CZ418597A3 - 1,6-disubstituted isochromans for treating headache during migraine - Google Patents

Abstract

The present invention is 1,6-disubstituted isochromans of formula (I) and aromatic bicyclic amines (ABA) which are useful for the treatment of headaches, especially migraine and cluster headaches and also useful as antipsychotics and for the treatment of other CNS and/or cardiovascular disorders and as analgesics.

Description

Technical field

The invention relates to isochroman-alkyl piperazinyl / piperidinyl aryl compounds which can be used for the treatment of headaches, in particular migraine and cluster headaches, as analgesics and also as antipsychotics and for the treatment of other CNS diseases and / or cardiovascular disorders.

BACKGROUND OF THE INVENTION

Chromates (also known as 1-benzopyrans where the oxygen atom is part of the aromatic ring) and isochromans (also known as the 2-benzopyrans where the oxygen atom is not part of the aromatic ring) are previously known as arylpiperazines (or 4-arylpiperidines). Chromates and arylpiperazines linked by an alkyl chain are also known. European Patent 300,908 discloses (1-benzopyran)] -alkyl- (piperazinyl or aminopiperidine) -aryls used as antiarrhythmic and anticoagulants. The compounds of the invention require -alkyl-piperazinyl (or piperidinyl) -aryl on carbon number 1 of the 2-benzopyran ring, as well as substitution at the 6-position of isochroman, useful for the treatment of vascular (migraine and cluster) headaches, CNS and cardiovascular diseases.

Various isochromans, thioisochromans, benzoxepines and benzothiepines are known with hydroxy, alkoxy or o-methylenedioxy substitution on aromatic rings and linked to arylpiperazines (piperidines) by alkyl chains. These compounds are used as antipsychotics and hypotensives. The compounds of the invention do not permit oxygen substitution on the aromatic ring of isochroman, thioisochroman, benzoxepine or benzothiepine on the aromatic system for use in CNS and cardiovascular disorders.

Yet another class of isochromans, thioisochromans, benzoxepines and benzothiepines with hydroxy, alkoxy or o-methylenedioxy functional groups attached to aromatic rings, and attached to arylpiperazines (piperidines) by alkyl chains, is used as antipsychotics and hypotensives. The compounds of the invention do not permit oxygen substitution on the aromatic ring of isochroman, thioisochroman, benzoxepines or the benzothiepine aromatic system for use in CNS and cardiovascular diseases.

· · · · * 9 9 9 «« «« 9 · ««

US Patent 4,179,510 and a number of its parts disclose isochromanalkylpiperazinyl (or aminopiperidinyl) -aryls with substituted oxygen on the aromatic ring of isochroman. These compounds are reported to be used as hypotensive and antipsychotic agents.

Also disclosed are isochroman-, isothiochroman-, 2-benzoxepine-, and 2-benzothiepine-alkyloxyethanols used to prepare the above compounds. In particular, 7,8-dimethoxybenzoxepines such as 1 - [(6,7-dimethoxyisochroman) alkyl] -4- (aryl) piperazines. Further disclosed are 2-benzoxepines-alkyl-piperazine (aminopiperidine) -aryls, 2-benzothiepines and 2-benzoxepines having an oxygen atom substituted on the aromatic ring used for the same purposes.

Danish Patent 8,001,981 discloses 1- (2-chlorophenyl) -4- [2- (1,2,3,4,5-tetrahydro-7,8-dimethoxy-2-benzoxepin-1-yl) ethyl] piperazine used as an antipsychotic agent.

International patent publication WO 92/18089 discloses isochromans-alkylpiperazinyl (or aminopiperidinyl) -aryls with the requirement that oxygen is present on the aromatic ring of isochroman, which are used on sensitized cells against drug resistance.

International patent publication WO 88/08424 discloses isochromans-alkylpiperazinyl (or aminopiperidinyl) -aryls with the requirement that oxygen is present on the aromatic ring of isochroman used in head injuries, spinal injuries and heart attacks.

International Patent Publication WO 90/15056 and US Patent 5,140,040 disclose isochromans, tetralins and dihydroanaphthalenes substituted with various alkylamines for the treatment of glaucoma, depression, hypertension, congestive heart failure and vascular contractility disorders.

US Patent 4,994,486 discloses isochroman-alkyl-amines for the treatment of psychoses, Parkinson's disease and addictive behaviors.

Japanese Patent 61083180 discloses isochroman-alkyl- (alkyl) amines as antiulcer agents.

European Patent 404,197 discloses isochroman-alkyl-piperazine-alkyl keto (alcohol) -aryls with bronchodilator and antiallergic activity.

Japanese patent 51125287 (J 52083846) discloses isochroman-alkyl-amines (piperazine) with antidepressant, analgesic, diuretic, anti-inflammatory and anti-asthmatic activity.

German patent DE 2,624,693 and English patent GB 1552004 disclose isochroman-alkyl-amines including arylpiperazines as analgesics, hypotensive drugs, antidepressants, diuretics, anti-inflammatory agents, muscle relaxants and vasodilators. The compounds differ from the compounds of the invention in that oxygen substitution on the aromatic ring of isochroman is desired.

Japanese Patent 57159713 discloses isochroman- and tetralin- (without alkyl arm) -piperazine-aryls as antiallergics. The compounds of the invention require at least one linking carbon.

US Patents 3,549,656 and 3,467,675 and Belgian Patent 678,035 disclose phthalate, isochroman, and isochromene-alkylene-amines for the treatment of depression.

European Patent 458,387 and US Patent 5,137,911 disclose isochroman-alkylene-piperazine-alkylene-aryls used as platelet coagulation inhibitors, as intracellular calcium antagonists and for the treatment of cardiac arrhythmias, angina pectoris, stroke and myocardial infarction.

German patent DE 3,409,612 discloses dimethoxyisochroman- and benzoxepinalkyl-amino-alkyls for the prevention of cardiovascular diseases or hypertension.

Japanese Patent 6,108,380 discloses isochromans-alkyl amines for the treatment of ulcers. European patent 457,686 discloses phthalate and indanalkylaminopiperidinylureas or carbamates for the treatment of stress, pain and schizophrenia.

J. Med. Chem., 25 (1), 75-81 (1982) discloses the 6,7-dimethoxyisochroman-alkylpiperazinyl-aryl type of compounds with hypotensive activity.

US Patent 5,032,598 and 5,215,989 generically associate the isochromans and tetralins of the invention when variable substituents are suitably selected.

International Publication No. WO 88/08424 and US Patent 5,120,843 disclose a dialkoxyisochroman containing a substituted pyridinylpiperazinylethyl side chain. However, the compounds of the invention do not allow alkoxy substitution.

International Publication No. WO 95/18118 (PCT / US94 / 13284) discloses various isochromans such as 6- (substituted) amino (6-NRR) and 6- (substituted) amide (6CO-NRR) isochromans used for the treatment of patients with diseases central nervous system including psychosis, parafrenia, psychotic depression, mania, schizophrenia and schizophrenic forms of the disease. These compounds are also used in the treatment of vascular headaches, especially migraine headaches. Other central nervous system diseases that can be treated with these compounds include anxiety, drug dependence, seizures, visual perception disorders, personality disorders, impaired attention in children and adults, post-traumatic stress syndrome, and arrhythmia. WO 95/18118 discloses racemic 1- (4-methoxyphenyl) -4- [2- (6-aminocarbonylisochroman-1-yl) ethylpiperazine (Example 138) and 1- (4-methoxyphenyl) -4- [2- (6-methylaminocarbonylisochroman- 1-yl) -ethylpiperazine (Example 139).

SUMMARY OF THE INVENTION

The 1,6-disubstituted isochromans are represented by the formula (I) wherein:

(I) W 1 is a nitrogen (-N-) or carbon atom (-CH-);

(II) X-i is:

(A) + _(CH2) n - wherein Πί is 0-3, (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 (ξ), (F) C ₃ -C ₈ cycloalkyl, (G) -C 1 -C ₃ alkyl-C ₃ -C ₈ cycloalkyl, (H) -NO (I) -ON, (J) -cf (K) -O-Rvi, where R m is.

(1) -H (2) C 1 -C 8 alkyl, · alkyl alkyl, alkyl, · alkyl · · · · · · · · (3) C ₂ -C ₈ alkenyl containing 1 to 3 double bonds (=), (4) C ₂ -C ₈ alkynyl containing 1 or 2 triple bonds (= 0, (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 ) _{n 2} -φ where n ₂ is 0 to 4 and wherein -φ is optionally substituted by one or two:

(a) -F, -Cl, -Br, -I, (b) -C =N, (c) -CF ₃ , (d) C 1 -C ₃ alkyl, (e) -O-R _1A , wherein R _1A is -H, C 1 -C ₆ alkyl, -CF _3, or -CH ₂ -φ, (f) -NR m R m where R m _A and R v w are the same or different, and wherein R m is -H, C 1 -C 6 alkyl , -CF ₃ or -CH ₂ -φ where Rm and _a are as defined above, (g) -CO _and R -NRm MB are as defined above, (h) -SO _{2 -NR-i} Ri.ib wherein _Rm and RMB are as defined above, (i) _and -SO ₂ -NRm -Rmb wherein _Rm and RMB are as defined above,

O) -no ₂ , (k) -O-SO ₂ -CF ₃ , (L) -N (R m) wherein R 1 are the same or different as defined above, (M) -CO -N (R m) ₂ wherein R m are the same or different as defined above, (N) -SO ₂ -R 1. ₃ , wherein R 1. ₃ je:

(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 1 or 2 triple bonds (ξ), (6) C ₃ -C ₈ cycloalkyl, (7) -C 1 -C ₃ alkyl -C ₃ -C ₈ cycloalkyl, (8) - (CH ₂ ) _{n 2} -φ where n ₂ is as defined above and -φ is optionally substituted by one or two:

· · · · · · · · · · · · · · · · · · · · · · · · · · · · F, -Cl, -Br, -I, (b) -CsN, (c) -CF _3i (d) C 1 -C ₃ alkyl, (e) -O-R 1-3A, wherein R 1. _3A is -H, _Ci-C6 alkyl, -CF ₃ or -CH ₂ -φ, (f) -NRvaA RI ₃ b, where RI _3A and RMB are identical or different and wherein R. _3A is as defined above, (g) -CO -NR 1. _3A RI ₃ b where Ri. _3A and RMB are as defined above, (h) -SO ₂ R -NRi- _{3A. 3} b, wherein Rv _3A and R are as defined above, (i) -NR ₁ -SO ₂ _ _{3A 3B} -Ri- where Ri. _3A and R 1. _3B are as defined above, (O) -no ₂ , (k) -O -SO 2 -CF ₃ , (9) -O-R 1A, wherein R 1 -a and R 1 are as defined above, (10) -NR 1. _3A Ri. _3B , wherein _3B R ₁₃ and R 1. _3B are as defined above, (O) -NR ₁ -SO ₂ -R _{1 -} , where R m and R 1-3 may be the same or different as defined above, (P) - (CH ₂ ) _n 2 -Φ, where n ₂ is as defined above, and wherein -φ is optionally substituted with one or two:

(1) -F, -Cl, -Br, -I, (2) -C 1 N, (3) -CF ₃ , (4) C 1 -C ₆ alkyl, (5) -O-R m, where R m is as defined above, (6) -N (R ₁ .I) _2, where R m are identical or different and are as defined above, (7) -CO-N (R _{1.1) 2,} where R m are identical or different and are as defined above, (8) -SO ₂ -N (R ₁ -i) ₂ , wherein R m are the same or different and are as defined above, (9) -NR m -SO ₂ -R m, wherein R m are the same or different; different and are 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-O -Qt-2, wherein Q 1. ₂ is defined below, (IV) R ₂ is identical to R _h R ₂ may be the same or different to R 1;

(V) Qi is:

(A) -CO -NQ1-1Q1.2, where Q1.1 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 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) ) ~ _(CH2) n7 -φ wherein n ₇ is 0 to 4 and where -φ is optionally substituted with one or two:

(a) -F, -Cl, -Br, -I, (b) -C =N, (c) -CF ₃ , (d) C 1 -C ₃ alkyl, (e) -O-Q 1 -ia, wherein Qma is -H, C 1 -C ₆ alkyl, -CF _3, or -CH ₂ -φ, (f) -NQ 1A Qi-ib, wherein Q 1 -AAQ 1 -B are the same or different, and wherein

Qi. _1B is -H, C 1 -C ₆ alkyl, -CF _3, or -CH ₂ -φ, and wherein Q 1 _{-A A} is as defined above, (g) -CO -NQ 1 _-A Amb, wherein Qma and Qmb are as defined above , (h) -SO ₂ -NQ1-1A Qmb, wherein Qma and Qmb are as defined above, (i) -NQi-ia-SO ₂ -Qmb, wherein Qma and Qmb are as defined above, (j) -NO ₂ , ( k) -O -SO ₂ -CF ₃ , and wherein Q _{V 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 1 or 2 triple bonds (=), (5) C ₃ -C ₈ cycloalkyl, (6) -C 1 -C ₃ alkyl -C ₃ -C ₈ cycloalkyl, (7) -CF (8) - (CH ₂ ) n ₂ -φ, wherein n ₂ is as defined above, and -φ is optionally substituted with one or two:

(a) -F, -Cl, -Br, -I, (b) -C =N, (c) -CF (d) C 1 -C ₆ alkyl, (e) -O-Q1.2A wherein Q1- 2A is:

(i) -H, (ii) _Ci-C6 alkyl, (iii) -CF (iv) - (CH ₂ H, (9) - _{(CH2) n9-2B} -Q _(CH2) nio -Q1- 2C, where n _{g 10} n are identical or different and from 0 to 4, where Qi. _2B is -O- or -NQi. _2D - where Qi. _2D:

(a) -H, (b) C 1 -C ₈ alkyl, (c) C ₂ -C ₈ alkenyl having 1 to 3 double bonds, (d) C ₂ -C ₈ alkynyl having 1 or 2 triple bonds, (e) C ₃ -C ₈ cycloalkyl, (f) -C 1 -C ₃ alkyl -C ₃ -C ₈ cycloalkyl, (9) -cf ₃ , (h) - (CH ₂ ) n -i, where nu is 0 to 4 and -φ is optionally substituted with one or two:

(i) F, -Cl, -Br, -I, (ii) -CsN, (iii) -CF ₃ · · · · · ········· ···· ·· ·· ·· ·· (IV) _Ci-C3 alkyl, (v) -O -Q1.2E wherein Q! .2e is -H, _Ci-C6 alkyl, _-CF3, or - CH ₂ -

Φ.

(vi) -NQi-2e Q1-2F, wherein Q1-2E and Q1-2F are the same or different, and wherein Q1.2F is -H, C 1 -C ₃ alkyl, -CF _3, or -ΟΗ ₂ -φ and where Qi. ₂ e is as defined above, (vii) -CO -NQ1.2E Qi-2f, wherein Qi. _2E and Qi. F ₂ are as defined above, (viii) -SO ₂ -NQ1-2E Q1-2F Qi- ₂ and f are as defined above, (ix) -SO ₂ -NQ1.2E -Q1-2F where Qi. _2E and Qi. _2F are as defined above, (x) -NO _2i (xi) -O -SO ₂ -CF ₃ , and wherein 0, 20 is identical to Q _{1 and} D ₁ and ₂ and Q 1. _2D may be the same or different, and wherein Q1-1 and 0, 2 together with the nitrogen atom form a 5 or a membered ring which may contain yet another nitrogen or oxygen atom;

(B) -S0 ₂ -NO,., Q-2, wherein Q m and Q ,. ₂ are as defined above, (C) -CO-O-O, i. ₃ , where 0 ,. ₃ jé:

(1) -H, (2) -O-, <3) C 1 -C ₆ alkyl, (4) C ₂ -C ₈ alkenyl containing 1 to 3 double bonds (-j, (5) C 2 -C ₈ alkynyl containing 1 or 2 triple bond (sj, (b) b ₃ -O- ₈ cycloalkyl, (7) -C ₁ -C ₃ -alkyl-C ₃ -C ₈ -cycloalkyl,

(8) - (CH ₂ ) n ₇ -φ, where n ₇ is as defined above and -φ is optionally substituted by one or two:

(a) -F, -Cl, -Br, -I, (b) -C =N, (c) -CF ₃ , (d) C 1 -C ₃ alkyl, (e) -O-Q- _3A , where Qi. _3A is -H, C 1 -C ₆ alkyl, -CF _3, or -CH ₂ -φ, (f) -NQ 1. _3A Qi- ₃ b, where Qi. _3A and are identical or different and where Q1-3B is -H, _Ci-C6 alkyl, -CF ₃ or -CH ₂ -φ, and where Qi_ _3A is as defined above, (g) -CO -NQi. Qi- _{3A, 3} B wherein Qi. _3A and Qi. _3B are as defined above, (h) -SO ₂ -NQ 1. _3A Q1-3B where Qi- _3A and _3B Qi- are as defined above, (i) -NQi. _3A -SO ₂ -Q. _3B, wherein Qi and Qi- _{3A. 3B} are defined above,

O) -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 -Q 1 . ₂ . wherein Q1-a and are as defined above, (F ') -NQm -CO-Q- ₂ , wherein and Q1. ₂ are defined above, (G) -C (Qi. ₃₎ = N-O -Qk where Qm is identical to qi. ₃ is as defined above, Q _{in 3} and Qi-4 may be the same or different, (H) -SO ₂ -Qi-3, wherein Qi- ₃ is as defined above, (I) -NiOvO -SO ₂ -Qi- ₃ , wherein Qm and Qi- ₃ is as defined above, (J) 5-oxadiazole substituted with one volitekně Qi- ₅ wherein Qi- _5:

(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 1 or 2 triple bonds (=), (6) C ₃ -C ₈ cycloalkyl, (7) -C 1 -C ₃ alkyl -C ₃ -C ₈ cycloalkyl, (8) -NO (9) -C = N, (10) -CF (11) -O-5a, wherein Q1-sa is:

(a) -H, (b) C 1 -C ₈ alkyl, (c) C ₂ -C ₈ alkenyl having 1 to 3 double bonds, (d) C ₂ -C ₈ alkynyl having 1 to 2 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) - (CH ₂ ) n - ₇ -φ, where n _{7 is} 0 to 4, (12) -NQ1.5aQi-5d, where Qvsa is as defined above, Qi-sd is:

(a) -H,

in · • ·

(b) C 1 -C ₈ alkyl, (c) C ₂ -C ₈ alkenyl having 1 to 3 double bonds (=), (d) C ₂ -C ₈ alkynyl having 1 to 2 triple bonds (ξ), (e) C ₃ -C ₈ cycloalkyl, (f) -C ₃ -C alkyl, - C ₃ -C ₈ cycloalkyl, (g) -CF _3, (h) - _{(CH2) n7} -φ wherein n ₇ is as defined above, (13) -CO-SD -NQ1.5A Qi wherein Qi aa Qi_ _5-sd defined above, (14) -SO ₂ -Q-5K, wherein Q-5kje:

(a) -H, (b) -CF ₃ , (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 -C ₃ alkyl, -C ₃ -C ₈ cycloalkyl, (h) - _{(CH2) n7} -Φ wherein n ₇ is as defined above, (15) -SO ₂ -NQi_ _5A -Qv5k wherein Qvsa and Qi_ to ₅ may be the same or different and are defined above, (16) - _{(CH2) n7} -Φ wherein n ₇ is as defined above and wherein -φ is optionally substituted with one or two:

(a) -F, -Cl, -Br, -I,

(b) -C = N, (c) -CF ₃ , (d) C 1 -C ₆ alkyl, (e) -O-Q 1 -sa, where C 18 is as defined above, (f) -NQ 1.5A Q 1 -d wherein Qi- Qvsd and _5A are as defined above, (g) -CO -NQi_5a Q1.5D where Qi. _5A and Qi. ₅ d are as defined above, (h) -SO ₂ Q -NQi- _5a-5d wherein Qi_ _5A-SD and Q are as defined above, (i) -SO ₂ -NQvsa -Q1-5D wherein Qi_ _5A and defined above, (j) -NO ₂ , (k) -O-SO ₂ -CF ₃ ;

(K) 3-oxadiazole optionally substituted with one Q1-5, wherein Q1.5 is as defined above, (L) triazole optionally substituted with one or two Q1-5, which may be the same or different, wherein Q1-5 is as defined above, (M) 5-thiadiazole optionally substituted with one Q1.5, wherein Q1.5 is as defined above, (N) 3-thiadiazole optionally substituted with one Q1-5, wherein Q1-5 is as defined above, (O) 2-oxazole optionally substituted one or two Q1-5 which may be the same or different, where Q1-5 is as defined above, (P) 2-thiazole optionally substituted with one or two Qi- _5, which may be identical or different, where Q1-5 is as defined above, (Q) 2-imidazole optionally substituted with one, two, or three Q1.5, which may be the same or different, where Q1.5 is as defined above; (R) 1-imidazole substituted with one, two or three Q1.5 which may be t identical or different, wherein Q1-5 is as defined above, (S) tetrazole optionally substituted with one Q1.5, where Q1.5 is as defined above, (T) cyclobutenedione optionally substituted with one Q1.1 and one Q1.5, where Qm and

Qt-5 are as defined above, (U) 1-pyrimidinyl optionally substituted with one Q1.5, wherein Q1-5 is as defined above, (V) 2-pyridinyl optionally substituted with one Q1.5, wherein Q1.5 is as defined above, ( W) 3-pyridinyl optionally substituted with one Q1-5, where Q1-5 is as defined above, (X) 4-pyridinyl optionally substituted with one Q1-5, where Qvsje defined above, (Y) -Z 1 -Z ₂ -CO -Q1 2, wherein Q ₁ is as defined above and Z ₁ is -O- or

-Nqi-i, wherein Q 1 -i is as defined above, wherein Z ₂ is -O- or

-N _q ii, where Qv-ι is as defined above, with the proviso that when X 1 is - (CH ₂ ) _n i -, where m is 0 and Ch is:

-CO -NQm Qi- ₂ ,

-SO ₂ -NQ1.1 Qi. ₂ or

-NQm Qi- ₂ ,

NCO-CO-Qi. ₂ , then Q _V1 and Q1. ₂ , both cannot be selected from:

-H,

-C 1 -C 6 alkyl,

-C ₃ -C ₇ cycloalkyl,

-C 1 -C ₃ alkyl - (C 3 -C ₇ ) cycloalkyl and pharmaceutically acceptable salts thereof.

Also disclosed are aromatic bicyclic amines of formula (ABA).

(ABA) where:

(I) W 1 is a nitrogen (-N-) or carbon (-CH-) atom;

(II) X f is - (CH ₂ ) n and m is 0, (III) Q 1 is (A) -CO ^- NQm Q1-2, wherein Qm is:

(1) Ή, (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 1 or 2 triple bonds ( =), (5) - (CH _{2) n7} -φ wherein n ₇ is 0 to 4 and where -φ is optionally substituted with one or two:

(a) -F, -Cl, -Br, -I, (b) -C =N, (c) -CF ₃ , (d) C 1 -C ₃ alkyl,

(e) -O-Qi-ia, wherein Qm _A is -H, C 1 -C ₆ alkyl, -CF _3, or - (CH) ₂ -φ, (f) -NQi- _1A Qi-ib, wherein Qma a Qi. _1B are the same or different and where Q 1. _1B is -H, C -C ₆ alkyl, -CF ₃ or -CH ₂ -φ, and where QMA is as defined above, (g) -CO -NQ1-1A Q1-1B where Q i and _V are as defined above QMB , (h) -SO ₂ -NQ 1. _1a Qmb where Qi. _1A and Qms are as defined above, (i) -NQma -SO ₂ -Qi-i _B wherein Q-ma and Qi-i _B are as defined above,

G) -no ₂ , (k) -O -SO ₂ -CF ₃ , and wherein:

(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, where n ₂ is as defined above and the -φ is optionally substituted with one or two:

(a) -F, -Cl, -Br, -I, (b) -CSN (c) -CF _3, (d) C 1 -C ₆ alkyl, (e) -O-2a -Q wherein the Čuta :

(i) -H, (ii) C 1 -C ₆ alkyl,

(lii) -CF ₃ , (iv) - (CH ₂ ) -Φ, (B) -SO ₂ -NQm Q1-2, wherein Qm and Qi. ₂ are defined above, (C) -NQm Qí.2 wherein Qm and Q1.2 are as defined above, (D) -CO -NQm -Qi- _2, wherein Qm and Qm are as defined above, (III) R1 is:

(A) -H, (B) -F, -Cl, -Br, -I, (C) C 1 -C ₈ alkyl, (D) -C = N, (E) -CF (F) -O- Rm, where Rm is:

(1) -H, (2) C 1 -C ₈ alkyl, (3) -CF (4) -SO 2 -CF ₃ , (5) - (CH ₂ ) n _{2 -} , where n ₂ is 0 to 4 (G) ) -N (R m) ₂ , wherein R m are the same or different and are as defined above, (H) -CO -N (R m) ₂ , wherein R m are the same or different and are as defined above, (I) -SO 2 -R m, where R ₃ is:

(1) -CF ₃ ; (2) C 1 -C ₈ alkyl; (3) -O-R 1-3A, wherein R 1. ₃ and is as defined above, (4) -NR1-3A R1-3b, wherein R1. _{3A, 3B} and Ri are as defined above, (J) -CO -rm wherein R m is as defined above;

(IV) R ₂ is identical to Ri, R ₂ may be identical with or different from R; and pharmaceutically acceptable salts thereof.

In addition, aromatic bicyclic amines are shown in Examples 1,2, 11, 12, 14, 24, 40, 72, 84, 86 and 88.

The invention consists of novel compounds, 1,6-disubstituted isochroman (I) and a small group of aromatic bicyclic amines (ABA), which is already described in its entirety in WO 95/18118 (PCT / US94 / 13284), with a unique spectrum of activity , highly active against vascular headache, especially against migraine and cluster headache. Methods for making the novel claimed compounds of the invention are known to those skilled in the art. Using the appropriate starting materials and sequencing the successive production steps (use of protecting groups, if necessary), the novel compounds of the invention are formed. The process of each step of the invention is known to the person skilled in the art. One of ordinary skill in the art could readily prepare from known compounds any of the 1,6-disubstituted isochromanes (I) or aromatic bicyclic amines (ABA) from known compounds without consulting or examples below.

Scheme A describes the formation of 6-bromoisochroman (VI), which is a useful intermediate for many 1,6-disubstituted isochromans (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 affords the isochromanate ester (III). Standard hydrolysis using lithium hydroxide in THF-water gives the acid (IV), which can be bound to many substituted arylpiperazines or 4-arylpiperidines to form amides (V). The arylpiperazine moiety carries R 1 and R ₂ substituents. It is preferred if the substuituenty Ri and _R2 on the aryl group prior to formation of 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 by known methods from known compounds. Many arylpiperazines are commercially available. Or known from the chemical literature. Those that are not commercially available or known can be prepared as shown in Schemes Q and R. These amides are reduced with borane to give bromoisochromanes (VI).

Scheme B describes the conversion of 6-bromoisochroman (VI) to the corresponding 6-amide and 6-ester analogs. The conversion of the aryl bromide to the primary amide is achieved by a metal halide exchange using t-butyl lithium and suppression of the resulting aryl anion by trimethylsilyl isocyanate. See J. Med. Chem., 36, 2208 (1993). The aryl anion can also be reacted with carbon dioxide gas followed by treatment with oxalyl chloride in DMF and further reaction with amines to directly form amides (IX). Alternatively, 6-bromoisochroman (VI) can be reacted with carbon monoxide in the presence of palladium acetate, 1,3-bisdiphenylphosphine propane, diisopropylamine and hexamethyldisilazane in solvents such as DMF to form amide (VII). Other palladium catalysts may also be used, for example in situ prepared palladium with organophosphines or preformed palladium phosphine catalysts. The amide (VII) can be converted to either substituted amides (IX) or esters (X) by the bis-BOC derivative (VIII) according to the procedure described in J. Org. Chem. 56, 5482 (1991). 6-bromoisochroman (VI) can be converted to N-methyl substituted amides (IX) directly using methylamine or N-methylformamide instead of hexamethyldisilazane in the palladium mediated reaction described above (see Examples 5 and 6). Alternatively, other N-substitutions can be obtained in the palladium-mediated reaction described above, using other primary or secondary amines instead of hexamethyldisilazane.

