 1,6-disubstituted isochroman for the treatment of migraine
专利摘要:
The present invention relates to the use of 1,6-disubstituted isoforms of formula (I) which are useful in the treatment of headache, in particular migraine and group headache, and which are useful in the treatment of psychotic and other CNS and / or cardiovascular disorders, Chroman and aromatic bicyclic amines (ABA). (I) 公开号:KR19990028550A 申请号:KR1019970709869 申请日:1996-06-07 公开日:1999-04-15 发明作者:마이클 디 엔니스；루쓰 이 텐브링크 申请人:파마시아 앤드 업죤 컴패니； IPC主号:
专利说明:
1, 6-disubstituted isochrone for the treatment of migraine (Also known as 1-benzopyrane, in which oxygen atoms are attached to aromatic rings) and isochroman (known as 2-benzopyranes, in which oxygen atoms are not attached to aromatic rings) Is known in the art as piperazine (or 4-arylpiperadine). Croman and arylpiperazine conjugated with an alkyl chain are also known. EP 300,908 discloses (1-benzopyran) -alkyl- (piperazinyl or aminopiperidine) -aryls useful as antiarrhythmics and anticonvulsants. The compounds of the present invention require alkyl-piperazinyl (or piperidinyl) -aryl at the 1-position carbon of the 2-benzopyran ring and also require substitution at the 6- Vascular headaches (migraine and cluster headache), and CNS cardiovascular disorders. A variety of isochroms, thioxymans, benzoichepsins and benzothiepins which have a hydroxy, alkoxy or o-methylenedioxy substituent on the aromatic ring and which are attached to the arylpiperazine (piperidine) by an alkyl chain are known . These compounds are disclosed as being useful as antipsychotics and hypotensive agents. The compounds of the present invention do not allow oxygen to be substituted on the aromatic rings of isochroman, thioisochroman, benzoheptin, or benzothiepine ring systems for utility in the CNS and cardiovascular disorders. Isochroman attached to the arylpiperazine (piperidine) by attachment of a hydroxy, alkoxy or o-methylenedioxy functional group to the aromatic ring and alkyl chain attached to the alkylphenyl, benzoxepine or benzothiepine Groups are known to be useful as psychotic and hypotensive agents. The compounds of the present invention do not allow oxygen to be substituted on the aromatic ring of the isochroman, thioxyman, benzenepine, or benzothiepin ring systems for utility in the CNS and cardiovascular disorders. U.S. Patent No. 4,179,510 and many of which are incorporated herein by reference disclose isochroman-alkyl-piperazinyl (or aminopiperidinyl) -aryls that require oxygen as a substituent on an isochroman aromatic ring. These compounds are disclosed as being useful as antihypertensive agents and antipsychotic agents. Also useful for preparing such compounds are isochroman, isothiocroman, 2-benzoxepine- and 2-benzothiepin-alkyloxyethanol. More specifically, 7,8-dimethoxybenzenespin is disclosed as 1 - [(6, 7-dimethoxyisochroman) alkyl] -4- (aryl) piperazine. In addition, 2-benzylsipine-alkyl-piperazine (aminopiperidine) -aryl, 2-benzothiepine and 2-benzoxepine all require an oxygen atom as a substituent on the aromatic ring and are useful for the same purpose Lt; / RTI > Dutch Patent No. 8,001,981 discloses 1- (2-chlorophenyl) -4- [2- (1,3,4,5-tetrahydro-7,8-dimethoxy- Yl) ethyl] piperazine. ≪ / RTI > International Patent Publication No. WO 92/18089 discloses isochroman-alkyl-piperazinyl (aminopiperidinyl) - aminopyrimidines which are useful in sensitizing cells for multi-tolerance and which need oxygen to be present on the aromatic ring of isochroman Aryl. ≪ / RTI > International Patent Publication No. WO 88/08424 discloses isochroman-alkyl-piperazinyl (or aminopiperidinyl) derivatives which are useful in the treatment of head injuries, spinal trauma and falcation, where oxygen needs to be present on the aromatic ring of isochroman ) -Aryl. ≪ / RTI > International patent publications WO 90/15056 and US 5,140,040 disclose isochroman, tetralin and dihydro analges substituted with various alkylamines for the treatment of glaucoma, depression, hypertension, congestive heart failure and vasospasm. Talen. ≪ / RTI > U.S. Patent No. 4,994,486 discloses isochroman-alkyl-amines for treating psychosis, Parkinson's disease and forms of poisoning. Japanese Patent No. 61083180 discloses isochroman-alkyl- (alkyl) amines as an anti-ulcer agent. EP 404,197 discloses isochroman-alkyl-piperazine-alkyl-keto (alcohol) aryls with bronchodilator and antiallergic activity. Japanese Patent No. 51125287 (J 52083846) discloses isochroman-alkyl-amines (piperazine) having antidepressant, analgesic, diuretic, anti-inflammatory and anti-asthmatic activity. German patent DE 2,624,693 and GB patent GB 1552004 disclose isochroman-alkyl-amines including arylpiperazine as a fusogenic agent, hypotensive agent, antidepressant agent, diuretic agent, anti-inflammatory agent, muscle relaxant and vasodilator have. These compounds differ from the compounds of the present invention in that oxygen needs to be displaced on the isochroman aromatic ring. Japanese Patent No. 57159713 discloses isochroman- and tetralin- (in the absence of an alkyl spacer) -piperazine-aryl as an antiallergic agent. The compounds of the present invention require at least one carbon as a linking group. U.S. Pat. Nos. 3,549,656 and 3,467,675, and Belgian Patent No. 678,035 disclose phthal-, isochroman- and isochroman-alkylene-amines for the treatment of depression. European Patent No. 458,387 and US Patent No. 5,137,911 are useful as platelet aggregation inhibitors and intracellular calcium antagonists and are useful as isochroman-alkylene-piperazines useful for the treatment of deep-seated sinus rhythms, angina, angina, -Alkylene-aryl. ≪ / RTI > German Patent DE 3,409,612 discloses dimethoxyisochroman and benzisepine-alkyl-amino-alkyl for the prevention of coronary heart disease or hypertension. Japanese Patent No. 6,831,808 discloses isochroman-alkyl-amines useful for treating ulcers. European Patent 457,686 discloses phthalals and indan alkylaminopiperidinyl ureas or carbamates for the treatment of stress, pain and schizophrenia. J. Med. Chem., 25 (I), 75-81 (1982) disclose 6,7-dimethoxyisochroman-alkyl-piperazinyl-aryl-type compounds having hypotensive activity. U.S. Pat. Nos. 5,032,598 and 5,215,989 generally include isochroman and tetralin of the present invention when various substituents are appropriately selected. International Patent Publication Nos. WO 88/08424 and U.S. Patent No. 5,120,843 disclose only dialkoxyisocycles containing substituted pyridinylpiperazinyl ethyl side chains. However, the compounds of the present invention do not allow alkoxy substitution. International Publication No. WO 95/18118 (PCT / US94 / 13284) describes a method of treating a person suffering from central nervous system disorders, including psychosis, paraphrenia, psychotic depression, mania, schizophrenia, Disclose only a variety of isochrons containing useful 6- (substituted) amino (6-NRR) and 6- (substituted) amide (6-CO-NRR) isochrons. Such compounds are also useful for the treatment of vascular headaches, particularly migraine. Other central nervous system disorders that can be treated with these compounds include anxiety, drug addiction, convulsive disorders, spectrum disorders, human disorders, lack of concentration in children and adults, post-traumatic stress syndrome and mood modulation. WO 95/18118 discloses a process for the preparation of racemic 1- (4-methoxyphenyl) -4- [2- (6-aminocarbonylisochroman-1-yl) 4-methoxyphenyl) -4- [2- (6-methylaminocarbonylisochroman-1-yl) - ethylpiperazine (example 139). [Summary of the Invention] Disclosed are 1,6-disubstituted isochroman of formula (I) and a pharmaceutically acceptable salt thereof: (I) Wherein: (I) W 1 is a nitrogen (-N-) or carbon (-CH-) atom; (II) X 1 is (A) - (CH 2 ) n1 -, wherein n 1 is 0 to 3; (B) -CH = CH-; (III) R < 1 > is: (A) -H; (B) -F, -CL, -Br-I; (C) C 1 -C 8 alkyl; (D) C 2 -C 8 alkenyl containing 1 to 3 double bonds (=); (E) C 2 -C 8 alkynyl containing one or two triple bonds (≡); (F) C 3 -C 8 cycloalkyl; (G) -C 1 -C 3 alkyl, -C 3 -C 8 cycloalkyl; (H) -NO 2; (I) -C [identical to] N; (J) -CF 3; (K) -OR 1-1 {wherein, R is 1-1; (1) -H; (2) C 1 -C 8 alkyl; (3) C 2 -C 8 alkenyl containing 1 to 3 double bonds (=); (4) C 2 -C 8 alkynyl containing one or two triple bonds (≡); (5) C 3 -C 8 cycloalkyl; (6) -C 1 -C 3 alkyl, -C 3 -C 8 cycloalkyl; (7) -CF 3; (8) -SO 2 -CF 3; (9) - (CH 2) n2 -φ [ wherein, n 2 is from 0 to 4, -φ optionally has one or two; (a) -F, -Cl, -Br, -I; (b) -C N; (c) -CF 3; (d) C 1 -C 3 alkyl; (e) -OR 1-1A , wherein R 1-1A is -H, C 1 -C 6 alkyl, -CF 3 or -CH 2 -φ; (f) -NR 1-1A R 1-1B wherein R 1-1A and R 1-1B are the same or different and R 1-1B is -H, C 1 -C 6 alkyl, -CF 3 or - CH 2 -φ and R 1-1 A is as defined above; (g) -CO-NR 1-1 A R 1-1B , wherein R 1-1A and R 1-1B are as defined above; (h) -SO 2 -NR 1-1A R 1-1B ( wherein, R 1-1A and 1-1B R are as defined above); (i) -NR 1-1 A -SO 2 -R 1-1B , wherein R 1-1A and R 1-1B are as defined above; (j) -NO 2; (k) -O-SO 2 -CF 3 ; (L) -N (R 1-1 ) 2 , wherein R 1-1 is the same or different and is as defined above; (M) -CO-N (R 1-1 ) 2 , wherein R 1-1 is the same or different and is as defined above; (N) -SO 2 -R 1-3 {wherein, R is 1-3; (1) -H; (2) -CF 3; (3) C 1 -C 8 alkyl; (4) C 2 -C 8 alkenyl containing 1 to 3 double bonds (=); (5) C 2 -C 8 alkynyl containing one or two triple bonds (≡); (6) C 3 -C 8 cycloalkyl; (7) -C 1 -C 3 alkyl, -C 3 -C 8 cycloalkyl; (8) - (CH 2) n2 -φ [ wherein, n 2 are as defined above, -φ optionally of one or two; (a) -F, -Cl, -Br, -I; (b) -C N; (c) -CF 3; (d) C 1 -C 3 alkyl; (e) -OR 1-3A , wherein R 1-3A is -H, C 1 -C 6 alkyl, -CF 3 or -CH 2 -φ; (f) -NR 1-3A R 1-3B , wherein R 1-3A and R 1-3B are the same or different and R 1-3B is -H, C 1 -C 6 alkyl, -CF 3 or - CH 2 -φ and R 1-3A is as defined above; (g) -CO-NR 1-3A R 1-3B , wherein R 1-3A and R 1-3B are as defined above; (h) -SO 2 -NR 1-3A R 1-3B ( wherein, R 1-3A and 1-3B R are as defined above); (i) -NR 1-3A- SO 2 -R 1-3B , wherein R 1-3A and R 1-3B are as defined above; (j) -NO 2; (k) -O-SO 2 -CF 3 is substituted by; (9) -OR 1-3A , wherein R 1-3A is as defined above; (10) -NR 1-3A R 1-3B , wherein R 1-3A and R 1-3B are as defined above; (O) -NR 1-1 -SO 2 -R 1-3 , wherein R 1-1 and R 1-3 are the same or different and are as defined above; (P) - (CH 2) n2 -φ [ wherein, n 2 are as defined above, -φ optionally of one or two; (1) -F, -Cl, -Br, -I; (2) -C N; (3) -CF 3; (4) C 1 -C 6 alkyl; (5) -OR 1-1 , wherein R 1-1 is as defined above; (6) -N (R 1-1 ) 2 , wherein R 1-1 is the same or different and is as defined above; (7) -CO-N (R 1-1 ) 2 , wherein R 1-1 is the same or different and is as defined above; (8) -SO 2 -N (R 1-1 ) 2 , wherein R 1-1 is the same or different and is as defined above; (9) -NR 1-1 -SO 2 - (R 1-1 ) wherein R 1-1 are the same or different and are as defined above; (10) -NO 2; (11) -O-SO 2 -CF 3 is substituted by; (Q) -CO-R 1-1 , wherein R 1-1 is as defined above; (R) -CO-OQ 1-2 , wherein Q 1-2 is as defined below; (IV) R 2 is defined the same as R 1 , R 2 may be the same as or different from R 1 ; (V) Q < 1 > (A) -CO-NQ 1-1 Q 1-2 [wherein Q 1-1 is; (1) -H; (2) C 1 -C 8 alkyl; (3) C 2 -C 8 alkenyl containing 1 to 3 double bonds (=); (5) C 2 -C 8 alkynyl containing one or two triple bonds (≡); (5) C 3 -C 8 cycloalkyl; (6) -C 1 -C 3 alkyl, -C 3 -C 8 cycloalkyl; (7) -CF 3; (8) -SO 2 -CF 3; (9) - (CH 2) n7 -φ [ wherein, n 7 is 0 to 4, -φ optionally of one or two; (a) -F, -Cl, -Br, -I; (b) -C N; (c) -CF 3; (d) C 1 -C 3 alkyl; (e) -OQ 1-1 A , wherein Q 1-1 A is -H, C 1 -C 6 alkyl, -CF 3 or -CH 2 -φ; (f) -NQ 1-1A Q 1-1B , wherein Q 1-1A and Q 1-1B are the same or different and Q 1-1B is -H, C 1 -C 6 alkyl, -CF 3 or - CH 2 -φ and Q 1-1 A is as defined above; (g) -CO-NQ 1-1A Q 1-1B , wherein Q 1-1A and Q 1-1B are as defined above; (h) -SO 2 -NQ 1-1A Q 1-1B ( wherein, Q 1-1A and 1-1B Q are as defined above); (i) -NQ 1-1 A- SO 2 -Q 1-1B , wherein Q 1-1A and Q 1-1B are as defined above; (j) -NO 2; (k) -O-SO 2 -CF 3 ; Q 1-2 is: (1) -H; (2) C 1 -C 8 alkyl; (3) C 2 -C 8 alkenyl containing 1 to 3 double bonds (=); (4) C 2 -C 8 alkynyl containing one or two triple bonds (≡); (5) C 3 -C 8 cycloalkyl; (6) -C 1 -C 3 alkyl, -C 3 -C 8 cycloalkyl; (7) -CF 3; (8) - (CH 2) n2 -φ [ wherein, n 2 are as defined, -φ optionally has one or two (a) -F, -Cl, -Br, -I; (b) -C N; (c) -CF 3; (d) C 1 -C 6 alkyl; (e) -OQ 1-2 A (wherein Q 1-2 A is; (i) -H; (ii) C 1 -C 6 alkyl; (iii) -CF 3; (iv) - (CH 2 ) -); (9) - (CH 2) n9 -Q 1-2B (CH 2) n10 -Q 1-2C { wherein, n 9, and n 10 is the same or different, from 0 to 4, Q is -O 1-2B - or -NQ 1-2D -, wherein Q is 1-2D; (a) -H; (b) C 1 -C 8 alkyl; (c) 1 to 3 double bonds (=) C 2 -C 8 alkenyl containing; (d) C 2 -C 8 alkynyl containing one or two triple bonds (≡); (e) C 3 -C 8 cycloalkyl; (f) -C 1 -C 3 alkyl, -C 3 -C 8 cycloalkyl; (g) -CF 3; (h) - (CH 2) n11 -φ [ At this time, the n 11 is from 0 to 4, -φ optionally has one or two; (i) -F, -Cl, -Br, -I; (ii) -C N; (iii) -CF 3; (iv) C 1 -C 3 alkyl; (v) -OQ 1-2 E, wherein Q 1-2 E is H, C 1 -C 6 alkyl, -CF 3 or -CH 2 -φ; (vi) -NQ 1-2 E Q 1-2F , wherein Q 1-2E and Q 1-2F are the same or different and Q 1-2F is -H, C 1 -C 6 alkyl, -CF 3, or CH 2- phi and Q < 1-2E > are as defined above); (vii) -CO-NQ 1-2E Q 1-2F , wherein Q 1-2E and Q 1-2F are as defined above; (viii) -SO 2 -NQ 1-2E Q 1-2F ( wherein, Q and Q 1-2E 1-2F are as defined above); (ix) -NQ 1-2 E- SO 2 -Q 1-2F , wherein Q 1-2E and Q 1-2F are as defined above; (x) -NO 2; (xi) -O-SO 2 -CF 3 is substituted with a - a; 1-2C Q is defined to be equal to Q 1-2D, Q 1-2C and 1-2D Q is the same or different}, and; Q 1-1 and Q 1-2 form , together with the nitrogen atom to which they are attached, a 5 or 6 membered ring which may contain one additional nitrogen or oxygen atom; (B) -SO 2 -NQ 1-1 Q 1-2 , wherein Q 1-1 and Q 1-2 are as defined above; (C) -CO-QQ 1-3 wherein Q < 1-3 > is; (1) -H; (2) -CF 3; (3) C 1 -C 8 alkyl; (4) C 2 -C 8 alkenyl containing 1 to 3 double bonds (=); (5) C 2 -C 8 alkynyl containing one or two triple bonds (≡); (6) C 3 -C 8 cycloalkyl; (7) -C 1 -C 3 alkyl, -C 3 -C 8 cycloalkyl; (8) - (CH 2) n7 -φ [ wherein, n 7 are as defined above, -φ optionally of one or two; (a) -F, -Cl, -Br, -I; (b) -C N; (c) -CF 3; (d) C 1 -C 3 alkyl; (e) -OQ 1-3 A , wherein Q 1-3 A is -H, C 1 -C 6 alkyl, -CF 3 or -CH 2 -φ; (f) -NQ 1-3A Q 1-3B , wherein Q 1-3A and Q 1-3B are the same or different and Q 1-3B is -H, C 1 -C 6 alkyl, -CF 3 or - CH 2 -φ and Q 1-3A is as defined above); (g) -CO-NQ 1-3A Q 1-3B , wherein Q 1-3A and Q 1-3B are as defined above; (h) -SO 2 -NQ 1-3A Q 1-3B ( wherein, Q 1-3A and 1-3B Q are as defined above); (i) -NQ 1-3A -SO 2 -Q 1-3B ( wherein, Q 1-3A and 1-3B Q are as defined above); (j) -NO 2; (k) -O-SO 2 -CF 3 ; (D) -CO-Q 1-3 , wherein Q 1-3 is as defined above; (E) -CO-imidazole; (F) -NQ 1-1 Q 1-2 , wherein Q 1-1 and Q 1-2 are as defined above; (F ') -NQ 1-1 -CO-Q 1-2 wherein Q 1-1 and Q 1-2 are as defined above; (G) -C (Q 1-3) = NOQ 1-4 ( wherein, Q 1-4 are defined the same as Q 1-3, Q 1-3 are as defined above, and Q 1-3 Q 1-4 may be the same or different; (H) -SO 2 - Q 1-3 , wherein Q 1-3 is as defined above; (I) -N (Q 1-1 ) -SO 2 -Q 1-3 wherein Q 1-1 and Q 1-3 are as defined above; (J) 5-oxadiazole optionally substituted by one Q 1-5 , wherein Q 1-5 is; (1) -H; (2) -F, -Cl, -Br, -I; (3) C 1 -C 8 alkyl; (4) C 2 -C 8 alkenyl containing 1 to 3 double bonds (=); (5) C 2 -C 8 alkynyl containing one or two triple bonds (≡); (6) C 3 -C 8 cycloalkyl; (7) -C 1 -C 3 alkyl, -C 3 -C 8 cycloalkyl; (8) -NO 2 ; (9) -C N; (10) -CF 3; (11) -OQ 1-5 A [wherein Q < 1-5A > (a) -H; (b) C 1 -C 8 alkyl; (c) 1 to 3 double bond, C 2 -C 8 alkenyl containing; (d) 1 or 2 triple bond, C 2 -C 8 alkynyl containing; (e) C 3 -C 8 cycloalkyl; (f) -C 1 -C 3 alkyl, -C 3 -C 8 cycloalkyl; (g) -CF 3; (h) -SO 2 -CF 3; (i) - (CH 2) n7 -φ is (wherein, n 7 is 0 to 4); (12) -NQ 1-5A Q 1-5D [wherein Q 1-5A is as defined above, Q 1-5D is: (a) -H; (b) C 1 -C 8 alkyl; (c) 1 to 3 double bond, C 2 -C 8 alkenyl containing; (d) C 2 -C 8 alkynyl containing one or two triple bonds (≡); (e) C 3 -C 8 cycloalkyl; (f) -C 1 -C 3 alkyl, -C 3 -C 8 cycloalkyl; (g) -CF 3; (h) - (CH 2) n7 is -φ (wherein, n 7 is as defined above); (13) -CO-NQ- 5A Q 1-5D , wherein Q 1-5A and Q 1-5D are as defined above; (14) -SO 2 -Q 1-5K [wherein, Q is 1-5K; (a) -H; (b) -CF 3; (c) C 1 -C 8 alkyl; (d) 1 to 3 double bonds (=) C 2 -C 8 alkenyl containing; (e) C 2 -C 8 alkynyl containing one or two triple bonds (≡); (f) C 3 -C 8 cycloalkyl; (g) -C 1 -C 3 alkyl, -C 3 -C 8 cycloalkyl; (h) - (CH 2) n7 is -φ (wherein, n 7 are as defined above); (15) -NQ 1-5 A -SO 2 -Q 1-5 K , wherein Q 1-5 A and Q 1-5 K may be the same or different and are as defined above; (16) - (CH 2) n7 -φ [ wherein, n 7 are as defined above, -φ optionally of one or two; (a) -F, -Cl, -Br, -I; (b) -C N; (c) -CF 3; (d) C 1 -C 6 alkyl; (e) -OQ 1-5 A , wherein Q 1-5 A is as defined above; (f) -NQ 1-5A Q 1-5D , wherein Q 1-5A and Q 1-5D are as defined above; (g) -CO-NQ- 5A Q 1-5D , wherein Q 1-5A and Q 1-5D are as defined above; (h) -SO 2 -NQ 1-5A Q 1-5D ( wherein, Q and Q 1-5D 1-5A is as defined above); (i) -NQ 1-5 A -SO 2 -Q 1-5 D , wherein Q 1-5 A and Q 1-5 D 1 are as defined above; (j) -NO 2; (k) -O-SO 2 -CF 3 ; (K) by a single Q 1-5, optionally substituted 3-oxadiazole (wherein, Q 1-5 are as defined above); (L) one or by two Q 1-5 which may be the same or different optionally substituted triazole (wherein, Q 1-5 are as defined above); (M) by a single Q 1-5 optionally substituted 5-thiadiazole (wherein, Q 1-5 are as defined above); (N) by a single Q 1-5, optionally substituted 3-thiadiazole (wherein, Q 1-5 are as defined above); (O) one or by two Q 1-5 which may be the same or different optionally substituted oxazol-2 (wherein, Q 1-5 are as defined above); (P) one or by two Q 1-5 which may be the same or different optionally substituted thiazol-2 (wherein, Q 1-5 are as defined above); (Q), one, two, or by Q 1-5 with three, same or different a 1-imidazole group optionally substituted (wherein, Q 1-5 are as defined above); (R) one, two, or by Q 1-5 with three, same or different a 1-imidazole group optionally substituted (wherein, Q 1-5 are as defined above); (S) by a single Q 1-5 optionally substituted tetrazole (wherein, Q 1-5 are as defined above); (T) Cyclobutenedione optionally substituted by one Q 1-1 and one Q 1-5 , wherein Q 1-1 and Q 1-5 are as defined above; (U) by a single Q 1-5, optionally substituted 1-pyrimidinyl (wherein, Q 1-5 are as defined above); (V) by a single Q 1-5 optionally substituted 2-pyridinyl (wherein, Q 1-5 are as defined above); (W) by a single Q 1-5, optionally substituted 3-pyridinyl (wherein, Q 1-5 are as defined above); (X) by a single Q 1-5 optionally substituted 4-pyrimidinyl (wherein, Q 1-5 are as defined above); (Y) -Z 1 -CO-Z 2 -Q 1-2 wherein Q 1-2 is as defined above and Z 1 is -O-; -NQ 1-1 -, wherein Q 1-1 is as defined above, and Z 2 is -O-; -NQ 1-1 -, wherein Q 1-1 is as defined above; Provided that X 1 is - (CH 2 ) n1 -, wherein n 1 is 0, and Q 1 is; -CO-NQ 1-1 Q 1-2 ; -SO 2 -NQ 1-1 Q 1-2 ; -NQ 1-1 Q 1-2 , or; In the case of -NQ 1-1 -CO-Q 1-2 , all of Q 1-1 and Q 1-2 are; -H; -C 1 -C 6 alkyl; -C 3 -C 7 cycloalkyl; (C 3 -C 7 ) cycloalkyl, and -C 1 -C 3 alkyl- (-C 3 -C 7 ) cycloalkyl. Also disclosed are aromatic bicyclic amines of formula (ABA) and their pharmaceutically acceptable salts: [Chemical formula ABA] Wherein: (I) W 1 is a nitrogen (-N-) or carbon (-CH-) atom; (II) X 1 is - (CH 2 ) n1 -, wherein n 1 is 0; (III) Q < 1 > is: (A) -CO-NQ 1-1 Q 1-2 {wherein Q 1-1 is; (1) -H; (2) C 1 -C 8 alkyl; (3) C 2 -C 8 alkenyl containing 1 to 3 double bonds (=); (4) C 2 -C 8 alkynyl containing one or two triple bonds (≡); (5) - (CH 2) n7 -φ [ wherein, n 7 is 0 to 4, -φ optionally of one or two; (a) -F, -Cl, -Br, -I; (b) -C N; (c) -CF 3; (d) C 1 -C 3 alkyl; (e) -OQ 1-1 A , wherein Q 1-1 A is -H, C 1 -C 6 alkyl, -CF 3 or -CH 2 -φ; (f) -NQ 1-1A Q 1-1B , wherein Q 1-1A and Q 1-1B are the same or different and Q 1-1B is -H, C 1 -C 6 alkyl, -CF 3 or - CH 2 -φ and Q 1-1 A is as defined above; (g) -CO-NQ 1-1A Q 1-1B , wherein Q 1-1A and Q 1-1B are as defined above; (h) -SO 2 -NQ 1-1A Q 1-1B ( wherein, Q 1-1A and 1-1B Q are as defined above); (i) -NQ 1-1 A- SO 2 -Q 1-1B , wherein Q 1-1A and Q 1-1B are as defined above; (j) -NO 2; (k) -O-SO 2 -CF 3 ; Q 1-2 is: (6) C 1 -C 8 alkyl; (7) C 2 -C 8 alkenyl containing 1 to 3 double bonds (=); (8) C 2 -C 8 alkynyl containing one or two triple bonds (≡); (9) - (CH 2) n2 -φ [ wherein, n 2 are as defined above, -φ optionally of one or two; (a) -F, -Cl, -Br, -I; (b) -C N; (c) -CF 3; (d) C 1 -C 6 alkyl; (e) -OQ 1-2 A (wherein Q 1-2 A is; (i) -H; (ii) C 1 -C 6 alkyl; (iii) -CF 3; (iv) -CH 2 is replaced by a -φ)]} a; (B) -SO 2 -NQ 1-1 Q 1-2 , wherein Q 1-1 and Q 1-2 are as defined above; (C) -NQ 1-1 Q 1-2 , wherein Q 1-1 and Q 1-2 are as defined above; (D) -NQ 1-1 -CO-Q 1-2, wherein Q 1-1 and Q 1-2 are as defined above; (III) R < 1 >is; (A) -H; (B) -F, -Cl, -Br, -I; (C) -C 1 -C 8 alkyl; (D) -C N; (E) -CF 3; (F) 1-1 -OR (wherein, R is 1-1; (1) -H; (2) C 1 -C 8 alkyl; (3) -CF 3; (4) -SO 2 -CF 3; (5) - (CH 2) n2 is -φ (where, n 2 is 0 to 4); (G) -N (R 1-1 ) 2 , wherein R 1-1 may be the same or different and are as defined above; (H) -CO-N (R 1-1 ) 2 , wherein R 1-1 may be the same or different and are as defined above; (I) -SO 2 -R 1-3 [wherein, R is 1-3; (1) -CF 3; (2) C 1 -C 8 alkyl; (3) -OR 1-3A (wherein R 1-3A is as defined above) (4) -NR 1-3A R 1-3B , wherein R 1-3A and R 1-3B are as defined above; (J) -CO-R 1-1 (wherein, R 1-1 is as defined above), and; (IV) R 2 is defined the same as R 1, and R 2 may be the same as or different from R 1 . Further aromatic bicyclic amines of Examples 1, 2, 11, 12, 14, 24, 40, 72, 84, 86 and 88 are further disclosed. The present invention relates to the use of isochroman-alkyl-piperazinyl / piperidinyl-piperidine derivatives useful as analgesics in the treatment of headache, particularly migraine and cluster headache, useful as antipsychotic agents and for treating other CNS and / ≪ / RTI > The present invention relates to novel compounds, 1, 6-disubstituted isochroman (I), and a unique activity spectrum, vasculopathological headache, as previously described in international publication WO 95/18118 (PCT / US94 / 13284) It consists of a small group of aromatic bicyclic amines (ABA), which have very high activity against migraine and cluster headache. The processes used to prepare the claimed novel compounds of the present invention are known to those skilled in the art. The novel compounds of the present invention are prepared by starting with an appropriate starting material and organizing the steps of the process in a particular order (using a protecting group if necessary). Processes for each step of the present invention are known to those skilled in the art. When the chemical structure of any 1, 6-disubstituted isochroman (I) or aromatic bicyclic amine (ABA) is presented, those skilled in the art will appreciate that the compounds Lt; / RTI > Scheme A describes the configuration of 6-bromoisocyanurate (VI), a useful intermediate for many 1, 6-disubstituted isochroman (I) and aromatic bicyclic amines (ABA). Reaction of 3-bromophenethanol (II) with ethyl 3, 3-diethoxypropionate in the presence of titanium tetrachloride in nitromethane or dichloromethane provides isochroman ester (III). The amide (V) can be obtained by standard hydrolysis using lithium hydroxide in THF-water to provide the acid (IV) and coupling it with variously substituted arylpiperazine or 4-arylpiperidine. The arylpiperazine moiety involves the R < 1 > and R < 2 > substituents. It is preferred to place the desired R < 1 > and R < 2 > substituents on the aryl group before generating the amide (V). The starting R < 1 > and R < 2 > aryl groups are known to those skilled in the art or can be readily prepared from known compounds by known methods. Many arylpiperazine residues are commercially available or known in the chemical literature. Residues that are not commercially available or not known can be readily prepared as illustrated in Schemes Q and R. These amides are reduced using borane to provide bromoisocyanurate (VI). Scheme B describes the conversion of 6-bromoisocyanurate (VI) to the corresponding 6-amide and 6-ester analogs. Conversion of the aryl bromide to the primary amide is achieved via metal-halogen exchange using t-butyllithium and quenching the resulting aryl anion with trimethylsilyl isocyanate [J. Mde. Chem., 35, 2208 (1993)]. The aryl anion may be treated with gaseous carbon dioxide, followed by treatment with oxalyl chloride in DMF, followed by reaction with an amine to provide the amide (IX) directly. Alternatively, 6-bromoisocyanurate (VI) can be converted to carbon monoxide and carbon monoxide in the presence of hexamethyldisilazane in a solvent such as palladium (II) acetate, 1,3-bisdiphenylphosphinopropane, diisopropylamine and DMF To give the amide (VII). Other palladium catalysts such as palladium (O) prepared in situ by the organophosphorus or the previously prepared palladium (O) phosphine catalyst can be used. The amide (VII) is prepared according to the method described in J. Am. Org. (IX) or ester (X) via the bis-BOC derivative (VIII) using the procedure described in J. Chem., 56, 5482 (1991). 6-bromoisocyanurate (VI) can be converted directly to the N-methyl substituted amide (IX) by using methylamine or N-methylformamide instead of hexamethyldisilazane in the above-described palladium- (See Examples 5 and 6). Alternatively, another pattern of N-substitution can be obtained using a primary or secondary amine instead of hexamethyldisilazane in the palladium-mediated reaction described above. Scheme C describes the enzymatic reaction of racemate (II). (-) - ester is selectively hydrolyzed as a result of mixing (II) with an enzyme such as lipase derived from Pseudomonas cepacia in aqueous solution (preferably pH 5-8) To obtain an acid (XI). The reaction is preferably carried out at room temperature (20 to 35 DEG C) using 5 to 20% by weight of enzyme. The reaction is monitored by known methods which remove aliquots, acidify and check by HPLC. When the reaction is complete, the product (XI), (-) - acid and product (XII), (+) - ester are recovered and separated by means of acid / base extraction techniques well known in the art. Any active compound can be used where appropriate in all processes illustrated in the schemes for preparing optically pure conversions of the above-described compounds. The undesired enantiomer, (+) - ethyl (isochroman-1-yl) acetate (XII) recovered from the kinetic resolution of the Pseudomonas cepania mediated enantiomer is converted into the racemic mixture during the subsequent further pseudomonas lipase treatment Can be effectively recycled again. This repetitive process optimizes the overall yield of the desired (-) - isochroman-1-yl-acetic acid (XI). Suitable bases for said racemization are bases having a pKa greater than 11, preferably greater than 12. The bases which can be manipulated are alkali metal amide bases, alkali metal alkoxides and alkali metal carbonates, all of which can induce the racemization. The base is preferably an alkali metal amide base or an alkali metal alkoxide, and more preferably an alkali metal alkoxide such as sodium or potassium t-butoxide or an ethoxide. Upon completion of the racemization, the reaction is terminated as a proton donor. Substantially, the proton donor is operable and refers to reactants, for example, with water. However, water is undesirable in terms of operation. Generally the proton donor is an acid. The most common proton donor (hydrochloric acid, ammonium chloride) used to label the enolate anion can be used for the quenching, but acetic acid or trifluoroacetic acid is preferred for ease of handling and purification Do. Scheme D describes the preparation of amides and esters bound to isochroman nuclei by a single carbon methylene spacer (I, X 1 = -CH 2 -). (VI) is treated with trimethylsilylacetylene in the presence of palladium (II) acetate, copper (I) iodide and triethylamine to provide acetylenic isochroman (XIII). Reaction of acetylenic isochroman (XIII) with a dialkylborane such as dicyclohexylborane followed by oxidation with basic hydrogen peroxide gives the carboxylic acid (XIV, Q 1-3 = H), from which the generalized Esters (XIV) or amides (XV) can be derived by standard techniques known to those skilled in the art. Scheme E illustrates amides and esters bonded to isochroman nuclei by two carbon spacers that can be saturated (I, X 1 = -CH 2 CH 2 -) or unsaturated (I, X 1 = -CH = CH-) ≪ / RTI > Treatment of the bromide (VI) with an acrylate ester in the presence of a palladium catalyst, preferably palladium (II) acetate, followed by treatment with 1, 3-bisdiphenylphosphinopropane and diisopropylamine in an organic solvent such as dimethylformamide (XVI). ≪ / RTI > (XVI) is hydrogenated by standard techniques known to those skilled in the art to give the saturated compound (XVII). Similarly, treatment of the bromide (VI) with acrylamide in the presence of a palladium catalyst, preferably palladium (II) acetate, followed by treatment with 1, 3-bisdiphenylphosphinopropane and di Treatment with isopropylamine affords (XVIII). (XVIII) is hydrogenated with standard techniques known to those skilled in the art to give the saturated compound (XIX). Scheme F describes the preparation of amides and esters bound to isochroman nuclei by a carbon-methylene spacer (I, X 1 = -CH 2 CH 2 CH 2 -) with three carbons. The carboxylic acid (X, Q 1-3 = H) is treated with 2 equivalents of propyl lithium to provide butyrophenone (XX). A solution of butyrophenone (XX) in morpholine with one equivalent of a sulfur element and morpholine is heated under reflux for 10 to 20 hours to provide the thiolactam (XXI) (see Org. Reactions, Vol III, Chapter 2 , pp. 83, 1946, John Wiley & Sons, New York "). Hydrolysis of the thiolactam (XXI) with aqueous hydrochloric acid gives the carboxylic acid (XXII, Q 1-3 = H), from which ester (XXII) and amide (XXIII) Can be readily obtained using procedures known to those skilled in the art. Scheme G describes the preparation of isochroman to produce a 6-acyl substituent such as an acid, ester, ketone or oxime. Metal-halogen exchange of aryl bromide (VI) produces an aryl-lithium reagent which is quenched with carbon dioxide to provide the carboxylic acid (X, Q 1-3 = H). Palladium-mediated carbonylation of aryl (IV) bromide in the presence of an alcohol to yield the corresponding ester (X) via the conditions documented in the literature. Similarly, (VI) is cross-coupled with phenol-mediated cross-linking with enol-ether to give ketone (XXIV) and standard acid hydrolysis of the enol-ether intermediate. Alternatively, treatment of the carboxylic acid (X, Q 1-3 = H) with two equivalents of an alkyl lithium reagent produces the corresponding ketone (XXIV). The ketone (XXIV) was condensed with either hydroxylamine or any readily available O-substituted hydroxylamine using a Dean Stark apparatus to remove water using toluene as the solvent to give the desired oxime XXV). Scheme H describes the preparation of sulfonamides (XXVII) and sulfone (XXIX). The aryl bromide (VI) is treated with t-butyllithium to carry out metal-halogen exchange, and the resulting aryllithium is quenched into a dialysis term to give the lithium salt (XXVI). The salt is treated with contaminating phosphorus and the resulting sulfonyl chloride is mixed with the appropriate amine to give the corresponding sulfonamide (XXVII). Alternatively, the aryl bromide (VI) is converted to aryl lithium as described above and quenched with a suitable bifluoride to provide the sulfide (XXVIII). The sulfide is then oxidized according to standard procedures using an oxidizing agent such as m-chloroperbenzoic acid to give sulfone (XXIX). Scheme I describes the preparation of sulfone (XXXIV) in which the sulfone moiety is bonded to the isochroman nucleus by a methylene tether having 1, 2 or 3 carbon atoms. In Schemes I through N, the presence of excess carbon atoms present in the exemplified functional groups (which become part of the X 1 linking group) need to have "n" from 0 to 2, which can be 1, 6-disubstituted isocro Corresponds to n 1 in (I). The carboxylic acid (XXX) can be reduced to the primary alcohol (XXXI) using known techniques and reagents such as lithium hydroxide aluminum or borane. The alcohol (XXXI) can be converted to the corresponding bromide (XXXII) using known techniques and reagents such as triflic acid or tetrafluorocarbon and triphenylphosphine. The bromide (XXXII) can be used to alkylate the thiol using techniques known to those skilled in the art to provide the sulfide (XXXIII). Sulfide (XXXIII) can be oxidized using standard oxidation techniques and reagents such as osmium tetroxide and N-methylmorpholine N-oxide. Scheme J describes the preparation of sulfonamides (XXXVII) in which the sulfonamide moiety is bonded to the isochroman nucleus by methylene tether having 1, 2 or 3 carbon atoms. The bromide (XXXII) is treated with sodium bisulfate in a 10% aqueous sodium