMF (5 ml) the 7- (3,4-methylenedioxyphenyl) -2,3-dihydro-1-benzoxepin-4-carboxylic acid was dissolved and the mixture was added to the mixture. -hydroxybenzotriazole (67 mg, 0.50 mmol), 4- [N-methyl-N- (4-tetrahydropyranyl) -aminomethyl] aniline (109 mg, 0.49 mmol), l-ethyl-3- (3-dimethylaminopropyl) hydrochloride carbodiimide (130 mg, 0.68 mmol), triethylamine (0.189 ml, 1.36 mmol) and 4-dimethylaminopyridine (3 mg). The mixture was stirred at room temperature for 18 hours and concentrated under reduced pressure. Ethyl acetate was added to the residue (60 ml), and the mixture was washed with water (5 ml x 3), a saturated sodium bicarbonate solution (3 ml x 3) and saturated brine (5 ml) in this order. The organic layer was dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified with column chromatography (silica gel 15 g, ethyl acetate). The desired fraction was concentrated under reduced pressure, and ethyl acetate was added to the residue. Insoluble materials were filtered, and the insoluble materials were washed with ethyl acetate and dried under reduced pressure to give 7- (3,4-methylenedioxyphenyl) -N- [4- [N-methyl-N- (4- tetrahydropyranyl) aminomethyl] phenyl] -2,3-dihydro-l-benzoxepin-4-carboxamide (Compound 300) (187 mg, 0.36 mmol, 81%). IR (KBr): 1653, 1597, 1514 cm "1. NMR-aH (CDC13): 1.55-1.85 (4H, m), 2.21 (3H, s), 2.55-2.80 (1H, m), 3.00-3.15 ( 2H,), 3.30-3.45 (2H, m), 3.58 (2H, s), 3.95-4.15 (2H, m), 4.30-4.45 (2H, m) 6.01 (2H, s), 6.88 (1H, d, J = 8.6Hz), 6.95-7.10 (3H, m), 7.20-7.65 (7H, m).

Working Example 301 (Production of Compound 301) In DMF (6 ml), 7-morpholino-2,3-dihydro-l-benzoxepin-4-carboxylic acid (200 mg, 0.73 mmol) was dissolved and the mixture was added to the mixture. at 0 ° C 1-hydroxybenzotriazole (108 mg, 0.80 mmol), 4- [N-methyl-N- (4-tetrahydropyranyl) -aminomethyl] aniline (176 mg, 0.80 mmol), l-ethyl-3- hydrochloride ( 3-dimethylaminopropyl) carbodiimide (209 mg, 1.09 mmol), triethylamine (0.304 ml, 2.18 mmol) and 4-dimethylaminopyridine (3 mg). The mixture was stirred at room temperature for 13 hours and concentrated under reduced pressure. Ethyl acetate was added to the residue (40 ml), and the mixture was washed with water (5 ml x 3), a saturated sodium bicarbonate solution (5 ml x 3) and saturated brine (5 ml) in this order. The organic layer was dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel 15 g, ethyl acetate / methanol = l / 0-> 9 / l). The desired fraction was concentrated under reduced pressure, and diethyl ether was added to the residue. Insoluble materials were filtered, and the insoluble materials were washed with diethyl ether and dried under reduced pressure to give N- [4- [N-methyl-N- (4-tetrahydropyranyl) aminomethyl] phenyl] -7-morpholino- 2,3-dihydro-l-benzoxepin-4-carboxamide (Compound 301) (248 mg, 0.52 mmol, 71%). IR (KBr): 1655, 1597, 1507 cm "1, NMR-aH (CDC13) d 1.5-1.85 (4H, m), 2.21 (3H, s), 2.55-2.75 (1H, m), 3.0-3.15 ( 6H,), 3.3-3.45 (2H, m), 3.57 (2H, s), 3.8-3.9 (4H, m), 3.95-4.1 (2H, m), 4.29 (2H, t, J = 4.7 Hz), 6.8-7.0 (3H, m), 7.15-7.35 (3H,), 7.5-7.6 (2H + 1H (amide-H), m).

Working Example 302 (Production of Compound 302) In DMF (6 ml) the 7- (4-methylphenyl) -2,3-dihydro-1-benzoxepin-4-carboxylic acid (140 mg, 0.50 mmol) was dissolved and the At 0 ° C, 1-hydroxybenzotriazole (74 mg, 0.55 mmol), 4- [N- (2-pyrimidinyl) -aminomethyl] aniline (100 mg, 0.50 mmol), and l-ethyl-3-hydrochloride were added at 0 ° C. 3-dimethylaminopropyl) -carbodiimide (144 mg, 0.75 mmol). The mixture was stirred at room temperature for 22 hours and concentrated under reduced pressure. Ethyl acetate was added to the residue (40 ml), and the mixture was washed with water (5 ml), a saturated sodium bicarbonate solution (5 ml x 3) and saturated brine (5 ml) in that order. The organic layer was dried with anhydrous sodium sulfate and concentrated to about 3 ml under reduced pressure. The insoluble, precipitated materials were filtered, and the insoluble materials were washed with ethyl acetate and dried under reduced pressure to give N- [4- [N- (2-pyrimidinyl) -aminomethyl] phenyl] -7- (4 methylphenyl) -2,3-dihydro-l-benzoxepin-4-carboxamide (Compound 302) (129 mg, 0.28 mmol, 56%). IR (KBr): 1647, 1591, 1518 cm "1, NMR-1H (DMSO-ds) d: 2.34 (3H, s), 2.9-3.05 (2H, m), 4.2-4.35 (2H, m), 4.46 (2H, d, J = 6.6Hz), 6.57 (1H, t, J = 4.8Hz), 7.04 (1H, d, J = 8.4Hz), 7.2-7.35 (5H, m), 7.5-7.75 (7H, m), 8.27 (2H, d, J = 4.8Hz), 9.91 (1H, s).

Working Example 303 (Production of Compound 303) To a mixture of 7- (2-methyl-lH-tetrazol-5-yl) -2,3-dihydro-l-benzoxepin-4-carboxylic acid (180 mg, 0.66 mmol ), 4- [N-methyl-N- (tetrahydropyran-4-yl) aminomethyl] aniline (160 mg, 0.73 mmol), 1-hydroxybenzotriazole (98 mg, 0.73 mmol) and DMF (10 ml) were added at 0 °. C l- [3- (dimethylamino) rovyl] -3-ethylcarbodiimide hydrochloride (190 mg, 0.99 mmol), and triethylamine (0.276 mL, 1.98 mmol) and the mixture was stirred at room temperature for 24 hours.

The mixture was concentrated under reduced pressure and ethyl acetate was added to the residue (40 ml). The mixture was washed with a saturated sodium bicarbonate solution (5 ml x 3) and saturated brine (5 ml) in this order. The organic layer was dried with anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel 15 g, ethyl acetate). The desired fraction was concentrated under reduced pressure, and ethyl acetate was added to the residue. The insoluble materials were filtered, and the insoluble materials were washed with ethyl acetate and dried under reduced pressure to give 7- (2-methyl-lH-tetrazol-5-yl) -N- [4- [N-methyl] -N- (tetrahydropyran-4-yl) aminomethyl] phenyl] -2,3-dihydro-l-benzoxepin-4-carboxamide (Compound 303) (217 mg, 0.46 mmol, 69%). IR (KBr): 1647, 1628, 1611, 1595, 1522 cm "1. RMN ^ H (DMS0-d6) d: 1.35-1.8 (4H,), 2.10 (3H, s), 2. 4-2.7 (1H, m), 2.9-3.1 (2H,), 3.15-3.4 (2H, m), 3.52 (2H, s), 3.8-4.0 (2H, m), 4.25-4.45 (2H,), 4.42 (3H, s), 7.16 (1H, d, J = 8.4Hz), 7.26 (2H, d, J = 8.4Hz), 7.40 (1H, s), 7.66 (2H, d, J = 8.4Hz), 7.92 (1H, dd, J = 1.9, 8. 4Hz), 8.19 (1H, d, J = 1.9Hz).

Working Example 304 (Production of Compound 304) To a mixture of 7- (1-methyl-lH-tetrazol-5-yl) -2,3-dihydro-l-benzoxepin-4-carboxylic acid (69 mg, 0.25 mmol ), 4- [N-methyl-N- (tetrahydropyran-4-yl) aminomethyl] aniline (61 mg, 0.28 mmol), 1-hydroxybenzotriazole (38 mg, 0.28 mmol) and DMF (4 ml) were added at 0 °. C l- [3- (dimethylamino) rovyl] -3-ethylcarbodiimide hydrochloride (97 mg, 0.51 mmol), and triethylamine (0.106 mL, 0.76 mmol) and the mixture was stirred at room temperature for 2 days. The mixture was concentrated under reduced pressure, and ethyl acetate was added to the residue. The mixture was washed with a saturated sodium bicarbonate solution. The organic layer was dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified with column chromatography (silica gel 10 g, ethyl acetate). The desired fraction was concentrated under reduced pressure, and ethyl acetate was added to the residue. The insoluble materials were filtered, and the insoluble materials were washed with ethyl acetate and dried under reduced pressure to give 7- (1-methyl-lH-tetrazol-5-yl) -N- [4- [N-methyl] -N- (tetrahydropyran-4-yl) aminomethyl] phenyl] -2,3-dihydro-l-benzoxepin-4-carboxamide (Compound 304) (84 mg, 0.18 mmol, 70%). IR (KBr): 1649, 1630, 1597, 1518 c "1. RMN-aH (DMSO-de) d: 1.35-1.8 (4H,), 2.10 (3H, s), 2.45-2.7 (1H, m), 2.95-3.1 (2H, m), 3.15-3.4 (2H,), 3.51 (2H, s), 3.8-4.0 (2H, m), 4.20 (3H, s), 4.3-4.45 (2H, m), 7.22 (1H, d, J = 8.4Hz), 7.26 (2H, d, J = 8.6Hz), 7.35 (1H, s) 7.64 (2H, d, J = 8.6Hz), 7.76 (1H, dd, J = 2.2 , 8.4Hz), 7.99 (1H, d, J = 2.2Hz).

Working Example 305 (Production of Compound 305) In DMF (12.0 ml) was dissolved lm.ethyl-7- (4-methylphenyl) -2,3-dihydro-l-benzoxepin-4-carboxylic acid hydrochloride (386 mg) and thionyl chloride (0.26 ml) was added to the mixture. The mixture was stirred at room temperature for 30 minutes and the solvent was evaporated under reduced pressure. The residue was dissolved in dichloromethane (10.0 ml). The acid chloride solution prepared in this manner was added dropwise at 0 ° C to a solution of 4- [[N-methyl-N- (tetrahydropyran-4-yl) amino] methyl] aniline (310 mg) and triethylamine (0.82 ml) in dichloromethane (4.0 ml). The mixture was stirred at 0 ° C for 10 minutes and then at room temperature for 22 hours. To the mixture was added water (100 ml) and the mixture was extracted with dichloromethane (100 ml, twice). The organic layer was dried with anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (75 g, ethyl acetate: ethanol = 9: 1) and recrystallized from ethanol to give l-methyl-7- (4-methylphenyl) -N- [ 4- [[N-methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl] -2,3-dihydro-l-benzoazepine-4-carboxamide (Compound 305) (250 mg, 43%). p.f. 178-181 ° C. NMR ^ H (200MHz, CDC13) d 1.64-1.76 (4H, m), 2.21 (3H, s), 2.38 (3H, s), 2.66 (1H, septet, J = 5.3Hz), 2.96 (2H, t, J = 4.4Hz), 3.09 (3H, s), 3.30-3.43 (2H + 2H, m), 3.58 (2H, s), 4.01-4.06 (2H, m), 6.88 (1H, d, J = 8.6Hz ), 7.23 (2H, d, J = 8.0Hz), 7.30 (2H, d, J = 8.4Hz), 7.42, (1H, s), 7.461 (2H, d, J = 8.2Hz), 7.466 (1H, dd, J = 8.3, 2.3Hz), 7.535 (2H, d, J = 8.4Hz), 7.539 (1H, d, J = 2.6Hz), 7.58 (1H, s). IR (KBr) 3337, 2949, 2851, 1653, 1516, 1501, 1341, 1304, 1238, 818, 521 cm. "1 Analysis Calculated for C2H27N302: C, 77.54; H, 7.52; N, 8.48. Found: C, 77.51; H, 7.43; N, 8.44.

Working Example 306 (Production of Compound 306) In water: ethanol: toluene (1: 1: 10, 18.0 ml) were dissolved 4-ethoxyphenyl borate (252 mg) and 7-bromo-1-methyl-N- [4 - [[N-methyl-N- (tetrahydropyran-4-yl) amino] -methyl] phenyl] -2,3-dihydro-l-benzoazepine-4-carboxamide (613 mg), and to the mixture was added potassium carbonate (420 mg). The mixture was stirred under an argon atmosphere for 30 minutes and to the mixture tetracistriphenylphosphine palladium (59 mg) was added. Under an argon atmosphere, the mixture was heated to reflux for 17 hours. The mixture was diluted with ethyl acetate (200 ml) and washed with water (50 ml) and saturated brine (50 ml). The organic layer was dried with anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (75 g, ethyl acetate: ethanol = 9: 1) and recrystallized from ethanol to give 7- (4-ethoxyphenyl) -1-methyl-N- [ 4- [[N-methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl] -2,3-dihydro-l-benzoazepine-4-carboxamide (Compound 306) (230 mg, 35%). p.f. 150.5-152 ° C. NMR ^ H (200MHz, CDC13) d 1.44 (3H, t, J = 7.0Hz), 1.64-1.77 (4H, m), 2.21 (3H, s), 2.57-2.72 (1H, m), 2.96 (2H, t, J = 4.5Hz), 3.08 (3H, s), 3.31-3.43 (2H + 2H, m), 3.57 (2H, s), 4.01-4.09 (2H, m), 4.07 (2H, q, J = 7.0Hz), 6.88 (1H, d, J = 8.4Hz), 6.95 (2H, d, J = 8.8Hz), 7.30 (2H, d, J = 8.6Hz), 7.40-7.55 (1H + 1H + 1H + 1H, hidden under 7.45 and 7.53), 7.47 (2H, d, J = 9.0Hz), 7.53 (2H, d, J = 8.8Hz). IR (KBr) 3372, 2955, 2847, 1680, 1605, 1595, 1518, 1503, 1314, 1240, 1194, 812 cm "1. Analysis Calculated for C33H39N03 • 0.5H20: C, 74.13; H, 7.54; N, 7.86 Found: C, 74.34; H, 7.31; N, 7.96.

Working Example 307 (Production of Compound 307) In water: ethanol: toluene (1: 1: 10, 18.0 ml) were dissolved 4-ethylphenyl borate (227 mg) and 7-bromo-1-methyl-N- [4 - [[N-methyl-N- (tetrahydropyran-4-yl) amino] -methyl] phenyl] -2,3-dihydro-l-benzoazepine-4-carboxamide (611 mg), and potassium carbonate (418 mg) was added to the mixture. The mixture was stirred under an argon atmosphere for 30 minutes and to the mixture tetracistriphenylphosphine palladium (59 mg) was added. Under an argon atmosphere, the mixture was heated to reflux for 17 hours and the mixture was diluted with ethyl acetate (200 ml) and washed with water (50 ml) and saturated brine (50 ml). The organic layer was dried with anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (75 g, ethyl acetate: ethanol = 9: 1) and recrystallized from ethanol to give 7- (4-ethylphenyl) -1-methyl-N- [4 - [[N-methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl] -2,3-dihydro-l-benzoazepine-4-carboxamide (Compound 307) (252 mg, 39%). p.f. 164-165 ° C. NMR-aH (200MHz, CDC13) d 1.27 (3H, t, J = 7.6Hz), 1.66-1.76 (4H, m), 2.21 (3H, s), 2.54-2.70 (1H, m), 2.69 (2H, q, J = 7.7Hz), 2.96 (2H, t, J = 4.7Hz), 3.09 (3H, s), 3.29-3.43 (4H, m), 3.57 (2H, s), 4.01-4.06 (2H, m ), 6.89 (1H, d, J = 8.6Hz), 7.26 (2H, d, J = 8.4Hz), 7.30 (2H, d, J = 8.8Hz), 7.40 (1H, s), 7.48 (1H, dd) , J = 8.6, 2.2Hz), 7.49 (2H, d, J = 9-.2Hz), 7.54 (2H, d, J = 8.8Hz), 7.55 (1H, d, J = 2.2Hz), 1H was concealed under 7.40-7.56. IR (KBr) 3364, 2946, 2851, 1653, 1514, 1341, 1304, 1233, 1188, 824, 575, 519 cm "1. Analysis Calculated for C33R39N302: C, 77.76; H, 7.71; N, 8.24 Found: C, 77.81; H, 7.64; N, 8.27 Working Example 308 (Production of Compound 308) In water: ethanol: toluene (1: 1: 10, 18.0 ml) were dissolved 4-trifluorophenyl borate (190 mg) and 7-broms-1-methyl-N- [4 - [[N-methyl-N- (tetrahydropyran-4-yl) amino] methyl] phenyl] -2,3-dihydro-l-benzoazepine-4-carboxamide (403 mg), and potassium carbonate was added to the mixture ( 276 mg). The mixture was stirred under an argon atmosphere for 30 minutes and to the mixture tetracistriphenylphosphine palladium (39 mg) was added. Under an argon atmosphere, the mixture was heated to reflux for 17 hours and the mixture was diluted with ethyl acetate (200 ml) and washed with water (50 ml) and saturated brine (50 ml). The organic layer was dried with anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (75 g, ethyl acetate: ethanol = 9: 1) and recrystallized from ethanol to give 1-methyl-N- [4- [[N-methyl-] N- (tetrahydropyran-4-yl) amino] -methyl] phenyl] -7- (4-trifluoromethylphenyl) -2,3-dih-idro-l-benzoazepine-4-carboxamide (Compound 308) (177 mg, 39% ). p.f. 187.5-188.5 ° C.

NMR-aH (200MHz, CDC13) d 1.69-1.77 (4H,), 2.21 (3H, s), 2.57-2.72 (1H, m), 2.98 (2H, t, J = 4.6Hz), 3.12 (3H, s) ), 3.37 (2H, td, J = 11.2, 3.3Hz), 3.38 (2H, t, J = 4.7Hz), 3.57 (2H, s), 4.01-4.06 (2H, m), 6.91 (1H, d, J = 8.4Hz), 7.30 (2H, d, J = 8.4Hz), 7.42 (1H, s), 7.49 (1H, dd, J = 8.4, 2.2Hz), 7.54 (2H, d, J = 8.4Hz) , 7.55 (1H, s), 7.58 (1H, d, J = 2.2Hz), 7.66 (4H, s). IR (KBr) 2949, 2847, 1651, 1603, 1516, 1325, 1163, 1115, 1073, 847, 812cm "1. Analysis Calculated for C32H33F3N302 C, 69.93; H, 6.24; N, 7.65 Found C, 69.66; H, 6.20; N, 7.71.

Working Example 309 (Production of Compound 309) In water: ethanol: toluene (1: 1: 10, 18.0 ml) were dissolved 4- (4-morpholino) phenyl borate (208 mg) and 7-bromo-l-methyl-N- [4- [[N-methyl-N- (tetrahydropyran-4-yl) amino] ] methyl] phenyl] -2,3-dihydro-l-benzoazepine-4-carboxamide (406 mg), and to the mixture was added potassium carbonate (278 mg). The mixture was stirred under an argon atmosphere for 30 minutes and to the mixture tetracistriphenylphosphine palladium (39 mg) was added. Under an argon atmosphere, the mixture was heated to reflux for 17 hours, the mixture was diluted with ethyl acetate (200 ml) and washed with water (50 ml) and saturated brine (50 ml). The organic layer was dried with anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (75 g, ethyl acetate: ethanol = 9: 1) and recrystallized from ethanol to give 1-methyl-N- [4- [[N-methyl-] N- (Tetrahydro-pyran-4-yl) amino] ethyl] phenyl] - [4- (4-morpholino) -phenyl] -2,3-dihydro-l-benzoazepine-4-carboxamide (Compound 309) (247 mg , 52%). p.f. 209-211 ° C. RM ^ H (200MHz, CDC13) d 1.64-1.77 (4H, m), 2.21 (3H, s), 2.57-2.75 (1H, m), 2.96 (2H, t, J = 5.2Hz), 3.09 (3H, s), 3.20 (2H, t, J = 4.8Hz), 3.18-3.22 (2H, m), 3.33-3.43 (4H, m), 3.58 (2H, s), 3.89 (4H, t, J = 4.8Hz ), 4.01-4.06 (2H, m), 6.88 (1H, d, J = 8.4H2), 6.97 (2H, d, J = 8.8Hz), 7.30 (2H, d, J = 8.8Hz), 7.41-7.56 (8H, m). IR (KBr) 2953, 2847, 1653, 1607, 1514, 1505, 1311, 1232, 1119, 926, 814, 735cm "1. Analysis Calculated for C35H42N4? 5¡C, 74.18; H, 7.47; N, 9.89. Found: C, 74.17; H, 7.39; N, 9.98.

Reference Example 187 In 1, 2-dichloroethane (50 ml) were suspended p-nitro-benzylamine hydrochloride (3.77 g), 4H-tetrahydropyran-4-one (2 g) and triethylamine (2.8 ml) and the mixture was added under cooling with ice, triacetoxy boron sodium hydride (5.92 g). Under a nitrogen atmosphere, the mixture was stirred at room temperature for 4 hours, and acetaldehyde (1.5 ml) and sodium triacetoxy borohydride (5.92 g) were added to the mixture under cooling with ice. Under a nitrogen atmosphere, the mixture was stirred at room temperature overnight. The solvent was evaporated, and the residue was neutralized with a sodium hydroxide solution. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with a column of silica gel (ethyl acetate / hexane) to give the N- (4-nitrobenzyl) -N- (tetrahydropyran-4-yl) ethylamine ( 4.0 g) as a yellow oil. NMR- ^ H (d ppm CDC13) 1.01 (3H, t, J = 6.9Hz), 1.52-1.73 (4H, m), 2.59 (2H, q, J = 6.9Hz), 2.68-2.83 (1H, m) , 3.34 (2H, dt, J = 3.6, 11.2Hz), 3.73 (2H, s), 3.99-4.06 (2H,), 7.54 (2H, d, J = 9.0Hz), 8.16 (2H, d, J = 9.0Hz). IR (pure) v: 2951, 2841, 1599, 1520cm "1.

Reference Example 188 In acetic acid (100 ml) N- (4-nitro-benzyl) -N- (tetrahydropyran-4-yl) ethylamine (4.0 g) was dissolved, and reduced iron (4.2 g) was added to the mixture. The mixture was stirred at room temperature overnight. The solvent was evaporated and ethyl acetate was added to the residue. The precipitated products were filtered, and the filtrate was washed with a solution of sodium hydroxide, water and saturated brine and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with a column of silica gel (methanol / triethylamine / ethyl acetate) to give 4- (N-ethyl-N- (tetrahydropyran-4-yl) aminomethyl) ) aniline (2.3 g) as a red oil. NMR-aH (d ppm, CDC13) 1.00 (3H, t, J = 7.1Hz), 1.52-1.70 (4H, m), 2.54 (2H, q, J = 7.1Hz), 2.66-2.82 (1H, m), 3.26-3.39 (2H, m), 3.52 (2H, s), 3.59 (2H, broad), 3.95-4.04 (2H, m), 6.64 (2H, d, J = 8.5Hz), 7.12 (2H, d, J = 8.5Hz).

Reference Example 189 In 1, 2-dichloroethane (75 ml) p-nitro-benzaldehyde (5 g) and 2-amino-1,3-propanediol (3.0 g) were suspended, and the mixture was added, under ice-cooling , triacetoxy boron sodium hydride (9.8 g). Under a nitrogen atmosphere, the mixture was stirred at room temperature for 3.5 hours. To the mixture, 37% formalin (3 ml) and triacetoxy boron sodium hydride (9.8 g) were added, while cooling with ice, and the mixture was stirred, under a nitrogen atmosphere, at room temperature overnight. Water was added to the mixture, and the mixture was concentrated. The residue was neutralized with a sodium hydroxide solution, saturated with sodium hydrochloride and extracted with ethyl acetate. The organic layer was dried with anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was purified with a column of silica gel (ethyl acetate) to give 2- (N-methyl-N- (4-nitro-benzyl) amino) -1,3-propanediol (3.0 g) as color crystals. yellow. p.f. 65-66 ° C. NMR-aH (d ppm, CDC13), 2.31 (3H, s), 2.93-3.06 (1H, m), 3.64-3.60 (4H, m), 3.92 (2H, s), 7.49 (2H, d, J = 8.8Hz), 8.20 (2H, d, J = 8.8Hz). IR (KBr) v; 3349, 2942, 2884, 1520cm_1. Analysis Calculated for C11H16 2O4: C54.99; H, 6.71; N, 11.66. Found: 0.55.14; H, 6.61; N, 11.55.