Scheme C describes the enzymatic decomposition of racemate (II). Mixing (II) with an enzyme, for example a lipase derived from Pseudomonas cepacia in an aqueous buffer (preferably pH 5-8) followed by selective hydrolysis of the (-) - ester results in (-) - acid (XI). It is preferred to carry out the reaction at room temperature (20-35 ° C) using 5-20 wt% enzyme. The reaction is monitored in a known manner by removing an aliquot, acidifying and performing HPLC. Upon completion of the reaction, products (XI), (-) acid and (XII), (+) - ester are removed and separated by acid / base separation techniques well known to those skilled in the art. These optically active compounds can be suitably used, if appropriate, by any of the above schemes for preparing optically pure variants of the disclosed compounds.

By-product, enantiomer, (+) - ethyl (isochroman-1-yl) acetate (XII), formed from Pseudomonas capacia, mediated by kinetic decomposition of enantiomers, is . * A can be effectively recycled back to the racemic mixture where it is then subjected to further treatment with Pseudomonas lipase. This repeated process optimizes the overall yield of the desired (-) - isochroman-1-yl-acetic acid (XI). Suitable bases for this racemization have a pK a greater than 11, preferably greater than 12. Suitable bases include alkali metal amides, alkali metal alkoxides and alkali metal carbonates which can induce racemization. Preferably, the bases are alkali metal amide bases, alkali metal alkoxides; more preferably, the bases are alkali metal alkoxides such as sodium or potassium t-butoxide or ethoxide. Towards the end of racemization, the reaction is quenched by a proton donor. Potentially any proton donor is possible, for example water can suppress the reaction. However, water is not the most appropriate. Mostly the proton donor is acid. The most common proton donors (hydrochloric acid, ammonium chloride) can also be used to suppress the enolate anions, but acetic acid or trifluoroacetic acid is preferably used for easier handling and purification.

Scheme D describes the preparation of amides and esters that are attached to the isochroman nucleus by one methylene arm (I, Χ _Ί = -CH ₂ -). Treatment of aryl bromide (VI) with trimethylsilylacetylene in the presence of palladium (II) acetate, copper iodide and triethylamine affords acetylene isochromate (XIII). Reacting isochromanone acetylene (XIII) with a dialkylborane such dicyklohexylboranem with subsequent oxidation with basic hydrogen peroxide gives the carboxylic acid (XIV Qi. ₃ = H) from which can derive the generalized esters (XIV) or amides (XV) by standard techniques, known to those skilled in the art.

Scheme E describes the preparation of amides and esters that are attached to the isochroman nucleus by a double carbon arm that can be either saturated (I, X 1 = CH ₂ C + ₁ -) netJO unsaturated (I, X 1 = -CH = CH-). Reaction of the bromide (VI) with an acrylate ester in the presence of a palladium catalyst, preferably palladium (II) acetate with 1,3-bis diphenylphosphinopropane and diisopropylamine in an organic solvent, for example dimethylformamide, yields (XVI). Hydrogenation (XVI) by standard techniques known to those skilled in the art produces saturated species (XVII). Similarly, reaction of bromide (VI) with acrylamide in the presence of a palladium catalyst, preferably palladium acetate followed by 1,3-bisdiphenylphosphinopropane and diisopropylamine in an organic solvent such as dimethylformamide yields (XVIII). Hydrogenation (XVIII) by standard techniques known to those skilled in the art produces saturated species (XIX).

• · • ·

Scheme F describes the preparation of amides and esters that are linked to the isochroman core by a three carbon methylene strap (I, X 1 = -CH 2 CH 2 CH 2 -). The carboxylic acid (X Qi_ ₃ = H) is treated with twice the amount propyllithia give butyrophenone (XX). A solution of butyrophenone (XX) in morpholine with an equivalent amount of elemental sulfur and morpholine is heated to reflux for 10-20 hours to give thiolactam (XXI, see Org. Reactions, Vol. III, Chapter 2, p. 83, 1946, John Wiley & New York). Hydrolysis of thiolactam (XXI) with aqueous hydrochloric acid using techniques known to those skilled in the art produces a carboxylic acid (XXII, Q1.3 = H) from which esters (XXII) and amides (XXIII) can be obtained using well-known techniques.

Scheme G describes the preparation of isochromans bearing a 6-acyl substituent, for example an acid, ester, ketone or oxime. The metal-halogen exchange of acrylic bromide (VI) produces an aryl-lithium reagent that can be quenched with carbon dioxide to form carboxylic acids (X, Q1.3 = H). Palladium-mediated carbonylation of the aryl bromide (IV) in the presence of an alcohol produces the corresponding esters (X) under conditions described in the literature. Similarly, palladium-mediated cross-interaction (VI) with ethanol esters produces ketones (XXIV) followed by standard acid hydrolysis of the enol-ether intermediate. Alternatively, reaction of a carboxylic acid (X, Q1.3 = H) with two equivalents of an alkyl lithium reagent provides the corresponding ketone (XXIV). Condensation of ketone (XXIV) with hydroxylamine or some suitable O-substituted hydroxylamine using toluene as solvent and a Dean-Stark water removal apparatus yields the desired oximes (XXV). Scheme H describes the preparation of sulfonamides (XXVII) and sulfones (XXIX). Reaction of the aryl bromide (VI) with t-butyl lithium results in a metal-halogen exchange and the resulting aryl lithium can be quenched with sulfur dioxide to form the lithium salt (XXVI). This salt is then reacted with phosphorus pentachloride 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 the aryl lithium products as described above, and the addition of the appropriate disulfide affords the sulfide (XXVIII). This sulfide is then oxidized using standard procedures and oxidants, for example, m-chloroperoxybenzoic acid to give the sulfone (XXIX).

• *

Scheme I describes the preparation of sulfones (XXXIV) wherein the sulfone moiety is attached to the isochroman nucleus using a methylene arm of 1, 2 or 3 carbon atoms. Thus, in Schemes I through N, this carbon atom (which became part of X!

arms) with functional meaning denoted by the index “n” = 0 to 2, which corresponds to ni u

1,6-disubstituted isochromans (I). The carboxylic acids (XXX) can be reduced to primary alcohols (XXXI) using known techniques and reagents, for example lithium aluminum hydride or borane. Alcohols (XXXI) can be converted to the corresponding bromides (XXXII) using known techniques and reagents such as phosphorus tribromide or tetrabromethane and triphenylphosphine. Bromides (XXXII) can be used to alkylate thiols by known techniques to form sulfides (XXXIII). Sulfides (XXXIII) can be oxidized to sulfones (XXXIV) 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 attached to the isochroman core with a methylene arm having 1, 2 or 3 carbon atoms. Bromides (XXXII) can react with sodium sulfite at reflux in a 10% aqueous sodium hydroxide solution to form the sulfonate salt (XXXV). The sulfonate salts are converted to sulfonyl chlorides (XXXVI) using phosphorus pentachloride and phosphorus oxychloride. Reaction (XXXVI) with amines (NQi-) ₂ ) Sulfonamides (XXXVII) are formed Scheme K describes the preparation of substituted imidazoles and triazoles that are attached to the isochroman nucleus by a methylene arm of 1, 2 or 3 carbon atoms In Scheme K, if "X" in the nitrogen substituent is a substituent The compounds are obtained by alkylation of the corresponding imidazoles or triazoles with bromides (XXXII) The imidazoles and triazoles are commercially available or can be prepared according to the procedure of the chemical literature using techniques already known. This gave compounds (XXXVIII).

Scheme L describes the preparation of imidazoles (XL) which are attached to the isochroman nucleus by a methylene arm having 1, 2 or 3 carbon atoms. The necessary oximamides are prepared from the corresponding nitriles using hydroxylamine hydrochloride and sodium in methanol according to the procedure described in J. Med. Chem., 36, 1529 (1993). Nitriles are commercially available or can be prepared as described in the chemical literature using techniques already known to those skilled in the art. The oxime amides are reacted with sodium hydride or sodium and further with an ester (XXXIX) according to the procedure described in J. Med. Chem., 36, 1529 (1993) to give heterocyclic products (XL). Scheme M describes the preparation of mono- (XLII) or di-substituted tetrazoles (XLIII), which are attached to the isochroman nucleus by a methylene arm having 1, 2 or 3 carbon atoms. The bromides (XXXII) convert to the corresponding nitriles (XLI) by a cyanide exchange reaction well known to those skilled in the art. These nitriles are then converted to the monosubstituted tetrazoles (XLII) by reaction of sodium azide in a solvent such as N-methyl-2-pyrrolidinone according to the procedure described in J. Med. Chem., 38, 1799 (1995). Monosubstituted tetrazoles are converted to di-substituted tetrazoles (XLIII) by a standard alkylation reaction (R-X, acetonitrile, triethylamine).

Scheme N describes the preparation of isomeric triazoles (XLIII) and (XLIV), which are attached to the isochroman nucleus by a methylene arm of 1, 2, or 3 carbon atoms. Nitriles (XLI) can be converted to imidoesters (XLII) using ethanolic hydrochloric acid according to the procedure described in J. Med. Chem., 38, 1799 (1995). By the same procedure, reaction of (XLII) with alkyl hydrazines (commercially available or prepared according to the literature) in a solvent such as ethanol and subsequent reaction with formic acid affords a mixture of (XLIII) and (XLIV). The mixture may be separated into components by standard laboratory techniques, for example chromatography or crystallization. Scheme O describes the preparation of substituted triazoles and oxidazoles from primary carboxamides (VII) using known methods, for example from J. Org. Chem., 44, 4160-4164 (1979). If “X” in (0-2) is nitrogen, the product is tetrazole. If “X” in (0-2) is oxygen, the product is oxadiazole. Reaction of amides (VII) with dimethylamide acetals in non-polar high boiling solvents such as toluene at 50-100 ° C affords intermediate (0-1). This intermediate is then reacted with hydrazine ether, 1-substituted hydrazines, hydroxylamine or N-substituted hydroxylamines in an acidic reaction medium (mostly acetic acid) at room temperature (20-25 ° C) to give said product (0-2).

Scheme P describes the preparation of monosubstituted oxazole derivatives (P-2) from the corresponding propargyl amides (P-1) using known methods, for example from J. Med. Chem., 36, 1529 (1993). Reaction of (P-1) with mercury (II) acetate at boiling with a condenser in acetic acid affords the shown oxazoles (P-2).

Scheme Q outlines the synthesis of piperazine (Q-3) wherein R 1 is R 1. is an electronegative substituent in the ortho or para position to the aniline nitrogen of piperazine. An amine (Q-1) and an aryl halide (Q-2) with a fluoride or bromide atom in the ortho · · e e e e e e e e e e e Or para position to the electronegative substituent is heated without dissolution in a polar solvent such as water, DMF, dimethylacetamide or other such solvent with a base (with excess (Q-1) or diisopropylethylamine, potassium carbonate and so on) similarly) at a suitable temperature (60-200 ° C) to give piperazine (Q-3).

Scheme R describes the synthesis of piperazines (R-3). Nitro aryl (R-1) is reduced to aniline (R-2) using hydrogen and a catalyst such as palladium on carbon, Raney nickel, stannous chloride and the like. Alternatively, (R-2) can be obtained commercially. Aniline (R-2) is heated (about 80 to 165 ° C) with bis (2-haloethyl) amine hydrochloride with or without the addition of a base in solvents such as THF, toluene, ethylene glycol or chlorobenzene to give piperazine (R-3) .

Scheme S illustrates the preparation of an important intermediate for the preparation of compounds claimed in the invention. Hydroxyamide (S-3) is prepared as a standard from hydroxy bromide (S-1; see Scheme T) by a palladium-mediated amidation reaction (as shown in Scheme B) or via an ester intermediate (S-2). This ester is synthesized from a (S-1) carbonylation reaction using palladium known to those skilled in the art and similar to the reaction described above. The conversion of (S-2) to the amide (S-3) is accomplished by reaction of (S-2) with an alcohol solution (usually methanol) containing the appropriate amination reagent in a similar manner as described in J. Org. Chem., 52, 2033-2036 (1987). This reaction may take place at room temperature (2025 ° C) or preferably at 50-100 ° C.

Scheme T illustrates two important alternative procedures leading to the compounds claimed in the invention. Reduction of the previously described acids (IV) under standard reaction conditions and reagents (preferably borane) affords the primary alcohol (S-1). This compound is then converted to the hydroxy amide (S-3) as described in Scheme S. This hydroxyamide is converted to the alkylating agent (T-2, X is usually a methanesulfonate or bromide) by standard chemical transformations used to alkylate the appropriate 4 -arylpiperazine or 4-arylpiperidine to give the final compound (XI). Alternatively, the hydroxybromide (S-1) is converted to an alkylating agent (T-1, X is usually a methanesulfonate or bromide) by standard chemical transformations and used to alkylate the appropriate 4-arylpiperazine or 4-arylpiperidine to form · Bromides (VI) · · · · · · · · · · · · · · · · · · · · · · · These bromides are then converted to the final compounds (IX) as described above.

Scheme U shows the conversion of the chiral bromine acid (U-1) representing (XI) in Scheme C to the alkoholamide (U-5) representing (S-3) in Scheme T. The bromoacid (U-1) is alkylated to the bromoester (U-2) using methods already known to those skilled in the art. An example is the reaction of bromoic acid (U-1) with 1,1 &apos; carbonyldiimidazole in a solvent such as THF to form the activated ester followed by reaction with an alcohol to form the bromoester (U-2). The bromoester (U-2) is then reacted under the conditions of Scheme V and converted from (V-1) to (V-2) to form the amidester (U-3). Hydrolysis of the amidester (U-3) with a water base to prevent also the hydrolysis of the amide group (U-3), followed by aqueous acid treatment, gives the acid amide (U-4). The acid amide (U-4) is then treated with reducing agents such as boron or bor-methyl sulfide in THF as the solvent to form the alcohol amide (U-5).

Scheme V shows a process for converting an ester (V-1) to a diamide (V-4). The ester (V1) prepared from bromoisochroman (T-1) and piperazine (Q-3), Scheme Q, according to the methods described in Scheme T. The ester (V-1) is converted to the amidester (V-2) using palladium acetate and co- a catalyst such as bis (diphenylphosphino) propane, diisopropylethylamine, carbon monoxide and methylamine as shown in Scheme B. The conversion solvent may be DMF, dimethylacetamide, N-methylformamide, acetonitrile with dimethylacetamide and N-methylformamide, preferably methyl amine. gas. The temperature is preferably 50 to 120 ° C. The amidester (V-2) is further converted to the corresponding amide acid (V-3) using an aqueous base followed by neutralization of the acid and formation of (V-3) or a salt thereof. When the ester is a tert-butyl ester, trifluoroacetic acid or hydrochloric acid is used in solutions such as ether or ethyl acetate to convert the amidester (V-2) to the corresponding amide acid (V-3). The acid amide (V-3) is then reacted with a coupling reagent and an amine to form the corresponding diamide (V-4) using methods already known to those skilled in the art, as shown in Scheme W.

Scheme W shows the synthesis of hydroxamic acid derivatives (W-7) and (W-8). These compounds are also prepared according to Schemes A and B. The alcohol group of the alcohol ester (S-2), Scheme S, is protected with a suitable protecting group, for example, a dihydropyranyl group that is stable under basic conditions to form · Tetrahydropyranyl ether (W-2). The ether group of the ether (W-2) is then hydrolyzed with an aqueous base and carefully acidified (not to remove the protective group) to form the carboxylic acid (W-3). The carboxylic acid (W-3) is then reacted with a condensing agent such as carbonyldiimidazole, diethyl cyanophosphonate, dicyclohexylcarbodiimide, or other suitable condensing agent (see, e.g., Major Methods of Peptide Bond Formation, Volume One of the Peptides: Asnalysis, Synthesis, Biology, E.Gross and J. Meinhofer, eds., Academic Press) in solvents such as dichloromethane or DMF and a base such as triethylamine in the presence of an amine such as O-alkyl, N-alkylhydroxylamine (prepared by Sulsky et al., Tet. Leti. 30, 31) -34 (1989) to form the etherhydroxamate (W-4) and then the protective group is removed from the etherhydroxamate (W-4) using the methods outlined in The Protective Groups in Organic Synthesis by Theodor W. Greene published by John Wiley and sons to form the hydroxamate alcohol ( The hydroxyl group of the alcohol hydroxamate (W-5) is then converted to the remaining group by one of many known methods such as methanesulfate formation. onate, tosylate, chloride, bromide or iodide to form hydroxamate (W-6); the hydroxamate (W-6) is then coupled with an amine such as piperazine (Q-3) of Scheme Q or piperazine (R-3) of Scheme R or commercially available amines to form the aminohydroxamate (W-7). The amine hydroxamate (W-7) can then be further converted to aminohydroxamic acids (W-8) when alkyl-1 is a protective group, for example benzyl with palladium on carbon or other known methods.

Scheme X shows the synthesis of carbamate (X-6). Phenol / aniline (X-1) is reacted with alkyl diethoxypropionate in a similar manner to the transformation of 3-bromophenethanol (II) to the corresponding isochroman ester (III) of Scheme A to form the phenol / aniline ester (X-2). The phenol / aniline ester (X-2) hydrolyzes to phenol / aniline acid (X-3) with an aqueous base followed by an aqueous acid. Phenol / aniline acid (X-3) is then condensed with piperazines (Q-3) of Scheme Q or (R-3) of Scheme R or with commercially available amines to phenol / aniline amide (X-4) using the methods of Scheme W. Phenol The aniline amide (X-4) is then reduced to the phenol / aniline amine (X-5) with reducing agents, for example borane or borane methylsulfide in solvents, for example THF. The phenol / aniline amine (X-5) is then reacted with 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) or sodium hydride or other such bases and an isocyanate in dichloromethane or THF as solvent to form the carbamate. / urea (X-6) · w · w · w · w · w · w · w · w · w · w · w · w · w · w · w · w · w · w · · · · · · · · ·

Scheme Y shows the synthesis of the racemate (Y-5) from the starting 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 solvents such as dichloromethane or nitromethane to form chlorophenol (Y2). The chlorophenol phenol (Y-2) is then converted to the leaving group using trifluoromethanesulfonic anhydride or N-phenyltrifluoromethanesulfonimide in the presence of a base such as triethylamine and addition of a catalyst such as 4-dimethylaminopyridine and a solvent such as dichloromethane to give triflate (Y-3). The triflate (Y-3) is then converted to the amide hydrochloride (Y-4) using palladium acetate) and a co-catalyst, diisopropylethylamine, carbon monoxide and methyl amine as shown in Scheme W. Conversion solvents include DMF, dimethylacetamide, N methylformamide and acetonitrile, dimethylacetamide and Nmethylformamide are preferred when methylamine gas is used. A suitable temperature is from about 50 ° C to 120 ° C. The amide chloride (Y-4) is then stirred at 60 ° C to 110 ° C in the presence of piperazine (Q-3) or (R-3) or commercial amines, base such as triethylamine or diisopropylethylamine and solvents such as ethylene glycol, THF, DMF or acetonitrile to form the amine amide (Y-5).

Scheme Z shows the production of many aniline-based derivatives (Z-2), (Z-3), (Z-4), (Z-5), (Z-6) and (Z-7). These compounds are standard aniline derivatives (Z-1), separately prepared from bromide (VI) by metal-halogen exchange (using n-butyllithium or t-buthyllithium), followed by addition of diphenylphosphoryl azide (mostly in THF at -78 ° C) and reduction by bis (2-methoxyethoxy) aluminum hydride. This conversion of (VI) to (Z-1) proceeds according to the chemically known pathway, see Tetrahedron Letters, 25, 429-432 (1984) and J. Am. Chem. Soc., 94, 6203-6205 (1972). Reaction conversions (Z-1) to derivatives (Z-2) - (Z-7) are standard transformations known to those skilled in the art and include acylations (typically with acid chlorides or anhydrides), mesylations, and standard lactam reductions as previously mentioned.

Scheme AA illustrates the preparation of monocarbon homologs of isochroman-6-carboxamides (AA-5). The process involves metal-halogen exchange of bromide (VI) using alkyllithium reagents (most commonly t-butyllithium) followed by suppression of the formed anion by DMF and formation of the aldehyde (AA-1). This aldehyde is reduced with standard reagents (for example sodium borohydride in THF) and the resulting alcohol. (AA-2) is converted to nitrile (AA-3) by activation with methanesulfonyl chloride and replacing the resulting methanesulfonate with a cyanide anion. Hydrolysis of the nitrile is performed with a solution (AA-3) in DMF with 30% hydrogen peroxide in the presence of potassium carbonate and shaking the reaction mixture at room temperature (20-25 ° C) for 20 hours. The resulting amide (AA-4) is converted to substituted amides (AA-5) as previously described.

Scheme BB illustrates the entire process for preparing possible amines, for example (BB2) by reducing the corresponding amides (BB-1) under standard amide reduction conditions as previously described (commonly with borane or lithium aluminum hydride in THF). Scheme CC shows that the functional groups of the arylpiperazine moieties of these molecules (R 1 and R ₂ ) can be transformed into other functional groups. Standard hydrogenolytic debenzylation of the aryl ether (CC-1) to give the corresponding phenol (CC-2) is described. Conversion of phenol (CC-2) to the corresponding triflurmethanesulfonate (CC-3) by standard methods is a typical example of phenol derivation, for example (CC-2). Conversion of the triflate (CC-3) to a variety of derivatives can be accomplished by palladium mediated coupling. For example, coupling (CC-3) with enol ethers results in ketone-substituted aryl derivatives. These reactions are conveniently carried out in DMF or acetonitrile using palladium acetate, 1,3bis (diphenylphosphino) propane and triethylamine at suitable temperatures (50-120 ° C).

Scheme DD shows an alternative preparation of isochroman-6-triazoles (DD-4) and isochroman-6-oxadiazoles (DD-6). The primary alcohol of the previously described amide (DD-1) is protected by standard techniques, preferably benzyl ether (P = -CH ₂ -phenyl). This compound reacts with amidacetals as described in Scheme O and the resulting intermediate (DD-2) reacts with hydrazine, substituted hydrazine, hydroxylamine or N-substituted hydroxylamines as described in Scheme O to form triazoles (DD-3) or oxadiazoles (DD -5). The protective group "P" is removed under standard conditions (commonly by hydrogenolysis using a metal catalyst conversion such as palladium or platinum) and the resulting alcohol can be activated (mostly as sulfonate ester or halide) and reacted with a suitable arylpiperazine as previously outlined in the scheme. T.

For 1,6-disubstituted isochromanes (I), ni = 0 or 1; preferably ni = 0. It is preferred that R is -O -rm, -CF _3i -C 0-N (Rm) _2, -CO-R m, and it is preferred that R m is C, -C ₃ alkyl. It is further preferred that R ₂ is -H. It is also advantageous that Qi is selected as A and A. · From the group consisting of -CO-NQm Q _V2 , -SO ₂ -, NQ _V1 Q _V2 and -NQ1.1 Q ₁ . ₂ ; more preferably, Q 1 is -CO-NQ _V1 Q _{1 -2} .

For aromatic bicyclic amines (ABA), it is preferred that W 1 is nitrogen (-N-) and it is also preferred that one of R 1 or R ₂ be -H. It is preferred that Q 1 is (A) -CONQ m Q _{1 - 2} and Q m is -H and when Q 1. ₂ is -CH ₃ (C 1-4 alkyl).

The 1,6-disubstituted isochroman (I) and the aromatic bicyclic amines (ABA) contain an asymmetric center and therefore form two enantiomers; "S", which is (-) and "R", which is (+). In some cases, both the (+) and (-) enantiomers are used in the same manner as the optically impure (racemic, ±) mixture. Therefore, they can be used in racemic form without separation. However, it is desired to use one of the enantiomers, the optically impure mixture can be resolved by methods already known. Preferred is the analysis of the racemic intermediate (II) by the lipase method described in Scheme C or by methods already known, see for example Optical Resolution Procedures for Chemical Compounds, Vol. 1, Amines and Related Compounds, Paul Newman, Optical Resolution Information Center, Manhattan College, Riverdale, NY, 10471, 1978. The optically impure mixture can also be resolved by chromatography on chiral stationary phases, see Chromatographic Enantioseparation, 2nd edition, John Wiley & Sons, NY. 1992. The optically pure compounds are then used in the same manner as the racemic mixture. In the patent application 1,6-disubstituted isochromans (I) of aromatic bicyclic amines (ABA) include both enantiomers, the same as their optically impure forms, most often their racemic mixture (±, dl).

Some 1,6-disubstituted isochroman (I) and aromatic bicyclic amines (ABA) contain two asymmetric centers and therefore the four existing stereoisomers (SS, RR, SR, RS) form two diastereomeric pairs of enantiomers that can be separated by known techniques. The 1,6-disubstituted isochroman (I) and aromatic bicyclic amines (ABA) in the patent application include all four enantiomers, as well as their optically impure forms, most commonly their racemic mixture (±).

The 1,6-disubstituted isochroman (I) and the aromatic bicyclic amines (ABA) are amines and form acid salts when reacted with a sufficiently strong acid. Pharmaceutically useful salts include both inorganic and organic salts thereof. Pharmaceutically useful salts are sometimes, but not always, preferred over pure amines because they form compounds that are more soluble in water and more crystalline.

· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

Preferred pharmaceutically usable salts include salts of methanesulfonic, hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, benzoic, citric, tartaric, fumaric, maleic, CH ₃ - (CH ₂ ) n -COOH, wherein n is 0 to 4, HOOC - ( CH ₂ ) _n COOH, wherein n is as defined above.

The 1,6-disubstituted isochroman (I) and the aromatic bicyclic amines (ABA) of the invention exhibit selective pharmacological properties and are useful for treating patients with vascular headaches, particularly migraine and cluster headaches. This 1,6-disubstituted isochroman (I) and aromatic bicyclic amines (ABA) are also useful as analgesic agents.

In clinical practice, the 1,6-disubstituted isochroman (I) and the aromatic bicyclic amines (ABA) of the invention are administered orally, nasally, rectally, vaginally or by injection in the form of pharmaceutical compounds containing the active ingredients either as a free base or a pharmaceutically acceptable acid addition salt. one or more pharmacologically acceptable carriers. Oral or nasal administration of 1,6-disubstituted isochroman (I) and aromatic bicyclic amines (ABA) is preferred.

For the therapeutic treatment of migraine or cluster headaches and for the treatment of pain, daily doses of 1,6-disubstituted isochroman (I) and aromatic bicyclic amines (ABA) from about 0.005 to 50 mg / kg for oral or nasal administration are suitable as analgesic agents. preferably about 0.1 to 30 mg / kg and about 0.05 to 10 mg / kg for parenteral administration, and preferably about 0.03 to 3 mg / kg. Dosages for clinical treatment of a patient will be readily apparent to those skilled in the art.

The exact dosage and frequency depend on the 1,6-substituted isochroman (I) and aromatic bicyclic amine (ABA) used, the specific treatment conditions, age, weight, general physical condition of the patient, other medical conditions, other medications used, and can be more accurately determined by measurement. the level or concentration of 1,6-disubstituted isochroman (I) and / or aromatic bicyclic amine (ABA) in the patient's blood and / or according to the patient's response to treatment.

The definitions and explanations below for use throughout the document also include a description and claims.

Chemical formulas characterizing different compounds or molecular fragments may contain various substituents in the specification and claims that define structural properties. These various substituents are described by letters or letters with a number in the subscript, such as “ΖΓ or“ R ”, where“ i ”denotes the total number. These various substituents are monovalent or bivalent, expressing a group attached to the formula by one or two chemical bonds. For example, Z 1 represents a bivalent and variable group of the formula CH ₃ -C (= Z 1) H. The groups R 1 and R 3 represent a monovalent variable substituent of the formula CH ₃ -CH ₂ -C (R 1) (R 3) -H. When chemical formulas are represented in a linear form as above, the various substituents contained in brackets bind to the atom directly to the left of the variable substituent in brackets. If there are several different substituents in brackets, each subsequent variable substituent binds directly to the preceding atom that is not in brackets. Thus, in the above formula, both R 1 and R 3 bind directly to the preceding carbon atom.

The chemical formulas or portions thereof shown in linear form represent atoms in a linear chain. Thus, the CH ₃ -O-CH ₂ -CH (R ₃ ) -CH ₃ represents a 2-substituted-1-methoxypropane compound. In a similar formula, "=" represents a double bond, for example, CH ₂ = C (R 1) -O -CH _3, and "s" represents a triple bond, for example, HC = C -CH (R 1) -CH ₂ -CH ₃ . Carbonyl groups are expressed in one of two possible ways: -CO- or -C (= O) -, where the first method is used more frequently for simplicity.