hydroxide solution at reflux to provide the sulfonate salt (XXXV). The sulfonate salt is converted to the sulfonyl chloride (XXXVI) using phosphorus pentachloride and phosphorus oxychloride. (XXXVI) is treated with an amine (NQ 1-1 Q 1-2 ) to provide the sulfonamide (XXXVII). Scheme K describes the preparation of substituted imidazoles and triazoles attached to the isochroman nucleus by methylene tether having 1, 2 or 3 carbon atoms. In Scheme K, when "X" in the substituent is nitrogen, the substituent is a triazole, and when "X" is a carbon atom, the substituent is imidazole. These compounds are obtained by alkylation of a lowered imidazole or triazole with a bromide (XXXII). Imidazoles and triazoles are commercially available or can be prepared as described in the chemical literature using techniques known in the art. This type of compound (XXXVIII) is obtained. Reaction Scheme L describes the preparation of oxadiazole (XL) coupled to isochroman nuclei by methylene tether having 1, 2 or 3 carbon atoms. The requisite oxime amide [J. Med. Chem., 36, 1529 (1993), using sodium metal and hydroxylamine hydrochloride in methanol. Nitriles are either commercially available or can be readily prepared as described in the chemical literature using techniques known to those skilled in the art. Oxime amide [J. Med. Chem., 36, 1529 (1993)] and further treated with ester (XXXIX) to give the heterocyclic product (XL). Scheme M describes the preparation of mono - (XLII) or disubstituted tetrazoles (XLIII) bound to isochroman nuclei by methylene terephthalic acid having 1, 2 or 3 carbon atoms. The bromide (XXXII) is converted to the corresponding nitrile (XLI) via a cyanide substitution reaction known to the person skilled in the art. Then, as described in J. Med. (XLII) by the action of sodium azide in a solvent such as N-methyl-2-pyrrolidinone according to the procedure described in J. Med. Chem., 38, 1799 (1995) . The monosubstituted tetrazole is converted to the tetrazole (XLIII) disubstituted by standard alkylation (R-X, acetonitrile, triethylamine). Scheme N describes the preparation of isomer triazoles (XLIII) and (XLIV) coupled to isochroman nuclei by methylene terephthalate having 1, 2 or 3 carbon atoms. The nitrile (XLI) was prepared as described in J. J. Med., Chem., 38, 1799 (1995)] by the action of ethanolic hydrochloric acid. After performing the same procedure as above, (XLII) was treated with alkyl hydrazine (prepared commercially or prepared by literature methods) in a solvent such as ethanol and then treated with formic acid to obtain a mixture of (XLIII) and (XLIV) . The mixture can be separated into its components by standard laboratory techniques such as chromatography or crystallization. Scheme O describes the preparation of substituted triazoles and oxadiazoles from primary carboxamides (VII) using methods known to those skilled in the art (see, for example, J. Org. Chem. , 44, 4160-4164 (1979)]. (0-2) where " X " is nitrogen, the product is triazole. (O-W) where " X " is oxygen, the product is oxadiazole. The amide (VII) is treated with dimethyl amide acetal in a non-polar high boiling solvent such as toluene at 50-100 ° C to give intermediate (0-1). The intermediate is reacted with hydrazine, 1-substituted hydrazine, hydroxylamine or N-substituted hydroxylamine under acidic conditions (generally acetic acid) at room temperature (20-25 ° C) to give the indicated product (0-2) . Scheme P describes the preparation of oxazole derivatives (P-2) monosubstituted from the corresponding propargylic amide (P-1) using methods known to those skilled in the art (see, for example, J. Med. Chem., 36, 1529 (1993)]. (P-1) is treated with mercuric acetate in refluxing acetic acid to produce the exemplified oxazole (P-2). Scheme Q describes the synthesis of piperazine (Q-3), where R 1 is an electron withdrawing substituent in ortho or para position to the aniline nitrogen of piperazine. (Q-1) and halogenated aryl (Q-2) in ortho or para positions to a substituent in which a fluorine or bromine atom is electron-withdrawing in a polar solvent such as water, DMF, dimethylacetamide or the like in a solvent (Q-1) or diisopropylethylamine, potassium carbonate, etc.) at elevated temperature (60 to 2--deg. C) to give piperazine (Q-3). Scheme R begins the synthesis of piperazine (R-3). The nitroaryl (R-1) is reduced with aniline (R-2) using a catalyst such as palladium on carbon, Raney nickel, tin chloride or the like and hydrogen. Alternatively, (R-2) can be commercially obtained. The aniline (R-2) is then reacted with bis (2-haloethyl) amine hydrochloride in a solvent such as THF, toluene, ethylene glycol or chlorobenzene, with or without the addition of a base, ) To obtain piperazine (R-3). Scheme S illustrates the preparation of important intermediates useful in the preparation of the claimed compounds. The hydroxyamide (S-3) is converted directly via a palladium-mediated amidation reaction (as exemplified in Scheme B) or via ester (S-2) ). ≪ / RTI > The ester is readily synthesized from (S-1) via a palladium-based carbonylation reaction known to a person skilled in the art similarly as previously described. The conversion of (S-2) to the amide (S-3) is described in J. Am. Org. (S-2) with an alcoholic solution (typically methanol) containing an appropriate amine reagent in a manner similar to that described in J. Chem., 52, 2033-2036 (1987). The reaction can be carried out at room temperature (20 to 25 ° C), or preferably at 50 to 100 ° C. Scheme T shows two important alternative attempts to the claimed compounds of the present invention. The acid (IV) described above is reduced using standard reducing conditions and reagents (preferably borane) to provide the primary alcohol (S-1). This compound is then converted to the hydroxyamide (S-3) as described in Scheme S. Hydroxyamide is converted to the alkylating agent T-2 by standard chemical modifications (typically X is mesylate or bromide) and used to alkylate the appropriate 4-arylpiperazine or 4-arylpiperidine to give the final compound IX). Alternatively, the hydroxy bromide (S-1) is converted to the alkylating agent (T-I, typical X is mesylate or bromide) by standard chemical modifications and the appropriate 4-arylpiperazine or Is used to alkylate 4-arylpiperidine to provide the bromide (VI). These halides are then converted to final compounds (IV) as described above. Scheme U discloses that chiral bromo acid (U-1), which is (XI) in Scheme C, is converted to amide alcohol (U-5) in Scheme T to (S-3). Bromic acid (U-1) is alkylated with the bromoester (U-2) using methods known to those skilled in the art. One example is treatment of bromic acid (U-1) with 1,1'-carbonyldiimidazole in a solvent such as THF to form the activated ester, followed by treatment with alcohol to form the bromoester (U-2) . The amide ester (U-3) is then provided by treatment under the conditions discussed for Scheme V to convert bromoester (U-2) from (V-1) to (V-2). The amide ester (U-3) is hydrolyzed with an aqueous base and care is taken to avoid hydrolysis of the amide group at (U-3), followed by treatment with aqueous acid to provide the acid amide (U-4). The amide alcohol (U-5) is obtained by treating the acid amide (U-4) as a solvent with borane in THF or a reducing agent such as borane-methylsulfide. Scheme V discloses a method for converting an ester (V-1) to a diamide (V-4). The ester (V-1) is prepared from bromoisocrombin (T-1) and piperazine (Q-3) of Scheme Q by the method discussed in Scheme T. The ester (V-1) can be converted to the amide ester (V) by treatment with a promoter such as bis (diphenylphosphino) propane, diisopropylethylamine, carbon monoxide and methylamine and palladium (II) -2). The solvent for the conversion is selected from DMF, dimethylacetamide, N-methylformamide and acetonitrile, and when methylamine gas is used dimethylacetamide and N-methylformamide are preferred. The preferred temperature is 50 to 120 占 폚. The amide ester (V-2) is further converted to the corresponding amide acid (V-3) using an aqueous base and then acid neutralized to provide (V-3) or a salt thereof. When the ester is tert-butyl ester, the amide ester (V-2) is converted to the corresponding amide acid (V-3) by using trifluoroacetic acid or hydrochloric acid in a solvent such as ether or ethyl acetate. The amidic acid (V-3) is then treated with a condensing agent and an amine to provide the corresponding diamide (V-4) using methods known to those skilled in the art, as discussed in Scheme W. Scheme W describes the synthesis of the hydroxamic acid derivatives (W-7) and (W-8). The compound may be prepared by the processes of Schemes A and B. [ The alcohol group (Scheme S) of the ester alcohol (S-2) is protected by a suitable protecting group such as a dihydropyranyl group and is stabilized under basic conditions to give tetrahydropyranyl ether (W-2). The ester group of the ether (W-2) is hydrolyzed with an aqueous base, followed by careful acidification (to avoid removal of the protecting group) to give the carboxylic acid (W-3). Then, the carboxylic acid (W-3) is condensed with a condensing agent such as carbonyldiimidazole, diethylcyanopropionate, dicyclohexylcarbodiimide, or other suitable condensing agent in a solvent such as dichloromethane or DMF (See, for example, Major Methods of Peptide Bond Formation, Analysis, Synthesis, Biology, E. Gross and J. Meienhofer, eds., Academic Press), and O-alkyl, N-alkylhydroxylamine (Prepared by the method as described in Sulsky et al., Tet. Lett. 3, 31-34 (1989)) with a base such as triethylamine to give the hydroxamate ether W-4). Hydroxamate ether (W-4) is Theodora W. (W-5) by deprotection using methods such as those described in Theodora W. Greene " Protective Groups in Organic Synthesis " (compiled by John Wiley and Sons). Hydroxamate alcohols The hydroxyl group of (W-5) can be converted into the leaving group by a number of methods known to those skilled in the art, such as by way of forming mesylerith, tosylate or chloride, bromide or iodide, (W-6) with an amine such as piperazine (Q-3) of scheme Q or piperazine (R-3) of scheme R or a commercially available amine Hydroxamate amine (W-7) is further treated with palladium on carbon or a method known to a person skilled in the art when alkyl-1-is a protecting group such as benzyl Hydroxamic acid It may be converted to (W-8). Scheme X begins the synthesis of carbamate (X-6). Aniline (X-1) is reacted with alkyldiethoxypropionate in a manner similar to modifying 3-bromophenethanol (II) with the corresponding isochroman ester (III) of Scheme A to give phenol / aniline Ester (X-2). The phenol / aniline ester (X-2) was treated with an aqueous base and then treated with aqueous acid to hydrolyze with phenol / aniline acid (XP3). The phenol / aniline acid (X-3) is condensed with piperazine (Q-3) of Scheme Q or with (R-3) or commercially available amine of Scheme R using methods as discussed in Scheme W to give phenol / aniline Amide (X-4). The phenol / aniline amide (X-4) is then reduced with phenol / aniline amine (X-5) in a solvent such as THF by a reducing agent such as borane or borane-methylsulfide. Phenol / aniline amine (X-5) is reacted with 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) or sodium hydride or other base and isocyanate in dichloromethane or THF as solvent, / Urea (X-6). Scheme Y describes the synthesis of the racemate (Y-5) starting with phenol (Y-1). Phenol (Y-1) is reacted with chloropropionaldehyde diethyl acetal in the presence of a Lewis acid such as boron trifluoride etherate or titanium tetrachloride in a solvent such as dichloromethane or nitromethane to provide chlorophenol (Y-2) . Optionally in the presence of a base such as triethylamine, optionally in the presence of a catalyst such as 4-dimethylaminopyridine or the like, in a solvent such as dichloromethane, using anhydrous trifluoromethane sulfonic acid or N-phenyltrifluoromethanesulfonimide, The phenol of phenol (Y-2) is converted into a leaving group to give triflate (Y-3). (Y-3) is converted to the chloride amide (Y-4) using palladium (II) acetate, cocatalyst, diisopropylethylamine, carbon monoxide and methylamine as discussed in Scheme W. Suitable solvents for the conversion include DMF, dimethylacetamide, N-methylformamide and acetonitrile, and when methylamine gas is used dimethylacetamide and N-methylformamide are preferred. The preferred temperature is about 50 to about 120 < 0 > C. The amide (Y-4) is then reacted with a base such as piperazine (Q-3) or (R-3) or a commercially available amine, triethylamine or diisopropylethylamine, and a base such as ethylene glycol, THF, In the presence of a solvent such as nitrile at 60-110 占 폚 to provide the amide amine (Y-5). Scheme Z describes the preparation of multiple aniline-based derivatives (Z-2), (Z-3), (Z-4), (Z-5), (Z-6) and (Z-7). The compounds are prepared via a metal-halogen exchange reaction (typically n-butyllithium or t-butyllithium), diphenylphosphoryl azide is added (generally at -78 [deg.] C in THF) and subsequently bis- (Z-1) which is itself reduced from the bromide (VI) by reduction with an aniline (Z-1-methoxyethoxy) aluminum hydride. The above conversion from (VI) to (Z-1) is well known in the art and is described in Tetrahedron Letters, 25, 429-432 (1984) and J. Am. Chem. Soc., 94, 6203-6205 (1972). (Z-1) to (Z-2) to (Z-7) is a standard variant known to the person skilled in the art and is acylated as described above (typically by acid chloride or anhydride) , Mesylation and standard lactam reduction. Scheme AA illustrates the preparation of one carbon approved isochroman-6-carboxamide (AA-5). The procedure involves metal-halogen exchange of the bromide (VI) using an alkyllithium reagent (typically t-butyllithium) followed by quenching the resulting anion with DMF to provide the aldehyde (AA-1). The aldehyde was reduced with a standard reagent (such as sodium borohydride in THF), the resulting alcohol (AA-2) was activated with methanesulfonyl chloride and the resulting mesylate was replaced with a cyanide anion to give nitrile (AA -3). Hydrolysis of the nitrile is carried out by treating the (AA-3) solution in DMF with 30% over-hydrogen in the presence of potassium carbonate and stirring the reaction mixture at room temperature (20-25 DEG C) for 20 hours. The resulting amide (AA-4) is converted to the substituted amide (AA-5) as described above. Scheme BB depicts the synthesis of the tertiary amide (BB-2), such as (BB-2), by reduction of the corresponding amide (BB-1) using standard amide reduction conditions as described above (typically using lithium aluminum hydride or borane in THF) ≪ / RTI > illustrates a generalized procedure for the preparation of amines. Scheme CC shows that the functional groups on the arylpiperazine portion of the molecule (i.e., R1 and R1) can be transformed to other functional groups. A standard hydrogenolytic degradative debenzylation of the aryl-ether (CC-1) to provide the corresponding phenol (CC-2) is illustrated. Conversion of phenol (CC-2) to the corresponding trifluoromethanesulfonate (CC-3) by standard methods illustrates typical derivatization of phenols such as (CC-2). The conversion of triflate (CC-3) to a number of derivatives can be achieved by palladium-mediated coupling. For example, coupling of (E-3) with enol-ether provides ketone-substituted aryl derivatives. The reaction is typically carried out using palladium (II) acetate, 1, 3-bis (diphenylphosphino) propane and triethylamine at elevated temperature (50-120 ° C) in DMF or acetonitrile. Scheme DD illustrates another preparation of isochroman-6-triazole (DD-4) and isochroman-6-oxadiazole (DD-6). Primary alcohols of the above amide (DD-1) is by standard techniques, preferably a benzyl ether-protected as (P = -CH 2 -phenyl). (DD-2) is reacted with hydrazine, substituted hydrazine, hydroxylamine or N-substituted hydroxylamine as described in Scheme 0, To produce triazole (DD-3) or oxadiazole (DD-5). The protecting group " P " is removed using standard conditions (typically hydrogenolysis using a transition metal catalyst such as palladium or platinum), the resulting alcohol can be activated (generally as a sulfonate ester or halide) Lt; RTI ID = 0.0 > T < / RTI > In the case of 1, 6-disubstituted isochrombin (I), n 1 is preferably 0 or 1, and more preferably n 1 is 0. R 1 is preferably -OR 1-1 , -CF 3 , -CO-N (R 1-1 ) 2 , -CO-R 1-1 , and R 1-1 is C 1 -C 3 alkyl desirable. R 2 is preferably -H. Q 1 is preferably selected from the group consisting of -CO-NQ 1-1 Q 1-2 , -SO 2 -NQ 1-1 Q 1-2 , and -NQ 1-1 Q 1-2 , Q 1 Is more preferably -CO-NQ 1-1 Q 1-2 . In the case of aromatic bicyclic amines (ABA), W 1 is preferably nitrogen (-N-), and one of R 1 or R 2 is preferably -H. Q 1 is (A) -CO-NQ 1-1 Q 1-2 , Q 1-1 is -H, and Q 1-2 is -CH 3 (C 1 alkyl). 1, 6-disubstituted isochroman (I) and aromatic bicyclic amines (ABA) have asymmetric centers, so that there are two mirror images of "S" Thereby producing an isomer. In some cases, both enantiomers (+) and (-) are useful in the same manner as optically impure (racemic, ±) mixtures. Thus, they can be used in racemic form without isolation. However, when it is desired to use one of the enantiomers, the optically impure mixture or intermediate can be separated by means known in the art. Suitable methods for separating the racemic intermediate (II) using the Rephasing method described in Scheme C, or alternatively by chemical methods known to those skilled in the art, can be used, for example, in Optical Resolution Procedures for Chemical Compounds , Vol 1, Amines and Related Compounds, Paul Newman, Optical Resolution Information Center, Manhattan College, Riverdale, NY, 10471, 1978. Optically impure mixtures can also be separated using chromatographic techniques on chiral stationary phases, see, e. G., Chromatographic Enantioseparation, 2nd edition, John Wiley & These optically pure compounds are then used in the same manner as the racemic mixture. When used in this patent, the 1, 6-disubstituted isochroman (I) and aromatic bicyclic amines (ABA) refer to and include both enantiomers as well as optically impure forms thereof, most commonly the racemic Mixture (±, dl). Some 1, 6-disubstituted isochroman (I) and aromatic bicyclic amines (ABA) have two asymmetric centers and thus four stereoisomers (SS, RR, SR, RS) The pair of isomers, i. E. One exists to generate SS, RR and the other to generate SR, RS. The diastereomeric pairs of the enantiomers can be readily separated by methods known to those skilled in the art. The 1, 6-disubstituted isochroman (I) and aromatic bicyclic amines (ABA) herein refer to and include the four enantiomers as well as optically impure forms thereof, most commonly the racemic mixture (± )to be. 1, 6-disubstituted isochroman (I) and aromatic bicyclic amine (ABA) are amines and form acid addition salts when reacted with sufficient strength of acid. Pharmaceutically acceptable salts include both inorganic salts and organic acid salts. Pharmaceutically acceptable salts are sometimes, but not always, preferable to the corresponding free amines because they produce more water soluble and more crystalline compounds. Preferred pharmaceutically acceptable salts include salts of methanesulfonic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, benzoic acid, citric acid, tartaric acid, fumaric acid, maleic acid, CH 3 - (CH 2 ) n- COOH, salts of HOOC- (CH 2 ) n -COOH wherein n is as defined above. The 1, 6-disubstituted isochroman (I) and aromatic bicyclic amines (ABA) of the present invention possess selective pharmacological properties and are useful for treating humans suffering from vascular headaches, particularly migraine and cluster headache. 1, 6-disubstituted isochroman (I) and aromatic bicyclic amines (ABA) are also useful as analgesics. In clinical practice, the 1,6-disubstituted isochroman (I) and aromatic bicyclic amines (ABA) of the present invention, together with one or more pharmaceutically acceptable carriers, can be used as free bases or as pharmaceutically acceptable acid addition salts Are generally administered orally, nasally, rectally, intracapsularly, or by injection in the form of pharmaceutical compositions containing the active ingredient (s). It is preferred that the 1, 6-disubstituted isochrombin (I) and aromatic bicyclic amine (ABA) are administered orally or non-orally. A suitable daily dose of 1, 6-disubstituted isochrombin (I) and aromatic bicyclic amine (ABA), when treating pain as a theraputic treatment and analgesic agent for migraine or cluster headache, Kg, preferably about 0.1 to about 30 mg / kg, and for parenteral administration, about 0.05 to about 10 mg / kg, preferably about 0.03 to about 3 mg / kg. The use and administration to a patient to be clinically treated will be readily apparent to those skilled in the art. The exact dose and frequency of administration will depend on the particular 1,6-disubstituted isochroman (I) or aromatic bicyclic amine (ABA) used, the particular condition being treated, the gastric neutrality of the condition being treated, the age, (I) and / or aromatic bicyclic amines (AVA) in the blood of a patient, as well as other medicinal treatments received by an individual as is known to those of ordinary skill in the art. And / or by measuring the patient ' s response to the particular condition to be treated. [Definition and Regulations] The following definitions and descriptions are related to terms used throughout the entire document, including both the specification and the claims. I. Definition of rules and variables for general formula The general formulas representing various compounds or molecular fragments in the specification and claims do not only include the volatile substituents, but can also clearly define the structural form. The variability substituents are identified by letters that are accompanied by a letter or numerical subscript, e.g., "Z 1 " or "R i " where "i" is an integer. These variant substituents may be monovalent or divalent, i.e. they represent groups attached to the formula by one or two chemical bonds. For example, the group Z 1 , when attached to the general formula CH 3 -C (= Z 1 ) H, represents a bivalent, volatile substituent. The groups R i and R j , when attached to the general formula CH 3 -CH 2 -C (R i ) (R j ) -H, represent a monovalent volatility substituent. The formula is represented as linear as above, and the variant substituents contained within the parentheses are bound to the immediate left atom of the variant substituent enclosed in parentheses. When two or more consecutive volatility substituents are enclosed in parentheses, each successive volatility substituent joins the immediately preceding atom that is not enclosed in parentheses. Therefore, in the general formula, R i and R j are both bonded to the preceding carbon atom. The linearly drawn formula, or a portion thereof, represents atoms in a linear chain. In general, the "-" sign indicates the bond between two atoms in the chain. Therefore, CH 3 -O-CH 2 (R i ) -CH 3 represents a 2-substituted-1-methoxypropane compound. In a similar manner, the "=" sign represents a double bond (for example: CH = CH (R i) -O-CH 3) "≡" represents a triple bond, display (e.g.: HC≡C-CH (R i) -CH 2 -CH 3). The carbonyl group is represented by one of two methods -CO- or -C (= O) -, but the former is preferred for simplicity. The chemical formula of a cyclic (ring) compound or a molecular fragment can be expressed in a linear form. Thus, the compound 4-chloro-2-methyl pyridine N * = C (CH 3) may be represented in a linear by -CH = CCI = CH = C * H, marked with an asterisk (*) atoms are bonded to each other Quot; ring " Similarly, the cyclic molecular fragment 4- (ethyl) -1-piperazinyl can be represented by -N * - (CH 2 ) 2 -N (C 2 H 5 ) -CH 2 -C * H 2 . The rigid cyclic (ring) structure for all compounds herein defines the orientation of the rings in the plane of the ring in the case of substituents attached to each carbon atom of a rigid cyclic compound. For saturated compounds having two substituents attached to carbon atoms that are part of the ring system, the -C (X 1 ) (X 2 ) - substituent may be in the axial or quadrature position relative to the ring, Lt; / RTI > However, the positions of the rings and the two substituents relative to each other remain fixed. When a substituent is present in the plane of the ring (in the direction of the equilibrium) rather than under or above the plane (axial direction), one substituent always lies on top of the other substituent. In the chemical structure depicting the compound, the substituent (X 1 ) present "under" the other substituent (X 2 ) will be identified as present in the alpha ( ) Configuration, It is identified by the dotted line attachment, ie the indication "- - -" or "...". The corresponding substituent (X 2 ) attached to "above" another substituent (X 1 ) is identified as a beta (β) configuration, which is indicated as a solid line attachment to a carbon atom. When the variability substituent is bivalent, the valency can be taken together or separately or both in defining the variable. For example, the variability R i attached to a carbon atom as -C (= R i ) - may be divalent and forms as an oxo or keto (thus forming a carbonyl group (-CO-)), or two Can be defined as individually attached monovalent volatility substituents -R ij and -R ik . When the divalent volatility substituent, R i , is defined as consisting of two univariate substituents, the definition used to define the divalent variable is the "α-R ij : β-R ik " form or some variant thereof . In this case both -R ij and -R ik are attached to the carbon atom to provide -C ( - R ij ) ( - R ik ) -. For example, when the bivalent variant substituent R 6 , -C (= R 6 ) - is defined as consisting of two univalent volatile substituents, the two univalent volatile substituents are α-R 6-1 : R 6-2 , ... - R 6-9 : - R 6-10 and the like , and -C ( R 6-1 ) ( R 6-2 ) -, -C ( - R 6-9 ) ( - R 6-10 ) -, and the like. Similarly, in the case of the divalent volatility substituent R 11 , -C (= R 11 ) -, the two monovalent volatility substituents are α-R 11-1 : β-R 11-2 . In the case of ring substituents in which there is no individual a and p orientation (e.g., due to the presence of a carbon-carbon double bond in the ring) and the valence bonded to a carbon atom that is not part of the ring, , and and are omitted. It can be defined that two distinct monovalent volatile substituents are taken together to form a bivariate variable, such that a bivariate variable is defined as two distinct monovariate variants. For example, in the formula -C 1 (R i ) HC 2 (R j ) H- (where C 1 and C 2 are each optionally defined as the first and second carbon), R i and R j are taken together (1) a second bond between C 1 and C 2 or (2) a bivalent group such as oxa (-O-), whereby the general formula represents an epoxide. When R i and R j together form a more complex body, for example the -XY- group, the orientation of the body causes C 1 to bond to X and C 2 to bond to Y in the general formula. Thus, by convention, "... R i and R j together form -CH 2 -CH 2 -O-CO-" means a lactone in which carbonyl is bonded to C 2 . However, when " ... R j and R i together form -CO-O-CH 2 -CH 2 ... ", this definition means a lactone in which carbonyl is bonded to C 1 . The carbon atom component of the variability substituent is indicated in one of two ways. The first method uses a prefix to the full name of the variable, such as "C 1 -C 4 ", where "1" and "4" represent the minimum and maximum values of the carbon atoms in the variable. The prefix is separated from the variable by a space. For example, " C 1 -C 4 alkyl " means an alkyl having from 1 to 4 carbon atoms (including isomeric forms unless the contrary indication is provided). When the single prefix is provided, the prefix indicates the total carbon atom content of the variable being defined. Thus, C 2 -C 4 alkoxycarbonyl represents a CH 3 - (CH 2 ) n -O-CO- group, wherein n is 0, 1 or 2. By the second method, the content of carbon atoms for each moiety to be defined is indicated separately by including "C i -C j " in parentheses and placing it in front of the part to be defined (without intermediate space). According to any of the above definitions, (C 1 -C 3 ) alkoxycarbonyl has the same meaning as C 2 -C 4 alkoxycarbonyl, meaning that "C 1 -C 3 " refers only to the carbon atom content of the alkoxy group . Similarly, C 2 -C 6 alkoxyalkyl and (C 1 -C 3 ) alkoxy (C 1 -C 3 ) alkyl define an alkoxyalkyl group containing from 2 to 6 carbon atoms, the two definitions being different, This is because the definition of an electron permits alone an alkoxy or alkyl moiety containing 4 or 5 carbon atoms, but the latter definition limits up to 3 carbon atoms in any of these groups. If the claims contain highly complex (cyclic) substituents, then in the nomenclature / definition the particular substituents will be indicated in parentheses, which corresponds to the same name / definition in one of the schemes which also represents the structural formula of the particular substituent do. [Description of Nomenclature] There are several methods for naming the compounds of the present invention and there is an important difference in the use of the terms "isochroman" or "3, 4-dihydro-1H-2-benzopyran" for bicyclic groups in the compound have. For example, one name for the compound of Example 6 is (S) - (-) - 1- [2- [4- [4- (aminocarbonyl) phenyl] -1- piperazinyl] ethyl] -N = Methyl isochroman-6-carboxamide or (S) - (1 -) - 1- (benzamid-4-yl) -4- [2- (6-methylaminocarbonylisochroman- Yl) ethylpiperazine. Another name is (S) -1- [2- [4- [4- (aminocarbonyl) phenyl] -1-piperazinyl] ethyl] -3,4-dihydro- -Benzopyran-6-carboxamide. ≪ / RTI > II. Justice All temperatures are in ° C. TLC means thin layer chromatography. HPLC refers to high pressure liquid chromatography. THF means tetrahydrofuran. DMF means dimethylformamide. DMSO means dimethyl sulfoxide. LDA means lithium diisopropylamide. p-TSA means p-toluenesulfonic acid monohydrate. TEA means triethylamine. BOC is 1, 1-dimethyl ethoxycarbonyl or tert to-be-butoxycarbonyl, it means a -CO-OC (CH 3). DMAP means dimethylaminopyridine, (CH 3 ) 2 -N-pyridin-1-yl. TFA means trifluoroacetic acid, CF 3 -COOH. Saline means saturated sodium chloride aqueous solution. Chromatography (column and flash chromatography) refers to purification / separation of the compound represented as (support; elution). The appropriate fractions are collected and concentrated to provide the desired compound (s). IR means infrared spectroscopy. CMR refers to the magnetic resonance spectroscopy of C-13, and chemical transitions are reported in ppm (δ) from TMS to summer. NMR means nuclear (proton) magnetic resonance spectroscopy, and chemical transfer is reported as ppm (δ) from tetramethylsilane to the summer. -phi means phenyl (C 6 H 5 ). [alpha] D means the shed angle (specific optical rotation) of the plane polarized light at 25 degrees by the sodium D line 589A. MS means mass spectroscopy expressed as m / e or mass / charge unit. [M + H] + means a positive ion of the parent atom plus a positive ion of the hydrogen atom. EI means electronic shock. CI means chemical ionization. FAB means rapid atomic bombardment. HRMS means high resolution mass spectroscopy. Ether means diethyl ether. &Quot; Pharmaceutically acceptable " means that the composition is acceptable to the patient from a pharmacological / toxicological standpoint and is acceptable for the manufacture of pharmaceutical chemicals from the physical / chemical viewpoints of composition, formulation, stability, patient acceptability and bioavailability It means possible. When solvents are used in pairs, the ratio of solvent used is volume / volume (v / v). Pharmaceutically acceptable anion salts include mesylate, chloride, sulphate, phosphate, nitrate, citrate, CH 3 - (CH 2 ) n-1 -COO 1 n wherein n 1 is 0 to 4, there is -1 OOC- (CH 2) n1 -COO -1, -1 OOC-CH = CH-COO -1, φ-COO -1 as described. Without further elaboration, it is believed that one skilled in the art can, using the preceding description, carry out the invention in its fullest extent. The following detailed examples illustrate how to make various compounds and / or perform various processes of the present invention, which are merely illustrative and should not be construed as limiting the disclosure in any way that precedes it. It will be appreciated by those skilled in the art that appropriate changes in procedures for both reactants and reaction conditions and techniques will be appreciated. [Production Example 1] 4- (piperazin-1-yl) benzamide A mixture of 4-fluorobenzamide (2.45 g, 17.6 mmol), piperazine (7.56 g, 87.9 mmol) and water (10 mL) was stirred at 100 <0> C for 24 hours. After cooling, the solid was collected, washed with water and toluene and dried under reduced pressure to give the title compound, mp = 240-248 占 폚; MS (M / Z) at 205; NMR (DMSO-d6) 2.59, 2.80, 3.14, 6.90, 7.02, 7.72 and 7.73 delta. [Production Example 2] N- [4- (trifluoromethyl) phenyl] piperazine 4-Bromobenzotrifluoride (19.70 g, 0.088 mol) and piperazine (37.71 g, 0.438 mol) are