Reference Example 190 In ethanol (50 ml) was dissolved 2- (N-methyl-N- (4-nitrobenzyl) amino) -1,3-propanediol (2.9 g), and the catalytic reduction was carried out with palladium on 5% carbon (0.15 g) at room temperature for 2 hours. The catalyst was filtered, and the solvent of the filtrate was evaporated. The residue was purified with a column of silica gel (methanol / triethylamine / ethyl acetate) to give the 2- (N- (4-aminobenzyl) -N-methylamino) -1,3-propanediol (0.6 g) as a amorphous product pale yellow. NMR-aH (d ppm, CDC13) 2.26 (3H, s), 2.37 (2H, broad), 2.91-2.99 (1H, m), 3.55-3.73 (6H, m), 6.65 (2H, d, J = 8.4 Hz), 7.08 (2H, d, J = 8.4Hz). GO . { KBr) v:, 3347, 2942, 2880, eiScm "1. Analysis Calculated for CnH18N202 • 0.1H20: C, 62.30; H, 8.65; N, 13.21, Found: C, 62.37; H, 8.79; N, 13.24.

Reference Example 191 In 1, 2-dichloroethane (50 ml) p-nitro-benzaldehyde (5 g), sarcosine methyl ester hydrochloride (4.6 g) and triethylamine (4.6 ml) were suspended and the mixture was added, under cooling with ice, sodium triacetoxy borohydride (9.8 g). Under a nitrogen atmosphere, the mixture was stirred at room temperature for 4 hours. To the mixture was added water, and the mixture was concentrated, neutralized with a sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with water and brine, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated and the residue was purified with a column of silica gel (ethyl acetate / hexane) to give the N- (4-nitro-benzyl) sarcosine methyl ester (6.3 g) as an oil colorless. NMR ^ H (d ppm CDC13) 2.39 (3H, m), 3.33 (2H, s), 3.73 (3H, s), 3.80 (2H, s), 7.55 (2H, d, J = 8.8Hz), 8.19 ( 2H, d, J = 8.8Hz). IR (pure) v; 2951, 2847, 1748cm "1.

Reference Example 192 J N- (4-nitro-benzyl) sarcosine methyl ester (5.96 g) was dissolved in acetic acid (100 ml) and reduced iron (7 g) was added little by little to the mixture. The mixture was stirred at room temperature overnight. The solvent was evaporated, and ethyl acetate was added to the residue. The precipitated products were filtered and the filtrate was washed with a solution of sodium hydroxide, water and saturated brine, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the resulting residue was purified with silica gel column chromatography (ethyl acetate / hexane) to give the N- (4-aminobenzyl) sarcosine methyl ester (3.0 g) as a red oil. NMR-XH (d ppm, CDC13) 2.36 (3H, m), 3.22 (2H, s), 3.55 (2H, s), 3.65 (2H, broad), 3.70 (3H, s), 6.65 (2H, d, J = 8.6Hz), 7.11 (2H, d, J = 8.6Hz). IR (pure) v: 3364, 2949, 1744cm "1.

Reference Example 193 In 1, 2-dichloroethane (50 ml), p-nitro-benzaldehyde (5 g) and 3-methoxypropylamine (3.1 g) were dissolved, and sodium triacetoxy borohydride was added to the mixture under ice cooling ( 9.8 g). Under a nitrogen atmosphere, the mixture was stirred at room temperature for 3 hours, and 37% formalin (3 ml) and triacetoxy boron sodium hydride (9.89 g) were added to the mixture under cooling with ice. of nitrogen, the mixture was stirred at room temperature for 3 hours, and water was added to the mixture, the mixture was concentrated, neutralized with a sodium hydroxide solution and extracted with ethyl acetate.The organic layer was washed with water and again subjected to extraction with IN hydrochloric acid, the aqueous layer was washed with ethyl acetate, neutralized with a 1N sodium hydroxide solution and extracted with ethyl acetate.The organic layer was washed with water and saturated brine. and dried with anhydrous magnesium sulfate.Under reduced pressure, the solvent was evaporated to give the N- (3-methoxy-propyl) -N-methyl-4-nitrobenzylamine (5.6 g) as a yellow oil. (5 ppm, CDC13) 1.72-1.85 (2H, m), 2.20 (3H, s), 2.47 (2H, t, J = 7.3Hz), 3.33 (3H, s), 3.43 (2H, t, J = 6.4Hz), 3.58 (2H, s), 7.50 (2H, d) , J = 9.0Hz), 8.18 (2H, d, J = 9.0Hz). IR (pure) v: 2805, 1605, 1520cm ~ 1.

Reference Example 194 In acetic acid (70 ml) N- (3-methoxy-propyl) -N-methyl-4-nitrobenzylamine (5.5 g) was dissolved and little iron was added to the mixture (6.4 g). The mixture was stirred at room temperature overnight. The solvent was evaporated and ethyl acetate was added to the residue. The precipitated products were filtered, the filtrate was washed with a solution of sodium hydroxide, water and saturated brine, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give 4- ((N-3-methoxypropyl-N-methyl) amino-methyl) aniline (4.4 g) as a red oil. RM ^ H (d ppm, CDC13) 1.71-1.85 (2H, m), 2.16 (3H, s), 2.42 (2H, t, J = 7.4Hz), 3.32 (3H, s), 3.37 (2H, s) , 3.41 (2H, t, J = 6.6Hz), 3.61 (2H, broad), 6.64 (2H, d, J = 8.4Hz), 7.08 (2H, d, J = 8.4Hz). IR (pure) v: 2946, 2795, 1615cm_1.

Reference Example 195 In ethanol (50 ml) was dissolved 7- (4-methylphenyl) -2, 3, 4, 5-tetrahydro-l-benzoxepin-5-one (1 g) and the mixture was added, under cooling with ice, boron sodium hydride (0.3 g). The mixture was stirred at room temperature for 30 minutes, and water was added to the mixture. The mixture was concentrated and extracted with ethyl acetate. The organic layer was washed with water and concentrated. The residue was dissolved in bis (2-methoxyethyl) ether (20 ml) and hydrochloric acid (5 ml) was added to the mixture. The mixture was stirred at 75 ° C for 1 hour, emptied into water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. The solvent was evaporated, and the precipitated 7- (4-methylphenyl) -2,3-dihydro-1-benzoxepine (0.78 g) was filtered with hexane to give colorless crystals.

RM -1H (200MHz, CDC13) d 1.28. { 6H, d, J = 7.0 Hz), 2.86--3.01 (? H, m), 6.22 (1H, d, J = 15.7 Hz), 7.23-7.33 (4H,), 7.56 (2H, d, J = 8.4 Hz), 7.85 (1H, d, J-15.7 Hz). IB_ (KBr) 2966, 1668, 1608, 1414, 1302, 1263, 1228, 804 cm Analysis Calculated for C? 6H? 602S Calculated C, 70.56; H, 5.92; S, 11.77 Found C, 70.23; H, 5.94; S, 11.62 Reference Example 199 Under an argon atmosphere, a solution of (E) -3- (5-Bromothiophen-2-yl) methyl acrylate (0.23 g), 4-tert-butyl-phenyl borate (0.3 g) and potassium carbonate (0.26 g) in toluene / ethanol / water (20/2/2 ml) was stirred at room temperature for 1 hour. To the mixture was added tetracistriphenylphosphine palladium (32 g) and the mixture was heated to reflux for 18 hours and then . cooled to room temperature. To the organic layer was added ethyl acetate, and the mixture was washed with saturated brine and dried with magnesium sulfate.

Under reduced pressure, the mixture was concentrated and the residue was purified with column chromatography (ethyl acetate / hexane = 1: 9) to give pale yellow crystals of (E) -3- [5- (4-tert-butyl-phenyl) thiophen-2-yl] methyl acrylate_ (204 mg). This compound was used for the next reaction, without being subjected to further purification. RM -aH (200MHz, CDC13) d 1.34 (9H, s), 3.80 (3H, s), 6.22 (1H, d, = 15.8 Hz), 7.21-7.30 (2H,), 7.42 (2H, d, J = 8.7 Hz), 7.55 (2H, d, J = 8.7 Hz), 7.76 (1H, d, J = 15.8 ? z). IR (KBr) 1716, 1622, 1436, 1302, 1232, 1207, 1165, 972, 806 cm-1 Reference Example 200 To a solution of methyl (E) -3- [5- (4-tert-butyl-phenyl) -thiophen-2-yl] acrylate (19 mg) of THF / ethanol (15/15 ml) a 2N sodium hydroxide solution (2.0 ml) was added at room temperature, and the mixture was stirred for 18 hours. To the mixture was added 1N hydrochloric acid (5 ml), and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the mixture was concentrated and the precipitated crystals were collected by filtration, which were washed with hexane to give yellow crystals of (E) -3- [5- (4-tert-butylphenyl) thiophen-2-acid. iljacrylic (149.7 mg), This compound was used to Jla following reaction, without subjecting yourself to further purification.

NMR-1H (200MHz, CDC13) d 1.35 (9H, s), 6.22 (1H, d, J = 15.6 Hz), 7.20-7.29 (2H, m), 7.43 (2H, d, J = 8.8 Hz), 7.56 (2H, d, J = 8.8 Hz), 7.85 (1H, d, 3 = 15.6 Hz). IR (KBr) 2962, 1678, 1612, 1414, 1302, 1232, 806 cm "1 Reference Example 201 To a solution of 4'-methylacetophenone (10.0 g) in ethanol (100 ml) was added an aqueous solution (50 ml) of hydroxyamine hydrochloride (7.77 g) and sodium acetate (9.36 g) at room temperature. , and the mixture was heated to reflux for 24 hours and then cooled. The mixture was concentrated and INN hydrochloric acid (150 ml) was added to the residue. The mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the mixture was concentrated, and the residue was purified with column chromatography (ethyl acetate / hexane = 1: 3) to give colorless crystals of 4'-methylacetophenone oxime. (10.89 g). NMR-aH (200MHz, CDCl3) d 2.28 (3H, s), 2.37 (3H, s), 7.19 (2H, d, J = 8.1 Hz), 7.53 (2H, d, J = 8.1 Hz), 8.55-8.69 (1H, m).

Reference Example 202 To a solution of 4'-methylacetophenone oxime (10.46 g) in DMF (250 ml) was added at 0 ° C sodium hydride (60%, 3.08 g), and mixture was stirred at room temperature for 1 hour . To the mixture was added a solution of 4-fluorobenzaldehyde (9.57 g) in THF (300 ml), and the mixture was stirred for 5 days. INN hydrochloric acid (200 ml) was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate.

Under reduced pressure, the mixture was concentrated, and the residue was purified with column chromatography (ethyl acetate / hexane = 1: 5) to give colorless crystals of 4- (4'-methyl-α-methylbenzylidene-aminoxy) benzaldehyde (11.23 g). p.f. 96-98 ° C NMR-aH (200MHz, CDC13) d 2.41 (3H, s), 2.47 (3H, s), 7.25 (2H, d, J = 7.8 Hz), 7.43 (2H, d, J = 8.8 Hz ), 7.69 (2H, d, J = 7.8 Hz), 7.88 (2H, d, J = 8.8 Hz), 9.93 (1H, s). IR (KBr) 1699, 1597, 1576, 1498, 1232, 1207, 1149, 916, 820 cm "1 Calculated Analysis for C? 6H? 5N02 Calculated C, 75.87; H, 5.97; N, 5.53, Found C, 75.73; H, 6.04; N, 5.48.

Reference Example 203 A solution of 4- (4'-methyl-a-methylbenzylidene-aminoxy) benzaldehyde (5.0 g) in INN hydrochloric acid / acetic acid (80 ml) was stirred at 100-110 ° C for 24 hours and then it was cooled to room temperature. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the mixture was concentrated and the residue was purified by column chromatography (ethyl acetate / hexane = 1: 9) to give colorless crystals of 2- (4-methylbenzyl) benzofuran-5-aldehyde (1.50 g) . p.f. 162-164 ° C NMR-1H (200MHz, CDC13) d 2.41 (3H, s), 7.06 (1H, s), 7.28 (2H, d, J = 8.0 Hz), 7.62 (1H, d, J = 8.4 Hz ), 7.77 (2H, d, J = 8.0 Hz), 7.84 (1H, dd, 1.8 Hz), 8.11 (1H, d, J = 1.8 Hz), 10.06 (1H, s). IR (KBr) 1697, 1292, 1271, 824, 798 cm "-i Analysis Calculated for C? 6H? 202 Calculated C, 81.34; H, 5.12. Found C, 81.21; H, 5.11.

Reference Example 204 To a solution of 2- (4-methylphenyl) benzofuran-5-carbaldehyde (500 mg) and 1-methylcyclohexene (1.2 ml) in DMF (15 ml) was added a solution (9 ml) of sodium chloride (80%, 1.5 g), and sodium acid phosphate (1.5 g) at room temperature, and the mixture was stirred for 3 hours. INN hydrochloric acid was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with sodium thiosulfate and saturated brine, and dried with magnesium sulfate. Under reduced pressure, the mixture was concentrated, and the precipitated crystals were collected by filtration, which were washed with diethyl ether to give colorless crystals of 2- (4-methylphenyl) benzofuran-5-carboxylic acid (395 mg). p.f. 279-283 ° C NMR-aH (200MHz, CDC13) d 2.38 (3H, s), 7.34 (2H, d, J = 8.2 Hz), 7.48 (1H, s), 7.70 (1H, d, J = 8.8 Hz ), 7.84 (2H, d, J = 8.2 Hz), 7.92 (1H, dd, J = 8.8, 1.2 Hz), 8.26 (1H, d, 3 = 1.2 Hz). IR (KBr) 2989, 1689, 1416, 1291, 768 cm "1 Calculated Analysis for C? SH? 203 Calculated C, 76.18; H, 4.79. Found C, 76.11; H, 4.74.

Reference Example 205 To a solution of ethyl vanilate (2.50 g) and triethylamine (3.6 ml) in dichloromethane (50 ml) was added at 0 ° C trifluoromethanesulfonic acid anhydride (2.6 ml) and the mixture was stirred for 1.5 hours. To the mixture was added water (15 ml) and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the mixture was concentrated, and the residue was purified by column chromatography (ethyl acetate / hexane = 1: 15) to give a yellow oil of ethyl 3-methoxy-4-trifluoromethanesulfonyloxybenzoate (3.96 g) . NMR ^ H (200MHz, CDC13) d 1.41 (3H, t, J = 7.1 Hz), 3.99 (3H, s), 4.41 (2H, q, J = 7.1 Hz), 7.28 (1H, d, J = 7.6Hz ), 7.67-7.72 (2H,). IR (pure) 1726, 1606, 1502, 1466, 1427, 1292, 1246, 1207, 1142, 1109, 1030, 833, 768, 617 cm " Reference Example 206 To a solution of ethyl 3-methoxy-4-trifluoromethanesulfonyloxybenzoate (3.95 g), 4-methylphenylacetylene (1.54 g) and triethylamine (5.0 ml) in DMF (40 ml) was added bistriphenylphosphine palladium dichloride (0.25 g). ), and the mixture was stirred at 100 ° C for 3 hours and then cooled to room temperature. Water was added to the mixture, and the mixture was extracted with diethyl ether. The organic layer was washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the mixture was concentrated, and the residue was purified by column chromatography (ethyl acetate / hexane = 1: 9) and recrystallized from ethyl acetate / hexane to give pale yellow crystals of 3-methoxy 4- [2- (4-Methylphenyl) ethynyl] -benzoic acid ethyl ester (2.02 g). p.f. 71-73 ° C NMR-aH (200MHz, CDC13) d 1.41 (3H, t, J = 7.1 Hz), 2.37 (3H, s), 3.97 (3H, s), 4.39 (2H, q, J = 7.1 Hz ), 7.16 (2H, d, J = 7.9 Hz), 7.47 (2H, d, J = 7.9 Hz), 7.53 (1H, d, J = 8.0 Hz), 7.57 (1H, d, J = 1.6 Hz). ), 7.63 (1H, dd, J = 8.0, 1.6 Hz). IR (KBr) 1711, 1410, 1294, 1236, 1099, 1036, 812, 762 cm "1 Calculated Analysis for C? 9H? 803 Calculated C, 77.53; H, 6.16 Found C, 77.48; H, 6.01.

Reference Example 207 A mixture of ethyl 3-methoxy-4- (4-ethylphenyl) ethynylbenzoate (1.5 g) and pyridinium chloride (9.0 g) was stirred at 200 ° C for 2 hours, and then cooled to 100 ° C. C. To the mixture was added DMF (20 ml), and the mixture was cooled to room temperature. To the mixture was added 1 N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate.

Under reduced pressure, the mixture was concentrated, and the precipitated crystals were collected by filtration, which were washed with diethyl ether and hexane to give pale yellow crystals of 2- (4-methylphenyl) benzofuran-6-carboxylic acid (0.84 g. ). p.f. 270-272 ° C NMR-aH (200MHz, DMSO-d6) d 2.38 (3H, s), 7.35 (2H, d, J = 8.2 Hz), 7.47 (1H, s), 7.72 (1H, d, J = 8.0 Hz), 7.85- 7.89 (3H, m), 8.11 (1H, s). IR (KBr) 2972, 1677, 1612, 1498, 1413, 1300, 1230, 798 cm "1 Calculated Analysis for C? 6H? 203 Calculated C, 76.18; H, 4.79. Found C, 76.05; H, 4.54.

Reference Example 208 To a solution of ethyl 7- (4-methylthiophenyl) -2,3-dihydro-l-benzoxepin-4-carboxylate (198.5 mg) in THF (20 ml) was added at 0 ° C 3-acid. 70% chloroperbenzoic acid (317 mg), and the mixture was stirred at 0 ° C for 30 minutes and then at room temperature for 1 hour. To the mixture was added a solution of sodium thiosulfate and the mixture was stirred for a few minutes and then extracted with ethyl acetate. The organic layer was washed with a saturated sodium bicarbonate solution and saturated brine, and dried with magnesium sulfate. Under reduced pressure, the mixture was concentrated, and the residue was purified with column chromatography (ethyl acetate / hexane = 1: 1) to give colorless crystals of 7- (4-methylsulfonylphenyl) -2, 3-dihydrole ethylbenzoxepin-4-carboxylate (221.8 mg). p.f. 150-153 ° C NMR- ^? (200MHz, CDC13) d 1.37 (3H, t, J = 7.2 Hz), 3.03 (2H, t, J = 4.5 Hz), 3.10 (3H, s), 4.30 (2H, q, J = 7.2 Hz), 4.33 (2H, t, J = 4.5 Hz), 7.10 (1H, d, J = 8.4 Hz), 7.50 (1H, dd, J = 8.4, 2.2 Hz), 7.60 (1H, d, J = 2.2 Hz), 7.65 (1H, s), 7.75 (2H, d, J = 8.4 Hz), 8.01 (2H, d, J = 8.4 Hz). IR (KBr) 1693, 1595, 1485, 1302, 1252, 1230, 1213, 1146, 1092, 825 cm "1 Calculated Analysis for C20H20O3S Calculated C, 64.50; H, 5.41; S, 8.61, Found C, 64.36; H, 5.40; S, 8.53.

Reference Example 209 To a solution of 7- (4-methylsulfonylphenyl) -2,3-dihydro-l-benzoxepin-4-carboxylate (180 mg) in THF / ethanol (5/5 ml) was added a solution at room temperature of 1N sodium hydroxide (1 ml), and the mixture was stirred for 4 days. To the mixture was added 1N hydrochloric acid (10 ml), and the mixture was concentrated under reduced pressure. The residue was extracted with ethyl acetate. Under reduced pressure, the mixture was concentrated. The resulting crystals were collected by filtration, which were washed with water, ethanol and diethyl ether to give colorless crystals of 7- (4-methylsulfonylphenyl) -2,3-dihydrobenzoxepin-4-carboxylic acid (148.2 mg). p.f. 275 ° C (dec.) RMN ^ H (200MHz, DMS0-d6) d 2.84-2.94 (2H, m), 3.25 (3H, s), 4.23-4.34 (2H, m), 7.10 (1H, d, J = 8.4 Hz), 7.64-7.75 (2H, m), 7.92-8.04 (5H, m). IR (KBr) 3018, 1674, 1308, 1267, 1147, 529, 783, 760, 636, 546cm_1 Analysis Calculated for C? 8H? 605S • 0.2H20 Calculated C, 62.13; H, 4.75; S, 9.21. Found C, 62.19; H, 4.69; S, 9.06.

Reference Example 210 A mixture of 4-bromothiophenol (24.8 g), ethyl 4-bromobutyrate (30.7 g) and potassium carbonate (36.2 g) in DMF (100 ml) was stirred at room temperature overnight. Under reduced pressure, the solvent was evaporated, and water was added to the residue. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the mixture was concentrated, and to the residue were added methanol (120 ml) and a solution of IN sodium hydroxide (240 ml). The mixture was stirred at room temperature overnight, and water was added to the mixture. The mixture was washed with ethyl acetate and concentrated hydrochloric acid was added to the aqueous layer to make the acidic solution. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate.

Under reduced pressure, the solvent was evaporated to a colorless prism of 4- (4-bromophenylthio) butyric acid (31.8 g). NMR ^ H (200MHz, CDC13) d 1.87-2.02 (2H, m), 2.53 (2H, t, J = 7.1 Hz), 2.96 (2H, t, J = 7.2 Hz), 7.21 (2H, d, J = 8.8 Hz), 7.41 (2H, d, J = 8.8 Hz). IR (KBr) 1699 cm "1 Calculated Analysis for C? 0HnO2BrS Calculated C, 43.65; H, 4.03, Found C, 43.70; H, 3.93.

Reference Example 211 A mixture of 4- (4-bromophenylthio) butyric acid (31.8 g) and polyphosphoric acid (250 g) was stirred at 100 ° C for 1 hour. The mixture was added to ice / water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated to give a brown color prism of 7-bromo-2,3,4,5-tetrahydro-1-benzo-tiepin-5-one (13.6 g). NMR ^ H (200MHz, CDC13) d 2.22-2.35 (2H, m), 2.94-3.08 (4H, m), 7.33 (1H, d, J = 8.0 Hz), 7.44 (1H, dd, J = 8.0, 2.6 Hz), 7.96 (1H, d, J = 2.6 Hz). IR (KBr) 1682 cm "1 Calculated Analysis for C? 0H9OBrS Calculated C, 46.71; H, 3.53, Found C, 46.71; H, 3.45.

Reference Example 212 To a solution of 7-bromo-2,3,4,5-tetrahydro-1-benzothiepin-5-one (13.5 g) in dimethyl carbonate (200 ml) was added sodium methoxide at room temperature ( 14.2 g), and the mixture was heated to reflux for 8 hours under a nitrogen atmosphere. INN hydrochloric acid was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated to give a brown color prism of methyl 7-bromo-5-oxo-2,3,4,5-tetrahydro-l-benzothiepin-4-carboxylate (11.5 g) RMN ^ H ( 200MHz, CDC13) d 2.40-2.84 (6H,), 3.16-3.27 (2H, m), 3.75 (3H, s), 4.47-4.56 (1H,), 7.33 (1H, d, J = 8.4 Hz), 7.47 (1H, dd, J = 8.4, 2.6 Hz), 7.99 (1H, d, J = 2.6 Hz). IR (KBr) 1750-cm "1 Calculated Analysis for C? 2Hn03BrS Calculated C, 45.73; H, 3. 52. Found C, 46.01; H, 3. 48.