The chemical formulas of cyclic (ring) compounds or molecular fragments may be expressed in linear form. Thus, 4-chloro-2-methylpyridine can be represented by the linear formula N * = C (CH ₃ ) -CH = CCl-CH = C * H, meaning that the asterisks (*) bind to each other so that creates a circle. Similar, cyclic molecular fragment, 4- (ethyl) -1-piperazinyl can be represented by the formula -N * - (CH ₂ ) ₂ -N (C ₂ H ₅ ) -CH ₂ -C * H ₂ . The rigid cyclic (ring) structure of each compound herein defines the orientation with respect to the planar ring structure for substituents attached to each carbon atom of the rigid cyclic compound. For saturated compounds with two substituents attached to the carbon atom that is part of the cyclic system, -C (X 1) (X ₂ ) - the two substituents may be in the axial or equatorial position relative to the ring and may change the axial / equatorial position. However, the position of the two substituents relative to each other and to the ring is fixed. Although a substituent may at times lie in a plane perpendicular to the ring (equit.) ) rather than above or below the circle (axially), one substance is always above the other. In the chemical structural formula expressing such compounds, the substituent (Xi), which is "below" another substituent (X ₂ ), is referred to as the alpha (a) configuration and is indicated by a dashed dotted or dotted line attached to a carbon atom, i.e. “---” or “. . . ". The corresponding substituent attached "above" (X ₂ ) to the second (Xi) is referred to as the beta (β) configuration and is indicated by a solid line to the carbon atom.

If the variable substituent is bivalent, the valencies may be variable, linked or separated by definition. For example, a variable R _b attached to a carbon atom such as C (= R j) - may be bivalent and defined as oxo or keto (forming a carbonyl group (-CO) or two separately attached monovalent variable substituents a R _H and β-R j-k. is a variable bivalent, R, is defined as a composite of two monovalent variable substituents, according to convention, the formula “α-Rj-j: β-Ri-k” or some variants thereof is used to denote bivalent variable substituents. For example, if a bivalent variable Re, defined as -C (= Re) - contains two monovalent carbon atoms, such as β-R 1 -k. variable substituents, the two monovalent variable substituents being α-R ei: β-R 6-2, · aR 6-9: β-Re-w, which is -C (aR 6-1) (β-R 6- 2) -, ... -C (aR 6-9) (β-Re-io) - etc. Similarly, for bivalent variable Rn, -C (= Rn) -, two monovalent in Ariable substituents are α-R ni: βRh- ₂ . For a ring substituent for which there is no particular aa β orientation (for example due to the presence of a carbon-carbon double bond in the ring) and for a substituent attached to a non-ring carbon atom, that rule, but the aa β designation is deleted.

Two separate monovalent variable substituents may also be defined as bivalent variable and two separate monovalent variable substituents may be defined as bivalent variable. For example, in the formula -C (R) H-C ₂ (R j) H (C 1 and C ₂ define arbitrarily a first and second carbon atom, respectively) R i and R j may be defined to together as (1) having a double bond between C1 and _C2 or (2) with a bivalent group such as oxa (-O-) and the formula then describes an epoxide. When R 1 and R 1 together form a more complex whole, for example -X -Y-, then the overall orientation is such that C1 in the above formula is bound to X and C ₂ binds to Y. Then according to ·· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·· designated “... R, and R, together form -CH ₂ -CH ₂ -O -CO- ... which represents the lactone in which the carbonyl binds them to C ₂ . However, when the labeled ... R 1 and R 1 together form -CO-O -CH ₂ -CH ₂ -, according to the provision this indicates a lactone in which the carbonyl binds to C 1.

The total number of carbon atoms in the variable substituents is indicated in one of two possible ways. The first method uses the prefix to denote variability as "Ci - C ₄ where" 1 "and" 4 "represent the minimum and maximum number of variable carbon atoms. The prefix is separated from the variable by a space. For example, "C 1 -C ₄ alkyl" refers to alkyl of 1 to 4 carbon atoms (including its isomeric forms unless otherwise indicated). Whenever this simple prefix is given, it means the total number of variable carbon atoms. According to this designation C ₂ -C ₄ describes the group CH ₃ - (CH) _n -O-CO-, wherein n is zero, one or two. According to the second method, the total number of carbon atoms of only a particular part is indicated separately by the designation "C 1 - C f" in parentheses immediately (without a space) in front of the part it indicates. According to this designation (C 1 -C ₃ ) alkoxycarbonyl has the same meaning as C ₂ -C ₄ alkoxycarbonyl, since "C 1 -C ₃ " means only 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 denote alkoxyalkyl groups having 2 to 6 carbon atoms. The foregoing definition particularly describes an alkoxy or allyl moiety containing 4 or 5 carbon atoms, while a further definition limits these groups to 3 carbon atoms.

Because the claims include a fairly large (cyclic) substituent, at the end of the naming / designation, this substituent has a reference (in parentheses) that corresponds to the same naming / designation in the schemes, where the chemical structural formula of a particular substituent is also indicated.

There are several methods for naming compounds of the invention that differ in principle by using the term "isochroman" or "3,4-dihydro-1H-2-benzopyran" for a bicyclic group in the compound. For example, one designation for the compound of Example 6 is (S) - (-) - 1- [2- [4- [4- (aminocarbonyl) phenyl] -1-piperazinyl] ethyl] -N-methylisochroman-6-carboxamide or (S) - (-) - 1- (Benzamid-4-yl) -4- [2- (6-methylaminocarbonylisochroman-1-yl) ethylpiperazine. Another name is (S) -1- [2- [4- [4 (aminocarbonyl) phenyl] -1-piperazinyl] ethyl] -3,4-dihydro-N-methyl-1H-2-benzopyran-6-carboxamide.

· · € € € € € € € € € € € € € € € € € € € € € € € € € € € · · · · ·

All temperatures are in degrees Celsius.

- (CH ₂ ) _n -COO ' ¹ , where n is as defined above,' ¹ OOC -CH = CH-COO * ¹ φ-COO ' ¹ .

TLC - thin layer chromatography

HPLC - high pressure liquid chromatography

THF - tetrahydrofuran

DMF - dimethylformamide

DMSO - dimethylsulfoxide

LDA - lithium diisopropylamide p-TSA - p-toluenesulfonic acid monohydrate

TEA - triethylamine

BOC - 1,1-dimethylethoxycarbonyl or tert-butoxycarbonyl -CO-OC (CH ₃ ) 3

DMAP-dimethylaminopyridine, (CH ₃ ) ₂ -N-pyridin-1-yl

TFA - trifluoroacetic acid, CF ₃ -COOH salt - saturated aqueous sodium chloride solution

Chromatography (column and flash chromatography - purification / separation by combining (loading; elution)) This means that certain functions are accumulated and concentrated to obtain the desired compound (s).

IR - infrared spectroscopy

CMR - C-13 magnetic resonance spectrometry, chemical shifts are expressed in ppm (δ) relative to TMS

NMP - nuclear (proton) magnetic resonance spectroscopy, chemical shifts are expressed in ppm (δ) relative to tetramethylsilane

-φ - phenyl (CeHs) • · · · [a] _D - angle of rotation of planar polarized light (specific optical rotation) at 25 ° C for sodium D line (589A)

MS - mass / energy or mass / charge mass spectrometry.

[M + H] ⁺ - positive ion containing donor and hydrogen atom

El - electron influence

Cl - chemical ionization

FAB - fast atom bombardment

HRMS - high resolution mass spectrometry

Ether diethyl ether

Pharmacological suitability refers to those properties of the substances that are suitable for the patient from a pharmacological / toxicological point of view and the manufacture of the pharmacological substance from a physic / chemical point of view with respect to the composition, form, stability, patient compatibility and bioavailability. If two solvents are used, the ratio of solvents used is volume / volume (v / v). Pharmacologically acceptable salt anions include methanesulfonate, chloride, sulfate, phosphate, nitrate, citrate, CH ₃ - (CH ₂ ) ni, where m is 0-4, ¹⁰ OOC- (CH ₂ ) _n i-COO ^-1 , wherein n is defined above, ' ¹ OOC-CH = CH-COO' ¹ , -φ-COO ' ¹ .

DETAILED DESCRIPTION OF THE INVENTION

According to the following processes of the invention, the same satisfactory result is obtained as with the known methods. The following detailed examples describe the preparation of various compounds and / or various processes of the invention and are set forth as illustrative, but not the only, to explain any preparation. Various variations of the methods, reagents, reaction conditions and techniques known in the art are apparent.

Preparation 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 ° C for 24 hours. After cooling, the solid was removed and washed with water and toluene and then dried under reduced pressure to give the title compound, mp = 240-248 ° C; MS (M / Z) at 205; NMR (DMSO-d 6) 2.59, 2.80, 3.14, 6.90, 7.02, 7.72 and 7.73 δ.

Preparation 2

N- [4- (trifluoromethyl) phenyl] piperazine

A 100 mL flask equipped with a stir bar was charged with 4-bromobenzotrifluoride (19.70 g, 0.088 mol) and piperazine (37.71 g, 0.438 mol). The reactants were heated to 130 ° C. After 48 hours, the mixture contained a significant amount of precipitate and cooled to 20-25 ° C. During cooling, the reaction mixture was diluted with sodium hydroxide (3N, 200 mL) to give an additional amount of precipitate, followed by extraction twice with ethyl acetate (200 mL). If the mixture is cooled to 2025 ° C before the addition of the aqueous base, a solid phase is formed in the reaction which makes further handling difficult. The combined organics were washed once with brine (300 mL), dried over magnesium sulfate, filtered and concentrated to give the title product. Recrystallization from hexanes gave the title compound, mp 87-89 ° C (86-88 ° C), R _f = 0.20 (methanol / dichloromethane, 7/93).

Example 1 (S) - (-) - 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] isochroman-6-carboxamide (S) - (VII) also known as (S) - ( -) - 1- (4-Methoxyphenyl) -4- [2- (6-aminocarbonylisochroman-1-yl) ethylpiperazine

Step 1: ethyl (6-bromoisochroman-1-yl) acetate (III)

A mixture of 3-bromophenethyl alcohol (II, 14.8 g) in dichloromethane (37 mL) was cooled to 0 ° C in an ice bath and argon atmosphere. Ethyl 3,3-diethoxypropionate (90%, 19.1 mL) was added via syringe. A solution of titanium tetrachloride (1 M in methylene chloride, 236 mL) was added dropwise to the reaction mixture via a tube and funnel over one hour. The reaction was then refluxed for 18 hours, then poured into a mixture of aqueous hydrochloric acid (1N) and brine (1/2) and extracted with methylene chloride. The organic phases are combined, dried over sodium sulfate, filtered and concentrated. The concentrate is purified by chromatography (silica gel; ethyl acetate / hexane, 10/90) to give ethyl (6-bromoisochroman-1-yl) acetate (III); R _f = 0.40 (ethyl acetate / hexane, 25/75); IR (neat) 1736, 1483, • · · ·

YJ · ·· · · · · · ·

- ² '······ · ······ ··· ···· · · · ·············

1374, 1288, 1280, 1183, 1163, 1110, 1050, 1037 cm ^-1 ; NMR (300 MHz, 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 δ; CMR (75 MHz, 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 13.9 δ; HRMS calculated for C ₁₃ H ₁₅ O ₃ Br = 298.0205, found = 298.0204.

Step 2: (R) - (+) - ethyl (6-bromoisochroman-1-yl) acetate (XII) and (S) - (-) - (6-bromoisochroman-1-yl) acetic acid (XI).

Ethyl (6-bromoisochroman-1-yl) acetate (III, 1st step, 29.49 g), Amano in P-30 lipase (15 g, lot # LPSAR01520, activity = 312.600 u / g) and buffer o pH 7 (590 mL). The reaction proceeds with vigorous stirring and hydrolysis is followed by HPLC. For clarification, a 100 μΙ aliquot containing hydrochloric acid (one drop) was added. Ethyl acetate (1.5 mL) was then added to the flask and mixed well. The resulting mixture was then filtered through celite and analyzed by HPLC (uBondapak C18 3.9 mm x 30 cm reverse phase column, 10% acetonitrile / 90% phosphate buffer (4 L water, 5.22 g sodium dihydrogen phosphate (hydrate), 0 76 ml phosphoric acid) gradient to 85/15 over 15 minutes, then isocratic elution at 2 ml / min, detector for 215 nm), (XI) R _t = 10.5 min, (XII) R _t = 13 , 5 min. When the reaction reaches the 50% conversion point, filtration is performed and the filtrate is washed several times with aqueous hydrochloric acid (1N) and several times with ethyl acetate. The filtrates were combined and extracted (twice) with ethyl acetate. The combined organic extracts were washed with an equivalent volume of saturated aqueous sodium carbonate (3x), dried over sodium sulfate, filtered and concentrated to give the enantiomers (XII). The washed saturated aqueous sodium carbonate was acidified with concentrated hydrochloric acid and extracted three times with methylene chloride, dried over sodium sulfate, filtered and concentrated to give (XI). The acid (XI) was measured for enantiomeric purity as described below. A mixture of the acid (XI, 15 mg) in THF (0.5 mL) is reduced with borane-THF complex (1M in THF, 0.12 mL) from 5 ° C to 20-25 ° C for 18 hours. The reaction was cooled to 0 ° C, quenched with methanol (0.1 mL), then warmed to 20-25 ° C and hydrochloric acid (1N, 0.4 mL) was added by pipette. The reaction was then heated to reflux for 10 minutes, the volatiles were removed under reduced pressure and the residue was partitioned between ethyl acetate and saturated aqueous sodium carbonate. The organic phases are separated, dried over magnesium, filtered and concentrated. The residue was weighed and dissolved to a concentration of 10 mg / ml with a solution of isopropanol in hexane (7%). The mixture is then measured on a Chiracel OJ column using the mixture.

hexane / isopropanol 90/10, 15 min, 1 mL / min), then 80/20 for an additional 10 min, (2 mL / min), wavelength 254 nm; (S) -alcohol R t = 12.46 min, (R) -alcohol R _t = 10.46 min. The ester (XII) can be analyzed in a similar manner by hydrolysis. (far infra). If desired, the enantiomerically rich ester can be transferred back to the next cycle of enzymatic hydrolysis if indicated by HPLC analysis. There was thus obtained (R) - (+) - ethyl (6-bromoisochroman-1-yl) acetate (XII) (96% subject to error); R _f = 0.40 (octanethylnatý / hexane, 25/75); [α] _D + 72 ° (c = 0.383, ethanol); IR (neat) 1736, 1483, 1374, 1288, 1280, 1183, 1163, 1110, 1050, 1037 cm ^-1 ; NMR (300 MHz, 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 MHz, 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, found = 298.0206. (S) - (-) - (6-Bromoisochroman-1-yl) acetic acid was isolated (99% ee); mp = 160161 ° C; R _f = start (ethyl acetate / hexane, 25/75); [α] _D = -90 ° (c = 1, ethanol); IR (neat) 1711, 1482, 1428, 14406, 1330, 1297, 1111, 1101, 1003, 971 cm ^-1 ; NMR (300MHz, CDCl 3) 7.30, 6.92, 5.17, 4.18-4.11, 3.86-3.78 and 3.04-2.69; CMR (75 MHz, 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 28.5 δ.

Step 3: (S) - (-) - 1- [2- (6-bromoisochroman-1-yl) acetyl] -4- (4-methoxyphenyl) piperazine (S) - (V)

Combine (S) - (-) - (6-bromoisochroman-1-yl) acetic acid (XI, Step 2, 3 g), N- (4-methoxyphenyl) piperazine (2.34 g) with dichloromethane (20 ml). ml) and cooled to 0 ° C. Diethyl cyanophosphate (2.0 mL) and triethylamine (1.7 mL) were added via syringe. In an ice bath, the mixture was stirred at 20-25 ° C for 18 hours. The reaction mixture was concentrated under reduced pressure to give a crude which was chromatographed (silica gel; ethyl acetate / hexane, 60-80 / 40-20) to give (S) - (-) 1- [2- (6-bromoisochroman) -1-yl) acetyl] -4- (4-methoxyphenyl) -piperazine (S) - (V) (after recrystallization from ethyl acetate / hexane), m.p. = 122-123 ° C; R _f = 0.26 (ethyl acetate / hexanes, 70/30); [α] _D = -86 ° (c = 0.99, ethanol); IR (suspension) 1639, 1512, 1446, 1439, 1249, 1214, 1112, 1030, 1028, 820 cm ^-1 ; NMR (300 MHz, CDCl ₃ ) 7.32-7.26, 7.00, 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 2.65 δ. 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, 50J, 46.1, 41.9, 39.9 and 2B, 7 δ .

Step 4: (S) - (-) - 1- [2- (6-bromoisochroman-1-yl) ethyl] -4- (4-methoxyphenyl) piperazine (S) - (VI) (S) - ( -) - 1- [2- (6-bromoisochroman-1-yl) acetyl] -4- (4-methoxyphenyl) -piperazine ((S) - (V), Step 3, 3.7 g) in THF ( 84 mL) was cooled to 0 ° C and borane-THF complex (1M in THF, 25 mL) was added via syringe. The ice bath was removed and the mixture was heated to reflux for 18 hours. The reaction was cooled to 0 ° C, slowly quenched with aqueous hydrochloric acid (1N, 100 mL) and refluxed for an additional 1.5 hours. The mixture was cooled to 20-25 ° C and the solvents were removed under reduced pressure, the aqueous residue was diluted with brine, and the pH was raised with aqueous sodium hydroxide. The mixture was extracted with dichloromethane and the combined organic phases were dried over sodium sulfate, filtered and concentrated. The concentrate was purified by recrystallization from ethyl acetate / hexane to give (S) - (-) - 1- [2- (6-bromoisochroman-1-yl) ethyl] -4- (4-methoxyphenyl) -piperazine (S) - (VI) melting point = 85-86 ° C; R _f = 0.23 (ethyl acetate); [α] _D = 48 ° (c = 0.73, ethanol); IR (neat) 1518, 1479, 1266, 1250, 1155, 1140, 1112, 1103, 1041, 818 cm ^-1 ; ¹ H 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 δ. CMR (75 MHz, 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 28.6 δ; HRMS calcd for C 22 H 27 Ν 2Ο2ΒΠ = 430.1256, found = 430.1270.

Step 5: (S) - (-) - 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] -isochroman-6-carboxamide (S) - (VII) (S) - ( -) - 1- [2- (6-bromoisochroman-1-yl) ethyl] -4- (4-methoxyphenyl) -piperazine ((S) - (VI), Step 4 364 mg), palladium acetate (98%) , 9.7 mg) and 1,3-bis-diphenylphosphinopropane (97%, 22 mg). Prepare a carbon monoxide atmosphere in the vial, and add DMF (2 mL), 1,1,1,3,3,3-hexamethyldisilazane (98%, 1.25 mL) and diisopropylethylamine (0.29 mL) via syringe to the reaction. ). The mixture was boiled at 100 ° C for 18 hours. After cooling to 20-25 ° C, the reaction is separated into two phases. The reaction was poured into aqueous hydrochloric acid (1N) and washed twice with ether. For the acidic solution, the pH is raised with aqueous sodium hydroxide solution and extracted three times with ethyl acetate. The ethyl acetate phases are combined and concentrated. It is then purified by chromatography (silica gel; methanol / dichloromethane, 5/95) to give (S) - (-) - 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] -isochroman-6-carboxamide ( S) - (VII), melting point = · · · · · · · · · · · · · · · · · · · · · · · · · ······················

186-187 [deg.] C .; Rf = 0.27 (methanol / ethyl acetate, 10/90); [α] _D = -53 ° (c = 0.92, methylene chloride / methanol (1/1); IR (suspension) 3366, 3198, 1628, 1642, 1602, 1514, 1437, 1245, 1109 and 815 cm -1). ¹ H NMR (300MHz, 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 δ; CMR (75 MHz, CDCl ₃ ) 168.7, 153.3, 145, 4, 142.0, 134.3, 131.0, 127.9, 124.8, 124.6, 117.8, 114.7, 74.2, 62.6, 55.2, 54.3, 53.2, 50.3, 32.8, 28.7 and 27.2 δ; HRMS calcd for C 23 H 29 N 3 O 3 = 395.2209, found = 395.2227.

Example 2 (R) - (+) - 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] -isochroman-6-carboxamide (R) - (VII), also known as (R) - ( +) - 1- (4-Methoxyphenyl) -4- (2- (6-aminocarbonylisochroman-1-yl) ethylpiperazine)

Step 1: (R) - (+) - 6- (bromoisochroman-1-yl) acetic acid (R) -IV.

To (R) - (+) - ethyl (6-bromoisochroman-1-yl) acetate (XII, EXAMPLE 1 2nd step, 13.3 g) in THF (150 mL) was added a mixture of lithium hydroxide (3M, 150 mL). The mixture was stirred at 20-25 ° C for 18 hours. The volatile solvents were removed under reduced pressure and the residue was then acidified to pH = 1 with aqueous hydrochloric acid. The remaining mixture was extracted with methylene chloride and the combined organics dried over sodium sulfate, filtered and concentrated. The concentrate was purified by recrystallization from dichloromethane / hexane to give (R) - (+) - 6- (bromoisochroman-1-yl) acetic acid (R) -IV, mp = 160-161 ° C; R _f = beginning (ethyl acetate / hexane, 25/75); [α] _D = + 83 ° (c = 0.99, ethanol); IR (neat) 1711, 1482, 1428, 14406, 1330, 1297, 1111, 1101, 1003 and 971 cm ^-1 ; NMR (300MHz, CDCl 3) 7.30, 6.92, 5.17, 4.18-4.11, 3.86-3.78 and 3.04-2.69 δ; CMR (75MHz, CDCl3) 175.7, 136.2, 135.1, 132.0, 129.6, 126.2, 120.8,

72.4, 63.1, 45.5, 41.1 and 28.5 δ.

Step 2: (R) - (+) - 1- [2- (6-bromoisochroman-1-yl) acetyl] -4- (4-methoxyphenyl) piperazine (R) - (V).

Following the procedure of Example 1, Step 3 with minor variations, starting from (R) - (+) - 6- (bromoisochroman-1-yl) acetic acid (Example 2, Step 1, (R) - (IV)) crude product. This was first purified by silica gel chromatography using a 6080% ethyl acetate / hexane gradient and the resulting solid was recrystallized (ethyl acetate / hexane) to give: (R) - (+) - [2- (6-bromoisochroman-1-) yl) acetyl] -4- (4-methoxyphenyl) -piperazine (R) - (V), m.p. = 122-123 ° C; R _f = 0.26 (ethyl acetate • · · · · · · · ·· · ·· * * ♦ 1 ······. ······ ··· · · · · · ··· · Hexane, 70/30); [α] _D = + 89 ° (c = 1.00, ethanol); IR (suspension) 1639, 1512, 1446, 1439, 1249, 1214, 1112, 1030, 1028, 820 cm ^-1 ; NMR (300 MHz, 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 2.65 δ; 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 δ.

Step 3: (R) - (+) - 1- [2- (6-bromoisochroman-1-yl) ethyl] -4- (4-methoxyphenyl) piperazine (R) - (VI).

Following the procedure of Example 1, Step 4 with minor variations, starting from (R) - (+) - 1- [2- (6-bromoisochroman-1-yl) acetyl] -4- (4-methoxyphenyl) piperazine (R) - (V) ((Example 2, Step 2) (R) - (+) - 1- [2- (6-bromoisochroman-1-yl) ethyl] -4 (4-methoxyphenyl) -piperazine (R) - (VI), m.p. = 85-86 ° C; R _f = 0.23 (ethyl acetate); [α] _D = 47 ° (c = 0.49 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 δ CMR (75 MHz, 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 28.9; HRMS calcd for C 22 H 27 N ₂ O ₂ Bri = 430.1256, found = 430.1274.

Step 4: (R) - (+) - 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] -isochroman-6-carboxamide (R) - (VII)

Following the procedure of Example 1, Step 5, with minor variations, starting from (R) - (+) - 1- [2- (6-bromoisochroman-1-yl) ethyl] -4- (4-methoxyphenyl) -piperazine (R). (VI)) (Example 2, Step 3) crude material. This was purified by flash chromatography (silica gel, 50 g; methanol / ethyl acetate, 5/95) to give (R) - (+) - 1- (2- (4- (4-methoxyphenyl) -1-piperazinyl] ethyl) isochroman -6-carboxamide (R) - (VII), m.p. = 187-187.5 ° C; R _f = 0.27 (methanol / ethyl acetate, 10/90); [α] _D = + 52 ° (c = 0.92, methylene chloride / methanol, 1/1) IR (suspension) 3366, 3198, 1628, 1642, 1602, 1514, 1437, 1245, 1109 and 815 cm ^-1 ; NMR (300 MHz, CDCl ₃ ) 7.61-7.58, 718, 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 δ 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 δ; HRMS calculated for C ₂₃ H ₂₉ N ₃ O ₃ = 395.2209, found = 395.2208.

Example 3 (S) - (-) - 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] -N-

methyl isochroman-6-methoxyphenyl) -4- [2- (6-ethylpiperazine) carboxamide (S) - (IX), also known as (S) - (-) - 1- (4-methylaminocarbonylisochroman-1-yl) -

Step 1:

(S) - (-) - N, N-di-t-butyloxycarbonyl-1- [2- [4- (4-methoxyphenyl) -1-piperazinyl-ethyl] -isochroman-6-carboxamide (S) - (VIII)

A mixture of (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) in dichloromethane (20 mL) were stirred at 20-25 ° C under an argon atmosphere. After 72 hours, the reaction is concentrated under reduced pressure and the product is purified by column chromatography (silica gel, eluting with a gradient of 25% ethyl acetate in hexane followed by 100% ethyl acetate) to give (S) - (-) - N, N- di-t-butyloxycarbonyl-1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] -isochroman-6-carboxamide (S) - (VIII), [α] _D = -32 ° (c = 0 , 7201, ethanol); HRMS calcd for C 33 H 45 N 3 O 7 = 595.3257, found = 595.3282.

Step 2: (S) - (-) - 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] -N-methyl-isochroman-6-carboxamide (S) - (IX)

A mixture of (S) - (-) - N, N-di-t-butoxycarbonyl-1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] -isochroman-6-carboxamide (S) - (VIII) (1.09 g) in dichloromethane (18 mL) in a sealable tube was quenched with nitrogen using acetone and carbon dioxide. Methylamine (excess; usually 50 equivalents) is then condensed into the cooled test tube, capped and warmed to room temperature. After shaking at room temperature for 16 hours, the contents of the tube are concentrated under reduced pressure and the resulting crude product is purified by column chromatography (silica gel; using methanol / dichloromethane 5/95) to give (S) - (-) - 1- [2- [ 4- (4-methoxyphenyl) -1-piperazinyl] ethyl] -N-methyl-isochroman-6-carboxamide (S) - (IX), [α] _D = -51 ° (c = 0.9953, methanol / dichloromethane, 1) / 1); Calcd for C24H31N3O3; C, 70.39; H, 7.63; N, 10.26. Found: C, 70.16; H, 7.84; N, 10.27.

EXAMPLE 4 (R) - (+) - 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] -N-methylisochroman-6-carboxamide (R) - (IX), also known as ( R) - (+) - 1- [2 • · · · · 0 · 0

[4- (4- methoxyphenyl) -4- [2- (6-methylaminocarbonylisochroman-1-yl) ethylpiperazine

Step 1: (R) - (+) - N, N-di-t-butoxycarbonyl-1- [2- [4- (4-methoxyphenyl) -1-

piperazinyljethyl] - Isochroman-6-carboxamide (R) - (VI 11)

Following the procedure of Example 3, Step 1, with minor variations, starting from (R) - (+) - 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] -isochroman-6-carboxamide ((R)) - (VII), Example 2, Step 4, 0.60 g), (R) - (+) - N, N-di-t-butoxycarbonyl-1- [2- [4- (4-methoxyphenyl) -1- piperazinyl] ethyl] -isochroman-6-carboxamide (R) - (VIII), which was used directly in the next step.