introduced into a 100 mL flask equipped with a rotating rod. The reaction is heated to 130 < 0 > C. After 48 hours, the mixture contained a significant amount of the precipitate and was cooled to 20-25 占 폚. During cooling, the reaction mixture is diluted with sodium hydroxide (3N, 200 mL) to produce an additional amount of precipitate and extracted twice with ethyl acetate (200 mL). When the reaction mixture is cooled to 20 to 25 占 폚 before the aqueous base is added, the reactants form a solid mass, making further manipulation difficult. The combined organics are washed once with brine (300 ml), dried over magnesium sulfate, filtered and concentrated to give the product. Recrystallization from hexane gave the title compound, mp 87-89 C ( Rf = 86-88 [deg.] C), Rf = 0.20 (methanol / dichloromethane, 7/93). [Example 1] (S) - (-) - l- (S) - (-) - l- (4-methoxyphenyl) -4- [2- (6-aminocarbonylisochroman- ) - [1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] -isochroman-6- carboxamide (S) Step 1: Ethyl (6-bromoisocyanate-1-yl) acetate (III) The mixture of 3-bromophenethyl alcohol (II, 14.8 g) in dichloromethane (37 ml) under argon is cooled to 0 < 0 > C by an ice bath. Ethyl 3, 3-diethoxypropionate (90%, 19.1 ml) is added via syringe. Titanium tetrachloride solution (1 M in methylene chloride, 236 mL) is added via cannula to the dropping funnel and semi-dropwise to the reaction mixture over 1 hour. The reaction is then refluxed for 18 hours and then poured into a mixture of aqueous hydrochloric acid (1N) and brine (1/2) and extracted with methylene chloride. Combine the organic phases, dry over sodium sulfate, filter and concentrate. The concentrate was purified by chromatography (silica gel; ethyl acetate / hexane, 10/90) to give ethyl (6-bromoisocyanate-1-yl) acetate (III); Rf = 0.40 (ethyl acetate / hexane, 25/75); IR (neat) 1736, 1483, 1374, 1288, 1280, 1183, 1163, 1110, 1050, 1037 cm -1 ; NMR (300㎒, CDCl 3) 7.30 , 7.28, 6.92, 5.17 4.20, 4.10, 3.79, 3.01-2.91, 2.87-2.65 and 1.28δ; CMR (75㎒, CDCl 3) 170.7 , 136.0, 135.5, 131.6, 129.1, 126.0, 120.2, 62.6, 60.5, 41.3, 28.3 and 13.9δ; HRMS calculated for C 13 H 15 O 3 Br = 298.0205, observed = 298.0204. Step 2: (R) - (+) - Ethyl (6-bromoisocyanate-1-yl) acetate (XII) and (S) XI) Amino P-30 lipase (15 g, lot # LPSAR01520, activity = 32,600 u / g) and pH buffer (590 ml) were added to a solution of ethyl (6- bromoisocyanate- . The reaction is stirred vigorously to effect hydrolysis followed by HPLC. An aliquot of 100 [mu] l is added to an optical transparency vial containing hydrochloric acid (1 drop). Ethyl acetate (1.5 ml) is added to the vial and the contents are mixed well. The resulting mixture was filtered through celite and purified by HPLC [mu] Bondapak C18 3.9 mm x 30 cm reverse phase column: 15% acetonitrile / 90% phosphate buffer (4 L water, 5.22 g sodium dihydrogen phosphate (hydrate), 0.76㎖ acid) gradient, iso greater raetik, 2㎖ / min, and black by the detection in 215㎚], (XI) R t = 10.5 min., (XII), R t = 13.5 minutes in a ratio. When the reaction reaches 50% conversion point, it is filtered and the filtrate is washed successively several times with water and aqueous hydrochloric acid (1N) and ethyl acetate. The filtrates are combined and extracted with ethyl acetate (twice). The combined organic extracts are washed with the same volume of saturated aqueous sodium carbonate (3 times), dried over sodium sulfate, filtered and concentrated to afford (XII), which is enriched in enantiomers. The saturated aqueous sodium carbonate wash is acidified with concentrated hydrochloric acid, extracted three times with methylene chloride, dried over sodium sulfate, filtered and concentrated to give (XI). The acid (XI) was assayed for enantiomeric purity as follows. The acid (XI, 15 mg) in THF (0.5 ml) is reduced with borane-THF complex (IM in THF, 0.12 ml) at -5 ° C to 20-25 ° C over 18 hours. The reaction was cooled to 0 < 0 > C and quenched with methanol (0.1 ml), then warmed to 20-25 [deg.] C and hydrochloric acid (IN, 0.4 ml) was added via pipette. The reaction is heated to reflux for 10 minutes, whereupon the volatiles are removed under reduced pressure and the residue is partitioned between ethyl acetate and saturated aqueous sodium carbonate. The organic phase was separated, dried over magnesium, filtered and concentrated. The residue is weighed and diluted with isopropanol / hexane (7%) solution to a concentration of 10 mg / ml. The mixture was purified on a Chiracel OJ column using 90/10 hexane / isopropanol (15 min, 1 mL / min) followed by 80/20 hexane / isopropanol (2 mL / min) do. Wavelength 254 nm; (S) - alcohol R t = 12.46 bun, (R) - alcohol R t = 10.46 min. The ester (XII) can be analyzed by hydrolysis in a similar manner (see below). If desired, the esters with enantiomeric amounts, when indicated by HPLC analysis, can again be enzymatically hydrolyzed. In this manner (R) - (+) - ethyl (6-bromoisocyanate-1-yl) acetate (XII) is obtained (96% ee); Rf = 0.40 (ethyl acetate / hexane, 25/75); [[alpha]] D = +72 [deg.] (c = 0.383, ethanol); IR (next) 1736, 1483, 1374, 1588, 1280, 1183, 1163, 1110, 1050, 1037 cm -1 ; NMR (300㎒, CDCl 3) 7.30 , 7.28, 6.92, 5.17, 4.20, 4.10, 3.79, 3.01-2.91, 2.87-2.65 and 1.28; CMR (75㎒, CDCl 3) 170.7 , 136.0, 135.5, 131.6, 129.1, 126.0, 120.2, 62.6, 60.5, 41.3, 28.3, 13.9; HRMS calculated for C 13 H 15 O 3 Br = 298.0205, observed = 298.0206. Also, (S) - (-) - (6-bromoisocroman-1-yl) acetic acid (XI) is isolated (99% ee); Melting point = 160-161 占 폚; R f = origin (ethyl acetate / hexane, 25/75); [ ] D = -90 (c = 1, ethanol); IR (neat) 1711, 1482, 1428, 14406, 1330, 1297, 1111, 1101, 1003, 971 cm -1 ; NMR (300㎒, CDCl 3) 7.30 , 6.92, 5.17, 4.18-4.11, 3.86-3.78 , and 3.04 to 2.69; CMR (75㎒, CDCl 3) 175.7 , 136.2, 135.1, 132.0, 129.6, 126.2, 120.8, 72.4, 63.1, 45.5, 41.4 and 28.5δ. Step 3: Preparation of (S) - (-) - 1- [2- (6-bromoisocroman-1-yl) acetyl] -4- (4- methoxyphenyl) (XI, step 2, 3 g), N- (4-methoxyphenyl-piperazine (2.34 g) and dichloromethane (20 g) Ml) is added and cooled to 0 DEG C. Diethylcyanophosphate (2.0 ml) and triethylamine (1.7 ml) are added via syringe, respectively. The ice bath cooling is stopped and the mixture is stirred at 20-25 DEG C for 18 The reaction mixture was concentrated under reduced pressure to give a crude material which was purified by chromatography (silica gel; ethyl acetate / hexane 60-80 / 40-20) to give (S) - (-) - 1- [2- (S) - (V) (hereinafter referred to as recrystallization from ethyl acetate / hexane), a melting point < RTI ID = 0.0 & = 122 to 123 ℃; R f = 0.26 (ethyl acetate / hexane, 70/30); [α] D = -86 ° (c = 0.99, ethanol); IR (mull) 1639, 1512, 1446, 1439, 1249 , 1214, 1112, 1030, 1028 , 820㎝ -1; NMR (300㎒, CDCl 3) 7.32-7.26, 7.00, 6.88, 5.27, 4.16-5.07, 3.89, 3.8 CMR (75 MHz, CDCl 3 ) 168.9, 154.3, 145.2, 136.5, 136.2, 131.7, 129.3, 126.4, 120.3, 118.8, 114.4, 73.4, 63.4 , 55.5, 51.3, 50.7, 46.1, 41.9, 39.9 and 28.7 [deg.]. Step 4: Preparation of (S) - (-) - 1- [2- (6-bromoisocarman-1-yl) ethyl] -4- (4- methoxyphenyl) ) (S) - (-) - 1- [2- (6-bromoisocrolemen-1-yl) acetyl] -4- (4- methoxyphenyl) -piperazine ((S) - (V), step 3, 3.7 g) is cooled to 0 C and a mixture of borane-THF complex (1 M in THF, 25 mL) is added via syringe. The ice bath is removed and the mixture is heated to reflux for 18 hours. The reaction is cooled to 0 < 0 > C and quenched with aqueous hydrochloric acid (IN, 100 ml) and refluxed for an additional 1.5 h. The mixture is cooled to 20-25 < 0 > C, the solvent is removed under reduced pressure, the aqueous residue is diluted with brine and basified to pH 14 with aqueous sodium hydroxide. The mixture is extracted with dichloromethane, the combined organic phases are dried over sodium sulfate, filtered and concentrated. The concentrate was purified by recrystallization from ethyl acetate / hexane to give (S) - (-) - 1- [2- (6-bromoisocroman-1- yl) ethyl] -4- (4-methoxyphenyl) -Piperazine (S) - (VI), melting point = 85-86 [deg.] C; R f = 0.23 (ethyl acetate); [[alpha]] D = -48 [deg.] (c = 0.73, ethanol); IR (neat) 1518, 1479, 1266, 1250, 1155, 1140, 1112, 1103, 1041, 818 cm -1 ; + H NMR (300㎒, CDCl 3 ) 7.29, 7.27, 6.97, 6.85, 4.78, 4.14-4.07, 3.76-3.69, 3.76, 3.10, 2.95, 2.70-2.50, 2.13 and 2.02δ; CMR (75㎒, CDCl 3) 153.5 , 145.5, 136.8, 136.0, 131.4, 129.0, 126.3, 119.7, 117.9, 114.2, 74.1, 62.5, 55.3, 54.4, 53.3, 50.4, 32.9 and 28.6δ; HRMS calculated for C 22 H 27 N 2 P 2 Br 1 = 430.1256, found = 430.1270. Step 5: (S) - (-) - l- [2- [4- (4-Methoxyphenyl) -1- piperazinyl] ethyl] -isochroman- VII) ((S) - (VI), step (S) - (-) - l- [2- (6-Bromoisopropan- 4.364 mg), palladium (II) acetate (98%, 9.7 mg) and 1, 3-bis-diphenylphosphinopropane (97%, 22 mg). A carbon monoxide atmosphere was created in the vial, and DMF (2 ml), 1,1,1,3,3,3-hexamethyldisilazane (98%, 1.25 ml) and diisopropylethylamine (0.297) is introduced. The mixture is heated to 100 < 0 > C for 18 hours. After cooling to 20-25 < 0 > C, the reaction was separated into two phases. The reaction mixture is poured into aqueous hydrochloric acid (1N) and washed twice with ether. The acidic solution is basified with aqueous sodium hydroxide and extracted three times with ethyl acetate. The ethyl acetate phases are combined and concentrated. This was purified by chromatography (silica gel; methanol / dichloromethane, 5/95) to give (S) - (-) - 1- [2- [4- (4-methoxyphenyl) -Isochroman-6-carboxamide (S) - (VII), melting point = 186-187 ° C; Rf = 0.27 (methanol / ethyl acetate, 10/90); [ ] D = -53 (c = 0.92, methylene chloride / methanol (1/1)); IR (mull) 3366, 3198, 1628, 1642, 1602, 1514, 1437, 1245, 1109 and 815 cm -1 ; NMR (300 MHz, CDCl 3 ) 7.61-7.58, 7.18, 6.85, 5.90, 4.86, 4.18-4.11, 3.80-3.72, 3.76, 3.10, 2.99, 2.73, 2.66-2.49, 2.15 and 2.04 CMR (75 MHz, CDCl 3 ) 168.7, 153.5, 145.4, 142.0, 134.3, 131.0, 127.9, 124.8, 124.6, 117.8, 114.1, 74.2, 62.6, 55.2, 54.3, 53.2, 50.3, 32.8, 28.7 and 27.2 delta; HRMS calculated for C 23 H 29 N 3 O 3 = 395.2209, found = 395.2227. [Example 2] (R) - (+) - (+) - l, also known as (R) - (+) - l- (4- methoxyphenyl) -4- [ (R) - (VII) < / RTI > < RTI ID = 0.0 & Step 1: (R) - (+) - 6- (Bromoisopropan-1-yl) acetic acid (R) -IV. A mixture of lithium hydroxide (3M, 150 ml) was added to a solution of (R) - (+) - ethyl (6-bromoisocyanate-1-yl) acetate (XII, g), and the mixture is stirred at 20 to 25 [deg.] C for 18 hours. The volatile solvents are removed under reduced pressure and the residue is acidified to pH = 1 with aqueous hydrochloric acid. The resulting mixture is extracted with methylene chloride, and the combined organic layers are dried over sodium sulfate, filtered and concentrated. The concentrate is purified by recrystallization from dichloromethane / hexane to give (R) - (+) - 6- (bromoisocyanate-1-yl) acetic acid (R) ; R f = origin (ethyl acetate / hexane, 25/75); [[alpha]] D = + 83 [deg.] (c = 0.99, ethanol); IR (neat) 1711, 1482, 1428, 14406, 1330, 1297, 1111, 1101, 1003 and 971 cm -1 ; NMR (300㎒, CDCl 3) 7.30 , 6.92, 5.17, 4.18-4.11, 3.86-3.78 and 3.04-2.69δ; CMR (75㎒, CDCl 3) 175.7 , 136.2, 135.1, 132.0, 129.6, 126.2, 120.8, 72.4, 63.1, 45.5, 41.1 and 28.5δ. Step 2: Preparation of (R) - (+) - 1- [2- (6-Bromoisopropan-1-yl) acetyl] -4- (4- methoxyphenyl) . The title compound was prepared in a manner analogous to that described in Example 1, but without significant changes except starting from (R) - (+) - 6- (Bromoisopropan-1-yl) acetic acid (example 2, step 1, (R) - (IV) The crude product is obtained according to the general procedure of step 3, which is first purified by silica gel chromatography using a gradient of 60-80% ethyl acetate / hexane and the resulting solid is recrystallized (ethyl acetate / hexane) R) - (+) - 1- [2- (6-Bromoisocyanat-1-yl) acetyl] -4- (4- methoxyphenyl) -piperazine (R) - (V) Melting point = 122 to 123 占 폚; Rf = 0.26 (ethyl acetate / hexane, 70/30); [[alpha]] D = +89 [deg.] (c = 1.00, ethanol); IR (mull) 1639, 1512, 1446, 1439, 1249, 1214, 1112, 1030, 1028 and 820 cm -1 ; NMR (300㎒, CDCl 3) 7.32-7.26 , 7.0, 6.88, 5.27, 4.16-4.07, 3.89, 3.80-3.60, 3.77, 3.05, 2.97-2.90, 2.76 and 2.65δ; CMR (75 MHz, CDCl 3 ) 168.9, 154.3, 145.2, 136.5, 136.2, 131.7, 129.3, 126.4, 120.3, 118.8, 114.4, 73.4, 63.4, 55.5, 51.3, 50.7, 46.1, 41.9, 39.9 and 28.7 Step 3: Preparation of (R) - (+) - 1- [2- (6-Bromoisopropan-1-yl) ethyl] -4- (R) - (V) (example (R) - (+) - l- [2- (6-Bromoisopropan- (R) - (+) - l- [2- (6-bromoisocroman-l-yl) -methanone was prepared according to the general procedure of Example 1, step 4, ) Ethyl] -4- (4-methoxyphenyl) -piperazine (R) - (VI), mp = 85-86 [deg.] C; R f = 0.23 (ethyl acetate); [[alpha]] D = + 47 [deg.] (c = 0.94, ethanol); IR (neat) 1518, 1479, 1266, 1250, 1155, 1140, 1112, 1103, 1041, and 818 cm -1 ; NMR (300 MHz, CDCl 3 ) 7.29, 7.27, 6.97, 6.85, 4.78, 4.14-4.07, 3.76-3.69, 3.76, 3.10, 2.95, 2.70-2.50, 2.13 and 2.02 CMR (75㎒, CDCl 3) 153.3 , 145.5, 136.8, 136.0, 131.4, 129.0, 126.3, 119.7, 117.9, 114.2, 74.1, 62.5, 55.3, 54.4, 53.3, 50.4, 32.9 and 28.6; C 22 H 27 HRMS calculated for N 2 O 2 Br 1 = 430.1256 , observed = 430.1274. Step 4: (R) - (+) - 1- [2- [4- (4-Methoxyphenyl) -1-piperazinyl] ethyl] -isochroman- VII) (R) - (VI) (example (R) - (+) - l- [2- (6-Bromoisopropan- (Silica gel, 50 g; methanol / ethyl acetate, 5/95) according to the general procedure of example 1, step 5, with little or no significant change except starting in step 2, step 3) To give (R) - (+) - 1- [2- [4- (4-methoxyphenyl) -1- piperazinyl] ethyl] -isochroman- (VII), melting point = 187 to 187.5 DEG C; Rf = 0.27 (methanol / ethyl acetate, 10/90); [[alpha]] D = + 52 [deg.] (c = 0.92, methylene chloride / methanol (1/1)); IR (mull) 3366, 3198, 1628, 1642, 1602, 1514, 1437, 1245, 1109 and 815 cm -1 ; NMR (300 MHz, CDCl 3 ) 7.61-7.58, 7.18, 6.85, 5.90, 4.86, 4.18-4.11, 3.80-3.72, 3.76, 3.10, 2.99, 2.73, 2.66-2.49, 2.15 and 2.04 CMR (75 MHz, CDCl 3 ) 168.7, 153.5, 145.4, 142.0, 134.3, 131.0, 127.9, 124.8, 124.6, 117.8, 114.1, 74.2, 62.6, 55.2, 54.3, 53.2, 50.3, 32.8, 28.7 and 27.2 delta; HRMS calculated for C 23 H 29 N 3 O 3 = 395.2209, found = 395.2208. [Example 3] (S) - ((S) - (-) - 1- (4-methoxyphenyl) -4- [2- (6-methylaminocarbonylisochroman- (IX) < RTI ID = 0.0 > (IX) -) - 1- [2- [4- (4-methoxyphenyl) Step 1: (S) - (-) - N, N-di-tert-butyloxycarbonyl- 1- [2- [4- (4- methoxyphenyl) -1- piperazinyl] Isochroman-6-carboxamide (S) - (VIII) (S) - (-) - 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] -isochroman-6- carboxamide ( S) - (VII) (Example 1, step 5, 0.71 g), di-tert-butyl dicarbonate (0.86 g) and 4-dimethylaminopyridine (0.02 g) Lt; / RTI > After 72 h, the reaction was purified by column chromatography (silica gel, gradient elution using 25% ethyl acetate in hexanes and elution with 100% ethyl acetate in vacuo) under reduced pressure to give (S) - (-) - N, N-di-tert-butyloxycarbonyl-1- [2- [4- (4- methoxyphenyl) -1- piperazinyl] ethyl] -isochroman-6- carboxamide ) - (VIII), [[alpha]] D = -32 [deg.] (C = 0.7201, ethanol); C 33 H 45 N 3 O HRMS calculated for 7 = 595.3257, found = 595.3282. Step 2: (S) - (-) - 1- [2- [4- (4-Methoxyphenyl) -1-piperazinyl] ethyl- ) - (IX) To a solution of (S) - (-) - N, N-di-tert-butyloxycarbonyl- 1- [2- [4- (4- methoxyphenyl) - 1-piperazinyl] ethyl] -isochroman-6-carboxamide (S) - (VIII) (1.09 g) is cooled under nitrogen with acetone and carbon dioxide. The methylamine is then condensed into the cold tube (in excess) (typically 50 minutes) and the tube is then sealed and allowed to warm to room temperature. After stirring for 16 hours at room temperature, the contents of the tube were concentrated under reduced pressure and the resulting crude product was purified by column chromatography (silica gel; using methanol / dichloromethane 5/95) to give (S) - (- Ethyl] -N-methyl-isochroman-6-carboxamide (S) - (IX), [[alpha] ] D = -51 (c = 0.9953, methanol / dichloromethane, 1/1); Anal Calcd for C 24 H 31 N 3 O 3 = C, 70.39; H, 7.63; N, 10.26, found = C, 70.16; H, 7.84; N, 10.27. [Example 4] Also known as (R) - (+) - l- (4-methoxyphenyl) -4- [2- (6-methylaminocarbonylisochroman- +) - 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] -N- methyl- isochroman-6- carboxamide Step 1: (R) - (+) - N, N-di-tert-butyloxycarbonyl-1- [2- [4- (4- methoxyphenyl) Isochroman-6-carboxamide (R) - (VIII) ((R) - (VII) (R) - (+) - l- [2- [4- (4- methoxyphenyl) - 1- piperazinyl] ethyl ]- isochroman- (R) - (+) - N, N-di-tert-butyl < / RTI > according to the general procedure of example 3, step 1, (R) - (VIII) which is obtained by reacting oxycarbonyl-1- [2- [4- (4-methoxyphenyl) -1- piperazinyl] ethyl] And used directly in the next step. Step 2: (R) - (+) - 1- [2- [4- (4-methoxyphenyl) -1- piperazinyl] ethyl] -N- methyl- isochroman-6- carboxamide R) - (IX) (R) - (+) - N, N-di-tert-butyloxycarbonyl-1- [2- [4- (4-methoxyphenyl) -1- piperazinyl] ethyl] (R) - (+) - 1- [2- [4- (4-fluorophenyl) (R) - (IX), [[alpha]] D = + 48 [deg.] (-) - lH-indol- c = 0.9746, methanol / dichloromethane, 1/1); HRMS calculated for C 24 H 31 N 3 O 3 = 409.2365, found = 409.2391. [Example 5] Also known as (S) - (-) - 1- (4-trifluoromethylphenyl) -4- [2- (6-methylaminocarbonylisochroman- (S) - (IX) < / RTI > < RTI ID = 0.0 & Step 1: (S) -1- [2- (6-Bromoisopropan-1-yl) acetyl] -4- (4- trifluoromethylphenyl) (Example 1, XI, 542 mg, 2.0 mmol), 10 mL of dichloromethane, 1- (4-trifluoromethyl) ) Piperazine (507 mg, 3.3 mmol) and diethyl cyanophosphate (0.33 ml, 2.2 mmol) were combined and cooled to 0 C and treated with triethylamine (0.42 ml, 3.0 mmol) And then heated to 20 to 25 ° C. After 16 h, the reaction mixture is concentrated. The concentrate was eluted with ethyl acetate / hexane (40/60) over silica gel (58 g, 230-400) and purified by LC to give (S) - (-) - 1- [2- (6-bromoisocyanate- Yl) acetyl] -4- (4-trifluoromethylphenyl) -piperazine (S) - (V), Rf = 0.25 (ethyl acetate / hexane, 40/60). Step 2: Preparation of (S) - (-) - 1- [2- (6-bromoisocroman-1-yl) ethyl] -4- (4-trifluoromethylphenyl) ) (S) - (V) ((S) - (-) - 1 - [2- (6-Bromoisopropan-1-yl) acetyl] -4- Step 1, 876 mg, 1.8 mmol) and 18.0 ml of freshly distilled tetrahydrofuran are combined and cooled to 0 < 0 > C. The mixture is treated dropwise with a 1 M solution of borane in tetrahydrofuran (5.4 mL, 5.4 mmol) while bubbling. The reaction is allowed to warm to 20-25 < 0 > C for 16 hours. At this time, the reaction product was treated with 1M hydrochloric acid (6.0 ml), refluxed with reflux condenser for 1 hour. The reaction is cooled to 20-25 < 0 > C and the volatiles are removed under reduced pressure. The resulting aqueous residue is diluted with water (30 mL), adjusted to pH > 10, and extracted twice with ethyl acetate (30 mL). The combined organic extracts are washed once with brine (30 ml), dried over magnesium sulfate, filtered and concentrated. The concentrate was purified by LC eluting with ethyl acetate / hexane (40/60) on silica gel (43 g, 230-400) to give (S) - (-) - 1- [2- (6-bromoisocro- Yl) ethyl] -4- (4-trifluoromethylphenyl) -piperazine (S) - (VI), melting point = 104-105 ° C; Rf = 0.30 (ethyl acetate / hexane, 40/60). Step 3: (S) - (-) - 1- [2- [4- (4-Trifluoromethylphenyl) -1- piperazinyl] ethyl] -N- methyl- isochroman-6- carboxamide (S) - (IX) (S) - (VI) (prepared according to the procedure described in step (b), starting from (S) - (-) - 1- [2- (6-bromoisocroman- 2, 703 mg, 1.5 mmol), palladium (II) acetate (17 mg, 0.075 mmol), 1,3-bis (diphenylphosphino) propane (37 mg, 0.09 mmol), 3.0 ml of dimethylformamide Isopropylethylamine (0.52 mL, 3.0 mmol) and N-methylformamide (1.8 mL, 30 mmol) were combined, and the mixture was purged with carbon monoxide in a vacuum chamber several times and then heated to 120 캜. After 16 hours, the mixture is cooled to 20 to 25 占 폚, treated with 25 ml of 1 M hydrochloric acid and stirred for 10 minutes. The acidic solution is adjusted to pH 12 and extracted three times with ethyl acetate (20 mL). The combined organic extracts are washed once with brine (30 ml), dried over magnesium sulfate, filtered and concentrated. The concentrate was purified by LC eluting with 33 g (230-400) of silica gel with acetone / hexane (40/60) to give (S) - (-) - 1- [2- [4- Methylphenyl) -1-piperazinyl] ethyl] -N-methyl-isochroman-6-carboxamide (S) - (IX), melting point = 169-170 ° C; R F = 0.30 (acetone / hexane (40/60)). [Example 6] Also known as (S) - (-) - 1- (benzamid-4-yl) -4- [2- (6-methylaminocarbonylisochroman- (-) - 1- [2- [4- [4- (aminocarbonyl) phenyl] -1- piperazinyl] ethyl] -N- methylisochroman-6- carboxamide Step 1. Preparation of (S) - (-) - 2- (6-bromoisocroman-2-yl) ethyl alcohol (XI) (Example 1, step 2, 16.27 g, 60 mmol) and 100 mL of tetrahydrofuran were added to a stirred solution of (S) - (-) - 2- (6-bromoisocroman- . This mixture is treated with a 10 M solution of borane methyl sulfide (180 mL, 0.18 mol), maintaining a temperature of 20-25 ° C in a water bath. After 1 h, the reaction mixture is cooled to 0 < 0 > C and quenched slowly with 160 ml of methanol. Note: Be careful about a 1-2 minute incubation period before the rapid and abrupt hydrogen evolution. The mixture is warmed to 20-25 < 0 > C and the volatiles are removed under reduced pressure. The resulting solid was diluted with 1 M sodium hydroxide (150 mL) and extracted three times with ethyl acetate (100 mL). The combined organic extracts are washed once with brine (100 ml), dried over magnesium sulfate, filtered and concentrated to give a solid. This material was recrystallized from ethyl acetate / hexane to give (S) - (-) - 2- (6-bromoisocroman-2-yl) ethyl alcohol (S-1), mp 95-96 ° C; Rf = 0.28 (acetone / hexane, 30/70). Step 2: (S) - (-) - 6-Bromo-1- (bromoethyl) isochromane (S) - (-) - 2- (6-bromoisocroman-2-yl) ethyl alcohol (S-1) (Step 1, 14.0 g, 54 mmol) and 91 mL of dichloromethane. The resulting mixture is treated with 25 ml of tetrahydrofuran. The suspension was treated with carbon tetrabromide (22.6 g, 68 mmol), cooled to 0 <0> C and treated portion-wise with triphenylphosphine (21.4 g, 68 mmol). The resulting mixture is allowed to warm to 20-25 [deg.] C for 3 hours, and then concentrated under reduced pressure to provide a solid. Triphenylphosphine oxide is removed by recrystallization from ethyl acetate / hexane with the mother liquor to provide a solid. The material was adsorbed onto 70 g of silica gel and purified by LC over 700 g (230-400) of silica gel eluting with ethyl acetate / hexane (5/95) to give (S) - (-) - 6- (Bromoethyl) isochroman (IV) is obtained, R f = 0.47 (10% acetone / hexane). Step 3: (S) - (-) - 4- [4- [2- (6-Bromoisocyanate-1-yl) ethyl] -1- piperazinyl] (Step 2, 17.22 g, 53.8 mmol), 14.36 g (67.0 mmol) 4- (piperazin-1-yl) - (- 1-yl) benzamide (Preparation 1), 10.43 g (80.7 mmol) of diisopropylethylamine and 125 ml of ethylene glycol are heated overnight to 85-90 占 폚. After cooling, water (300 ml) is added, and the resulting solid is collected by filtration. The cake is washed three times with water (about 200 mL total), then with toluene (about 200 mL total). The filter cake is dried under reduced pressure. After drying, the crude product is slurried in methanol / dichloromethane and silica gel is added to adsorb the mixture. After removal of the solvent, the silica gel slurry is poured onto the top of a silica gel column equilibrated with dichloromethane / methanol (95/5). Elution was begun with dichloromethane / methanol (95/5) and elution was then eluted with dichloromethane / methanol (92/8) and the appropriate fractions were combined and concentrated to give (s) - (-) - Yl] ethyl] -1-piperazinyl] benzamide (VI) is obtained in the form of a white solid. Step 4: (S) - (-) - 1- [2- [4- [4- (Aminocarbonyl) phenyl] -1- piperazinyl] ethyl] -N- methylisochromanyl- amides (s) - (-) - 4- [4- [2- (6-Bromoisocyanat-1-yl) ethyl] -1-piperazinyl] benzamide Mmol) are slurried in 55 mL of anhydrous DMF and degassed (evacuated with argon) using a vacuum chamber. A three-necked round bottom flask containing palladium acetate (0.084 g, 0.376 mmol) and 1,3-bis (diphenylphosphino) propane (0.232 g, 0.564 mmol) in an additional 10 mL DMF ), And the flask is placed in an oil bath. Diisopropylethylamine (2.6 mL, 15.3 mmol) was added and the mixture was again degassed briefly and released into argon. Carbon monoxide is blown into the surface of the mixture, at which time the temperature of the bath is raised to 60 占 폚. As the temperature is raised, the mixture becomes homogeneous and puts a needle tip slightly below the surface of the solution. After bubbling carbon monoxide into the solution for a few minutes, the methylamine gas is also bubbled into the solution. Carbon monoxide and methylamine are added continuously for 6 hours or until the starting material is consumed, then the mixture is cooled and the DMF is removed under reduced pressure. The residue is added to a silica gel column and eluted with methanol / dichloromethane (8/92) until less polar impurities are eluted. The appropriate fractions were then combined and concentrated and crystallized from methanol / dichloromethane to give (S) - (-) - 1- [2- [4- [4- (amino Carbonyl) phenyl] -1-piperazinyl] ethyl] -N-methylisochromanyl-6-carboxamide (IX), melting point 231.5-232.5 DEG C. [Example 7] 1- [2- [4- (4-methylphenyl) -piperazinyl] ethyl-isochroman-6- carboxamide (VII) Step 1: 6-Bromoisopropion-1-yl-acetic acid (IV) Following the general procedure of Example 2, Step 1, with the exception that racemic ethyl 6-bromoisocyanate-1-yl-acetate (III) was used, 6-bromoisocroman-1-yl- (IV), melting point 160-161 DEG C; NMR (300㎒, CDCl 3) 7.30 , 6.92, 5.17, 4.18-4.11, 3.86-3.78 and 3.04-2.69δ. Step 2: 1- [2- (6-Bromoisopropan-1-yl) acetyl] -4- (4-methylphenyl) -piperazine (V) Following the general procedure of Example 1, step 3, but without significant changes except using racemic 6-bromoisocyanate-1-yl-acetic acid (IV) and 4- methylphenylpiperazine, 1- [2- Yl) acetyl] -4- (4-methylphenyl) -piperazine (V) which is then subjected to flash chromatography (80 g of silica gel, ethyl acetate / hexane, 50/50) f = 0.20 (ethyl acetate / hexane, 50/50); IR (neat) 1642, 1515, 1481, 1462, 1443, 1234, 1208, 1107, 1031, and 813 cm -1 ; NMR (300 MHz, CDCl 3 ) 7.30, 7.09, 7.01, 6.84, 5.26, 4.13-4.07, 3.95-3.87, 3.82-3.60, 3.12, 3.05-2.89, 2.77, 2.65 and 2.28 delta; CMR (75 MHz, CDCl 3 ) 168.2, 148.3, 136.5, 136.8, 131.7, 129.6, 129.2, 126.3, 121.2, 116.8, 73.3, 63.3, 60.2, 48.7, 45.9, 41.7, 39.8, 26.6 and 20.3 Step 3: l- [2- (6-Bromoisopropan-l-yl) -ethyl] -4- (4- methylphenyl) -piperazine The general procedure of Example 1, Step 4, with no significant changes but using 1- [2- (6-bromoisocroman-1-yl) acetyl] -4- (4-methylphenyl) -piperazine Ethyl] -4- (4-methylphenyl) piperazine (VI), R f = 0.21 (ethyl acetate / hexane, 50/50); IR (neat) 2941, 2925, 2818, 1515, 1481, 1379, 1239, 1143, 1111 and 813 cm -1 ; NMR (300㎒, CDCl 3) 7.32-7.26 , 7.07, 6.97, 6.84, 4.78, 4.41-3.07, 3.78-3.69, 3.16, 2.94, 2.7-2.48, 2.26, 2.15-1.90δ; (75 MHz, CDCl 3 ) 149.0, 136.9, 136.1, 131.4, 129.4, 129.0, 128.9, 126.3, 119.8, 116.1, 74.1, 62.6, 54.4, 53.2, 49.5, 33.0, 28.6 and 20.2 Step 4: Preparation of 1- [2- [4- (4-methylphenyl) -1-piperazinyl] ethyl- isochroman- The general procedure of Example 1, Step 5, with no significant changes except using 1- [2- (6-bromoisoxazol-l-yl) -ethyl] -4- (4- methylphenyl) -piperazine Ethyl isochroman-6-carboxamide VII is obtained according to the procedure, R f = 0.2 (methanol / ethyl acetate < RTI ID = , 10/90); IR (mull) 3373, 3180, 1647, 1623, 1571, 1520, 1406, 1242, 1111 and 817 cm -1 ; NMR (300㎒, CDCl 3) 7.59 , 7.18, 7.07, 6.84 6.05, 4.86, 4.13, 3.77, 3.17, 3.00, 2.76-2.45, 2.26, 2.14 and 2.02δ; HRMS calculated for C 23 H 29 N 3 O 2 = 379.2260, observed = 379.2269. [Example 8] 1- [2- [4- (4-chlorophenyl) -1-piperazinyl] ethyl-isochroman-6- carboxamide (VII) Step 1: 1- [2- (6-Bromoisopropan-1-yl) acetyl] -4- (4- chlorophenyl) piperazine (V) Following the general procedure of Example 1, step 3, but without significant changes except using racemic 6-bromoisocyanate-1-yl-acetic acid (IV) and 4- chlorophenylpiperazine, 1- [2- Yl) acetyl] -4- (4-methylphenyl) -piperazine (V). Rf = 0.20 (ethyl acetate / hexane, 50/50); IR (mull) 1642, 1594, 1496, 1482, 1443, 1275, 1232, 1107, 1030 and 821 cm -1 ; NMR (300㎒, CDCl 3) 7.32-7.21 , 7.01, 6.84, 5.26, 4.11, 3.94, 3.79-3.60, 3.14, 3.09-2.89, 2.77 and 2.65δ; CMR (75 MHz, CDCl 3 ) 178.1, 148.5, 136.0, 131.8, 129.1, 128.8, 125.8, 125.9, 120.0, 117.5, 73.0, 63.2, 49.7, 49.2, 55.0, 41.9, 39.6 and 28.5 Step 2: l- [2- (6-Bromoisopropan-l-yl) -ethyl] -4- (4- chlorophenyl) piperazine (VI) The general procedure of Example 1, Step 4, with no significant changes except using 1- [2- (6-bromoisocyanate-1-yl) acetyl] -4- (4-chlorophenyl) Ethyl] -4- (4-chlorophenyl) piperazine (VI), melting point = 94-96 占 폚; Rf = 0.22 (ethyl acetate / hexane, 50/50); IR (mull) 1500, 1483, 1448, 1248, 1242, 1152, 1144, 1113, 1102 and 815 cm -1 ; NMR (300㎒, CDCl 3) 7.32-7.26 , 7.19, 6.97, 6.83, 4.78, 4.14-4.07, 3.78-3.69, 3.16, 3.00-2.90, 2.7-2.48 , and 2.15-1.90δ; CMR (75 MHz, CDCl 3 ) 149.6, 137.1, 136.0, 131.4, 129.1, 128.7, 126.3, 124.6, 120.0, 116.9, 74.0, 62.6, 54.3, 53.3, 53.0, 48.9, 33.0 and 28.6 Step 3: l- [2- [4- (4-Chlorophenyl) -1-piperazinyl] ethyl isochroman-6- carboxamide (IX) The title compound was prepared in analogy to the procedure described in Example 1, step 5 but without significant changes except using 1- [2- (6-bromo isoquinolin-l-yl) -ethyl] -4- (4- chlorophenyl) -piperazine Following the general procedure, 1- [2- [4- (4-chlorophenyl) -1-piperazinyl] ethyl isochroman-6-carboxamide VII is obtained, mp = 169-171 ° C; Rf = 0.22 (methanol / ethyl acetate, 10/90); IR (mull) 3365, 1649, 1661, 1623, 1500, 1403, 1241, 1112, 1096 and 821 cm -1 ; NMR (300㎒, CDCl 3) 7.59 , 7.18, 6.84, 6.05, 4.88, 4.15, 3.77, 3.17, 3.00, 2.76-2.45, 2.14 and 2.02δ. [Example 9] 1- [2- [4- (4-phenylmethyloxyphenyl) -1-piperazinyl] ethyl] -isochroman-6- carboxamide (VII) Step 1: 1- (4-Phenylmethyloxyphenyl) -4- [2- (6-bromoisocroman-1-yl) acetyl] piperazine (V) Following the general procedure of Example 1, step 3, but using 6-bromoisocyanate-1-yl-acetic acid (IV) and 4-phenylmethyloxypiperazine, 1- (4-phenylmethoxyphenyl) -4- [2- (6-bromoisocroman-1-yl) acetyl] piperazine (V), R f = 0.47 (ethyl acetate); IR (mull) 1510, 1481, 1463, 1453, 1445, 1239, 1231, 1101 and 1207 cm -1 ; NMR (300㎒, CDCl 3) 7.43-7.25 , 7.00, 5.27, 5.02, 4.23-4.06, 3.93-3.87, 3.80-3.59, 3.06, 2.98-2.89, 2.76 and 2.65δ; CMR (75㎒, CDCl 3) 168.9 , 153.4, 145.3, 137.1, 136.4, 136.2, 131.6, 129.3, 128.4, 127.8, 127.3, 126.4, 120.2, 118.6, 115.5, 73.3, 70.3, 63.4, 51.1, 50.5, 46.0, 41.8, 39.8 and 28.7 delta. Step 2: l- (4-Phenylmethyloxyphenyl) -4- [2- (6-bromoisochroman-l-yl) The procedure of Example 1, Step 4 (4) was carried out without significant changes except that 1- (4-phenylmethoxyphenyl) -4- [2- According to the general procedure, 1- (4-phenylmethyloxyphenyl) -4- [2- (6-bromoisocroman-1-yl) -ethyl] piperazine (VI) ° C; R f = 0.43 (ethyl acetate); Step 3: Preparation of 1- [2- [4- (4-phenylmethyloxyphenyl) -1-piperazinyl] ethyl] -isochroman- Example 1, step 5 < RTI ID = 0.0 > (5) < / RTI > without significant change except using 1- (4-phenylmethyloxyphenyl) -4- [2- 1- [2- [4- (4-phenylmethyloxyphenyl) -1-piperazinyl] ethyl] -isochroman-6-carboxamide (VII) is obtained following the general procedure of < [Example 10] 1- [2- [4- (4-butoxyphenyl) -1-piperazinyl] ethyl] isochroman-6-carboxamide (VII) Step 1: 1- [2- (6-Bromoisopropan-1-yl) acetyl] -4- (4- Following the general procedure of Example 1, step 3, but without significant changes except using racemic 6-bromoisocyanate-1-yl-acetic acid (IV) and 4-butoxyphenylpiperazine, 1- [2- (6-bromoisocyanate-1-yl) acetyl] -4- (4-butoxyphenyl) -piperazine (V), R f = 0.24 (ethyl acetate / hexane, 50/50); Step 2: l- [2- (6-Bromoisopropan-l-yl) -ethyl] -4- (4-butoxyphenyl) -piperazine The title compound was prepared in analogy to Example 1, Step 4, with no significant change except that 1- [2- (6-bromo isoquinolin-1-yl) acetyl] -4- (4-butoxyphenyl) Following the general procedure, 1- [2- (6-bromoisocroman-1-yl) ethyl] -4- (4-butoxyphenyl) piperazine (VI) is obtained. R f = 0.43 (ethyl acetate); HRMS calcd for C 25 H 33 N 2 O 2 Br 1 = 473.1804, found = 473.1796. Step 3: 1- [2- [4- (4-Butoxyphenyl) -1-piperazinyl] ethyl] isochroman- Example 1, step 5 < RTI ID = 0.0 > (5-methoxy-phenyl) Therefore, a general procedure, 1-Only [2- [4- (4-butoxy-phenyl) -1-piperazinyl] ethyl] chroman was obtained isopropyl-6-carboxamide (VII), R f = 0.19 (Methanol / ethyl acetate, 10/90); HRMS calculated for C 26 H 3 N 3 O 3 = 437.2678, found = 437.2678. [Example 11] 1- [2- [4- (4-diethylaminophenyl) -1-piperazinyl] ethyl] isochroman-6-carboxamide (VII) Step 1: Preparation of 1- [2- (6-bromo isoquinolin-1-yl) acetyl] -4- (4- Following the general procedure of Example 1, step 3, but without significant changes except using 6-bromoisocyanate-1-yl-acetic acid (IV) and 4- diethylaminophenylpiperazine, 1- [2- Yl) acetyl] -4- (4-diethylaminophenyl) piperazine (V), R f = 0.21 (acetone / hexane, 30/70); Step 2: l- [2- (6-Bromoisopropan-l-yl) -ethyl] -4- (4-diethylaminophenyl) -piperazine The