Reference Example 213 A solution of methyl 7-bromo-5-oxo-2,3,4,5-tetrahydro-l-benzothiepin-4-carboxylate (24.94 g) in THF (200 ml) was cooled to -20 ° A solution of boron sodium hydride (2.99 g) in methanol (30 ml) was added dropwise to the mixture. While the temperature of the mixture was maintained at -15 to 20 ° C, the mixture was stirred for 1 hour. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated and the residue (24.38 g) was dissolved in THF (200 ml). To the mixture was added triethylamine (26 ml) and then to the mixture was added dropwise at 0 ° C methanesulfonyl chloride (9.2 ml). The mixture was stirred at 0 ° C for 30 minutes and then at room temperature for 15 hours. To the mixture was added dropwise 1, 8-diaza-bicyclo [5, 4, 0] -7-undecene (17.9 g), and the mixture was stirred for 3 hours. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with magnesium sulfate. Under reduced pressure, the mixture was concentrated, and the residue was purified by column chromatography (ethyl acetate / hexane = 1: 10). Under reduced pressure, the mixture was concentrated, and the resulting crystals were recrystallized with ethyl acetate / hexane to give pale yellow crystals of methyl 7-bromo-2,3-dihydro-l-benzothiepin-4-carboxylate (11.0 g ). p.f. 94-95 ° C ^ H (200MHz, CDC13) d 2.94-3.00 (2H, m), 3.15-3.21 (2H, m), 3.83 (3H, s), 7.28-7.33 (2H, m), 7.51 ( 1H, d, J = 1.2 Hz), 7.70 (1H, s). Analysis Calculated for C? 2Hn02BrS Calculated C, 48. 17; H, 3. 71 Found C, 48. 37; H, 3. 77 Reference Example 214 Under an argon atmosphere, a mixture of methyl 7-bromo-2,3-dihydro-l-benzothiepin-4-carboxylate (1.5 g), 4-methoxyphenyl borate (0.84 g) and potassium carbonate (1.39 g) in toluene / ethanol / water (50/5/5 ml) was stirred at room temperature for 1 hour. To the mixture was added tetracistriphenylphosphine palladium (0.17 g), and the mixture was heated to reflux for 24 hours and then cooled. The mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the mixture was concentrated, and the residue was purified by column chromatography (ethyl acetate / hexane = 1: 15-> 1: 9-1: 4-1: 2) to give pale yellow crystals. of methyl 7- (4-methoxyphenyl) -2,3-dihydro-l-benzothiepin-4-carboxylate (1.40 g). p.f. 117-120 ° C NMR ^ H (200MHz, CDC13) d 2.97-3.04 (2H, m), 3.19-3.25 (2H, m), 3.84 (3H, s), 3.86 (3H, s), 6.98 (2H, d, J = 8.8 Hz), 7.39 (1H, dd, J = 8.0, 2.2 Hz), 7.48-7.54 (3H, m), 7.57 (1H, d, J = 2.2 Hz), 7.88 (1H, s broad) . IR (KBr) 1716, 1630, 1606, 1520, 1479, 1431, 1281, 1250, 1221, 1186, 1020, 835, 814 cm "1 Calculated Analysis for C? GH? 803 S Calculated C, 69.91; H, 5.56.

Found C, 70.22; H, 5.65 Reference Example 215 To a solution of methyl 7- (4-methoxyphenyl) -2,3-dihydro-l-benzothiepin-4-carboxylate (0.50 g) in ethanol / THF (10/10 ml) was added at room temperature a solution of sodium hydroxide IN (2 ml), and the mixture was stirred for 18 hours. INN hydrochloric acid (2 ml) was added to the mixture. Under reduced pressure, the mixture was concentrated. To the mixture water was added and the precipitated products were collected by filtration, which were washed with 2-propanol, diethyl ether and hexane to give a pale yellow solid of 7- (4-methoxyphenyl) -2,3-dihydro acid. -l-benzo-tiepin-4-carboxylic acid (508 mg). This compound was used for the next reaction, without being subjected to further purification. RM -1H (200MHz, DMSO-d6) d 2.87 (2H, t, J = 5.7Hz), 3.11 (2H, t, J = 5.7Hz), 3.80 (3H, s), 7.01 (2H, d, J = 8.8 Hz), 7.33-7.42 (2H, m), 7.50-7.55 (2H, m), 7.62 (2H, d, J = 8.8 Hz). IR (KBr) 3356, 1633, 1608, 1518, 1358, 1246, 1178, 1020, 825 cm "1 Reference Example 216 Under an atmosphere of argon, a mixture of 7-bromo-2,3-dihydro-1-benzothiepin -4-methyl carboxylate (0.70 g), 4-morpholinophenyl borate (581.3 mg) and potassium carbonate (0.65 g) in toluene / ethanol / water (20/2/2 ml) was stirred at room temperature for 1 hour. To the mixture was added tetracistriphenylphosphine palladium (0.14 g), and the mixture was heated to reflux for 20 hours and then cooled. The mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the mixture was concentrated, and the residue was purified with column chromatography (ethyl acetate / dichloromethane = 1: 4) to give yellow crystals of 7- (4-morpholinophenyl) -2,3-dihydro- Methyl l-benzothiepin-4-carboxylate (664.4 mg). p.f. 154-156 ° C NMR ^ H (200MHz, CDC13) d 2.97-3.02 (2H, m), 3.20-3.25 (6H, m), 3.84 (3H, s), 3.87-3.91 (4H, m), 6.98 ( 2H, d, J = 8.8 Hz), 7.35-7.43 (1H, m), 7.49-7.58 (4H, m), 7.88 (1H, s). IR (KBr) 1709, 1 606, 1520, 1448, 1274, 1242, 1232, 120, 926, 81 6 cm "1 Analysis Calculated for C22H23N03S Calculated C, 69.26; H, 6. 08; N, 3 .67 .

Found C, 69.43; H, 6.01; N, 3.81 Reference Example 217 To a solution of methyl 7- (4-morpholinophenyl) -2,3-dihydro-l-benzothiepin-4-carboxylate (0.55 g) in ethanol / THF (30/30 ml) was added at room temperature. At room temperature a 1N sodium hydroxide solution (1.8 ml) was added and the mixture was stirred for 6 days and then heated to reflux for 2 hours. INN hydrochloric acid (1.8 ml) was added to the mixture. The resulting solid was collected by filtration, which was washed with ethanol and diethyl ether to give a yellow powder of 7- (4-morpholinophenyl) -2,3-dihydro-l-benzo-tiepin-4-carboxylic acid (502.2 mg). p.f. 280 ° C (dec.) NMR-aH (200MHz, DMSO-d6) d 2.88 (2H, t, J = 5.3Hz), 3.05-3.25 (6H,), 3.67-3.82 (4H, m), 7.02 (2H , d, J = 8.7 Hz), 7.43-7.54 (2H, m), 7.61 (2H, d, J = 8.7 Hz), 7.75 (1H, s), 7.81 (1H, s) IR (KBr) 2967, 1709 , 1684, 1608, 1520, 1232, 1120, 926, 814 cm "1 Calculated Analysis for C2? H2? N03S Calculated C, 68.64; H, 5.76; N, 3.81, Found C, 68.68; H, 5.62; N, 3.69 .

Reference Example 218 Under an argon atmosphere, a mixture of methyl 7-bromo-2,3-dihydro-l-benzothiepin-4-carboxylate (1.5 g), 3-4-methylenedioxyphenyl borate (0.92 g) and potassium carbonate (1.39 g) in toluene / ethanol / water (50/5/5 ml) was stirred at room temperature for 1 hour. To the mixture was added tetracistriphenylphosphine palladium (0.29 g), and the mixture was heated to reflux for 16 hours and cooled. The mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the mixture was concentrated, and the residue was purified with column chromatography (ethyl acetate / hexane = 1: 2) to give pale yellow crystals of 7- (3,4-methylenedioxyphenyl) -2,3-dihydro-1-benzothiepin-4-carboxylic acid methyl ester (1.55 g). p.f. 126-129 ° C NMR ^ H (200MHz, CDC13) d 2.97-3.06 (2H, m), 3.19-3.24 (2H, m), 3.84 (3H, s), 6.01 (2H, s), 6.88 (1H, d, J = 8.8 Hz), 7.02-7.08 (2H,), 7.35 (1H, dd, J = 8.0, 1.8 Hz), 7.50 (1H, d, J = 8.4 Hz), 7.53 (1H, d, J = 1.8 Hz) , 7.87 (1H, broad s). IR (KBr) 1709, 1471, 1435, 1248, 1223, 1186, 1034, 928, 804 c "1 Analysis Calculated for C19H16O4S Calculated C, 67.04; H, 4.74.

Found C, 67.19; H, 4.61 Reference Example 219 To a solution of methyl 7- (3,4-methylenedioxyphenyl) -2,3-dihydro-l-benzothiepin-4-carboxylate (0.6 g) in ethanol / THF (10/10 ml) was added at room temperature a solution of sodium hydroxide IN (2 ml) and the mixture was stirred for 64 hours. INN hydrochloric acid (3 ml) was added to the mixture, and the mixture was concentrated. The resulting solid was collected by filtration, which was washed with water, 2-propanol and diisopropyl ether to give a pale yellow powder of 7- (3,4-methylenedioxyphenyl) -2,3-dihydro-1-benzothiepin. -4-carboxylic acid (510.6 mg). p.f. 227-229 ° C NMR-aH (200MHz, DMSO-d6) d 2.86-2.92 (2H, m), 3.14-3.20 (2H, m), 6.07 (2H, s), 6.99 (1H, d, J = 8.2 Hz), 7.21 (1H, dd, J = 8.2, 1.8 Hz), 7.33 (1H, d, J = 1.8 Hz), 7.44-7.53 (2H, m), 7.77-7.82 (2H, m). IR (KBr) 2895, 1672, 1473, 1288, 1252, 1225, 1039, 933, 806 cm "1 Calculated Analysis for C? 8Hi4? 4S Calculated C, 66.24; H, 4.32, Found C, 66.01; H, 4.44.

Reference Example 220 To a suspension of 4-phenylpiperidine (5.0 g) in acetonitrile (100 ml) was added triethylamine (8.64 ml) and then a solution of p-toluenesulphonyl chloride was added dropwise at 0 ° C. 6.50 g) in acetonitrile (30 ml). The mixture was stirred at 0 ° C for 2 hours. Under reduced pressure, the solvent was evaporated and water was added to the residue. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the mixture was concentrated, and the resulting crystals were collected by filtration, which were washed with hexane to give colorless crystals of 1- (4-methylphenylsulfonyl) -4-phenylpiperidine (8.93 g). p.f. 153-154 ° C NMR-1H (200MHz, CDC13) d 1.83-1.95 (4H, m), 2.26-2.43 (3H, m), 2.45 (3H, s), 3.87-3.99 (2H, m), 7.13- 7.30 (5H, m), 7.35 (2H, d, J = 8.0 Hz), 7.69 (2H, d, J = 8.0 Hz). IR (KBr) 1336, 1165, 1092, 933, 725, 700, 651, 577, 546 cm Analysis Calculated for CnH2? N02S Calculated C, 68.54; H, 6.71; N, 4.44. Found C, 68.31; H, 6.64; N, 4.40.

Reference Example 221 To a solution of 1- (4-methylphenylsulfonyl) -4-phenylpiperidine (1.0 g) and 1,1-dichloromethyl methyl ether (0.57 ml) in dichloromethane (5 ml) was added a solution of tetrachloride at 0 ° C. of titanium (0.7 ml) in dichloromethane (5 ml), and the mixture was stirred at room temperature for 2 hours. The mixture was added to stirred ice / water to stop the reaction. The mixture was extracted with ethyl acetate. The organic layer was washed with a solution of sodium bicarbonate and saturated brine and dried with magnesium sulfate. Under reduced pressure, the mixture was concentrated, and the residue was purified with column chromatography (ethyl acetate / hexane = 1: 4- »1: 2) to give pale yellow crystals of 4- [1- (4- methylphenylsulfonyl) -piperidin-4-yl] benzaldehyde (0.381 g). (469.4 mg of the starting materials were collected) p.f. 134-137 ° C NMR-aH (200MHz, CDC13) d 1.75-1.96 (4H, m), 2.29-2.58 (3H, m), 2.46 (3H, s), 3.90-4.03 (2H, m), 7.29- 7.37 (4H, m), 7.69 (2H, d, J = 8.4 Hz), 7.82 (2H, d, J = 8.4 Hz), 9.97 (1H, s). IR (KBr) 1 697, 1 603, 1333, 1159, 937, 721, 581, 54 6 cm "1 Analysis is calculated for C? 9H2? N03S Calculated C, 66.; H 6. 16; N, 4 08 Found C, 66.31; H, 6.08; N, 4.3Í Reference Example 222 To a suspension of (3-carboxypropyl) triphenyl-phosphonium bromide (16.5 g) in THF (170 ml) was added at room temperature potassium t-butoxide (8.63 g), and the mixture was stirred at 60 ° C. ° C for 10 minutes and then cooled to room temperature. To the mixture was added a solution of 4- [l- (4-methylphenylsulfonyl) pipeyridin-4-yl] benzaldehyde (4.40 g) in THF (20 ml) and the mixture was stirred at 60 ° C for 1 hour. 'hour. To the mixture was added water (80 ml) and the mixture was extracted with toluene (80 ml). To the aqueous layer, IN hydrochloric acid was added to make the pH 3 solution, and the mixture was extracted with ethyl acetate. The organic layer was washed three times with a 2% sodium bicarbonate solution, and then with 1N hydrochloric acid and saturated brine (x3). Under reduced pressure, the mixture was concentrated and the residue was dissolved in THF (150 ml). To the mixture was added Pd-C (0.5 g), and the mixture was stirred under a hydrogen atmosphere for 5 hours. The Pd-C was removed by filtration and the filtrate was concentrated under reduced pressure. The resulting crystals were collected by filtration, which were washed with hexane to give colorless crystals of 5- [4- [1- (4-methylphenylsulfonyl) piperidin-4-yl] phenyl] pentanoic acid (4.63 g) • m.p. 164-170 ° CR N-1H (200MHz, CDC13) d 1.58-1.70 (4H, m), 1.79-1.91 (4H, m), 2.25-2.42 (5H, m), 2.45 (3H, s), 2.54- 2.65 (2H, m) _, 3.84-3.97 (2H, m), 7.04 (2H, d, J = 8.2 Hz), 7.10 (2H, d, J = 8.2 Hz), 7.34 (2H, d, J = 8.3 Hz), 7.68 (2H, d, J = 8.3 Hz). IR (KBr) 2937, 1703, 1335, 1163, 926, 725, 546 cm "1 Calculated Analysis for C23H29N04S Calculated C, 66.48; H, 7.03; N, 3.37, Found C, 66.66; H, 7.00; N, 3.50.

Reference Example 223 To a solution of 5- [4- [1- (4-methylphenylsulfonyl) -piperidin-4-yl] phenyl] pentanoic acid (0.50 g) in THF (10 ml) were added oxalyl chloride at room temperature. (0.21 ml) and one drop of DMF, and the mixture was stirred for 1 hour. Under reduced pressure, the mixture was concentrated and the residue was dissolved in dichloromethane (10 ml). To the mixture was added at 0 ° C aluminum chloride (0.35 g), and the mixture was stirred at 0 ° C for 30 minutes and then at room temperature for 5 minutes. The mixture was added to ice / water, and the mixture was extracted with ethyl acetate. The organic layer was washed with IN hydrochloric acid, a saturated sodium bicarbonate solution and saturated brine, and dried with magnesium sulfate. Under reduced pressure, the mixture was concentrated, and the residue was purified by column chromatography (ethyl acetate / hexane = 1: 2) to give colorless crystals of 3- [l- (4-methylphenylsulfonyl) -piperidin-4- il] -6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one (0.32 g). p.f. 165-169 ° C NMR ^ H (200MHz, CDC13) d 1.74-1.93 (8H, m), 2.24-2.43 (3H, m), 2.46 (3H, s), 2.68-2.76 (2H, m), 2.85-2.95 (2H, m), 3.85-4.00 (2H, m), 7.14 (1H, d, J = 8.0 Hz ), 7.22 (1H, dd, J = 8.0, 1.8 Hz), 7.35 (2H, d, J = 8.2 Hz), 7.50 (1H, d, J = 1.8 Hz), 7.68 (2H, d, J = 8.2 Hz ). IR (KBr) 1674, 1333, 1242, 1161, 1093, 933, 721, 546 cm "1 Calculated Analysis for C23H27N03S Calculated C, 69.49; H, 6.85; N, 3.52. Found C, 69.10; H, 6.62; N, 3.71.

Reference Example 224 To a solution of 3- [1- (4-methylphenylsulfonyl) -piperidin-4-yl] -6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one (3.25 g) in carbonate of dimethyl (50 ml) was added sodium methoxide (2.21 g) at room temperature, and the mixture was heated to reflux for 4.5 hours and cooled to room temperature. INN hydrochloric acid (100 ml) was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the mixture was concentrated to give a crude product (3.91 g). The resulting crude product was dissolved in THF (150 ml), a solution of sodium boron hydride (0.31 g) in methanol (10 ml) was added to the mixture at -40 ° C. The mixture was stirred at -10 to -20 ° C for 1 hour. To the mixture was added a solution of sodium boron hydride (0.31 g) in methanol (10 ml) and the mixture was stirred for 1.5 hours. To the mixture was added acetone (2 ml) and the mixture was stirred for 30 minutes. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the mixture was concentrated, and the residue was dissolved in THF (40 ml). To the mixture was added triethylamine (3.42 ml). To the mixture was added at 0 ° C methanesulfonyl chloride (0.95 ml), and the mixture was stirred at 0 ° C for 30 minutes and then at room temperature for 30 minutes. To the mixture was added 1,8-diaza-bicyclo [5, 4, 0] -7-undecene (3.7 ml), and the mixture was stirred for 14 hours. The mixture was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the mixture was concentrated and the residue was purified by column chromatography (ethyl acetate / hexane = 1: 2) to give colorless crystals of 4- [1- (4-methylphenylsulfonyl) piperidin-4-yl] -6,7-dihydro-5H-benzocyclohepten-8-carboxylic acid methyl ester (2.01 g). p.f. 169-173 ° C NMR ^ H (200MHz, CDC13) d 1.75-1.92 (2H, m), 1.95-2.09 (2H, m), 2.26-2.43 (3H, m), 2.45 (3H, s), 2.62 ( 2H, t, J = 6.2 Hz), 2.75-2.80 (2H, m), 3.81 (3H, s), 3.87-3.98 (2H, m), 6.98-7.10 (3H, m), 7.35 (2H, d, J = 8.6 Hz), 7.65 (1H, s), 7.68 (2H, J = 8.6 Hz). IR (KBr) 1709, 1433, 1336, 1234, 1198, 1161, 1092, 933, 721, 548 cm "1 Calculated Analysis for C25H29N04S Calculated C, 68.31; H, 6.65; N, 3.19, Found C, 68.23; H, 6.60; N, 3.04.

Reference Example 225 To a solution of methyl 4- [l- (4-methylphenylsulfonyl) piperidin-4-yl] -6,7-dihydro-5H-benzocyclohepten-8-carboxylate (1.0 g) in ethanol / THF (20/40 ml) a solution of sodium hydroxide IN (2.7 g) was added at room temperature, and the mixture was stirred for 13 hours. Under reduced pressure, the mixture was concentrated. Water was added to the mixture and the mixture was washed with ethyl acetate. To the aqueous layer was added IN hydrochloric acid (5 ml), and the mixture was extracted with ethyl acetate / THF. The organic layer was washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the mixture was concentrated, and the resulting colorless crystals were collected by filtration, which were washed with hexane to give colorless crystals of 4- [1- (4-methylphenylsulfonyl) piperidin-4-yl] -6 , 7-dihydro-5H-benzocyclohepten-8-carboxylic acid (565.4 mg). p.f. 255-257 ° C NMR-1H (200MHz, CDC13) d 1.74-1.94 (4H, m), 1.96-2.11 (2H, m), 2.28-2.48 (3H, m), 2.46 (3H, s), 2.65 ( 2H, t, J = 6.6 Hz), 2.78-2.84 (2H, m), 3.87-4.01 (2H, m), 7.00-7.12 (3H, m), 7.35 (2H, d, J = 8.2 Hz), 7.72 (2H, d, J = 8.2 Hz), 7.77 (1H, s). IR (KBr) 3008, 1674, 1352, 1294, 1273, 1255, 1163, 931, 721, 548 cm "1 Calculated Analysis for C24H27N04S Calculated C, 67.74; H, 6.40; N, 3.29, Found C, 67.97; H, 6.69; N, 311.

Reference Example 226 In THF (126 ml), 5-bromo-2-methyl-thiophene (10.5 g) was dissolved, and 1.6N / hexane (40.8 ml) was added dropwise at -78 ° C to the mixture. ). The mixture was stirred for 1 hour, and a solution of trimethyl borate (18.5 g) in THF (40 ml) was added dropwise to the mixture. The mixture was stirred for 15 minutes and warmed to room temperature. To the mixture was added 10% sulfuric acid (63 ml), and the mixture was stirred for 15 minutes. The mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was removed, and the resulting residue was washed with isopropyl ether to give 5-methyl-2-thienyl borate (4.6 g) • NMR ^ H (200MHz, CDC13) d 2.59 (3H, s), 6.93 (1H, d, J = 3.4Hz), 7.79 (1H, d, J = 3.4Hz) Reference Example 227 In toluene / ethanol / water (10/1/1) (24 ml), methyl 7-bromo-2,3-dihydro-l-benzoxepin-4-carboxylate (560 ml) was dissolved and the mixture 5-methyl-2-thienyl borate (875 mg) and potassium carbonate (1.56 g) were added. The mixture was stirred at room temperature for 30 minutes. To the mixture was added tetracistriphenylphosphine palladium (260 mg), and the mixture was stirred at 100 ° C for 24 hours and cooled to room temperature. The mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was removed and the resulting residue was purified by column chromatography on silica gel (hexane / acetone = 12 / l) to give 7- (5-methyl-2-thienyl) -2, 3 methyl-dihydro-l-benzoxepin-4-carboxylate (345 mg). NMR ^ H (200MHz, CDC13) d 2.28 (3H, s), 2.99 (2H, t, J = 4.8Hz), 3.83 (3H, s), 4.28 (2H, t, J = 4.8Hz), 6.82 (1H , d, J = 1.2Hz), 7.05 (1H, d, J = 8.4Hz), 7.45 (1H, dd, J = 8.4, 2.4), 7.54 (1H, d, J = 2.4Hz), 7.61 (1H, s) Reference Example 228 In THF (10.5 ml) and methanol (5.2 ml), methyl 7- (5-methyl-2-thienyl) -2,3-dihydro-l-benzoxepin-4-carboxylate (525 mg) was dissolved, and sodium hydroxide IN (10.5 ml) was added to the mixture. The mixture was stirred at room temperature for 2 hours. Under reduced pressure, the organic solvent was removed, and ethyl acetate was added to the residue. The mixture was extracted with water, and 6N hydrochloric acid was added to the aqueous layer to make the solution pH 4-5, which was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was removed to give 7- (5-methyl-2-thienyl) -2,3-dihydro-l-benzoxepin-4-carboxylic acid (410 mg). R N-aH (200MHz, DMS0-d6) d 2.23 (3H, s), 2.87 (2H, t, J = 4.4Hz), 4.24 (2H, t, J = 4.4Hz), 6.99 (1H, d, J = 8.4Hz), 7.07 (1H, s), 7.31 (1H, d, J = 1.4Hz), 7.49 (1H, dd, J = 8.4, 2.2Hz), 7.58 (1H, s), 7.74 (1H, d , J = 2.2Hz).

Reference Example 229 In toluene / ethanol / water (10/1/1) (12 ml), methyl 7-bromo-2,3-dihydro-l-benzoxepin-4-carboxylate (700 ml) was dissolved and mixed 5-methyl borate (422 mg) and potassium carbonate (0.98 g) were added. The mixture was stirred at room temperature for 30 minutes and tetracistriphenylphosphine palladium (136 mg) was added to the mixture. The mixture was stirred at 100 ° C for 13 hours and cooled to room temperature, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was removed and the resulting residue was purified by column chromatography on silica gel (hexane / acetone = 3 / l) to give 7- (3-thienyl) -2,3-dihydrole methyl-benzoxepin-4-carboxylate (610 mg).