Step 2: (R) - (+) - 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] -N-methyl- izochroman-6- carboxamide (R) - (IX)

Following the procedure of Example 3, Step 2, with minor variations, it results from

default (R) - (+) - N, N-di-t-butoxycarbonyl-1- [2- [4- (4-methoxyphenyl) -1-

piperazinyl] ethyl] -isochroman-6-carboxamide (R) - (VIII) (R) - (+) - 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] -N-methyl-isochroman- 6-carboxamide (R) - (1X), [α] _D = + 48 ° (c = 0.9745, methanol / dichloromethane, 1/1); HRMS calcd for C 24 H 31 N 3 O 3 = 409.2365, found = 409.2391.

Example 5 (S) - (-) - 1- [2- [4- (4-Trifluoromethylphenyl) -1-piperazinyl] ethyl] -N-methylisochroman-6-carboxamide (S) - (IX), also known as (S) S) - (-) - 1- (4-Trifluoromethylphenyl) -4- [2- (6-methylaminocarbonylisochroman-1-yl) ethylpiperazine

Step 1: (S) - (-) - 1- [2- (6-bromoisochroman-1-yl) acetyl] -4- (4-trifluoromethylphenyl) piperazine (S) - (V) (S) - (-) 1- (6-bromoisochroman-1-yl) acetic acid (Example 1, XI, 542 mg, 2.0 mmol), 10 mL dichloromethane, 1- (4-trifluoromethyl) piperazine (507 mg, 3.3 mmol) and The diethyl cyanophosphonate (0.33 mL, 2.2 mmol) was mixed and cooled to 0 ° C, triethylamine (0.42 mL, 3.0 mmol) was added without visible change and the mixture was warmed to 20-25 ° C. After 16 hours, the reaction mixture was concentrated. The concentrate was purified by LC on 58 g (230-400) silica gel, eluting with ethyl acetate / hexane (40/60) to give (S) - (-).

) -1- [2- (6-bromoisochroman-1-yl) acetyl] -4- (4-trifluoromethylphenyl) -piperazine (S) - (V), Rf = 0.25 (ethyl acetate / hexane (40/60) ).

Step 2: (S) - (-) - 1- [2- (6-bromoisochroman-1-yl) ethyl] -4- (4-trifluoromethylphenyl) piperazine (S) - (VI).

(S) - (-) - 1- [2- (6-bromoisochroman-1-yl) acetyl] -4- (4-trifluoromethylphenyl) -piperazine (S) - (V) (Step 1, 876 mg, 1 (8 mmol) and 18.0 ml of freshly distilled tetrahydrofuran were cooled to 0 ° C. The mixture was treated with a drop of a 1M solution of borane in tetrahydrofuran (5.4 mL, 5.4 mmol) to give a foam. Heat the reaction at 20-25 ° C for 16 hours. The reaction was then treated with 1M hydrochloric acid (6.0 mL), refluxed and refluxed for 1 hour. The reaction is then cooled to 20-25 ° C and the volatiles are removed under reduced pressure. The resulting aqueous residue was diluted with water (30 mL), adjusted to pH > 10, and extracted twice with ethyl acetate (30 mL). The combined organic extracts were washed once with brine (30 mL), dried over magnesium sulfate, filtered, and concentrated. The concentrate was purified by LC on 43 g (230-400) silica gel and eluted with ethyl acetate / hexane (40/60) to give (S) - (-) - 1- [2- (6-bromoisochroman-1-yl)] acetyl] -4- (4-trifluoromethylphenyl) -piperazine (S) (VI), m.p. = 104-105 ° C; R _f = 0.30 (ethyl acetate / hexane, 40/60).

Step 3: (S) - (-) - 1- [2- [4- (4-Trifluoromethylphenyl) -1-piperazinyl] ethyl] -N-methylisochroman-6-carboxamide (S) - (IX)

Combine (S) - (-) - 1- [2- (6-bromoisochroman-1-yl) ethyl] -4- (4-trifluoromethylphenyl) piperazine (S) - (VI) (Step 2, 703 mg, 1.5 mmol), palladium acetate (17 mg, 0.075 mmol), 1,3-bis (diphenylphosphino) propane (37 mg, 0.09 mmol), 3.0 mL of dimethylformamide, diisopropylethylamine (0.52 mL, 3, 0 mmol) and N-methylformamide (1.8 mL, 30 mmol), purified six times with carbon monoxide under vacuum and heated to 120 ° C. After 16 hours, the mixture was cooled to 20-25 ° C, treated with 25 mL of 1M hydrochloric acid and stirred for 10 minutes. The acidic solution was adjusted to pH 12 and then extracted three times with ethyl acetate (20 mL). The combined organic extracts were washed once with brine (30 mL), dried over magnesium sulfate, filtered, and concentrated. The concentrate was purified by LC on 33 g (230-400) silica gel and eluted with acetone / hexane (40/60) to give (S) - (-) - 1- [2- [4- (4-trifluoromethylphenyl) -1] (piperazinyl) ethyl] -N-methylisochroman-6-carboxamide (S) - (IX), m.p. = 169-170 ° C; R _f = 0.30 (acetone / hexane 40/60).

Example 6 (S) - (-) - 1- [2- [4- [4- (aminocarbonyl) phenyl] -1-piperazinyl] ethyl] -N-methylisochroman-6-carboxamide (R) - (IX), also known as (S) - (-) - 1- (Benzamid-4-yl) 4- [2- (6-methylaminocarbonylisochroman-1-yl) ethylpiperazine

Step 1: (S) - (-) - 2- (6-bromoisochroman-2-yl) ethyl alcohol (S) - (-) - 2- (6-bromoisochroman-2-yl) acetic acid (XI) ( Example 1, Step 2 (16.27 g, 60 mmol) was mixed with 100 mL tetrahydrofuran. To this mixture was added a 10M solution of boron methyl sulfide (18.0 mL, 0.18 mol) at 20-25 ° C in a water bath. After 1 hour, the reaction mixture was cooled to 0 ° C and 160 mL of methanol was slowly added. Note: the reaction starts after 1-2 minutes of violent hydrogen formation. The mixture is warmed to 20-25 ° C and the volatiles are removed under reduced pressure. The resulting solid was diluted with 1M sodium hydroxide (150 mL) and extracted three times with ethyl acetate (100 mL). The obtained organic extracts were washed once with brine (100 mL), dried over magnesium sulfate, filtered and concentrated to give a solid. This raw material is recrystallized from ethyl acetate / hexane of (S) - (-) - 2- (6-bromoisochroman-2-yl) ethyl alcohol (S-1), m.p. = 95-96 ° C; R _f = 0.28 (acetone / hexane 30/70).

Step 2: (S) - (-) - 6-bromo-1- (bromoethyl) isochroman (S) - (-) - 2- (6-bromoisochroman-2-yl) ethyl alcohol (S-1) (1 Step (14.0 g, 54 mmol) was mixed with 91 mL of dichloromethane. To the resulting mixture was added 25 mL of tertrahydrofuran. The suspension was then treated with carbon tetrabromide (22.6 g, 68 mmol), cooled to 0 ° C, and triphenylphosphine (21.4 g, 82 mmol) was gradually added. The resulting mixture was heated at 20-25 ° C for three hours, followed by concentration of the reduced pressure and formation of a solid. The triphenylphosphine oxide is removed by recrystallization from ethyl acetate / hexane to give a solid phase with the parent alcohol. This material was absorbed into 70 g of silica gel and purified by LC on 700 g (230-400) silica gel eluting with ethyl acetate / hexane (5/95) to give (S) - (-) - 6-bromo-1- ( bromoethyl) isochroman (IV), R _f = 0.47 (10% acetone / hexane).

* ·

Step 3: (S) - (-) - 4- [4- [2- (6-bromoisochroman-1-yl) ethyl] -1-piperazinyl] benzamide

A mixture of (S) - (-) - 6-bromo-1- (bromoethyl) isochroman (IV) (Step 2, 17.22 g, 53.8 mmol), 14.36 g (67.0 mmol) 4- (piperazinyl-1-yl) benzamide (Preparation 1, 10.43 g (80.7 mmol) of diisopropylethylamine and 125 mL of ethylene glycol was heated at 85-90 ° C overnight. After cooling, water (300 mL) was added, resulting in The solid is collected and filtered, the filter cake is washed three times with water (about 200 mL in total and then with toluene (about 200 mL in total)), and the filter cake is dried under reduced pressure, after drying the crude product is suspended in methanol / dichloromethane and added. After removal of the solvent, the silica gel slurry is poured onto the top of a silica gel column with dichloromethane / methanol (95/5), starting with dichloromethane / methanol (95/5) and then dichloromethane / methanol (92/8). eluting with (S) - (-) - 4- [4- [2- (6-bromoisochroman-1-yl) ethyl] -1-piperazinyl] -benzamide (VI), which was obtained as a solid upon collection certain fractions and concentration.

Step 4: (S) - (-) - 1- [2- [4- [4- (aminocarbonyl) phenyl] -1-piperazinyl] ethyl] -N-methylisochromanyl-6-carboxamide (S) - (-) - 4 - [4- [2- (6-bromoisochroman-1-yl) ethyl] -1-piperazinyl] -benzamide (VI) (Step 3, 3.34 g, 7.52 mmol) was suspended in 55 mL of dry DMF and gas was removed under vacuum (using argon). The suspension was then transferred to the bottom of a three-necked flask (using 10 ml DMF rinse flask) containing palladium acetate (0.084 g, 0.376 mmol) and 1,3-bis (diphenylphosphino) propane (0.232 g, 0.564 mmol) and the flask is placed in an oil bath. Diisopropylethylamine (2.6 mL, 15.3 mmol) was added and the mixture was again slightly pressurized with argon. When the bath temperature reaches 60 ° C, the carbon monoxide purges on the surface of the mixture and after a few minutes also methylamine. Within 6 hours, carbon monoxide and methyl amine are added or the starting material is consumed, then the mixture is cooled and DMF is removed under reduced pressure. pressure. The residue was applied to a silica gel column and eluted with methanol / dichloromethane (8/92) until less polar impurities were eluted. The eluent is then added to a methanol / dichloromethane (10/90) mixture and after collection and concentration of certain fractions and crystallization from a methanol / dichloromethane mixture, (S) - (-) - 1- [2- [4- [4- ( aminocarbonyl) phenyl] -147 piperazinyl] ethyl] -N-methylisochromanyl-6-carboxamide (IX), m.p. = 231.5232.5 Deň: 32 ° C.

Example 7 1- [2- [4-4-Methylphenyl) -1-piperazinyl] ethyl-isochroman-6-carboxamide (VII)

Step 1: 6-bromoisochroman-1-yl-acetic acid (IV)

Following the procedure of Example 2, Step 1, with minor variations, 6-bromo-iso-chroman-1-yl-acetic acid (IV) racemic ethyl 6-bromoisochroman-1-yl acetate (IV), m.p. = 160-161 ° C; NMR (300 MHz, CDCl ₃ ) 7.30, 6.92, 5.17, 4.18-4.11, 3.86-3.78 and 3.04-2.69 δ.

Step 2: 1- [2- (6-bromoisochroman-1-yl) acetyl] -4- (4-methylphenyl) -piperazine (V)

Following the procedure of Example 1, Step 3 with minor variations, 6-bromoisochroman-1-yl-acetic acid (IV) and methylphenylpiperazine, 1- (2- (6-bromoisochroman-1-yl) acetyl) -4- (4-methylphenyl) are formed ) piperazine (V) which is then analyzed by flash chromatography (silica gel 80 g; ethyl acetate / hexane, 50/50) _Rf = 0.20 (ethyl acetate / hexane, 50/50); IR (neat) 1642, 1515, 1481, 1462, 1443, 1234, 1208, 1107, 1031 and 813 cm -1. ¹ H 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 δ; CMR (75 MHz, CDCl ₃ ) 168.2, 148.3, 136.5, 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, 29.8, 26.6 and 20.3 δ.

Step 3: 1- [2- (6-bromoisochroman-1-yl) acetyl] -4- (4-methylphenyl) -piperazine (VI)

Following the procedure of Example 1.4. of the small variation step, 1- (2- (6-bromoisochroman-1-yl) acetyl] -4- (4-methylphenyl) -piperazine (V) yields 1- (2- (6-bromoisochroman-1-yl) acetyl) -4 - (4-methylphenyl) -piperazine (VI), R _f = 0.21 (ethyl acetate / hexane, 50/50); IR (neat), 29.41, 29.25. 2818, 1515, 1481, 1379 1239, 1143, 1111 and 813 cm ^-1 ; NMR (300 MHz, CDCl ₃ ) 7.32-7.26-7.07, 6.97, 6.84, 4.78,

4.14- 3.07, 3.78-3.69, 3.16, 2.94, 2.7-2.48, 2.26, 2.15-1.90 δ; CMR (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 δ.

Step 4: 1- [2- [4-4-methylphenyl) -1-piperazinyl] ethyl-isochroman-6-carboxamide (IX)

Following the procedure of EXAMPLE 1, Step 5, with minor variations, 1- [2- (6-bromoisochroman-1-yl) acetyl] -4- (4-methylphenyl) -piperazine (VI) 1- [2- [44] is formed. methylphenyl) -1-piperazinyl] ethylizochroman-6-carboxamide (VII), R _f = 0.2 (methanol / ethyl acetate, 10/90); IR (suspensions) 3373, 3180, 1647, 1623, 1571, 1520, 1406, 1242, 1111 and 817 cm ^-1 ; NMR (300 MHz, 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 2.02 δ; HRMS calcd for C ₂₃ H ₂₉ N ₃ O ₂ = 379.2260, found = 379.2269.

Example 8 1- [2- [4-4-chlorophenyl) -1-piperazinyl] ethyl isochroman-6-carboxamide (VII)

Step 1: 1- [2- (6-bromoisochroman-1-yl) acetyl] -4- (4-chlorophenyl) piperazine (V)

Following the procedure of Example 1, Step 3, with minor variations, racemic 6-bromoisochroman-1-yl-acetic acid (IV) and 4-chlorophenylpiperazine of 1- [2- (6-bromoisochroman-1-yl) acetyl] -4- (4-chlorophenyl) piperazine (V), Rf = 0.20 (ethyl acetate / hexane, 50/50); IR (suspension) 1642, 1594, 1496, 1482, 1443, 1275, 1232, 1107, 1030, and 821 cm ^-1 ; NMR (300 MHz, 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 2.65 δ; CMR (75 MHz, CDCl ₃ ) 178.1, 148.5, 136.0, 131.8, 129.1, 128.8, 125.8, 125.0, 120.0, 117.5, 73, 0, 63.2, 49.7, 49.2, 55.0, 41.9, 39.6 and 28.5 δ.

Step 2: 1- [2- (6-bromoisochroman-1-yl) acetyl] -4- (4-chlorophenyl) piperazine (VI)

Following the procedure of Example 1, Step 4 with minor variations, 1- [2- (6-bromoisochroman-1-yl) acetyl] -4- (4-chlorophenyl) piperazine (V) 1- [2- (6-bromoisochroman- 1-yl) acetyl] -4- (4-chlorophenyl) piperazine (VI), m.p. = 94-96 ° C; R _f = 0.22 (ethyl acetate / hexane, 50/50); IR (suspension) 1500, 1483, 1448, 1248, 1242, 1152, 1144, 1113, 1102 and 815 cm ^-1 ; NMR (300 MHz, 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 2.15.1.90 δ; 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 δ.

• ·

Step 3: 1- [2- [4-4-chlorophenyl) -1-piperazinyl] ethylisochroman-6-carboxamide (IX)

Following the procedure of Example 1, Step 5, with minor variations, 1- [2- (6-bromoisochroman-1-yl) acetyl] -4- (4-chlorophenyl) piperazine (VI) 1- [2- [4-] is formed. 4-chlorophenyl) -1-piperazinyl] ethylisochroman-6-carboxamide (VII), m.p. = 169-171 ° C; _Rf = 0.22 (methanol / ethyl acetate, 10/90); IR (slurry) 3365, 1649, 1661, 1623, 1500, 1403, 1241, 1112, 1096 and 821 cm ^-1 ; NMR (300 MHz, 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 2.02 δ.

Example 9 1- [2- [4-4-Phenylmethyloxyphenyl) -1-piperazinyl] ethyl] -isochroman-6-carboxamide (VII)

Step 1: 1- (4-Phenylmethoxyphenyl) -4- [2- (6-bromoisochroman-1-yl) acetyl] piperazine (V)

Following the procedure of Example 1, Step 3, with minor variations, racemic 6-bromoisochroman-1-yl-acetic acid (IV) and 4-phenylmethyloxopiperazine of 1- (4-phenylmethoxyphenyl) -4- [2- (6-bromoisochroman- 1-yl) acetyl] piperazine (V), R _f = 0.47 (ethyl acetate); IR (suspension) 1510, 1481, 1463, 1453, 1445, 1239, 1231, 1101, and 1027 cm ^-1 ; NMR (300 MHz, 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 2.65 δ; CMR (75 MHz, 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 δ.

Step 2: 1- (4-phenylmethoxyphenyl) -4- [2- (6-bromoisochroman-1-yl) ethyl] piperazine (VI)

Following the procedure of Example 1, Step 4, with minor variations, 1- (4-phenylmethoxyphenyl) -4- [2- (6-bromoisochroman-1-yl) acetyl] piperazine (VI) 1- (4-phenylmethoxyphenyl) was formed. -4- [2- (6-bromoisochroman-1-yl) acetyl] piperazine (VI), m.p. = 8790 ° C; R _f = 0.43 (ethyl acetate); IR (neat) 1578, 1517, 1452, 1258, 1153, 1113, 1054, 1049, 818, and 737 cm ^-1 ; NMR (300 MHz, CDCl ₃ ) 7.43-7.26 (m 7H, aromatic H), 6.97 (d 1H, J = 8.2 Hz), 6.90 (with broad baseline, 4H, aromatic) H), 5.1 (2H, PhC-H ₂ ), 4.77 (wt, 1H, J = 5.5 Hz, PhC-H), 4.14-4.07 (m, 1H), 3, 74

1H, J a = 3.9Hz, Jb = 9.4 Hz), 3.11 (t, 4H, J = 4.9 Hz, four of pip-H), 2.95 (m, 1H), 2.72 54 (several m, 7H), 2.11 (m, 1H, pip CH-H), 2.02 (m, 1H, pip CH-H) δ; CMR (75 MHz, CDCl ₃ ) 153.0, 145.1, 137.4, 137.1, 136.3, 131.6, 128.5, 127.8, 126.5, 120.0, 118, 0, 115.6, 74.3, 70.5, 62.8, 54.6, 53.5, 50.5, 33.1 and 28.9 δ.

Step 3: 1- [2- [4-4-Phenylmethyloxyphenyl) -1-piperazinyl] ethyl] -isochroman-

6-carboxamide (VII)

Following the procedure of Example 1, Step 5, with small variations, 1- (4-phenylmethoxyphenyl) -4- [2- (6-bromoisochroman-1-yl) ethyl] piperazine (VI) is obtained 1- [2- [4-4phenylmethyloxyphenyl] -1-piperazinyl] ethyl] -isochroman-6-carboxamide (VII), IR (suspension) 33.68, 31.78, 1647, 1623, 1611, 1570, 1515, 1334, 124.6 and 1111 cm ^-1 ; NMR (300 MHz, CDCl ₃ ) 7.58 (m, 2H, aromatic H), 7.43.7.30 (m, 5H, aromatic H), 7.15 (d, 1H, J = 8.4 Hz) , aromatic H), 6.90 (s, 4H, aromatic H), 6.20-5.80 (two broad singlets, C (O) NH ₂ ), 5.0 (s, 2H, PhC-H ₂ - O), 4.87 (mt, 1H, J = 5.8 Hz), 4.184.10 (m, 1H), 3.81-3.73 (m, 1H), 3.10 (t, 4H, J = 4.8 Hz, four of pip-H), 3.0 (m, 1H), 2.75 (m, 1H), 2.650-2.54 (m, 6H), 2.15 (m, 1H) 2.05 (m, 1H) .delta. CMR (75 MHz, CDCl ₃ ) 169.0, 152.9, 145.8, 142.3, 137.3, 137.3, 134.5, 131.3, 128.5, 128.1, 127, 8, 127.4, 125.0, 124.9, 118.0, 115.5, 74.5, 70.4, 62.8, 54.6, 53.4, 50.4, 33.1 and 29,0 δ.

Example 10 1- [2- [4-4-Butoxyphenyl) -1-piperazinyl] ethyl] -isochroman-6-carboxamide (VII)

Step 1: 1- [2- (6-bromoisochroman-1-yl) acetyl] -4- (4-buthophoxyphenyl) piperazine (V)

Following the procedure of Example 1, Step 3, with minor variations, racemic 6-bromoisochroman-1-yl-acetic acid (IV) and 4-butoxyphenylpiperazine of 1- [2 (6-bromoisochroman-1-yl) acetyl] -4- ( 4-butopxyfenyl) piperazine (V), R _f = 0.24 (ethyl acetate / hexane, 50/50); IR (suspension) 1640, 1513, 1482, 1441, 1422, 1245, 1232, 1103, 1031, 829 cm ^-1 ; NMR (300 MHz, CDCl 3) 7.29, 7.00, 6.90, 5.26, 4.13-4.07, 3.92, 3.93-3.87, 3.80-3.60 , 3.06, 2.98-2.89, 2.76, 2.65, 1.74, 1.48, 0.96 δ. (CMR 75 MHz, CDCl ₃ ) 168.8, 153.8, 145.0, 136.4, 136.2, 131.6, 129.3, 126.3, 120.2, 118.7,

115.1, 73.3, 67.9, 63.3, 51.2, 50.7, 46.1, 41.8, 39.8, 31.3, 28.7, 19.1, 17, 3 and 13.7 δ.

· ♦ · · · «« «« · · · · · · · · · ·

Step 2: 1- [2- (6-bromoisochroman-1-yl) ethyl] -4- (4-butopxyphenyl) piperazine (VI)

Following the procedure of Example 1, Step 4, with minor variations, 1- (2- (6-bromoisochroman-1-yl) acetyl] -4- (4-butopoxyphenyl) -piperazine (V) 1- (2- (6-bromoisochroman-1)) was formed. yl) ethyl] -4- (4-butopxyfenyl) piperazine (VI), R _f = 0.43 (ethyl acetate); IR (neat) 2957, 2931, 28872, 1511, 1481, 1261, 1243, 1233 1112, 1057 cm ^-1 ; NMR (300 MHz, CDCl ₃ ) 7.32 (d, 2H, J = 8.3 Hz, aromatic H), 7.06 (d, 1H, J = 8.3 Hz, aromatic H), 6.85 (q, 4H, J = 9.7 Hz, aromatic H), 4.80 (wd, 1H, J = 6.1 Hz), 4.13-4.08 (m, 1H 3.98-3.89 (m, 3H), 3.71 (dzt, 1H, J _a = 3.7 Hz, J _b = 13.7 Hz), 3.28 (broad s, 4H), 3.10-2.72 (broad m, 7H), 2.65 (mzd, 1H), J = 16.5 Hz), 2.40 (m, 1H), 2.22 (m, 1H), 1 74 (quintet, 2H, J = 6.6 Hz), 1.46 (sextet, 2H, J = 7.3 Hz), 1.25 (t, 2H, J = 7.0 Hz), 0.96 ) t, 3H, J = 7.3 Hz) δ; HRMS calculated 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-6-carboxamide (VII)

Following the procedure of Example 1, Step 5, with minor variations, 1- [2- (6-bromoisochroman-1-yl) -ethyl] -4- (4-butopxyphenyl) -piperazine (VI) 1- (2- ( 4-4butoxyfenyl) -1-piperazinyl] ethyl] isochroman-6-carboxamide (VII), R _f = 0.18 (methanol / ethyl acetate), 10/90); IR (suspension) 3364, 2820, 1647, 1624, 1570, 1413, 1260, 1245, 1111 cm &^lt; -1 &gt;; NMR (300 MHz, CDCl ₃ ) 7.60, (m, 2H, aromatic H), 7.18 (d, 1H, J = 8.5 Hz, aromatic H), 6.86 (q, 4H, J = 9.2 Hz, aromatic H), 6,205.80 (two broad singlets, C (O) NH ₂ ), 4.85 (wd, 1H, J = 18 Hz), 4.15 (m, 1H), 3, 90 (t, 2H, J = 6.5Hz, -O-C-H ₂ -CH ₂ CH ₂ Me), 3.77 (m, 1H), 3.10 (t, 4H, J = 4.8 Hz, four of pip-H), 2.96 (m, 1H), 2.80-2.50 (m, 6H), 2.15 (m, 1H), 2.05 (m, 1H), 1 , 74 (quintet, 2H, J = 6.8 Hz, -OCH ₂ CH ₂ -CH ₂ Me), 1.48 (quintet, 2H, J = 7.5 Hz, -OCH ₂ CH ₂ CH ₂ -Me) 0.96 (t, 3H, J = 7.3 Hz, -OCH ₂ CH ₂ CH ₂ CH ₃ ) δ; CMR (75 MHz, CDCl ₃ ) 169.1, 160.8,

153.4, 145.6, 142.4, 134.6, 131.3, 130.3, 128.2, 127.6, 125.1, 125.0, 118.1, 115.1, 74, 5, 68.1, 62.9, 54.7, 53.5, 50.6, 41.4, 33.2, 31.5, 29.0, 19.3 and 13.9 δ; HRMS calcd for C ₂₆ H ₃₅ 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: 1- [2- (6-bromoisochroman-1-yl) acetyl] -4- (4-diethylaminophenyl) -piperazine (V) Following the procedure of Example 1, Step 3 with minor variations, racemic 6-bromoisochroman is formed 1-yl-acetic acid (IV) and 4diethylaminofenylpiperazinu 1 - [2- (6-bromoizochroman-1 -vinyl) acetyl] -4- (4diethylaminofenyl) piperazine (V), R _f = 0.21 (acetone / hexane , 30/70); IR (suspension) 1633, 1518, 1482, 1446, 1423, 1261, 1232, 1196, 1109, 809 cm &^lt; -1 ^&gt;; ¹ H NMR (300 MHz, CDCl ₃ ) 7.32-7.26 (m, 2H, aromatic H), 7.0 (d, 1H, J = 8.2 Hz, aromatic H), 6.88 (d , 2H, J = 9.0 Hz, aromatic H), 6.68 (d, 2H, J = 9.0 Hz, aromatic H), 5.27 (mz dm, 1H, J = 5.9 Hz, ArC) -H), 4.16-4.07 (m, 1H), 3.89 (m, 1H), 3.89 (m, 1H), 3.76 (m, 2H), 3.64 (m, 2H), 3.28 (q, 4H, J = 7.1 Hz, two of PhNC-H _2), 2.98 (m, 5H), 2.76 (DZD, 1H, _J = 3.7 Hz ), J _b = 14.9 Hz), 2.65 (wt, 1H, J = 16.4 Hz) 1.12 (t, 6H, J = 7.0 Hz, two of NCH ₂ CH ₃ δ; CMR (75 MHz, CDCl ₃ ) 168.8, 143.2, 141.6, 136.4, 136.2, 131.6,

129.2, 126.3, 120.2, 119.2, 113.7, 73.3, 63.3, 51.6, 46.1, 44.6, 41.9, 39.8, 33, 1, 28.6 and 12.4 δ.

Step 2: 1- [2- (6-bromoisochroman-1-yl) acetyl] -4- (4-diethylaminophenyl) -piperazine (VI)

Following the procedure of Example 1, Step 4, with minor variations, 1- [2- (6-bromoisochroman-1-yl) acetyl] -4- (4-diethylaminophenyl) -piperazine (V) 1 [2- (6- bromoisochroman-1-yl) acetyl] -4- (4-diethylaminophenyl) -piperazine (VI), R f = 0.26 (ethyl acetate); IR (neat) 2931, 2965, 2814, 1516, 1374, 1262, 1232, 1144, 1109, 813 cm ^-1 ; NMR (300 MHz, CDCl ₃ ) 7.3-7.26 (m, 2H, aromatic H), 6.68 (d, 2H, J = 9.0 Hz, aromatic H), 4.77 (mzd, 1H) J = 5.9 Hz, ArC-H), 4.14-4.07 (m, 1H), 3.74 (dzf, 1H, J _a = 3.9 Hz, J _b = 9.3 Hz) , 3.26 (q, 4H, J = 7.1 Hz, two of PhNC-H _2), 3.08 (t, 4H, J = 4.8 Hz, four of pip-H), 2.95 ( m, 1H), 2.70-2.53 (m, 7H), 2.11 (m, 1H, pipCHH), 2.00 (m, 1H, pipCH-H), 1.11 (t, 6H, J = 7.0 Hz, two of NCH ₂ CH ₃ ) δ; HRMS calcd for C ₁₄ H ₁₅ N ₅ O ₁ Bn 0.152, C ₄ H ₈ O ₂ = 472.1964, found = 472.1956.