title compound was prepared in analogy to Example 1, Step 4, with the exception that 1- [2- (6-bromoisocroman-1-yl) acetyl] -4- (4-diethylaminophenyl) piperazine (V) According to the general procedure, R f = 0.26 ((R) - (R) -2,3-dihydro- Ethyl acetate); C 25 H 34 N 3 O 1 Br 1 · HRMS calculated for 0.152 C 4 H 8 O 2 = 472.1964, observed = 472.1956. Step 3: Preparation of 1- [2- [4- (4-diethylaminophenyl-1-yl) -piperazinyl] ethyl] -isochroman- Example 1, step 5 < RTI ID = 0.0 > (5) < / RTI > without significant changes, except using 1- [2- (6- bromo- isoquinolin- Therefore, the general procedure, 1-Only [2- [4- (4-diethylamino-phenyl) -1-piperazinyl] ethyl] chroman was obtained isopropyl-6-carboxamide (VII), R f = 0.25 (methanol / ethyl acetate, 10/90); NMR (300㎒, CDCl 3) 7.59 , 7.18, 6.87, 6.68, 6.1, 5.7, 4.87, 4.13, 3.78, 3.26, 3.06, 2.78-2.57, 2.17, 2.05 and 1.11δ. [Example 12] 1- [2- [4- (3-Trifluoromethylphenyl) -1-piperazinyl] ethyl] isochroman-6-carboxamide (VII) Step 1: 1- [2- (6-Bromoisopropan-1-yl) acetyl] -4- (3- trifluoromethylphenyl) Following the general procedure of Example 1, step 3, but without significant changes except using 6-bromoisocyanate-1-yl-acetic acid (IV) and 3-trifluoromethylphenylpiperazine, 1- [2- Yl) acetyl] -4- (3-trifluoromethylphenyl) piperazine (V), Rf = 0.30 (ethyl acetate / hexane, 40/60); Step 2: l- [2- (6-Bromoisopropan-l-yl) -ethyl] -4- (3- trifluoromethylphenyl) -piperazine The procedure of Example 1, Step 4 (4) was carried out without significant changes except that 1- [2- (6-bromoisocroman-1-yl) acetyl] -4- (3-trifluoromethylphenyl) piperazine Following the general procedure, the product is obtained. This material was purified by LC (silica gel, 230-400, 142 g, ethyl acetate / hexane, 30/70) to give l- [2- (6-bromoisochroman- 1- yl) -Trifluoromethylphenyl) piperazine (VI), Rf = 0.40 (ethyl acetate / hexane, 40/60); Step 3: 1- [2- [4- (3-Trifluoromethylphenyl) -1-piperazinyl] ethyl] isochroman- Example 1, step 5 < RTI ID = 0.0 > (5) < / RTI > without significant changes, except using 1- [2- (6- bromo- isoquinolin- ≪ / RTI > to give the product. This material was purified by LC (silica gel, 230-400, 120 g, acetone / hexane, 50/50) to give 1- [2- [4- (3- trifluoromethylphenyl) -1- piperazinyl] ethyl] Chromane-6-carboxamide (VII). This material was recrystallized from ethyl acetate / hexane to give 1- [2- [4- (3- (trifluoromethylphenyl) -1-piperazinyl] ethyl] isochroman-6-carboxamide (VII) Melting point = 129-131 [deg.] C; Rf = 0.22 (acetone / hexane, 50/50); C 23 H 26 F 3 N 3 HRMS (EI) for O 2 calculated = 433.1977, observed = 433.1979. [Example 13] 1- [2- [4- (4-methylsulfonylphenyl) -1-piperazinyl] ethyl] -isochroman-6- carboxamide (VII) Step 1: 1- [2- (6-Bromoisopropan-1-yl) acetyl] -4- (4- methylsulfonylphenyl) -piperazine (V) The product is obtained according to the general procedure of Example 1, step 3, with no significant changes except using racemic 6-bromoisocyanom-1-yl-acetic acid (IV) and 4-methylsulfonylphenylpiperazine. This material was purified by LC (silica gel, 230-400, 150 g, ethyl acetate) to give 1- [2- (6-bromoisochroman-1-yl) acetyl] -4- (4-methylsulfonylphenyl) (V), Rf = 0.30 (ethyl acetate); C 22 H 25 BrN HRMS (EI ) calculated for 2 O 4 S = 492.0719, observed = 492.0714. Step 2: Preparation of l- [2- (6-bromo isoquinolin-l-yl) -l-ethyl] -4- (4- methylsulfonylphenyl) -piperazine The title compound was prepared in analogy to Example 1, step 4, with the exception that 1- [2- (6-bromoisocroman-1-yl) acetyl] -4- (4-methylsulfonylphenyl) piperazine (V) Therefore, a general procedure, to afford l- [2- (6-feeders soak only 1-yl) -1-ethyl] -4- (4-methylsulfonyl-phenyl) piperazine (VI), R f = 0.26 (ethyl acetate); C 22 H 27 BrN 2 O HRMS (EI) calcd for 3 S = 480.0906, observed = 480.0903 Step 3: Preparation of 1- [2- [4- (4-methylsulfonylphenyl) -1-piperazinyl] ethyl] isochroman- The title compound was prepared in a manner similar to that described in Example 1, except that significant changes were used except that 1- [2- (6-bromo isoquinolin-1-yl) -1-ethyl] -4- (4-methylsulfonylphenyl) piperazine (VI) Following the general procedure of step 5, the product is obtained. This material was purified by LC (silica gel, 230-400 mesh, 75 g, methanol / dichloromethane, 5/95) to give 1- [2- [4- (4- methylsulfonylphenyl) ] Isochroman-6-carboxamide (VII), melting point = 217-219 C; Rf = 0.17 (methanol / dichloromethane, 5/95); HRMS (FAB) calcd for C 23 H 29 N 3 O 4 S + H 1 = 444.1957, found = 444.1959. [Example 14] (S) - (VII) < / RTI > < RTI ID = 0.0 & (S) - (-) - l- [2-Bromoisopropan-l-yl) 13.15 g, 28.0 mmol), the product is obtained according to the general procedure of Example 1, step 5, with no significant change. This material was purified by LC (silica gel, 230-400 mesh, 780 g, methanol / dichloromethane, 5/95) to give the crude product which was recrystallized from methanol / ethyl acetate to give (S) - (S) - (VII), melting point = 166 to 168 < 0 > C, , Rf = 0.20 (methanol / dichloromethane, 5/95); C 23 H 26 F 3 N 3 HRMS (EI) calcd for O 2 = 433.1977, observed = 433.1978. [Example 15] 1-piperazinyl] ethyl] -N-methyl-isochroman-6-carboxamide (IX) Step 1: 1- [2- (6-Bromoisopropan-1-yl) acetyl] -4- (4- Following the general procedure of Example 1, step 3, but without significant changes except using racemic 6-bromoisocyanate-1-yl-acetic acid (IV) and 4-ethoxyphenylpiperazine, 1- [2- (6-bromoisocyanate-1-yl) acetyl] -4- (4-ethoxyphenyl) piperazine (V). Rf = 0.46 (ethyl acetate / hexane, 70/30); HRMS calculated for C 23 H 27 N 2 O 3 Br = 458.1205, found = 458.1217. Step 2: l- [2- (6-Bromoisopropan-l-yl) -ethyl] -4- (4-ethoxyphenyl) -piperazine The general procedure of Example 1, Step 4, without significant changes, except that 1- [2- (6-bromoisocroman-1-yl) acetyl] -4- (4-ethoxyphenyl) piperazine (V) Ethyl) -4- (4-ethoxyphenyl) piperazine (VI), R f = 0.56 (ethyl acetate: ethyl acetate) to give 1- [2- (6-bromoisocroman- / n-hexane, 70/30); Step 3: 1- [2- [4- (4-Ethoxyphenyl) -1-piperazinyl] ethyl] -N- methylisochroman- The general procedure of Example 5, Step 3, with no significant changes except using 1- [2- (6-bromoisocrohman-1-yl) ethyl] -4- (4-ethoxyphenyl) piperazine (VI) Ethyl] -N-methyl isochroman-6-carboxamide (IX), melting point = < RTI ID = 0.0 > 148 to 149 占 폚; Rf = 0.22 (methanol / methylene chloride, 5/95); [Example 16] Ethyl] -N-methylisochroman-6-carboxamide < RTI ID = 0.0 > (IX) < Step 1: 1- [2- (6-Bromoisopropan-1-yl) acetyl] -4- (4- propoxyphenyl) Following the general procedure of Example 1, step 3, but without significant changes except using racemic 6-bromoisocyanom-1-yl-acetic acid (IV) and p-propoxyphenylpiperazine, 1- [2- (6-bromoisocyanate-1-yl) acetyl] -4- (4-propoxyphenyl) piperazine (V), R f = 0.50 (ethyl acetate / hexane, 70/30); HRMS calculated for C 24 H 29 N 2 O 3 Br = 472.1362, found = 472.1356. Step 2: l- [2- (6-Bromoisopropan-l-yl) -ethyl] -4- (4- propoxyphenyl) The general procedure of Example 1, Step 4, without significant changes, except that 1- [2- (6-bromoisocroman-1-yl) acetyl] -4- (4- propoxyphenyl) piperazine (V) Ethyl] -4- (4-propoxyphenyl) piperazine (VI), R f = 0.52 (ethyl acetate / Hexane, 70/30); HRMS calculated for C 24 H 31 N 2 O 2 Br 1 = 458.1561, found = 458.1569 Step 3: 1- [2- [4- (4-Propoxyphenyl) -1-piperazinyl] ethyl] -N- methylisochroman- The general procedure of Example 5, Step 3, with no significant change except using 1- [2- (6-bromoisocyanate-1-yl) ethyl] -4- (4-propoxyphenyl) piperazine The product is obtained according to the procedure. Ethyl] -N-methylisochroman-6-carboxamide (IX) was obtained by recrystallization from hot ethyl acetate and hexane to give 1- [2- [4- (4-propoxyphenyl) , Rf = 0.20 (methanol / methylene chloride, 5/95); [Example 17] Ethyl] -N-methylisochroman-6-carboxamide (IX) < EMI ID = Step 1: (S) - (-) - 1- [2- (6-Bromoisopropan-1-yl) acetyl] -4- (4- trifluoromethoxyphenyl) V) (S) - (-) - l- [2- (6-Bromoisopropionyl-piperazin-l-yl) -ethanone following the general procedure of Example 1, step 3, with no significant changes except using 4-trifluoromethoxyphenylpiperazine. Yl) acetyl] -4- (4-trifluoromethoxyphenyl) piperazine (S) - (V), [ ] D = -70 ° (c = 0.68, ethanol); Rf = 0.52 (ethyl acetate / hexane, 70/30); C 22 H 22 N 2 F 3 O HRMS calcd for 3 Br = 498.0766, observed = 498.0764. Step 2: (S) - (-) - 1- [2- (6-Bromoisopropan-l-yl) -ethyl] -4- (4- trifluoromethoxyphenyl) (VI) Using (S) - (-) - 1- [2- (6-bromoisocroman-1-yl) acetyl] -4- (4-trifluoromethoxyphenyl) piperazine (S) - (V) (S) - (-) - 1- [2- (6-Bromoisocyanate-1-yl) -ethyl] -4- ( 4-trifluoromethoxyphenyl) piperazine (S) - (VI), R f = 0.54 (ethyl acetate / hexane, 70/30); C 22 H 24 N 2 O 2 F 3 Br HRMS calculated for one (+1) = 486.0954, observed = 486.0956. Step 3: (S) - (-) - 1- [2- [4- (4-Trifluoromethoxyphenyl) -1-piperazinyl] ethyl] -N- methylisochroman- (S) - (IX) (S) - (-) - 1- [2- (6-bromoisocroman-1-yl) ethyl] -4- (4-trifluoromethoxyphenyl) piperazine The product is obtained according to the general procedure of example 5, step 3, with no significant changes. Recrystallization from hot ethyl acetate and hexanes gave (S) - (-) - 1- [2- [4- (4- trifluoromethoxyphenyl) -1- piperazinyl] ethyl] Carboxamide (S) - (IX), R f = 0.20 (methanol / methylene chloride, 5/95); HRMS calculated for C 24 HN 3 O 3 F 3 = 463.2083, found = 463.2086. [Example 18] (S) - (IX - (-) - l- [2- [4- (4-ethylphenyl) -1- piperazinyl] ethyl] -N- methylisochroman- ) Step 1: Preparation of (S) - (-) - 1- [2- (6-bromoisocroman-1-yl) acetyl] -4- (S) - (-) - 1- [2- (6-Bromoisopropionyl-1-yl) -pyrimidine Following the general procedure of Example 1, step 3, ) Acetyl] -4- (4-ethylphenyl) piperazine (S) - (V), Rf = 0.70 (ethyl acetate / hexane, 70/30); [ ] D = -81 (c = 0.7, ethanol) Step 2: Preparation of (S) - (-) - 1- [2- (6-bromoisocroman-1-yl) Except that (S) - (-) - 1- [2- (6-bromoisocroman-1-yl) acetyl] -4- (S) - (-) - l- [2- (6-Bromoisopropan-l-yl) -ethyl] -4- Phenyl) piperazine (S) - (VI), Rf = 0.61 (ethyl acetate / hexane, 70/30); HRMS calcd for C 23 H 29 N 2 O 1 Br 1 = 430.1444, found = 430.1443. Step 3: (S) - (-) - 1- [2- [4- (4-Ethylphenyl) -1- piperazinyl] ethyl] -N- methylisochroman- - (IX) Except that (S) - (-) - 1- [2- (6-bromoisocroman-1-yl) ethyl] -4- And following the general procedure of example 5, step 3, without significant change. Recrystallization from hot ethyl acetate and hexane gave (S) - (-) - 1- [2- [4- (4-ethylphenyl) -1- piperazinyl] ethyl] -Carboxamide (S) - (IX), melting point = 138-140 DEG C; Rf = 0.28 (methanol / methylene chloride, 5/95); [ ] D = -50 (c = 0.93, methanol / methylene chloride, 50/50); HRMS calculated for C 25 H 33 N 3 O 3 = 407.2573, observed = 407.2581. [Example 19] (S) - ((S) - (-) - 1- (2- [4- (4-ethoxyphenyl) -1- piperazinyl] ethyl] -N- methylisochroman- IX) Step 1: Preparation of (S) - (-) - 1- [2- (6-bromoisocroman-1-yl) acetyl] -4- (S) - (-) - 1- [2- (6-Bromoisocyanate-1-yl) -ethanone was synthesized following the general procedure of Example 1, step 3, with no significant changes except using 4-ethoxyphenylpiperazine. Yl) acetyl] -4- (4-ethoxyphenyl) piperazine (S) - (V); Rf = 0.60 (ethyl acetate / hexane, 70/30); [[alpha]] D = -78 [deg.] (c = 0.82, ethanol); HRMS calcd for C 23 H 27 N 2 O 3 Br = 458.1205, found = 458.1203. Step 2: (S) - (-) - 1- [2- (6-Bromoisocyanat-1-yl) ) Except that (S) - (-) - 1- [2- (6-bromoisocroman-1-yl) acetyl] -4- (4-ethoxyphenyl) piperazine (S) - (S) - (-) - 1- [2- (6-Bromoisocyanate-1-yl) -ethyl] -4- Ethoxyphenyl) piperazine (S) - (VI), melting point = 85-87 [deg.] C; Rf = 0.28 (ethyl acetate / n-hexane, 30/70); [[alpha]] D = -46 [deg.] (c = 0.60, ethanol); Step 3: (S) - (-) - 1- [2- [4- (4-ethoxyphenyl) -1- piperazinyl] ethyl] -N- methylisochroman- ) - (IX) (S) - (VI) was used instead of (S) - (-) - 1- [2- (6-bromoisocroman-1- yl) ethyl] -4- (S) - (-) - 1- [2- [4- (4-ethoxyphenyl) -1-piperazinyl] ethyl] - N-methyl-isochroman-6-carboxamide (S) - (IX). Recrystallization from hot ethyl acetate and hexane gave the purified product, mp = 156- 157 C; Rf = 0.20 (methanol / methylene chloride, 5/95); [ ] D = -48 (c = 0.94, methanol / methylene chloride, 50/50); HRMS calculated for C 25 H 33 N 3 O 3 = 423.2522, observed = 423.2518. [Example 20] (S) - (-) - 1- [2- [4- (4-phenylmethyloxyphenyl) -1- piperazinyl] ethyl] -N- methylisochroman- (IX) Step 1: (S) - (-) - 1- [2- (6-Bromoisopropan-1-yl) acetyl] -4- ) The product is obtained following the general procedure of Example 1, step 3, with no significant changes except using 4-pheylmethyloxyphenylpiperazine (3.38 g, 12.6 mmol). This material was purified by HPLC, eluting with ethyl acetate / hexanes (70/30) on silica gel cartridge to give (S) - (-) - l- [2- (6-bromoisocroman- (S) - (V), Rf = 0.30 (ethyl acetate / hexane, 50/50); [[alpha]] D = -34 [deg.] (c = 0.50, methanol); Step 2: (S) - (-) - 1- [2- (6-Bromoisopropan-l-yl) -ethyl] -4- (4- phenylmethyloxyphenyl) VI) (V) (5.96 g, 11.4 mmol) was added to a solution of (S) - (-) - 1- [2- (6-bromoisocroman- 1- yl) acetyl] -4- (4- phenylmethyloxyphenyl) (S) - (-) - l- [2- (6-bromoisocroman-l-yl) -ethyl] -4- ( 4-phenyloxyphenyl) piperazine (S) - (VI), Rf = 0.40 (ethyl acetate / hexane, 50/50); [[alpha]] D = -63 [deg.] (c = 0.925, methanol); Step 3: (S) - (-) - 1- [2- [4- (4-Phenylmethyloxyphenyl) -1- piperazinyl] ethyl] -N- methylisochroman-6- carboxamide S) - (IX) (S) - (VI), 5.08 g (0.15 mmol) of (S) - (-) - 1- [2- , 11.4 mmol), the product is obtained according to the general procedure of example 5, step 3, with no significant changes. This material was purified by LC (silica gel, 230-400 mesh, 270 g; ethyl acetate) and recrystallized from ethyl acetate to give (S) - (-) - 1- [2- [4- Phenyl) -1-piperazinyl] ethyl-N-methylisochroman-6-carboxamide (S) - (IX), melting point = 164-167 ° C; Rf = 0.40 (methanol / ethyl acetate, 5/95); [[alpha]] D = -40 [deg.] (c = 0.9323, methanol); C 30 H 35 N 3 O 3 HRMS (EI) calculated = 485.2678, observed = 485.2675 for. [Example 21] (R) - ((R) - (+) - 1- [2- [4- (4-ethoxyphenyl) -1- piperazinyl] ethyl] -N- methylisochroman- IX) Step 1: (R) - (+) - 1- [2- (6-Bromoisopropan- (R) - (+) - l- [2- (6-Bromoisocyanate-l-methoxyphenyl) piperazine following the general procedure of example 2, step 2, with the exception that 4-ethoxyphenylpiperazine was used. Yl) acetyl] -4- (4-ethoxyphenyl) piperazine (RV), Rf = 0.60 (ethyl acetate / hexane, 70/30); [[alpha]] D = + 76 [deg.] (c = 0.71, ethanol); HRMS calculated for C 23 H 27 N 2 O 3 Br (on Br 81 ion) = 460.1185, found = 460.1179. Step 2: (R) - (+) - 1- [2- (6-Bromoisocyanate-1-yl) (RV) - (+) - l- [2- (6-Bromoisopropan-l-yl) acetyl] -4- (4-ethoxyphenyl) piperazine (R) - (+) - l- [2- (6-Bromoisocyanate-l-yl) -ethyl] -4- (4-ethoxyphenyl) Pyrazine (R-V1), Rf = 0.25 (ethyl acetate / n-hexane, 30/70); [[alpha]] D = + 43 [deg.] (c = 0.73, ethanol); HRMS calcd for C 23 H 29 N 2 O 2 Br 1 = 444.1413, found = 444.1413. Step 3: (R) - (+) - 1- [2- [4- (4-ethoxyphenyl) -1- piperazinyl] ethyl] -N- methylisochroman- -IX) Except that (R) - (+) - l- [2- (6-bromoisocroman-l-yl) ethyl] -4- (R) - (+) - 1- [2- [4- (4-ethoxyphenyl) -1-piperazinyl] ethyl] -N- Methyl isochroman-6-carboxamide (R-IX). Rf = 0.20 (methanol / methylene chloride, 5/95); [ ] D = + 49 (c = 0.93, methanol / methylene chloride, 50/50) HRMS calculated for C 25 H 33 N 3 O 3 = 423.2522, observed = 423.2516. [Example 22] Ethyl] -N-methylisochroman-6-carboxamide (IX) < EMI ID = Step 1: 1- [2- [4- (3-Trifluoromethylphenyl) -1-piperazinyl] ethyl] -N, N-di-tert-butyloxycarbonylisochroman- Amide (VIII) The title compound was prepared in analogy to the procedure described in example 3, step 1, with the exception that 1- [2- [4- (3-trifluoromethylphenyl) -1-piperazinyl] ethyl] -isochroman- The crude product is provided according to the general procedure. This material was purified by LC (silica gel, 230-400 mesh, 60 g; acetone / hexane, 25/75) to give 1- [2- [4- (3- trifluoromethylphenyl) -1- piperazinyl] ethyl] -N, N-di-tert-butyloxycarbonylisochroman-6-carboxamide (VIII), R f = 0.37 (acetone / hexane, 25/75). Step 2: 1- [2- [4- (3-Trifluoromethylphenyl) -1-piperazinyl] ethyl] -N- methyl- isochroman- 1- [2- [4- (3-Trifluoromethylphenyl) -1-piperazinyl] ethyl] -N, N-di-tert-butyloxycarbonylisochroman- , 1.13 g, 1.8 mmol), the title compound was obtained following the general procedure of Example 3, Step 2, with no significant change. This material was purified by LC (silica gel, 230-400 mesh, 66 g; acetone / hexane, 50/50) to give 1- [2- [4- (3- trifluoromethylphenyl) -1- piperazinyl] ethyl] -N-methylisochroman-6-carboxamide (IX) which is recrystallized from ethyl / acetate / hexane, melting point = 142-143 DEG C; Rf = 0.33 (acetone / hexane, 50/50); HRMS (EI) calculated for C 24 H 28 F 3 N 3 O 2 = 447.2133, found = 447.2132. [Example 23] Ethyl] -N-methylisochroman-6-carboxamide < RTI ID = 0.0 > (IX) < Step 1: Preparation of 1- [2- [4- (4-methylsulfonylphenyl) -1-piperazinyl] ethyl] -N, N-di-tert-butyloxycarbonylisochroman- Amide (VIII) (825 mg, 1.9 mmol) instead of 1- [2- [4- (4-methylsulfonylphenyl) -1-piperazinyl] ethyl] -isochroman-6- carboxamide The crude product is provided according to the general procedure of Example 3, Step 1. This material was purified by LC (silica gel, 230-400 mesh, 58 g; acetone / hexane, 45/55) to give 1- [2- [4- (4- methylsulfonylphenyl) -N, N-di-tert-butyloxycarbonylisochroman-6-carboxamide (VIII), Rf = 0.20 (acetone / hexane, 40/60). Step 2: 1- [2- [4- (4-Methylsulfonylphenyl) -1-piperazinyl] ethyl] -N- methyl- isochroman-6-carboxamide (IX) (4-methylsulfonylphenyl) -1-piperazinyl] ethyl] -N, N-di-tert-butyloxycarbonylisochroman- , 650 mg, 1.0 mmol), the title compound was obtained following the general procedure of Example 3, Step 2, with no significant change. This material was purified by LC (silica gel, 230-400 mesh, 71g; methanol / dichloromethane, 5/95) to give 1- [2- [4- (4- methylsulfonylphenyl) ] -N-methylisochroman-6-carboxamide (IX), Rf = 0.30 (methanol / dichloromethane, 5/95); HRMS (EI) calculated for C 24 H 31 N 3 O 4 S = 457.2035, found = 457.2032, KF water = 0.87%; Molten solvate = 0.53%, ethyl acetate and 0.34% hexane. [Example 24] 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] isochroman-6-carboxamide (VII) Step 1: 1- [2- (6-Bromoisopropan-1-yl) acetyl] -4- (4- methoxyphenyl) Following the general procedure of Example 1, step 3, but without significant changes except using racemic 6-bromoisocyanate-1-yl-acetic acid (IV) and 4- methoxyphenylpiperazine, 1- [2- (6-bromoisocyanate-1-yl) acetyl] -4- (4-methoxyphenyl) piperazine (V), R f = 0.26 (ethyl acetate / hexane, 70/30); Step 2: l- [2- (6-Bromoisopropan-l-yl) -ethyl] -4- (4-methoxyphenyl) -piperazine The general procedure of Example 1, Step 4, without significant changes, except that 1- [2- (6-bromoisocyanate-1-yl) acetyl] -4- (4-methoxyphenyl) piperazine Yl) -ethyl] -4- (4-methoxyphenyl) piperazine (VI), R f = 0.23 (ethyl acetate ); Step 3: Preparation of 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] isochroman- THF (18 ml) was added to a dried 100 ml round bottom flask, and the mixture was cooled to -78 캜 with a dry ice / acetone bath. Tert-Butyl lithium (1.7 M, 5.4 mL, 9.2 mmol) in hexane is added simultaneously. After stirring for 5 min, a solution of 1- [2- (6-bromoisochroman-1-yl) ethyl] -4- (4-methoxyphenyl) piperazine (VI) in THF (20 mL) . After stirring at -78 占 폚 for 15 minutes, trimethylsilyl isocyanate (0.88 ml, 6.55 mmol) and dioxane (3.52 ml) are added via syringe, respectively. After 15 minutes, the cold bath is removed and the reaction is stirred at 20-25 < 0 > C for 1.5 h. The reaction mixture is quenched with saturated aqueous ammonium chloride, the volatiles are removed under reduced pressure and the residue is basified with aqueous sodium hydroxide. The crude basic solution is extracted with methylene chloride. The organic extracts are combined, dried over sodium sulfate, filtered and concentrated. The crude material was purified by flash chromatography (silica gel, 25g) using a gradient of 0-10% methanol / ethyl acetate to give 1- [2- [4- (4- methoxyphenyl) -1- piperazinyl] Ethyl] -isochroman-6-carboxamide (VII), melting point = 180-182 DEG C; Rf = 0.27 (methanol / ethyl acetate, 10/90); HRMS calculated for C 23 H 29 N 3 O 3 = 395.2209, found = 395.2219. [Example 25] Ethyl] -N-propylisochroman-6-carboxamide (IX) < EMI ID = Step 1: Preparation of 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] -N, N-di-tert-butyloxycarbonylisochroman- (VIII) , Without significant change except starting with 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] -isochroman-6- carboxamide (VII, Following the general procedure of step 3 of example 3, the title compound was obtained from 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] -N, N-di-tert-butyloxycarbonyl Isochroman-6-carboxamide (VIII). Step 2: Preparation of 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] -N-propyl-isochroman- Ethyl] -N, N-di-tert-butyloxycarbonylisochroman-6-carboxamide (VIII, 566 mg, 0.95 mmol) and 20 mL of dichloromethane are placed in a recovery flask equipped with an oven-dried 100 mL spin bar. The mixture is treated with propylamine (0.78 ml, 9.5 mmol). After 16 hours, the volatiles are removed under reduced pressure to provide the crude product. This material was purified by LC (silica gel, 230-400 mesh, 30g; methanol / ethyl acetate, 5/95) to give 1- [2- [4- (4- methoxyphenyl) -1- piperazinyl] ethyl] -N-propyl isochroman-6-carboxamide (IX), melting point = 147-149 DEG C; Rf = 0.37 (methanol / ethyl acetate, 5/95); [Example 26] 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] -N-allyloxochroman-6-carboxamide (IX) The crude product is provided according to the general procedure of example 25, step 2, with no significant changes except using allylamine (0.69 mL, 9.1 mmol). Purify the material by LC (silica gel, 230-400 mesh, 30 g; methanol / ethyl acetate 3/97) to give the product which is recrystallized from ethyl acetate / hexane, mp = 146-148 캜; Rf = 0.34 (methanol / ethyl acetate, 5/95); HRMS (EI) calculated for C 26 H 33 N 3 O 3 = 435.2522, found = 435.2516. [Example 27] 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] -N-ethyl isochroman-6-carboxamide (IX) The crude product is provided according to the general procedure of example 25, step 2, with no significant changes except using ethylamine (about 2 mL, condensed at 0 C). This material is purified by LC (silica gel, 230-400 mesh, 30 g; methanol / ethyl acetate 5/95) to provide the product. This material was triturated with ethyl acetate / hexane to give 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] -N- ethyl isochroman- Amide < RTI ID = 0.0 > (IX), < / RTI > Rf = 0.30 (methanol / ethyl acetate, 5/95); [Example 28] 1-piperazinyl] ethyl] -N-propargyl-isochroman-6-carboxamide (IX) The crude product is provided following the general procedure of Example 25, Step 2, with no significant changes except using propargylamine (1.6 mL, 23.0 mmol). This material was purified by LC eluting with ethyl acetate on 75 g (230-400) of silica gel to give the product which was recrystallized from ethyl acetate / hexanes to give 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] -N-propargyl-isochroman-6-carboxamide (IX), melting point = 162-164 ° C; Rf = 0.40 (methanol / ethyl acetate, 5/95); HRMS (EI) calcd for C 26 H 31 N 3 O 3 = 433.2365, found = 433.2367. [Example 29] (IX) < RTI ID = 0.0 > 1- [2- [4- (4- The crude product is provided following the general procedure of Example 25, Step 2, with little change, except using 4-methoxyphenylmethylamine (1.2 mL, 9.2 mmol). The crude product was purified by LC on 67 g of silica gel using methanol / ethyl acetate as eluent to give 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] -N- -Methoxyphenylmethyl) -isochroman-6-carboxamide (IX), melting point = 162-163 C; Rf = 0.40 (methanol / ethyl acetate, 10/90); [[alpha]] D = -40 [deg.] C (c = 0.98, ethanol); C 31 H 37 N 3 O 4 HRMS calculated = 515.2784, observed = 515.2806 for. [Example 30] Phenyl] methyl-isochroman-6-carboxamide < RTI ID = 0.0 > (IX) < To an oven dried 15 mL microvial equipped with a Claisen condenser, a water cooled condenser, and a hose adapter was added 1- (2- (6-bromoisocyanate-1-yl) -ethyl) -4- (98%, 17.2 mg, 0.075 mmol) and 1,3-bis-diphenylphosphinopropane (97%, 38.3 mg, , 0.09 mmol). A carbon monoxide atmosphere is created in the vial. DMF (3.75 ml), phenylmethylamine (1.15 ml, 10.5 mmol) and diisopropylethylamine (0.52 ml, 3 mmol) were introduced into the reaction vessel via a syringe. The mixture is heated to 100 < 0 > C over 10 hours. After cooling to 20 to 25 캜, it is separated into two phases. The reaction mixture is poured into ethyl acetate. The mixture is washed once with aqueous sodium hydroxide (1N). The organic layer was concentrated under reduced pressure to remove excess solvent and reagent to give a crude product which was purified by flash chromatography using 100 g of silica gel as eluent to give 1- [2- [4- (4- Methoxyphenyl) -1-piperazinyl] ethyl] -N-phenylmethyl-isochroman-6-carboxamide (IX), melting point = 153.0 to 153.5 DEG C; Rf = 0.25 (methanol / ethyl acetate, 10/90); HRMS calculated for C 30 H 35 N 3 O 3 = 485.2678, observed = 485.2664. [Example 31] (IX) < RTI ID = 0.0 > 1- [2- [4- (4- The crude product was provided according to the general procedure in Example 30, with no significant change except using n-butyl amine (1.04 mL, 10.5 mmol), which was purified by flash chromatography using 100 g of ethyl acetate as the eluent on silica gel To give the product which is recrystallized from hot ethyl acetate to give the title compound, mp = 158.5-159.5 C; R f = 0.28 (ethyl acetate); [Example 32] Methylphenylmethyl] -isochroman-6-carboxamide (IX) < / RTI > < RTI ID = 0.0 & The title compound was prepared following the general procedure of Example 30, but with no significant change except using (R) - (+) - alpha -methylphenylmethylamine (98%, 0.90 ml, 7 mmol), which was purified on 100 g silica gel Purify by flash chromatography using a 0-4% methanol gradient in ethyl acetate. The product was recrystallized from hot methylene chloride / ethyl acetate / hexanes to give 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] -N - [(R) Methyl] isochroman-6-carboxamide (IX) as a mixture of diastereomers, mp = 140.5-141.0 [deg.] C; R f = 0.28 (ethyl acetate); [[alpha]] D = + 25 [deg.] (c = 0.94, ethanol); [Example 33] Methylphenylmethyl] isochroman-6-carboxamide (IX) was obtained in the same manner as in [1- [2- [4- (4-methoxyphenyl) The title compound was prepared according to the general procedure of Example 30, but with no significant change except using (S) - (-) - alpha -methylphenylmethylamine (98%, 0.90 ml, 7 mmol), which was purified on 100 g silica gel Purify by flash chromatography using a methanol gradient from 0 to 7% in ethyl acetate. The product was recrystallized from hot methylene chloride / ethyl acetate / hexanes to give 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] -N - [(S) Methyl] isochroman-6-carboxamide (IX) as a mixture of diastereomers, mp = 141.0-141.5 DEG C; R f = 0.28 (ethyl acetate); [[alpha]] D = -24 [deg.] (c = 0.98, ethanol); [Example 34] 1-piperazinyl] ethyl] -N-phenylisochroman-6-carboxamide (IX) < The crude product was provided according to the general procedure in Example 30, with no significant changes except using alanine (0.64 mL, 7 mmol), which was purified by column chromatography on silica gel with ethyl acetate / hexane (75/25) on silica gel (29 g, 230-400) To give 1- [2- [4- (4-methoxyphenyl) 1-piperazinyl] ethyl] -N-phenylisochroman-6-carboxamide (IX) f = 0.25 (ethyl acetate / hexane, 72/25); [Example 35] Phenyl] methyl-N-methyl-isochroman-6-carboxamide (IX) < EMI ID = The crude product was provided according to the general procedure of Example 30, but with no significant change except phenylmethyl methylamine (1.4 mL, 10.5 mmol), which was purified by column chromatography on silica gel (77 g, 230-400) ) And purified by LC eluting with increasing acetone / hexane (60/40) to give the product. This material is dissolved in ether and treated with gaseous hydrochloric acid to produce a solid. Free base R f = 0.30 (acetone / hexane, 40/60); This salt C 31 H 37 N 3 O 3 HRMS (EI) calculated = 499.2835, observed = 499.2842 for. [Example 36] (IX) < RTI ID = 0.0 > 1- [2- [4- (4- A freshly distilled tetrahydrofuran (6 ml) was added to a flame-dried 50 ml flask equipped with a stirrer and a dropping funnel, cooled to -78 캜, 1.7 M tert-butyllithium solution (3.0 ML, 5.0 mmol). The resulting mixture was treated with l- (2- (6-bromo isoquinolin-l-yl) -ethyl) -4- (4- methoxyphenyl) piperazine (VI, 1.08 g, 2.5 mmol) And treated dropwise with 7 ml of tetrahydrofuran (507 mg, 3.3 mmol). The aryllithium is stirred for 10 minutes and treated with carbon monoxide (completely dried). Ten minutes after the addition, the aryl carboxylate is warmed to 20 to 25 DEG C with the addition of the suspended gas. The mixture is treated with dimethylformamide (2 drops), followed by addition of oxalyl chloride (0.33 ml, 3.75 mmol), where large amounts of gas are generated and the color becomes dark. After 45 minutes, the mixture is treated with dimethylamine gas. After 20 minutes the added amine was suspended and the reaction mixture was diluted with 40 mL of 5 M sodium hydroxide and extracted twice with ethyl acetate (40 mL). The combined organic layers were washed once with brine (30 mL), dried over magnesium sulfate, filtered and concentrated to give the product which was eluted with acetone / hexane (50/50) on silica gel (63-400 g) LC to give l- [2- [4- (4-methoxyphenyl) 1-piperazinyl] ethyl] -N, N- dimethylisochroman-6- carboxamide (IX) = 94 to 96 占 폚; Rf = 0.31 (acetone / hexane, 50/50); C 25 H 33 N 3 O HRMS (EI) calcd for 3 = 423.2522, found = 423.2520. [Example 37] Ethyl] -N-methylisochroman-6-carboxamide (IX) < RTI ID = 0.0 > 1- [2- [4- (4-methoxyphenyl) 1-piperazinyl] propanoic acid was prepared following the general procedure of Example 36 while maintaining the same amounts of the other reactants without significant changes except using methylamine gas. Ethyl] -N-methylisochroman-6-carboxamide (IX) which is recrystallized from ethyl acetate to give the title compound, mp = 174-176 ° C; Rf = 0.40 (methanol / dichloromethane, 5/95); HRMS (EI) calculated for C 24 H 31 N 3 O 3 = 409.2365, found = 409.2366. [Example 38] Ethyl] -N-methylisochroman-6-carboxamide < RTI ID = 0.0 > (IX) < (VI, Example 8, step 2, 188 mg, 0.43 mmol) and methylamine < RTI ID = 0.0 > To give the product following the general procedure of example 36 and purification via LC eluting with 10% (230-400) of silica gel with 40% acetone / hexanes to give 1- [2- [ Ethyl] -N-methylisochroman-6-carboxamide (IX), melting point = 158-160 DEG C; Rf = 0.21 (40% acetone / hexanes); HRMS (EI) calculated for C 23 H 28 ClN 3 O 2 = 413.1870, found = 413.1867. [Example 39] 1- [2- [4- (4-chlorophenyl) -1-piperazinyl] ethyl] -N, N- dimethylisochroman- 6- carboxamide (IX) (VI, Example 8, step 2, 188 mg, 0.43 mmol) and < RTI ID = 0.0 > dimethylamine < / RTI & (27%) of 1- [2- [4- (4-chlorophenyl) 1-piperazinyl] ethyl] -N, N- Dimethylisochroman-6-carboxamide (IX) is obtained as product. This material is converted to the hydrochloride salt with gaseous hydrochloric acid and recrystallized, mp = 119-122 ° C; Rf = 0.41 (40% acetone / hexanes); This salt HRMS (EI) calculated for C 24 H 30 ClN 3 O 2 = 427.2026, found = 427.2020. [Example 40] 1- [2- [4-phenylpiperazinyl] ethyl] isochroman-6-carboxamide (VII) Step 1: l- [2- (6-Bromoisopropan-l-yl) -acetyl] -4- phenylpiperazine (V) Following the general procedure of Example 1, step 3, but without significant changes except using racemic 6-bromoisocyanate-1-yl-acetic acid (IV, Example 7, step 1) and N-phenylpiperazine, 1- [2- (6-bromoisocyanate-1-yl) -acetyl] -4-piperazine (V), R f = 0.20 (ethyl acetate); HRMS (EI) calculated for C 21 H 23 BrN 2 O 2 = 414.0943, found = 414.0937. Step 2: l- [2- (6-Bromoisopropan-l-yl) -ethyl] -4- phenylpiperazine (V) Following the general procedure of Example 1, Step 4, but without significant changes except using 1- [2- (6-bromoisocrochman-1-yl) -acetyl] -4-phenyl-piperazine (V) Yl] -ethyl] -4-phenylpiperazine (VI) which is dissolved in ether (30 ml) and treated with gaseous hydrochloric acid. This crude salt is recrystallized from ethyl acetate / hexane, mp = 241-242 占 폚; Rf = 0.25 (40% ethyl acetate / hexanes); This salt Step 3: 1- [2- [4-Phenylpiperazinyl] ethyl] -isochroman-6-carboxamide (VII) To a flame-dried 50 ml flask equipped with a stir bar and a dropping funnel was added freshly distilled tetrahydrofuran (2 ml), cooled to -78 캜, and a tert-butyllithium solution (1.7 M, 1.3 ML, 2.3 mmol). The resulting mixture was stirred for 5 minutes and a solution of 1- [2- (6-bromoisochroman-1-yl) -ethyl] -4-phenylpiperazine (VI, 431 mg, 1.1 mmol) in 6 mL of tetrahydrofuran Solution. The aryllithium was stirred for 10 minutes and then added to a flame-dried 25 < RTI ID = 0.0 > (I) < / RTI > solution with a spinning rod containing freshly distilled trimethylsilylisocyanate (0.22 ml, 1.6 mmol) and 2 ml tetrahydrofuran, Ml < / RTI > of flask through a cannula. The