NMR-aH (200MHz, CDC13) d 3.00 (2H, t, J = 4.2Hz), 3.83 (3H, s), 4.30 (2H, t, J = 4.2Hz), 7.01 (1H, d, J = 8.4Hz ), 7.33-7.40 (3H,), 7.49 (1H, dd, J = 8.4, 2.4), 7.66 (1H, d, J = 2.4Hz), 7.64 (1H, s) Reference Example 230 In THF (24 ml) and methanol (6 ml) methyl 7- (3-thienyl) -2,3-dihydro-l-benzoxepin-4-carboxylate (610 mg) was dissolved and the mixture was mixed with water. added sodium hydroxide (12 ml). The mixture was stirred at room temperature for 3 hours. Under reduced pressure, the organic solvent was removed, and ethyl acetate was added to the residue. The mixture was extracted with water, and 6N hydrochloric acid was added to the aqueous layer to make the solution pH 4-5, which was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was removed to give 7- (3-thienyl) -2,3-dihydro-l-benzoxepin-4-carboxylic acid (500 mg). NMR-aH (200MHz, DMSO-d6) d 2.87 (2H, t, J = 4.6Hz), 4.24 (2H, t, J = 4.6Hz), 7.00 (1H, d, J = 8.4Hz), 7.60-7.85 (4H, m), 7.84-7.89 (2H, m) Reference Example 231 In ether (160 ml) 3-methylthiophene was dissolved (20 g) and to the mixture was added N, N-tetramethylethylenediamine (26 g). To the mixture was added dropwise at room temperature n-butyl lithium 1.6N / hexane (140 ml), and the mixture was heated to reflux for 30 minutes. The mixture was cooled to -70 ° C and a solution of trimethyl borate was added dropwise to the mixture. (63.5 g) in THF (64 ml). The mixture was stirred for 30 minutes and warmed to room temperature. To the mixture was added 10% sulfuric acid (285 ml), and the mixture was stirred for 15 minutes. The mixture was washed with water and dried with magnesium sulfate. Under reduced pressure, the solvent was removed, and the resulting residue was washed with isopropyl ether to give 4-methyl-2-thienyl borate (6.0 g). NMR- (200MHz, CDC13) d 2.36 (3H, s), 7.35 (1H), 7.78 (1H, s) Reference Example 232 In toluene / ethanol / water (10/1/1) (8.4 ml), methyl 7-bromo-2,3-dihydro-l-benzoxepin-4-carboxylate (500 ml) was dissolved and mixed 4-methyl-2-thienyl borate (334 mg) and potassium carbonate (651 g) were added. The mixture was stirred at room temperature for 30 minutes and to the mixture tetracistriphenylphosphine palladium (97 mg) was added. The mixture was stirred at 100 ° C for 24 hours and cooled to room temperature. The mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was removed and the resulting residue was purified by column chromatography on silica gel (hexane / acetone = 8/1) to give 7- (4-methyl-2-thienyl) -2, 3 -dihydro-l-benzoxepin-4-carboxylic acid methyl ester (432 mg). NMR-aH (200MHz, CDC13) d 2.28 (3H, s), 2.99 (2H, t, J = 4.8Hz), 3.83 (3H, s), 4.28 (2H, t, J = 4.8Hz), 6.82 (1H , d, J = 1.2Hz), 7.05 (1H, d, J = 8.4Hz), 7.45 (1H, dd, J = 8.4, 2.4Hz), 7.54 (1H, d, J = 2.4Hz). 7.61 (1H, s) Reference Example 233 In THF (10 ml), methyl 7- (4-methyl-2-thienyl) -2,3-dihydro-l-benzoxepin-4-carboxylate (420 mg) was dissolved and hydroxide was added to the mixture. NaOH 1 (8.4 ml). The mixture was stirred at room temperature for 15 hours. Under reduced pressure, the organic solvent was removed, and ethyl acetate was added to the residue. The mixture was extracted with water, and 6N hydrochloric acid was added to the aqueous layer to make the solution pH 4-5, which was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was removed to give 7- (4-methyl-2-thienyl) -2,3-dihydro-l-benzoxepin-4-carboxylic acid (320 mg). NMR ^ H (200MHz, DMSO-d6) d 2.23 (3H, s), 2.87 (2H, t, J = 4.4Hz), 4.24 (2H, t, J = 4.4Hz), 6.99 (1H, d, J = 8.4Hz), 7.07 (1H, s), 7.31 (1H, d, J = 1.4Hz), 7.49 (1H, dd, J = 8.4, 2.2Hz), 7.58 (1H, s), 7.74 (1H, d, J = 2.2Hz) Reference Example 234 To methyl 7-bromo-2,3-dihydro-l-benzoxepin-4-carboxylate (500 mg) were added 4-fluorophenyl borate (272 mg), potassium carbonate (537 mg), water ( 1.5 ml), ethanol (1.5 ml) and toluene (5 ml). Under an argon atmosphere, the mixture was stirred at room temperature for 1 hour, and to the mixture tetracistriphenylphosphine palladium (61 mg, 3 mol%) was added. Under an argon atmosphere, the mixture was heated to reflux for 21 hours, and ethyl acetate (100 ml) was added to the mixture. The mixture was washed with water (50 ml) and saturated brine (50 ml), and dried with anhydrous magnesium sulfate. Under reduced pressure, the organic solvent was removed, and the residue was purified by silica gel column chromatography to give 7- (4-fluoro-phenyl) -2, 3-dihydro-1-benzoxepin-4-carboxylate of methyl (310 mg, 59%) as pale yellow crystals. NMR tR (200MHz, CDC13) d 3.01 (2H, t, J = 4.1Hz), 3.83 (3H, s), 4.31 (2H, t, J = 4.8Hz), 7.03-7.17 (3H, m), 7.40- 7.54 (4H, m), 7.66 (1H, s).

Reference Example 235 To methyl 7- (4-fluorophenyl) -2,3-dihydro-l-benzoxepin-4-carboxylate (0.27 g) was added THF (5.0 ml), ethanol (10.0 ml) and a hydroxide solution Na 2N (1.0 ml), and the mixture was stirred at room temperature for 19 hours. Under reduced pressure, the solvent was removed, and the residue was diluted with water (100 ml). The organic layer was made acidic with hydrochloric acid, and the mixture was extracted with ethyl acetate (100 ml). The organic layer was dried with anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was crystallized and washed with hexane to give 7- (4-fluorophenyl) -2,3-dihydro-1-benzoxepin-4-carboxylic acid (0.22 g, 86%) as colorless crystals. XH NMR (200MHz, CDC13) d 3.03 (2H, t, J = 4.8Hz), 4.33 (2H, t, J = 4.6Hz), 7.05-7.17 (3H, m), 7.43-7.55 (4H,), 7.76 (1H, s).

Reference Example 236 To 4-bromophenoxybutyric acid (75.0 g) polyphosphoric acid (873 g) was added, and the mixture was stirred at 100 ° C for 45 minutes. The mixture was emptied on ice (approximately 1.5 kg), and the mixture was extracted with ethyl acetate (1.5 L and 0.5 L). The organic layer was washed with water (400 ml x 3), a solution of sodium hydroxide IN (400 ml x 2), a saturated sodium hydrogen carbonate solution (400 ml x 2), water (400 ml x 3) and saturated brine (400 ml x 3), and dried with anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 7-bromo-2,3,4,5-tetrahydro-1-benzoxepin-5-one (38.6 g, 55%, 132.5 ° C / 0.33 mmHg) as a yellow oil pale.

Reference Example 237 To a solution of 5-bromo-2-fluorobenzaldehyde (0.49 g, 2.62 mmole) and ethyl 3-mercaptopropionate (0.37 ml, 2.88 mmole) in N, N-dimethylformamide (10 ml) was added potassium carbonate. (0.90 g, 6.55 mmol) and the mixture was stirred at room temperature for 1 hour and then at 70 ° C for 15 hours. The mixture was poured into ice water and made pH 4 with IN hydrochloric acid. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, and dried with magnesium sulfate. The solvent was evaporated, and the residue was purified by column chromatography on silica gel [hexane: ethyl acetate (5: 1)] to give ethyl 6-bromo-2H-thiochromen-3-carboxylate (0.45 g. , 58%) as a yellow powder, a part of which was recrystallized with ethanol to give pale yellow needles. p.f. 87 ° C NMR- ^ H (CDC13) d: 7.47 (1H, broad s), 7.26-7.38 (2H, m), 7.14 (1H, d, J = 8.0), 4.31 (2H, q, J = 7.4) , 3.73 (2H, d, J = 1.2), 1.36 (3H, d, J = 7.4). Calculated for C? 2HnBr02S: C; 48.17, H; 3.71. Found: C; 48.07, H; 3.77.

Reference Example 238 A solution of ethyl 6-bromo-2H-thiochromen-3-carboxylate (1.00 g, 3.34 mmol), 4-methylphenyl borate (0.55 g, 4.01 mmol) and tetracistriphenylphosphine palladium (0.19 g, 0.167 mmol) in 2M sodium carbonate (3.5 ml), ethanol (3 ml) and toluene (25 ml) was stirred at 80 ° C for 24 hours. Water was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with 0.5N hydrochloric acid and saturated brine, and dried with magnesium sulfate. The solvent was evaporated, and the residue was purified by column chromatography on silica gel [hexane: ethyl acetate (5: 1)] to give 6- (4-methylphenyl) -2H-thiochromen-3-carboxylate. ethyl (1.02 g, 99%) as a yellow powder, mp 87 ° C NMR ^ H (CDC13) d: 7.62 (1H, broad s), 7.40-7.46 (4H, m), 7.22-7.31 (3H, m), 4.31 (2H, q, J = 7.0), 3.77 ( 2H, d, J = 1.0), 2.40 (3H, s), 1.37 (3H, t, J = 7.0). Analysis Calculated for C? 9H1802S: C; 73.52, H; 5.84. Found: C; 73.51, H; 5.65.

Reference Example 239 To a solution of ethyl 6- (4-methylphenyl) -2H-thio-chromen-3-carboxylate (2.12 g, 6.84 mmol) in tetrahydrofuran (20 ml) and acetonitrile (20 ml) was added dropwise drop sodium hydroxide IN (7 ml) and the mixture was stirred at 60 ° C for 2.5 hours. The solvent was evaporated, and the residue was dissolved in diethyl ether. The mixture was extracted with water. The organic layer was extracted with 0.5N sodium hydroxide, and both of the aqueous layers were made pH 3 with 6N hydrochloric acid. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated to give 6- (4-methyl-phenyl) -2H-thiochromen-3-carboxylic acid (1.83 g, 95%) as a yellow powder, m.p. 244 ° C NMR ^ H (DMSO-d6) d: 7.44 (1H, d, J = 1.8), 7.21-7.32 (4H, m), 7.05 (1H, d, J = 8.4), 6.95 (2H, d, J = 8.2), 3.41 (2H, d, J = l.0), 2.02 (3H, s). Analysis is Calculated for C? 7H? 402S • 0. 25H20: C; 71.18, H; 5.09. Found: C; 70.90, H; 4.80.

Reference Example 240 To a solution of 4-nitrobenzaldehyde (6.0 g, 37. 7 mmol) and ethyl ß-aminopropionate hydrochloride (6.1 g, 37.7 mmol) in 1,2-dichloroethane (120 ml) was added triethylamine (5.3 ml, 37.7 mmol) and at 0 ° C triacetoxy boron hydride was added little by little. (11.8 g, 52. 8 mmol). The mixture was stirred at room temperature for 1 hour, and 37% formalin was added to the mixture. (4.0 ml, 49.0 mmol) and then at 0 ° C triacetoxy boron hydride (11.08 g, 52.8). The mixture was stirred at room temperature for 14 hours and the mixture was neutralized with saturated sodium hydrogen carbonate and extracted with dichloromethane. The extract was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated to give the crude product, which was purified by column chromatography on silica gel [hexane: ethyl acetate (3: 2] to give 3- (N-methyl-N- (4-nitrobenzyl) )) ethyl aminopropionate (9.34 g, 93%) as a yellow oil, NMR-aH (CDC13) d: 8.17 (2H, dd, J = 8.8, 1.8), 7.49 (2H, d, J = 8.8), 4.15 (2H, q, J = 7.4), 3.61 (2H, s), 2.76 (2H, t, J = 7.2), 2.52 (2H, t, J = 7.2), 2.22 (3H, s), 1.26 (3H , t, J = 7.4) Analysis Calculated for C? 3H? 8N20: C; 58.63, H; 6.81, N; 10.52. Found: C; 58.24, H; 6.78, N; 10.23.

Reference Example 241 To a solution of 4-nitrobenzaldehyde (2.0 g, 13.2 mmol) and 2-methoxyethylamine (1.15 mL, 13.2 mmol) in 1,2-dichloroethane (40 mL) was added triethylamine (1.9 ml) and at 0 ° C triacetoxy boron hydride (4.1 g) was added little by little. The mixture was stirred at room temperature for 1 hour, and then at 0 ° C triacetoxy boron hydride (4.1 g). The mixture was stirred at room temperature for 14 hours, neutralized with a saturated sodium hydrogen carbonate solution and extracted with dichloromethane. The extract was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated to give the crude product which was filtered with silica gel column chromatography [hexane: ethyl acetate (1: 2)] to give 4- ((N- (2-methoxy-ethyl) -N-methyl) aminomethyl) nitrobenzene (2.75 g, 93%) as a pale yellow oil. NMR-'H (CDC13) d: 8.18 (2H, d, J = 8.8), 7.53 (2H, d, J = 8.8), 3.66 (2H, s), 3.53 (2H, t, J = 5.6), 3.35 (3H, s), 2.63 (2H, t, J = 5.6), 2.28 (3H, s). Analysis Calculated for Ci4H2o 203: C; 63.62, H; 7.63, N; 10.60. Found: C; 63.54, H; 7.59, N; 10.51.

Reference Example 242 To a solution of 4-nitrobenzaldehyde (1.76 g, 11.7 mmol) and 4-aminocyclohexanol (1.34 g, 13.2 mmol) in 1,2-dichloroethane (30 ml) was added triethylamine (1.6 ml) and at 0 ° C triacetoxy boron hydride (3.7 g) was added little by little. The mixture was stirred at room temperature for 1 hour, and to the mixture 37% formalin (1.2 ml) and then at 0 ° C triacetoxy boron hydride (3.7 g) were added. The mixture was stirred at room temperature for 14 hours, neutralized with saturated sodium hydrogen carbonate and extracted with dichloromethane. The extract was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated to give the crude product, which was purified by column chromatography on silica gel [ethyl acetate: ethanol (2: 1)] to give (E) -4- ((N- (4-hydroxy-cyclohexyl) -N-methyl) ) aminomethyl) nitrobenzene (2.08 g, 67%) as pale yellow crystals, a portion of which were recrystallized from ether / hexane to give pale yellow needles, mp 87 ° C NMR-aH (CDC13) d: 8.17 (2H, d, J = 8.6), 7.51 (2H, d, J = 8.6), 3.51-3.65 (1H, m), 2.39-2.56 (1H, m) , 2.18 (3H, s), 1.83-2.12 (4H, m), 1.20-1.51 (4H, m). Analysis Calculated for Ci4H2oN203: C; 63.62, H; 7.63, N; 10.68. Found: C; 63.54, H; 7.59, N; 10.51.

Reference Example 243 To a solution of (E) -4- ((N- (4-hydroxy cyclohexyl) -N-methyl) aminomethyl) nitrobenzene (1.07 g, 4.05 mmol) in ethyl acetate (30 ml) was added Pd / C 5% (0.43 g) and the mixture was stirred under a hydrogen atmosphere for 3.5 hours. The mixture was filtered with semisite and the filtrate was concentrated. The resulting residue was purified with silica gel column chromatography [ethyl acetate: methanol: triethylamine 9: 1: 0.02]] to give (E) -4- ((N- (4-hydroxy-cyclohexyl) - N-methyl) aminomethyl) aniline (0.27 g, 28%) as a yellow powder. p.f. 105 ° C. NMR-aH (CDC13) d: 7.09 (2H, d, J = 8.6), 6.65 (2H, d, J = 8.6), 3.46-3.70 (1H, m), 3.45 (2H, s), 2.35-2.53 (1H, m), 2.16 (3H, s), 1.84-2.10 (4H, m), 1.19-1.51 ( 4H, m).

Reference Example 244 To a solution of ethyl 3- (N-methyl-N- (4-nitro-benzyl)) aminopropionate (1.51 g, 5.68 mmol) in acetic acid (30 ml) was added iron (1.27 g, 22.7 g. mmoles) and the mixture was stirred for 14 hours. The solvent was evaporated and the precipitated products were filtered with seals and washed with ethyl acetate. The filtrate was diluted with water, made basic with potassium carbonate and extracted with ethyl acetate. The extract was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated, and the residue was purified by column chromatography on silica gel [ethyl acetate: ethanol (2: 1)] to give 3- (N-methyl-N- (4-aminobenzyl)) aminopropionate. of ethyl (0.70 g, 52%) as a brown oil. NMR ^ H (CDCl 3) d: 7.07 (2H, d, J = 8.6), 6.64 (2H, d, J = 8.6), 4.13 (2H, q, J = 6.8), 3.41 (2H, s), 3.30- 3.60 (2H, m), 2.73 (2H, t, J = 7.4), 2.51 (2H, t, J = 7.4), 2.19 (3H, s), 1.25 (3H, t, J = 6.8).

Reference Example 245 To a solution of 4- ((N- (2-methoxyethyl) -N-methyl) aminomethyl) nitrobenzene (1.1 g, 4.91 mmol) in acetic acid (20 ml) was added iron (1.1 g, 19.6 mmol) ) and the mixture was stirred for 15 hours. The solvent was evaporated, and the precipitated products were filtered with seals and washed with ethyl acetate. The filtrate was diluted with water, made basic with potassium carbonate and extracted with ethyl acetate. The extract was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated, and the residue was purified by column chromatography on silica gel [ethyl acetate: methanol: triethylamine (7: 1: 0.02)] to give 4- ((N- (2-methoxyethyl) - N-methyl) -aminomethyl) aniline (880 mg, 92%) as a brown oil. NMR ^ H (CDC13) d: 7.09 (2H, d, J = 8.4), 6.64 (2H, d, J = 8.4), 3.50 (2H, t, J = 5.8), 3.45 (2H, s), 3.33 ( 3H, s), 2.57 (2H, t, J = 5.8), 2.24 (3H, s).

Reference Example 246 To a solution of 4-nitrobenzaldehyde (6.04 g, 40.0 mmol), N-methylethanolamine (3.00 g, 40.0 mmol) and triethylamine (5.6 mL, 40.0 mmol) in tetrahydrofuran. (200 ml) was added triacetoxy boron hydride (26.8 g, 120 mmol), and the mixture was stirred for 21 hours. The mixture was diluted with ethyl acetate, and washed with saturated sodium hydrogen carbonate and saturated brine. The extract was dried and the solvent was evaporated to give a crude product, which was purified by silica gel column chromatography [ethyl acetate methanol] (4: 1)] to give 4- ((N- (2-hydroxy-ethyl) -N-methyl) aminomethyl) nitrobenzene (7.08 g, 84%) as a yellow oil. NMR-1H (CDC13) d: 8.20 (2H, d, J = 8.8), 7.50 (2H, d, J = 8.8), 3.68 (2H, s), 3.68 (2H, t, J = 5.6), 2.64 ( 2H, t, J = 5.6), 2.52-2.70 (1H,), 2.26 (3H, s).

Reference Example 247 To a solution of 4- ((N- (2-hydroxyethyl) -N-ethyl) aminomethyl) nitrobenzene (2.95 g, 14.1 mmol) in acetic acid (60 mL) was added iron (3.14 g, 56.2 mmol. ), and the mixture was stirred for 23 hours. The solvent is evaporated, and the precipitated products are filtered and sealed with ethyl acetate. The filtrate was diluted with water, made pH 10 with potassium carbonate and extracted with ethyl acetate. The extract was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated and the residue was purified by column chromatography on silica gel [ethyl acetate: methanol: triethylamine (5: 1: 0.3)] to give 4- ((N- (2-hydroxyethyl) -N -methyl) aminomethyl) aniline (1.25 g, 49%) as a brown oil. NMR-aH (CDC13) d: 7.07 (2H, d, J = 8.4), 6.65 (2H, d, J = 8.4), 3.61 (2H, t, J = 5.2), 3.46 (2H, s), 2.57 ( 2H, t, J = 5.2), 2.20 (3H, s).

Reference Example 248 To THF (60 ml) was added at -70 ° C n-butyllithium (1.59M hexane solution, 63 ml, 100 mmol). The mixture was added dropwise (taking approximately 1 hour) a solution of 2,6-dibromopyridine (23.69 g, 100 mmol) in THF (140 ml at -60 ° C, and the mixture was stirred at -70 ° C for 15 minutes.) To the mixture was added DMF (12 ml), and the mixture was stirred at the same temperature for 15 minutes. minutes A solution of 20% ammonium chloride (100 ml) was added to the mixture, and the organic layer was separated The aqueous layer was extracted with ethyl acetate (100 ml), and the organic layer was mixed with the layer The organic layer was dried with anhydrous sodium sulfate and concentrated under reduced pressure.The residue was purified by column chromatography (silica gel 150 g, ethyl acetate / hexane = 1/20), and the fraction The residue was concentrated under reduced pressure, Diisopropyl ether (15 ml) was added to the residue and the insoluble materials were filtered, which were washed with diisopropyl ether (5 ml × 3) and dried under reduced pressure to give the 6-bromo- 2-pyridinecarbaldehyde (2.05 g, 11.0 mmol, 11%). IR (KBr): 1732 cm "1. NMR-aH (CDC1) d: 7.65-8.00 ( 3H, m), 10.01 (1H, s).

Reference Example 249 In THF (10 ml) sodium hydride was suspended (60%, 440 mg, 11.0 mmol) and a solution of diethylphosphonoethyl acetate (2.47 g, 11.0 mmol) in THF (10 ml) was added to the mixture at -30 ° C. The mixture was stirred at the same temperature for 30 minutes, and a solution of 6-bromo-2-pyridinecarbaldehyde (1.86 g, 10.0 mmol) in THF (10 ml) was added to the mixture at -30 ° C. While the temperature of the mixture was heated to -30 ° C to -10 ° C, the mixture was stirred for 1.5 hours. To the mixture was added diethyl ether (40 ml), and the mixture was washed with water (20 ml, 5 ml x 2) and saturated brine (5 ml). The organic layer was dried with anhydrous magnesium sulfate and concentrated under reduced pressure.

To the residue hexane (10 ml) was added, and the mixture was cooled to 0 ° C. The insoluble, precipitated materials were filtered, which were washed with cooled hexane to 0 ° C, and dried under reduced pressure to give ethyl 6-bromo-2-pyridine-acrylate (2.00 g, 7.81 mmol, 78%). IR (KBr): 1717, 1703 cm "1. RMN-aH (CDC13) d: 1.34 (3H, t, J = 7.1Hz), 4.28 (2H, q, J = 7.1Hz) 6.96 (1H, d, 15.8Hz), 7.30-7.65 (4H, m).

Reference Example 250 In 1, 2-dimethoxyethane (4 ml), ethyl 6-bromo-2-pyridine acrylate (512 mg, 2.00 mmol) and 4-methylphenyl borate (299 mg, 2.20 mmol) were dissolved and added to the mixture. Sodium carbonate (424 mg, 4.00 mmol), water (2 ml) and tetracis- (triphenylphosphine) palladium (116 mg, 0.10 mmol). The mixture was stirred at 80 ° C for 10 hours. To complete the reaction, 4-tolyl borate (150 mg, 1.10 mmol) and tetracis (triphenyl-phosphine) palladium (116 mg, 0.10 mmol) were added at 80 ° C to the mixture, and the mixture was stirred for 14 hours. To the mixture was added ethyl acetate (30 ml), and the mixture was water (5 ml x 2) and saturated brine (5 ml). The organic layer was dried with anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel 15 g, ethyl acetate / hexane = 1/19), and the desired fraction was concentrated under reduced pressure to give 6- (4-methylphenyl) -2-pyridine acrylate of ethyl (495 mg, 1.85 mmol, 93%). IR (KBr): 1713 cm "1. RMN-2H (CDC13) d: 1.36 (3H, t, J = 7.1Hz), 2.42 (3H, s), 4.30 (2H, q, J = 7.1Hz), 7.10 (1H, d, 15.6Hz), 7.25-7.35 (3H, m), 7.65-7.85 (3H, m), 7.99 (2H, d, J = 8.2Hz).

Reference Example 251 In methanol (5 ml), ethyl 6- (4-methyl-phenyl) -2-pyridine acrylate (465 mg, 1.74 mmol) was suspended, and a solution of sodium hydroxide was added to the mixture at 0 ° C. 1N (5.22 ml). The mixture was stirred at room temperature for 20 hours. To the mixture was added at 0 ° C INN hydrochloric acid (5.22 ml), and the methanol was evaporated under reduced pressure. The aqueous layer was extracted with ethyl acetate (30 ml20 ml). The organic layer was dried with anhydrous sodium sulfate and concentrated under reduced pressure. To the residue was added diisopropyl ether (5 ml), and the insoluble materials were filtered, which were washed with diisopropyl ether and dried under reduced pressure to give 6- (4-methylphenyl) -2-pyridine acrylic acid (344 mg, 1.44 mmoles, 83%). NMR ^ H (CDC13) d: 2.43 (3H, s), 7.15 (1H, d, 15.5Hz), 7.25-7.40 (1H, m), 7.31 (2H, d, J = 8.5Hz), 7.70-7.85 ( 2H, m), 7.84 (1H, d, J = 15.5Hz), 8.00 (2H, d, J = 8.5Hz).