Step 3: 1- [2- [4-4-Diethylaminophenyl) -1-piperazinyl] ethyl] -isochroman-6-carboxamide (VII)

Following the procedure of Example 1, Step 5, with minor variations, 1- [2- (6-bromoisochroman-1-yl) -ethyl] -4- (4-diethylaminophenyl) piperazine (VI) 1- [2- [4] is formed. (4-diethylaminophenyl) -1-piperazinyl] ethyl] isochroman-6-carboxamide (VII), Rt = 0.25

(methanol / ethyl acetate, 10/90); NMR (300 MHz, 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, 5 and 1.11 δ.

Example 12 1- [2- [4- (3-Trifluoromethylphenyl) -1-piperazinyl] ethyl] isochroman-6-carboxamide (VII)

Step 1: 1- (2- (6-bromoisochroman-1-yl) acetyl) -4- (3-trifluoromethylphenyl) -piperazine (V)

Following the procedure of Example 1, Step 3, with minor variations, racemic 6-bromoisochroman-1-yl-acetic acid (IV) and 3- trifluoromethylphenylpiperazine of 1- [2- (6-bromoisochroman-1-yl) acetyl] -4 was obtained. - (3-trifluoromethylphenyl) -piperazine (V), Rf = 0.30 (ethyl acetate / hexane, 40/60); IR (liquids) 1643, 1610, 1592, 1496, 1482, 1448, 1374, 1351, 1320, 1309, 1282, 1233, 1164, 1121, 1076 cm ^-1 ; NMR (300 MHz, CDCl ₃ ) 7.34 (m, 3h, aromatic), 7.08 (m, 4H, aromatic), 5.25 (broad d, 1H, J = 5.6 Hz, methine), 4 11 (m, 1H, OCH _{2 a} ), 3.94 (m, 1H, O = CN-CH _{2 a} ), 3.80-3.65 (m, 4H, O = CN-CH ₂ b _C d, OCH _{2 b} ) 3.23 (m, 4H, Ph-NCH _{2 s} ), 2.95 (m, 2H, Ph-CH _2a & N-COCH _2a ), 2.78 (dd, 1H, J = 14.8 Hz & J) = 3.7 Hz, N-CO- _CH2b ), 2.66 (bd, 1H, J = 16.4 Hz, Ph- _CH2b ) δ; CMR (75 MHz, CDCl ₃ ) 169.2, 151.1, 136.4, 136.3, 131.8, 131.4, 129.7, 1129.5, 126.5, 126.0, 122, 4, 120.5, 119.2, 116.6, 112.7, 73.6, 63.6, 49.2, 48.8, 41.6,

45.8, 41.6, 40.0 and 28.8 δ; MS (EI, m / z) = 482;

Step 2: 1- [2- (6-bromoisochroman-1-yl) -ethyl] -4- (3-trifluoromethylphenyl) -piperazine (VI)

Following the procedure of Example 1, Step 4, with minor variations, 1- (2- (6-bromoisochroman-1-yl) acetyl) -4- (3-trifluoromethylphenyl) -piperazine (V) was formed, and the product was purified by LC (silica gel, 230-400, 142 g; ethyl acetate / hexane, 30/70) to give 1- [2- (6-bromoisochroman-1-yl) acetyl] -4- (3-trifluoromethylphenyl) -piperazine (VI), Rf = 0.40 (ethyl acetate / hexane, 40/60); IR (liquids) 2824, 1610, 1496, 1481, 1449, 1357, 1319, 1293, 1239, 1164, 1123, 1076, 993, 949, and 695 cm ^-1 NMR (300 MHz, CDCl 3) 7.32 (m, 3H, aromatic), 7.07 (m, 3H, aromatic), 6.97 (d, 1H, J = 8.2 Hz, aromatic), 4, 79 (broad d, 1H, J = 5.7 Hz, methine), 4.11 (m, 1H, OCH _2a ), 3.73 (m, 7H, Ph-NC (H ₂ ) -CH ₂ -NCH ₂₎ &Amp; Ph-CH _2b ), 2.10 (m, 1H, C (H) -CH _{2 a} ), 2.00 (m, 1H, C (H) -CH _{2 b} ) δ; CMR (75 MHz, CDCl ₃ ) 151 , 4, 137.0, 136.3, 131.7, 131.4 (qrt, J _CF = 36Hz), • ·

• ·

129.5, 129.3, 126.5, 126.2, 120.0, 118.6, 115.7 (d, J _F = 4 Hz), 112.1 (d, J _CF = 4 Hz) ,

74.2, 62.9, 54.5, 53.2, 48.7, 33.2, 28.9 δ; MS (EI, m / z) = 468.

Step 3: 1- [2- [4- (3-Trifluoromethylphenyl) -1-piperazinyl] ethyl] isochroman-6-carboxamide (VII)

Following the procedure of Example 1, Step 4, with minor variations, 1- [2- (6-bromoisochroman-1-yl) acetyl] -4- (3-trifluoromethylphenyl) -piperazine (VI) was formed. Purify by LC (silica gel, 230-400, 120 g; acetone / hexane, 50/50) to give 1- [2 - [- 4- (3-trifluoromethylphenyl) -1-piperazinyl] ethyl] isochroman-6-carboxamide (VII). This was recrystallized from ethyl acetate / hexane to give 1- (2- (4- (3-trifluoromethylphenyl) -1-piperazinyl] ethyl] isochroman-6-carboxamide (VII), mp = 129-131 ° C; R _f = 0.22 (acetone / hexane, 50/50) IR (suspension) 3383, 1647, 1618, 1606, 1567, 1407, 1359, 1322, 1312, 1287, 1161, 1139, 1115, 1098, 952 cm ^-1 ; NMR (300 MHz, CDCl ₃ ) 7.60, 7.33, 7.18, 7.07, 6.00, 4.88, 4.14, 3.77, 3.24, 3.01, 2, 78-2.48, 2.01 δ; CMR (75 MHz, CDCl ₃ ) 169.1, 151.4, 142.4, 134.6, 131.5, (qrt, J _CF = 32 Hz),

131.4, 139.5, 128.2, 125.1, 122.5, 118.6, 115.8 (d, J _CF = 4Hz), 112.1 (d, J _CF = 4Hz),

74.4, 63.0, 54.5, 53.2, 48.7, 33.2, 29.1 δ; HRMS (EI) calculated for C ₂₃ H ₂₆ F ₃ N ₃ O ₂ = 433.1977, found = 433.1979.

Example 13 1- [2- [4- (4-Methylsulfonylphenyl) -1-piperazinyl] ethyl] -isochroman-6-carboxamide (VII)

Step 1: 1- [2- (6-bromoisochroman-1-yl) acetyl] -4- (4-methylsulfonylphenyl) piperazine (V)

Following the procedure of Example 1, Step 3, with minor variations, racemic 6-bromoisochroman-1-yl-acetic acid XIV) and 4-methylsulfonylphenylpiprazine are obtained. 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) -piperazine (V), R _f = 0.30 (ethyl acetate); IR (suspension) e) 1639, 1593, 1508, 1481, 1405, 1295, 1239, 1145, 1105, 1096, 1027, 1000, 958, 825, 779 cm ^-1 ; NMR (300 MHz, CDCl ₃ ) 7.77 (d, 2H, J = 8.9 Hz, aromatic), 7.28 (m, 2H, aromatic), 7.00 (d, 1H, J = 8.2 Hz, aromatic), 6.91 (d, 2H, J = 9.0 Hz, aromatic), 5.24 (broad d, 1H, J = 5.7 Hz, methine), 4.10 (m, 1H, OCH _{2 a} ), 3.94 (m, 1H, O = CN-CH _{2 a} ), 3.78-3.60 (m, 4H, OCH _{2 b} , Q = CN-CH 2 _b d), 3.38 (m, 4H, Ph-N-CH _{2 s} ), 3.00-2.88 (m, 5H, Ph-CH _{2 a} , CH ₃ , NC = O-

CH _2a ), 2.78 (dd, 1H, J = 14.7 Hz & 3.6 Hz, NC = O-CH _2b ), 2.65 (broad d, 1H, J = 16.4 Hz, Ph -CH _2b ) δ; CMR (75 MHz, CDCl ₃ ) 169.3, 153.9, 136.3, 131.8, 129.5, 129.2,

126.4, 120.5, 114.1, 73.7, 63.6, 47.5, 47.2, 45.5, 44.9, 41.3, 40.0 and 28.8 δ; HRMS (EI) calculated for C ₂₂ H ₂ O4S 5BrN ₂ = 492.0719, found = 1492.0714.

Step 2 1- [2- (6-bromoisochroman-1-yl) -1-ethyl] -4- (4-methylsulfonylphenyl) piperazine (VI)

Following the procedure of Example 1, Step 4, with minor variations, 1- [2- (6-bromoisochroman-1-yl) acetyl] -4- (4-methylsulfonylphenyl) piperazine (V) 1- [2- (6-bromoisochroman) is formed. -1-yl) -1-ethyl] -4- (4-methylsulfonylphenyl) piperazine (VI), R _f = 0.26 (ethyl acetate); IR (suspension) 3586, 1592, 1507, 1481, 1424, 1405, 1296, 1249, 1145, 1109, 1095, 1004, 956, 822, 779 cm ^-1 ; NMR (300 MHz, CDCl ₃ ) 7.75 (d, 2H, J = 9.0 Hz, aromatic), 7.27 (m, 2H, aromatic), 6.95 (d, 1H, J = 8.3) Hz, aromatic), 6.90 (d, 2H, J = 9.0 Hz, aromatic), 4.78 (broad d, 1H, J = 5.7 Hz, methine), 4.10 (m, 1H, OCH _{2 a} ), 3.74 (m, 1H, OCH _{2 b} ), 3.35 (t, 4H, J = 5.0 Hz, Ph-NCH _{2 s} ), 3.00 (s, 3H, CH ₃ ), 2 94 (m, 1H, Ph-CH _{2 a} ), 2.54 (m, 7H, Ph-NC (H ₂ ) -CH ₂ -NCH ₂ and two of Ph-CH _2b ), 2.09 (m, 1H , C (H) -CH _2a ) δ; CMR (75 MHz, CDCl ₃ ) 154.3, 136.9, 136.4,

131.7, 129.3, 129.1, 128.6, 126.4, 120.1, 113.8, 74.1, 62.9, 54.4, 52.9, 47.3, 45, 0, 33.1 and 28.9 δ; HRMS (EI) calculated for C ₂₂ H ₂₇ BrN ₂ O ₃ S = 480.0906, found = 480.0903.

Step 3: 1- [2- [4- (4-methylsulfonylphenyl) -1-piperazinyl] ethyl] isochroman-6-carboxamide (VII)

Following the procedure of Example 1, Step 5, with minor variations, 1- [2- (6-bromoisochroman-1-yl) -ethyl] -4- (4-methylsulfonylphenyl) -piperazine (VI) was formed. This material was purified by LC (silica gel, 230-400 mesh size, 75 g; methanol / dichloromethane, 5/95) to give 1- [2- [4- (4-methylsulfonylphenyl) -1-piperazinyl] ethyl] isochroman-6- carboxamide (VII), m.p. = 217-219 ° C, R _f = 0.17 (methanol / dichloromethane, 5/95); IR (suspension) 3433, 1668, 1619, 1587, 1568, 1507, 1288, 1140, 1115, 1105, 1095, 1023, 998, 812, 780 cm ^-1 . NMR (300 MHz, DMSO-d 6) 790 (br s) , 1H, NH), 7.66 (m, 4H, aromatic), 4.79 (broad d, 1H, J =

6.5 Hz, methine, 4.08 (m, 1H, OCH _{2 a} ), 3.67 (m, 1H, OCH _2b ), 3.32 (t, 4H, J = 4.0 Hz, Ph-N -CH _2s), 3.08 (s, 3H, _CH3), 2.88 (m, 1H, OCH _2), 2.71 (dm, 1H, J = 16.4 Hz, Ph56

CH _2b), 2.53 (m, 5H, Ph-NC _{(H2) -CH2S} -VNH _2), 2.37 (m, 1H, NCH _2b), 2.13 (m, 1H, C (H 1 CH ₂ ), 1.98 (m, 1H, C (H) -CH _{2 b} ) δ; CMR (75 MHz, _DMSO- d) 168.2, 154.3, 141.8,

134.1, 132.6, 129.0, 128.9, 128.5, 125.6, 125.2, 114.0, 74.1, 62.7, 54.6, 53.0, 47, 2,

44.7, 32.9 and 29.0 δ; HRMS (FAB) Calcd for C 24 H 25 N 5 O 5 S + H, = 444.1957, found = 444.1959.

Example 14 (S) - (-) - 1- [2- [4- (4-Trifluoromethylphenyl) -1-piperazinyl] ethyl] isochroman-6-carboxamide (S) - (VII)

Following the procedure of Example 1, Step 5 with minor variations, (S) - (-) - 1- [2- (6-bromoisochroman-1-yl) -1-ethyl] -4- (4-trifluoromethylphenyl) -piperazine ( VI, Example 5, Step 2 (13.15 g, 28.0 mmol) of product. Purify by LC (silica gel, 230400 mesh size, 780 g; methanol / dichloromethane, 5/95) to give a crude product which is recrystallized from methanol / ethyl acetate to give (S) - (-) - 1- [2]. [4- (4-Trifluoromethylphenyl) -1-piperazinyl] ethyl] isochroman-6-carboxamide (S) - (VII), m.p. = 166-168 ° C; _Rf = 0.20 (methanol / dichloromethane, 5/95); [α] D = -50 ° (c = 0.8533, methanol); IR (slurry) 3365, 3203, 1654, 1619, 1337, 1317, 1243, 1164, 1149, 1138, 1122, 1114, 1107, 1074, 825 cm ^-1 ; NMR (300 MHz, CDCl ₃ ) 7.57 (m, 2H, aromatic), 7.42 (d, 2H, J = 8.7 Hz, aromatic), 7.14 (d, 1H, J = 7.8) Hz, aromatic), 6.87 (d, 2H, J = 8.7 Hz), 4.83 (broad d, 1H, J = 5.8 Hz, methine), 4.10 (m, 1H, OCH _2a) 1.73 (m, 1H, OCH _2b ), 3.25 (t, 4H, J = 4.9 Hz, Ph-N-CH _{2 s} ), 2.97 (m, 1H, Ph-CH _{2 a} , 2.68-2.45 (m, 7H, Ph-NC (H ₂ ) -CH _{2 s} -NCH _{2 s} , Ph-CH _{2 b} ), 2.13 (m, 1H, C (h) CH _{2 a} ) 2.02 (m, 1H, C (H) -CH _{2 b} ) δ; CMR (75 MHz, CDCl ₃ ) 169.6, 153.2, 142.1, 134.5, 131.3, 128.2, 126.5 , 126.3 (d, J _CF = 4Hz), 125.0 (d, J CF = 4Hz), 122.9, 120.5 (qrt, J CF = 33Hz), 114.5, 74.4, 63.0 , 54.5, 53.0, 47.8, 32.8 and 29.0 δ; HRMS (EI) calculated for C ₂₃ H ₂₆ F ₃ N ₃ O ₂ = 433.1977, found = 433.1978.

Example 15 1- [2- [4- (4-Ethoxyphenyl) -1-piperazinyl] ethyl] -N-methyl-isochroman-6-carboxamide (IX)

Step 1: 1- [2- (6-bromoisochroman-1-yl) acetyl] -4- (4-ethoxyphenyl) -piperazine (V)

Following the procedure of Example 1, Step 3, with minor variations, racemic 6-bromoisochroman-1-yl-acetic acid (IV) and 4-ethoxyphenylpiprazine 1- [2- (6-bromoisochroman-1-yl) acetyl] -4- (4-ethoxyphenyl) -piperazine (V), Rf = 0.46 (ethyl acetate / hexane, 70/30); IR (neat) 1641, 1511, 1480, 1463, 1443, 1278, 1243,

1231, 1108, 1049 cm ^-1 ; NMR (300 MHz, CDCl ₃ ) 7.28 (m, 25, aromatic H), 7.0 (d, 1H, J = 8.2 Hz, aromatic H), 6.86 (d, 4H, J = 8) 2 Hz, aromatic H), 5.25 (mt, 1H, J = 6.5 Hz, PhC-H), 4.11 (m, 1H), 3.99 (q, 2H, J = 7.0 Hz, Proc-H ₂ ), 3.89 (m, 1H), 3.80-3.59 (m, 4H), 3.05 (t, 4H, J = 5.0 Hz), 3.03- 2.89 (m's 2H), 2.77 (DZD, 1H, _J =

3.6 Hz, J _b = 14.9 Hz), 2.66 (wd, 1H, J = 16.4 Hz), 1.39 (t, 3H, J = 7.0 Hz, PhOCH ₂ CH ₃ ) δ; CMR (75 MHz, CDCl ₃ ) 168.9, 153.6, 145.0, 136.4, 136.2, 131.6, 129.3, 126.4, 120.2, 118.7, 115, 1, 73.3, 63.7, 63.55, 63.47, 63.4, 51.2, 50.7, 46.0,

41.8, 39.8, 28.7, 14.8 δ; HRMS calculated for C ₂₃ H ₂₇ N ₂ O ₃ Br = 458.1205, found = 458.1217.

Step 2: 1- [2- (6-bromoisochroman-1-yl) -ethyl] -4- (4-ethoxyphenyl) -piperazine (VI)

Following the procedure of Example 1, Step 3, with minor variations, 1- (2- (6-bromoisochroman-1-yl) acetyl) -4- (4-ethoxyphenyl) -piperazine (V) 1- (2- (6-bromoisochroman-1-)) is formed. yl) ethyl] -4- (4-ethoxyphenyl) piperazine (VI), R _f = 0.56 (ethyl acetate (hexane, 70/30); IR (neat) 2850, 2810, 1512, 1482, 1251, 1231, 1153, 1108, 1048, 826 cm ^-1 ; NMR (300 MHz, CDCl ₃ ) 7.29 (d, 1H, J = 8.3 Hz, aromatic H), 7.27 (s, 1H, aromatic H ), 6.97 (d, 1H, J = 8.3 Hz, aromatic H), 6.85 (q, 4H, J = 9.7 Hz, aromatic H), 4.78 (wd, 1H, J = 6.1 Hz), 4.14-4.07 (m, 1H), 3.97 (q, 2H, J = 7.0 Hz, PhOC-H ₂ ), 3.76-3.69 (m, 1H), 3.10 (t, 4H, J = 4.9 Hz, 4 of pip-H), 2.95 (m, 1H), 2.70-2.50 (m's, 7H, four of pip- H); H, two PhCH-H and NCH-H), 2.13 (m, 1H, PhCHCH-H), 2.02 (m, 1H, PhCHCH-H), 1.38 (t, 3H, J = 6, 9 Hz, PhOCH ₂ CH ₃ ) δ CMR (75MHz, CDCl ₃ ) 153.1, 145.6, 137.1, 136.3, 131.6, 129.3, 126.5, 1120.0,

118.1, 115.2, 74.3, 62.8, 55.6, 53.5, 50.6, 33.2, 28.9, 15.0 δ.

Step 3: 1- [2- [4- (4-ethoxyphenyl) -1-piperazinyl] ethyl] -N-methyl-isochroman-6-carboxamide (IX)

Following the procedure of Example 5, Step 3, with minor variations, 1- (2- (6-bromoisochroman-1-yl) ethyl) -4- (4-ethoxyphenyl) -piperazine (VI) 1- (2- (4- (4 (ethoxyphenyl) 1-piperazinyl] ethyl] -N-methyl-isochroman-6-carboxamide (IX), m.p. = 148-149 °; R _f = 0.22 (methanol / methylene chloride, 5/95); IR (suspension) 3334, 1633, 1536, 1515, 1310, 1245, 1237, 1146, 1108, 1050 cm ^-1 ; NMR (300 MHz, CDCl ₃ ) 7.54 (s, 2H, aromatic H), 7.15 (d, 1H, J = 8.5 Hz, aromatic H), 6.85 (dzd, 4H, J _a = 9.2 Hz, J _b = • ·

19.2 Hz, four aromatic H), 6.15 (broad s, 1H, C (O) NH), 4.85 (wd, 1H, J = 6.0 Hz, PhC-H), 4.13 ( m, 1H, PhCH ₂ CH-H), 3.97 (q, 2H, J = 7Hz, PhOC-H ₂ ), 3.77 (m, 1H, PhCH ₂ CH-H), 3.10 (t , 4H, J = 4.8 Hz, four of pip-H), 3.00 (d, 3H, J = 4.9 Hz, C (O) _NHC-H3), 3.00 (m, 1H, NCH-H), 2.76-2.45 (several s, 7H, four pip-H, two PhCHH and NCH-H), 2.14 (m, 1H, PhCHCH-H), 2.02 (m, 1H, PhCHCH-H, 1.37 (t, 3H, J = 7.0 Hz, PhOCH ₂ CH ₃ δ; CMR (75MHz, CDCl ₃ ) 168.0, 153.1, 145.6, 141.6 , 134,5,

132.7, 127.7, 126.3, 125.0, 124.4, 118.1, 115.2, 74.5, 63.8, 62.9, 54.7, 53.5, 50.6,

33.2, 29.1, 26.8 and 15.0 δ.

Example 16 1- [2- [4- (4-Propoxyphenyl) -1-piperazinyl] ethyl] -N-methyl-isochroman-6-carboxamide (IX)

Step 1: 1- [2- (6-bromoisochroman-1-yl) acetyl] -4- (4-propoxyphenyl) -piperazine (V)

Following the procedure of Example 1, Step 3, with minor variations, racemic 6-bromoisochroman-1-yl-acetic acid (IV) and p-propoxyphenylpiperazine 1 - [- 2 (6-bromoisochroman-1-yl) acetyl] -4- (4-propoxy-phenyl) -piperazine (V), R _f = 0.50 (ethyl acetate / hexane, 70/30); IR (neat) 1641, 1511, 1481, 1464, 1443, 1278, 1242, 1230, 12108, 825 cm ^-1 ; NMR (300 MHz, CDCl ₃ ) 7.28 (m, 2H, aromatic H), 7.0 (d, 1H, J = 802 Hz, aromatic H), 6.87 (d, 4H, J = 8.2) Hz, aromatic H), 5.25 (mt, 1H, J = 6.5 Hz, PhC-H), 4.11 (m, 1H), 3.87 (t, 2H, J = 7.0 Hz, Proc-H ₂ ), 3.86 (m, 1H), 3.80-3.59 (m, 4H), 3.05 (t, 4H, J = 5.0 Hz), 3.03-2- 89 (m's, 2H), 2.77 (DZD, 1H, _J =

3.6 Hz, J _b = 14.9 Hz), 2.66 (wd, 1H, J = 16.4 Hz), 1.78 (sextet, 2H, J = 7.0 Hz, PhOCH ₂ CH ₂ ) 1.02 (t, 3H, J = 7.0 Hz, PhOCH ₂ CH ₃ ) δ; CMR (75MHz, CDCl ₃ ) 168.9,

153.6, 145.0, 136.4, 136.2, 131.6, 129.3, 126.4, 118.7, 115.1, 69.8, 63.4, 41.8, 39, 8,

28.7, 22.5 and 10.4 δ; HRMS calcd for C ₂₄ H 29 N ₂ O ₃ Br = 472.1362, found = 472.1356.

Step 2: 1- [2- (6-bromoisochroman-1-yl) -ethyl] -4- (4-propoxyphenyl) -piperazine (VI)

Following the procedure of Example 1, Step 4 with minor variations, 1 - [- 2- (6-bromoisochroman-1-yl) acetyl] -4- (4-propoxyphenyl) -piperazine (V) 1 - [- 2 ( 6-bromoisochroman-1-yl) -ethyl] -4- (4-propoxyphenyl) piperazine (VI), R _f = 0.52 (ethyl acetate / hexane, 70/30); IR (suspension) 1516, 1448, 1261, 1244, 1196, 1131, 1117, 1103, 1005, 985 cm ^-1 ; NMR (300 MHz, CDCl ₃ ) 7.29 (d, 1H, J = 8.3 Hz, aroatic H), 7.27 (s, 1H, aromatic H), 6.97 (d, 1H, J = 8) 3 Hz, aromatic H), 6.85 (q, 4H, J =

9.7 Hz, aromatic H), 4.78 (mt, 1H, J = 6.0 Hz, PhC-H), 4.13 (m, 1H, PhCH ₂ CHH), 3.10 (t, 4H, J = 4.8 Hz, four of pip-H), 3.00 (m, 1H, NCH-H), 2.76-2.45 (several m, 7H, four pip-H, two PhcH-H and NCH-H), 2.14 (m, 1H, PhCHCH-H), 2.02 (m, 1H, PhCHCH-H), 1.77 (sextet, 2H, J = 6.9 Hz, PhOCH ₂ CH ₂₎ 1.01 (t, 3H, J = 7.6 Hz, PhOCH ₂ CH ₂ CH ₃ ) δ; CMR (75MHz, CDCl ₃ ) 153.3, 145.4, 136.8, 136.2, 131.5, 129.2,

126.4, 119.9, 118.1, 115.0, 69.8, 62.7, 54.5, 53.3, 50.4, 32.9, 28.7, 22.6, 10, 4 δ; HRMS calculated for 0 ₂₄ Η ₃ ιΝ ₂ 0 ₂ Βγ! = 458.1561, found = 458.1569.

Step 3: 1- [2- [4- (4-Propoxyphenyl) -1-piperazinyl] ethyl] -N-methyl-isochroman-6-carboxamide (IX)

Following the procedure of Example 5, Step 3, with minor variations, 1- (2- (6-bromoisochroman-1-yl) -ethyl) -4- (4-propoxyphenyl) -piperazine (VI) is formed from recrystallization from hot ethyl acetate and hexane. gives rise to 1- [2- [4- (4-propoxy-phenyl) -1-piperazinyl] ethyl] -N-methylisochroman-6-carboxamide (IX), R _f = 0.20 (methnol / methylene chloride, 5/95); IR (suspension) 3296, 1635, 1569, 1559, 1553, 1512, 1289, 1251, 1242, 1109 cm ^-1 ; NMR (300 MHz, CDCl ₃ ) 7.54 (s, 2H, aromatic H), 7.15 ( d, 1H, J = 8.5 Hz, aromatic H), 6.58 (dzd, 4H, J _a = 9.2 Hz, J _b = 19.2 Hz, four aromatic H), 6.15 (broad d 1 H, C (O) NH), 4.85 (mzd, 1H, J = 6.0 Hz, PhCH), 4.13 (m, 1H, PhCH ₂ CH-H), 3.86 (t, 2H J = 6.6 Hz, PhOC-H ₂ ), 3.77 (m, 1H, PhCH ₂ CH-H), 3.10 (t, 4H, J = 4.8 Hz, four of pip-H) , 3.00 (d, 3H, J = 4.9 Hz, C (O) _NHC-H3), 3.00 (m, 1H, NCH-H), 2.76-2.45 (several m, 7H, four pip-H, two PhCH-H and NCH-H), 2.14 (m, 1H, PhCHCH-H), 2.02 (m, 1H, PhCHCH-H), 1.77 (sextet, 2H , J = 6.9 Hz, PhOCH ₂ CH ₂ ), 1.01 (t, 3H, J = 7.4 Hz, PhOCH ₂ CH ₂ CH ₃ ) δ; CMR (75MHz, CDCl ₃ ) 167.9, 153.2, 145.4, 141.5, 134.3, 132.5, 127.5, 124.9, 124.3, 118.0, 115.0 , 69.8, 62.8, 54.5, 53.4, 50.5, 33.0, 30.5, 28.9, 26.7, 22.5 and 10.4 δ.