resulting mixture was warmed to 20-25 ° C for 2 hours, diluted with 25 mL of saturated ammonium chloride, the volatiles removed under reduced pressure, the pH adjusted to 13, extracted twice with ethyl acetate (35 mL) do. The combined organic layers are washed once with brine (25 mL), dried over magnesium sulfate, filtered and concentrated. This material was purified by LC eluting with 27 g (230-400) of silica gel with 5% methanol / ethyl acetate to give 1- [2- [4-phenylpiperazinyl] ethyl] isochroman- (VII), < / RTI > C 22 H 27 N 3 HRMS ( EI) calcd for O 2 = 365.2103, observed = 365.2108. [Example 41] 1- [2- [4- (3,4-Dichlorophenyl) -piperazinyl] ethyl] isochroman-6- carboxamide (VII) Step 1: 1- [2- (6-Bromoisopropan-l-yl) -acetyl] -4- (3,4- dichlorophenyl) -piperazine (V) The general procedure of Example 1, Step 3, but without significant changes, except using racemic 6-bromoisocroman-1-yl-acetic acid (IV, Example 7, step 1) and 3,4-dichlorophenylpyrazine -Acetyl] -4- (3,4-dichlorophenyl) -piperazine (V) is obtained according to the general procedure for the preparation of 1- [2- (6-Bromoisopropan- Step 2: l- [2- (6-Bromoisopropan-l-yl) -ethyl] -4- (3,4- dichlorophenyl) -piperazine The general procedure of Example 1, Scheme 4, except using 1- [2- (6-bromoisocyanate-1-yl) -acetyl] -4- (3,4- dichlorophenyl) -piperazine Yl) -ethyl] -4- (3,4-dichlorophenyl) -piperazine (VI), which was isolated on 100 g of silica gel Flash chromatography using 40% to 50% ethyl acetate in hexanes gradient, R f = 0.25 (ethyl acetate / hexanes, 25/75); HRMS calculated for C 21 H 23 N 2 O 1 Br 1 Cl 2 = 468.0371, observed = 418.0363. Step 3: l- [2- [4- (3,4-Dichlorophenyl) piperazinyl] ethyl] -isochroman-6- carboxamide (VII) The title compound was prepared in the same manner as in Example 40, Step 3 (b) except that significant changes were used except that 1- [2- (6-bromoisocleman-1-yl) -ethyl] -4- (3,4-dichlorophenyl) piperazine Therefore, a general procedure, 1- [2- [4- (3,4-dichloro-phenyl) piperazinyl] ethyl] should yield a 6-carboxamide (VII) isopropyl croissant, R f = 0.13 (Ethyl acetate); C 22 H 26 N 3 F HRMS calculated for 1 O 2 = 433.1324, observed = 433.1325. [Example 42] 1- [2- [4- (4-fluorophenyl) -1-piperazinyl] ethyl] isochroman-6-carboxamide (VII) Step 1: 1- [2- (6-Bromoisopropan-1-yl) -acetyl] -4- (4- fluorophenyl) The general procedure of Example 1, Step 3, but without significant changes except using racemic 6-bromoisocroman-1-yl-acetic acid (IV, Example 7, step 1) and 4-difluorophenylpiperazine -Acetyl] -4- (4-difluorophenyl) -piperazine (V) is obtained according to the general procedure for the preparation of 1- [2- (6-Bromoisopropan- HRMS calculated for C 21 H 22 N 2 O 2 FBr = 432.0843, found = 432.0849. Step 2: l- [2- (6-Bromoisocyanat-l-yl) -ethyl] -4- (4- fluorophenyl) -piperazine The procedure of Example 1, Step 4 (V) was carried out without significant changes except that 1- [2- (6-bromoisocroman-1-yl) -acetyl] -4- (4- fluorophenyl) Yl) -ethyl] -4- (4-fluorophenyl) -piperazine (VI) was obtained following the general procedure for the preparation of 1- [2- (6-bromoisocro- Flash chromatography on silica gel using a gradient of 40% to 50% ethyl acetate in hexanes, R f = 0.26 (25% ethyl acetate / hexanes); HRMS calculated for C 21 H 24 N 2 O 1 Br 1 F 1 = 418.1056, found = 418.1057. Step 3: Preparation of 1- [2- [4- (4-difluorophenyl) 1- piperazinyl] ethyl] isochroman- The title compound was prepared in the same manner as in Example 40, Step 3, but without significant changes except using 1- [2- (6-bromoisocleman-1-yl) -ethyl] -4- (4- fluorophenyl) piperazine Following the general procedure, R f = 0.09 (1 H) is obtained, starting from 1- [2- [4- (4- fluorophenyl) -1- piperazinyl] ethyl] -isochroman- (Ethyl acetate); C 22 H 26 N 3 F HRMS calculated for 1 O 2 = 383.2009, observed = 383.2010. [Example 43] 1- [2- [4- (3-ethoxyphenyl) -1-piperazinyl] ethyl] isochroman-6- carboxamide (VII) Step 1: Preparation of 1- [2- (6-bromo isoquinolin-1-yl) -acetyl] -4- (3-ethoxyphenyl) -piperazine Following the general procedure of example 1, step 3, but without significant changes except using racemic 6-bromoisocroman-1-yl-acetic acid (IV, Example 7, step 1) and 3-ethoxyphenylpiperazine Thus, 1- (2- (6-bromo isoquinolin-1-yl) -acetyl] -4- (3-ethoxyphenyl) piperazine (V) was obtained and then, on 200 g of silica gel, Flash chromatography using ethyl acetate, Rf = 0.28 (50% ethyl acetate in hexanes); HRMS calculated for C 23 H 27 N 2 O 3 Br 1 = 458.1205, found = 458.1215. Step 2: 1- [2- (6-Bromoisopropan-1-yl) -ethyl] -4- (3-ethoxyphenyl) -piperazine The procedure of Example 1, Step 4 (4) was carried out without significant changes except that 1- [2- (6-bromoisocyanate-1-yl) -acetyl] -4- (3-ethoxyphenyl) -Piperazine (VI) was obtained following the general procedure of < RTI ID = 0.0 > 1- [2- (6-Bromoisopropan- Using an ethyl acetate gradient from 40% to 50% in hexanes, Rf = 0.30 (50% ethyl acetate / hexanes); HRMS calcd for C 23 H 29 N 2 O 2 Br 1 = 444.1413, found = 444.1400. Step 3: Preparation of 1- [2- [4- (3-ethoxyphenyl) -1-piperazinyl] ethyl] isochroman- The general procedure of Example 36 was followed without significant changes except using 1- [2- (6-bromoisoxyman-1-yl) -ethyl] -4- (3-ethoxyphenyl) piperazine (VI) Thus, 1- [2- [4- (3-ethoxyphenyl) -piperazinyl] ethyl] isochroman-6-carboxamide VII is obtained, mp = 208-210 ° C; Rf = 0.14 (10% methanol / ethyl acetate); HRMS calculated for C 24 H 31 N 3 O 3 = 409.2365, found = 409.2364. [Example 44] (S) - ((4-methoxyphenyl) -1-piperazinyl] ethyl] -N-methylisochroman-6-carboxamide IX) Step 1: Preparation of (S) - (-) - 1- [2- (6-bromoisocroman-1-yl) acetyl] -4- (4- methoxyphenyl) ) The crude product was provided according to the general procedure of Example 1, step 3, with no significant changes except using 4-methoxyphenylpiperidine (421 mg, 2.2 mmol), which was purified by chromatography on silica gel (53 g, 230-400) Eluting with acetate / hexane and purification by LC to give (S) - (-) - l- [2- (6-bromoisocroman- l-yl) -acetyl] -4- (4-methoxyphenyl) (S) - (V), Rf = 0.26 (50% ethyl acetate / hexanes); [[alpha]] D = -86 [deg.] (c = 0.4975, methanol); Step 2: (S) - (-) - 1- [2- (6-Bromoisopropan-l-yl) -ethyl] -4- (4- methoxyphenyl) VI) (S) - (-) - 1- [2- (6-bromoisocroman-1-yl) -acetyl] -4- (4- methoxyphenyl) piperidine To give the product following the general procedure of Example 1, step 4 and purification by LC eluting with 47% (230-400) of silica gel with 75% ethyl acetate / hexane to yield (S) - (S) - (VI), R f < RTI ID = 0.0 > = 0.28 (75% ethyl acetate / hexanes); [[alpha]] D = -46 [deg.] (c = 0.6677, methanol); HRMS (EI) calcd for C 23 H 28 BrNO 2 = 429.1304, found = 429.1286. Step 3: (S) - (-) - 1- [2- [4- (4-Methoxyphenyl) -1- piperazinyl] ethyl] -N- methylisochroman-6- carboxamide ) - (IX) (S) - (VI, 445mg, < RTI ID = 0.0 > 1.03 mmol), the product was obtained according to the general procedure of example 5, step 3 and was purified by LC, eluting with 24% (230-400) of silica gel on 75% acetone / hexanes to give (S) - ((4-methoxyphenyl) -1-piperazinyl] ethyl] -N-methylisochroman-6-carboxamide IX), R f = 0.36 (75% acetone / hexanes); HRMS (EI) for C 25 H 32 N 2 O 3 calculated = 408.2413, observed = 408.2414. [Example 45] (S) - (-) - 1- [2- [4- (4-Trifluoromethylphenyl) -1-piperazinyl] ethyl] -N, N- dimethylisochroman-6- carboxamide ) - (IX) (S) - (VI), (S) - (-) - 1- [2- (6-Bromoisocroman-1-yl) -ethyl] -4- (4- trifluoromethylphenyl) -piperazine Example 5, step 2, 21.17 g, 45.1 mmol) provided the product according to the general procedure of example 6, step 4, with no significant change except using 3-5% (S) - (-) - 1- [2- [4- (4-Trifluoromethylphenyl) -1-piperazinyl] ethyl] -N, N-dimethylcarbamoylmethyl- Dimethyl isochroman-carboxamide (S) - (IX), melting point = 149-115 DEG C; Rf = 0.43 (5% methanol / dichloromethane); [[alpha]] D = -46 [deg.] (c = 0.988, methanol); [Example 46] Ethyl] piperazine (P-2) was obtained in the same manner as in [1- (4-methoxyphenyl) -4- A 25 ml oven-dried flask equipped with a stir bar and reflux condenser was charged with 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] Carboxamide (IX, Example 28, 433 mg, 1.0 mmol) and mercury acetate (19 mg, 0.06 mmol). The mixture is diluted with 12 mL of acetic acid and heated under reflux. After 3 hours, the reaction is cooled to 20-25 < 0 > C, the volatiles are removed under reduced pressure, the residue is diluted with 35 mL of 1 M sodium hydroxide and extracted twice with ethyl acetate (30 mL). The combined organic extracts are washed once with brine (20 ml), dried over magnesium sulfate, filtered and concentrated. This material was combined with crude material from the same 0.25 mmol scale reaction and purified by LC eluting with 41 g (230-400) of silica gel with 25% acetone / hexane to give 1- (4-methoxyphenyl) Yl) ethyl] piperazine (P-2) which is recrystallized from ethyl acetate / hexanes to give the title compound as a white amorphous solid, = 129 to 130 캜; Rf = 0.40 (50% acetone / hexanes); [Example 47] (Z-1) < RTI ID = 0.0 > 1- [2- (6-aminoisochroman- To a 10 mL oven-dried, two necked round bottom flask under argon atmosphere was added 1- [2- (6-bromoisochroman-1-yl) -ethyl] -4- (4- methoxyphenyl) Piperazine (VI, 406 mg, 0.94 mmol). The mixture is cooled to -78 [deg.] C and tert-butyllithium (1.7 M in pentane, 1.081 ml, 1.83 mmol) is added dropwise. After stirring at -78 [deg.] C for 15 min, aryllithium was added via cannula to a solution of diphenylphosphoryl azide (98%, 0.188 ml, 0.85 mmol) in THF (9 ml) at -78 < The reaction mixture is maintained at -78 [deg.] C for 2 h, then is warmed to -20 [deg.] C over 40 min and cooled again to -78 [deg.] C. Sodium bis (2-methoxyethoxy) aluminum hydride (3.4 M in toluene, 1.11 ml, 3.77 mmol) is slowly added via syringe. When the reaction was heated to 0 ° C, effervescence of nitrogen was observed. The reaction mixture is stirred at 0 < 0 > C for 2 hours and at 20-25 [deg.] C for 30 minutes. After cooling to 0 ° C, the reaction is quenched very slowly into water. After the boil settled, the crude material was warmed to 20-25 ° C and filtered over a glass frit until no more product was observed by TLC in the filtrate, otherwise washed with water and ethyl acetate do. The combined filtrates are transferred to a separatory funnel, salted out with sodium chloride, stirred, and the layers are separated. The organic layer is washed once with 1% aqueous sodium hydroxide, once with brine, dried over sodium sulfate, filtered and concentrated. After two flash chromatographies on 20 g of silica gel using 5% methanol / methylene chloride as eluent, a mixture of 1- [2- (6-aminoisochroman-1-yl) -Methoxyphenyl) piperazine (Z-1), R f = 0.18 (5% methanol / methylene chloride); HRMS calculated for C 22 H 29 N 3 O 3 = 367.2260, observed = 367.2255. [Example 48] (S) - (Z-1) - (4-methoxyphenyl) (S) - (VI) was used instead of (S) - (-) - 1- [2- (6-bromoisocroman-1- yl) -ethyl] -4- (4- methoxyphenyl) piperazine (S) - (-) - 1- [2- (6-aminoisochroman-1-yl) -ethyl] -4- (4-methoxy Phenyl) piperazine (S) - (Z-1), Rf = 0.18 (5% methanol / methylene chloride); [ ] D = -53 (c = 1.04, ethanol); HRMS calculated for C 22 H 29 N 3 O 2 = 367.2260, observed = 367.2258. [Example 49] (S) - (-) - N- [isochroman-1- [2- [4- (4- methoxyphenyl) piperazin- 1- yl] ethyl] (Z-2) Acetic anhydride (0.32 mL, 3.43 mmol) is cooled to 0 < 0 > C. 98% formic acid (0.20 ml, 5.2 mmol) is added dropwise to acetic anhydride to form acetic formic anhydride. The mixture is heated to 55 < 0 > C for 2 hours and cooled to 0 < 0 > C. THF (2 ml) was added via syringe followed by the addition of (S) - (-) - 1- [2- (6- aminoisochroman- (S) - (Z-1, 600 mg, 1.63 mmol) is added to a solution of (4-methoxyphenyl) piperazine. The reaction is warmed to 20-250 < 0 > C and stirred for 3 hours. The reaction was concentrated and flash chromatographed to give (S) - (-) - N- [isochroman-1- [2- [4- (4- methoxyphenyl) piperazin- (S) - (Z-2), R f = 0.20 (5% methanol / methylene chloride); HRMS calculated for C 23 H 29 N 3 O 3 = 395.2209, observed = 395.2210. [Example 50] (S) - (-) - N- isochroman-1- [2- [4- (4- methoxyphenyl) piperazin- 1 -yl] ethyl] (Z-2) To a 25 ml round bottom flask was added (S) - (-) - 1- [2- (6-aminoisochroman-1-yl) -ethyl] -4- (4- methoxyphenyl) piperazine (Z-1, 200 mg, 0.54 mmol) and 4-dimethylaminopyridine (6.7 mg, 0.054 mmol). Methylene chloride (7 ml) is added via syringe and the reaction vessel is cooled to 0 < 0 > C. Triethylamine (0.114 mL, 0.82 mmol) and acetyl chloride (0.042 mL, 0.60 mmol) were then added via syringe, respectively. The ice bath is removed after 15 minutes and the reaction is stirred at 20 to 25 [deg.] C for 1.5 hours. The reaction is then partitioned between 0.5 M aqueous sodium hydroxide and methylene chloride. The layers are separated and the aqueous portion is extracted once more with methylene chloride. Combine the organic layers, dry with sodium sulfate, filter and concentrate. The concentrate was chromatographed on 17 g of silica gel using 5% methanol in methylene chloride as eluent to give (S) - (-) - N- [isochroman- 1- [2- [4- (4-methoxyphenyl ) Piperazin-1-yl] ethyl] -6- yl] acetamide (S) - (Z-2), R f = 0.18 (5% methanol / methylene chloride); [[alpha]] D = -44 [deg.] (c = 0.93, 50% ethanol / methylene chloride); HRMS calculated for C 24 H 31 N 3 O 3 = 409.2365, found = 409.2358. [Example 51] (S) - (-) - N- isochroman-1- [2- [4- (4- methoxyphenyl) piperazin- 1 -yl] ethyl] (Z-2) (S) - (-) - N- [isochroman-1- [2- [4- (4-methoxyphenyl) piperazin-1-ylmethyl] Yl] ethyl] -6-yl] benzamide (S) - (Z-2), R f = 0.30 (methanol / methylene chloride); [ ] D = -40 (c = 1.0, 50% ethanol / methylene chloride); HRMS calculated for C 29 H 33 N 3 O 3 = 471.2522, found = 471.2525. [Example 52] (S) - (-) - N- isochroman-1- [2- [4- (4- methoxyphenyl) piperazin- 1 -yl] ethyl] (Z-2) (S) - (-) - N- [isochroman-1- [2- [4- (4-methoxyphenyl) Yl] ethyl] -6-yl] propionamide (S) (Z-2), R f = 0.22 (5% methanol / methylene chloride); [[alpha]] D = -44 [deg.] (c = 0.97, 50% ethanol / methylene chloride); [Example 53] (S) - (-) - N- isochroman-1- [2- [4- (4- methoxyphenyl) piperazin- 1 -yl] ethyl] (Z-2) (S) - (-) - N- [isochroman-1- [2- [4- (4-methoxyphenyl) piperazine Yl] ethyl] -6- yl] acrylamide (S) (Z-2), R f = 0.22 (5% methanol / methylene chloride); [ ] D = -40 (c = 0.79, 50% ethanol / methylene chloride); C 25 H 31 * HRMS calculated for N 3 O 3 = 421.2365, observed = 421.2358. [Example 54] (S) - (-) - N- [isochroman-1- [2- [4- (4- methoxyphenyl) piperazin- 1 -yl] ethyl] - (Z-2) (-) - N- [isochroman-1- [2- [4- (4-methoxyphenyl) Phenyl) piperazin-1-yl] ethyl] -6-yl] isobutyramide (S) (Z-2), R f = 0.27 (5% methanol / methylene chloride); [ ] D = -42 (c = 0.94, 50% ethanol / methylene chloride); HRMS calculated for C 26 H 35 N 3 O 3 = 437.2678, found = 437.2680. [Example 55] (S) - (Z-4) - (4-methoxyphenyl) piperazin- (S) - (-) - N- [isochroman-1- [2- [4- (4- methoxyphenyl) piperazin- 1 -yl] ethyl] (S) - (-) - 1- [2- (6-ethylaminoisoquinoline-2-carbaldehyde) was prepared following the general procedure of Example 5, step 2, Yl) -ethyl] -4- (4-methoxyphenyl) piperazine (S) (Z-4), R f = 0.32 (5% methanol / methylene chloride); [[alpha]] D = -46 [deg.] (c = 0.54, 50% ethanol / methylene chloride); HRMS calculated for C 24 H 33 N 3 O 2 = 395.2573, found = 395.2573. [Example 56] (S) (Z-4) (S) - (-) - 1- (4-methoxyphenyl) -4- [2- (S) - (-) - N- [isochroman-1- [2- [4- (4- methoxyphenyl) piperazin- 1 -yl] ethyl] (S) - (-) - l- (4-methoxyphenyl) -4- (4-methoxyphenyl) -4-piperidinone Following the general procedure of Example 5, step 2, Ethyl] piperazine (S) - (Z-4), R f = 0.52 (50% acetone / hexanes); [[alpha]] D = -41 [deg.] (c = 0.69, 50% ethanol / methylene chloride); HRMS calculated for C 25 H 35 N 3 O 2 = 409.2729, observed = 409.2722. [Example 57] (S) - (Z-4) (S) - (-) - 1- (4-methoxyphenyl) -4- [2- Acetic anhydride (0.32 mL, 3.43 mmol) is cooled to 0 < 0 > C. 98% formic acid (0.20 ml, 5.2 mmol) was added dropwise to acetic anhydride to yield acetic anhydride form. The mixture is heated to 55 [deg.] C for 2 hours and cooled to -15 [deg.] C using an ethylene glycol / carbon dioxide bath. THF (10 ml) was added via syringe followed by the addition of (S) - (-) - l- [2- (6-aminoisochroman- (S) - (Z-1, Example 48, 1.99 g, 5.41 mmol) was added to a solution of (4-methoxyphenyl) The reaction is stirred for 2 h at -15 < 0 > C. The reaction is warmed to 20-25 < 0 > C and the volatiles are removed under reduced pressure to give a yellow oil. A solution of the crude material in THF (30 mL) is placed in a 250 mL round bottom flask equipped with a reflux condenser. The mixture is cooled to 0 < 0 > C and borane methyl sulfite complex (10M, 1.73 ml, 17.3 mmol) is slowly added via syringe. If the boiling sinks, remove the ice bath. The mixture is heated again to reflux for 3 hours and then left at 20 to 25 [deg.] C for 3 days. The reaction is cooled to 0 占 폚, methanol (30 ml) is added dropwise (boiling) and stirred at 20 25 占 폚 for 1 hour and then refluxed for 2 hours. After cooling to 20-25 < 0 > C, volatiles are removed under reduced pressure, the aqueous residue is basified with aqueous sodium hydroxide and extracted with 80 ml of ethyl acetate (3 times). The organic extracts are combined, dried over sodium sulfate, filtered and concentrated to give the crude product. The crude material was purified by flash chromatography using 25% acetone / hexane as eluent to give (S) - (-) - l- (4-methoxyphenyl) -4- [2- (6-methylaminoisochromane -1-yl) ethyl] piperazine (S) - (Z-2) HRMS calculated for C 23 H 31 N 3 O 2 = 381.2416, found = 381.2415. [Example 58] (S) - (Z-7) (S) - (-) - 1- (4-methoxyphenyl) -4- [2- The title compound was obtained from (S) - (-) - 1- (4-methoxyphenyl) -4- [2- (6-dimethylaminoisochroman- (S) - (Z-7), R f = 0.22 (acetone / hexane, 25/75); [Example 59] (S) - (-) - (2- (6-ethylmethylaminoisochroman-1-yl) 7) Further, from the production method described in Example 57, (S) - (-) - 1- [2- (6-ethylmethylaminoisochroman-1-yl) -ethyl] -4- ) Piperazine (S) - (Z-7), R f = 0.22 (acetone / hexane, 25/75); [ ] D = -54 (c = 0.83, ethanol / methylene chloride); [Example 60] (S) - (-) - N- [isochroman-1- [2- [4- (4-methoxyphenyl) piperazin- 1- yl] ethyl] (S) - (Z-5) (S) - (Z-4) was obtained as a colorless oil from (S) - (-) - (4-methoxyphenyl) -4- [2- (6-methylaminoisochroman- Following the general procedure of Example 50, but without significant changes except use, the title compound is obtained, R f = 0.26 (methanol / methylene chloride, 5/95); [[alpha]] D = -38 [deg.] (c = 0.69, ethanol / methylene chloride (50/50); [Example 61] (S) - (-) - N- isochroman-1- [2- [4- (4- methoxyphenyl) piperazin- 1- yl] ethyl] Amide (S) - (Z-5) (S) - (Z-4) - (-) - 1- (4- methoxyphenyl) -4- [2- (6-methylaminoisochroman- ) - N - [isochroman-1- [2- [4- (4-methoxyphenyl) piperazine < Yl] ethyl] -6-yl] -N-methylisobutyramide (S) - (Z-5), Rf = 0.33 (5% methanol / methylene chloride); [[alpha]] D = -34 [deg.] (c = 0.88, 50% ethanol / methylene chloride); HRMS calcd for C 27 H 37 N 3 O 3 = 451.2835, found = 451.2827. [Example 62] (S) - (-) - N- isochroman-1- [2- [4- (4- methoxyphenyl) piperazin- 1 -yl] ethyl] -6- yl] -methanesulfonamide ) - (Z-3) (S) - (Z-1) - (4-methoxyphenyl) -piperazine (200 mg, 0.54 mmol) and 4-dimethylaminopyridine (6.7 mg, 0.054 mmol). Pyridine (2 ml) is added via syringe, the mixture is cooled to 0 C and methanesulfonyl chloride (0.045 ml, 0.60 mmol) is introduced. The ice bath is removed after 15 minutes and the reaction is stirred at 20 to 25 [deg.] C for 1.5 hours. The reaction is diluted with water and extracted twice with ethyl acetate. The organic layers are combined, washed once with a saturated aqueous solution of sulfuric acid, washed with water, dried over magnesium sulfate, filtered and concentrated. The concentrate was chromatographed on 25 g of silica gel using 50% acetone / hexane as eluent to give (S) - (-) - N- [isochroman- 1- [2- [4- (4-methoxyphenyl) Yl] ethyl] -6-yl] methanesulfonamide (S) - (Z-3), R f = 0.21 (5% methanol / methylene chloride); [ ] D = -43 ° (c = 0.89, 50% ethanol / methylene chloride); C 23 H 31 N 3 O 4 HRMS calculated for S 1 = 445.2035, observed = 445.2031. [Example 63] (S) - (X) - (S) - (-) - 6- amino-1- [2- [4- 6) (S) - (Z-1) - (4-methoxyphenyl) -piperazine (376 mg, 1.0 mmol) is added to acetonitrile (4 mL). Methyl isocyanate (0.091 ml, 1.53 mmol) is slowly added via syringe. Additional acetonitrile (7 ml) is added and the reaction is stirred at 20-25 [deg.] C for 3 h. The precipitate was filtered and washed successively with ethyl acetate and hexane to give the crude product which was purified by flash chromatography using 5% methanol / methylene chloride to give (S) - (-) - 6- (S) - (X-6), R f = 0.07 (5% methanol, / Methylene chloride); [[alpha]] D = -43 [deg.] (c = 0.75, 50% ethanol / methylene chloride); HRMS calculated for C 24 H 32 N 4 O 3 = 424.2474, found = 42473. [Example 64] Ethyl] isochroman, tert-butyl carbamate (S) - (-) - 6-Amino-1- [2- [4- (4- methoxyphenyl) piperazin- (X-6) (S) - (Z-1) - (4-methoxyphenyl) -piperazine (200 mg, 0.54 mmol) and sodium hexamethyldisilazane (200 mg, 1.09 mmol). THF (2 mL) is added via syringe and the reaction is stirred for 15 minutes. Di-tert-butyl pyrocarbonate (108 mg, 0.50 mmol) was added as a solution in THF (2 mL). The mixture is stirred at 20-25 < 0 > C for 20 hours. Pour the reaction into water (40 mL). The volatiles are removed under reduced pressure and the aqueous residue is extracted with ethyl acetate (2 x 50 mL). Combine the organic layers, dry with sodium sulfate, filter and concentrate. The concentrate was chromatographed on 30 g of silica gel using 5% methanol / methylene chloride as eluent to give (S) - (-) - 6-amino-1- [2- [4- (4-methoxyphenyl) -1-yl] ethyl] isochromane, tert-butyl carbamate (S) - (X-6), R f = 0.38 (5% methanol / methylene chloride); [ ] D = -39 (c = 0.65, 50% ethanol / methylene chloride); [Example 65] Ethyl] piperazine (BB-2) was obtained in the same manner as in [1- (4-methoxyphenyl) -4- A significant change was made except that 1- [2- [4- (4-methoxyphenyl) -piperazinyl] ethyl] -N-methyl-isochroman-6- carboxamide (IX, Following the general procedure of example 1, step 4, without isolation, the crude product is obtained. This material was purified by LC eluting with 13% (230-400) of silica gel using 5% 3M ammonia in methanol / dichloromethane to give 1- (4-methoxyphenyl) -4- [2- Aminomethylisochroman-1-yl) ethyl] piperazine (BB-2), melting point = 74-76 占 폚; R f = 0.36 (5% 3M NH 3 in methanol / dichloromethane); HRMS (EI) calculated for C 24 H 33 N 3 O 2 = 395.2573, found = 395.2573. [Example 66] Ethyl] piperazine (BB-2) was obtained in the same manner as in [1- (4-methoxyphenyl) -4- [2- (6-dimethylaminomethylisochroman- Except that 1 - [2- [4- (4-methoxyphenyl) -l-piperazinyl] ethyl] -N, N- dimethylisochroman-6- carboxamide (IX, The crude product was obtained following the general procedure of Example 1, step 4, with no significant change, which was eluted with 100% dichloromethane on 13 g (230-400) of silica gel and gradually eluted with 5% 3M ammonia in methanol / dichloromethane Ethyl) piperazine (BB-2) was prepared by reacting 1- (4-methoxyphenyl) -4- [2- (6- dimethylaminomethylisochroman- Melting point = 95 to 98 占 폚; Rf = 0.33 (5% 3M ammonia in methanol / dichloromethane); C 25 H 35 N HRMS (EI ) for 3 O 2 calculated = 409.2729, observed = 409.2733. [Example 67] 1-piperazinyl] ethyl] isochroman-6-carboxylic acid, ethyl ester (X) A 10 ml oven-dried flask equipped with a stir bar, reflux condenser and a 3-way adapter was charged with 1- [2- (6-bromoisocroman-1-yl) (II) (11 mg, 0.05 mmol), 1,3-bis (diphenylphosphino) -piperazine (VI, Example 24, step 2, 431 mg, 1.0 mmol) Propanol (25 mg, 0.06 mmol), 2.5 mL of dimethylformamide, diisopropylethylamine (0.35 mL, 2.0 mmol) and ethanol (1.2 mL, 20 mmol). The resulting mixture is reduced in pressure to carbon monoxide and purified six times and heated to 100 < 0 > C. After 18 hours, the mixture is cooled to 20-25 < 0 > C, concentrated under high vacuum, diluted with 20 mL of 1 M sodium hydroxide and extracted twice with ethyl acetate (20 mL). The combined organics were washed once with chlorine (20 ml), dried over magnesium sulfate, filtered and concentrated to give the product. This material was purified by LC eluting with 22 g (230-400) of silica gel with 30% acetone / hexane to give 1- [2- [4- (4- methoxyphenyl) -1- piperazinyl] ethyl] 6-carboxylic acid, ethyl ester (X), melting point = 117-19 < 0 >C; Rf = 0.45 (35% acetone / hexane); [Example 68] Ethyl] isochroman, hydrochloride salt (XXIV), < RTI ID = 0.0 > (10 ml) was added to an oven-dried 10 ml flask equipped with a mechanical stirrer and a reflux condenser was added 1- [2- (6-bromoisochroman-1-yl) -ethyl] -4- (4- methoxyphenyl) (II) (11 mg, 0.05 mmol), 1,3-bis (diphenylphosphino) propane (25 mg, 0.06 mmol), thallium acetate (II) (290 mg, 1.1 mmol), 3.0 ml of dimethylformamide, triethylamine (0.28 ml, 2.0 mmol) and vinyl butyl ether (0.65 ml, 5.0 mmol). The mixture is heated to 100 < 0 > C and after 20 h the mixture is cooled to 20-25 [deg.] C, treated with hydrochloric acid (IM, 6 ml) and stirred for 1 h. The mixture is concentrated under high vacuum, diluted with 20 mL of 5 M sodium hydroxide, and extracted twice with ethyl acetate (20 mL). The combined organics are washed once with brine (20 ml), dried over magnesium sulfate, filtered and concentrated. This material is purified on an LC eluting with 27 g (230-400) of silica gel with 25% acetone / hexane. This material was dissolved in a mixture of ethyl acetate / methanol and treated with gaseous hydrochloric acid to form a solid which was recrystallized from ethyl acetate / methanol to give 6-acetyl-1- [2- [4- (4-methoxyphenyl ) 1-piperazinyl] ethyl] -isochromane, hydrochloride salt (XXIV), melting point = 195-197 ° C; Rf = 0.15 (30% acetone / hexane); This salt HRMS (EI) calculated for C 24 H 30 N 2 O 3 = 394.2256, found = 394.2262. [Example 69] 1-piperazinyl] ethyl] isochroman (AA-1), < RTI ID = 0.0 & (VI, Example 24, step 2, 2.80 g, 6.5 mmol) and l- (2-methoxyphenyl) (16 ml) and cooled to -78 < 0 > C. The mixture is treated with a 1.7 M solution of tert-butyllithium (7.7 mL, 13.0 mmol). After 15 minutes, the aryllithium is treated with dimethylformamide (1.0 mL, 13 mmol). The reaction was warmed to 20.degree. To 25.degree. C. over 1.5 hours, then diluted with 75 mL of water and extracted twice with ethyl acetate (75 mL). The combined organics were washed once with brine (50 mL), dried over magnesium sulfate, filtered and concentrated to give a crude product. This material was purified by LC eluting with 160 g (230-400) of silica gel with 30% acetone / hexane to give 6-formyl-1- [2- [4- (4- methoxyphenyl) ] Ethyl] -isochromane (AA-1-), R f = 0.28 (30% acetone / hexanes); C 23 H 28 HRMS (EI) for N 2 O 3 calculated = 380.2100, observed = 380.2098. [Example 70] 4-methoxyphenyl) piperazin-1-yl] ethyl-1-yl] acetamide (AA- Step 1: Preparation of 1- [2- (6-hydroxymethylisochroman-1-yl) -ethyl] -4- (4-methoxyphenyl) piperazine (AA- Ethyl] isochroman (AA-1, Example 71, 2.51 g, 6.6 mmol) and 25 mL of a solution of 6-formyl-1- [2- [4- (4- methoxyphenyl) piperazin- The methanol is mixed and cooled to 0 占 폚. The mixture is treated with portions of sodium borohydride (500 mg, 13.2 mmol). The reaction is gradually warmed to 20-25 ° C over 2 hours, diluted with 75 mL of water and extracted twice with ethyl acetate (75 mL). The combined organics are washed once with brine (50 mL), dried over magnesium sulfate, filtered and concentrated. This material was purified by LC eluting with methanol / dichloromethane (5/95) on 130 g (230-400) of silica gel to give 1- [2- (6-hydroxymethylisochroman- ] -4- (4-methoxyphenyl) piperazine (AA-2), R f = 0.15 (35% acetone / hexanes); Step 2: Preparation of 1- [2- (6-cyanomethylisochroman-1-yl) -ethyl] -4- (4-methoxyphenyl) piperazine (AA- (AA-2, 2.33 g, 6.1 mmol), 61 mL of dichloro < RTI ID = 0.0 > Methane and triethylamine (1.3 mL, 9.1 mmol) were mixed and cooled to 0 < 0 > C. The mixture is treated with methanesulfonyl chloride (0.52 mmol, 6.7 mmol). The reaction is warmed to 20-25 < 0 > C over 1.5 h and concentrated under reduced pressure. The crude mesylate is diluted with 31 mL of dimethylsulfoxide and treated with sodium cyanide (896 mg, 18.3 mmol). The mixture is heated to 60 < 0 > C. After 2 hours, the volatiles were removed under high vacuum and the resulting residue was diluted with 100 mL of water and extracted twice with ethyl acetate (75 mL). The combined organics are washed once with brine (75 ml), dried over magnesium sulfate, filtered and concentrated. This material was purified by LC eluting with 88 g (230-400) of silica gel with 35% acetone / hexane to give 1- [2- (6-cyanomethylisochroman-1-yl) - (4-methoxyphenyl) piperazine (AA-3), melting point = 118-119 DEG C; Rf = 0.36 (35% acetone / hexane); Step 3: Preparation of 2- [isochroman-1- [2- [4- (4-methoxyphenyl) piperazin- 1 -yl] ethyl- (AA-3, 785 mg, 2.0 mmol), 5.0 mL of dimethylformamide (2 mL) and 1-methyl-2- Amide and potassium carbonate (39 mg, 0.28 mmol). The mixture is treated with 30% hydrogen peroxide solution (0.24 mL, 2.3 mmol). After 20 hours, the reaction is diluted with 100 mL of dichloromethane, washed once with water (20 mL), once with brine (20 mL), dried over magnesium sulfate, filtered and concentrated. This material was recrystallized from ethyl acetate / hexane to give 2- [isochroman-1- [2- [4- (4-methoxyphenyl) piperazin- 1 -yl] ethyl- -4), melting point = 159-161 C; Rf = 0.15 (5% methanol / dichloromethane); [Example 71] 5-yl] -N-methylacetamide (AA-5) was obtained in the same manner as in [ Yl] ethyl] -6-yl] acetamide (AA-4, 446 mg, 1.09 mmol) was used as a starting material in place of 2- [4- The crude product is obtained according to the general procedure of Example 3, Step 1, with no significant changes. This material was purified by LC over 40 g (230-400) of silica gel eluting with 50% ethyl acetate / hexane to give 2- [isochroman-1- [2- [4- (4- methoxyphenyl) piperazine Yl] ethyl] -6-yl] -N, N-di-tert-butyloxycarbonylacetamide, Rf = 0.45 (60% ethyl acetate / hexanes). This material was reacted with methylamine according to the general procedure of example 3, step 2, with no significant change to give the desired product which was purified by LC (silica gel, eluting with 60% acetone / hexane over 13 g (AA-5) was reacted with 2- [4- (4-methoxyphenyl) piperazin-1-yl] ethyl] Melting point = 147-148 占 폚, Rf = 0.20 (50% acetone / hexane); [Example 72] (CC-2), < RTI ID = 0.0 > 1- [2- [4- (4- hydroxyphenyl) -piperazinyl] ethyl] -isochroman- 1-piperazinyl] ethyl] isochroman-6-carboxamide (CC-1, Example 9, 0.42 mmol, 200 mg), carbon phase Palladium (10%, 20 mg), ethanol (5 ml) and methylene chloride (2 ml) are combined. After 4 days, the starting material is consumed. The reaction mixture is filtered on a celite layer and washed several times with ethanol, methanol, methylene chloride and ethyl acetate. The filtrates are combined and concentrated. The crude material was recrystallized from hot ethanol containing methanol to give 1- [2- [4- (4-hydroxyphenyl) -1-piperazinyl] ethyl] isochroman-6- carboxamide (CC- 2), < / RTI > HRMS calculated for C 22 H 27 O 3 = 382.2131, found = 382.2136. [Example 73] (S) - (-) - 1- [2- [4- (4-hydroxyphenyl) -1- piperazinyl] ethyl] -N- methylisochroman- To a Parr flask was added (S) - (-) - 1- [2- [4- (4-phenylmethyloxyphenyl) -1- piperazinyl] ethyl] -N- methylisochroman- 50 mg of methanol, 25 ml of tetrahydrofuran and 10% palladium-on-carbon (200 mg) are added to the reaction mixture. The resulting black suspension is placed under 40 psi hydrogen and vortexed. After 60 hours, the pressure is reduced to 27 psi of hydrogen and the reaction mixture is filtered through celite and concentrated. The concentrate was recrystallized from methanol / ethyl acetate to give (S) - (-) - 1- [2- [4- (4- hydroxyphenyl) -1- piperazinyl] ethyl] Carboxamide (S) - (CC-2), melting point = 154 to 162 캜, Rf = 0.11 (5% methanol / ethyl acetate); [ ] D = -53 (c = 0.9681, methanol); HRMS (EI) calculated for C 23 H 29 N 3 O 3 = 395.2209, found = 395.2212. KF water = 4.28%. [Example 74] (S) - (-) - 1- [2- [4- (4-Trifluoromethanesulfonyloxyphenyl) -1- piperazinyl] ethyl] -N- methyl-isochroman- Amide (S) - (CC-3) (S) - (-) - 1- [2- [4- (4-hydroxyphenyl) -1-piperazinyl] ethyl] (CC-2, 959 mg, 2.4 mmol), 24 mL of dichloromethane and N-phenyltrifluoromethane-sulfonimide (910 mg, 2.5 mmol). The mixture was cooled to 0 < 0 > C and treated with triethylamine (0.51 mL, 3.6 mmol), with no visible changes occurring. After 16 hours, the mixture is diluted with 75 mL of 1M sodium hydroxide and extracted twice with dichloromethane (75 mL). The combined organics were washed once with brine (50 mL), dried over magnesium sulfate, filtered and concentrated. This material was purified by LC eluting with 88 g (230-400) of silica gel with 5% methanol / dichloromethane to give (S) - (-) - 1- [2- [4- (4- (CC-3), R f = 0.34 (5% methanol / dichloromethane) to give the title compound Methane); [[alpha]] D = -39 [deg.] (c = 0.9447, methanol); HRMS (FAB) calcd for C 24 H 28 F 3 N 3 O 3 S + H 1 = 528.1780, found = 528.1791. [Example 75] (S) - (IX) (S) - (-) - 1- [2- [4- ) (S) - (-) - 1- [2- [4- (4-trifluoromethanesulfonyloxyphenyl) -1- piperazinyl] ethyl] -N- methylisochroman-6- carboxamide (S) - (CC-3, 527 mg, 1.0 mmol), Palladium (II) acetate (11 mg, 0.05 mmol), 1,3-bis (diphenylphosphino) propane (25 mg, 0.06 mmol) Dimethylformamide, triethylamine (0.28 mL, 2.0 mmol) and butyl vinyl ether (0.65 mL, 5.0 mmol) are combined. The resulting mixture is heated to 50 < 0 > C. After 16 hours, the reaction is cooled to 20-25 < 0 > C, treated with 8 mL of 1M hydrochloric acid and stirred for 1 hour. The acidic mixture is concentrated under reduced pressure, diluted with 15 ml of 1M sodium hydroxide and extracted twice with dichloromethane (25 ml). The combined organics were washed with brine (15 mL), dried over magnesium sulfate, filtered and concentrated. This material was purified by LC, eluting with 50% acetone / hexane over 36 g (230-400) of silica gel and recrystallized from ethyl acetate / hexane to give (S) - (-) - 1- 2- 4- - (4-acetylphenyl) -1-piperazinyl] ethyl] -N-methylisochroman-6-carboxamide (S) f = 0.20 (50% acetone / hexane); [[alpha]] D = -41 [deg.] (c = 0.8481, methanol); C 25 H 31 N 3 O 3 HRMS (EI) calculated for = 421.2365, observed = 421.2365. [Example 76] (S) - (-) - 3- [isochroman-1- [2- [4- (4-methoxyphenyl) piperazin- 1 -yl] ethyl] Acrylamide (S) - (XVIII) (S) - (VI) (431.4 < RTI ID = 0.0 > (4-Methoxyphenyl) mg, 1.0 mmol), palladium (II) acetate (98%, 11.4 mg, 0.05 mmol) and 1,3-bis-diphenylphosphinopropane (97%, 24.6 mg, 0.06 mmol). Thereby forming an argon atmosphere. DMF (4.1 ml), dimethyl acrylamide (0.72 ml, 7.0 mmol) and diisopropylethylamine (0.35 ml, 2.0 mmol) were introduced into the reaction vessel via a syringe. The mixture is heated to 100 < 0 > C over 18 h. After cooling to 20-25 < 0 > C, the reaction is diluted with aqueous sodium hydroxide and extracted three times with ethyl acetate. Organics are compounded and concentrated. The residual DMF is removed under high vacuum. The crude material was purified by flash chromatography using 80 g of silica gel with 5% methanol / methylene chloride as eluent to give a solid which was recrystallized from hot ethyl acetate / hexane to give (S) - (-) - 3- (XVIII) was obtained as a white solid from the title compound as a colorless solid. ≪ 1 > H NMR (400 MHz, DMSO-d6) Melting point = 120-121 占 폚, Rf = 0.30 (5% methanol / methylene chloride); [Example 77] (S) - (-) - 1- (4-methoxyphenyl) -4- [2- (6- (1,2,4- triazol- ] Piperazine (S) - (O-2) Step 1: (S) - (-) - 1- [2- [4- (4-Methoxyphenyl) -1- piperazinyl] ethyl] -N- dimethylaminomethylene isochroman- (S) - (O-1) (S) - (VIII, 395.5 mg (S) - (2- (4-methoxyphenyl) -1-piperazinyl] ethyl] isochroman- , 1 mmol) and N, N-dimethylformamide dimethylacetal (94%, 0.34 ml, 2.4 mmol) and toluene (1 ml). The reaction mixture is heated to 90 < 0 > C for 1.5 hours. After cooling to 20 to 25 占 폚, the volatiles are removed under reduced pressure. The crude material was purified by flash chromatography using 90% of silica gel with 5% methanol / methylene chloride as eluent to give (S) - (-) - 1- [2- [4- (4-methoxyphenyl) (S) - (O-1), melting point = 134 to 135.5 占 폚, Rf = 0.28 (5% methanol / Methylene chloride); [[alpha]] D = -47 [deg.] (c = 0.96, 50% methylene chloride / ethanol); Step 2: (S) - (-) - 1- (4-Methoxyphenyl) -4- [2- (6- (1,2,4- triazol- ] Ethyl] piperazine (S) - (O-2) (S) - (-) - 1- [2- [4- (4-methoxyphenyl) -1- piperazinyl] ethyl] -N-dimethylaminomethylene isochroman- - (O-1, 208 mg, 0.46 mmol) and glacial acetic acid (1 mL) are combined under an argon atmosphere. Dihydrate hydrazine (0.045 ml, 0.92 mmol) was added dropwise via syringe under vigorous stirring. And stirred at 20 to 25 占 폚 for 24 hours. The reaction mixture is diluted with water and partitioned between saturated aqueous sodium bicarbonate and methylene chloride. The organics are combined, dried with sodium sulfate, filtered and concentrated. The concentrate was purified by flash chromatography using 6 g of silica gel with 5% methanol / methylene chloride as eluent to give (S) - (-) - 1- (4- methoxyphenyl) -4- [2- Ethyl] piperazine (S) - (O-2), melting point = 195.5-196 ° C, R f = 0.11 (5% methanol / methylene chloride); [Example 78] (S) - (-) - 1- (4-methoxyphenyl) -4- [2- (6-2- Yl] ethyl] piperazine (S) - (O-2) (S) - (-) - 1- (4-methoxyphenyl) -4- [2- (6- (2 -methyl-1,2,4-triazol-3-yl) chroman-isobutyl-1-yl] ethyl] piperazine (S) - to give an (O-2), R f = 0.17 (5% methanol / Methylene chloride); [Example 79] (S) - (-) - 1- (4-methoxyphenyl) -4- [2- (6- Yl] ethyl] piperazine (S) - (O-2) (S) - (-) - 1- (4-methoxyphenyl) -4- [2- (6- ( 3-yl) isochroman-1-yl] ethyl] piperazine (S) - (O-3), R f = 0.28 (5% Methanol / methylene chloride); [Example 80] (S) - (-) - 1- (4-methoxyphenyl) -4- [2- (6- (1,2,4- oxadiazol- Ethyl] piperazine (S) - (O-2) (S) - (-) - l- [2- [4- (4-methoxyphenyl) -1-piperazin- l-yl) (4-fluorophenyl) ethyl] -N-ethyl] -N-dimethylaminomethyleneisochroman-6-carboxamide (S) - (O-1, Example 77, step 1, 450.6 mg, 1.0 mmol) 83.4 mg, 1.2 mmol) is added in one portion. The mixture is stirred at 20 to 25 DEG C for a total of 70 minutes. The reaction is diluted with water and the pH is adjusted to 8 with saturated aqueous sodium bicarbonate. The aqueous mixture is extracted twice with methylene chloride. Combine the organics, dry with sodium sulfate, filter and concentrate. This material (R f = 0.18 (5% methanol / methylene chloride)) is dissolved in a mixture of acetic anhydride (2 ml) and anhydrous p-dioxane (2 ml). An argon atmosphere is established and the reaction is heated to 90 < 0 > C for 2 hours. After cooling to 20-25 < 0 > C, the reaction is diluted with water and the pH is raised to 8 with saturated aqueous sodium bicarbonate. The aqueous mixture is extracted twice with methylene chloride. The organics are combined, dried with sodium sulfate, filtered and concentrated. The concentrate was purified by flash chromatography using 50 g of silica gel with 4% methanol / methylene chloride as eluent to give (S) - (-) - 1- (4- methoxyphenyl) -4- [2- Ethyl] piperazine (S) - (O-2), melting point = 126-127 ° C, Rf = 0.36 (5% methanol / methylene chloride); [Example 81] (S) - (-) - N-methyl-1- [2- [4- (4- propiophenyl) -1- piperazinyl] ethyl] isochroman- IX) Step 1: (S) - (-) - 6-Bromo-1- (2-hydroxyethyl) isochroman (S) (S) - (XI, Example 1, step 2, 16.27 g, 60 mmol) and 100 mL of tetrahydrofuran were added to a stirred solution of (S) - (-) - (6-bromoisocroman- do. This material is treated with 10 M borane methyl sulfide (18.0 mL, 0.18 mol), maintaining a temperature of 20-25 ° C in a water bath. After 1 hour, the mixture is cooled to 0 < 0 > C and slowly quenched with 160 ml of methanol. Note: The introduction period of about 1 to 2 minutes is before the rapid and abrupt generation of hydrogen. The mixture is warmed to 20-25 < 0 > C and the volatiles are removed under reduced pressure. The resulting mixture is diluted with 1 M sodium hydroxide (150 mL) and extracted three times with ethyl acetate (100 mL). The combined organics are washed once with brine (100 mL), dried over magnesium sulfate, filtered and concentrated. This material is recrystallized from ethyl acetate / hexane to give (S) - (-) - 6-bromo-1- (2-hydroxyethyl) isochroman (S) - (S- = 95 to 96 캜, R f = 0.28 (30% acetone / hexane); [[alpha]] D = -107 [deg.] (c = 0.4069, methanol); Step 2: (S) - (-) - 1- (2-Hydroxyethyl) isochroman-6-carboxylic acid, methyl ester (S) (S) - (S) - (-) - 6-bromo-1- (2-hydroxyethyl) isochromane (S) - (S-1, 5.14 g, 20.0 mmol), palladium acetate (49.5 mg, 1.2 mmol), 40.0 mL of dimethylformamide, diisopropylethylamine (10.5 mL, 60.0 mmol) and methanol (16 mL, 0.40 mmol) . The resulting mixture is purged with carbon monoxide 6 times under reduced pressure and heated quickly to 75 占 폚. The reaction mixture is stirred for 19 hours. During this period, the mixture is cooled to 20 to 25 占 폚, diluted with 200 ml of water and extracted twice with dichloromethane (200 ml). The combined organics are washed once with water (100 ml), once with brine (100 ml), dried over magnesium sulfate, filtered and concentrated. This material was purified by LC eluting with 300 g (230-400) of silica gel with 50% ethyl acetate / hexane to give (S) - (-) - 1- (2- hydroxyethyl) isochroman- Carboxylic acid, methyl ester (S) - (S-2), melting point = 56-58 C, Rf = 0.23 (50% ethyl acetate / hexanes); [[alpha]] D = -114 [deg.] (c = 0.8773, methanol); Step 3: (S) - (-) - 1- (2-Hydroxyethyl) -N-methyl isochroman-6-carboxamide (S) (S) - (S-2, 473 mg, 2.0 mmol) and 8.0 mL of 6M methylamine / methanol . The reaction vessel is sealed with a Teflon screw cap and the mixture is heated to 75 ° C. After 20 h, the reaction mixture was cooled to 20-25 ° C, concentrated under reduced pressure and triturated with hexane to give (S) - (-) - 1- (2- hydroxyethyl) Carboxamide (S) - (S-3), melting point = 99-101 ° C, R f = 0.20 (5% methanol / dichloromethane); [ ] D = -119 (c = 0.8674, methanol); Step 4: (S) - (-) - 1- (2-Methanesulfonyloxyethyl) -N-methyl isochroman- (S) - (S-3, 338 mg, 1.6 mmol), 16 ml of dichloro < RTI ID = 0.0 & Methane and triethylamine (0.34 mL, 2.4 mmol) are combined and cooled to 0 < 0 > C. The mixture is treated with methanesulfonyl chloride (0.15 mL, 1.95 mmol). After 15 min, the reaction was washed once with 10 ml of dichloromethane and 15 ml of water, once with 15 ml of brine, dried over magnesium sulfate, filtered and concentrated to give (S) - (-) - 1 - (2-methanesulfonyloxyethyl) -N-methyl-isochroman-6-carboxamide (S) - (T-2), R f = 0.35 (60% acetone / hexanes); Step 5: (S) - (-) - N-methyl-1- [2- [4- (4- propionylphenyl) -1- piperazinyl] ethyl] -isochroman-6- carboxamide S) - (IX) (S) - (T-2, 509 mg, 1.5 mmol), 4 ' (622 mg, 4.5 mmol) in acetonitrile (7.5 ml) was heated at 50 < 0 > C overnight and then further refluxed for 5 hours. The reaction mixture is cooled to 20-25 < 0 > C and concentrated to give a residue which is partitioned between water and dichloromethane. The aqueous layer is extracted twice more with dichloromethane and the combined organic layers are washed once with water, once with brine, dried over magnesium sulfate, filtered and concentrated. This material was purified by LC eluting with 36 g (230-400) of silica gel with 60% acetone / hexane. This material was recrystallized from methanol / ethyl acetate to give (S) - (-) - N-methyl- 1- [2- [4- (4- propionylphenyl) -1- piperazinyl] ethyl) Carboxamide (S) - (IX), melting point = 160-161 ° C, R f = 0.20 (50% acetone / hexane); [Example 82] (S) - (-) - 1- [2- [4- (4-Trifluoroacetylphenyl) -1- piperazinyl] ethyl] -N- methylisochroman- - (IX) The crude product is obtained following the general procedure of example 81, step 5, with little or no significant change except using 4'-piperazinonitrile methyl fluorene (504 mg, 1.95 mmol). This material was purified by LC eluting with 59 g (230-400) of silica gel with 50% acetone / hexane to give (S) - (-) - 1- [2- [4- (4- ) -1-piperazinyl] ethyl] -N-methyl isochroman-6-carboxamide (S) - (IX), R f = 0.20 (60% acetone / hexanes); [Example 83] (IX) < RTI ID = 0.0 > 1- < / RTI > [1- [2- [4- (4-methoxyphenyl) The crude product is obtained following the general procedure of Example 30, with little or no significant change except using pyrrolidine (1.26 ml, 15.0 mmol). This material was purified by flash chromatography using 100 g of silica gel with a gradient of 5-10% methanol / ethyl acetate as eluent to give the purified product. Recrystallization from methylene chloride and hexane gave 1- [1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] -isochroman-6- yl] carbonyl] pyrrolidine (IX), melting point = 156.0 to 156.5 DEG C; Rf = 0.35 (10% methanol / ethyl acetate); [Example 84] (+/-) - 1- [2- (4-phenyl-1-piperidinyl) ethyl] isochroman-6- carboxamide Step 1. (+/-) - 2- (6-Bromoisopropion-1-yl) acetic acid (III, Example 1, step 1; 0.77 g, 2.58 mmol), sodium hydroxide (2N, 1.9 ml) and ethanol (5 ml) ML) is stirred for 75 minutes, at which time the ethanol is removed under reduced pressure. A few millimeters of water is added to the residue and an amount of hydrochloric acid (4N) is added to adjust the pH of the mixture to about 2. The mixture was extracted with ether, and the organic layer was dried over magnesium sulfate and concentrated (+/-) - 2 to give the (bromo feeders soak only 1-yl) acetic acid (IV), NMR (CDCl 3) 2.69-2.97 , 3.83, 4.16, 5.18, 6.94 and 7.32 delta. Step 2. Preparation of (+/-) - 2- (6-bromoisocroman-1-yl) ethyl alcohol Methyl sulfide (0.86 g, 9.1 mmol) was added to (+/-) - 2- (6-bromoisocroman-1-yl) acetic acid (IV, step 1; 0.82 g, 3.0 mmol) in anhydrous THF Mmol). After stirring for 2.5 hours, methanol is added and the mixture is concentrated under reduced pressure. Methanol is again added and the mixture is concentrated more than once. The residue was partitioned between dichloromethane and aqueous sodium bicarbonate and the organic layer was dried over sodium sulfate and concentrated to give (+/-) - 2- (6-bromoisocroman-1-yl) ethyl alcohol (S-1) is obtained, NMR (CDCl 3) 2.0, 2.2, 2.64, 2.69, 3.02, 3.70-3.79, 3.82-3.86, 4.15, 4.92, 7.28δ. Step 3. Preparation of (+/-) - 1- [2- (6-bromoisocroman-1-yl) ethyl] -4-phenylpiperidine (S-1, step 2; 0.599 g, 2.33 mmol), 4 (4-chlorobenzyloxy) Cooled mixture of dimethylaminopyridine (0.016 g, 0.131 mmol), diisopropylethylamine (0.49 ml, 2.81 mmol) and anhydrous THF (7.5 ml). The ice bath is removed and the mixture is warmed to 20-25 < 0 > C. When the mesylation reaction is complete (by TLC), ethylene glycol (2.4 ml), diisopropylethylamine (1.0 ml, 5.7 mmol) and 4-phenylpiperidine (0.452 g, 2.80 mmol) The mixture is heated at 80 < 0 > C overnight. After cooling, the mixture is poured into water and extracted with dichloromethane. The combined organic layers are dried over sodium sulfate and concentrated under reduced pressure. The residue was chromatographed (silica gel; methanol / dichloromethane, 2/98) to give (+/-) - 1- [2- (6-bromoisocroman- to give the Dean (VI), NMR (CDCl 3 ) 1.85, 1.99-2.17, 2.46-2.60, 2.65-2.71, 2.95, 3.09, 3.74, 4.10, 4.77, 6.99 and 7.17-7.32δ. Step 4. Preparation of (+/-) - 1- [2- (4-phenyl-1-piperidinyl) ethyl] isochroman- (VI) (step 1; 0.422 g, 1.05 mmol), DMF (2.7 mL), and N-methylpyrrolidinone , 1,1,1,3,3,3-hexamethyldisilazane (Aldrich: 1.6 mL, 7.58 mmol), diisopropylethylamine (0.38 mL, 2.18 mmol), palladium (II) acetate (0.012 g, 0.053 mmol), and 1,3-bis (diphenylphosphino) propane (0.026 g, 0.064 mmol) was degassed under reduced pressure six times and discharged as carbon monoxide each time. The mixture is heated to 90 < 0 > C overnight, after which the cooled mixture is poured into hydrochloric acid (1N, 11 ml) and extracted with ether. The pH of the aqueous layer is adjusted to 12 using aqueous sodium hydroxide. The aqueous layer is extracted three times with ethyl acetate and the combined organic layers are washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was chromatographed (silica gel; methanol / dichloromethane / ammonium hydroxide, 2/98/0.5) to give (+/-) - 1- [2- (4- phenyl- 1- piperidinyl) ethyl] only, to obtain a 6-carboxamide (VII), NMR (CDCl 3 ) 1.83, 1.99-2.22, 2.51-2.62, 2.74-2.79, 2.97-3.08, 3.78, 4.14, 4.87, 5.63, 6.05, 7.19-7.33 And 7.59 delta. [Example 85] Methyl-1- [2- (4-phenyl-1-piperidinyl) ethyl] isochroman-6- carboxamide, maleic acid salt Step 1. Preparation of (+/-) - N-bis- (tert-butyloxycarbonyl) -1- [2- (4-phenyl- 1 -piperidinyl) ethyl] isochroman- (VII) (Example 84, 0.231 g, 0.634 mmol), 4-dimethylaminopyridine (+/-) - N < / RTI > (2-methoxyphenyl) propanoate following the general procedure of example 3, step 1, with the exception that di-tert-butyl dicarbonate (0.0098 g, 0.0802 mmol) (VIII), which is chromatographed on silica gel, to give the title compound as a colorless solid, (-) - bis- (tert- butyloxycarbonyl) -1- [2- (4- phenylpiperidinyl) ethyl] isochroman- Kel silica; methanol / dichloromethane, 2/98), NMR (CDCl 3 ) 1.39, 1.84, 2.00-2.20, 2.44-2.63, 2.71-2.81, 2.94-3.15, 3.78, 4.14, 4.89, 7.20-7.30 and 7.60- 7.65δ. Step 2. Synthesis of N-methyl-1- [2- (4-phenyl-1-piperidinyl) ethyl] isochroman- (+/-) - N-bis (tert-butyloxycarbonyl) -1- [2- (4-phenyl-1-piperidinyl) ethyl] isoquinoline Methylamine gas is condensed into a glass high pressure reaction vessel containing 6-carboxamide (VIII, step 1, 0.2818 g, 0.499 mmol) and dichloromethane (4 ml). A few milliliters of methylamine is condensed into the liquid, then the vessel is sealed and the mixture is warmed to 20 to 25 DEG C with stirring. After stirring overnight, the vessel is re-cooled to -78 ° C and the seal is released. After warming to 20 to 25 ° C, the reaction was concentrated under reduced pressure and the resulting residue was chromatographed (silica gel; methanol / dichloromethane, 3/97 to 5/95) to give N-methyl-1- [2- (4-phenyl-1-piperidinyl) ethyl] isochroman-6-carboxamide (IX). N-methyl-1- [2- (4-phenyl-1-piperidinyl) ethyl] isochroman-6- carboxamide was treated with maleic acid (0.0360 g, 0.310 mmol) in dichloromethane / -methyl-1- [2- (4-phenyl-1-piperidinyl) ethyl] iso only give a chroman-6-carboxamide, maleic acid salt (B-IX), NMR (CDCl 3) 1.84, 2.05-2.20, 2.52-2.66, 2.72-2.78, 3.01, 3.41, 3.49, 3.78, 4.13, 4.85, 6.12, 7.16-7.32 and 7.53 delta. [Example 86] (+/-) - 1- [2- [4- (2,4-Dichlorophenyl) -1-piperazinyl] ethyl] isochroman-6- carboxamide Step 1. Preparation of 1- (2,4-dichlorophenyl) piperazine A mixture of 1,3-dichloro-4-fluorobenzene (Q-2) (4.21 g, 25.5 mmol), piperazine (Q-1, 11.0 g, 128 mmol) and dimethylacetamide (15 mL) Lt; RTI ID = 0.0 > 165 C < / RTI > and the mixture is cooled and partitioned between dichloromethane and aqueous sodium bicarbonate. The organic layer was dried with sodium sulfate and concentrated under high vacuum to give 1- (2,4-dichlorophenyl) piperazine (Q-3), which was pure enough for use in step 2 without further purification. Step 2. Synthesis of (+/-) - 1- [2- (6-bromoisocroman-1-yl) ethyl] -4- (2,4-dichlorophenyl) piperazine (S-1) (Example 84, step 2; 0.60 (6-bromo-isochroman-1-yl) ethyl alcohol 2.49 mmol) and diisopropylethylamine (0.49 ml, 2.81 mmol), methanesulfonyl chloride (0.22 ml, 2.84 mmol) and anhydrous THF (7.5 ml) To a mesylate (T-1). The mesylate was treated with diisopropylethylamine (1.0 mL, 5.7 mmol), l- (2,4-dichlorophenyl) piperazine (Q-3, step 1; 0.65 g, 2.82 mmol) and ethylene glycol (+/-) - 1- [2- (6-Bromoisocyanat-1-yl) ethyl] -4- (2,4- dichlorophenyl) -methanone was obtained by chromatography (silica gel; methanol / dichloromethane, 2/98) ) to obtain the piperazine (VI), NMR (CDCl 3 ) 2.01, 2.10, 2.55-2.71, 2.95, 3.05, 3.74, 4.11, 4.78, 6.96, 7.18 and 7.26-7.36δ. Step 3. Preparation of (+/-) - 1- [2- [4- (2,4-dichlorophenyl) -1-piperazinyl] ethyl] isochroman- (VI, step 1; 0.373 g, 0.794 mmol) in methylene chloride (10 mL) was added dropwise a solution of (+/-) - 1- [2- (6-bromoisocroman- 0.095 g of (+/-) - 1- [2- [4- (2,4-dichlorophenyl) -1-piperazin- possess] ethyl] iso-chroman-6-car give the carboxamide (VII), and after chromatography (silica gel; methanol / dichloromethane, 2/98), NMR (CDCl 3 ) 2.05, 2.15, 2.50-2.80, 3.05, 3.78, 4.15, 4.87, 5.62, 6.04, 6.96, 7.19, 7.35 and 7.60 delta. [Example 87] (+/-) -N-methyl-1- [2- [4- (2,4-dichlorophenyl) -1-piperazinyl] ethyl] isochroman- Step 1. Preparation of (+/-) - N-bis (tert-butyloxycarbonyl) -1- [2- [4- (2,4-dichlorophenyl) -1- piperazinyl] ethyl] -6-carboxamide (+/-) - 1- [2- [4- (2,4-Dichlorophenyl) -1-piperazinyl] ethyl] isochroman- (0.0982 g, 0.450 mmol), 4-dimethylaminopyridine (0.0046 g, 0.0377 mmol) and di-tert-butyl dicarbonate (0.0982 g, 0.498 mmol) (Tert-butyloxycarbonyl) -1- [2- [4- (2,4-dichlorobenzyloxy) -2-methyl- dichlorophenyl) possess -1-piperazinyl] ethyl] iso-chroman-6 to afford the carboxamide (VIII), NMR (CDCl 3 ) 1.40, 2.05, 2.17, 2.51-2.79, 2.95, 3.05, 3.78, 4.15 , 4.89, 6.96, 7.19, 7.35 and 7.60-7.66 [delta]. Step 2. Preparation of (+/-) -N-methyl-1- [2- [4- (2,4-dichlorophenyl) -1- piperazinyl] ethyl] isochroman- (+/-) - N-bis (tert-butyloxycarbonyl) -1- [2- [4- (2,4-dichlorophenyl) (Silica gel; methanol / dichloromethane, 1.5: 1) to give the title compound as a colorless solid, mp < RTI ID = 0.0 > 98.5 to 3/97 to 5/95). This material was crystallized from acetonitrile / hexane to give (+/-) - N-methyl- 1- [2- [4- (2,4- dichlorophenyl) -1- piperazinyl] ethyl] isochroman- -Carboxamide < / RTI > (IX). MS (m / z) = 447; IR (mineral oil; strongest peak) 1637, 1478, 1572, 1558, 1450, 3289 and 1107 cm -1 ; NMR (CDCl 3) 2.05, 2.16 , 2.52-2.78, 3.03, 3.77, 4.13, 4.86, 6.10, 6.96, 7.17, 7.36 and 7.54δ. [Example 88] 1- [2- [4- (3-Chloro-4-methoxyphenyl) -1-piperazinyl] ethyl] isochroman- Step 1. l- (3-Chloro-4-methoxyphenyl) piperazine (0.860, 4.80 mmol), potassium carbonate (1.11 g, 8.00 mmol), and dimethylacetamide (R-2, 0.633 g, 4.00 mmol), bis (2- chloroethyl) amine hydrochloride 6 ml) was stirred at 100 < 0 > C for 18 hours and then cooled. The mixture is partitioned between dichloromethane, water and aqueous sodium bicarbonate, and the organic layer is dried over sodium sulfate and concentrated. The residue was purified by chromatography; and (silica gel, methanol / dichloromethane, 8/92) to give the 1- (3-chloro-4-methoxyphenyl) piperazine (R-3), NMR ( CDCl 3) 3.05, 3.86 , 6.80, 6.87 and 6.99 delta. Step 2. Synthesis of (+/-) - 1- [2- (6-bromoisocleman-1-yl) ethyl] -4- (S-1, Example 84, step 3, 0.450 g, 1.75 mmol) following the general procedure of example 84, step 3, using (+/-) 1.84 mmol, 1.81 mmol) and anhydrous THF (5.6 ml) were added to a solution of mesylate (0.012 g, 0.0990 mmol), diisopropylethylamine (0.32 ml, 1.84 mmol), methanesulfonyl chloride . Additional portions of diisopropylethylamine (0.18 mL, 1.03 mmol) and methanesulfonyl chloride (0.08 mL, 1.03 mmol) were added to complete mesylate formation. Followed by the addition of diisopropylethylamine (0.65 mL, 4.26 mmol), l- (3-chloro-4-methoxyphenyl) piperazine (step 1; 0.398 g, 1.75 mmol) and ethylene glycol (1.8 mL) . The mixture is stirred for 3 hours at 80 DEG C and after stirring overnight at 20 to 25 DEG C, the mixture is again heated at 80 DEG C for 4 hours. Additional 1- (3-chloro-4-methoxyphenyl) piperazine (0.0443 g, 0.195 mmol) is added and the mixture is further heated for 3 hours. After cooling, the mixture is partitioned between dichloromethane and aqueous sodium bicarbonate, the organic layer is dried over sodium sulfate and concentrated. The residue was chromatographed (silica gel; methanol / dichloromethane, 2/98) to give (+/-) - 1- [2- (6-bromoisocroman- 1- yl) ethyl] -4- 4-methoxyphenyl) to obtain the piperazine (VI), NMR (CDCl 3 ) 2.01, 2.10, 2.52-2.71, 2.96, 3.10, 3.75, 3.85, 4.10, 4.78, 6.77-6.87, 6.98 and 7.29δ. Step 3. Preparation of (+/-) -1- [2- [4- (3-chloro-4-methoxyphenyl) -1- piperazinyl] ethyl] isochroman- (+/-) - 1- [2- (6-Bromoisocyanate-1-yl) ethyl] -4- (VI), step 2 (0.420 g, 0.902 mmol), DMF (2.3 mL), 1,1,1,3,3,3-hexamethyldisilazane (1.4 mL, 6.64 mmol), di (+ / -) was prepared using isopropyl ethyl amine (0.34 mL, 1.95 mmol), palladium (II) acetate (0.0110 g, 0.049 mmol) and 1,3- bis (diphenylphosphino) propane (0.024 g, 0.0575 mmol) -) - 1- [2- [4- (3-chloro-4-methoxyphenyl) -1-piperazinyl] ethyl] isochroman-6- carboxamide VII. After chromatography (silica gel; methanol / dichloromethane, 2/98) to, NMR (CDCl 3) 2.05, 2.15, 2.53-2.64, 2.74-2.79, 3.02, 3.11, 3.77, 3.84, 4.14, 4.87, 5.60, 6.04, 6.77-6.87, 6.98, 7.18 and 7.60 delta. [Example 89] (+/-) - 1- [2- [4- (3-chloro-4-methoxyphenyl) -1- piperazinyl] ethyl] -N- methylisochroman- Step 1. Synthesis of (+/-) - N-bis (tert-butyloxycarbonyl) -1- [2- [4- (3-chloro-4- methoxyphenyl) Isochroman-6-carboxamide (+/-) - 1- [2- [4- (3-chloro-4-methoxyphenyl) -1-piperazinyl] ethyl] iso (0.0086 g, 0.0704 mmol) and di-tert-butyl dicarbonate (0.186 g, 0.355 mmol) were added to a solution of 4-amino- (Tert-butyloxycarbonyl) -1- [2- [4- (3-tert-butyloxycarbonylamino) -chloro-4-methoxyphenyl) -1-piperazinyl] ethyl] should yield a croissant isopropyl-6-carboxamide (VIII), NMR (CDCl 3 ) 1.39, 2.03, 2.14, 2.48-2.64, 2.73 -2.80, 3.00, 3.11, 3.78, 3.85, 4.14, 4.88, 6.80-6.88-6.98, 7.20 and 7.60-7.65 delta. Step 2. Preparation of (+/-) -N-methyl-1- [2- [4- (3-chloro-4- methoxyphenyl) -1- piperazinyl] ethyl] isochroman- (Tert-Butyloxycarbonyl) -1- [2- [4- (3-chloro-4-methylpiperazin-1-yl) -methanone following the general procedure of example 85, step 3, (VIII, step 1; 0.183 g, 0.290 mmol) was used to obtain 0.118 g of the product, which was purified by chromatography (silica gel; methanol: ethyl acetate = / Dichloromethane, 2/98). The product was crystallized from ethyl acetate / methanol / hexane and then crystallized from ethyl acetate / dichloromethane to give (+/-) - l- [2- [4- (3-chloro-4- methoxyphenyl) Yl] ethyl] -N-methylisochroman-6-carboxamide (IX), MS (m / z) = 443; IR (mineral oil; strongest peak) 1508, 1642, 3266, 1112, 1548, 1274 and 949 cm -1 ; NMR (CDCl 3) 2.09, 2.21 , 2.58-2.77, 3.01, 3.15, 3.76, 3.85, 4.15, 4.88, 6.12, 6.77-6.88, 6.98, 7.17 and 7.54δ. [Example 90] N- (2-hydroxyethyl) -1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] isochroman-6- Step 1. (+/-) - 1-2- (6-Bromoisocyanate-1-yl) acetyl-4- (4- methoxyphenyl) piperazine (IV), 4.66 g (0.0172 mol), dichloromethane (18 mL), DMF (18 mL), and the mixture was stirred at -78 & (R-3) (Aldrich; 4.78 g, 0.021 mol) and triethylamine (6.5 mL, 0.022 mol) 0.047 mol) is stirred at 20 25 占 폚 for 2.5 hours. Saturated sodium bicarbonate (100 ml) is added to the mixture, and the mixture is stirred for 20 minutes, at which time it is extracted with dichloromethane. The combined organic layers are dried over magnesium sulfate and concentrated under reduced pressure. The residue is washed twice with hexane (discarded) and the residue is again concentrated under reduced pressure. The residue was chromatographed (silica gel; ethyl acetate / hexane, 50/50) to give (+/-) - 1- (2- (6-bromoisocroman- phenyl), to obtain the piperazine (V), NMR (CDCl 3 ) 2.63-2.69, 2.74-2.80, 2.90-3.08, 3.59-3.96, 4.11, 5.26, 6.87, 7.01, 7.31δ. Step 2. Preparation of (+/-) - l- [2- (6-bromoisocroman-l-yl) ethyl] -4- methoxyphenylpiperazine (+/-) - l- (2- (6-bromoisoquinolin-l-yl) -methanone Following the general procedure of Example 1, step 4, but substituting borane-methyl sulfide (14 ml) 4.83 g of (+/-) - 1- [2- (6-bromoisoquinolin-2-yl) acetyl] -4- (4- methoxyphenyl) piperazine 1- yl) ethyl] -4-methoxyphenyl provides a piperazine (VI), NMR (CDCl 3 ) 2.00, 2.12, 2.49-2.71, 2.95, 3.10, 3.75, 4.11, 4.78, 6.87, 6.97 and 7.29δ . Step 3. Preparation of (+/-) - 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] isochroman- Yl) ethyl] -4- (methoxyphenyl) piperazine (VI) was prepared according to the general procedure of example 84, step 4, using (+/-) - 1- [2- Step 2; 4.29 g, 9.95 mmol) was added to a solution of (+/-) - 1- [2- [4- (4- methoxyphenyl) -1- piperazinyl] ethyl] isochroman-6- carboxamide provides VII), NMR (CDCl 3) 2.06, 2.16, 2.54-2.79, 2.99, 3.11, 4.15, 4.87, 5.64, 6.06, 6.87, 7.19 and 7.59δ. Step 4. Preparation of (+/-) - N-bis (tert-butyloxycarbonyl) -1- [2- [4- (4- methoxyphenyl) -1- piperazinyl] ethyl] isochroman- 6-carboxamide (+/-) - 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] isochroman-6- carboxamide Amide (VII, step 3, 1.97 g, 4.97 mmol), 4-dimethylaminopyridine (0.0816 g, 0.0668 mmol) and di- 1-piperazinyl] ethyl] isochroman-6-carboxamide (VIII) as a white solid. NMR (CDCl3): [delta] (CDCl 3) 1.39, 2.03, 2.15, 2.53-2.78, 2.99, 3.11, 3.77, 4.13, 4.88, 6.85, 7.21 and 7.63δ. Step 5. Preparation of N- (2-hydroxyethyl) -1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] isochroman- (+/-) - N-bis (tert-butyloxycarbonyl) -1- [2- [4- (methoxyphenyl) -1- piperazinyl] ethyl] isochroman- (VIII, step 4; 0.216 g, 0.362 mmol), dichloromethane (7 mL) and ethanolamine (0.2 mL, 3.31 mmol) was stirred overnight at 20-25 ° C. The mixture is partitioned between water and dichloromethane. The combined organic layers are dried over sodium sulfate and concentrated under reduced pressure. The residue was chromatographed (silica gel; methanol / dichloromethane, (4/96) to give the product which was crystallized from dichloromethane / hexane / ethyl acetate to give 0.090 g of N- (2-hydroxyethyl) -1- [ MS (m / z) 439; IR (mineral oil) (mineral oil) (IX) as a colorless oil. the strongest peak) 1514, 1631, 1554, 1031, 3293, 1249 and 1613cm -1; NMR (CDCl 3) 2.05, 2.15, 2.51-2.78, 3.01, 3.11, 3.63, 3.77, 3.85, 4.13, 4.86, 6.59, 6.87 , 7.17 and 7.57 delta. [Example 91] 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] -N- (phenylmethoxy) isochroman- (+/-) - N-bis (tert-butyloxycarbonyl) -1- [2- [4- (4-methoxyphenyl) -1- piperazinyl] ethyl] isochroman- Benzylhydroxylamine hydrochloride (0.0645 g, 0.4041 mmol) and diisopropylethylamine (0.12 ml, 0.345 mmol) in THF (7 ml) 0.689 mmol) in acetonitrile (5 mL) is heated at reflux for 7 hours. The mixture was then stirred for 2 days at 20-25 ° C whereupon O-benzylhydroxylamine hydrochloride (0.323 g, 2.03 mmol) and diisopropylethylamine (0.35 mL, 2.01 mmol) were added . After stirring overnight at 85-90 < 0 > C, THF is concentrated off under reduced pressure and the residue is partitioned between dichloromethane and water. The combined organic layers are dried over sodium sulfate and concentrated under reduced pressure to give the crude material. This material was chromatographed (silica gel; methanol / dichloromethane, 4/96) to give the product which was crystallized from hexane / ethyl acetate / dichloromethane / methanol to give the title compound, MS (m / z) 501; NMR (CDCl 3) 2.03, 2.12 , 2.48-2.75, 2.98, 3.10, 3.77, 4.11, 4.84, 5.05, 6.86, 7.14, 7.41 and 8.43δ. [Example 92] (+/-) - 1- [1- [2- [4- (4-methoxyphenyl) -1- piperazinyl] ethyl] isochroman-6- yl] -4-methylpiperazine (+/-) - N-bis (tert-butyloxycarbonyl) -1- [2- [4- (4-methoxyphenyl) -1- piperazinyl] ethyl] isochroman- (0.4 ml, 3.6 mmol) in THF (11 ml), diisopropylethylamine (0.6 ml, 3.44 mmol) and 1-methylpiperazine (VIII, Example 7, step 4; 0.211 g, 0.355 mmol) Is stirred over 20 to 25 < 0 > C over the weekend, then the THF is removed under reduced pressure and the residue is partitioned between dichloromethane and water. The combined organic layers are dried over magnesium sulfate and concentrated under reduced pressure to give a crude product. The crude product is chromatographed (silica gel; methanol / dichloromethane, 2/98 to 4/96). Precipitation of the product from ethyl acetate and hexane afforded the title compound, part of which was recrystallized from ethyl acetate, MS (m / z) 478; NMR (CDCl 3) 2.09, 2.32 , 2.48-2.75, 2.99, 3.11, 3.47, 3.76, 4.13, 4.86, 6.86 and 7.18δ. [Example 93] (+/-) - N-hydroxy-1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] -N- methylisochroman- (+/-) - N-bis (tert-butyloxycarbonyl) -1- [2- [4- (4-methoxyphenyl) -1- piperazinyl] ethyl] isochroman- (0.71 g, 0.344 mmol), dichloromethane (71 ml), N-methylhydroxylamine hydrochloride (0.271 g, 3.25 mmol) and diisopropylethylamine (0.604 g , 3.44 mmol) is stirred at 20-25 < 0 > C overnight. The mixture is then partitioned between dichloromethane and water. The combined organic layers are dried over sodium sulfate and concentrated under reduced pressure. Crystallization from hexane / methanol / dichloromethane / ethyl acetate gave the title compound, MS (m / / z) 425; NMR (CDCl 3) 2.05, 2.17 , 2.54-2.77, 3.00, 3.11, 3.42, 3.77, 4.13, 4.85, 6.87, 7.17 and 7.33δ. [Example 94] (S) - (-) - 1- [2- [4- [4- (tert-butyloxycarbonyl) phenyl] -1- piperazinyl] ethyl] -N- methylisochroman-6- Vaxamide (V-2) Step 1: 4-Fluorobenzoic acid, tert-butyl ester To a solution of 4-fluorobenzoic acid (18.7 g, 0.133 mol) in DMF (140 ml) was added 1,1-carbonyldiimidazole (21.6 g, 0.134 mol). The mixture is heated to 40 < 0 > C for 1 hour, at which time t-butanol (26 mL, 0.272 mol) and DBU (20.5 mL, 0.137 mol) are added. After stirring overnight at 40 ° C the cooled mixture was poured into ethyl ether (1300 ml), washed with hydrochloric acid (10%, 250 ml) and then with water (250 ml) followed by sodium carbonate (10% Ml). The ether layer is dried over sodium sulfate and concentrated under reduced pressure. The residue was chromatographed (silica gel; ethyl acetate / hexane, 10/90) to give 4-fluorobenzoic acid, tert-butyl ester (Q-2); MS (m / z) 196; NMR (CDCl 3) 1.59, 7.07 and 7.99δ. Step 2. Preparation of 4- (piperazin-1-yl) benzoic acid, tert-butyl ester A mixture of 4-fluorobenzoic acid, tert-butyl ester (Q-2) (step 1; 20.5 g, 0.105 mol), piperazine (52.8 g, 0.613 mol) and dimethylacetamide Lt; 0 > C for 160 minutes. After cooling, the solid is filtered off and washed with hexane. The combined filtrates are concentrated under high vacuum and the residue is partitioned between dichloromethane and water. The combined organic layers are dried over sodium sulfate and concentrated under reduced pressure. The solid, slightly soaked in solvent, is slurried in hexane, and the solid is collected and washed with hexane. The solid is dried at 