Reference Example 252 In 1,2-dimethoxyethane (12 ml), methyl 7-bromo-2,3-dihydro-l-benzoxepin-4-carboxylate (566 mg, 2.00 mmol) and 3,4-methylenedioxyphenyl borate were dissolved. (465 mg, 2.80 immoles). To the mixture were added sodium carbonate (424 mg, 4.00 mmol), water (2 ml) and tetracis (triphenylphosphine) palladium (162 mg, 0.14 mmol), and the mixture was stirred at 80 ° C for 14 hours. To the mixture was added ethyl acetate (30 ml), and the mixture was extracted with water (5 ml x 2) and saturated brine (5 ml). The organic layer was dried with anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel 15 g, ethyl acetate / hexane = 1/19), and the desired fraction was concentrated under reduced pressure. Diisopropyl ether was added to the residue and the insoluble materials were filtered, which were washed with diisopropyl ether and dried under reduced pressure to give 7- (3,4-methylene-dioxyphenyl) -2,3-dihydro-1-benzoxepin. Methyl-4-carboxylate (434 mg, 1.34 mmol, 67%). IR (KBr): 1705 cm "1. RMN-aH (CDC13) d: 2.95-3.10 (2H, m), 3.83 (3H, s), 4. 25-4.35 (2H, m), 6.01 (2H, s), 6.87 (1H, d, J = 8.6Hz), 6. 95-7.10 (3H, m), 7.40 (1H, dd, J = 8.4, 2.4Hz), 7.47 (1H, d, J = 2.2Hz), 7.65 (1H, s).

Reference Example 253 In methanol (5 ml) was suspended 7- (3,4-methylenedioxy-phenyl) -2,3-dihydro-l-benzoxepin-4-carboxylate (399 mg, 1.23 mmole), and the mixture was added a solution of sodium hydroxide IN (3.69 ml). The mixture was stirred at room temperature for 20 hours, and INN hydrochloric acid (3.69 ml) was added to the mixture. The mixture was concentrated under reduced pressure, and water was added to the residue. The insoluble materials were filtered, which were washed with water and diethyl ether and dried under reduced pressure to give 7- (3,4-methylenedioxyphenyl) -2,3-dihydro-1-benzoxepin-4-carboxylic acid (321 mg, 1.03 mmol, 84%). RM ^ H (DMSO-de) d 2.80-2.95 (2H, m), 4.15-4.35 (2H, m), 6.05 (2H, s), 6.97 (1H, d, J = 8.1Hz), 7.01 (1H , d, J = 8.4Hz), 7.16 (1H, dd, J = 8.1, 1.7Hz), 7.29 (1H, d, J = 1.7Hz), 7.53 (1H, dd, J = 8.4, 2.3Hz, 7.63 ( 1H, 7.74 (1H, d, J = 2.3Hz Reference Example 254 In THF (10 ml), 1,2-methylenedioxy-4-bromobenzene (24. CO g, 119 mmol) was dissolved and the mixture was added dropwise at -55 ° C or less n-butyllithium. (1.6M hexane solution, 82 ml, 131 mmol). The mixture was stirred at -70 ° C for 30 minutes, and the resulting mixture was added dropwise at -60 ° C or less to a solution of borate ds trimethyl (18.61 g, 179 mmol) in tetrahydrofuran (50 ml) with the use of a cannula. The mixture was stirred at -70 ° C for 1 hour and then for 2 hours with heating at room temperature. AA hydrochloric acid (130 ml) and diethyl ether (150 ml) were added thereto, and the organic layer was added. separated. The organic layer was washed with water (50 x 2 ml) and saturated brine (50 ml), dried with anhydrous magnesium sulfate and concentrated under reeduced pressure. After addition diisopropyl ether (40 ml) was added, and the insoluble materials were filtered, which were filtered. washed co-diisopropyl ether (30 ml x 4) and dried under reduced pressure to give the borate of 3,4-methylenedioxyphenyl (6.79 g, 40.9 mmol, 34! NMR ^ H (DMSO-ds) d 5.99 (2H, s) 8-6.95 (1H, m) 7.25-7.45 (2H, m).

Reference Example 255 In methanol (250 ml) 5-nitrosalicylic acid (50.0 g, 273 mmol) was suspended, and sulfuric acid (6 ml) was added to the mixture. The mixture was stirred at 100 ° C for 24 minutes, and cooled to room temperature. The insoluble, precipitated materials were filtered, which were washed with anhydrous methanol (containing 20% water) and methanol and dried under reduced pressure to give the methyl 5-nitro-salicylate (38.5 g, 195 mmol, 72%). R N-aH (CDC13) d: 4.04 (3H, s), 7.10 (1H, d, J = 9.5Hz), 8.35 (1H, dd, J = 2.7, 9.5Hz), 8.81 (1H, d, J = 2.7Hz), 11.45 (1H, s, OH).

Reference Example 256 In DMF (50 ml), methyl 5-nitrosalicylate (1.97 g, 10.0 mmol) was dissolved and ethyl 4-bromobutyrate (1.57 ml, 11.0 mmol) and potassium carbonate (2.76 g, 20.0) were added to the mixture. mmoles). The mixture was stirred at 110 ° C for 5 hours, and the mixture was concentrated under reduced pressure. Ethyl acetate was added to the residue, and the mixture was washed with water and a 10% potassium carbonate solution.The organic layer was dried with anhydrous magnesium sulfate and concentrated under reduced pressure.The residue was purified with chromatography on a column (silica gel 30 g, ethyl acetate / hexane = 1/5-l / 3), and the desired fraction was concentrated under reduced pressure to give ethyl 4- (2-methoxycarbonyl-4-nitrophenoxy) butyrate (2.51 g, 8.06 immoles, 81%). RMN-aH (CDC13) d: 1.26 (3H, t, J = 7.2Hz), 2.1-2.3 (2H, m), 2.60 (2H, t, J = 7.1Hz) ), 3.93 (3H, s), 4.15 (2H, q, J = 7.2Hz), 4.23 (2H, t, J = 6.1Hz), 7.06 (1H, d, J = 9.4Hz), 8.35 (1H, dd) , J = 2.8, 9.4Hz), 8.71 (1H, d, J = 2.8Hz).

Reference Example 257 In THF (25 ml), ethyl 4- (2-methoxy-carbonyl-4-nitrophenoxy) butyrate (2.37 g, 7.61 mmol) was dissolved and 10% palladium-carbon was added to the mixture. (containing 50% water, 0.94 g). The mixture was subjected to catalytic reduction at room temperature for 4 hours. The insoluble materials were filtered and the filtrate was dried with anhydrous magnesium sulfate and concentrated under reduced pressure to give ethyl 4- (4-amino-2-methoxycarbonyl-phenoxy) butyrate (2.20 g). IR (KBr): 1730 cm "1.

NMR-aH (CDCI3) d: 1.25 (3H, t, J = 7.2Hz), 2.0-2.2 (2H, m), 2.56 (2H, t, J = 7.3Hz), 3.88 (3H, s), 4.00 ( 2H, t, J = 6.0Hz), 4.14 (2H, q, J = 7.2Hz), 6.75-6.9 (2H, m), 7.1-7.2 (1H, m).

Reference Example 258 A mixture of ethyl 4- (4-amino-2-methoxycarbonyl-phenoxy) butyrate (2.20 g), bis (2-chloroethyl) ether (0.195 ml, 7.81 mmol), potassium carbonate (3.24 g, 23.4 mmoles), sodium iodide (2.34 g, 15.6 mmol) and DMF (20 ml) was stirred at 70 ° C for 24 hours, and the mixture was concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was dried with anhydrous sodium sulfate and concentrated under reduced pressure.

The residue was purified with column chromatography (silica gel 30 g, ethyl acetate / hexane = 1/4), and the desired fraction was concentrated under reduced pressure to give ethyl 4- (2-methoxy-carbonyl-4-morpholinophenoxy) butyrate (2.18 g) . IR (KBr): 1732 cm "1. RMN-aH (CDCI3) d: 1.25 (3H, t, J = 7.1Hz), 2.0-2.2 (2H, m), 2.57 (2H, t, J = 7.1Hz) , 3.0-3.15 (4H, m), 3.8-3.9 (4H, m), 3.89 (3H, s), 4.04 (2H, t, J = 6.0Hz), 4.14 (2H, q, J = 7.1Hz), 6.92 (1H, d, J = 9.0Hz), 7.04 (1H, dd, J = 3.1, 9.0Hz), 7.36 (1H, d, J = 3.1Hz).

Reference Example 259 In THF (15 ml) diisopropylamine was dissolved (1018 ml), and n-butyllithium (4.2 ml) was added dropwise at 0 ° C to the mixture. The mixture was stirred at the same temperature for 30 minutes. To the mixture was added dropwise a solution of ethyl 4- (2-methoxycarbonyl-4-morpholinophenoxy) butyrate (1829 mg, 5.18 mmol) in THF (5 ml) at -78 ° C, the ice bath was removed and the mixture was stirred for 7 hours. A solution of 10% ammonium chloride (30 ml) was added to the mixture at 0 ° C, and the mixture was extracted with ethyl acetate (30 ml x 3). The organic layer was dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel 50 g, ethyl acetate / hexane = 1/5), and the desired fraction was concentrated under reduced pressure to give 7-morpholino-5-oxo-2, 3 4, 5-tetrahydro-1-benzoxepin-4-carboxylic acid ethyl ester (924 mg, 2.89 mmol, 56%).

Reference Example 260 In THF (10 ml), 7-morpholino-5-oxo-2,3,4,5-tetrahydro-2-benzoxepin-4-carboxylic acid ethyl ester (924 mg, 2.89 mmol) was dissolved and the mixture was mixed. a solution of boron sodium hydride (164 mg, 4.34 mmol) in methanol (3 ml) was added at -30 ° C. The mixture was stirred at -20 ° C to -15 ° C for 30 minutes, and the mixture was cooled to -50 ° C, to which water (15 ml) was added. The mixture was extracted with ethyl acetate (15 ml x 3), and the organic layer was dried with anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in THF (10 ml) and triethylamine (2.02 ml, 14.5 mmol) and methanesulfonyl chloride (0.336 ml, 4.34 mmol) were added to the mixture at 0 ° C. The mixture was stirred at room temperature for 17 hours and concentrated under reduced pressure. Water was added to the residue (15 ml), and the mixture was extracted with ethyl acetate (20 ml x 3). The organic layer was dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel 30 g, ethyl acetate / hexane = 1/5), and the desired fraction was concentrated under reduced pressure to give 7-morpholino-2,3-dihydrole ethylbenzoxepin-4-carboxylate (691 mg, 2.28 mmol, 79%). IR (KBr): 1703 cm "1. RMN-aH (CDC13) d: 1.35 (3H, t, J = 7.2Hz), 2.9-3.0 (2H, m), 3.05-3.15 (4H, m), 3.8- 3.9 (4H, m), 4.22 (2H, t, J = 4.8Hz), 4.28 (2H, q, J = 7.2Hz), 6.8-7.0 (3H, m), 7.54 (1H, s).

Reference Example 261 In methanol (8 ml) was dissolved 7-morpholino-2,3-dihydro-l-benzoxepin-4-carboxylic acid ethyl ester (800 mg, 2.64 mmoles) and a solution of sodium hydroxide was added to the mixture. (8 ml). The mixture was stirred at room temperature for 12 hours, and INN hydrochloric acid (8 ml) was added to the mixture. The organic solvent was evaporated under reduced pressure, and the precipitated, insoluble materials were filtered, which were washed with water and diisopropyl ether and dried under reduced pressure to give the acid 7-morpholino-2,3-dihydro-l-benzoxepin. -4-carboxylic acid (649 mg, 2.36 mmol, 89%). NMR-aH (CDC13) d: 2.97 (2H, t, J = 4.5Hz), 3.05-3.15 (4H,), 3.8-3.95 (4H, m), 4.25 (2H, t, J = 4.5Hz), 6.8 -7.0 (3H,), 7.67 (1H, s).

Reference Example 262 A mixture of 4-nitrobenzylamine (6.09 g, 40.0 mmol), 2-chloropyrimidine (4.82 g, 42.1 mmol), triethylamine (11.2 mL, 80.4 mmol) and ethanol (120 mL) was stirred at 110 ° C for 24 hours, and the mixture was concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate-THF. The organic layer was dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-ethanol to give N- (4-nitrobenzyl) -N- (2-pyrimidinyl) amine (0.99 g, 4.3 mmol, 11%). NMR ^ H (CDC13) d: 4.77 (2H, d, J = 6.4Hz), 5.59 (1H, m), 6.62 (1H, t, J = 4.9Hz), 7.51 (2H, d, J = 8.6Hz) , 8.19 (2H, d, J = 8.6Hz), 8.30 (2H, d, J = 4.9Hz).

Reference Example 263 In THF (20 ml) and methanol (20 ml) was dissolved N- (4-nitrobenzyl) -N- (2-pyrimidinyl) amine (921 mg, 4.00 mmol), and the mixture was added at 0 °. C Nickel bromide (137 mg) and boron sodium hydride (955 mg). The mixture was stirred at room temperature for 30 minutes and concentrated under reduced pressure. To the residue were added ethyl acetate, THF and water, and the insoluble materials were filtered. The aqueous layer was extracted with ethyl acetate-THF, and the organic layer was dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified with column chromatography (silica gel 30 g, ethyl acetate / hexane = 1/1), and the desired fraction was concentrated under reduced pressure. Diethyl ether was added to the residue, and the insoluble materials were filtered, which were washed with diethyl ether and dried under reduced pressure to give 4- [N- (2-pyrimidinyl) aminomethyl] aniline (208 mg, 1.04 mmol, 26%). RM ^ H (CDC13) d: 4.50 (2H, d, J = 5.4Hz), 5.32 (1H, m), 6.54 (1H, t, J = 4.7Hz), 6.66 (2H, d, J = 8.3Hz) , 7.15 (2H, d, J = 8.3Hz), 8.29 (2H, d, J = 4.7Hz).

Reference Example 264 A mixture of methyl 7-bromo-2,3-dihydro-l-benzoxepin-4-carboxylate (1416 mg, 5.00 mmol), zinc cyanide (352 mg, 3.00 mmol), tetracis (triphenylphosphine) palladium (347 mg, 0.30 mmol) and DMF (10 ml) was stirred at 80 ° C for 3 hours. The mixture was concentrated under reduced pressure, and ethyl acetate was added to the residue. The insoluble materials were filtered, which were washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The resulting crude product was recrystallized from ethyl acetate to give methyl 7-cyano-2,3-dihydro-l-benzoxepin-4-carboxylate (800 mg, 3.49 mmol, 70%). IR (KBr): 2222, 1721 cm "1.

NMR-aH (CDCI3) d: 2.95-3.1 (2H, m), 3.84 (3H, s), 4.3-4.4 (2H, m), 7.05 (1H, d, J = 8.8Hz), 7.50 (1H, dd) , J = 2.0, 8.8HZ), 7.52 (1H, s), 7.66 (1H, d, J = 2.0Hz).

Reference Example 265 In toluene (15 ml), methyl 7-cyano-2,3-dihydro-l-benzoxepin-4-carboxylate (642 mg, 2.80 mmol) was suspended, and trimethylsilylazide (0.929 ml, 7.00 m) was added to the mixture. mmoles) and dibutyl tin oxide (70 mg, 0.28 mmol). The mixture was stirred at 100 ° C for 24 hours and concentrated under reduced pressure. Methanol was added to the residue, and the mixture was concentrated under reduced pressure. Ethyl acetate was added to the residue, and the mixture was extracted with a saturated sodium bicarbonate solution (30 ml, 10 ml x 2). To the aqueous layer was added 6N hydrochloric acid to make the solution about pH 1, and the mixture was extracted with ethyl acetate and THF (30 ml, 50 ml) and (10 ml / 10 ml) x2). The organic layer was dried with anhydrous magnesium sulfate and concentrated under reduced pressure, ethyl acetate was added to the residue. The insoluble materials were filtered, which were washed with ethyl acetate and dried under reduced pressure to give methyl 7- (lH-tetrazol-5-yl) -2,3-dihydro-l-benzoxepin-4-carboxylate (662 mg, 2.43 mmol, 87%). NMR-1 ^ (DMSO-de) d: 2.85-3.0 (2H, m), 3.78 (3H, s), 4.25-4.4 (2H,), 7.21 (1H, d, J = 8.6Hz), 7.60 (1H , s), 7.94 (1H, dd, J = 2.1, 8.6Hz), 8.16 (1H, d, J = 2.1Hz).

Reference Example 266 In DMF (6 ml), 7- (lH-tetrazol-5-yl) -2,3-dihydro-1-benzoxepin-4-carboxylic acid methyl ester (400 mg, 1.47 mmol) was dissolved and the mixture was mixed. Sodium hydride (60%, 90 mg, 2.3 mmol) was added at 0 ° C. The mixture was stirred at the same temperature for 15 minutes, and methyl iodide (0.28 ml, 4.4 mmol) was added to the mixture at 0 ° C. While the temperature of the mixture was heated from 0 ° C to room temperature, the mixture was stirred for 3 hours. To the mixture was added at 0 ° C water (30 ml), and the mixture was extracted with ethyl acetate. The organic layer was dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified with column chromatography (silica gel 40 g, ethyl acetate / hexane = 1 / 8-> 1/2), and the first desired fraction, eluted was concentrated under reduced pressure to give the 7- Methyl (2-methyl-lH-tetrazol-5-yl) -2,3-dihydro-l-benzoxepin-4-carboxylate (334 mg, 1.17 mmol, 79%). The second desired, eluted fraction was concentrated under reduced pressure to give 7- (1-methyl-1H-tetrazol-5-yl) -2,3-dihydro-1-benzozepine-4-carboxylic acid methyl ester (76 mg, 0.27 mmoles). 7- (2-Methyl-lH-tetrazol-5-yl) -2,3-dihydro-l-benzoxepin-4-carboxylic acid methyl ester. IR (KBr): 1705 cm "1 .R N-aH (CDC13) d: 2.95-3.1 (2H, m), 3.83 (3H, s), 4.25-4.4 (2H, m), 4.39 (3H, s) , 7.09 (1H, d, J = 8.4Hz), 7.69 (1H, s), 8.00 (1H, dd, J = 2.2, 8.4Hz), 8.15 (1H, d, J = 2.2Hz). 7- (1-Methyl-1H-tetrazol-5-yl) -2,3-dihydro-1-benzoxepin-4-carboxylic acid methyl ester; IR (KBr): 1705 cm-1. 1H-NMR (CDCl3) d: 3.0-3.1 (2H, m), 3.84 (3H, s), 4.3-4.45 (2H, m), 4.20 (3H, s), 7.17 (1H, d, J = 8.4Hz ), 7.61 (1H, s), 7.63 (1H, dd, J = 2.2, 8.4Hz), 7.75 (1H, d, J = 2.2Hz).

Reference Example 267 In methanol (7 ml) and THF (7 ml) was suspended 7- (2-methyl-lH-tetrazol-5-yl) -2,3-dihydro-l-benzoxepin-4-carboxylic acid methyl ester ( 324 mg, 1.13 mmol) and a solution of sodium hydroxide was added to the mixture. (3.4 ml). The mixture was stirred at 50 ° C for 4 hours, and 1N hydrochloric acid (3.4 ml) was added to the mixture under cooling with ice. The mixture was concentrated under reduced pressure- and water was added to the residue. The insoluble materials were filtered, which were washed with water and dried under reduced pressure to give the acid 7- (2-methyl-lH-tetrazol-5-yl) -2,3-dihydro-l-benzoxepin-4- carboxylic acid (295 mg, 1.08 mmol, 96%).

Reference Example 268 In methanol (3 ml) and THF (3 ml), methyl 7- (2-methyl-lH-tetrazol-5-yl) -2,3-dihydro-l-benzoxepin-4-carboxylate was dissolved ( 76 mg, 0.27 mmole), and a solution of sodium hydroxide was added to the mixture. (0.8 ml). The mixture was stirred at 50 ° C for 4 hours, and 1N hydrochloric acid (0.8 ml) was added to the mixture under cooling with ice. The mixture was concentrated under reduced pressure and water was added to the residue. The insoluble materials were filtered, which were washed with water and dried under reduced pressure to give the acid 7- (l-methyl-lH-tetrazol-5-yl) -2,3-dihydro-l-benzoxepin-4- carboxylic acid (69 mg, 0.25 mmol, 95%).

Reference Example 269 In THF (500 ml), 4- [(benzyloxy) carbony] -aminobutyric acid (25.0 g) was dissolved and methyl iodide (37.4 g) was gradually added at -5 ° C. Under a nitrogen atmosphere, the mixture was stirred at 0 ° C for 15 minutes and then at room temperature for 24 hours. To the mixture was added ethyl acetate (300 ml) and then water (800 ml). The mixture was made pH 11 with sodium hydroxide and washed with ether (400 ml x 2). The aqueous layer was made pH 2 with concentrated hydrochloric acid and extracted with ethyl acetate (1000 ml and 500 ml x 3). The organic layer was washed with a 1M sodium thiosulfate solution (300 ml) and dried with magnesium sulfate. The solvent was evaporated under reduced pressure to give 4- [(benzyloxy) carbonyl] -4-methyl-aminobutyric acid (26.3 g). NMR aH (200MHz, CDC13) d 1.88 (2H, m), 2.35-2.37 (2H,), 2.93 (3H, s), 3.36 (2H, t, J = 6.6Hz), 5.13 (2H, s), 7.35 (5H, s ).

Reference Example 270 To dichloromethane (1000 ml) was added anhydrous magnesium sulfate (50.6 g) and then concentrated sulfuric acid (6.0 ml) at room temperature. The mixture was stirred at room temperature for 15 minutes, and to the mixture was added 4- [(benzyloxy) carbonyl] -4-methyl-aminobutyric acid (26.3 g) and then tert-butanol (50.5 ml). The mixture was completely sealed and stirred at room temperature for 18 hours. A saturated sodium hydrogen carbonate solution was added to the mixture to dissolve all of the magnesium sulfate, and the mixture was stirred. The organic layer was separated, washed with saturated brine (400 ml) and dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel (250 g, hexane: ethyl acetate = 5: 1) to give 4- [(benzyloxy) -carbonyl] -4- Terbutyl methylaminobutyrate (17.2 g, 53%). NMR aH (200MHz, CDC13) d 1.44 (9H, s), 1.82 (2H, quintet, J = 6.6Hz), 2.21 (2H, t, J = 6.2Hz), 2.93 (3H, s), 3.31 (2H, t, J = 7.1Hz), 5.13 (2H, s), 7.35 (5H, s).

Reference Example 271 In methanol (70 ml), 4- [(benzyloxy) carbonyl] -4-methylaminobutyrate tert -butyl (6.06 g) was dissolved, and 10% palladium-carbon (580 mg) was added to the mixture. Under a hydrogen atmosphere, the mixture was stirred at room temperature for 3 hours, and 10% palladium-carbon was removed. The solvent was evaporated under reduced pressure to give tert-butyl 4-methylaminobutyrate (3.35 g, 98%). 2H NMR (200MHz, CDC13) d 1.45 (9H, s), 1.72 (1H, broad s), 1.77 (2H, quintet, J = 7.2Hz), 2.27 (2H, t, J = 7.3Hz), 2.43 (3H , s), 2.61 (2H, t, J = 7.1Hz).

Reference Example 272 In DMF (5.0 ml), tert-butyl 4-methyl-butylbutyrate (1050 mg) was dissolved, and a solution of 5-bromo-2-fluorobenzaldehyde (1025 mg) in DMF was added to the mixture at room temperature. (1.0 ml) and then potassium carbonate (837 mg). The mixture was stirred at 70 ° C for 60 hours, and water (50 ml) was added to the mixture at room temperature. The mixture was extracted with ethyl acetate (50 ml x 3), and the organic layer was washed with saturated brine (50 ml x 3) and dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography on silica gel (75 g, hexane: ethyl acetate = 10: 1) to give 4- (4-bromo-2-formyl) N-methylanilino) tert-butyl butyrate (1620 mg, 90%). NMR tR (200MHz, CDC13) d 1.42 (9H, s), 1.88 (2H, quintet, J = 7.4Hz), 2.22 (2H, t, J = 7.3Hz), 2.88 (3H, s), 3.14 (2H, t, J = 7.3Hz), 7.01 (1H, d, J = 8.6Hz), 7.55 (1H, dd, J = 8.7, 2.5Hz), 7.88 (1H, d, J = 2.6Hz), 10.19 (1H, s).

Reference Example 273 In ter-butanol (250 ml), 4- (4-bromo-2-formyl-N-methylanilino) tert-butyl butyrate was dissolved (4.54 g) and potassium tert-butoxide (1.43 g), and the mixture was heated to reflux for 1 hour and cooled. To the mixture was added water (500 ml), and the mixture was extracted with ethyl acetate (500 ml x 2). The aqueous layer became weakly acidic with hydrochloric acid. (approximately 12.5 ml), and the mixture was extracted with ethyl acetate (500 ml). Both of these organic layers were washed with saturated brine (250 ml) and dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography on silica gel (200 g, hexane: ethyl acetate) = 10: 1-1: 1) to give 7-bromo-1- methyl-2, 3-dihydro-l-benzoazepin-4-carboxylic acid terbutyl ester (3.33 g, 77%) and 7-bromo-l-methyl-2,3-dihydro-lH-l-benzoxepin-4-carboxylic acid ( 0.60 g, 17%). 7-Bromo-1-methyl-2-, 3-dihydro-l-benzoazepine-4-carboxylic acid tert-butyl ester; 1R-NMR (200MHz, CDC13) d 1.53 (9H, s), 2.80 (2H, t, J = 4.8Hz), 3.00 (3H, s), 3.21 (2H, t, J = 4.7Hz), 6.65 (1H, d, J = 8.8Hz), 7.25 (1H, dd, J = 8.8, 2.2Hz), 7.39 (1H, d, J = 2.6Hz), 7.46 (1H, s). 7-bromo-l-methyl-2,3-dihydro-lH-l-benzoazepine-4-carboxylic acid; NMR aH (200MHz, CDC13) d 2.85 (2H, t, J = 4.8Hz), 3.03 (3H, s), 3.25 (2H, t, J = 4.9Hz), 6.67 (1H, d, J = 9.2Hz) , 7.29 (1H, dd, J = 8.8, 2.2Hz), 7.44 (1H, d, J = 2.6Hz), 7.67 (1H, s).