Example 17 (S) - (-) - 1- [2- [4- (4-Trifluoromethoxyphenyl) -1-piperazinyl] ethyl] -N-methylisochroman-6-carboxamide (IX)

Step 1: (S) - (-) - 1- [2- (6-bromoisochroman-1-yl) acetyl] -4- (4-trifluoromethoxyphenyl) piperazine (S) - (V)

Following the procedure of Example 5, Step 3, with minor variations, 4-trifluoromethoxyphenylpiperazine (S) - (-) - 1- [2- (6-bromoisochroman-1-yl) acetyl] -4- (4-trifluoromethoxyphenyl) piperazine (S) is formed. - (V), [α] _D = -70 ° (c = 0.68, ethanol); R _f = 0.52 ·· ···· (ethyl acetate / hexane, 70/30); IR (neat) 1641, 1511, 1482, 1465, 1445, 1266, 1232, 1211, 1160, 1108 cm ^-1 ; NMR (300 MHz, CDCl ₃ ) 7.28 (m, 2H, aromatic H), 7.14 (d, 2H, J = 8.9 Hz, aromatic H), 7.0 (d, 1H, J = 8) 2 Hz, aromatic H), 6.87 (d, 2H, J = 8.9 Hz, aromatic H), 5.205 (wd, 1H, J = 6.5 Hz, PhC-H), 4.11 (m 1 H, 3.92 (m, 1H), 3.75 (m, 4H), 3.16 (t, 4H, J = 5.0 Hz), 3.03-2.89 (M's, 2H) 1.67 (dzd, 1H, J _a = 3.6 Hz, J _b = 14.9 Hz), 2.66 (wd, 1H, J = 16.4 Hz) δ; CMR (75MHz, CDCl ₃ ) 1678.9, 149.8, 145.0, 136.9, 136.4, 131.6, 129.3, 126.3, 122.0, 120.7, 117.1 , 73,4,

63.4, 49.8, 48.2, 45.8, 42.0, 39.8, 28.7 δ; HRMS calcd for C ₂₂ H ₂₂ N ₂ F ₃ O ₃ Br = 498.0766, found = 498.0764.

Step 2: (S) - (-) - 1- [2- (6-bromoisochroman-1-yl) -ethyl] -4- (4-trifluoromethoxyphenyl) piperazine (S) - (VI)

Following the procedure of Example 1, Step 3, minor variations gave (S) - (V) - (-) - 1- [2- (6-bromoisochroman-1-yl) acetyl] -4- (4-trifluoromethoxyphenyl) piperazine. ) (S) - (-) - 1- [2- (6-bromoisochroman- 1-yl) -ethyl] -4- (4-trifluoromethoxyphenyl) piperazine (S) - (VI), R _f = 0.54 ( ethyl acetate / hexane, 70/30); [α] = -42 (c = 1.1, ethanol); IR (neat) 2825, 1513, 1281, 1263, 1240, 1204, 1184, 1157, 1112, 1106 cm ^-1 ; NMR (300 MHz, CDCl ₃ ) 7.29 (d, 1H, J = 8.3 Hz, aromatic H), 7.27 (s, 1H, aromatic H), 7.11 (d, 2H, J = 9) Hz, aromatic H), 6.97 (d, 1H, J = 8.2 Hz, aromatic H), 6.87 (q, 2H, J = 9.1 Hz, two aromatic H), 4.78 (wd) 1 H, J = 6.0 Hz, PhC-H), 4.11 (m, 1H, PhCH ₂ CH-H), 3.18 (t, 4H, J = 4.8 Hz, four of pip-H) 1.00 (m, 1H, NCH-H), 2.76-2-45 (several m, 7H, four pip-H, two PhCH-H) δ; CMR (75MHz, CDCl ₃ ) 150.0, 136.5, 135.5, 131.5, 129.2, 126.3, 121.9, 120.1, 116.4, 74.1, 62.7 , 54.9, 53.1, 49.1, 33.0 and

28.7 δ; HRMS calcd for ¢22 ^ 4 ^ (^ 36 ^ (+1) = 486.0954, found = 486.0956).

Step 3: (S) - (-) - 1- [2- [4- (4-Trifluoromethoxyphenyl) -1-piperazinyl] ethyl] -N-methyl isochroman-6-carboxamide (S) - (IX)

Following the procedure of Example 5, Step 3, minor variations resulted from (S) - (-) - 1- (2- (6-bromoisochroman-1-yl) ethyl) -4- (4-trifluoromethoxyphenyl) -piperazine (S) - (VI) Product Recrystallization from hot ethyl acetate and hexane affords (S) - (-) - 1- [2- [4- (4-trifluoromethoxyphenyl) -1-piperazinyl] ethyl] -N-methylisochroman-6-carboxamide (S). ) (IX), R _f = 0.20 (methanol / methylene chloride, 5/95); IR (mull) 1636, 1614, 1572,

1551, 1513, 1450, 1270, 1238, 1157, 1107 cm ^-1 ; NMR (300 MHz, CDCl ₃ ) 7.54 (s, 2H, aromatic H), 7.15 (d, 1H, J = 8.9 Hz, two aromatic H), 6.19 (broad d, 1H, C (O) NH), 4.86 (mzd, 1H, J = 6.0 Hz, PhC-H), 4.13 (m, 1H, PhCH ₂ CH-H), 3.77 (m, 1H, PhCH) ₂ CH-H), 3.18 (t, 4H, J = 4.8 Hz, four of pip-H), 3.00 (d, 3H, J = 4.9 Hz, C (O) NHC-H) ₃ ), 3.00 (m, 1H, NCH-H), 2.76-2.45 (several m, 7H, four pip-H, two PhCH-H and NCH-H), 2.14 (m, 1H, PhCHCH-H), 2.02 (m, 1H, PhCHCH-H) δ; CMR (75MHz, CDCl ₃ ) 167.8, 149.8, 144.7, 141.3, 134.3, 132.6, 127.5, 124.8, 124.3,

121.8, 116.5, 86.2.74.3, 62.8, 54.54, 63.4, 48.9, 32.9, 28.9 and 26.7 δ; HRMS calculated for C ₂₄ H _{N 3} O ₃ F ₃ = 463.2083, found = 463.2086.

Example 18 (S) - (-) - 1- [2- [4- (4-Ethyl-phenyl) -1-piperazinyl-ethyl] -N-methyl-isochroman-6-carboxamide (S) - (IX)

Step 1: (S) - (-) - 1- [2- (6-bromoisochroman-1-yl) acetyl] -4- (4-ethylphenyl) -piperazine (S) - (V)

Following the procedure of Example 1, Step 3, minor variations gave 4-ethylphenylpiperazine (S) - (-) - 1- [2- (6-bromoisochroman-1-yl) acetyl] -4- (4-ethylphenyl) piperazine (S) - (V), R _f = 0.70 (ethyl acetate / hexane, 70/30); [α] _D = -81 ° (c = 0.7 ethanol); IR (neat) 1640, 1614, 1516, 1482, 1462, 1444, 1428, 1232, 1108 and 826 cm ^-1 ; NMR (300 MHz, CDCl ₃ ) 7.27 (m, 2H, aromatic H), 7.11 (d, 2H, J = 8.4 Hz, aromatic H) 7.0 (d, 1H, J = 8, 2 Hz, aromatic H), 6.86 (d, 2H, J = 8.2 Hz, aromatic H), 5.25 (wd, 1H, J = 6.5 Hz, PhC-H), 4.08 ( m, 1H), 3.89 (m, 1H), 3.803.59 (m, 4H), 3.11 (t, 4H, J = 5.0 Hz), 3.03-2.89 (m's, 2H) ), 2.77 (dzd, 1H, J _a = 3.6 Hz, J _b = 14.9 Hz), 2.66 (m 1H), 2.57 (q, 2H, J = 7.6 Hz) , PhC-H ₂ ), 1.20 (t, 3H, J = 7.6 Hz, PhCH ₂ CH ₃ ) δ; CMR (75MHz, CDCl ₃ ) 169.0, 149.0, 136.5, 136.3, 131.8,

129.4, 128.6, 126.5, 120.4, 116.9, 73.5, 63.5, 50.3, 49.8, 46.1, 41.9, 39.9, 28, 8, 27.9 and 15.7 δ. ²

Step 2: (S) - (-) - 1- [2- (6-bromoisochroman-1-yl) -ethyl] -4- (4-ethylphenyl) -piperazine (S) - (VI) •

Following the procedure of Example 1, Step 4, minor variations resulted from (S) - (-) - 1- [2- (6-bromoisochroman-1-yl) acetyl] -4- (4-ethylphenyl) -piperazine (S) - ( V) (S) - (-) - 1 - (2- (6bromizochroman 1-yl) -ethyl] -4- (4-ethylphenyl) piperazine (S) - (VI), R _f = 0.61 ( ethyl acetate / hexane, 30/70) IR (suspension) 2960, 2929, 2819, 1516, 1481, 1379, 1237, 1143, 1111 and 822 cm ^-1 ; NMR (300 MHz, CDCl ₃ ) 7.29 (d) 1 H, J = 8.3 Hz, aromatic H), 7.27 (s, 1H, aromatic H), 7.09 (d, 2H, J = 8.6 Hz, aromatic H), 6.98 (d , 1H, J = 8.2 Hz, aromatic H), 6.87 (d, 2H, J = 8.6 Hz, aromatic H), 4.77 (wd, 1H, J = 6.0 Hz, PhC- H), 4.13 (m, 1H, PhCH ₂ CH-H), 3.75 (m, 1H, PhCH ₂ CH-H), 3.17 (t, 4H, J = 4.8 Hz, four of pip-H), 3.00 (m, 1H, NCH-H), 2.70-2.53 (several m, 9H, four pip-H, two PhCH-H, PhC-H ₂ and NCH-H) 2.14 (m, 1H, PhCHCH-H), 2.02 (m, 1H, PhCHCHH), 1.20 (t, 3H, J = 7.6 Hz, PhCH ₂ CH ₃ )) δ; CMR (75MHz, CDCl ₃ ) 149.4, 137.1,

136.3, 135.6, 135.6, 131.6, 129.3, 128.4, 126.5, 120.0, 116.3, 74.3, 62.8, 54.7, 53.5,

49.6, 33.5, 30.3, 28.9, 27.9, and 15.7 δ; HRMS calculated for C ₂₃ H ₂ gN 0iBri ₂ = 430.1444, found = 430.1443.

Step 3: (S) - (-) - 1- [2- [4- (4-ethylphenyl) -1-piperazinyl] ethyl] -N-methylisochroman-6-carboxamide (S) - (IX)

Following the procedure of Example 5, Step 3, slight variations resulted from (S) - (-) - 1- (2 (6-bromoisochroman-1-yl) ethyl) -4- (4-ethylphenyl) -piperazine (S) - (V) desired product Recrystallization from hot ethyl acetate and hexane affords (S) - (-) - 1- (2- (4- (4-ethylphenyl) ethyl) -N-methyl-isochroman-6-carboxamide (S) - (IX), m.p. = 138140 ° C; R _f = 0.28 (methanol / methylene chloride, 5/95); [α _D ] = -50 ° (c = 0.93, methanol / methylene chloride, 50/50) IR (suspension) 3321, 13635, 1614, 1539, 1405, 1312, 1238, 1107 and 822 cm ^-1 ; NMR (300 MHz, CDCl ₃ ) 7.54 (s, 2H, aromatic H), 7.15 ( d, 1H, J = 8.6 Hz, aromatic H), 7.09 (d, 2H, J = 8.5 Hz, 2 aromatic H), 6.86 (d, 2H, J = 6.0 Hz, PhC-H), 4.13 (m, 1H, PhCH ₂ CH-H), 3.77 (m, 1H, PhCH ₂ CH-H), 2.76-2.45 (several m, 9H, four pip -H, two PhCH-H, PhC-H ₂ and NCH-H), 2.14 (m, 1H, PhCHCHH), 2.02 (m, 1H, PhCHCH-H), 1.20 (t, 3H, J = 7.6 Hz, PhCH ₂ CH ₂ CH ₃ ) δ; CMR (75MHz, CDCl ₃ ) 168.0, 149.3, 141.6, 135.7, 134.5, 132.7, 128.4 , 127.7, 125.0,

124.4, 116.3, 62.9, 54.7, 53.4, 49.6, 33.1, 29.1, 27.9, 26.8 and 15.7 δ; HRMS calculated for C ₂₅ H ₃₃ N ₃ O ₃ = 407.2573, found = 407.2581.

Example 19 (S) - (-) - 1- (2- [4- (4-ethoxyphenyl) -1-piperazinyl] ethyl] -N-methylisochroman-6-carboxamide (S) - (IX)

Step 1: (S) - (-) - 1- [2- (6-bromoisochroman-1-yl) acetyl] -4- (4-ethoxyphenyl) -piperazine (S) - (V)

Following the procedure of Example 1, Step 3 results from 4-ethoxyphenylpiperazine (S) - (-) 1- [2- (6-bromoisochroman-1-yl) acetyl] -4- (4-ethoxyphenyl) -piperazine (S) - (V), R _f = 0.60 (ethyl acetate / hexane, 70/30); [ _α ] _D = -78 ° (c = 0.82, ethanol); IR (neat) 1627, 1515, 1478, 1441, 1429, 1250, 1230, 1102, 1031 and 821 cm ^-1 ; NMR (300 MHz, CDCl ₃ ) 7.28 (m, 2H, aromatic H), 7.0 (d, 1H, J H = 8.2 Hz, aromatic H), 6.86 (d, 4H, J = 8) 2 Hz, aromatic H), 5.25 (mt, 1H, J = 6.5 Hz, PhC-H), 4.11 (m, 1H), 3.99 (q, 2H, J = 7.0 Hz, PhOC-H ₂ ), 3.89 (m, 1H), 3.80-3.59 (m, 4H), 3.05 (t, 4H, J = 5.0 Hz), 3.03- 2.89 (m's, 2H), 2.77 (dzd, 1H, J _a = 3.6 Hz, J _b = 14.9 Hz), 2.66 (mzd, 1H, J = 16.4 Hz), 1.39 (t, 3H, J = 7.0 Hz, PhCH ₂ CH ₃ ) δ; CMR (75MHz, CDC ₃ )

168.9, 153.5, 145.2, 136.3, 136.2, 131.6, 129.3, 126.4, 118.7, 115.1, 73.3, 63.7,

63.4, 51.2, 50.7, 46.1, 41.9, 39.8, 28.7 and 14.8 δ; HRMS calculated for C ₂₃ H ₂₇ N ₂ O ₃ Br = 458.1205, found = 458.1203.

Step 2: (S) - (-) - 1- [2- (6-Bromo-iso-chroman-1-yl) -ethyl] -4- (4-ethoxy-phenyl) -piperazine (S) - (VI)

Following the procedure of Example 1, Step 4, (S) - (-) - 1- [2- (6-bromoisochroman-1-yl) acetyl] -4- (4-ethoxyphenyl) -piperazine (S) - (V) ( S) - (-) - 1- [2- (6-bromoisochroman-1-yl) -ethyl] - (4-ethoxyphenyl) -piperazine (S) - (VI), m.p. = 85-87 ° C; R _f = 0.28 (ethyl acetate / n-hexane, 30/70); [α] _D = -46 ° (c = 0.60, ethanol); IR (neat) 1516, 1476, 1261, 1246, 1196, 1130, 1117, 1104, 1060 and 932 cm ^-1 ; NMR (300 MHz, CDCl ₃ ) 7.29 (d, 1H, J = 8.3 Hz, aromatic H), 7.27 (s, 1H, aromatic H), 6.97 (d, 1H, J = 8) 3 Hz, aromatic H), 6.85 (q, 4H, J = 9.7 Hz, aromatic H), 4.78 (wd, 1H, J = 6.1 Hz), 4.14-4.07 (m, 1H), 3.97 (q, 2H, J = 7.0 Hz, _PhOC-H2), 3.76-3.69 (m, 1H), 3.10 (t, 4H, J = 4.9 Hz, four of pip-H), 2.95 (m, 1H), 2.70-2.50 (m's, 7H, four pip-H, two PhCH-H and NCH-H), 2, 13 (m, 1H, PhCHCH-H), 2.02 (m, 1H, PhCHCH-H), 1.38 (t, 3H, J = 6.9 Hz, PhOCH ₂ CH ₃ ) δ; CMR (75MHz, CDCl ₃ ) 153.1, 145.6, 137.1, 136.3,

131.6, 129.3, 126.5, 1120, 0, 118.1, 115.2, 74.3, 62.8, 55.6, 53.5, 50.6, 33.2, 28, 9 and 15.0 δ.

Step 3: (S) - (-) - 1- [2- [4- (4-ethoxyphenyl) -1-piperazinyl] ethyl] -N-methylisochroman-6-carboxamide (S) - (IX) · · · · · · · · · · · · · · · · · · · · · · · · · ·

Following the procedure of Example 5, Step 3, minor variations gave (S) - (-) - 1- [2- (6-bromoisochroman-1-yl) ethyl] -4- (4-ethoxyphenyl) piperazine (S) - ( VI) (S) - (-) - 1- (2- (4- (4-ethoxyphenyl) -1-piperazinyl] ethyl) -N-methyl-isochroman-6-carboxamide (S) - (IX) Recrystallization from hot acetate ethyl acetate and hexane gave the purified product, m.p. = 156-157 ° C; R _f = 0.20 (methanol / methylene chloride, 5/95); [α] _D = -48 ° (c = 0.94, ethanol) IR (suspension) 3334, 1633, 1536, 1515, 1310, 1245, 1237, 1146, 1108 and 1050 cm ^-1 ; NMR (300 MHz, CDCl ₃ ) 7.54 (s, 2H, aromatic H), 7, 15 (d, 1H, J = 8.5 Hz, aromatic H), 56.85 (dzd, 4H, J _a = 9.2 Hz, J _b = 19.2 Hz, four aromatic H), 6.15 ( broad d, 1H, C (O) NH), 4.85 (mzd, 1H, J = 6.0 Hz, PhC-H), 4.13 (m, 1H, J = 4.8 Hz, four of pip -H), 3.00 (d, 3H, J = 4.9 Hz, C (O) _NHC-H3), 3.00 (m, 1H, NCH-H), 2.76-2.45 ( several m, 7H, four pip-H, two PhCHCH-H and NCH-H), 2.14 (m, 1H, PhCHCH-H), 2.02 (m, 1H, PhCHCH-H) 1.37 (t , 3H, J = 7.0Hz, PhOCH ₂ CH ₃ ) δ CMR (75MHz, CDCl ₃ ) 168.0, 153.1, 145.6, 141.6, 134.5, 132.7, 127.7, 126.3, 125.0,

124.4, 118.1, 115.2, 74.5, 63.8, 62.9, 54.7, 53.5, 50.6, 33.2, 29.1, 26.8 and 15.0 δ ; HRMS calcd for C 24 H 25 N 5 O 5 = 423.2522, found = 432.2518.

Example 20 (S) - (-) - 1- [2- [4- (4-Phenylmethoxyphenyl) -1-piperazinyl] ethyl] -N-methylisochroman-6-carboxamide (S) - (IX)

Step 1: (S) - (-) - 1- [2- (6-bromoisochroman-1-yl) acetyl] -4- (4-phenylmethyloxyphenyl) piperazine (S) - (V)

Following the procedure of Example 1, Step 3, with slight variations, 4-phenylmethyloxyphenylpiperazine (3.38 g, 12.6 mmol) was formed. The material was purified by silica gel column chromatography eluting with ethyl acetate / hexane (70/30) to give (S) - (-) - 1- [2- (6-bromoisochroman-1-yl) acetyl] -4- ( 4fenylmethyloxyfenyl) piperazine (S) - (V), R _f = 0.30 (ethyl acetate / hexane, 50/50); [α] D = -34 ° (c = 0.50, methanol); NMR (300 MHz, CDCl ₃ ) 7.35 (m, 7H, aromatic), 6.96 (d, 1H, J = 8.2 Hz, aromatic), 6.90 (m, 4H, aromatic), 5, 26 (broad d, J = 5.4 Hz, methine), 5.02 (s, 2H, _Ph-CH2 -O), 4.09 (m, 1H, OCH _2), 3.89 (m, 1H O = CN-CH _2a ), 3.81-3.64 (m, 4H, OCH _2b , (Κ-Ν-ΰΗ2 _ω ), 3.05 (m, 4H, Ph-N-CH _{2 s} ), 3 .00-2.89 (m, 2H, Ph-CH ₂ & NC = O-CH _2b ), 2.66 (broad d, 1H, J = 16.4 Hz, Ph-CH _2b ) δ; CMR (75MHz CDCI ₃ ) 169.0, 153.6, 145.5, 137.3, 136.6, 131.8, 129.4, 128.6, 127.9,

127.5, 126.5, 120.4, 118.8, 115.7, 76.7, 73.5, 70.5, 63.5, 51.3, 50.7, 46.2, 42, 0, 40.0 and 28.8 δ.

Step 2: (S) - (-) - 1- [2- (6-bromoisochroman-1-yl) ethyl] -4- (4-phenylmethyloxyphenyl) piperazine (S) - (VI)

Following the procedure of Example 1, Step 4, minor variations gave (S) - (-) - 1- [2- (6-bromoisochroman-1-yl) acetyl] -4- (4-phenylmethyloxyphenyl) piperazine (V, 5.96). g, 11.4 mmol) (S) - (-) - 1- [2- (6-bromoisochroman-1-yl) -ethyl] -4- (4-phenylmethyloxyphenyl) piperazine (S) - (VI), R _f = 0.40 (ethyl acetate / hexane, 50/50); [α] _D = -63 ° (c = 0.925, methanol); NMR (300 MHz, CDCl ₃ ) 7.27 (m, 7H, aromatic), 6.91 (d, 1H, J = 8.3 Hz, aromatic), 6.83 (s, 4H, aromatic), 4, 94 (s, 2H, _Ph-CH2 -O), 4.73 (broad d, 1H, J = 5.7 Hz, methine), 4.03 (m, 1H, OCH _2), 3.67 (m 1 H, OCH _2b ), 3.05 (t, 4H, J = 4.8 Hz, Ph-NCH ₂ s), 2.88 (m, 1H, Ph-CH _{2 a} ), 2.60 (m, 7H Ph-NC (H ₂ ) -CH ₂ -NCH ₂ - (PhCH _{2 b} ), 2.05 (m, 1H, C (H) -CH _2a ), 1.97 (m, 1H, C (H) -CH _2b ) δ; CMR (75MHz, CDC ₃ )

153.1, 145.8, 137.4, 136.9, 136.3, 131.7, 129.3, 128.5, 127.9, 127.5, 126.5, 120.1,

118.2, 115.6, 70.5, 62.9, 54.6, 53.4, 50.4, 32.9 and 28.9 δ.

Step 3: (S) - (-) - 1- [2- [4- (4-Phenylmethyloxyphenyl) -1-piperazinyl] ethyl] -N-methyl-isochroman-6-carboxamide (S) - (IX)

Following the procedure of Example 5, Step 3, slight variation results from (S) - (-) - 1- [2- (6-bromoisochroman-1-yl) ethyl] -4- (4-phenylmethyloxyphenyl) piperazine (S) - ( VI, 5.08 g, 11.4 mmol) of product. Purify by LC (silica gel, 230-400 porosity, 270 g; ethyl acetate) and recrystallize from ethyl acetate to give (S) - (-) - 1- [2- [4- (4-phenylmethoxyphenyl) -1-piperazinyl] ethyl 1-N-methyl-isochroman-6-carboxamide (S) - (IX), m.p. = 164-167 ° C; _Rf = 0.40 (methanol / ethyl acetate, 5/95); [α] D = -40 ° (c = 0.9323, methanol); IR (suspensions) 3302, 1639, 1544, 1515, 1498, 1314, 1291, 1272, 1252, 1153, 1138, 1111, 818, 735, and 695 cm ^-1 ; NMR (300 MHz, CDCl ₃ ) 7.53 (m, 2H, aromatic), 7.54 (m, 2H, aromatic), 7.43-7-23 (m, 5H, aromatic), 7.14 (d , 1H, J = 8.6 Hz, aromatic), 6.89 (s, 4H, aromatic), 6.19 (br m, NH), 5.01 (s, 2H, Ph-CH ₂₎ 4, 86 (broad d, 1H, J = 5.9 Hz, methine), 4.14 (m, 1H, OCH _{2 a} ), 3.76 (m, 1H, OCH _2b ), 3.10 (t, 4H, J = 4.8 Hz, Ph-N-CH _{2 s} ), 3.00 (d, 4H, J = 4.8 Hz, N-CH ₃ & PhCH _{2 a} ), 2.76-2.49 (m, 7H, Ph-NC (H ₂ -CH _{2 s} , Ph-CH _{2 b} ), 2.14 (m, 1H, C (H) -CH _{2 a} ), 2.04 (m, 1H, C (H) -CH _{2 b} ) δ; CMR (75MHz, CDCl ₃ ) 168.0, 153.0, 145.9, 141.6, 137.4,

134.5, 132.7, 128.5, 127.9, 127.7, 127.5, 125.0, 124.4, 118.0, 115.6, 145.9, 141.6,

137.4, 134.5, 132.7, 128.5, 127.9 and 26.9 δ; MS (EI, m / z) = 485; HRMS (EI) calcd for C 30 H 35 N 3 O 3 = 485.2678, found = 485.2675.

• · · · ·

Example 21 (R) - (+) - 1- [2- [4- (4-ethoxyphenyl) -1-piperazinyl] ethyl] -N-methylisochroman-6-carboxamide (R) - (IX)

Step 1: (R) - (+) - 1- [2- (6-bromoisochroman-1-yl) acetyl] -4- (4-ethoxyphenyl) piperazine (R-V)

Following the procedure of Example 2, Step 2, with minor variations, 4-methoxy-phenylpiperazine (R) - (+) - 1- [2- (6-bromoisochroman-1-yl) acetyl] -4- (4-ethyloxy-phenyl) -piperazine (RV) was formed. R _f = 0.60 (ethyl acetate / hexane, 70/30); [α] _D = + 76 ° (c = 0.71, ethanol); IR (neat) 1626, 1515, 1478, 1442, 1249, 1246, 1230, 1102, 1030, and 821 cm ^-1 ; NMR (300 MHz, CDCl ₃ ) 7.28 (m, 2H, aromatic H), 7.0 (d, 1H, J = 8.2 Hz, aromatic H), 6.86 (d, 4H, J = 8) 2 Hz, aromatic H), 5.25 (mt, 1H, J = 6.5 Hz, PhC-H), 4.11 (m, 1H), 3.99 (q, 2H, J = 7.0 Hz, PhOC-H ₂ ), 3.89 (m, 1H), 3.803.59 (m, 4H), 3.05 (t, 4H, J = 5.0 Hz), 3.03-2.89 ( m's, 2H), 2.77 (dzd, 1H, J _a = 3.6 Hz, J _b = 14.9 Hz), 2.66 (mzd, 1H, J = 16.4 Hz), 1.39 ( t, 3H, J = 7.0 Hz, PhCH ₂ CH ₃₎ 6; CMR (75MHz, CDCl ₃ ) 168.9, 153.6, 145.0, 136.4, 136.2, 131.6, 129.3, 126.4,

120.2, 118.7, 115.1, 73.3, 63.7, 63.55, 63.47, 63.4, 51.2, 50.7, 46.0, 41.8, 39, 8, 28.7 and 14.8 δ; HRMS calcd for C ₂₃ H ₂₇ N ₂ O ₃ Br (at 81 Br atom) = 460, 1185, found = 460.1179.

Step 2: (R) - (+) - 1- [2- (6-Bromo-iso-chroman-1-yl) -ethyl] -4- (4-ethyloxy-phenyl) -piperazine (R-VI)

Following the procedure of Example 2, Step 3, slight variation results from (R) - (+) - 1- [2- (6-bromoisochroman-1-yl) acetyl] -4- (4-ethyloxyphenyl) -piperazine (RV) (R). ) - (+) - 1 - [2- (6-bromoisochroman-1-yl) -ethyl] -4- (4-ethoxyphenyl) piperazine (R-VI), R _f = 0.25 (ethyl acetate / n-hexane , 30/70); [ _α ] _D = + 43 ° (c = 0.73 ethanol); IR (neat) 2820, 1511, 1478, 1446, 1250, 1225, 1116, 1108, 1047 and 825 cm ^-1 ; NMR (300 MHz, CDCl ₃ ) 7.29 (d, 1H, J = 8.3 Hz, aromatic H), 7.27 (s, 1H, aromatic H), 6.97 (d, 1H, J = 8) 3 Hz, aromatic H), 6.85 (g, 4H, J = 9.7 Hz, aromatic H), 4.78 (wd, 1H, J = 6.1 Hz), 4.14-4.07 (m, 1H), 3.97 (q, 2H, J = 7.0 Hz, _PhOC-H2), 3.76-3.69 (m, 1H), 3.10 (t, 4H, J = 4.9 Hz, four of pip-H), 2.95 (m, 1H), 2.70-2.50 (m's, 7H, four pip-H, two PhCH-H and NCH-H), 2, 13 (m, 1H, PhCHCH-H), 2.02 (m, 1H, PhCHCH-H), 1.38 (t, 3H, J = 6.9 Hz, PhOCH ₂ CH ₃ ) δ; CMR (75MHz, CDCI ₃ ) 153.1, 145.6, 137.8, 136.3, 131.6, 129.3, · · · · ··· · · · · · • · · · · ··· · ·

126.5, 1120.0, 118.1, 115.2, 74.3, 62.8, 55.6, 53.5, 50.6, 33.2, 28.9 and 15.0 δ; HRMS calcd for ΟηΗ ^ ΝζΟζΒγι = 444.1413, found = 444.1413.