20 to 25 [deg.] C under reduced pressure to give tert-butyl-4- (piperazin-1-yl) benzoate. The filtrate was concentrated and the resulting residue was chromatographed (silica gel; methanol / dichloromethane / ammonium hydroxide, 3.5 / 96.5 / 0.5 to 7/93 / 0.5) to give further product 4- (piperazin- Yl) benzoic acid, tert-butyl ester (Q-3); MS (m / z) 262; NMR (CDCl 3) 1.57, 3.01 , 3.25, 6.84 and 7.87δ. Step 3. Synthesis of (S) - (-) - 4- [4- [2- (6-bromoisocroman-1-yl) ethyl] -1- piperazinyl] benzoic acid, tert- One) (S) - (-) - 2- (6-Bromoisopropan-1-yl) ethyl alcohol (S-1) (Example 6, step Butyl ester (Q-3) (step 2; 5.42 g, 0.0206 moles) provides the title compound. MS ( m / z) 500; NMR (CDCl 3) 1.57, 2.02 , 2.12, 2.50-2.70, 2.95, 3.32, 3.73, 4.10, 4.79, 6.85, 6.97, 7.29 and 7.86δ. Step 4. Synthesis of (S) - (-) - 1- [2- [4- (4- tert -butyloxycarbonyl) phenyl] -1- piperazinyl] ethyl- Carboxamide (S) - (-) - 4- [4- [2- (6-Bromoisocyanat-1-yl) ethyl] -1-piperazinyl (0.0616 g, 0.274 mmol), 1,3-bis (diphenylphosphino) benzoic acid, tert-butyl ester (V-1) (step 3; 2.63 g, 5.25 mmol) Propane (0.164 g, 0.396 mmol) and diisopropylethylamine (1.8 mL, 0.0103 mol). The mixture is degassed again and discharged into argon. The mixture is heated to 60-65 < 0 > C, during which carbon monoxide is bubbled through the mixture. After a few minutes, methylamine is also bubbled into the mixture. After heating at 60 to 65 DEG C for 6.5 hours, the mixture is stored in the refrigerator overnight. The mixture was then filtered through diatomaceous earth and washed with additional portions of palladium (II) acetate (0.065 g, 0.290 mmol), 1,3-bis (diphenylphosphino) propane (0.162 g, 0.392 mmol) Ethylamine (1.8 mL, 0.0103 mol) is added to the filtrate, which is heated at 60 < 0 > C for 4 hours with the addition of carbon monoxide and methylamine gas, after which the mixture is cooled and concentrated under reduced pressure. The residue is partitioned between dichloromethane and water. The combined organic layers are washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure. The residue is chromatographed (silica gel; methanol / dichloromethane, 2/98 to 4/96). The impure fractions were combined and rechromatographed (silica gel; methanol / dichloromethane, 2/98) to give the title compound, MS (m / z) 479; NMR (CDCl 3) 1.56, 2.03 , 2.16, 2.48-2.79, 3.01, 3.32, 3.76, 4.14, 4.86, 6.08, 6.84, 7.15, 7.53 and 7.86 δ. [Example 95] 6-ol, methylcarbamate ester (X-6), and the like. Step 1. (+/-) - 2- (6-Hydroxyisochroman-1-yl) acetic acid, ethyl ester To a cooled mixture of 3-hydroxyphenethyl alcohol (X-1) (2.9 g, 21 mmol) and ethyl 3,3, -diethoxypropionate (4.75 g, 25 mmol) in nitromethane (5 ml) Trifluoride etherate (3.44 ml) is added. After the addition is complete (about 5 min), the reaction is stirred for an additional 60 min. The mixture is then partitioned between dichloromethane and aqueous ammonium chloride. The organic layer is dried over sodium sulfate and concentrated. The residue was chromatographed (silica gel; ethyl acetate / hexane, 10/90 to 30/70) to give (+/-) - 2- (6-hydroxyisochroman- 2) to yield, NMR (CDCl 3) 1.28, 2.6-3.0, 3.79, 4.09, 4.21, 5.07, 5.19, 6.60, 6.67 and 6.91δ. Step 2. (+/-) - 2- (6-Hydroxyisochroman-1-yl) acetic acid Sodium hydroxide (2N, 10 ml) was added to (6-hydroxyisochroman-1-yl) acetic acid, ethyl ester (X-2) (step 1; 2.38 g, 10.1 mmol) in ethanol (10-15 ml) . The mixture is stirred overnight, and then the ethanol is removed under reduced pressure. The resulting aqueous mixture is then diluted with several mL of brine, acidified with hydrochloric acid (3N), and the mixture is extracted with ethyl ether and concentrated. The residue is partitioned between aqueous sodium bicarbonate and dichloromethane to remove residual starting material. The organic phase is removed, the aqueous layer is acidified with concentrated hydrochloric acid and extracted with ether. The ether layer is dried over magnesium sulfate and concentrated. The concentrate was crystallized from THF / hexane / dichloromethane (+/-) - 2 to give the acid (X-3) (only the 6-hydroxy-iso-chroman-1-yl), NMR (CDCl 3) 2.1- 3.0, 3.81, 4.15, 5.2, 6.59, 6.68 and 6.90 delta. Step 3. (+/-) - 2- (6-Hydroxyisochroman-1-yl) acetyl-4- (4- methoxyphenyl) piperazine (Step 2; 0.361 g, 1.73 mmol), 1- (4-methoxyphenyl) piperazine di (trimethylsilyl) To the mixture of hydrochloride (0.458 g, 1.73 mmol), dichloromethane (5 mL) and DMF (0.5 mL) was added triethylamine (0.80 mL, 5.72 mmol) followed by diethylcyanophosphonate (0.29 mL, 1.91 mmol Is added. After stirring for 50 minutes, water is added and the mixture is stirred for 1 hour. The mixture is then extracted with dichloromethane, the organic layers are separated, combined and washed with aqueous sodium bicarbonate. The organic layer is dried with sodium sulfate and concentrated. The residue was crystallized from ethyl acetate dichloromethane-methanol to give (+/-) - 1-2- (6-hydroxysiucochm-1-yl) acetyl-4- (4- methoxyphenyl) piperazine NMR (DMSO) 2.57-2.63, 2.73-2.90, 2.97, 3.64, 3.69, 3.95, 5.03, 6.51, 6.57, 6.8-7.0 and 9.27 [deg.]. Step 4. Preparation of (+/-) - 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] isochroman- (X-4) (step 3; 0.375 g, 0.98 mmol) was added to a solution of (+/-) - 1-2- (6-hydroxyisochroman- ), Borane methyl sulfide (0.28 ml, 2.9 mmol) and THF (15 ml) is stirred at 20-25 ° C over night and stirred at 80 ° C for 2 hours. After cooling, the mixture is treated with methanol and concentrated under reduced pressure. Addition and concentration of methanol are repeated two more times, and the residue is stirred in hydrochloric acid / acetone (4N, 1/9, 5 ml) for 3 hours. The acetone is then removed under reduced pressure, and the residue is partitioned between dichloromethane and aqueous sodium bicarbonate. The organic layer is dried with sodium bicarbonate and concentrated. The residue was crystallized from dichloromethane / hexane to give (+/-) - 1- [2- [4- (4-methoxyphenyl) -1- piperazinyl] ethyl] isochroman- 5) the compounds, NMR (CDCl 3) 2.05, 2.21, 2.5-2.7, 2.94, 3.13, 3.70, 3.76, 4.140, 4.82, 6.41, 6.57 and 6.80-6.91δ. Step 5. Synthesis of (+/-) - 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] isochroman-6-ol, methylcarbamate ester A solution of (+/-) - 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] isochroman-6-ol (X- Methyl isocyanate (0.031 ml; 0.52 mmol) was added to a mixture of the compound of step 4 (0.064 g, 0.17 mmol) and DBU (0.032 g, 0.21 mmol). After stirring for 1.5 hours, the mixture is partitioned between dichloromethane and dilute sodium hydroxide. The organic layer is dried with sodium bicarbonate and concentrated. The residue was crystallized from ether / hexane by chromatography (silica gel; methanol / dichloromethane, 2/98) to give (+/-) - 1- [2- [4- (4- methoxyphenyl) Yl] ethyl] isochroman-6-ol, methyl carbamate ester (X-6), MS (m / z) 425; NMR (CDCl 3) 2.04, 2.12 , 2.65, 2.90, 3.11, 3.75, 3.77, 4.11, 4.83, 4.98, 6.82-6.95 and 7.08δ. [Example 96] (+/-) - 1- [2- [4- (4-aminocarbonyl) phenyl] -1- piperazinyl] ethyl] -N- methylisochromanyl-6-carboxamide Step 1. (+/-) - l- (2-Chloroethyl) isochroman-6-ol To a mixture of 3-hydroxyphenethyl alcohol (Y-1) (0.074 g, 0.537 mmol) and chloropropionaldehyde diethyl acetal (0.107 g, 0.64 mmol) in nitromethane (0.5 ml) was added boron trifluoride-etherate (0.007 ml, 0.054 mmol). After stirring for 100 minutes, water is added and the mixture is partitioned between dichloromethane, water and brine. The organic layer was dried over sodium sulfate and concentrated and the residue was chromatographed (silica gel; ethyl acetate / hexane, 10/90) to give a small amount of (+/-) - 1- (2-ethoxyethyl) isochroman- (+/-) - 1- (2-chloroethyl) isochroman-6-ol (Y-2) containing 6-ol. Use this material without further purification in the step 2, NMR (CDCl 3) 2.15-2./38 , 2.62, 2.68, 2.91, 3.6-3.8, 4.10, 4.89, 5.08, 6.59, 6.68 and 6.95δ. Step 2. Preparation of (+/-) - 1- (2-chloroethyl) isochroman-6-ol, trifluoromethanesulfonate ester (Y-2, step 1; 0.079 g, 0.371 mmol), triethylamine (0.0413 g, 0.408 mmol) cooled at -78 & Anhydrous trifluoromethane sulfonic acid (0.069 g, 0.408 mmol) was added to a mixture of 4-dimethylaminopyridine (0.0009 g, 0.0074 mmol) and dichloromethane (1 ml). The cooling bath is then removed and the mixture is slowly warmed to 20-25 占 폚. After stirring for a total of 60 minutes, the mixture is partitioned between dichloromethane and aqueous ammonium chloride. The organic layer was dried over sodium sulfate and concentrated and the residue was chromatographed (silica gel; ethyl acetate / hexane, 10/90) to give (+/-) - 1- (2- chloroethyl) isochroman- to obtain a sulfonate ester (Y-3) fluoroalkyl, NMR (CDCl 3) 2.24, 2.31, 2.73, 2.78, 3.00, 3.67, 3.80, 4.12, 4.94 and 7.05-7.18δ. Step 3. (+/-) - l- (2-Chloroethyl) -N-methylisochroman-6-carboxamide A solution of (+/-) - 1- (2-chloroethyl) isochroman-6-ol, trifluoromethanesulfonate ester (Y-3, step 2; 0.291 g, 0.844 mmol) in DMF The mixture was degassed under reduced pressure for 5 minutes, then palladium (II) acetate (0.019 g, 0.084 mmol) and 1,3-bis (diphenylphosphino) propane (0.52, 0.127 mmol) were added. A carbon monoxide gas is bubbled through and diisopropylethylamine (0.29 mL, 1.69 mmol) is added. The methylamine gas is bubbled and the bath temperature is raised to 50 < 0 > C. Addition of methylamine gas and carbon monoxide is continued for 1 hour, at which time additional palladium acetate (0.010 g) and 1,3-bis (diphenylphosphino) propane (0.025 g) are added. After an additional 4 hours the mixture is cooled and then partitioned between ether, aqueous ammonium chloride, brine-ammonium chloride and brine. The organic phase is separated, dried over magnesium sulphate and concentrated. The residue was chromatographed (silica gel; methanol / dichloromethane, 2/98) to give (+/-) - l- (2- chloroethyl) -N-methylisochroman- to thereby obtain, NMR (CDCl 3) 2.20, 2.33, 2.73, 2.79, 2.97, 3.01, 3.65, 4.12, 4.95, 6.09, 7.14, 7.53 and 7.56δ. Step 4. Synthesis of (+/-) - 1- [2- [4- [4- (aminocarbonyl) phenyl] -1-piperazinyl] ethyl] -N-methylisochromanyl-6-carboxamide (Y-4, step 3; 0.0937 g, 0.369 mmol), 4- (piperazin-1-ylmethyl) Diisopropylethylamine (0.0716 g, 0.554 mmol), sodium iodide (0.007 g) and ethylene glycol (2 ml) were stirred at 100 占 폚 After heating for 6.5 hours, an additional 0.056 g of 4- (piperazin-1-yl) benzamide is added. After stirring for an additional 24 h at 100 < 0 > C the mixture is allowed to cool (stirring the residue over the weekend). Water is then added and the mixture is extracted with dichloromethane. Concentrate the organic extracts and combine with the residue on the rubber (from which the aqueous layer is poured). The combined crude product was chromatographed (silica gel; methanol / dichloromethane, 6/94) to give (+/-) - 1- [2- [4- [4- (aminocarbonyl) phenyl] ethyl -N- methylisobutyl chromanyl-6 to give a car-carboxamide (Y-5), NMR ( CDCl 3) 2.05, 2.18, 2.5-2.8, 3.02, 3.32, 3.77, 4.13, 4.88, 4.8-6.0, 6.12, 6.89, 7.16, 7.54 and 7.72 delta. [Example 97] (R) - (+) - 1- [2- [4- [4- (aminocarbonyl) phenyl] -1- piperazinyl] ethyl] -N- methylisochromanyl-6-carboxamide (+/-) - 1- [2- [4- [4- (aminocarbonyl) phenyl] -1-piperazinyl] ethyl] -N- methylisochromanyl-6-carboxamide , Example 96) was separated into its (+/-) enantiomers and detected at 295 nm using ethyl alcohol / isopropyl alcohol / triethylamine in a ratio of 4/1 / 0.08 (V / V) ≪ / RTI > column by prep-chromatography. Pig 1 Synthesis of (S) - (-) - 1- [2- [4- [4- (aminocarbonyl) phenyl] -1- piperazinyl] ethyl] -N- methylisochromanyl- (R) - (+) - 1- [2- [4- [4- (aminocarbonyl) phenyl] -1- piperazinyl] ethyl] -N-methylisochromanyl-6-carboxamide (Y-5). MS (m / z) 422. [Example 98] (S) - (-) - 1- [2- [4- (4-cyanophenyl) -1-piperazinyl] ethyl] -N- methylisochroman- Step 1. Preparation of 1- (4-cyanophenyl) piperazine A mixture of 4-fluorobenzamide (Q-2, 0.700 g, 5.78 mmol), piperazine (2.49 g, 28.9 mmol) and water (5 mL) was heated at 100 <0> C for 85 min and then cooled. Water (5-10 ml) is added and the mixture is partitioned between ethyl acetate, aqueous sodium bicarbonate and brine-aqueous sodium bicarbonate. The organic layer was dried over magnesium sulfate and concentrated to 1 - (4-cyanophenyl) to give piperazine (Q-3), NMR ( CDCl 3) 1.77, 3.02, 3.28, 6.85 and 7.49δ. Step 2. Preparation of (S) - (-) - 2- (6-bromoisocroman-1-yl) ethyl alcohol Borane-methylsulfide (3.1 ml, 33.2 mmol) was added to a solution of (S) - (-) - 2- (6-bromoisocroman- 1-yl) acetic acid (XI, ) And THF (40 ml). Gas generation and proper heat generation follow. After stirring for 2.5 hours, methanol is slowly added to quench excess borane-methyl sulfide. The mixture is then concentrated under reduced pressure and methanol is added to the residue. Again the mixture is concentrated and methanol is added. After final concentration from methanol, the residue is partitioned between dichloromethane, aqueous hydrochloric acid and aqueous sodium bicarbonate. The organic layer is dried over sodium sulfate and concentrated. The residue is chromatographed (silica gel; methanol / dichloromethane, 4/96) to give (S) - (-) - 2- (6-bromoisocroman- 1 -yl) ethyl alcohol , NMR (CDCl 3) 2.03, 2.20, 2.60-2.70, 3.02, 3.70-3.85, 4.16, 4.93, 6.93 and 7.29δ. Step 3. (S) - (-) - 6-Bromo-1- (2-bromoethyl) isochromane To a mixture of triphenylphosphine (9.60 g, 36.6 mmol), carbon tetrabromide (6.06 g, 18.3 mmol) and dichloromethane (25 mL, cooled to about 20 C to regulate the exotherm resulting from mixing the reagents) (S) - (-) - 2- (6-bromoisocroman-1-yl) ethyl alcohol (S-1, step 2; 2.35 g, 9.1 mmol) in dichloromethane do. The cooling bath was removed and the mixture was stirred for 40 minutes, at which time hexane was added dropwise until no more cloudiness appeared. The mixture is left in the refrigerator overnight, then the solid is filtered off. The solid was washed with ether and the combined filtrate was concentrated and the residue was chromatographed (silica gel; ethyl acetate / hexane, 10/90) to give (S) - (-) - 6- - bromoethyl) to give the isopropyl chroman (T-1), NMR ( CDCl 3) 2.22-2.46, 2.66, 2.71, 2.94, 3.51, 3.62, 4.09, 4.84, 6.94 and 7.29δ. Step 4. Synthesis of (S) - (-) - 4- [4- [2- (6-bromoisocroman-1- yl) ethyl] -1- piperazinyl] benzonitrile (T-1, step 3, 1.53 g, 4.79 mmol), 1- (4-cyanophenyl) piperazine The mixture of racemic (Q-3, step 1, 0.987 g, 5.27 mmol), diisopropylethylamine (0.681 g, 5.27 mmol) and ethylene glycol (5 ml) was heated at 95 < The residue was purified by chromatography (silica gel; methanol / dichloromethane, 2/98) to give (S) - (-) - l- 4- [4- [2- possess (6-feeders soak only 1-yl) ethyl] -1-piperazinyl] to give the benzonitrile (VI), NMR (CDCl 3 ) 2.00, 2.12, 2.48- 2.72, 2.95, 3.33, 3.73, 4.10, 4.80, 6.85, 6.96, 7.38 and 7.49 delta. Step 5. Synthesis of (S) - (-) - 1- [2- [4- (4-cyanophenyl) -1- piperazinyl] ethyl] -N- methylisochroman- (S) - (-) - 4- [4- [2- (6-Bromoisocyanate-1-yl) ethyl] -1-piperazin- Yl] benzonitrile (VI, step 4, 1.61 g) was added to a solution of (S) - (-) - 1- [2- [4- Isoxomycin-6-carboxamide (IX). MS (m / z) at 404; IR (mineral oil, strongest peak) 1603, 1635, 2210, 1517 and 1553 cm -1 ; NMR (CDCl 3) 2.05, 2.18 , 2.48-2.78, 3.00, 3.01, 3.34, 3.76, 4.12, 4.88, 6.08, 6.85, 7.15, 7.49, 7.53 and 7.54δ. [Example 99] (S) - (-) - 1- [2- [4- [4- (aminocarbonyl) phenyl] -1- piperazinyl] ethyl- 6-carboxamide Step 1. Synthesis of (S) - (-) - 1- [2 - [(tetrahydropyran-2-yl) oxy] ethyl] isochroman- (S-2, Example 81, step 2, 1.36 g, 5.76 mmol), dichloromethane (10 mL) and methanol (10 mL) (0.0142, 0.0747 mmol) and 3,4-dihydro-2H-pyran (1.6 mL, 0.0175 mol) were stirred at 20 to 25 ° C for 45 minutes. The mixture is then partitioned between aqueous sodium bicarbonate and dichloromethane. The combined organic layers are dried over sodium sulfate and concentrated under reduced pressure. The residue was chromatographed (silica gel; ethyl acetate / hexane, 5/95 to 15/85) to give (S) - (-) - 1- [2- (tetrahydropyran-2-yl) oxy] ethyl] chroman-6-carboxylic acid to afford the methyl ester (W-2), NMR ( CDCl 3) 1.53, 1.69-1.80, 2.04, 2.23, 2.73-2.79, 2.98, 3.51-4.13, 4.60, 4.92, 7.18, 7.80 And 7.83 [delta]. Step 2. Synthesis of (S) - (-) - 1- [2- [(tetrahydropyran-2-yl) oxy] ethyl] isochroman- (W-2, step 1, 1.55 g, 4.85 mmol) in THF (10 mL) was added dropwise to a solution of (S) - (-) - 1- [2 - [(tetrahydropyran-2-yl) oxy] ethyl] isochroman- ), Ethanol (12 ml), sodium hydroxide (2N, 3.6 ml, 7.2 mmol) and water (1 ml) is stirred at 20 25 占 폚 for 6.5 hours and the mixture is stored in the refrigerator overnight. The mixture is then stirred for an additional 2.5 hours at 20 to 25 < 0 > C and then concentrated under reduced pressure. Water (6 ml) is added and the resulting mixture is cooled in an ice / water bath. The pH of the mixture is adjusted to pH 5 using hydrochloric acid (4N) and the resulting slurry is extracted with dichloromethane. The combined organic layers were dried over magnesium sulfate and concentrated under reduced pressure to give (S) - (-) - 1- [2 - [(tetrahydropyran-2-yl) oxy] ethyl] isochroman- 3), MS (m / z) = 306; NMR (CDCl 3) 1.55, 1.70-1.84 , 2.08, 2.26, 2.77-2.82, 3.01, 3.54, 3.66-4.17, 4.63, 4.96, 7.23 and 7.88δ. 3. Synthesis of (S) - (-) - N-methyl-N- (phenylmethoxy) -1- [2 - [(tetrahydropyran-2- yl) oxy] ethyl] isochroman- amides 1'-Carbonyldiimidazole (0.064 g, 0.39 mmol) was added to a solution of (S) - (-) - 1- [2 - [(tetrahydropyran-2- yl) oxy] ethyl] isochroman- Carboxylic acid (W-3, step 2; 0.109 g, 0.356 mmol) and THF (2 mL). The mixture was stirred at 20 to 25 캜 for 2 hours and then N-methyl, O-benzylhydroxylamine (Tetrahedron Letters, 30, 31-34 (1989)], (0.054 g, 0.39 mmol) The residue was purified by chromatography (silica gel; methanol / dichloromethane: methanol / dichloromethane: methanol / dichloromethane) to give the title compound as a colorless oil, which was dissolved in dichloromethane Methane, 2/98) to give (S) - (-) - N-methyl-N- (phenylmethoxy) -1- [2- 6, to obtain a carboxylic acid (W-4), NMR ( CDCl 3) 1.50-1.65, 1.70-1.90, 2.07, 2.28, 2.67, 2.72, 2.92, 3.36, 3.53, 3.66-3.95, 4.02, 4.11, 4.62, 4.69 , 4.92, 7.07-7.14, 7.30, 7.36 and 7.45 delta. Step 4. Synthesis of (S) - (-) - 1- (2-hydroxyethyl) -N-methyl-N-phenylmethoxyisochroman- (S) - (-) - N-methyl-N- (phenylmethoxy) -1- [2 - [(tetrahydropyran-2- yl) oxy] ethyl] isochroman-6- carboxamide 4, step 3; 0.131 g, 0.308 mmol) was stirred in a mixture of acetic acid / THF / water (4/2/1, 5 mL) at 20-25 <0> C for 2 hours, then at 60 < And store it in the refrigerator overnight. The solvent is then removed and the resulting mixture is partitioned between dichloromethane and water. The organic layer is dried over sodium sulfate, concentrated and the residue is chromatographed (silica gel; methanol / dichloromethane, 2/98) to give the crude product. NMR of this material indicates the presence of tetrahydropyranyl (THP) type protons, methanol (2 ml) and p-toluenesulfonic acid hydrate (0.006 g) are added and the mixture is stirred overnight. The solvent is then removed under reduced pressure and the residue is partitioned between dichloromethane and aqueous sodium bicarbonate. The organic layer was dried over sodium sulfate and concentrated to give (S) - (-) - 1- (2-hydroxyethyl) -N-methyl-N-phenylmethoxyisochroman-6-carboxamide (W- is obtained, NMR (CDCl 3) 2.07, 2.25, 2.64, 2.70, 3.02, 3.38, 3.77, 3.86, 4.19, 5.01, 7.06, 7.08, 7.31, 7.37 and 7.46δ. Step 5. Synthesis of (S) - (-) - 1- [2- [4- [4- (aminocarbonyl) phenyl] -1- piperazinyl] ethyl- Chroman-6-carboxamide (S) - (-) - 1- (2-hydroxyethyl) -N-methyl-N-phenylmethoxyisochroman-6-carboxamide (W-5, Step 4 Methanesulfonyl chloride (0.043 g, 0.377 mmol) was added to a cold mixture of diisopropylethylamine (0.049 g, 0.377 mmol) and 4-dimethylaminopyridine (0.0018 g, 0.014 mmol) do. The mixture is stirred for 1.5 hours and then partitioned between dichloromethane and aqueous sodium bicarbonate. The organic layer is dried over sodium sulfate and concentrated to give the mesylate (W-6). (Q-3, Preparation 1, 0.071 g, 0.348 mmol), diisopropylethylamine (0.075 ml, 0.580 mmol) and ethylene glycol (0.3 ml) . A small amount of dichloromethane is used to flush the sides of the flask. The mixture is heated at 85 < 0 > C for 2.5 hours and then cooled. Add water and leave the mixture in the refrigerator overnight. Then poured along the supernatant, the residue was purified by chromatography; and (silica gel, methanol / dichloromethane, 4/96 to 6/94) to give the title compound, NMR (CDCl 3) 2.08, 2.20, 2.5-2.75, 2.95, 3.34 , 3.37, 3.76, 4.13, 4.69, 4.89, 5.7, 6.89, 7.10, 7.29, 7.47 and 7.72 delta. [Example 100] (S) - (-) - 1- [2- [4- [4- (aminocarbonyl) phenyl] -1- piperazinyl] ethyl] -N- methyl-N- 6-carboxamide (S) - (-) - 1- [2- [4- [4- (4-aminocarbonylphenyll-1-piperazinyllethyll-N- (phenylmethoxy) isochroman- (10%, 0.0068 g) and methanol (3 ml) was stirred under hydrogen atmosphere at approximately 1 atmosphere, and the mixture was stirred at room temperature for 1 hour. Ethyl acetate (1 mL) is added to help dissolve the starting material. Stirring is continued in a hydrogen atmosphere and additional palladium on charcoal (10%, 0.0068 g) is added after 8 hours. Upon consumption of the starting material (about 28 hours), the palladium on charcoal is filtered off and the filtrate is concentrated. The residue was chromatographed (silica gel; methanol / dichloromethane, 8/92 to 15/85) to give (S) - (-) - 1- [2- [4- [4- (aminocarbonyl) phenyl] -Piperazinyl] ethyl] -N-hydroxy-N-methylisochroman-6-carboxamide (W-8). NMR (DMSO) 1.89, 2.10, 2.45, 2.65-2.70, 2.85, 3.21, 3.66, 4.02, 4.77, 6.90, 6.98, 7.22, 7.36, 7.41, 7.68, 7.72 and 9.94 [ [Example 101] (+/-) - 1- [2- [4- [4- (4- (aminosulfonyl) phenyl] -1- piperazinyl] ethyl] -N- methylisochroman- Step 1. Preparation of 4- (piperazin-1-yl) benzenesulfonamide A mixture of 4-fluorobenzenesulfonamide (Q-2, 6.95 g) and pyrazine (17.1 g) in water (30 ml) was heated at 100 <0> C overnight. The solid was then collected, washed with water and toluene and dried under reduced pressure to give 4- (piperazin-1-yl) benzenesulfonamide (Q-3). MS (m / z) = 241; IR (mineral oil, highest peak) 1160, 822, 1332, 608, 1593 and 1137 cm -1 ; NMR (DMSO) 2.81, 3.17, 2.3, 7.01, 7.07 and 7.61 delta. Step 2. Synthesis of (+/-) - 1- [2- [4- [4- (aminosulfonyl) phenyl] -1-piperazinyl] ethyl] -N- methylisochroman- (Y-4, Example 96, step 3 < RTI ID = 0.0 > (CDCl3) < / RTI & , (0.024 g, 0.095 mmol) and 4- (piperazinyl-l-yl) benzenesulfonamide (Q- Sulfonyl) phenyl] -1-piperazinyl] ethyl] -N-methyl isochroman-6-carboxamide (Y-5). NMR (CDCl 3) 2.05, 2.19 , 2.5-2.8, 3.01, 3.34, 3.42, 3.79, 4.16, 4.89, 6.41, 6.91, 7.18, 7.54, 7.56, and 7.76δ. Following the general procedure of Example 94 (Scheme V), without significant change, the corresponding compounds of the Examples 102-104 were obtained using the corresponding reactants: [Example 102] (S) - (-) - N-methyl-1- [2- [4- [4- (methylaminocarbonyl) phenyl] -1- piperazinyl] ethyl] isochroman- [Example 103] (S) - (-) - N-methyl-1- [2- [4- [4- (dimethylaminocarbonyl) phenyl] -1- piperazinyl] ethyl] isochroman- [Example 104] (S) - (-) - N-methyl-1- [2- [4- [4- (n-propylaminocarbonyl) phenyl] -1- piperazinyl] ethyl] isochroman- amides Following the general procedure of Example 100, with no significant changes, the corresponding compounds of Examples 105 to 108 were obtained using the reactants corresponding to the products: [Example 105] (S) - (-) - N-hydroxy-N-methyl-1- [2- [4- [4- (trifluoromethyl) phenyl] -1- piperazinyl] ethyl] isochroman- - carboxamide [Example 106] (S) - (-) - 1- [2- [4- [4- (chlorophenyl) -1- piperazinyl] ethyl] -N-hydroxy-N-methylisochroman- [Example 107] (S) - (-) - l- [2- [4- (4-cyanophenyl) -1-piperazinyl] ethyl] -N-hydroxy-N-methylisochroman- [Example 108] (S) - (-) - N-hydroxy-N-methyl-1- [2- [4- [4- (methylcarbonyl) phenyl] -1- piperazinyl] ethyl] isochroman- Carboxamide Following the general procedure of Scheme DD without significant changes, the compounds of Examples 109-120 are obtained as known to those skilled in the art. [Example 109] (S) -4- [4- [2- [6- (1,2,4-triazol-3-yl) isochroman- 1-yl] ethyl] -1- piperazinyl] [Example 110] (S) -4- [4- [2- [6- (2-methyl-1,2,4-triazol-3-yl) isochroman-1-yl] ethyl] Benzamide [Example 111] (S) -4- [4- [2- [6- (1,2,4-oxadiazol-5-yl) isochroman-1-yl] ethyl] -1- piperazinyl] [Example 112] (S) -1- [2- [6- (1,2,4-triazol-3-yl) isochroman-1-yl] ethyl] -4- [4- trifluoromethylphenyl] piperazine [Example 113] (S) -1- [2- [6- (2-methyl-1,2,4-triazol-3-yl) isochroman- 1 -yl] ethyl] -4- [4- ] Piperazine [Example 114] (S) -1- [2- [6- (1,2,4-oxadiazol-5-yl) isochroman-1-yl] ethyl] -4- [4-trifluoromethylphenyl] piperazine [Example 115] (S) -1- [4-acetylphenyl] -4- [2-6- (1,2,4- triazol-3-yl) isochroman-1-yl] ethyl] piperazine [Example 116] (S) -1- [4-acetylphenyl] -4- [2-6- (2-methyl-1,2,4- triazol- [Example 117] (S) -1- [4-acetylphenyl] -4- [2-6- (1,2,4-oxadiazol-5- yl) isochroman-1-yl] ethyl] piperazine [Example 118] Yl] ethyl] isochroman-6-yl] -N, N-dimethylacrylamide [Example 119] Yl] ethyl] isochroman-6-yl] -N, N-dimethylacrylamide [Example 120] Yl] ethyl] isochroman-6-yl] -N, N-dimethylacrylamide In the general formula (E-#) of the example, Scheme A Scheme B Scheme C Scheme D Scheme E Scheme F Scheme G Scheme H Scheme I Scheme J Scheme K Reaction formula L Scheme M Scheme N Scheme O Scheme P Reaction formula Q Scheme R Scheme S Reaction T Reaction formula U Scheme V Reaction formula W Scheme X Scheme Z Reaction AA Scheme BB Scheme CC Reaction formula DD
权利要求:
Claims (38) [1" claim-type="Currently amended] 1, 6-disubstituted isochroman of formula (I) and a pharmaceutically acceptable salt thereof: (I) Wherein: (I) W 1 is a nitrogen (-N-) or carbon (-CH-) atom; (II) X 1 is (A) - (CH 2 ) n1 -, wherein n 1 is 0 to 3, (B) -CH = CH-; (III) R < 1 > is: (A) -H (B) -F, -Cl, -Br-I, (C) C 1 -C 8 alkyl, (D) C 2 -C 8 alkenyl containing 1 to 3 double bonds (=), (E) C 2 -C 8 alkynyl containing 1 or 2 triple bonds (≡) (F) C 3 -C 8 cycloalkyl, (G) -C 1 -C 3 alkyl, -C 3 -C 8 cycloalkyl, (H) -NO 2, (I) -C N, (J) -CF 3, (K) -OR 1-1 {wherein R 1-1 is (1) -H, (2) C 1 -C 8 alkyl, (3) C 2 -C 8 alkenyl containing 1 to 3 double bonds (=), (4) C 2 -C 8 alkynyls containing 1 or 2 triple bonds (≡) (5) C 3 -C 8 cycloalkyl, (6) -C 1 -C 3 alkyl, -C 3 -C 8 cycloalkyl, (7) -CF 3, (8) -SO 2 -CF 3, (9) - (CH 2) n2 -φ [ wherein, n 2 is from 0 to 4, -φ optionally has one or two (a) -F, -Cl, -Br, -I, (b) -C N, (c) -CF 3, (d) C 1 -C 3 alkyl, (e) -OR 1-1A , wherein R 1-1A is -H, C 1 -C 6 alkyl, -CF 3 or -CH 2 -φ, (f) -NR 1-1A R 1-1B , wherein R 1-1A and R 1-1B are the same or different and R 1-1B is -H, C 1 -C 6 alkyl, -CF 3 or - CH 2 -φ, R 1-1 A is as defined above), (g) -CO-NR 1-1 A R 1-1B , wherein R 1-1A and R 1-1B are as defined above, (h) -SO 2 -NR 1-1A R 1-1B , wherein R 1-1A and R 1-1B are as defined above, (i) -NR 1-1 A -SO 2 -R 1-1B , wherein R 1-1A and R 1-1B are as defined above, (j) -NO 2, (k) -O-SO 2 -CF 3 ] (L) -N (R 1-1 ) 2 , wherein R 1-1 is the same or different and is as defined above, (M) -CO-N (R 1-1 ) 2 , wherein R 1-1 is the same or different and is as defined above, (N) -SO 2 -R 1-3 , wherein R 1-3 is (1) -H, (2) -CF 3 , (3) C 1 -C 8 alkyl, (4) C 2 -C 8 alkenyl containing 1 to 3 double bonds (=), (5) C 2 -C 8 alkynyl containing one or two triple bonds (≡) (6) C 3 -C 8 cycloalkyl, (7) -C 1 -C 3 alkyl, -C 3 -C 8 cycloalkyl, (8) - (CH 2) n2 -φ [ wherein, n2 are as defined above, -φ optionally one or two (a) -F, -Cl, -Br, -I, (b) -C N, (c) -CF 3, (d) C 1 -C 3 alkyl, (e) -OR 1-3A , wherein R 1-3A is -H, C 1 -C 6 alkyl, -CF 3 or -CH 2 -φ, (f) -NR 1-3A R 1-3B , wherein R 1-3A and R 1-3B are the same or different and R 1-3B is -H, C 1 -C 6 alkyl, -CF 3 or - CH 2 -φ, R 1-3A is as defined above), (g) -CO-NR 1-3A R 1-3B , wherein R 1-3A and R 1-3B are as defined above, (h) -SO 2 -NR 1-3A R 1-3B , wherein R 1-3A and R 1-3B are as defined above, (i) -NR 1-3A -SO 2 -R 1-3B , wherein R 1-3A and R 1-3B are as defined above, (j) -NO 2, (k) -O-SO 2 -CF 3 ] (9) -OR 1-3A , wherein R 1-3A is as defined above, (10) -NR 1-3A R 1-3B , wherein R 1-3A and R 1-3B are as defined above, (O) -NR 1-1 -SO 2 -R 1-3 , wherein R 1-1 and R 1-3 are the same or different and are as defined above, (P) - (CH 2) n2 -φ [ wherein, n 2 are as defined above, -φ optionally has one or two (1) -F, -Cl, -Br, -I, (2) -C N, (3) -CF 3, (4) C 1 -C 6 alkyl, (5) -OR 1-1 , wherein R 1-1 is as defined above, (6) -N (R 1-1 ) 2 , wherein R 1-1 is the same or different and is as defined above, (7) -CO-N (R 1-1 ) 2 , wherein R 1-1 is the same or different and is as defined above, (8) -SO 2 -N (R 1-1 ) 2 , wherein R 1-1 is the same or different and is as defined above, (9) -NR 1-1 -SO 2 - (R 1-1 ), wherein R 1-1 is the same or different and is as defined above, (10) -NO 2 , (11) -O-SO 2 -CF 3 ] (Q) -CO-R 1-1 , wherein R 1-1 is as defined above, (R) -CO-OQ 1-2 , wherein Q 1-2 is as defined below, (IV) R 2 is defined the same as R 1 , R 2 may be the same as or different from R 1 , (V) Q 1 is (A) -CO-NQ 1-1 Q 1-2 [wherein Q 1-1 is (1) -H, (2) C 1 -C 8 alkyl, (3) C 2 -C 8 alkenyl containing 1 to 3 double bonds (=), (4) C 2 -C 8 alkynyls containing 1 or 2 triple bonds (≡) (5) C 3 -C 8 cycloalkyl, (6) -C 1 -C 3 alkyl, -C 3 -C 8 cycloalkyl, (7) -CF 3, (8) -SO 2 -CF 3, (9) - (CH 2) n7 -φ [ wherein, n 7 is 0 to 4, -φ optionally of one or two (a) -F, -Cl, -Br, -I, (b) -C N, (c) -CF 3, (d) C 1 -C 3 alkyl, (e) -OQ 1-1 A , wherein Q 1-1 A is -H, C 1 -C 6 alkyl, -CF 3 or -CH 2 -φ, (f) -NQ 1-1A Q 1-1B , wherein Q 1-1A and Q 1-1B are the same or different and Q 1-1B is -H, C 1 -C 6 alkyl, -CF 3 or - CH 2 -φ, Q 1-1 A is as defined above), (g) -CO-NQ 1-1A Q 1-1B , wherein Q 1-1A and Q 1-1B are as defined above, (h) -SO 2 -NQ 1-1A Q 1-1B , wherein Q 1-1A and Q 1-1B are as defined above, (i) -NQ 1-1 A- SO 2 -Q 1-1B , wherein Q 1-1A and Q 1-1B are as defined above, (j) -NO 2, (k) -O-SO 2 -CF 3 ] Q 1-2 (1) -H, (2) C 1 -C 8 alkyl, (3) C 2 -C 8 alkenyl containing 1 to 3 double bonds (=), (4) C 2 -C 8 alkynyls containing 1 or 2 triple bonds (≡) (5) C 3 -C 8 cycloalkyl, (6) -C 1 -C 3 alkyl, -C 3 -C 8 cycloalkyl, (7) -CF 3, (8) - (CH 2) n2 -φ [ wherein, n 2 are as defined above, -φ optionally has one or two (a) -F, -Cl, -Br, -I, (b) -C N, (c) -CF 3, (d) C 1 -C 6 alkyl, (e) -OQ 1-2 A (wherein Q 1-2 A is (i) -H, (ii) C 1 -C 6 alkyl, (iii) -CF 3, (iv) - (CH 2 ) -, (9) - (CH 2) n9 -Q 1-2B (CH 2) n10 -Q 1-2C { this time, and n9 and n10 are the same or different and are from 0 to 4, Q is -O- or 1-2B -NQ 1-2D -, wherein Q is 1-2D (a) -H, (b) C 1 -C 8 alkyl, (c) 1 to 3 of C 2 -C 8 alkenyl group which contains a double bond, (d) C 2 -C 8 alkynyl containing one or two triple bonds, (e) C 3 -C 8 cycloalkyl, (f) -C 1 -C 3 alkyl, -C 3 -C 8 cycloalkyl, (g) -CF 3, (h) - (CH 2) n11 -φ [ wherein, n 11 is from 0 to 4, -φ optionally has one or two (i) -F, -Cl, -Br, -I, (ii) -C N, (iii) -CF 3, (iv) C 1 -C 3 alkyl, (v) -OQ 1-2 E, wherein Q 1-2 E is -H, C 1 -C 6 alkyl, -CF 3 or -CH 2 -φ, (vi) -NQ 1-2 E Q 1-2F , wherein Q 1-2E and Q 1-2F are the same or different and Q 1-2F is -H, C 1 -C 6 alkyl, -CF 3 or - CH 2 -φ, and Q 1-2 E is as defined above), (vii) -CO-NQ 1-2E Q 1-2F , wherein Q 1-2E and Q 1-2F are as defined above, (vii) -SO 2 -NQ 1-2E Q 1-2F ( wherein, Q and Q 1-2E 1-2F are as defined above), (ix) -NQ 1-2 E- SO 2 -Q 1-2F , wherein Q 1-2E and Q 1-2F are as defined above, (x) -NO 2, (xi) a -O-SO 2 -CF 3 is substituted with -, 1-2C Q is defined to be equal to Q 1-2D, Q 1-2C and 1-2D Q is the same or different}, and Q 1-1 and Q 1-2 form , together with the nitrogen atom to which they are attached, a 5 or 6 membered ring which may contain one additional nitrogen or oxygen atom] (B) -SO 2 -NQ 1-1 Q 1-2 , wherein Q 1-1 and Q 1-2 are as defined above, (C) -CO-OQ 1-3 wherein Q 1-3 is (1) -H, (2) -CF 3 , (3) C 1 -C 8 alkyl, (4) C 2 -C 8 alkenyl containing 1 to 3 double bonds (=), (5) C 2 -C 8 alkynyl containing one or two triple bonds (≡) (6) C 3 -C 8 cycloalkyl, (7) -C 1 -C 3 alkyl, -C 3 -C 8 cycloalkyl, (8) - (CH 2) n7 -φ [ wherein, n 7 are as defined above, -φ optionally has one or two (a) -F, -Cl, -Br, -I, (b) -C N, (c) -CF 3, (d) C 1 -C 3 alkyl, (e) -OQ 1-3 A , wherein Q 1-3 A is -H, C 1 -C 6 alkyl, -CF 3 or -CH 2 -φ, (f) -NQ 1-3A Q 1-3B , wherein Q 1-3A and Q 1-3B are the same or different and Q 1-3B is -H, C 1 -C 6 alkyl, -CF 3 or - CH 2 -φ, Q 1-3A is as defined above), (g) -CO-NQ 1-3A Q 1-3B , wherein Q 1-3A and Q 1-3B are as defined above, (h) -SO 2 -NQ 1-3A Q 1-3B ( wherein, Q 1-3A and 1-3B Q is as defined above), (i) -NQ 1-3A- SO 2 -Q 1-3B , wherein Q 1-3A and Q 1-3B are as defined above, (j) -NO 2, (k) -O-SO 2 -CF 3 ] (D) -CO-Q 1-3 , wherein Q 1-3 is as defined above, (E) -CO-imidazole, (F) -NQ 1-1 Q 1-2 , wherein Q 1-1 and Q 1-2 are as defined above, (F ') -NQ 1-1 -CO-Q 1-2 wherein Q 1-1 and Q 1-2 are as defined above, (G) -C (Q 1-3) = NOQ 1-4 ( wherein, Q 1-4 are defined the same as Q 1-3, Q 1-3 are as defined above, and Q 1-3 Q 1-4 may be the same or different), (H) -SO 2 -Q 1-3 (wherein, Q 1-3 are as defined