Reference Example 274 In water: ethanol: toluene (1: 1: 10, 18.0 ml) 4-methylphenyl borate (276 mg) and 7-bromo-l-methyl-2,3-dihydro-l-benzoazepin- were dissolved 4-tert-butyl carboxylate (571 mg), and to the mixture was added potassium carbonate (560 mg). The mixture was stirred under an argon atmosphere for 30 minutes, and to the mixture tetracistriphenylphosphine palladium (78 mg) was added. Under an argon atmosphere, the mixture was heated to reflux for 19.5 hours. The mixture was diluted with ethyl acetate (300 ml) and washed with water (100 ml) and saturated brine (100 ml). The organic layer was dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography on silica gel (120 g, hexane-α-hexane: ethyl acetate = 10: 1) to give 1-methyl-7- (4 -methylphenyl) -2, 3-dihydro-l-benzoazepin-4-carboxylic acid tert-butyl ester (422 mg, 72%).

NMR aH (200MHz, CDC13) d 1.54 (9H, s), 2.38 (3H, s), 2.83 (2H, t, J = 4.9Hz), 3.06 (3H, s), 3.28 (2H, t, J = 4.9 Hz), 6.85 (1H, d, J = 8.4Hz), 7.23 (2H, d, J = 8.0Hz), 7.447 (1H, dd, J = 8.6, 2.4Hz), 7.463 (2H, d, J = 8.2 Hz), 7.53 (1H, d, J = 2.2Hz), 7.67 (1H, s).

Reference Example 275 In ethyl acetate (7.0 ml), 1-methyl-7- (4-methylphenyl) -2, 3-dihydro-1-benzoazepine-4-carboxylic acid tert-butyl ester (490 mg) was dissolved and the 4N hydrochloric acid (ethyl acetate) (7.0 ml) was added to the mixture. The mixture was stirred at room temperature during hours. The solvent was evaporated under reduced pressure, and the residue was washed with hexane (10 ml x 3) to give l-methyl-7- (4-methylphenyl) -2,3-dihydro-l-benzoazepin-4 hydrochloride. -carboxylic (443 mg, 96%). p.f. 249-252 ° C (decomp.). NMR tR (200MHz, DMSO-d6) d 2.32 (3H, s), 2.75 (2H, t, J = 4.6Hz), 3.03 (3H, s), 3.25 (2H, t, J = 4.9Hz), 6.92 (1H, d, J = 8.6Hz), 7.22 (2H, d, J = 8.2Hz), 7.53 (1H, dd, J = 8.8, 2. 4Hz), 7.55 (2H, d, J = 8.2Hz), 7.65 (1H, d, J = 2.4Hz), 7. 68 (1H, s). IR (KBr) 3021, 2469, 1707, 1466, 1190, 1107, 810, 530 cm "1. Analysis Calculated for C? 9H? 9N02 • HCl • 0.3H20: C, 68.08; H, 6.19; N, 4.18 Found: C, 67.97; H, 6.13; N, 4.05 Reference Example 276 In DMF (12.0 ml), 7-bromo-1-methyl-2-, 3-dihydro-1-benzoazepine-4-carboxylic acid hydrochloride (600 mg) was dissolved, and thionyl chloride was added to the mixture ( 0.39 ml). The mixture was stirred at room temperature for 15 minutes. The solvent was evaporated under reduced pressure, and the residue was dissolved in dichloromethane (14.0 ml). The acid chloride solution obtained in this manner was added dropwise at 0 ° C to a solution of 4- [[N-methyl-N- (tetrahydropyran-4-yl) amino] methyl] aniline (562 mg) and triethylamine (1.48 ml) in dichloromethane (5.5 ml). The mixture was stirred at 0 ° C for 10 minutes and then at room temperature for 5 hours. To the mixture was added water (100 ml), and the mixture was extracted with dichloromethane (100 ml x 3). The organic layer was dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography on silica gel (150 g, ethyl acetate: ethanol = 10: 1) to give 7-bromo-1-methyl-N- [ 4- [[N-methyl-N- (tetrahydropyran-4-yl) amino] methyl] -phenyl] -2,3-dihydro-l-benzoazepine-4-carboxamide (767 mg, 75%). p.f. 62-64 ° C. 1R NMR (200MHz, CDC13) d 1.63-1.79 (4H,), 2.21 (3H, s), 2. 57-2.72 (1H, m), 2.94 (2H, t, J = 4.2Hz), 3.03 (3H, s), 3. 27-3.44 (2H + 2H, m), 3.57 (2H, s), 4.00-4.07 (2H, m), 6. 70 (1H, d, J = 8.8Hz), 7.20 (1H, s), 7.26-7.303 (2H, m), 7. 301 (1H, dd, J = 8.6, 2.4Hz), 7.42 (1H, d, J = 2.6Hz), 7. 50-7.55 (1H + 2H, m). IR (KBr) 3264, 2949, 2843, 1655, 1597, 1514, 1499, 1406, 1314, 1246, 1182, 810 cm "1 Analis is calculated for C25H30N3O2Br • 0.25H20: C, 61.41; H, 6.29; N, 8.59, Found: C, 61.45; H, 6.25; N, 8.32.

Working Example 310 (Production of Compound 310) In anhydrous methanol, N, N-dimethyl-N- (4- (((7- (4-methylphenyl) -2,3-dihydro-1-benzoxepin-4-iodide was dissolved. -yl) carbonyl) amino) benzyl) tetrahydro-2H-pyran-4-aminium (14.2 g), and the mixture was subjected to the column of ion exchange resin (DOWEX SBR, 20-50 mesh, Cl type) and eluted with anhydrous methanol.The solvent of the resulting fraction was evaporated and acetone was added to the residue to give crude crystals, which is recrystallized with ethanol to give the N, N-dimethyl-N- (4- (((7- (4-methylphenyl) -2,3-dihydro-l-benzoxepin-4-yl chloride) carbonyl) -amino) benzyl) -tetrahydro-2H-pyran-4-aminium (Compound 310) (10.4 g) as colorless crystals NMR-aH (d ppm, DMSO-d6) 1.76-2.00 (2H, m), 2.14 -2.20 (2H,), 2.35 (3H, s), 2.89 (6H, s), 3.01 (2H, t, J = 4.5Hz), 3.29-3.46 (2H, m), 3.55-3.69 (1H, m), 4.04 -4.09 (2H, m), 4.31 (2H, t, J = 4.5Hz), 4.50 (2H, s), 7.06 (1H, d, J = 8.4Hz), 7.27 (2H, d, J = 8.4Hz), 7.46 (1H, s), 7.53-7.59 (5H, m), 7.79 (1H, d, J = 2.2Hz) , 7.92 (2H, d, J = 8.4Hz), 10.34 (1H, s). IR (KBr) v 2973, 2849, 1645, lSldcm "1. Analysis Calculated for C32H37C1N203: C72.10; H, 7.00; N, 5.25; Cl, 6.65, Found C, 72.03; H, 6.83; N, 5.38; Cl , 6.47.

Working Example 311 (Production of Comd 311) In dichloromethane (5 ml) was suspended 7- (4-methyl-phenyl) -2,3-dihydro-l-benzoxepin-4-carboxylic acid (0.25 g), and the The mixture was added, under cooling with ice, oxalyl chloride (0.16 ml) and dimethylformamide (catalytic amount). The mixture was stirred at room temperature for 2 hours, and the solvent was evaporated. The residue was dissolved in tetrahydrofuran (20 ml), and the mixture was added dropwise to a solution of 4- ((N, N-bis (2-methoxy-ethyl) amino) methyl) aniline (0.24 g) and triethylamine. (0.4 ml) in tetrahydrofuran (10 ml) under cooling with ice. Under a nitrogen atmosphere, the mixture was stirred at room temperature overnight, and the solvent was evaporated. Water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated and the residue was purified with a column of silica gel (ethyl acetate) to give crude crystals, which were recrystallized with ethyl acetate-hexane to give the N- (4- (N , N-bis (2-methoxyethyl) -amino) methyl) phenyl) -7- (4-methylphenyl) -2,3-dihydro-l-benzoxepin-4-carboxamide (Comd 311) (0.25 g) as colorless crystals, pf 110-112 ° C. NMR-XH (d ppm, CDCl3) 2.39 (3H, s), 2.74 (4H, t, J = 6.0Hz), 3.07 (2H, t, J = 4.4Hz), 3.32 (6H, s), 3.48 (4H) , t, J = 6.0Hz), 3.69 (2H, s), 4.35 (2H, t, J = 4.4Hz), 7.05 (1H, d, J = 8.0Hz), 7.24 (2H, d, J = 8.4Hz ), 7.33 (2H, d, J = 8.8Hz), 7.43-7.55 (6H, m), 7.61 (1H, s). IR (KBr) v: 3287, 2876, ldSlcm "1. Analysis Calculated for C3? H36N204: C, 74.37; H, 7.25; N, 5.60, Found C, 74.33; H, 7.15; N, 5.45.

Working Example 312 (Production of Comd 312) In dichloromethane (5 ml), 7- (4-methyl-phenyl) -2,3-dihydro-l-benzoxepin-4-carboxylic acid (0.25 g) was suspended and the The mixture was added, under cooling with ice, oxalyl chloride (0.23 ml) and dimethylformamide (catalytic amount). The mixture was stirred at room temperature for 2 hours, and the solvent was evaporated. The residue was dissolved in tetrahydrofuran (20 ml), and the mixture was added dropwise to a solution of 4 - ((N- (3-ethoxypropyl) -N-methylamino) methyl) aniline hydrochloride (0.3 g) and triethylamine (0.62 ml) in tetrahydrofuran (10 ml) under cooling with ice. Under a nitrogen atmosphere, the mixture was stirred at room temperature overnight, and the solvent was evaporated. Water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated and the residue was purified with a column of silica gel (methanol / triethylamine / ethyl acetate) to give crude crystals, which were recrystallized with ethyl acetate-hexane to give the N- ( 4 - ((N- (3-ethoxypropyl) -N-methylamino) methyl) phenyl) -7- (4-methylphenyl) -2, 3-dihydro-l-benzoxepin-4-carboxamide (Comd 312) (0.3 g) as colorless crystals, m.p. 119-122 ° C. NMR ^ H (d ppm, CDC13) 1.19 (3H, t, J = 7.1Hz), 1.65-1.85 (2H, m), 2.19 (3H, s), 2.39 (3H, s), 2.46 (2H, t, J = 7.2Hz), 3.08 (2H, t, J = 4.8Hz), 3.42-3.52 (6H, m), 4.36 (2H, t, J = 4.8Hz), 7.06 (1H, d, J = 8.4Hz), 7.24 (2H, d, J = 8.0Hz), 7.30 (2H, d, J = 8.8Hz), 7.44-7.58 (7H,). IR (KBr) v: 2975, 2872, 1647, lSldcm "1. Analysis Calculated for C3? H36N203: C76.83; H, 7.49; N, 5.78, Found C, 76.73; H, 7.31; N, 5.95.

Working Example 313 (Production of Comd 313) In THF (5 ml) the 7- (4-methylphenyl) -2,3-dihydro-l-benzoxepin-4-carboxylic acid (0.25 g) was dissolved and the mixture was mixed. they added, under cooling with ice, oxalyl chloride (0.16 ml) and dimethylformamide (catalytic amount). The mixture was stirred at room temperature for 2 hours, and the solvent was evaporated. The residue was dissolved in tetrahydrofuran (15 ml), and the mixture was added dropwise to a solution of 4- ((N- (1, 3-dimethoxypropan-2-yl) -N-methylamino) methyl) aniline (0.23 g) and triethylamine (0.5 ml) in tetrahydrofuran (10 ml), under cooling with ice. Under a nitrogen atmosphere, the mixture was stirred at room temperature overnight, and the solvent was evaporated. Water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated and the residue was purified with a column of silica gel (ethyl acetate / hexane) to give crude crystals, which were recrystallized with ethyl acetate-hexane to give the N- (4- ((N- (1,3-dimethoxypropan-2-yl) -N-methylamino) methyl) -phenyl) -7- (4-methylphenyl) -2,3-dihydro-l-benzoxepin-4-carboxamide (Compound 313 ) (0.25 g) as colorless crystals, mp 128-132 ° C. NMR-aH (d ppm, CDC13) 2.31 (3H, s), 2.39 (3H, s), 3.00- 3.09 (3H, m), 3.35 (6H, s), 3.44-3.63 (4H, m), 3.71 ( 2H, s), 4.35 (2H, t, J = 4.7Hz), 7.05 (1H, d, J = 8.4Hz), 7.24 (2H, d, J = 8.0Hz), 7.33 (2H, d, J = 8.8Hz), 7.43-7.58 (7H, m). IR (KBr) V: 3285, 2882, 1651, 1516cm_1. Analysis Calculated for C3? H36N204: C74.37; H, 7.25; N, 5.60. Found C, 74.17; H, 7.05; N, 5.75.

Working Example 314 (Production of Compound 314) In THF (5 ml) the 7- (4-ethylphenyl) -2,3-dihydro-1-benzoxepin-4-carboxylic acid (0.25 g) was dissolved and the mixture was they added, under cooling with ice, oxalyl chloride (0.16 ml) and dimethylformamide (catalytic amount). The mixture was stirred at room temperature for 2 hours, and the solvent was evaporated. The residue was dissolved in tetrahydrofuran (15 ml), and the mixture was added dropwise to a solution of 4- ((N- (2-methoxyethyl) -N-methylamino) -methyl) aniline (0.21 g) and triethylamine ( 0.37 ml) in tetrahydrofuran (10 ml), under ice-cooling. Under a nitrogen atmosphere, the mixture was stirred at room temperature overnight, and the solvent was evaporated. Water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated and the residue was purified with a column of silica gel (methanol / triethylamine / ethyl acetate) to give crude crystals, which were recrystallized with ethyl acetate-hexane to give the N- ( 4 - ((N- (2-methoxyethyl) -N-methylamino) methyl) phenyl) -7- (4-methylphenyl) -2, 3-dihydro-l-benzoxepin-4-carboxamide (Compound 314) (0.24 g) as colorless crystals. p.f. 121-122 ° C. NMR-aH (d ppm, CDC13) 2.26 (3H, s), 2.39 (3H, s), 2.60 (2H, t, J = 5.8Hz), 3.07 (2H, t, J = 4.5Hz), 3.35 (3H , s), 3.49-3.54 (4H, m), 4.35 (2H, t, J = 4.5Hz), 7.05 (1H, d, J = 8.4Hz), 7.24 (2H, d, J = 8.8Hz), 7.31 (2H, d, J = 8.8Hz), 7.43-7.56 (6H, m), 7.62 (1H, s). IR (KBr) v: 3287, 2926, 1651, lSldcm "1. Analysis Calculated for C29H 2N203: C, 76.29; H, 7.06; N, 6.14, Found C, 75.99; H, 7.02; N, 6.22.

Working Example 315 (Production of Compound 315) In water / ethanol / toluene (1: 1: 10, 18.0 ml), 4-trifluoromethoxyphenyl borate (208 mg) and 7-bromo-1-methyl-N- [4] were dissolved. - [[N-methyl-N- (tetrahydro-2H-pyran-4-yl) amino] methyl] phenyl] -2,3-dihydro-l-benzazepine-4-carboxamide (407 mg), and the mixture was added potassium carbonate (279 mg). Under an argon atmosphere, the mixture was stirred for 30 minutes, and the mixture was added tetracistriphenylphosphine palladium (39 mg). Under an argon atmosphere, the mixture was refluxed for 16 hours, and the mixture was diluted with ethyl acetate (200 ml). The mixture was washed with water (50 ml) and saturated brine (50 ml), and the organic layer was dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography on silica gel (75 g, ethyl acetate -> ethyl acetate / ethanol = 20: 1) and recrystallized with ethanol to give 1-methyl-N- [ 4- [[N-methyl-N- (tetrahydro-2 H -pyran-4-yl) amino] methyl] phenyl] -7- (4-trifluoromethoxyphenyl) -2,3-dihydro-l-benzazepine-4-carboxamide ( Compound 315) (148mg, 31%). p.f. 182-183 ° C. NMR aH (200MHz, CDCl3) d 1.63-1.76 (4H, m), 2.20 (3H, s), 2.56-2.72 (1H, m), 2.96 (2H, t, J = 4.6Hz), 3.09 (3H, s) ), 3.30-3.43 (4H, m), 3.56 (2H, s), 4.01-4.06 (2H, m), 6. 89 (1H, d, J = 8.6Hz), 7.25 (2H, d, J = 8.2Hz), 7.30 (2H, d, J = 8.6Hz), 7.40 (1H, s), 7.48 (1H, dd, J = 8.6, 2.4Hz), 7. 51-7.58 (6H, m). IR (KBr) 2951, 2847, 1651, 1514, 1501, 1260, 1221, 1163, 806, 733 cm "1 Analis is calculated for C 2 H 34 N 303 F 3: C, 67.95; H, 6.06; N, 7.43, Found: C, 67.74; H, 5.87; N, 7.68.

Working Example 316 (Production of Compound 316) In water / ethanol / toluene (1: 1: 10, 18.0 ml) 4- (1-piperidinyl) phenyl borate (179 mg) and 7-bromo-1-methyl were dissolved -N- [4- [[N-methyl-N- (tetrahydro-2 H -pyran-4-yl) amino] methyl] phenyl] -2,3-dihydro-l-benzazepine-4-carboxamide (353 mg), and to the mixture was added potassium carbonate (242 mg). Under an argon atmosphere, the mixture was stirred for 40 minutes, and to the mixture tetracistriphenylphosphine palladium (34 mg) was added. Under an argon atmosphere, the mixture was heated to reflux for 15 hours, and the mixture was diluted with ethyl acetate (200 ml). The mixture was washed with water (50 ml) and saturated brine (50 ml), and the organic layer was dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography on silica gel (75 g, ethyl acetate / ethanol = 9: 1) and recrystallized from ethanol to give 1-methyl-N- [4- [[N-methyl-N- (tetrahydro-2 H -pyran-4-yl) amino] methyl] phenyl] -7- [4- (1-piperidinyl) phenyl] -2,3-dihydro-l- benzazepin-4-carboxamide (Compound 316) (79 mg, 19%). p.f. 202-204 ° C. NMR aH (200MHz, CDC13) d 1.59-1.77 (10H, m), 2.21 (3H, s), 2.57-2.73 (1H, m), 2.95 (2H, t, J = 4.4Hz), 3.07 (3H, s) ), 3.19 (4H, t, J = 5.1Hz), 3.31-3.43 (4H,), 3.57 (2H, s), 4.01-4.06 (2H, m), 6.86 (1H, d, J = 8.4Hz), 6.99 (2H, d, J = 8.8Hz), 7.30 (2H, d, J = 8.6Hz), 7.39-7.50 (5H, m), 7.54 (2H, d, J = 8.4Hz), 7.57 (1H, s ). IR (KBr) 2938, 2849, 1645, 1607, 1505, 1314, 1235, 910, 812, 733cm_1.

Analysis Calculated for C36H44N402: C, 76.56; H, 7.85; N, 9.92. Found: C, 76.53; H, 7.79; N, 10.01 Working Example 317 (Production of Compound 317) In water / ethanol / toluene (1: 1: 10, 60.0 ml) were dissolved 4-methylphenyl borate (658 mg) and 7-bromo-1-formyl-N- [4 - [[N-methyl-N- (tetrahydro-2H-pyran-4-yl) amino] methyl] phenyl] -2,3-dihydro-l-benzazepine-4-carboxamide (2.01 g), and the mixture was added potassium carbonate (1.34 mg). Under an argon atmosphere, the mixture was stirred for 30 minutes, and to the mixture tetracistriphenylphosphine palladium (186 mg) was added. Under an argon atmosphere, the mixture was refluxed for 17 hours, and the mixture was diluted with ethyl acetate (750 ml). The mixture was washed with water (200 ml) and saturated brine (100 ml), and the organic layer was dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography on silica gel (150 g, ethyl acetate -> ethyl acetate / ethanol = 20: 1) and recrystallized from ethanol to give the -formyl-7- (4-methylphenyl) -N- [4- [[N-methyl-N- (tetrahydro-2H-pyran-4-yl) amino] methyl] phenyl] -2, 3-dihydro-l- benzazepin-4-carboxamide (Compound 317) (669 mg, 33%). p.f. 229-230.5 ° C. NMR tR (200MHz, CDC13) d 1.69-1.79 (4H, m), 2.21 (3H, s), 2.41 (3H, s), 2.57-2.72 (1H, m), 3.04 (2H, t, J = 4.9Hz), 3.37 (2H, td, J = 10.2, 3.1Hz), 3.57 (2H, s), 3. 93 (2H, t, J = 5.5Hz), 4.01-4.07 (2H, m), 7.21 (1H, d, J = 8.2Hz), 7.29 (2H, d, J = 7.6Hz), 7.32 (2H, d, J = 8.4Hz), 7. 50 (2H, d, J = 8.8Hz), 7.54 (2H, d, J = 8.8Hz), 7.58 (1H, s), 7.59 (1H, dd, J = 8.2, 2.2Hz), 1H was hidden under 7.55 - 7.58, 7.71 (1H, d, J = 2.2Hz), 8.56 (1H, s). IR (KBr) 2946, 2847, 1667, 1597, 1516, 1497, 1360, 1316, 814, 733 cm "1 Analysis calculated for C 32 H 35 N 303: C, 75.41; H, 6.92; N, 8.25, Found: C, 75.45; H, 6.95; N, 8.18.

Working Example 318 (Production of Compound 318) To l-formyl-7- (4-methylphenyl) -N- [4- [[N-methyl-N- (tetrahydro-2H-pyran-4-yl) amino] methyl] ] phenyl] -2,3-dihydro-l-benzazepine-4-carboxamide (1177 mg) was added IN hydrochloric acid (20 ml), and the mixture was stirred at 100 ° C for 1 hour. The mixture was diluted with ethyl acetate (50 ml) and made weakly basic with a saturated sodium hydrogen carbonate solution (45 ml). To the mixture were added ethyl acetate (250 ml) and water (100 ml)., and separated. The organic layer was dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography on silica gel (75 g, ethyl acetate / ethanol = 9: 1) to give 7- (4-methyl-phenyl) -N - [4- [[N-methyl-N- (tetrahydro-2 H -pyran-4-yl) amino] methyl] phenyl] -2,3-dihydro-l-benzazepine-4-carboxamide (Compound 318) (804 mg , 72%) as an amorphous product. NMR tR (200MHz, CDC13) d 1.69-1.80 (4H, m), 2.21 (3H, s), 2.38 (3H, s), 2.58-2.72 (1H, m), 2.96 (2H, t, J = 4.4Hz ), 3.37 (2H, td, J = 11.4, 3.1Hz), 3.47 (2H, t, J = 4.8Hz), 3.57 (2H, s), 4.01-4.07 (2H, m), 4.53-4.70 (1H, broad), 6.71 (1H, d, J = 8.4Hz), 7.22 (2H, d, J = 7.8Hz), 7.28-7.32 (4H,), 7.35 (1H, dd, J = 8.4, 2.2Hz), 7.42 (1H, s), 7.46 (1H, s), 7.48 (1H, d, J = 2.0Hz), 7.54 (2H, d, J = 8.6Hz). IR (KBr) 3330, 2949, 2847, 1651, 1609, 1514, 1507, 1408, 1316, 910, 812, 735 cm "1. Analysis Calculated for C3? H35N302: C, 77.31; H, 7.32; N, 8.72. Found: C, 77.44; H, 7.12; N, 8.78.