Step 3: (R) - (+) - 1- [2- [4- (4-ethoxyphenyl) -1-piperazinyl] ethyl] -N-methylisochroman-6-carboxamide (R) - (IX)

Following the procedure of Example 5, Step 3, slight variation results from (R) - (+) - 1- [2- (6-bromoisochroman-1-yl) ethyl] -4- (4-ethyloxyphenyl) piperazine (R-VI). (R) - (+) - 1 - [2- [4- (4-ethoxyphenyl) -1 - piperazinyl] ethyl] -N-methylisochroman-6-carboxamide (R) - (IX), R _f = 0.20 ( methanol / methylene chloride, 5/95); [ _{α D} ] = + 49 ° (c = 0.93 methanol / methylene chloride, 50/50); IR (suspension) 3334, 1633, 1536, 1515, 1310, 1245, 1237, 1146, 1108 and 1050 cm ^-1 ; NMR (300 MHz, CDCl ₃ ) 7.54 (s, 2H, aromatic H), 7.15 (d, 1H, J = 4.8 Hz, four of pip-H), 3.00 (d, 3H, J = 4.9 Hz, C (O) NHC-H), 4.85 (mzd, 1H, J = 6.0 Hz, PhC-H), 4.13 (m, 1H, NCH-H), 3 97 (q, 2H, J = 7 Hz, _PhOC-H2), 3.77 (m, 1H, CH ₂ Ph-H), 2.76-2.45 (some m, 7H, four pip-H two PhCH-H and NCH-H), 2.14 (m, 1H, PhCHCH-H), 2.02 (m, 1H, PhCHCH-H), 1.37 (t, 3H, J = 7.0 Hz, PhOCH ₂ CH ₃ ) δ; CMR (75MHz, CDCl ₃ ) 168.0, 153.1, 145.6, 141.6, 134.5, 132.7, 127.7, 126.3, 125.0,

124.4, 118.1, 115.2, 74.5, 63.8, 62.9, 54.7, 53.5, 50.6, 33.2, 29.1, 26.8 and 15, 0 δ; HRMS calculated for C ₂₅ H ₃₃ N ₃ O ₃ = 423.2522, found = 423.2516.

Example 22 1- [2- [4- (3-Trifluoromethylphenyl) -1-piperazinyl] ethyl] -N-methylisochroman-6-carboxamide (IX)

Step 1: 1- [2- [4- (3-trifluoromethylphenyl) -1-piperazinyl] ethyl] -N, N-di-t-butyloxycarbonyl isochroman-6-carboxamide (VI11)

Following the procedure of Example 3, Step 1, slight variations gave 1- [2- [4- (3-trifluoromethylphenyl) -1-piperazinyl] ethyl] -isochroman-6-carboxamide as a crude product. Purify by LC (silica gel, 230-400 porosity, 60 g; acetone / hexane, 25/75) to give 1- [2- [4- (3-trifluoromethylphenyl) -1-piperazinyl] ethyl] -N, N -di-tbutyloxykarbonylizochroman-6-carboxamide (VIII), R _f = 0.37 (acetone / hexane 25/75).

Step 2: 1- [2- [4- (3-Trifluoromethylphenyl) -1-piperazinyl] ethyl] -N-methylisochroman-6-carboxamide (IX)

Following the procedure of Example 3, Step 2, with minor variations, 1- [2- [4- (3-trifluoromethylphenyl) -1-piperazinyl] ethyl] -N, N-di-t-butyloxycarbonylisochroman-668 carboxamide (VIII, 1, 13 g, 1.8 mmol) of crude product. Purify by LC (silica gel, 230-400 porosity, 66 g; acetone / hexane, 50/50) to give 1- (2- (4- (3-trifluoromethylphenyl) -1-piperazinyl] ethyl) -N, N-di -t-butyloxycarbonylisochroman-6-carboxamide (IX), which recrystallizes from ethyl acetate / hexane, mp = 142-143 ° C; R _f = 0.33 (acetone / hexane, 50/50); IR (suspension) 3307, 1637, 1612, 1606, 1558, 1443, 1311, 1290, 1247, 1151, 1136, 1122, 1109, 1099 and 951 cm ^-1 ; NMR (300 MHz, CDCl 3) 7.55 (m, 2H, aromatic), 7 33 (t, 1H, J = 8.0 Hz, aromatic), 7.12 (d, 1H, J = 8.6 Hz, aromatic), 7.6 (m, 4H, aromatic), 6.14 ( broad m, 1H, NH), 4.87 (broad d, 1H, J = 5.9 Hz, methine), 4.14 (m, 1H, OCH _{2 a} ), 3.76 (m, 1H, OCH _2b ) , 3.24 (t, 4H, J = 5.0 Hz, _Ph-N-CH2s), 3.00 (d, 4H, J = 4.9 Hz, _NCH3 & Ph-CH _2a) 2.76-2.48 (m, 7H, Ph-NC (H ₂ ) -CH _{2 s} -NCH _{2 s} , Ph-CH _{2 b} ), 2.15 (m, 1H, C (H) -CH _{2 a} ), 2 .05 (m, 1H, C (H) CH _{2 b} ) δ; CMR (75MHz, CDCl 3) 168.0, 151.4, 141.6, 134.5, 132.7, 131.4 (qrt, J _CF = 32 Hz), 129.5, 127.7, 125.0, 124.4, 118.6, 115.7, (d, J _CF = 4Hz), 112.1 (d, J _CF = 4Hz),

74.4, 63.0, 54.6, 53.2, 48.7, 33.2, 29.1 and 26.9 δ; HRMS (EI) calculated for C ₂₄ H ₂₈ F ₃ N ₃ O ₂ = 447.2133, found = 447.2132.

Example 23 1- [2- [4- (4-Methylsulfonylphenyl) -1-piperazinyl] ethyl] -N-methylisochroman-6-carboxamide (IX)

Step 1: 1- [2- [4- (4-methylsulfonylphenyl) -1-piperazinyl] ethyl] -N, N-di-t-butyloxycarbonylisochroman-6-carboxamide (VI11)

Following the procedure of EXAMPLE 3, Step 1 with minor variations, the crude product was obtained from 1- [2- [4- (4-methylsulfonylphenyl) -1-piperazinyl] ethyl] -isochroman-6-carboxamide (825 mg, 1.9 mmol). Purify by LC (silica gel, 230-400 porosity, 58 g; acetone / hexane 45/55) to give 1- [2- [4- (4-methylsulfonylphenyl) -1-piperazinyl] ethyl] -N, N-di t-butyloxycarbonylisochroman-6-carboxamide (VIII), Rf = 0.20 (acetone / hexane, 40/60).

Step 2: 1- [2- [4- (4-methylsulfonylphenyl) -1-piperazinyl] ethyl] -N-methylisochroman-6-carboxamide (IX)

Following the procedure of Example 3, Step 2, slight variations resulted in 1- (2- (4- (4-methylsulfonylphenyl) -1-piperazinyl] ethyl) -N, N-di-t-butyloxycarbonylisochroman-6-carboxamide (VIII, 650 mg, 1, The product was purified by LC (silica gel, 230-400 porosity, 71 g; methanol / dichloromethane, 5/95) to give 1- [2 - (-)]. 4-methylsulfonylphenyl) -1-piperazinyl] ethyl] -N-methylisochroman-6-carboxamide (IX), Rf = 0.30 (methanol / dichloromethane, 5/95); IR (suspension) 1645, 1612, 1593, 1571, 1545, 1508, 1496, 1409, 1296, 1145, 1106, 1095, 957 and 780 cm ^-1 ; NMR (300 MHz, CDCl ₃ ) 7.73 (d, 2H, J = 8.9 Hz, aromatic), 7 55 (m, 2H, aromatic), 7.15 (d, 1H, J = 7.9 Hz, aromatic), 6.91 (d, 1H, J = 8.9 Hz, aromatic), 6.14 ( broad d, 1H, J = 4.4 Hz, NH), 4.86 (broad d, 1H, J = 6.2 Hz, methine), 4.12 (m, 1H, OCH _2a ), 3.75 ( m, 1H, OCH _2b ), 3.35 (t, 4H, J = 4.9 Hz, Ph-N-CH _{2 s} ), 2.99 (broad s, 7H, N-CH ₃ , OCH ₃ , Ph- CH _2a ), 2.75-2.46 (m, 7H, P) h-NC (H ₂ ) -CH ₂ -NCH _{2 s} , Ph-CH _2b ), 2.14 (m, 1H, C (H) -CH _2a ), 2.02 (m, 1H, C (H) - CH _{2 (b} )) δ; CMR (75MHz, CDCl ₃ ) 167.9, 154.3, 141.4,

134.5, 132.7, 129.1, 128.6, 127.7, 124.9, 124.5, 113.8, 74.3, 63.0, 54.5, 52.9, 47.3, 45.0, 33.1, 29.1 and 26.8 δ; HRMS (EI) calculated for C ₂₄ H ₃₁ N ₃ O ₄ S = 457.2035, found = 457.2032; free water content = 0.87%; liquid solvents = 0.53% ethyl acetate and 0.34% hexane.

Example 24 1- [2- [4- (4-Methoxy-phenyl) -1-piperazinyl] -ethyl] -isochroman-6-carboxamide (VII)

Step 1: 1- [2- (6-bromoisochroman-1-yl) acetyl] -4- (4-methoxyphenyl) -piperazine (V)

Following the procedure of Example 1, Step 3, minor variations resulted from racemic 6-bromoisochroman-1-yl-acetic acid (IV) and 4- methoxyphenylpiperazine 1- (2- (6-bromoisochroman-1-yl) acetyl) -4- (4- methoxyphenyl) -piperazine (V), R _f = 0.26 (ethyl acetate / hexane, 70/30); IR (mull) 1639, 1512, 1446, 1439, 1249, 1214, 1030, 1028 and 820 cm ^-1; NMR (300 MHz, CDCl ₃ ) 7.32-7.26 (m, 2H, aromatic H), 7.0 (d, 1H, J = 8.2 Hz, aromatic H), 6.88 (d, 4H) aromatic H), 5.27 (mt, 1H, J = 5.9 Hz, ArC-H), 4.16-4.07 (m, 1H), 3.89 (m, 1H), 3.80 -3.60 (m, 4H), 3.77 (s, 3H, -OC-H ₃ ), 3.05 (m, 4H, four of pip-H), 2.97-2.90 (m, 2H), 2.76 (dzd, 1H, J _a = 3.7 Hz, J _b = 14.9 Hz), 2.65 (mzd, 1H, J = 16.4 Hz) δ; CMR (75MHz, CDCI) 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, 28.7 δ.

Step 2: 1- [2- (6-bromoisochroman-1-yl) ethyl] -4- (4-methoxyphenyl) -piperazine (VI)

Following the procedure of Example 1, Step 4 with minor variations, 1- (2- (6-bromoisochroman-1-yl) acetyl) -4- (4-methoxyphenyl) -piperazine (V) 1- (2- (6-bromoisochroman-1)) yl) acetyl] -4- (4 - methoxyphenyl) piperazine (VI), R _f = 0.23 (ethyl acetate); IR (neat) 1518, 1479, 1250, 1155, 1140, 1112, 1103, 1041 and 818 cm ^-1 ; NMR (300 MHz, CDCl ₃ ) 7.29 (d, 1H, J = 8.3 Hz, aromatic H), 7.27 (s, 1H, aromatic H), 6.97 ( d, 1H, J = 8.3 Hz, aromatic H), 6.85 (q, 4H, J = 9.7 Hz, aromatic H), 4.78 (wd, 1H, J = 6.1 Hz), 4.14-4.07 (m, 1H), 3.76-3.69 (m, 1H), 3.76 (s, 3H, -OC H _3), 3.10 (t, 4H, J = 4.9 Hz, four of pip-H), 3.95 (m, 1H), 2.70-2.50 (m's, 7H), 2.13 (m, 1H, pipCH-H), 2, Δ (m, 1H, pipCH-H) δ; CMR (75MHz, 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 28.6 δ.

Step 3: 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] isochroman-6-carboxamide (VII)

A dry 100 mL round bottom flask was charged with THF (18 mL) and cooled to 78 ° C in a dry ice / acetone bath. Then t-butyllithium in hexane (1.7 M, 5.4 mL, 9.2 mmol) was added in one portion. After stirring for 5 minutes, a mixture of 1- (2- (6-bromoisochroman-1-yl) acetyl] -4- (4-methoxyphenyl) -piperazine (VI) in THF (20 mL) was added via a tube. Trimethylsilyl isocyanate (0.88 mL, 6.55 mmol) and dioxane (3.52 mL) were added via a tube at 15 ° C. After 15 minutes, the cooling mixture was removed and the reaction was stirred at 20-25 ° C for 1.5 hours. The reaction mixture was then quenched with saturated aqueous ammonium chloride, the volatiles were removed under reduced pressure, and the residue was adjusted to basic pH with aqueous sodium hydroxide. Purify by flash chromatography (silica gel, 25 g; 0-10% methanol / ethyl acetate gradient) to give 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] isochroman-6-carboxamide (VII). mp = 180-182 ° C, R _f = 0.27 (methanol / ethyl acetate, 10/90 IR (suspensions) 3366, 3198, 1628, 1642, 1602, 1514, 1437, 1245, 1109 and 815 cm ^-1 ; NMR (300 MHz, CDCl ₃ ) 7.617.58 (m, 2H, aromatic H), 5.90 (very broad d, 2H, C (O) NH ₂ ), 4.86 (wd, 1H, J = 5, 8 Hz, PhC-H), 4.18-4.11 (m, 1H), 3.80-3.72 (m, 1H), 3.76 (s, 3H, PhOC-H ₃ ), 3, 10 (t, 4H, J = 4.8 Hz, four of pip-H), 2.99 (m, 1H), 2.73 (wt, 1H, J = 16.4 Hz), 2.66-

2.49 (m's, 6H), 2.15 (m, 1H, pip CH-H), 2.04 (m, 1H, pip CH-H) δ; CMR (75MHz, 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 δ; HRMS calcd for C ₂₃ H ₂₉ N ₃ O ₃ = 395.2209, found = 395.2219.

* · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

Example 25 1- [2- [4- (4-Methoxyphenyl) -1-piperazinyl] ethyl] -N-propylisochroman-6-carboxamide (IX)

Step 1: 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] -N, N-di-t-butyloxycarbonyl isochroman-6-carboxamide (VI11)

Following the procedure of Example 3, Step 1, minor variations resulted in 1- (2- (4- (4-methoxyphenyl) -1-piperazinyl] ethyl) isochroman-6-carboxamide (VII,

Example 24: 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] -N, N-di-t-butyloxycarbonyl isochroman-6-carboxamide (VIII).

Step 2: 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] -N-propyl iso-chroman-6-carboxamide (IX)

An oven-dried 100 mL stir bar flask was charged with 1- (2- (4- (4-methoxyphenyl) -1-piperazinyl] ethyl) -N, N-di-t-butyloxycarbonylisochroman-6-carboxamide (VII, 566 mg, 0.95 mmol) and 20 mL of dichloromethane and treated with propylamine (0.78 mL, 9.5 mmol) After 16 hours, the volatiles were removed under reduced pressure to give the crude product, which was purified by LC (silica gel). porosity 230400, 30 g; methanol / ethyl acetate, 5/95) to give 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] -N-propyl-isochroman-6-carboxamide (IX), m.p. = 147149 ° C; R f = 0.37 ethanol / ethyl acetate (5/95); IR (suspension) 3302, 2815, 1639, 1539, 1515, 1320, 1310, 1293, 1278, 1247, 1153, 1112, 1107, 1041 and 824 cm ^-1 ; NMR (300 MHz, CDCl ₃ ) 7.54 (m, 2H, aromatic, 7.16 (d, 1H, J = 8.6 Hz, aromatic), 6.87 (m 4H, aromatic), 6.16 (broad t, 1H, NH), 4.87 (broad d, 1H, J = 6 Hz, methine), 4.14 (m, 1H, OCH _2a ), 3.76 (m, 4H, _OCH3 OCH & _2b), 2.17 (m, 1H, C (H (CH ₂ ), 2,77,2,53 (m, 7H, Ph-NC (H ₂ ) -CH _{2 s} -NCH _{2 s} , Ph-CH _{2 b} ), 2,17 (m, 1H, C (H) -CH _2a ) , 2.05 (m, 1H, C (H) -CH _2b), 1.63 (sxt, 2H, J = 7.4 Hz, C _{(H3) -CH2),} 0.98 (t, 3H , J = 7.4 Hz, CH ₃ -C (H ₂ ) δ; CMR (75MHz, CDCl ₃ ) 167.1, 153.6, 145.5, 141.3, 134.3, 132.7,

127.4, 124.8, 124.2, 117.9, 114.2, 74.3, 62.8, 55.4, 54.5, 53.3, 50.4, 41.5, 33, 0, 28.9, 22.8 and 11.6 δ; MS (EI, m / z) = 437;

EXAMPLE 26 1- [2- [4- (4-Methoxyphenyl) -1-piperazinyl] ethyl] -N-allylisochroman-6-carboxamide (IX)

Following the procedure of Example 25, Step 2, with minor variations, crude product was obtained from allylamine (0.69 mL, 9.1 mmol). Purify by LC (silica gel, porosity 230-400, 30 g; methanol / ethyl acetate 3/97) to give a product which is recrystallized from ethyl acetate / hexane, mp = 146-148 ° C; _Rf = 0.34 (methanol / ethyl acetate, 5/95); IR (suspensions) 3295, 2814, 1640, 1536, 1515, 1494, 1443, 1310, 1281, 1246, 1148, 1107, 1037, 923, and 823 cm ^-1 ; NMR (300 MHz, CDCl ₃ ) 7.57, 7.17, 6.85, 6.2, 5.92, 5.26, 5.19, 4.87, 4.08, 3.76, 3, 11, 3.01, 2.78-2.50,

127.8, 125.1, 124.5, 118.2, 116.8, 114.4, 74.6, 63.0, 55.6, 54.7, 53.5, 50.7, 42, 5, 33.2 and 29.1 δ; MS (EI, m / z) = 435; 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-ethylisochroman-6-carboxamide (IX)

Following the procedure of Example 25, Step 2, with minor variations, the crude product was formed from ethylamine (about 2 mL, condensed at 0 ° C). Purify by LC (silica gel, porosity 230-400, 30 g; methanol / ethyl acetate 5/95) to give the product. This material was triturated with ethyl acetate / hexane to give 1- (2- (4- (4-methoxyphenyl) -1-piperazinyl] ethyl) -N-ethyl-isochroman-6-carboxamide (IX), mp = 127-129 ° C; R _f = 0.30 (methanol / ethyl acetate, 5/95); IR (mull) 3308, 2815, 1640, 1541, 1514, 1442, 1359, 1312, 1283, 1246, 1149, 1112, 1037 and 826 ^cm-1; NMR (300 MHz, _CDCl3) 7.55 (m, 2H, aromatic), 7.16 (d, 1H, J = 8.6 Hz, aromatic), 6.87 (m, 4H, aromatic 6.12 (broad t, 1H, NH), 4.87 (broad d, 1H, J =

8.1 Hz, methine, 4.15 (m, 4H, OCH _{2 a} ), 3.77 (m, 4H, OCH ₃ and OCH _2b ), 3.49 (qt, 2H, J =

7.2 Hz, N (H) -CH ₂ ), 3.11 (t, 4H, J = 4.8 Hz, Ph-N-CH _{2 s} ), 3.00 (m, 1H, Ph-CH _{2 a} ), 2 , 77-

2.50 (m, 1H, Ph-NC (H ₂ ) -CH ₂ -NCH _{2 s} , Ph-CH _2b ), 2.15 (m, 1H, C (H) -CH _2a ), 2.05 (m 1 H, C (H) -CH _2b ), 1.25 (t, 3H, J = 7.2 Hz, CH ₃ -C (H ₂ ) δ; CMR (75MHz, CDCl ₃ ) 166.9,

153.4, 14, 4, 141.2, 134.1, 132.5, 127.3, 124.7, 124.1, 117.8, 114.1, 74.2, 62.6, 55, 2,

54.3, 53.2, 50.3, 34.6, 32.9, 28.7 and 14.6 δ; MS (EI, m / z) = 423;

Example 28 1- (2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] -N-propargylisochroman-6-carboxamide (IX)

Following the procedure of Example 25, Step 2, with minor variations, the crude product was obtained from propargylamine (1.6 mL, 23.0 mmol). This material was purified by LC on 75 g (230-400) silica gel eluting with ethyl acetate, the product recrystallized from ethyl acetate / hexane to give 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] -N-propargyl-isochroman-6-carboxamide (IX), m.p. = 162-164 ° C; _Rf = 0.40 (methanol / ethyl acetate, 5/95); IR (suspensions) 3287, 1643, 1636, 1611, 1535, 1515, 1495, 1443, 1303, 1283, 1246, 1147, 1107, 1033, and 822 cm ^-1 ; NMR (300 MHz, CDCl 3) 7.57 (m, 2H, aromatic), 7.17 (d, 1H, J = 8.6 Hz, aromatic), 6.85 (m, 4H, aromatic), 6.35 (broad t, 1 Η, NH), 4.88 (broad d, 1H, J = 8.0 Hz, methine), 4.25 (DD, 2H, J = 5.2 Hz and J = 2.5 Hz) N (H) -CH ₂ ), 4.12 (m, 1H, OCH _{2 a} ), 3.76 (m, 4H, OCH ₃ and OCH _2b ), 3.10 (t, 4H, J = 4.8 Hz, Ph-N-CH _{2 s} ), 3.01 (m, 1H, Ph-CH _{2 a} ), 2.78-

2.50 (m, 7H, Ph-NC _{(H2) -CH2S,} Ph-CH _2b), 2.29 (t, 1H, J = 2.5 Hz, alkyl), 2.18 (m, 1H , C (H) -CH _2a), 2.05 (m, 1H, C (H) -CH _2b) δ; CMR (75MHz, CDCl ₃ ) 166.7, 153.6, 145.5, 142.0, 134.4, 131.6, 127.6, 124.9, 124.4, 118.0, 114.2 , 79.3, 74.3, 71.8, 62.7, 55.4,

54.5, 53.3, 50.4, 33.0, 29.6 and 28.8 δ; MS (EI, m / z) = 433; HRMS (EI) calculated for C ₂₆ H ₃₁ N ₃ O ₃ = 433.2365, found 433.2367.

Example 29 1- [2- [4- (4-Methoxyphenyl) -1-piperazinyl] ethyl] -N- (4-methoxyphenylmethyl) -isochroman-6-carboxamide (IX)

Following the procedure of Example 25, Step 2, with minor variations, 4-methoxyphenylmethylamine (1.2 mL, 9.2 mmol) was obtained from the crude product. This was purified by flash chromatography on 67 g of silica gel using methanol / ethyl acetate (10/90); [α] _D = -40 ° (c = 0.98, ethanol); IR (suspension) 3306, 1642, 1540, 1515, 1313, 1251, 1244, 1235, 1110, 1036 cm ^-1 ; NMR (300 MHz, CDCl ₃ ) 7.57 (m, 2H, aromatic H), 7.28 (d, 2H, J = 8.7 Hz, aromatic H), 7.16 (d, 2H, J = 8) 7 Hz, aromatic H), 6.92-6.82 (m's, 6H, aromatic H), 6.27 (m, 1H, C (O) NH), 4.86 (wt, 1H, J = 5) 8 Hz, PhC-H), 4.8-4.11 (m, 1H), 3.80 (s, 3H, PhOC-H ₃ ), 3.80-3-72 (m, 1H), 3 76 (s, 3H, _PhOC-H3), 3.10 (t, 4H, J = 4.8 Hz, four of pip-H), 2.99 (m, 1H), 2.73 (MH, 1 H, J = 16.4 Hz), 2.66-2.49 (m's, 6H), 2.15 (m, 1H, pip CH-H), 2.04 (m, 1H, pip CH-H) δ; CMR (75MHz, CDCl ₃ ) 166.9, 145.7, 141.7, 134.5, 132.4, 130.2, 129.3,

127.7, 125.0, 124.5, 118.12, 114.4, 114.2, 74.5, 62.9, 55.5, 55.3, 54.6, 53.5, 50.6,

43.6, 33.1, 29.0 δ; HRMS calcd for C 31 H 37 N 3 O 4 = 515.2784, found 515.2806.

· «···· ··

Example 30 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] -N-phenylmethylisochroman-6-carboxamide (IX)

Oven-dried 15 ml tube, equipped with a Claisen condenser, water condenser and adapter, is charged with 1- [2- (6-bromoisochroman-1-yl) acetyl] -4- (4-methoxyphenyl) -piperazine (VI, 646 mg, 1.5 mmol), palladium acetate (98%, 17.2 mg, 0.075 mmol) and 1,3-bis-diphenylphosphinopropane (97%, 38.3 mg, 0.09 mmol). A carbon monoxide atmosphere is maintained in the tube. DMF (3.75 mL), phenylmethylamine (1.15 mL, 10.5 mmol) and diisopripylethylamine (0.52 mL, 3 mmol) were added via syringe to the reaction vial. The mixture was heated to 100 ° C for 10 hours. After cooling to 20-25 ° C, it is separated into two phases. The reaction mixture was then poured into ethyl acetate. The mixture was washed once with aqueous sodium hydroxide (1N). The organic layer was then condensed under reduced pressure to remove excess solvents and reactants to give a crude product which was purified by flash chromatography on 100 g of silica gel using ethyl acetate as eluent to give 1- (2- (4- (4-methoxyphenyl) -1-). piperazinyl] ethyl] -N-phenylmethyl-isochroman-6-carboxamide (IX), m.p. = 153.0-153.5 ° C; R _f = 0.25 (methanol / ethyl acetate, 10/90); IR ( 3263, 2819, 1640, 1543, 1513, 1245, 1234, 1112, 1039, and 826 cm ^-1 ; NMR (300 MHz, CDCl 3) 7.58 (d, 2H, J = 6.9 Hz, aromatic H) 7.36-7.28 (m's, 5H, aromatic H), 6.42 (t, 1H, C (O) NH), 4.86 (wd, 1H, J = 5.8 Hz, PhC-H) ), 4.64 (d, 2H, J = 5.7 Hz, _PhC-H2), 4.17-4.10 (m, 1H), 3.80-3.72 (m, 1H), 3 76 (s, 3H, PhOC-H ₃ ), 3.10 (t, 4H, J = 4.8 Hz, four of pip-H), 2.99 2.73 (wd, 1H, J = 16, 4 Hz, 2.66-2.49 (m's, 6H), 2.15 (m, 1H, pip CH-H), 2.04 (m, 1H, pip CH-H) δ; CMR (75MHz, CDCl ₃ )

189.7, 167.1, 153.8, 145.7, 141.8, 138.2, 134.5, 132.4, 128.8, 127.9, 127.8, 127.6, 125, 1, 124.6, 74.5, 62.9, 55.6, 54.6, 53.5, 50.6, 44.1, 33.1, 29.0 δ; HRMS calculated for ΰ ₃₀ Η; 35 Ν ₃ Ο ₃ = 485.2678, found = 485.2664.