above), (I) -N (Q 1-1 ) -SO 2 -Q 1-3 wherein Q 1-1 and Q 1-3 are as defined above, (J) 5-oxadiazole optionally substituted by one Q 1-5 wherein Q 1-5 is (1) -H, (2) -F, -Cl, -Br, -I (3) C 1 -C 8 alkyl, (4) C 2 -C 8 alkenyl containing 1 to 3 double bonds (=), (5) C 2 -C 8 alkynyl containing one or two triple bonds (≡) (6) C 3 -C 8 cycloalkyl, (7) -C 1 -C 3 alkyl, -C 3 -C 8 cycloalkyl, (8) -NO 2 , (9) -C N, (10) -CF 3, (11) -OQ 1-5 A [wherein Q 1-5 A is (a) -H, (b) C 1 -C 8 alkyl, (c) 1 to 3 of C 2 -C 8 alkenyl group which contains a double bond, (d) C 2 -C 8 alkynyl containing one or two triple bonds, (e) C 3 -C 8 cycloalkyl, (f) -C 1 -C 3 alkyl, -C 3 -C 8 cycloalkyl, (g) -CF 3, (h) -SO 2 -CF 3, (i) - [wherein a, n 7 is 0 to 4)], (CH 2) n7 -φ (12) -NQ 1-5A Q 1-5D wherein Q 1-5A is as defined above and Q 1-5D is (a) -H, (b) C 1 -C 8 alkyl, (c) 1 to 3 of C 2 -C 8 alkenyl group which contains a double bond, (d) C 2 -C 8 alkynyl containing one or two triple bonds (≡) (e) C 3 -C 8 cycloalkyl, (f) -C 1 -C 3 alkyl, -C 3 -C 8 cycloalkyl, (g) -CF 3, (h) - (CH 2) n7 -φ [ wherein, n 7 is as defined above)], (13) -CO-NQ- 5A Q 1-5D , wherein Q 1-5A Q 1-5D is as defined above, (14) -SO 2 -Q 1-5K [wherein Q 1-5K is (a) -H, (b) -CF 3, (c) C 1 -C 8 alkyl, (d) 1 to 3 double bonds (=) C 2 -C 8 alkenyl group containing, (e) C 2 -C 8 alkynyl containing 1 or 2 triple bonds (≡) (f) C 3 -C 8 cycloalkyl, (g) -C 1 -C 3 alkyl, -C 3 -C 8 cycloalkyl, (h) - (CH 2) n7 -φ [ wherein, n 7 is as defined above)], (15) -NQ 1-5 A -SO 2 -Q 1-5 K , wherein Q 1-5 A and Q 1-5 K may be the same or different and are as defined above, (16) - (CH 2) n7 -φ ( In this case, n7 are as defined above, -φ is randomly different one or two (a) -F, -Cl, -Br, -I, (b) -C N, (c) -CF 3, (d) C 1 -C 3 alkyl, (e) -OQ 1-5 A , wherein Q 1-5 A is as defined above, (f) -NQ 1-5A Q 1-5D , wherein Q 1-5A and Q 1-5D are as defined above, (g) -CO-NQ- 5A Q 1-5D , wherein Q 1-5A and Q 1-5D are as defined above, (h) -SO 2 -NQ 1-5A Q 1-5D ( wherein, Q and Q 1-5D 1-5A is as defined above), (i) -NQ 1-5A- SO 2 -Q 1-5D , wherein Q 1-5A and Q 1-5D are as defined above, (j) -NO 2, (k) -O-SO 2 -CF 3 ] (K) by a single Q 1-5, optionally substituted 3-oxadiazole (wherein, Q 1-5 are as defined above), (L) or one by Q 1-5 in two may be the same or different optionally substituted triazole (wherein, Q 1-5 are as defined above), (M) by a single Q 1-5 optionally substituted 5-thiadiazole (wherein, Q 1-5 are as defined above), (N) by a single Q 1-5, optionally substituted 3-thiadiazole (wherein, Q 1-5 are as defined above), (O) one or by two Q 1-5 which may be the same or different optionally substituted oxazol-2 (wherein, Q 1-5 are as defined above), (P) by a one or two Q 1-5 which may be the same or different optionally substituted thiazol-2 (wherein, Q 1-5 are as defined above), (Q) a, (the same as this time, 1-5 Q are defined above) or both by Q 1-5 in three may be the same or different 2-imidazole group optionally substituted, (R) one, two, or by Q 1-5 with three, same or different a 1-imidazole group optionally substituted (wherein, Q 1-5 are as defined above), (S) a tetrazole optionally substituted by one Q < 1-5 > wherein Q < 1-5 > is as defined above, (T) Cyclobutenedione optionally substituted by one Q 1-1 and one Q 1-5 , wherein Q 1-1 and Q 1-5 are as defined above, (U) by a single Q 1-5, optionally substituted 1-pyrimidinyl (wherein, Q 1-5 are as defined above), (V) by a single Q 1-5 optionally substituted 2-pyridinyl (wherein, Q 1-5 are as defined above), (W) by a single Q 1-5, optionally substituted 3-pyridinyl (wherein Q 1-5 are as defined above), (X) by a single Q 1-5 optionally substituted 4-pyridinyl (wherein, Q 1-5 are as defined above), (Y) -Z 1 -CO-Z 2 -Q 1-2 wherein Q 1-2 is as defined above and Z 1 is -O-, -NQ 1-1 -, wherein Q 1-1 is as defined above and Z 2 is -O-, or -NQ 1-1 -, wherein Q 1-1 is as defined above, With the proviso that when X 1 is - (CH 2 ) n1 - (wherein n 1 is 0) and Q 1 is -CO-NQ 1-1 Q 1-2 , -SO 2 -NQ 1-1 Q 1-2 , NQ 1-1 Q 1-2 , or In the case of -NQ 1-1 -CO-Q 1-2 , both Q 1-1 and Q 1-2 are -H, -C 1 -C 6 alkyl, -C 3 -C 7 cycloalkyl, -C 1 -C 3 alkyl, - (C 3 -C 7) can not be selected from cycloalkyl. [2" claim-type="Currently amended] The method according to claim 1, (I) W 1 is nitrogen ( ) Or carbon ( ) Atom; (II) X 1 is (A) - (CH 2 ) n1 -, wherein n 1 is 0 to 3, (B) -CH = CH-; (III) R < 1 > is: (A) -H (B) -F, -Cl, -Br-I, (C) C 1 -C 8 alkyl, (D) C 2 -C 8 alkenyl containing 1 to 3 double bonds (=), (E) C 2 -C 8 alkynyl containing 1 or 2 triple bonds (≡) (F) C 3 -C 8 cycloalkyl, (G) -C 1 -C 3 alkyl, -C 3 -C 8 cycloalkyl, (H) -NO 2, (I) -C N, (J) -CF 3, (K) -OR 1-1 {wherein R 1-1 is: (1) -H, (2) C 1 -C 8 alkyl, (3) C 2 -C 8 alkenyl containing 1 to 3 double bonds (=), (4) C 2 -C 8 alkynyls containing 1 or 2 triple bonds (≡) (5) C 3 -C 8 cycloalkyl, (6) -C 1 -C 3 alkyl, -C 3 -C 8 cycloalkyl, (7) -CF 3, (8) -SO 2 -CF 3, (9) - (CH 2) n2 -φ [ wherein, n 2 is from 0 to 4, -φ optionally has one or two (a) -F, -Cl, -Br, -I, (b) -C N, (c) -CF 3, (d) C 1 -C 3 alkyl, (e) -OR 1-1A , wherein R 1-1A is -H, C 1 -C 6 alkyl, -CF 3 or -CH 2 -φ, (f) -NR 1-1A R 1-1B , wherein R 1-1A and R 1-1B are the same or different and R 1-1B is -H, C 1 -C 6 alkyl, -CF 3 or - CH 2 -φ, R 1-1 A is as defined above), (g) -CO-NR 1-1 A R 1-1B , wherein R 1-1A and R 1-1B are as defined above, (h) -SO 2 -NR 1-1A R 1-1B , wherein R 1-1A and R 1-1B are as defined above, (i) -NR 1-1 A -SO 2 -R 1-1B , wherein R 1-1A and R 1-1B are as defined above, (j) -NO 2, (k) -O-SO 2 -CF 3 ] (L) -N (R 1-1 ) 2 , wherein R 1-1 is the same or different and is as defined above, (M) -CO-N (R 1-1 ) 2 , wherein R 1-1 is the same or different and is as defined above, (N) -SO 2 -R 1-3 , wherein R 1-3 is (1) -H, (2) -CF 3 , (3) C 1 -C 8 alkyl, (4) C 2 -C 8 alkenyl containing 1 to 3 double bonds (=), (5) C 2 -C 8 alkynyl containing one or two triple bonds (≡) (6) C 3 -C 8 cycloalkyl, (7) -C 1 -C 3 alkyl, -C 3 -C 8 cycloalkyl, (8) - (CH 2) n2 -φ [ wherein, n2 are as defined above, -φ optionally one or two (a) -F, -Cl, -Br, -I, (b) -C N, (c) -CF 3, (d) C 1 -C 3 alkyl, (e) -OR 1-3A , wherein R 1-3A is -H, C 1 -C 6 alkyl, -CF 3 or -CH 2 -φ, (f) -NR 1-3A R 1-3B , wherein R 1-3A and R 1-3B are the same or different and R 1-3B is -H, C 1 -C 6 alkyl, -CF 3 or - CH 2 -φ, R 1-3A is as defined above), (g) -CO-NR 1-3A R 1-3B , wherein R 1-3A and R 1-3B are as defined above, (h) -SO 2 -NR 1-3A R 1-3B , wherein R 1-3A and R 1-3B are as defined above, (i) -NR 1-3A -SO 2 -R 1-3B , wherein R 1-3A and R 1-3B are as defined above, (j) -NO 2, (k) -O-SO 2 -CF 3 ] (9) -OR 1-3A , wherein R 1-3A is as defined above, (10) -NR 1-3A R 1-3B , wherein R 1-3A and R 1-3B are as defined above, (O) -NR 1-1 -SO 2 -R 1-3 , wherein R 1-1 and R 1-3 are the same or different and are as defined above, (P) - (CH 2) n2 -φ [ wherein, n 2 are as defined above, -φ optionally has one or two (1) -F, -Cl, -Br, -I, (2) -C N, (3) -CF 3, (4) C 1 -C 6 alkyl, (5) -OR 1-1 , wherein R 1-1 is as defined above, (6) -N (R 1-1 ) 2 , wherein R 1-1 is the same or different and is as defined above, (7) -CO-N (R 1-1 ) 2 , wherein R 1-1 is the same or different and is as defined above, (8) -SO 2 -N (R 1-1 ) 2 , wherein R 1-1 is the same or different and is as defined above, (9) -NR 1-1 -SO 2 - (R 1-1 ), wherein R 1-1 is the same or different and is as defined above, (10) -NO 2 , (11) -O-SO 2 -CF 3 ] (IV) R 2 is defined the same as R 1 , R 2 may be the same as or different from R 1 ; (V) Q 1 is (A) -CO-NQ 1-1 Q 1-2 [wherein Q 1-1 is (1) -H, (2) C 1 -C 8 alkyl, (3) C 2 -C 8 alkenyl containing 1 to 3 double bonds (=), (4) C 2 -C 8 alkynyls containing 1 or 2 triple bonds (≡) (5) C 3 -C 8 cycloalkyl, (6) -C 1 -C 3 alkyl, -C 3 -C 8 cycloalkyl, (7) -CF 3, (8) -SO 2 -CF 3, (9) - (CH 2) n7 -φ [ wherein, n 7 is 0 to 4, -φ optionally of one or two (a) -F, -Cl, -Br, -I, (b) -C N, (c) -CF 3, (d) C 1 -C 3 alkyl, (e) -OQ 1-1 A , wherein Q 1-1 A is -H, C 1 -C 6 alkyl, -CF 3 or -CH 2 -φ, (f) -NQ 1-1A Q 1-1B , wherein Q 1-1A and Q 1-1B are the same or different and Q 1-1B is -H, C 1 -C 6 alkyl, -CF 3 or - CH 2 -φ, Q 1-1 A is as defined above), (g) -CO-NQ 1-1A Q 1-1B , wherein Q 1-1A and Q 1-1B are as defined above, (h) -SO 2 -NQ 1-1A Q 1-1B , wherein Q 1-1A and Q 1-1B are as defined above, (i) -NQ 1-1 A- SO 2 -Q 1-1B , wherein Q 1-1A and Q 1-1B are as defined above, (j) -NO 2, (k) -O-SO 2 -CF 3 ] Q 1-2 (1) -H, (2) C 1 -C 8 alkyl, (3) C 2 -C 8 alkenyl containing 1 to 3 double bonds (=), (4) C 2 -C 8 alkynyls containing 1 or 2 triple bonds (≡) (5) C 3 -C 8 cycloalkyl, (6) -C 1 -C 3 alkyl, -C 3 -C 8 cycloalkyl, (7) -CF 3, (8) - (CH 2) n2 -φ [ wherein, n 2 are as defined, -φ optionally has one or two (a) -F, -Cl, -Br, -I, (b) -C N, (c) -CF 3, (d) C 1 -C 6 alkyl, (e) -OQ 1-2 A (wherein Q 1-2 A is (i) -H, (ii) C 1 -C 6 alkyl, (iii) -CF 3 alkyl, (iv) - (CH 2 ) -, (9) - (CH 2) n9 -Q 1-2B (CH 2) n10 -Q 1-2C { wherein, n 9, and n 10 is the same or different, from 0 to 4, Q is -O 1-2B - or -NQ 1-2D -, wherein Q is 1-2D (a) -H, (b) C 1 -C 8 alkyl, (c) 1 to 3 of C 2 -C 8 alkenyl group which contains a double bond, (d) C 2 -C 8 alkynyl containing one or two triple bonds, (e) C 3 -C 8 cycloalkyl, (f) -C 1 -C 3 alkyl, -C 3 -C 8 cycloalkyl, (g) -CF 3, (h) - (CH 2) n11 -φ [ wherein, n 11 is from 0 to 4, -φ optionally has one or two (i) -F, -Cl, -Br, -I, (ii) -C N, (iii) -CF 3, (iv) C 1 -C 3 alkyl, (v) -OQ 1-2 E, wherein Q 1-2 E is -H, C 1 -C 6 alkyl, -CF 3 or -CH 2 -φ, (vi) -NQ 1-2 E Q 1-2F , wherein Q 1-2E and Q 1-2F are the same or different and Q 1-2F is -H, C 1 -C 6 alkyl, -CF 3 or - CH 2 -φ, and Q 1-2 E is as defined above), (vii) -CO-NQ 1-2E Q 1-2F , wherein Q 1-2E and Q 1-2F are as defined above, (vii) -SO 2 -NQ 1-2E Q 1-2F ( wherein, Q and Q 1-2E 1-2F are as defined above), (ix) -NQ 1-2 E- SO 2 -Q 1-2F , wherein Q 1-2E and Q 1-2F are as defined above, (x) -NO 2, (xi) a -O-SO 2 -CF 3 is substituted with -, 1-2C Q is defined to be equal to Q 1-2D, Q 1-2C and 1-2D Q is the same or different}, and (B) -SO 2 -NQ 1-1 Q 1-2 , wherein Q 1-1 and Q 1-2 are as defined above, (C) -CO-OQ 1-3 wherein Q 1-3 is (1) -H, (2) -CF 3 , (3) C 1 -C 8 alkyl, (4) C 2 -C 8 alkenyl containing 1 to 3 double bonds (=), (5) C 2 -C 8 alkynyl containing one or two triple bonds (≡) (6) C 3 -C 8 cycloalkyl, (7) -C 1 -C 3 alkyl, -C 3 -C 8 cycloalkyl, (8) - (CH 2) n7 -φ [ wherein, n 7 are as defined above, -φ optionally has one or two (a) -F, -Cl, -Br, -I, (b) -C N, (c) -CF 3, (d) C 1 -C 3 alkyl, (e) -OQ 1-3 A , wherein Q 1-3 A is -H, C 1 -C 6 alkyl, -CF 3 or -CH 2 -φ, (f) -NQ 1-3A Q 1-3B , wherein Q 1-3A and Q 1-3B are the same or different and Q 1-3B is -H, C 1 -C 6 alkyl, -CF 3 or - CH 2 -φ, Q 1-3A is as defined above), (g) -CO-NQ 1-3A Q 1-3B , wherein Q 1-3A and Q 1-3B are as defined above, (h) -SO 2 -NQ 1-3A Q 1-3B ( wherein, Q 1-3A and 1-3B Q is as defined above), (i) -NQ 1-3A- SO 2 -Q 1-3B , wherein Q 1-3A and Q 1-3B are as defined above, (j) -NO 2, (k) -O-SO 2 -CF 3 ] (D) -CO-Q 1-3 , wherein Q 1-3 is as defined above, (E) -CO-imidazole, (F) -NQ 1-1 Q 1-2 , wherein Q 1-1 and Q 1-2 are as defined above, (G) -C (Q 1-3) = NOQ 1-4 ( wherein, Q 1-4 are defined the same as Q 1-3, Q 1-3 are as defined above, and Q 1-3 Q 1-4 may be the same or different), (H) -SO 2 -Q 1-3 (wherein, Q 1-3 are as defined above), (I) -N (Q 1-1 ) -SO 2 -Q 1-3 wherein Q 1-1 and Q 1-3 are as defined above, (J) 5-oxadiazole optionally substituted by one Q 1-5 wherein Q 1-5 is (1) -H, (2) -F, -Cl, -Br, -I (3) C 1 -C 8 alkyl, (4) C 2 -C 8 alkenyl containing 1 to 3 double bonds (=), (5) C 2 -C 8 alkynyl containing one or two triple bonds (≡) (6) C 3 -C 8 cycloalkyl, (7) -C 1 -C 3 alkyl, -C 3 -C 8 cycloalkyl, (8) -NO 2 , (9) -C N, (10) -CF 3, (11) -OQ 1-5 A [wherein Q 1-5 A is (a) -H, (b) C 1 -C 8 alkyl, (c) 1 to 3 of C 2 -C 8 alkenyl group which contains a double bond, (d) C 2 -C 8 alkynyl containing one or two triple bonds, (e) C 3 -C 8 cycloalkyl, (f) -C 1 -C 3 alkyl, -C 3 -C 8 cycloalkyl, (g) -CF 3, (h) -SO 2 -CF 3, (i) - [wherein a, n 7 is 0 to 4)], (CH 2) n7 -φ (12) -NQ 1-5A Q 1-5D wherein Q 1-5A is as defined above and Q 1-5D is (a) -H, (b) C 1 -C 8 alkyl, (c) 1 to 3 of C 2 -C 8 alkenyl group which contains a double bond, (d) C 2 -C 8 alkynyl containing one or two triple bonds (≡) (e) C 3 -C 8 cycloalkyl, (f) -C 1 -C 3 alkyl, -C 3 -C 8 cycloalkyl, (g) -CF 3, (h) - (CH 2) n7 -φ [ wherein, n 7 is as defined above)], (13) -CO-NQ- 5A Q 1-5D , wherein Q 1-5A and Q 1-5D are as defined above, (14) -SO 2 -Q 1-5K [wherein Q 1-5K is (a) -H, (b) -CF 3, (c) C 1 -C 8 alkyl, (d) 1 to 3 double bonds (=) C 2 -C 8 alkenyl group containing, (e) C 2 -C 8 alkynyl containing 1 or 2 triple bonds (≡) (f) C 3 -C 8 cycloalkyl, (g) -C 1 -C 3 alkyl, -C 3 -C 8 cycloalkyl, (h) - (CH 2) n7 -φ [ wherein, n 7 is as defined above)], (15) -NQ 1-5 A -SO 2 -Q 1-5 K , wherein Q 1-5 A and Q 1-5 K may be the same or different and are as defined above, (16) - (CH 2) n7 -φ ( In this case, n7 are as defined above, -φ is randomly different one or two (a) -F, -Cl, -Br, -I, (b) -C N, (c) -CF 3, (d) C 1 -C 6 alkyl, (e) -OQ 1-5 A , wherein Q 1-5 A is as defined above, (f) -NQ 1-5A Q 1-5D , wherein Q 1-5A and Q 1-5D are as defined above, (g) -CO-NQ- 5A Q 1-5D , wherein Q 1-5A and Q 1-5D are as defined above, (h) -SO 2 -NQ 1-5A Q 1-5D ( wherein, Q and Q 1-5D 1-5A is as defined above), (i) -NQ 1-5A- SO 2 -Q 1-5D , wherein Q 1-5A and Q 1-5D are as defined above, (j) -NO 2, (k) -O-SO 2 -CF 3 ] (K) by a single Q 1-5, optionally substituted 3-oxadiazole (wherein, Q 1-5 are as defined above), (L) or one by Q 1-5 in two may be the same or different optionally substituted triazole (wherein, Q 1-5 are as defined above), (M) by a single Q 1-5 optionally substituted 5-thiadiazole (wherein, Q 1-5 are as defined above), (N) by a single Q 1-5, optionally substituted 3-thiadiazole (wherein, Q 1-5 are as defined above), (O) one or by two Q 1-5 which may be the same or different optionally substituted oxazol-2 (wherein, Q 1-5 are as defined above), (P) by a one or two Q 1-5 which may be the same or different optionally substituted thiazol-2 (wherein, Q 1-5 are as defined above), (Q) a, (the same as this time, 1-5 Q are defined above) or both by Q 1-5 in three may be the same or different 2-imidazole group optionally substituted, (R) one, two, or by Q 1-5 with three, same or different a 1-imidazole group optionally substituted (wherein, Q 1-5 are as defined above), (S) a tetrazole optionally substituted by one Q < 1-5 > wherein Q < 1-5 > is as defined above, (T) Cyclobutenedione optionally substituted by one Q 1-1 and one Q 1-5 , wherein Q 1-1 and Q 1-5 are as defined above, (U) by a single Q 1-5, optionally substituted 1-pyrimidinyl (wherein, Q 1-5 are as defined above), (V) by a single Q 1-5 optionally substituted 2-pyridinyl (wherein, Q 1-5 are as defined above), (W) by a single Q 1-5, optionally substituted 3-pyridinyl (wherein Q 1-5 are as defined above), (X) by a single Q 1-5 optionally substituted 4-pyridinyl (wherein, Q 1-5 are as defined above), With the proviso that when X 1 is - (CH 2 ) n1 - (where n1 is 0) and Q 1 is -CO-NQ 1-1 Q 1-2 , -SO 2 -NQ 1-1 Q 1-2 , -NQ 1-1 Q 1-2 , or In the case of -NQ 1-1 -CO-Q 1-2 , both Q 1-1 and Q 1-2 are -H, -C 1 -C 6 alkyl, -C 3 -C 7 cycloalkyl, C 1 -C 3 alkyl- (C 3 -C 7 ) cycloalkyl, and a pharmaceutically acceptable salt thereof. [3" claim-type="Currently amended] The method according to claim 1, 1,6-disubstituted isochroman (I) wherein W 1 is a nitrogen atom. [4" claim-type="Currently amended] The method according to claim 1, 1,6-disubstituted isochroman (I) wherein W 1 is a carbon atom. [5" claim-type="Currently amended] The method according to claim 1, 1 , 6-disubstituted isochroman (I) wherein X 1 is - (CH 2 ) n1 -. [6" claim-type="Currently amended] 6. The method of claim 5, 1,6-disubstituted isochroman (I) wherein n 1 is 0 or 1. [7" claim-type="Currently amended] The method according to claim 1, 1,6-disubstituted isochroman (I) wherein X 1 is -CH = CH-. [8" claim-type="Currently amended] The method according to claim 1, 1 , 6-disubstituted isochroman (I) wherein R 1 is -OR 1-1 , -CF 3 , -CO-N (R 1-1 ) 2 and -CO-R 1-1 . [9" claim-type="Currently amended] 8. The method of claim 7, R 1-1 is C 1 -C 3 alkyl, isopropyl 1,6-disubstituted chroman (I). [10" claim-type="Currently amended] The method according to claim 1, 1,6-disubstituted isochroman (I) wherein R 2 is -H. [11" claim-type="Currently amended] The method according to claim 1, Q 1 is selected from the group consisting of -CO-NQ 1-1 Q 1-2 , -SO 2 -NQ 1-1 Q 1-2 and -NQ 1-1 Q 1-2 , and 1,6-disubstituted iso Chromman (I). [12" claim-type="Currently amended] 11. The method of claim 10, Q 1 is -CO-NQ 1-1 Q 1-2 , 1, 6-disubstituted isochroman (I). [13" claim-type="Currently amended] 12. The method of claim 11, The pharmaceutically acceptable anion salt is selected from the group consisting of methanesulfonate, hydrochloride, hydrobromide, sulfate, phosphate, nitrate, benzoate, citrate, tartrate, fumarate, maleate, CH 3 - (CH 2 ) n -COOH where n is the only salt, HOOC- (CH 2) n -COOH ( where n is 1,6-disubstituted iso-chroman is selected from the group consisting of a salt of the same as defined above) of from 0 to 4) (I) . [14" claim-type="Currently amended] The method according to claim 1, 1 , 6-disubstituted isochroman (I) wherein R 1 is (Q) -CO-R 1-1 or -CO-OQ 1-2 . [15" claim-type="Currently amended] 15. The method of claim 14, (S) - (-) - 1- [2- [4- (4-trifluoroacetylphenyl) -1-piperazinyl] ethyl] -N- methylisochroman- 6-Disubstituted isochroman (I). [16" claim-type="Currently amended] The method according to claim 1, 1 , 6-disubstituted isochroman (I) wherein Q 1 is (Y) -Z 1 -CO-Z 2 -Q 1-2 . [17" claim-type="Currently amended] 17. The method of claim 16, (S) - (-) - 6-amino-1- [2- [4- (4-methoxyphenyl) piperazin- 1- yl] ethyl] isochromanemethylurea, (S) - (-) - 6- amino-1- [2- [4- (4- methoxyphenyl) piperazin- 1 -yl] ethyl] isochroman- (+/-) -1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] isochroman-6-ol methylcarbamate ester. - Discrete isochroman (I). [18" claim-type="Currently amended] The method according to claim 1, (I) wherein Q 1 is (F ') -NQ 1-1 -CO-Q 1-2 . [19" claim-type="Currently amended] 19. The method of claim 18, (S) - (-) - N- isochroman-1- [2- [4- (4- methoxyphenyl) piperazin- 1 -yl] ethyl] (S) - (-) - N- [isochroman-1- [2- [4- (4-methoxyphenyl) piperazin- 1-yl] ethyl] Selective 1,6-disubstituted isochroman (I). [20" claim-type="Currently amended] The method according to claim 1, 1,6-disubstituted isochroman (I) which forms a 5 or 6 membered ring together with the nitrogen atom to which Q 1-1 and Q 1-2 are attached. [21" claim-type="Currently amended] 21. The method of claim 20, (I) wherein the 5 or 6 membered ring is selected from the group consisting of pyrrolidines, piperidines, piperazines and morpholines. [22" claim-type="Currently amended] 21. The method of claim 20, Yl) -4-methylpiperazine, which is a 1,6-di-tert-butyl-2- (4-methoxyphenyl) piperazinyl] ethyl] isochroman- Isochroman (I). [23" claim-type="Currently amended] The method according to claim 1, 1- [2- [4- (4-methylsulfonylphenyl) -1-piperazinyl] ethyl] isochroman- (S) - (-) - 1- [2- [4- (4-Trifluoromethoxyphenyl) -1-piperazinyl] ethyl] -N- methylisochroman- 1- [2- [4- (4-methylsulfonylphenyl) -1-piperazinyl] ethyl] -N-methylisochroman- 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] -N-allyloxochroman- 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] -N- propargylsulfochroman-6-carboxamide, 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] -N- (4-methoxyphenylmethyl) isochroman- 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] -N-phenylmethylisochroman- - [(R) - [alpha] -methylphenylmethyl] -isochroman-6-carboxamide, 1- [2- [4- (4-methoxyphenyl) - [(S) - [alpha] -methylphenylmethyl] -isochroman-6-carboxamide, 1- [2- [4- (4-methoxyphenyl) 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] -N-phenylisochroman- 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] -N-phenylmethyl-N-methylisochroman- Yl] ethyl] piperazine, < / RTI > < RTI ID = 0.0 & (S) - (-) - N- [isochroman-1- [2- [4- (4- methoxyphenyl) piperazin- 1 -ethyl] 1- (4-methoxyphenyl) -4- [2- (6-methylaminomethylisochroman-1-yl) ethyl] piperazine, 1- (4-methoxyphenyl) -4- [2- (6-dimethylaminomethylisochroman-1-yl) ethyl] piperazine, 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] isochroman-6- 6-acetyl-1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] 6-formyl-1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] isochroman, Yl] ethyl] -6- < RTI ID = 0.0 > yl] acetamide, < Yl] ethyl] -6-yl] -N-methylacetamide, < RTI ID = 0.0 & (S) - (-) - 3- [isochroman-1- [2- [4- (4-methoxyphenyl) piperazin- 1 -yl] ethyl] Acrylamide, (S) - (-) - 1- (4-methoxyphenyl) -4- [6- (1,2,4- triazol- , (S) - (-) - 1- (4-methoxyphenyl) -4- [2- [6- -Yl] ethyl] piperazine, (S) - (-) - 1- (4-methoxyphenyl) -4- [2- [6- (2-phenylmethyl-1,2,4- triazol- 1-yl] ethyl] piperazine, (S) - (-) - 1- (4-methoxyphenyl) -4- [2- [6- (1,2,4- oxadiazol- Ethyl] piperazine, 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] isochroman-6- yl] carbonyl] pyrrolidine, N- (2-hydroxyethyl) -1- [2-4- (4-methoxyphenyl) -1-piperazinyl] ethyl] isochroman- 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] -N- (phenylmethoxy) isochroman- (+/-) - N-hydroxy-1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] -N- methylisochroman- (S) - (-) - 1- [2- [4- (4-aminocarbonyl) phenyl] -1- piperazinyl] ethyl] 6-carboxamide, (S) - (-) - 1- [2- [4- [4- (aminocarbonyl) phenyl] -1- piperazinyl] ethyl] -N- Carboxamide, (S) - (-) - N-hydroxy-N-methyl-1- [2- [4- [4- (trifluoromethyl) phenyl] -1- piperazinyl] ethyl] isochroman- - carboxamide, (S) - (-) - 1- [2- [4- (4-chlorophenyl) -1- piperazinyl] ethyl] -N- (S) - (-) - l- [2- [4- (4-cyanophenyl) -1-piperazinyl] ethyl] -N-hydroxy-N-methylisochroman- , (S) - (-) - N-hydroxy-N-methyl-1- [2- [4- [4- (methylcarbonyl) phenyl] -1- piperazinyl] ethyl] isochroman- Carboxamide, (S) -4- [4- [2- [6- (1,2,4-triazol-3-yl) isochroman- 1-yl] ethyl] -1- piperazinyl] (S) -4- [4- [2- [6- (2-methyl-1,2,4-triazol-3-yl) isochroman-1-yl] ethyl] Benzamide, (S) -4- [4- [2- [6- (1,2,4-oxadiazol-5-yl) isochroman-1-yl] ethyl] -1- piperazinyl] (S) -1- [2- [6- (1,2,4-triazol-3-yl) isochroman-1-yl] ethyl] -4- [4- trifluoromethylphenyl] piperazine, (S) -1- [2- [6- (2-methyl-1,2,4-triazol-3-yl) isochroman- 1 -yl] ethyl] -4- [4- ] Piperazine, (S) -1- [2- [6- (1,2,4-oxadiazol-5-yl) isochroman-1-yl] ethyl] -4- [4-trifluoromethylphenyl] piperazine , (S) -1- [4- acetylphenyl] -4- [2- [6- (1,2,4-triazol-3-yl) isochroman-1-yl] ethyl] piperazine, (S) -1- [4- acetylphenyl] -4- [2- [6- (2-methyl-1,2,4- triazol- Rajin, (S) -1- [4- acetylphenyl] -4- [2- [6- (1,2,4-oxadiazol-5-yl) isochroman-1-yl] ethyl] piperazine, Yl] ethyl] -isochroman-6-yl] -N, N-dimethylacrylamide, Yl] ethyl] -isochroman-6-yl] -N, N-dimethylacrylamide, N- [ 1-yl] -N, N-dimethylacrylamide selected from the group consisting of 3- [1- [2- [4- (4-acetylphenyl) piperazin- 1-yl] ethyl] , 6-disubstituted isochroman (I). [24" claim-type="Currently amended] An aromatic bicyclic amine of formula (ABA) and a pharmaceutically acceptable salt thereof: The formula ABA Wherein: (I) W 1 is nitrogen (-N-) or carbon (288t-2) atoms; (II) X 1 is - (CH 2 ) n1 -, wherein n 1 is 0; (III) Q < 1 > is: (A) -CO-NQ 1-1 Q 1-2 {wherein Q 1-1 is (1) -H (2) C 1 -C 8 alkyl, (3) C 2 -C 8 alkenyl containing 1 to 3 double bonds (=), (4) C 2 -C 8 alkynyls containing 1 or 2 triple bonds (≡) (5) - (CH 2) n7 -φ [ wherein, n 7 is 0 to 4, -φ optionally of one or two (a) -F, -Cl, -Br, -I, (b) -C N, (c) -CF 3, (d) C 1 -C 6 alkyl, (e) -OQ 1-1 A , wherein Q 1-1 A is -H, C 1 -C 6 alkyl, -CF 3 or -CH 2 -φ, (f) -NQ 1-1A Q 1-1B , wherein Q 1-1A and Q 1-1B are the same or different and Q 1-1B is -H, C 1 -C 6 alkyl, -CF 3 or - CH 2 -φ, Q 1-1 A is as defined above), (g) -CO-NQ 1-1A Q 1-1B , wherein Q 1-1A and Q 1-1B are as defined above, (h) -SO 2 -NQ 1-1A Q 1-1B , wherein Q 1-1A and Q 1-1B are as defined above, (i) -NQ 1-1 A- SO 2 -Q 1-1B , wherein Q 1-1A and Q 1-1B are as defined above, (j) -NO 2, (k) -O-SO 2 -CF 3 ] Q 1-2 (6) C 1 -C 8 alkyl, (7) C 2 -C 8 alkenyl containing 1 to 3 double bonds (=), (8) C 2 -C 8 alkynyl containing 1 or 2 triple bonds (≡) (9) - (CH 2) n2 -φ [ wherein, n2 are as defined above, -φ optionally one or two (a) -F, -Cl, -Br, -I, (b) -C N, (c) -CF 3, (d) C 1 -C 3 alkyl, (e) -OQ 1-2 A (wherein Q 1-2 A is (i) -H, (ii) C 1 -C 6 alkyl, (iii) -CF 3 (iv) - (CH 2 ) -, (B) -SO 2 -NQ 1-1 Q 1-2 , wherein Q 1-1 and Q 1-1 are as defined above, (C) -NQ 1-1 Q 1-2 , wherein Q 1-1 and Q 1-2 are as defined above, (D) -NQ 1-1 -CO-Q 1-2 wherein Q 1-1 and Q 1-2 are as defined above, (III) R < 1 > (A) -H, (B) -F, -Cl, -Br, -I, (C) C 1 -C 8 alkyl, (D) -C N, (E) -CF 3, (F) -OR 1-1 wherein R 1-1 is (1) -H (2) C 1 -C 8 alkyl, (3) -CF 3, (4) -SO 2 -CF 3, 5 - is (CH 2) n2 -φ (wherein, n 2 is 0 to 4)], (G) -N (R 1-1 ) 2 , wherein R 1-1 may be the same or different and are as defined above, (H) -CO-N (R 1-1 ) 2 , wherein R 1-1 may be the same or different and are as defined above, (I) -SO 2 -R 1-3 [wherein, R 1-3 is (1) -CF 3 , (2) C 1 -C 8 alkyl, (3) -OR 1-3A , wherein R 1-3A is as defined above, (4) -NR 1-3A R 1-3B , wherein R 1-3A and R 1-3B are as defined above, (J) -CO-R 1-1 (wherein, R 1-1 is as defined above), and; (IV) R 2 is defined the same as R 1, and R 2 may be the same as or different from R 1 . [25" claim-type="Currently amended] 25. The method of claim 24, An aromatic bicyclic amine (ABA) wherein W < 1 > is (-N-). [26" claim-type="Currently amended] 25. The method of claim 24, An aromatic bicyclic amine (ABA) wherein one of R 1 and R 2 is -H. [27" claim-type="Currently amended] 25. The method of claim 24, Q 1 is (A) -CO-NQ 1-1 Q 1-2 aromatic bicyclic amine (ABA). [28" claim-type="Currently amended] 28. The method of claim 27, Q 1-1 A -H aromatic bicyclic amine (ABA). [29" claim-type="Currently amended] 28. The method of claim 27, Q 1-2 is an aromatic bicyclic amine (ABA) with -CH 3 . [30" claim-type="Currently amended] 28. The method of claim 27, The pharmaceutically acceptable anion salt is selected from the group consisting of methanesulfonate, hydrochloride, hydrobromide, sulfate, phosphate, nitrate, benzoate, citrate, tartrate, fumarate, maleate, CH 3 - (CH 2 ) n -COOH Wherein n is from 0 to 4, HOOC- (CH 2 ) n -COOH, wherein n is as defined above. [31" claim-type="Currently amended] 28. The method of claim 27, The substituted amino compound (S) - (-) - 1- [2- [4- (4-methoxyphenyl) -1- piperazinyl] ethyl] -N- methylisochroman- (R) - (+) - 1- [2- [4- (4-methoxyphenyl) -1- piperazinyl] ethyl] -N- methylisochroman- (S) - (-) - 1- [2- [4- (4-Trifluoromethylphenyl) -1- piperazinyl] ethyl] -N- methylisochroman- (S) - (-) - 1- [2- [4- (4-aminocarbonyl) phenyl] -1- piperazinyl] ethyl] -N- methylisochroman- 1- [2- [4- (4-ethoxyphenyl) -1-piperazinyl] ethyl] -N-methylisochroman- 1- [2- [4- (4-propoxyphenyl) -1-piperazinyl] ethyl] -N-methylisochroman- (S) - (-) - 1- [2- [4- (4-ethylphenyl) -1- piperazinyl] ethyl] -N- methylisochroman- (S) - (-) - 1- [2- [4- (4-ethoxyphenyl) -1-piperazinyl] ethyl] -N- methylisochroman- (S) - (-) - 1- [2- [4- (4-phenylmethyloxyphenyl) -1- piperazinyl] ethyl] -N- methylisochroman- (R) - (+) - 1- [2- [4- (4-ethoxyphenyl) -1- piperazinyl] ethyl] -N- methylisochroman- 1- [2- [4- (3-trifluoromethylphenyl) -1-piperazinyl] ethyl] -N-methylisochroman- 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] -N-propylisochroman- 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] -N-methylisochroman- 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] -N-butylisochroman- 1- [2- [4- (4-chlorophenyl) -1-piperazinyl] ethyl] -N-methyl isochroman- (S) - (-) - 1- [2- [4- (4-methoxyphenyl) -1-piperidinyl] ethyl] -N- methylisochroman- (S) - (-) - 1- [2- [4- (4-hydroxyphenyl) -1-piperazinyl] ethyl] -N- methylisochroman- (S) - (-) - 1- [2- [4- (4-trifluoromethanesulfonyloxyphenyl) -1- piperazinyl] ethyl] -N- methylisochroman-6- carboxamide , (S) - (-) - 1- [2- [4- (4-acetylphenyl) -1-piperazinyl] ethyl] -N- methylisochroman- (S) - (-) - N-methyl-1- [2- [4- (4-propionylphenyl) -1- piperazinyl] ethyl] isochroman- N-methyl-1- [2- (4-phenyl-1-piperidinyl) ethyl] isochroman- (+/-) -N-methyl-1- [2- [4- (2,4-dichlorophenyl) -1-piperazinyl] ethyl] -isochroman- (+/-) - 1- [2- [4- (3-chloro-4-methoxyphenyl) -1- piperazinyl] ethyl] -N- methylisochroman- (S) - (-) - 1- [2- [4- [4-t-butyloxycarbonyl) phenyl] -1- piperazinyl] ethyl] -N- methylisochroman- amides, (+/-) - 1- [2- [4- [4-Aminocarbonyl) phenyl] -1-piperazinyl] ethyl] -N- methylisochromanyl- (R) - (+) - 1- [2- [4- [4-aminocarbonyl) phenyl] -1- piperazinyl] ethyl] -N- methylisochromanyl- (+/-) - 1- [2- [4- [4-aminosulfonyl) phenyl] -1-piperazinyl] ethyl] -N- methylisochroman- (S) - (-) - N-methyl-1- [2- [4- [4-methylaminocarbonyl) phenyl] -1- piperazinyl] ethyl] isochroman- (S) - (-) - N-methyl-1- [2- [4- [4- (dimethylaminocarbonyl) phenyl] -1- piperazinyl] ethyl] isochroman- (S) - (-) - N-methyl-1- [2- [4- [4- (n-propylaminocarbonyl) phenyl] -1- piperazinyl] ethyl] isochroman- Aromatic amorphous amines (ABA) selected from the group consisting of amides. [32" claim-type="Currently amended] 32. The method of claim 31, The substituted amino compound (S) - (-) - 1- [2- [4- (4-Trifluoromethylphenyl) -1-piperazinyl] ethyl] -N- methylisochroman-6-carboxamide and (S) - (-) - l- [2- [4- [4- (aminocarbonyl) phenyl] -1- piperazinyl] ethyl] -N-methyl isochroman-6-carboxamide An aromatic bicyclic amine (ABA) selected from the group. [33" claim-type="Currently amended] 28. The method of claim 27, The substituted amino compound 1- [2- [4- (4-chlorophenyl) -1-piperazinyl] ethyl] -N, N- dimethylisochroman- (S) - (-) - 1- [2- [4- (4-Trifluoromethylphenyl) -1-piperazinyl] ethyl] -N, N-dimethylisochroman-6-carboxamide An aromatic bicyclic amine (ABA) selected from the group. [34" claim-type="Currently amended] 25. The method of claim 24, The substituted amino compound 1- [2- (6-aminoisochroman-1-yl) -ethyl] -4- (4-methoxyphenyl) piperazine, (S) - (-) - l- [2- (6-aminoisochroman-l-yl) -ethyl] -4- (4-methoxyphenyl) piperazine, (S) - (-) - 1- [2- (6-ethylaminoisochroman-1-yl) -ethyl] -4- (4-methoxyphenyl) piperazine, (S) - (-) - 1- (4-methoxyphenyl) -4- [2- (6-propylaminoisochroman- (S) - (-) - 1- (4-methoxyphenyl) -4- [2- (6-methylaminoisochroman- (S) - (-) - 1- (4-methoxyphenyl) -4- [2- (6-dimethylaminoisochroman- An aromatic bicyclic amine selected from the group consisting of (S) - (-) - 1- [2- (6-ethylmethylaminoisochroman-1-yl) ethyl] -4- (4-methoxyphenyl) piperazine (ABA). [35" claim-type="Currently amended] 25. The method of claim 24, The substituted amino compound (S) - (-) - N- [isochroman-1- [2- [4- (4- methoxyphenyl) piperazin- 1- yl] ethyl] (S) - (-) - N- isochroman-1- [2- [4- (4- methoxyphenyl) piperazin- 1 -yl] ethyl] (S) - (-) - N- [isochroman-1- [2- [4- (4-methoxyphenyl) piperazin- 1- yl] ethyl] (S) - (-) - N- [isochroman-1- [2- [4- (4-methoxyphenyl) piperazin- 1- yl] ethyl] -6- yl] isobutyramide, (S) - (-) - N- [isochroman-1- [2- [4- (4-methoxyphenyl) piperazin- 1- yl] ethyl] , (S) - (-) - N- isochroman-1- [2- [4- (4- methoxyphenyl) piperazin- 1- yl] ethyl] Aromatic amorphous amines (ABA) selected from the group consisting of amides. [36" claim-type="Currently amended] (S) - (-) - 1- [2- [4- (4-methoxyphenyl) -1- piperazinyl] ethyl] isochroman- (R) - (+) - 1- [2- [4- (4-methoxyphenyl) -1- piperazinyl] ethyl] isochroman- 1- [2- [4- (4-diethylaminophenyl) -1-piperazinyl] ethyl] isochroman- 1- [2- [4- (3-Trifluoromethylphenyl) -1-piperazinyl] ethyl] isochroman- (S) - (-) - 1- [2- [4- (4-Trifluoromethylphenyl) -1-piperazinyl] ethyl] isochroman- 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] isochroman- 1- [2- [4-phenylpiperazinyl] ethyl] isochroman-6-carboxamide, 1- [2- [4- (4-hydroxyphenyl) -1-piperazinyl] ethyl] isochroman- (+/-) - 1- [2- (4-phenyl-1-piperidinyl) ethyl] isochroman-6- (+/-) - 1- [2- (2- [4- (2,4-dichlorophenyl) -1-piperazinyl] ethyl] isochroman- An aromatic bicyclic amine selected from the group consisting of 1- [2- [4- (3-chloro-4-methoxyphenyl) -1-piperazinyl] ethyl] isochroman-6-carboxamide. [37" claim-type="Currently amended] 37. The method of claim 36, (S) - (-) - 1- [2- [4- (4-methoxyphenyl) -1- piperazinyl] ethyl] isochroman- (R) - (+) - 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] isochroman-6-carboxamide. [38" claim-type="Currently amended] 37. The method of claim 36, The pharmaceutically acceptable anion salt is selected from the group consisting of methanesulfonate, hydrochloride, hydrobromide, sulfate, phosphate, nitrate, benzoate, citrate, tartrate, fumarate, maleate, CH 3 - (CH 2 ) n -COOH Wherein n is from 0 to 4, HOOC- (CH 2 ) n -COOH, wherein n is as defined above.
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公开号 | 公开日 HU9802226A2|2000-08-28| HU9802226A3|2000-11-28|
引用文献:
公开号 | 申请日 | 公开日 | 申请人 | 专利标题
法律状态:
1996-02-06|Priority to US1123496P 1996-02-06|Priority to US60/011.234 1996-06-07|Application filed by 파마시아 앤드 업죤 컴패니 1999-04-15|Publication of KR19990028550A
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