Working Example 319 (Production of Compound 319) In dimethylformamide (5 ml), 7- (4-ethoxyphenyl) -l-methyl-2,3-dihydro-l-benzazepine-4-carboxylic acid hydrochloride (0.5 g) was dissolved. ), thionyl chloride (0.25 ml) was added to the mixture under cooling with ice. The mixture was stirred at room temperature for 45 minutes, and the solvent was evaporated. The residue was dissolved in tetrahydrofuran (15 ml), and the mixture was added dropwise to a suspension of 4- ((N- (3-ethoxypropyl) -N-methylamino) ethyl) aniline dihydrochloride (0.41 g) and triethylamine. (1.2 ml) in tetrahydrofuran (10 ml), under cooling with ice. Under a nitrogen atmosphere, the mixture was stirred at room temperature overnight, and the solvent was evaporated. Water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated and the residue was purified with a column of silica gel (methanol / triethylamine / ethyl acetate) to give crude crystals, which were recrystallized with ethyl acetate-hexane to give the N- ( 4- ((N- (3-ethoxypropyl) -N-methylamino) methyl) phenyl) -7- (4-ethoxyphenyl) -l-methyl-2,3-dihydro-l-benzazepine-4-carboxamide (Compound 319) (0.39 g) as pale yellow crystals, mp 129-131 ° C. NMR-aH (d ppm, CDC13) 1.19 (3H, t, J = 6.9Hz), 1.44 (3H, t, J = 7.1Hz), 1.76-1.84 (2H,), 2.19 (3H, s), 2.46 ( 2H, t, J = 7.4Hz), 2.97 (2H, t, J = 4.6Hz), 3.09 (3H, s), 3.35 (2H, t, J = 4.8Hz), 3.41-3.52 (6H, m), 4.07 (2H, q, J = 7.1Hz), 6.88 (1H, d, J = 8.4Hz), 6.95 (2H, d, J = 8.8Hz), 7.29 (2H, d, J = 8.8Hz), 7.40- 7.55 (8H, m). IR (KBr) v: 2978, 2868, 1651, 1607, 1516, ISOScm "1. Analysis Calculated for C33H4? N303: C75.ll; H, 7.83; N, 7.96, Found C, 74.90; H, 7.98; N, 7.97.

Working Example 320 (Production of Compound 320) In water / ethanol / toluene (1: 1: 10, 18.0 ml) were dissolved 4-ethylthiophenyl borate (264 mg) and 7-bromo-1-methyl-N- [4 - [[N-methyl-N- (tetrahydro-2H-pyran-4-yl) amino] methyl] phenyl] -2,3-dihydro-l-benzazepine-4-carboxamide (439 mg), and the mixture was added potassium carbonate (301 mg). Under an argon atmosphere, the mixture was stirred for 30 minutes, and to the mixture tetracistriphenylphosphine palladium (42 mg) was added. Under an argon atmosphere, the mixture was heated to reflux for 17.5 hours, and the mixture was diluted with ethyl acetate (200 ml). The mixture was washed with water (50 ml) and saturated brine (50 ml), and the organic layer was dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography on silica gel (75 g, ethyl acetate-ethyl acetate / ethanol = 9: 1) and recrystallized from ethanol to give the (4-Ethylthiophenyl) -1-methyl-N- [4- [[N-methyl-N- (tetrahydro-2 H -pyran-4-yl) amino] methyl] phenyl] -2,3-dihydro-l-benzazepin -4-carboxamide (Compound 320) (168 mg, 34%). p.f. 139-141 ° C. NMR t (200MHz, CDCl3) d 1.34 (3H, t, J = 7.3Hz), 1.63-1.76 (4H, m), 2.21 (3H, s), 2.57-2.72 (1H, m), 2.98 (2H, q , J = 7.3Hz) 2H around ad 2.96 was hidden by d 2.98, 3.10 (3H, s), 3.31-3.43 (4H, m), 3.57 (2H, s), 4.00-4.07 (2H, m), 6.89 (1H, d, J = 8.6Hz), 7.28-7.40 (6H, m), 7.466 (1H, dd, J = 8.5, 2.3Hz), 7.473 (1H, s), 7.52-7.56 (4H,). IR (KBr) 2948, 2845, 1645, 1597, 1514, 1489, 1408, 1314, 1244, 1188, 812 cm "1. Analysis Calculated for C33H39N302S: C, 73.16; H, 7.26; N, 7.76. Found: C, 72.96; H, 7.08; N, 7.64.

Working Example 321 (Production of Compound 321) In DMF (10.0 ml), 7- (4-methylphenyl) -1 - [(trifluoromethyl) sulfonyl] -2,3-dihydro-l-benzazepine-4-carboxylic acid was dissolved. (387 mg), thionyl chloride (0.175 ml) was added to the mixture. The mixture was stirred at room temperature for 1 hour, and excess thionyl chloride and DMF were evaporated under reduced pressure. The residue was dissolved in dichloromethane (10.0 ml), and the mixture was added dropwise to a solution of 4- [[N-methyl-N- (tetrahydro-2H-pyran-4-yl) amino] methyl dihydrochloride] aniline (331 mg) and triethylamine (0.98 ml) in dichloromethane (15.0 ml) at 0 ° C. The mixture was stirred at room temperature for 4 hours, and water (50 ml) was added to the mixture. The mixture was extracted with dichloromethane (100 ml x 3), and the organic layer was dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography on silica gel (35 g, ethyl acetate-ethyl acetate / ethanol = 9: 1) and recrystallized with ethanol to give the (4-methylphenyl) -N- [4- [[N-methyl-N- (tetrahydro-2 H -pyran-4-yl) amino] methyl] phenyl] -1- [(trifluoromethyl) sulfonyl] -2, 3- dihydro-1-benzazepine-4-carboxamide (Compound 71) (251 mg, 43%). p.f. 185-187 ° C.

NMR aH (200MHz, CDC13) d 1.70-1.77 (4H, m), 2.21 (3H, s), 2.41 (3H, s), 2.57-2.72 (1H, m), 3.11 (2H, t, J = 5.9Hz), 3.37 (2H, td, J = 11.3, 2.9Hz), 3.58 (2H, S), 4. 02-4.08 (4H, m), 7.26-7.35 (4H,), 7.46-7.61 (8H, m), 7. 64 (1H, s). IR (KBr) 1661, 1516, 1497, 1393, 1314, 1223, 1194, 1142, 812 cm "1. Analysis calculated for C 32 H 34 F 3 N 304 S: C, 62.63; H, 5.58; N, 6.85, Found: C, 62.58; H, 5.57; N, 6.91.

Working Example 322 (Production of Compound 322) To a solution of 7- (4-methylphenyl) -2,3-dihydrobenzoxepin-4-carboxylic acid (280 mg) and 2 - [(4-aminophenyl) methylamino] pyridine (199 mg) in DMF (4 ml) was added, under cooling with ice, diethyl cyanophosphate (0.18 ml) and triethylamine (0.17 ml), and the mixture was stirred at 0 ° C for 30 minutes and then at room temperature for 1 hour . To the mixture was added DMAP (1 piece), and the mixture was stirred at room temperature for 18 hours. Under ice-cooling, a solution of sodium bicarbonate was added to the mixture and the mixture was extracted with ethyl acetate, washed with brine, dried (anhydrous magnesium sulfate) and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate / hexane = 1/1) and recrystallized from ethyl acetate / hexane to give N- [4- [(pyrid-2-yl) aminomethyl) ] phenyl] -7- (4-methylphenyl) -2,3-dihydro-l-benzoxepin-4-carboxamide (Compound 72) (97 mg) as colorless crystals, mp 189-190 ° C H-NMR (200MHz, CDC13) d: 2.39 (3H, s), 3.07 (2H, t, J = 4.6), 4.36 (2H, t, J = 4.6), 4.49 (2H, d, J = 4.6), 4.9-5.0 (1H, broad m), 6.38 (1H, d, J = 8.4), 6.60 (1H, dd, J - 5.2, 7.2), 7.06 (1H, d, J = 8.4), 7.2-7.6 (12H, m), 8.05-8.15 (1H, m). IR (KBr) 1651, 1597, 1522, 1491, 1439, 1316, 1254, 812, 772cm_1 Analysis for C30H27N302 • 0.2H20 Calculated C, 77.46; H, 5.94; N, 9.03: Found C, 77.24; H, 5.96; N, 8.91.

Reference Example 277 A solution of p-nitrobenzyl bromide (10 g) in THF (50 ml) was added dropwise to a solution of bis (2-methoxyethyl) -amine (6.8 g) and triethylamine (10 ml) in THF (50 ml). Under a nitrogen atmosphere, the mixture was stirred at room temperature overnight, and the solvent was evaporated. Water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give N, N-bis (2-methoxyethyl) -4-nitrobenzylamine (10.8 g) as a yellow oil. NMR-XH (d ppm, CDC13) 2.76 (4H, t, J = 5.6Hz), 3.31 (6H, s), 3.48 (4H, t, J = 5.6Hz), 3.83 (2H, s), 7.54 (2H) , d, J = 8.8Hz), 8.17 (2H, d, J = 8.8Hz). IR (pure) v: 2878, 1599, 1520cm "1.

Reference Example 278 In acetic acid (200 ml) N, N-bis (2-methoxyethyl) -4-nitrobenzylamine (10.5 g) was dissolved and reduced iron (11 g) was added little by little to the mixture. The mixture was stirred at room temperature overnight, and the solvent was evaporated. Ethyl acetate was added to the residue and the precipitates were filtered. The filtrate was washed with a solution of sodium hydroxide, water and saturated brine, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated and the residue was purified by column chromatography on silica gel (ethyl acetate) to give 4- ((N, N-bis (2-methoxyethyl) amino) -methyl) aniline (6.2 g) as a red oil.

NMR ^ H (d ppm, CDC13) 2.71 (4H, t, J = 6.3Hz), 3.31 (6H, s) 3.46 (4H, t, J = 6.3Hz), 3.59 (2H, s), 6.63 (2H, d, J = 8.4Hz), 7.10 (2H, d, J = 8.4Hz). IR (pure) v: 3353, 2874, 2818, ldlScm "1.

Reference Example 279 In 1, 2-dichloroethane (50 ml), p-nitro-benzaldehyde (5 g) and 3-ethoxypropylamine (3.75 g) were dissolved, and triacetoxy boron sodium hydride was added to the mixture under ice-cooling. (9.8 g). Under a nitrogen atmosphere, the mixture was stirred at room temperature overnight and 37% formalin (3.5 ml) and triacetoxy boron sodium hydride (9.8 g) were added to the mixture under cooling with ice. Under a nitrogen atmosphere, the mixture was stirred at room temperature for 8 hours, and the solvent was evaporated. The residue was neutralized with a solution of IN sodium hydroxide, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and subjected again to extraction with IN hydrochloric acid. The mixture was washed with ethyl acetate, neutralized with IN sodium hydroxide and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give the N- (3-ethoxypropyl) -N-methyl-4-nitrobenzylamine (6.6 g) as a yellow oil. NMR-aH (d ppm, CDC13) 1.18 (3H, t, J = 7.0Hz), 1.72-1.86 (2H, m), 2.20 (3H, s), 2.48 (2H, t, J = 7.6Hz) 3.41- 3.52 (4H, m), 3.58 (2H, s), 7.50 (2H, d, J = 8.8Hz), 8.17 (2H, d, J = 8.8Hz). IR (pure) v: 2859, 1520, 1346cm "1.

Reference Example 280 In THF (60 ml) were suspended N- (3-ethoxypropyl) -N-methyl-4-nitrobenzylamine (6.0 g), iron (III) chloride (0.06 g) and active charcoal (0.6 g) , and to the suspension, hydrazine monohydrate (4.1 ml) was added dropwise at 60-65 ° C. The mixture was stirred at 65 ° C for 4 hours, and hydrazine monohydrate (15 ml) was added to the mixture. The mixture was stirred at 65 ° C for 4 hours and filtered. The solvent of the filtrate was evaporated and the residue was extra with ethyl acetate. The organic layer was washed with saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated. The residue was dissolved in 2-propanol, and hydrochloric acid (6 ml) was added to the mixture. The solvent was evaporated and the precipitated 4- ((N- (3-ethoxypropyl) -N-methylamino) -methyl) aniline hydrochloride (5.8 g) was filtered with ethyl acetate and washed with ethyl acetate-hexane to give a yellow powder. p.f. 173-175 ° C. NMR-1H (d ppm, CDC13 + CD30D) 1.16 (3H, t, J = 7.0Hz), 2.18 (2H, broad), 2.72 (3H, s), 3.05-3.29 (2H, m), 3.40-3.52 ( 4H, m), 4.22-4.43 (2H, m), 7.58 (2H, d, J = 8.2Hz), 7.78 (2H, d, J = 8.2Hz), 11.86 (1H, broad). IR (KBr) v: 1651cm_1. Analysis Calculated for C? 3H22N20 • 2HC1: C, 52.88; H, 8.19; N, 9.49. Found C, 52.61; H, 8.05; N, 9.55.

Reference Example 281 In 1, 2-dichloroethane (50 ml), p-nitro-benzylamine hydrochloride (3 g) and 1,3-dimethoxyacetone (1.9 g) and triethylamine (2.2 ml) were suspended and the mixture was added, under reduced pressure, triacetoxy boron sodium hydride (4.7 g). Under a nitrogen atmosphere, the mixture was stirred at room temperature for 5 hours, and 37% formalin (1.8 ml) and triacetoxy boron sodium hydride (5 g) were added to the mixture under cooling with ice. Under a nitrogen atmosphere, the mixture was stirred at room temperature overnight, and the solvent was evaporated. The residue was neutralized with a solution of IN sodium hydroxide and extra with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with a column of silica gel (ethyl acetate / hexane) to give the N- (1,3-dimethoxy-propan-2-yl) -N-methyl -4-Nitrobenzylamine (3.2 g) as a yellow oil. NMR-aH (d ppm, CDC13) 2.32 (3H, s), 2.97-3.09 (1H, m), 3.36 (6H, s) 3.44-3.63 (4H, m), 3.85 (2H, s), 7.53 (2H , d, J = 9.0Hz), 8.17 (2H, d, J = 9.0Hz). IR (pure) v: 2880, 1520, 1346cm ~ 1.

Reference Example 282 N- (1,3-dimethoxy-propan-2-yl) -N-methyl-4-nitrobenzylamine (3.1 g) was dissolved in acetic acid (100 ml), and reduced iron (3.2) was added to the mixture. g) little by little. The mixture was stirred at room temperature overnight, and the solvent was evaporated. Ethyl acetate was added to the residue, and the precipitated products were filtered. The filtrate was washed with a solution of sodium hydroxide, water and saturated brine, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in ethyl acetate. To the mixture was added 4N hydrochloric acid-ethyl acetate, and the precipitated products were filtered and washed with diethyl ether. The mixture was dissolved in water and the mixture was neutralized with a solution of IN sodium hydroxide and extra with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give 4 - ((N- (1, 3-dimethoxypropan-2-yl) -N-methylamino) ethyl) -aniline (2.4 g) as a red oil. NMR-XH (d ppm, CDC13) 2.29 (3H, s), 2.95-3.07 (1H,), 3.34 (6H, s), 3.42-3.58 (4H, m), 3.61 (2H, s), 6.64 (2H , d, J = 8.4Hz), 7.11 (2H, d, J = 8.4Hz). IR (pure) v: 3357, 2880, 1615, ldldcm "1.

Reference Example 283 In 1,2-dichloroethane (50 ml), p-nitro-benzaldehyde (5 g) and 2-methoxyethylamine (2.7 g) were dissolved and added to the mixture., under cooling with ice, triacetoxy boron sodium hydride (9.8 g). Under a nitrogen atmosphere, the mixture was stirred at room temperature for 4 hours, and 37% formalin (3.8 ml) and triacetoxy boron sodium hydride (10 g) were added to the mixture under cooling with ice. Under a nitrogen atmosphere, the mixture was stirred at room temperature overnight, and the solvent was evaporated. The residue was neutralized with a 1N sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with a column of silica gel (ethyl acetate / hexane) to give the N- (2-methoxyethyl) -N-methyl-4-nitrobenzylamine (5.9 g) as a yellow oil. NMR ^ H (d ppm, CDC13) 2.28 (3H, s), 2.63 (2H, t, J = 5.6Hz), 3.35 (3H, s), 3.52 (2H, t, J = 5.6Hz), 3.65 (2H , s) 7.52 (2H, d, J = 8.8Hz), 8.18 (2H, d, J = 8.8Hz). IR (pure) v: 2814, 1605, 1520, 1346cm ~ 1 Reference Example 284 N- (2-methoxy-ethyl) -N-methyl-nitrobenzylamine (5.9 g) was dissolved in acetic acid (100 ml), and reduced iron (7.5 g) was added little by little to the mixture. The mixture was stirred at room temperature overnight, and the solvent was evaporated. Ethyl acetate was added to the residue, and the precipitated products were filtered. The filtrate was washed with a solution of sodium hydroxide, water and saturated brine, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give 4- ((N- (2-methoxyethyl) -N-methylamino) methyl) aniline (3.4 g) as a red oil. NMR ^ H (d ppm, CDC13) 2.24 (3H, s), 2.57 (2H, t, J = 6.0Hz), 3.33 (3H, s), 3.44 (2H, s), 3.50 (2H, t, J = 6.0Hz), 6.64 (2H, d, J = 8.4Hz) 7.09 (2H, d, J = 8.4Hz). IR (pure) v: 3349, 2813, 1615, lSldcm "1.

Reference Example 285 In THF (350 ml), 5-broananthranilic acid (40.06 g) was dissolved, and the mixture was cooled to 0 ° C. To the mixture was added dropwise a solution of 10.0M borane dimethylsulfide in THF (54.5 ml) and the mixture was stirred at room temperature for 4.5 hours. The mixture was cooled to 0 ° C, and a 3N sodium hydroxide solution was added dropwise to the mixture. The mixture was stirred at room temperature overnight, and granulated sodium hydroxide was added to the mixture to adjust the mixture to pH 11. The aqueous layer was saturated with potassium carbonate, and the THF layer was separated. The aqueous layer was extracted with ether (100 ml x 5). The organic layers were combined and dried with magnesium sulfate. The solvent was evaporated under reduced pressure to give (2-amino-5-bromophenyl) methanol (36.66 g, 100%).

NMR-2H (200MHz, CDCl 3) d 4.62 (2H, s), 7.20 (1H, s), 7.23-7.26 (1H, m).

Reference Example 286 To acetone (300 ml) was added (2-amino-5-bromophenyl) methanol (23.32 g) and active manganese dioxide (58.5 g), and the mixture was stirred at room temperature for 17.5 hours and filtered . The solvent was evaporated under reduced pressure to give 2-amino-5-bromobenzaldehyde (16.41 g, 71%). NMR aH (200MHz, CDC13) d 6.10-6.20 (2H, broad), 6.57 (1H, d, J = 8.8Hz), 7.38 (1H, dd, J = 8.8, 2.4Hz), 7.59 (1H, d, J = 2.4Hz), 9.81 (1H, s).

Reference Example 287 To acetic anhydride (34.8 ml) formic acid (17.0 ml) was added at 0 ° C, and the mixture was stirred at 60 ° C for 2 hours, cooled and diluted with THF (200 ml) . In THF (100 ml) 2-amino-5-bromobenzaldehyde (16.40 g) was dissolved, and the mixture was added dropwise to the previously prepared solution of formic acid anhydride in THF at 0 ° C. The mixture was stirred at 0 ° C for 2 hours, and the solvent was evaporated under reduced pressure. The residue was washed with hexane and filtered to give 4-bromo-2-formylphenylformamide (15.24 g, 82%). NMR aH (200MHz, CDC13) d 7.72 (1H, dd, J = 8.8, 2.6Hz), 7.83 (1H, d, J = 2.6Hz), 8.53 (1H, s), 8.68 (1H, d, J = 9.2 Hz), 9.88 (1H, s), 10.94 (1H, broad).

Reference Example 288 To 4-bromo-2-formylphenylformamide (18.07 g), ethyl 4-bromobutyrate (30.9 g) and potassium carbonate (21.9 g) was added DMF (160 ml), and the mixture was stirred at 70 ° C. C for 24 hours. The mixture was diluted with ethyl acetate (1400 ml), washed with water (300 ml x 3) and saturated brine (150 ml), and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography on silica gel (300 g, hexane: ethyl acetate = 4: 1- »1: 1) to give 4- (4-bromine -2, N-diformilanilino) ethyl butyrate (21.56 g, 80%). 2H NMR (200MHz, CDC13) (syn: anti = 5: 2 or 2: 5) d 1.23 (2.1H, t, J = 7.2Hz), 1.25 (0.9H, t, J = 7.2Hz), 1.87 (2H , quintet, J = 7.5Hz), 2.35 (1.4H, t, J = 7.3Hz), 2.36 (0.6H, t, J = 6.8Hz), 3.78 (0.6H, t, J = 7.5Hz), 3.85 ( 1.4H, t, J = 7.6Hz), 4.10 (1.4H, q, J = 6.9Hz), 4.15 (0.6H, q, J = 7.2Hz), 7.17 (0.3H, d, J = 8.4Hz), 7.24 (0.7H, d, J = 8.6Hz), 7.81 (0.3H, dd, J = 8.4, 2.4Hz), 7.82 (0.7H, dd, J = 8.4, 2.4Hz), 8.09 (0.3H, d, J = 2.4Hz), 8.10 (0.7H, d, J = 2.4Hz), 8.19 (0.7H, s), 8.39 (0.3H, s), 9.92 (0.3H, s), 10.04 (0.7H, s) .

Reference Example 289 In t-butanol (500 ml) were dissolved 4- (4-bromo-2, N-diformilanilino) ethyl butyrate (15.32 g) and potassium t-butoxide (5.53 g) and the mixture was heated to reflux for 30 minutes. To the mixture were added water (500 ml) and IN hydrochloric acid (50 ml), and the mixture was extracted with ethyl acetate (1000 ml). The organic layer was washed with saturated brine (200 ml) and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography on silica gel (300 g, hexane: ethyl acetate = 4: 1-1: 1) to give 7-bromo-l-formyl -2, ethyl 3-dihydro-l-benzazepin-4-carboxylate (3.13 g, 22%) and 7-bromo-l-formyl-2,3-dihydro-l-benzazepine-4-carboxylic acid (1.39 g, 10%). Ethyl 7-Bromo-l-formyl-2, 3-dihydro-l-benzazepine-4-carboxylate; p.f. 150.5-152 ° C. NMR aH (200MHz, CDC13) d 1.34 (3H, t, J = 7.1Hz), 2.93 (2H, t, J = 4.9Hz), 3.80 (2H, t, J = 5.7Hz), 4.28 (2H, q, J = 7.2Hz), 7.00 (1H, d, J = 8.4Hz), 7.50 (1H, dd, J = 8.4, 2.2Hz), 7.57 (1H, s), 7.66 (1H, d, J = 2.2Hz) 46 (1H, IR (KBr) 1707, 1678, 1491, 1358, 1265, 1235, 1194, 1088 cm. "Analysis Calculated for Ci 4 H 4 N 0 3 Br: C, 51.87; H, 4.35; N, 4.32 Found: C, 51.81; H, 4.35; N, 4.19, 7-bromo-l-formyl-2,3-dihydro-l-benzazepine-4-carboxylic acid, mp 248-249.5 ° C. lR NMR (200MHz, DMS0-d6) d 2.73 (2H, td, J = 5.1, 1.2Hz), 3.67 (2H, t, J = 5.9Hz), 7.33 (1H, d, J = 8.4Hz), 7.57 (1H, s), 7.61 (1H, dd, J = 8.4 2.6Hz), 7.91 (1H, d, J = 2.4Hz), 8.48 (1H, s), IR (KBr) 1665, 1491, 1431, 1360, 1300, 1281, 1252, 1196, 999, 918, 841, 754 cm "1. Analysis Calculated for C? 2H? 0N03Br: C, 48.67; H, 3.41; N, 4.73. Found: C, 48.70; H, 3.56; N, 4.54.

Reference Example 290 In sodium hydroxide IN (13.0 ml) and THF: ethanol (1: 1, 50 ml) was dissolved in ethyl 7-bromo-l-formyl-2,3-dihydro-l-benzazepine-4-carboxylate (2.77 g), and the mixture was stirred at room temperature for 15 hours. To the mixture was added 1N hydrochloric acid (12.5 ml), and the mixture was concentrated. Water was added to the residue (200 ml), and the mixture was adjusted to pH 2 with IN hydrochloric acid. The mixture was extracted with ethyl acetate (300 ml x 3), and the organic layer was dried with magnesium sulfate. The solvent was evaporated under reduced pressure to give 7-bromo-l-formyl-2,3-dihydro-l-benzazepine-4-carboxylic acid (2.52 g, 100%).

Reference Example 291 To a solution of 7-bromo-l-formyl-2,3-dihydro-l-benzazepine-4-carboxylic acid (3.28 g) in DMF (30 ml) was added dropwise thionyl chloride ( 2.0 ml) at 0 ° C, and the mixture was stirred at room temperature for 30 minutes. Under reduced pressure, thionyl chloride and DMF were evaporated, and the residue was dissolved in dichloromethane (40 ml). To a solution of 4- [[N-methyl-N- (tetrahydro-2H-pyran-4-yl) amino] methyl] aniline (3.90 g), and triethylamine (11.6 ml) in dichloromethane (40 ml) was added drop drop the previously prepared chloride solution at 0 ° C, and the mixture was stirred at room temperature for 7 hours. The mixture was concentrated under reduced pressure and the residue was diluted with ethyl acetate (400 ml), washed with water (100 ml x 2) and saturated brine (50 ml), and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography on silica gel (200 g, ethyl acetate - ethyl acetate / ethanol = 10: 1) to give 7-bromo-1- formyl-N- (4- [[N-methyl-N- (tetrahydro-2H-pyran-4-yl) amino] methyl] -phenyl] -2,3-dihydro-l-benzazepine-4-carboxamide (2.13 g , 39%). p.f. 173-175 ° C. NMR aH (200MHz, CDC13) d 1.66-1.77 (4H,), 2.21 (3H, s), 2.58-2.73 (1H, m), 3.02 (2H, t, J = 4.8Hz), 3.37 (2H, td, J = 10.3, 2.9Hz), 3.58 (2H, s), 3.87 (2H, t J = 5.5Hz), 4.02-4.08 (2H, m), 7.03 (1H, d, J = 8.4Hz), 7.32 (2H) , d, J = 8.4Hz), 1H was hidden under 7.27-7.34, 7.50 (1H, s), 7.51 (1H, dd, J = 8.5, 2.3Hz), 7.52 (2H, d, J = 8.4Hz); 7.65 (1H, d, J = 2.2Hz), 8.49 (1H, s). IR (KBr) 2953, 2845, 1669, 1599, 1520, 1358, 1316, 1260, 1192, 733 cm "1. Analysis Calculated for C25H2sN3? 3Br: C, 60.24; H, 5.66; N, 8.343. Found: C, 60.15; H, 5.69; N, 8.49.

Reference Example 292 To 7-bromo-l-methyl-2,3-dihydro-l-benzazepin-4-carboxylic acid t-butyl ester (4.0 g), 4-ethoxyphenyl borate (2.35 g), a carbonate solution of 1M potassium (25 ml) and ethanol (25 ml) was added toluene (100 ml), and the mixture was stirred under an argon atmosphere at room temperature for 30 minutes. To the mixture was added tetracistriphenylphosphine palladium (0.55 g), and the mixture was heated to reflux under an argon atmosphere overnight. The organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated and the residue was purified with a column of silica gel (ethyl acetate / hexane) to give 7- (4-ethoxyphenyl) -l-methyl-2,3-dihydro-l- t-butyl benzazepin-4-carboxylate (4.0 g) as yellow crystals, mp 140-142 ° C. NMR-1H (d ppm, CDC13) 1.43 (3H, t, J = 7.0Hz), 1.54 (9H, s), 2.82 (2H, t, J = 4.8Hz), 3.05 (3H, s), 3.27 (2H , t, J = 4.8Hz), 4.07 (2H, q, J = 7.0Hz), 6.83 (1H, d, J = 8.4Hz), 6.95 (2H, d, J = 8.8Hz), 7.38-7.49 (4H , m), 7.66 (1H, s). IR (KBr) n: 2978, 1694cm "1. Analysis Calculated for C24H29N03: C, 75.96; H, 7.70; N, 3.69, Found C, 75.91; H, 7.89; N, 3.49.

Reference Example 293 In dimethoxyethane (100 ml), 7- (4-ethoxyphenyl) -l-methyl-2,3-dihydro-l-benzazepine-4-carboxylic acid t-butyl ester (4.0 g) was dissolved and added to the mixture. 6N hydrochloric acid (25 ml). The mixture was heated to reflux for 3 hours, and the solvent was evaporated. The yellow, precipitated powder was filtered and washed with ethyl acetate-hexane to give 7- (4-ethoxyphenyl) -l-methyl-2,3-dihydro-l-benzazepine-4-carboxylic acid hydrochloride (3.8 g). p.f. 245-254 ° C (dec.). NMR-aH (d ppm, DMSO-de) 1.35 (3H, t, J = 7.0Hz), 2.77 (2H, broad), 3.02 (3H, s), 3.25 (2H, broad), 4.05 (2H, q, J = 7.0Hz), 6.94-6.98 (3H, m), 7.49-7.68 (5H,). IR (KBr) v: 2976, 2880, 2475, 1701cm "1.

Reference Example 294 In IN hydrochloric acid (25 ml) and ethanol (20 ml) was dissolved 7-bromo-l-formyl-2,3-dihydro-l-benzazepin-4-carboxylic acid ethyl ester (1165 mg), and the The mixture was heated to reflux for 2 hours. The mixture was neutralized with a saturated sodium hydrogen carbonate solution and the mixture was extracted with ethyl acetate (300 ml). The organic layer was washed with water (100 ml) and dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography on silica gel (150 g, hexane / ethyl acetate = 9: 1) to give 7-bromo-2,3-dihydrole -benzazepin-4-carboxylic acid ethyl ester (628 mg, 59%). p.f. 120-121 ° C. NMR aH (200MHz, CDC13) d 1.34 (3H, t, J = 7.1Hz), 2.86 (2H, td, J = 4.8, 1.2Hz), 3.36 (2H, t, J = 4.8HZ), 4.25 (2H, q, J = 7.1Hz), 4.51-4.66 (1H, broad), 6.49 (1H, d, J = 8.8Hz), 7.15 (1H, dd, J = 8.7, 2.3Hz), 7.39 (1H, d, J = 2.2Hz), 7.53 (1H, s). IR (KBr) 3377, 2978, 1694, 1493, 1248, 1209, 1173, 1090, 812 cm. "1 Calculated for C? 3H14BrN02: C, 52.72; H, 4.76; N, 4.73 Found: C, 52.54; H, 4.88; N, 4.60.

Reference Example 295 In dichloromethane (30 ml), 7-bromo-2,3-dihydro-l-benzazepine-4-carboxylic acid ethyl ester (457 mg) and triethylamine (1.29 ml) were dissolved and drop was added to the mixture. drop at 0 ° C trifluoromethanesulfonic acid anhydride (1.56 ml). The mixture was stirred at 0 ° C for 4 hours, and water (50 ml) was added to the mixture at 0 ° C. The mixture was extracted with dichloromethane (100 ml), and the organic layer was dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography on silica gel (50 g, hexane / ethyl acetate = 9: 1) to give 7-bromo-l- [(trifluoromethyl) sulfonyl ] Ethyl -2, 3-dihydro-l-benzazepin-4-carboxylate (516 mg, 78%). NMR tR (200MHz, CDC13) d 1.36 (3H, t, J = 7.5Hz), 3.00 (2H, t, J = 6.0Hz), 3.91-4.03 (2H, m), 4.30 (2H, q, J = 7.2 Hz), 7.38 (1H, d, J = 8.4Hz), 7.45 (1H, dd, J = 8.8, 2.2Hz), 7.63 (1H + 1H, s). IR (KBr) 2982, 1713, 1487, 1397, 1252, 1227, 1194, 1142, 1100, 1090, 700, 627 cm "1.

Reference Example 296 In water / ethanol / toluene (1: 1: 10, 36.0 ml) 4-methylphenyl borate (194 mg) and 7-bromo-1- [(trifluoromethyl) sulfonyl] -2, 3-dihydro were dissolved ethyl-l-benzazepin-4-carboxylate (510 mg), and to the mixture was added potassium carbonate (395 mg). The mixture was stirred under an argon atmosphere for 30 minutes, and to the mixture i was added tetracistriphenylphosphine palladium (138 mg). Under an argon atmosphere, the mixture was refluxed for 17 hours, and the mixture was diluted with ethyl acetate (150 ml) and washed with water (50 ml) and saturated brine (50 ml). The organic layer was dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography on silica gel (50 g, hexane / ethyl acetate = 9: 1) to give 7- (4-methylphenyl) -1- [ (trifluoromethyl) -sulfonyl] -2,3-dihydro-1-benzazepine-4-carboxylic acid ethyl ester (469 mg, 90%). NMR aH (200MHz, CDC13) d 1.37 (3H, t, J = 7.2Hz), 2.41 (3H, s), 3.02 (2H, t, J = 6.0Hz), 3.99-4.05 (2H, m), 4.31 ( 2H, q, J = 7.1Hz), 7.27 (2H, d, J = 8.0HZ), 7.43-7.56 (4H, m), 7.60-7.68 (1H, m), 7.77 (1H, s). IR (KBr) 2982, 1709, 1495, 1395, 1246, 1225, 1192, 1152, 1096, 812, 642, 588 cm "1.

Reference Example 297 In a solution of sodium hydroxide IN (3.0 ml) and THF / ethanol (1: 1, 12.0 ml) was dissolved ethyl 7- (4-methylphenyl) -1- [(trifluoromethyl) sulfonyl] - 2,3-dihydro-l-benzazepine-4-carboxylic acid (463 mg), and the mixture was stirred at room temperature for 14 hours. The mixture was neutralized with IN hydrochloric acid (3.5 ml) and concentrated. Water was added to the residue (40 ml), and the mixture was extracted with ethyl acetate (100 ml x 3). The organic layer was dried with anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give 7- (4-methylphenyl) -1- [(trifluoromethyl) sulfonyl] -2,3-dihydro-1-benzazepin- 4-carboxylic acid (393 mg, 91%).

RMR tR (200MHz, "DMSO-de) d 2.39 (3H, s), 2.94 (2H, t, J = 6.2Hz), 4.00-4.08 (2H, m), 7.28 (2H, d, J = 8.6Hz) , 7.41-7.49 (1H, m), 7.56 (2H, d, J = 8.4Hz), 7.61-7.66 (1H, m), 7.73-7.77 (1H, m), 8.00 (1H, s).

Reference Example 298 To a solution of 4-nitrobenzaldehyde (3.02 g) and 2-aminopyridine (1.88 g) in 1,2-dichloroethane (70 ml) were added triacetoxy boron sodium hydride (5.93 g) and acetic acid (1.14 ml). ) and the mixture was stirred under a nitrogen atmosphere at room temperature for 2 hours and concentrated. To the residue was added a solution of sodium bicarbonate, and the mixture was extracted with ethyl acetate, washed with brine, dried (anhydrous magnesium sulfate) and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate / hexane = 1/1), and ethyl acetate / diethyl ether and 1N hydrochloric acid were added to the purified materials. The aqueous layer was extracted and washed with diethyl ether, and sodium carbonate was added to the mixture. The mixture was extracted with ethyl acetate, and the extract was dried (anhydrous magnesium sulfate), concentrated and recrystallized from ethyl acetate / hexane to give 2- [(4-nitrophenyl) methylamino] -pyridine (1.63 g) as pale yellow crystals. p.f. 131-132 ° C 2 H NMR (200MHz, CDC13) d: 4.67 (2H, d, J = 6.0), 4.9- 5.1 (1H, broad m), 6.37 (1H, d, J = 8.4), 6.63 (1H, dd, J = 5.1, 6.9), 7.35-7.45 (1H, m), 7.52 (2H, d, J = 8.8), 8. 15-8.25 (1H,), 8.18 (2H, d, J = 8.8). IR (KBr) 1601, 1516, 1460, 1348, 1281, 1159, 999, 772cm "1. Analysis for C? 2HnN302 Calculated C, 62.87; H, 4.84; N, 1 8. 33: Found C, 62.69; H, 4.69; N, 18.20.

Reference Example 299 To a solution of nickel bromide (44 mg) in methanol (4 ml) / THF (4 ml) was added boron sodium hydride (40 mg), and the mixture was stirred. To the mixture was added 2- [(4-nitrophenyl) methylamino] pyridine (0.92 g) and then boron sodium hydride (414 mg), and the mixture was stirred at room temperature for 1 hour. To the mixture was added nickel bromide (44 mg) and boron sodium hydride (454 mg), and the mixture was stirred at room temperature for 2 hours. The insoluble materials were filtered with sealant, and a solution of sodium bicarbonate was added to the filtrate. The mixture was extracted with ethyl acetate and washed with brine. The extract was dried (anhydrous magnesium sulfate) and concentrated, and the residue was purified twice with silica gel column chromatography (ethyl acetate / hexane = 1/1) to give 2- (4- aminophenyl) methylamino] pyridine (369 g) as a pale red solid. NMR-aH (200MHz, CDC13) d: 3.4-3.8 (2H, broad), 4.36 (2H, d, J = 5.2), 4.7-4.85 (1H, broad), 6.37 (1H, d, J = 8.4), 6.58 (1H, dd, J = 5.2, 8.0), 6.66 (2H, d, J = 8.4), 7.15 (2H, d, J = 8.4), 7.35-7.45 (1H, m), 8.05- 8.15 (1H, m). IR (KBr) 1603, 1578, 1514, 1443, 1335, 1294, 1159, 818, 770cm "1.

Industrial Applicability The compound of the formula (I ') or a salt thereof of the present invention has potent CCR5 antagonistic activity and can be used advantageously for the treatment or prophylaxis of infectious diseases of several HIV in humans (e.g. AIDS).

Sequence List IDENT. of Sequence No Sequence Length 34 Sequence Type nucleic acid number of individual chain Straight topology Sequence class other synthetic nucleic acid DNA Sequence: CAGGATCCGA TGGATTATCA AGTGTCAAGT CCAA 34 IDENT. of Sequence No. 2 Sequence Length 34 Sequence Type Nucleic Acid Number of Individual Chain Straight Topology Sequence Class Other Synthetic Nucleic Acid DNA Sequence: TCTAGATCAC AAGCCCACAG ATATTTCCTG CTCC 34 It is noted that in relation to this date, the best method known to the applicant to carry out the said invention, is that which is clear from the present description of the invention.

Having described the invention as above, the content of the following claims is claimed as property.

Claims (40)

1. A pharmaceutical composition for antagonizing CCR5, characterized in that it comprises a compound of the formula: wherein R1 is a ring of 5 to 6 members, optionally substituted; W is a divalent group of the formula: wherein ring A is an optionally substituted 5 to 6 membered aromatic ring, X is an optionally substituted carbon atom, an optionally substituted nitrogen atom, a sulfur atom or an oxygen atom, and ring B is a ring of 5 to 7 members, optionally substituted; Z is a chemical bond or a divalent group; R2 is (a) an optionally substituted amino group in which a nitrogen atom can form a quaternary ammonium, (b) an optionally substituted nitrogen-containing heterocyclic ring group which may contain a sulfur atom or an oxygen atom as atoms constituting the ring and wherein a nitrogen atom can form a quaternary ammonium, (c) a group that is attached through a sulfur atom or (d) a group of the formula: (0) wherein k is 0 or 1, and when k is 0, a phosphorus atom can form a phosphonium; and R5 'and R0' are independently an optionally substituted hydrocarbon group, an optionally substituted hydroxy group or an optionally substituted amino group, and R5 'and R6' may be linked together to form a cyclic group in conjunction with the adjacent phosphorus atom, or a salt of it.

2. A composition according to claim 1, characterized in that R1 is benzene, furan, thiophene, pyridine, cyclopentane, cyclohexane, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine or tetrahydropyran, each of which can be substituted.

3. A composition according to claim 1, characterized in that R1 is an optionally substituted benzene.

4. A composition according to claim 1, characterized in that ring A is furan, thiophene, pyrrole, pyridine or benzene, each of which can be substituted.

5. A composition according to claim 1, characterized in that ring A is an optionally substituted benzene.

6. A composition according to claim 1, characterized in that W is a group of the formula: wherein each symbol is as defined in claim 1.

7. A composition according to claim 1, characterized in that W is a group of the formula: wherein each symbol is as defined in claim 1.

8. A composition according to claim 7, characterized in that ring B is a ring group of 5 to 7 members of the formula: where Y is -Y '- (CH2) m- (Y' is -S-, -0-, -NH- or -CH2-, and m is an integer of 0-2), -CH = CH- or -N = CH-), which may have a substituent in any possible position.

9. A composition according to claim 8, characterized in that Y is -Y'- (CH2) 2- (Y 'is -S-, -0-, -NH- or -CH2-).

10. A composition according to claim 8, characterized in that Y is - (CH2) 2-, - (CH2) 3- or -0- (CH2) 2-.

11. A composition according to claim 10, characterized in that ring A is an optionally substituted benzene.

12. A composition according to claim 1, characterized in that Z is an alkylene of 1 to 3 carbon atoms, optionally substituted.

13. A composition according to claim 1, characterized in that Z is a divalent group of the formula: -Z '- (CH2) n- (Z' is -CH (OH) -, -C (O) - or -CH2- , and n is an integer of 0-2) in which an optional methylene group can be substituted.

14. A composition according to claim 1, characterized in that Z is methylene.

15. A composition according to claim 1, characterized in that Z is substituted in the para position of the benzene ring.

16. A composition according to claim 1, characterized in that R2 is (a) an optionally substituted amino group wherein a nitrogen atom can form a quaternary ammonium, (b) a nitrogen-containing heterocyclic ring group, optionally substituted which can contain a sulfur atom or an oxygen atom such as the atoms that make up the ring and where a nitrogen atom can form a quaternary ammonium, (c) a group that binds through a sulfur atom or (d) a Formula group: (0) wherein k is 0 or 1, and when k is 0, a phosphorus atom can form a phosphonium; and R5 and R6 are independently an optionally substituted hydrocarbon group or an optionally substituted amino group, and R5 and R6 can be linked together to form a cyclic group in conjunction with the adjacent phosphorus atom.

17. A composition according to claim 1, characterized in that R2 is (a) an optionally substituted amino group wherein a nitrogen atom can form a quaternary ammonium, (b) a nitrogen-containing heterocyclic ring group, optionally substituted which can contain a sulfur atom or an oxygen atom as the atoms that constitute the ring and wherein the nitrogen atom can form a quaternary ammonium or (c) a group of the formula: wherein R5 and R4 are independently an optionally substituted hydrocarbon group, and R5 and R6 can be joined together to form a cyclic group together with the adjacent phosphorus atom.

18. A composition according to claim 1, characterized in that R2 is an optionally substituted amino group in which a nitrogen atom can form a quaternary ammonium.

19. A composition according to claim 1, characterized in that R2 is a group of the formula: -N + RR'R "wherein R, R 'and R" are independently an aliphatic hydrocarbon group, optionally substituted or a group of the heterocyclic ring, alicyclic, optionally substituted.

20. A pharmaceutical composition for antagonizing CCR5, characterized in that it comprises a compound of the formula: wherein R1 is an optionally substituted benzene or an optionally substituted thiophene; Y "is -CH2-, -S- or -0-; and R, R 'and R" are independently an optionally substituted aliphatic hydrocarbon group or an optionally substituted heterocyclic, alicyclic ring group.

21. A composition according to claim 20, characterized in that R and R 'are independently an acyclic hydrocarbon group, optionally substituted.

22. A composition according to claim 20, characterized in that R and R 'are independently an alkyl group of 1 to 6 carbon atoms, optionally substituted.

23. A composition according to claim 20, characterized in that R "is an optionally substituted alicyclic hydrocarbon group or a heterocyclic, alicyclic, optionally substituted heterocyclic ring group.

24. A composition according to claim 20, characterized in that R "is a cycloalkyl group of 3 to 8 carbon atoms, optionally substituted.

25. A composition according to claim 20, characterized in that R "is an optionally substituted cyclohexyl.

26. A composition according to claim 20, characterized in that R "is a group of the heterocyclic, alicyclic, saturated, optionally substituted ring.

27. A composition according to claim 20, characterized in that R "is an optionally substituted tetrahydropyryl, an optionally substituted tetrahydrothiopyranyl or an optionally substituted piperidyl.

28. A composition according to claim 20, characterized in that R "is an optionally substituted tetrahydropyranyl.

29. A pharmaceutical composition for antagonizing CCR5, characterized in that it comprises a compound of the formula: where X is an anion.

30. A composition according to claim 29, characterized in that X is a halogen atom.

31. A pharmaceutical composition for antagonizing CCR5, characterized in that it comprises N-methyl-N- [4- [[2- (4-methylphenyl) -6,7-dihydro-5H-benzocyclohepten-8-yl] carbonyl] amino iodide ] benzyl] -piperidinium, N-methyl-N- [4 - [[[7- (4-methylphenyl) -2,3-dihydro-l-benzoxepin-4-yl] carbonyl] amino] benzyl] piperidinium iodide, N- [4- [N-methyl-N- (tetrahydropyran-4-yl) aminomethyl] -phenyl] -7- (4-methylphenyl) -2, 3-dihydro-l-benzoxepin-4-carboxamide, N- [4- [N-methyl-N- (tetrahydropyran-4-yl) aminomethyl] -phenyl] -7- (4-morpholinophenyl) -2, 3- dihydro-l-benzoxepin-4-carboxamide, 7- (4-ethoxyphenyl) -N- [4- [N-methyl-N- (tetrahydropyran-4-yl) aminomethyl] phenyl] -2, 3-dihydro-l- benzoxepin-4-carboxamide, N, N-dimethyl-N- [4 - [[2- (4-methylphenyl) -6,7-dihydro-5H-benzocyclohepten-8-yl] carbonyl] amino] benzyl] iodide -N- (tetrahydropyran-4-yl) ammonium, N, N-dimethyl-N- [4- [[7- (4-methylphenyl) -2, 3-dihydro-l-benzoxepin-4-yl] chloride] carbonyl] amino] benzyl] -N- (4-oxocyclohexyl) ammonium, N, N-dimethyl-N- [4- [[7- (4-ethoxyphenyl) -2,3-dihydro-l-benzoxepin- chloride] 4-yl] carbonyl] amino] benzyl] -N- (tetrahydropyran-4-yl) ammonium, or a salt thereof.

32. A composition according to claim 1, characterized in that it is for the treatment or prophylaxis of an infectious disease of HIV.

33. A composition according to claim 1, characterized in that it is for the treatment or prophylaxis of AIDS.

34. A composition according to claim 1, characterized in that it is for the prevention of the progress of AIDS.

35. A composition according to claim 32, characterized in that it is used in combination with a protease inhibitor and / or a reverse transcriptase inhibitor.

36. A composition according to claim 35, characterized in that the reverse transcriptase inhibitor is zidovudine, didanosine, zalcitabine, lamivudine, stavudine, nevirapine or delavirdine.

37. A composition according to claim 35, characterized in that the protease inhibitor is saquinavir, ritonavir, indinavir or nelfinavir.

38. The use of the compound as claimed in claim 1 or a salt thereof in combination with a protease inhibitor and / or a reverse transcriptase inhibitor for the treatment or prophylaxis of an infectious disease of HIV.

39. A method for antagonizing CCR5, characterized in that it comprises administering to a mammal in need thereof an effective amount of a compound of the formula: wherein R1 is an optionally substituted 5 to 6 membered ring; W is a divalent group of the formula: wherein ring A is an optionally substituted 5 to 6 membered aromatic ring, X is an optionally substituted carbon atom, an optionally substituted nitrogen atom, a sulfur atom or an oxygen atom, and ring B is a ring of 5 to 7 members optionally substituted; Z is a chemical bond or a divalent group; R2 is (a) an optionally substituted amino group in which a nitrogen atom can form a quaternary ammonium, (b) an optionally substituted nitrogen-containing heterocyclic ring group which may contain a sulfur atom or an oxygen atom as atoms constituting the ring and wherein a nitrogen atom can form a quaternary ammonium, (c) a group that is attached through a sulfur atom or (d) a group of the formula: wherein k is 0 or 1, and when k is 0, a phosphorus atom can form a phosphonium; and R5 'and R6' are independently an optionally substituted hydrocarbon group, an optionally substituted hydroxy group or an optionally substituted amino group, and R5 'and R6' may be linked together to form a cyclic group in conjunction with the adjacent phosphorus atom, or a salt of it.

40. The use of a compound of the formula wherein R1 is an optionally substituted 5 to 6 membered ring; W is a divalent group of the formula: wherein ring A is an optionally substituted 5 to 6 membered aromatic ring, X is an optionally substituted carbon atom, an optionally substituted nitrogen atom, a sulfur atom or an oxygen atom, ring B is a ring from 5 to 7 members optionally substituted; Z is a chemical bond or a divalent group, R2 is (a) an optionally substituted amino group in which a nitrogen atom can form a quaternary ammonium, (b) a nitrogen-containing heterocyclic ring group, optionally substituted which can contain a sulfur atom or an oxygen atom as atoms that make up the ring and where a nitrogen atom can form a quaternary ammonium, (c) a group that binds through a sulfur atom or (d) a group of the formula: wherein k is 0 or 1, and when k is 0, a phosphorus atom can form a phosphonium; and R5 'and R6' are independently an optionally substituted hydrocarbon group, an optionally substituted hydroxy group or an optionally substituted amino group, and R5 'and R6' may be linked together to form a cyclic group in conjunction with the adjacent phosphorus atom, or a salt thereof, for the preparation of a medicament for antagonizing CCR5.