Example 31 1- [2- [4- (4-Methoxyphenyl) -1-piperazinyl] ethyl] -N-butylisochroman-6-carboxamide (IX)

Following the procedure of Example 30 with minor variations, n-butylamine (1.04 mL, 10.5 mmol) was obtained, which was purified by flash chromatography on 100 g of silica gel using ethyl acetate as eluent to give the product which was recrystallized from hot ethyl acetate to give the title compound, m.p. = 158.5-159.5 ° C; R _f = 0.28 (ethyl acetate); IR (suspension)

3301, 2816, 1637, 1537, 1515, 1444, 1308, 1244, 1111 and 823 cm ^-1 ; NMR (300 MHz, CDCl ₃ ) 5.53, 7.16, 6.87, 6.10, 4.85, 3.80-3.67, 3.45, 3.11, 3.10, 2, 73, 2.66-2.49, 2.15, 2.04, 1.59, 1.43, 0.96 δ; CMR (75MHz, CDCl3) 167.3, 153.8, 145.7, 141.5,

134.5, 132.9, 127.6, 125.0, 124.4, 118.2, 114.4, 74.5, 63.0, 55.6, 54.7, 53.5, 50, 6, 40.0, 39.8, 33.2, 31.8, 29.1, 20.2, 13.8 δ.

Example 32 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] -N - [(R) -amethylphenylmethyl] -isochroman-6-carboxamide (IX)

Following the procedure of Example 30 with slight variation, (R) - (+) - Amethylphenylnethylamine (98%, 0.90 mL, 7 mmol) gave a crude product which was purified by flash chromatography on 100 g silica gel using a gradient of 0-4% methanol. in ethyl acetate. The product was recrystallized from hot methylene chloride / ethyl acetate / hexane to give 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] -N - [(R) -amethylphenylmethyl] isochroman-6-carboxamide ( IX) as mixtures of diastereomers, m.p. = 140.5-141.0 ° C; R _f = 0.28 (ethyl acetate); [α] _D = + 25 ° (c = 0.94, ethanol); IR (suspension) 3310, 1636, 1530, 1514, 1495, 1275, 1148, 1110, 700 cm &^lt; -1 &gt;; NMR (300 MHz, CDCl 3) 7.58 (d, 2H, J = 6.9 Hz, aromatic H), 7.41-7.28 (m's, 5H, aromatic H), 7.16 (d, 1H, J = 8.7 Hz, aromatic H), 6.85 (q, 4H, J = 9.2 Hz, aromatic H). 6.29 (d, 1H, J = 7.8Hz, C (O) NH), 5.34 (quintet, 1H, J = 7.2Hz, PhC-H), 4.86 (wd, 1H, J = 5.8 Hz, PhC-H). 4.17-4.10 (m, 1H), - 3.80-3.72 (m, 1H), 3.76 (s, 3H, PhOCH _3), 3.10 (t, 4H, J = 4, 8 Hz, four of pip-H), 2.99 (, m 1H), 2.73 (mt, 1H, J = 16.4 Hz), 2.66-2.49 (m's, 6H), 2, 15 (m, 1H, pip CH-H), 2.04 (m, 1H, pip CH-H), 1.61 (d, 3H, J =

6.9 Hz, PhC (H) CH ₃₎ δ; CMR (75MHz, CDCl ₃ ) 166.2, 153.7, 145.7, 143.0, 141.7,

134.5, 132.6, 128.7, 127.6, 127.4, 126.2, 125.0, 124.5, 118.1, 114.4, 74.5, 62.9,

55.5, 54.6, 53.4, 50.5, 49.1, 33.1, 29.0, 21.6 δ ..

Example 33 1- [2- [4- (4-Methoxyphenyl) -1-piperazinyl] ethyl] -N - [(S) -amethylphenylmethyl] isochroman-6-carboxamide (IX)

Following the procedure of Example 30 with slight variation, (S) - (-) - Amethylphenylnethylamine (98%, 0.90 mL, 7 mmol) gave a crude product which was purified by flash chromatography on 100 g silica gel using a gradient of 0-7% methanol. in ethyl acetate. The product was recrystallized from hot methylene chloride / ethyl acetate / hexane to give 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] -N - [(S) -a76. ·

methylphenylmethyl] isochroman-6-carboxamide (IX) as a mixture of diastereomers, m.p. = 140.0-141.5 ° C; R _f = 0.28 (ethyl acetate); [α] _D = -24 ° (c = 0.98, ethanol); IR (suspension) 3310, 1636, 1530, 1514, 1495, 1275, 1148, 1110, 700 cm &^lt; -1 &gt;; NMR (300 MHz, CDCl ₃ ) 7.58 (d, 2H, J = 6.9 Hz, aromatic H), 7.41-7.28 (m's, 5H, aromatic H), 7.16 (d, 1H) J = 8.7 Hz, aromatic H), 6.85 (q, 4H, J = 9.2 Hz, aromatic H), 6.29 (d, 1H, J = 7.8 Hz, C (O)) NH), 5.34 (quintet, 1H, J = 7.2 Hz, PhC-H), 4.86 (wd, 1H, J = 5.8 Hz, PhC-H). 4.17-4.10 (m, 1H), - 3.80-3.72 (m, 1H), 3.76 (s, 3H, PhOCH _3), 3.10 (t, 4H, J = 4, 8 Hz, four of pip-H), 2.99 (m IH), 2.73 (mzd, 1H, J = 16.4 Hz), 2.66-2.49 (m's, 6H), 2.15 (m, 1H, pip CH-H), 2.04 (m, 1H, pip CH-H), 1.61 (d, 3H, J =

6.9 Hz, PhC (H) CH ₃₎ δ; CMR (75MHz, CDCl ₃ ) 166.2, 153.7, 145.7, 143.0, 141.7,

134.5, 132.6, 128.7, 127.6, 127.4, 126.2, 125.0, 124.5, 118.1, 114.4, 74.5, 62.9,

55.5, 54.6, 53.4, 50.5, 49.1, 33.1, 29.0, 21.6 δ ..

Example 34 1- [2- [4- (4-Methoxyphenyl) -1-piperazinyl] ethyl] -N-phenylisochroman-6-carboxamide (IX)

Following the procedure of Example 30 with minor variations, an aniline (0.64 mL, 7 mmol) was obtained which was purified by LC chromatography on 29 g (230400) silica gel, eluting with ethyl acetate / hexane (75/25) to give 1 g. - [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] -N-phenyl-isochroman-6-carboxamide (IX), R _f = 0.25 (ethyl acetate / hexane, 75/25); IR (suspension) 2817, 1652, 1599, 1531, 1513, 1442, 1320, 1298, 1246, 1145, 1112, 1038, 823, 754, 693 cm ^-1 ; NMR (300 MHz, CDCl ₃ ) 7.87 (s, 1H, NH), 7.63 (m, 4H, aromatic), 7.37 (t, 2H, J = 7.7 Hz, aromatic), 7, 21 (d, 1H, J = 7.9 Hz, aromatic), 7.18 (t, 1H, J = 6.3 Hz, aromatic), 6.85 (m, 4H, aromatic), 4.88 (broad) d, 1H, J = 6.0 Hz, methine, 4.15 (m, 1H, OCH _{2 a} ), 3.76 (m, 4H, OCH ₃ and OCH _2b ), 3.11 (t, 4H, J = 4.9 Hz, Ph-N-CH ₂ S), 2.15 (m, 1H, C (H) -CH _{2 -} ), 2.05 (m, 1H, C (H) -CH _{2 b} )) δ; CMR (75MHz, CDCl ₃ ) 165.5, 153.8, 145.7, 142.2, 137.9,

134.8, 133.0, 129.1, 127.8, 125.3, 124.6, 124.5, 118.2, 114.4, 74.5, 62.9, 55.6, 54, 7,

53.5, 50.6, 33.2, 29.1 δ.

Example 35 1- [2- [4- (4-Methoxyphenyl) -1-piperazinyl] ethyl] -N-phenylmethyl-N-methyl-isochroman-6-carboxamide (IX)

Following the procedure of Example 30 with minor variations, a crude product was obtained from phenylmethymethylamine (1.4 mL, 10.5 mmol) which was purified by LC chromatography.

chromatography on 77 g (230-400) silica gel eluting with acetone / hexane (40/60), gradually increasing the acetone / hexane (60/40) ratio to give the product. Dissolve in ether and treat with gaseous hydrochloric acid to form a solid. The free base _Rf = 0.30 (acetone / hexane, 40/60); IR (suspension) 3423, 2352, 2192, 1627, 1513, 1495, 1400, 1331, 1310, 1294, 1259, 1193, 1106, 1073, 1028 cm ^-1 ; NMR Free Base (300 MHz, CDCl ₃ ) 7.26 (m, 8H, aromatic), 6.84 (m, 4H, aromatic), 4.84 (bs, 1H, methine), 4.75 (bs, 1H) , Ph-CH ₂ -N), 4.54 (m, 1H, Ph-CH _2b -N), 4.12 (m, 1H, OCH _{2 a} ), 3.76 (m, 4H, OCH ₃ and OCH _2b) ), 3.08 (t, 4H, J = 4.7 Hz, Ph-CH _{2 s} , Ph-CH _{2 s} ), 3.02-2.88 (m, 4H, NCH ₃ and PH-CH _{2 a} ), 2 64 (m, 7H, Ph-NC (H ₂ ) -CH ₂ -NCH _{2 s} , Ph-CH _2b ), 2.15 (m, 1H, C (H) -CH _2a ), 2.05 (m, 1H, C (H) -CH _2b) δ; HRMS (EI) calculated for C ₃₁ H ₃₇ N ₃ O ₃ = 499.2835, found = 499.2842.

Example 36 1- [2- [4- (4-Methoxyphenyl) -1-piperazinyl] ethyl] -N, N-dimethylisochroman-6-carboxamide (IX)

A flame dried 50 mL flask equipped with a stir bar and an addition funnel was charged with fresh distilled tetrahydrofuran (6 mL), cooled to -78 ° C, and a 1.7 M solution of tert-butyllithium (3.0 mL, 5.0 mmol) was added. . A solution of 1- (2-) 6-bromoisochroman-1-yl) ethyl) -4- (4-methoxyphenyl) piperazine (VI, 1.08 g, 2.5 mmol) and 4 mL of tetrahydrofuran was added dropwise over 10 minutes. (507 mg, 3.3 mmol). The aryllithium is stirred for 10 minutes and then carbon monoxide (preferably dry) is added. After this addition, the aryl carboxylate is heated to 20-25 ° C with the suspended gas added in 10 minutes. Diethylformamide (2 drops) and oxalyl chloride (0.33 mL, 3.75 mmol) were added to the mixture, generating a large amount of gas and dark color. After 45 minutes, the mixture was treated with gaseous dimethylamine. After 20 minutes, the addition of the amine is stopped and the reaction mixture is dissolved in 40 mL of 5M sodium hydroxide and extracted twice with ethyl acetate (40 mL). The combined organics were washed twice in brine (30 mL), dried over magnesium sulfate, filtered and concentrated to give the product, purified by LC chromatography on 63 g (230-400) silica gel, eluting with acetone / hexane (50/50) and to form 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] -N, N-dimethyl-isochroman-6-carboxamide (IX), m.p. = 9496 °; R _f = 0.31 (acetone / hexane, 50/50); IR (suspension) 2808, 2792, 1624, 1610, 1513, 1488, 1444, 1414, 1275, 1253, 1231, 1152, 1109, 1036, 833 cm &^lt; -1 &gt;; NMR (300 MHz, CDCl ₃ ) 7.19 (m, 2H, aromatic), 7.12 (d, 1H, J = 7.9 Hz, aromatic), 6.85 (m, 4H,

aromatic), 4.85 (broad d, 1H, J = 56.0 Hz, methine), 4.13 (m, 1H, OCH _2a ), 3.76 (m,

4H, OCH ₃ and OCH _2b ), 3.13-3.00 (m, 11H, NCH ₃ s, Ph-NCH ₂ s, Ph-CH _2a ), 2.65 (m, 7H, Ph-NC (H) ₂ ) -CH ₂ -NCH _{2 and} Ph-CH _2b ), 2.17 (m, 1H, C (H) -CH _{2 a} ), 2.05 (m, 1H, C (H) -CH _2b ) δ; CMR (75MHz, CDCl ₃ ) 171.2, 153.5, 145.5, 139.4,

134.2, 134.0, 127.5, 124.6,

124.4, 117.9, 114.2, 74.3, 62.7, 55.3, 54.5, 53.3, 50.4, 39.4, 35.1, 33.0, 28, 8 δ;

HRMS (EI) calculated for C ₂₅ H ₃₃ N ₃ O ₃ = 423.2522, found = 423.2520.

Example 37 1- [2- [4- (4-Methoxyphenyl) -1-piperazinyl] ethyl] -N-methylisochroman-6-carboxamide (IX)

Following the procedure of Example 30, with slight variation, it is formed from methylamine gas and retaining the amount of all other reagents 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] -N-methylisochroman-6-carboxamide (IX), which recrystallizes from ethyl acetate to give the title compound, m.p. = 174-176 ° C; _Rf = 0.40 (methanol / dichloromethane, 5/95); IR (suspensions) 3270, 1639, 1543, 1515, 1418, 1319, 1260, 1248, 1235, 1152, 1141, 1112, 1037, 832, and 820 cm ^-1 ; NMR (300 MHz, CDCl ₃ ) 7.53 (m, 2H, aromatic), 7.16 (d, 1H, J = 8.6 Hz, aromatic), 6.87 (m, 4H, aromatic), 19 ( broad m, 1H, NH), 4.86 (broad d, 1H, J = 5.9 Hz, methine), 4.14 (m, 1H, OCH _{2 a} ), 3.76 (m, 4H, OCH ₃ and OCH _2b ), 3.10 (t, 4H, J = 4.8Hz, Ph_N-CH _{2 s} ), 3.00 (d, 4H, N-CH ₃ and Ph-CH _{2 a} ), 2.77-2.49 ( m, 7H, Ph-NC (H ₂ ) -CH _{2 s} -NCH _{2 s} , Ph-CH _2b ), 2.14 (m, 1H, C (H) -CH _2a ), 2.05 (m, 1H, C (H) -CH _2b ) δ CMR (75MHz, CDCl ₃ ) 168.0, 153.8,

145.7, 141.6, 134.5, 132.7, 125.0, 124.4, 118.2, 114.4, 74.5, 62.9, 55.6, 54.6, 53, 5,

50.6, 33.1, 29.1, 26.8 δ; HRMS (EI) calculated for C ₂₄ H ₃₁ N ₃ O ₃ = 409.2365, found = 409.2366.

Example 38 1- [2- [4- (4-Chloro-phenyl) -1-piperazinyl] -ethyl] -N-methyl-isochroman-6-carboxamide (IX)

Following the procedure of Example 36 with minor variations, 1- (2- (6-bromoisochroman-1-yl) ethyl) -4- (4-chlorophenyl) -piperazine (VI, Example 8, Step 2, 188 mg, 0.43) was formed. mmol) and methilamine product, which is purified by LC on 10 g (230-400) silica gel eluting with 40% acetone / hexane to give 1- [2- [4- (4-chlorophenyl) -1-piperazinyl] ethyl] -N -methyl-isochroman-6-carboxamide (IX), m.p. = 158160 ° C; R _f = 0.21 (40% acetone / hexane); IR (suspension) 3319, 3263, 1613, 1597, 1571, 1545, 1497 , 1334, 1314, 1239, 1150, 1139, 1109, 816 cm ^-1 ; NMR (300 MHz, CDCl ₃ ),

7.54 (broad s, 2H, aromatic), 7.16 (m, 3H, aro, matic), 6.84 (d, 2H, J = 9.0 Hz, aromatic), 6.21 (broad m, 1H, NH), 4.86 (broad d, 1H, J = 6.0 Hz, methine), 4.12 (m, 1H, OCH _{2 a} ), 3.77 (m, 1H, NH), 3.17 (t, 4H, J = 4.8 Hz, Ph-N-CH _{2 s} ), 3.00 (d, 4H, J = 4.9 Hz, N-CH ₃ and Ph-CH _{2 a} ), 2.77- 2.45 (m, 7H, Ph-NC _{(H2) -CH2S} -NC _{2 s,} Ph-CH _2b)

2.18 (m, 1H, C (H) -CH _{2 a} ), 2.05 (m, 1H, C (H (-CH _2b ) δ); CMR (75MHz, CDCl ₃ ) 167.7,

149.7, 141.3, 134.2, 132.4, 128.7, 127.4, 124.7, 124.2, 124.1, 112.9, 74.2, 62.7,

54.3, 53.0, 48.9, 32.9, 28.8, 26.6 δ; HRMS (EI) calculated for C ₂₃ H ₂₈ CIN ₃ O ₂ =

413.1870, found 413.1867.

Example 39 1- [2- [4- (4-Chloro-phenyl) -1-piperazinyl] -ethyl] -N, N-dimethyl-isochroman-6-carboxamide (IX)

Following the procedure of Example 36 with minor variations, 1- [2- (6-bromoisochroman-1-yl) -ethyl] -4- (4-chlorophenyl) -piperazine (VI, Example 8, Step 2, 188 mg, 0.43) was formed. mmol) and dimethylamine 50 mg (27%) of 1- [2- [4- (4-chlorophenyl) -1-piperazinyl] ethyl] -N, N-dimethyl-isochroman-6-carboxamide (IX). This material was converted to the dichloride salt using gaseous hydrochloric acid and recrystralized, m.p. = 119-122 ° C; R _f = 0.41 (40% acetone / hexane); IR (suspension) 3411, 2507, 2421, 2336, 1628, 1570, 1496, 1397, 1334, 1286, 1263, 1170, 1110, 1095, 1057 cm ^-1 ; free base; NMR (300 MHz, CDCl ₃ ) 7.20 (m, 4H aromatic), 7.12 (d, 1H, J = 7.9 Hz, aromatic), 6.83 (d, 2H, J = 9.1 Hz) , aromatic), 4.86 (broad d, 1H, J = 6.0 Hz, methine), 4.13 (m, 1H, OCH _{2 a} ), 3.76 (m, 1H, OCH _2b ), 3.18 (t, 4H, J = 4.9 Hz, PhNCH _{2 s} ), 3.10-3.00 (m, 1H, NCH ₃ with Ph-CH _{2 a} ), 2.60 (m, 7H, Ph-NC (H) ₂ ) -CH _{2 s} -NCH ₂ and Ph-CH _{2 b} ), 2.14 (m, 1H, C (H) -CH _{2 a} ), 2.60 (m, 1H, C (H) -CH _{2 b} )) δ ; CMR (75MHz, CDCl ₃ ) 171.3, 149.7, 139.3, 134.3, 134.1, 128.8, 127.5, 124.7, 124.5, 117.0, 74.3 ,

62.8, 54.4, 53.0, 48.9, 39.4, 35.2, 32.9, 28.8 δ; HRMS calcd for C 24 H 25 ClN 4 O = 427.2026, found = 427.2020.

Example 40 1- [2- [4-phenylpiperazinyl] ethyl] isochroman-6-carboxamide (VII)

Step 1: 1- [2- (6-bromoisochroman-1-yl) acetyl] -4-phenylpiperazine (V)

Following the procedure of Example 1.3. step with minor variations, it is formed from racemic 6-bromoisochroman-1-yl-acetic acid (IV, Example 7, step 1) and N-phenylpiperazine [2- (6-bromoisochroman-1-yl) acetyl] -4-phenylpiperazine (V) _Rf = 0.20 (40% ethyl acetate / hexane); IR (suspensions) 1641, 1599, 1495, 1482, 1442, 1406, 1329, 1278, 1232.

1171, 1156, 1107, 1027, 760, 694 cm ^-1 ; NMR (300 MHz, CDCl ₃ ) 7.29 (m, 4H, aromatic), 7.00 (d, 1H, J = 8.2 Hz, aromatic), 6.91 (m, 3H, aromatic), 5, 26 (broad d, 1H, J = 5.8 Hz, methine), 4.11 (m, 1H, OCH _2a ), 3.91 (dt, 1H, J = 136 Hz and J = 5.1 Hz, O = CN-CH _{2 a} ), 3.72 (m, 4H, O = CN-CH 2 _bcd OCH _{2 b} ), 3.18 (t, 4H, J = 4.9 Hz, PhNCH ₂ s), 2.95 ( m, 2H, Ph-CH _{2 a} and N-CO-CH _{2 a} ), 2.76 (dd, 1H, J = 14.8 Hz and J = 4.9 Hz, N-CO-CH _2b ), 2.65 ( bd, 1H, J = 16.4 Hz, Ph- _CH2b ); CMR (75MHz, CDCI ₃ ) 168.8,

150.7, 136.2, 136.1, 131.5, 129.2, 129.0, 126.2, 120.2, 120.1, 116.3, 73.2, 63.3,

49.5, 49.0, 45.8, 41.6, 39.7, 28.5 δ; HRMS (EI) calculated for C ₂₁ H ₂₃ BrN ₂ O ₂ = 414.0943, found 414.0937.

Step 2: 1- [2- (6-bromoisochroman-1-yl) ethyl] -4-phenylpiperazine (VI)

Following the procedure of Example 1.4. a small variation step results from 1- (2- (6-bromoisochroman-1-yl) acetyl] -4-phenylpiperazine (V) 1- (2- (6-bromoisochroman-1-yl) ethyl) -4-phenylpiperazine (VI) The crude salt was recrystallized from ethyl acetate / hexane, mp = 241-242 ° C; R _f = 0.25 (40% ethyl acetate / hexane); IR (suspension) 2532, 2510, 2482, 2348, 2205, 1596, 1494, 1425, 1407, 1112, 1100, 980, 884, 764, 694 cm ^-1 ; free base NMR (300 MHz, CDCl ₃₎ 7.26 (m, 4H, aromatic), 6.94 (m, 3H, aromatic), 6.85 (t, 1H, J = 7.3 Hz, aromatic), 4.78 (broad d, 1H, J = 5.8 Hz, methine), 4.11 (m, 1H, OCH _{2 a} ), 3.74 (m, 1H, OCH _2b ), 3.20 (t, 4H, J =

4.9 Hz, Ph-NCH ₂ s), 2.93 (m, 1H, Ph-CH _{2 a} ), 2.65 (m, 7H, Ph-NC (H ₂ ) -CH ₂ -NCH ₂ and PhCH _2b ), 2.09 (m, 1H, C (H) -CH _2a), 2.00 (m, 1H, C (H) -CH _2b) δ; CMR (75MHz, CDC ₃ )

151.6, 137.8, 136.3, 131.6, 129.3, 129.1, 126.5, 120.0, 119.6, 116.0, 74.3, 62.8,

54.6, 53.4, 49.1, 33.2, 28.8, δ; MS (EI, m / z) = 400;

Step 3: 1- [2- [4-phenylpiperazinyl] ethyl] isochroman-6-carboxamide (VII)

A flame dried 10 mL flask equipped with a stir bar and funnel was charged with fresh distilled tetrahydrofuran (2 mL), cooled to -78 ° C and mixed with a solution of tert-butyllithium (1.7M, 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 was added dropwise. The aryl lithium was stirred for 10 minutes and added to a flame dried 25 mL bar bottle containing freshly distilled trimethylsilyl isocyanate (0.22 mL, 1.6 mmol) and 2 mL tetrahydrofuran, also cooled to -78 ° C, via a tube. The resulting mixture was heated at 2025 ° C for 2 hours, diluted with 25 mL saturated ammonium chloride, the volatiles were removed under reduced pressure, adjusted to pH 13, extracted twice with ethyl acetate (35 mL), and the combined organic extracts were washed twice with brine. (25 mL), dried over magnesium chloride, filtered, and concentrated. Purify by LC on 27 g (230-400) silica gel eluting with 5% methanol / ethyl acetate to give 1- [2- [4-phenylpiperazinyl] ethyl] isochroman-6-carboxamide (VII), IR (suspension) 3350, 3189, 3057, 1663, 1600, 1570, 1503, 1496, 1427, 1336, 1238, 1143, 1110, 760, 692 cm ^-1 ; NMR base (300 MHz, CDCl ₃ ), 7.599 (m, 2H, aromatic), 7.26 (t, 2H, J = 8.2 Hz, aromatic), 7.18 (d, 1H, J = 8.5 Hz, aromatic), 6.93 (d, 2H, J = 7.9 Hz, aromatic), 6.85 (t, 1H, J = 7.2 Hz, aromatic), 6.10 (broad s, 1H, NH), 5.75 (broad s, 1H, NH), 5.75), 4.88 (broad d, 1H, J = 5.9 Hz, methine), 4.15 (m, 1H, OCH _2a ) 3.77 (m, 1H, OCH _2b ), 3.21 (t, 4H, J = 4.9 Hz, Ph-N-CH 2 · 3.02 (m, 1H, PhCH _{2 a} )), 2.79 -2.50 (m, 7H, Ph-NC (H ₂ ) -CH ₂ -NCH _{2 s} , Ph-CH _2b ), 2.16 (m, 1H, C (H) -CH _2a , 2.05 (m) , 1H, C (H) -CH _{2 b} ) δ; CMR (75MHz, CDCl ₃ ) 169.0, 151.3, 142.4, 134.6, 131.3,

129.1, 128.2, 125.1, 124.9, 119.7, 116.0, 74.5, 62.9, 54.6, 53.4, 49.1, 33.1, 29.0 δ ; HRMS (EI) calculated for C ₂₂ H ₂₇ N ₃ O ₂ = 365.2103, actual = 365.2108.

Example 41 1- (2- (4- (3,4-Dichlorophenyl) -1-piperazinyl) ethyl] isochroman-6-carboxamide (VII). Step: 1- (2- (6-bromoisochroman-1-yl) acetyl) -4- (3,4-dichlorophenyl) piperazine (V)

Following the procedure of Example 1.3. step with minor variations it is formed from racemic 6-bromoisochroman-1-yl acetic acid (IV, Example 7, step 1) and 3,4-dichlorophenylpiperazine 1- [2- (6-bromoisochroman-1-yl) acetyl] -4- ( 3,4-dichlorophenyl) piperazine (V), IR (suspension) 1640, 1592, 1482, 1448, 1406, 1275, 1234, 1206, 1140, 1107 cm ^-1 ; NMR (300 MHz, CDCl ₃ ) 7.32-7.26 (m, 3H, aromatic H), 7.01 (d, 1H, J = 8.2 Hz, aromatic H), 6.96 (d, 1H) , J = 2.8 Hz, aromatic H), 6.74 (dzd, 1H, J _a = 2.8 Hz, J _b = 8.9 Hz, aromatic H), 5.24 (wd, 1H, J = 9.6 Hz, 4.11 (m, 1H), 3.9 (m, 1H), 3.79-3.60 (m's, 4H), 3.16 (m, 4H), 3.09-2 .89 (m, 2H), 2.77 (dzd, 1H, J _a = 3.6 Hz, J _b = 14.8 Hz), 2.65 (d, 1H, J = 10.3 Hz) δ; CMR (75MHz, CDCl ₃ ) 168.0, 150.1,

136.2, 132.8, 131.7, 130.5, 129.4, 126.4, 123.0, 120.8, 117.7, 115.7, 73.5, 63.5,

48.5, 47.9, 45.2, 41.5, 39.9, 28.7 δ;

• · · · · ·

Step 2: 1- (2- (6-bromoisochroman-1-yl) ethyl) -4- (3,4-dichlorophenyl) piperazine (VI)

Following the procedure of Example 1.4. step with minor variations, it results from 1- (2- (6-bromoisochroman-1-yl) acetyl] -4- (3,4-dichlorophenyl) -piperazine (V) 1- (2- (6-bromoisochroman-1-yl) -ethyl) -4- (3,4-dichlorophenyl) piperazine (VI) which was purified by flash chromatography on 100 g of silica gel using 40% -50% gradient of ethyl acetate in hexane, R _f = 0.25 (ethyl acetate / hexane, 25 IR (neat) 2825, 1593, 1483, 1467, 1455, 1449, 1380, 1239, 1142, 1111 cm ^-1 ; NMR (300 MHz, CDCl ₃ ) 7.32-7.24 (m, 2H, aromatic H), 6.98 (m, 2H, aromatic H), 6.73 (dzd, 1H, J _a = 2.9 Hz, J _b = 8.9 Hz, aromatic H), 4.78 ( m / z, 1H, J = 5.8 Hz), 4.12 (m, 1H), 3.73 (m, 1H), 3.16 (t, 4H, J = 5.0 Hz), 3.00- 2.90 (m, 1H), 2.7-2.48 (m, 7H), 2.12 (m, 1H) δ; CMR (75MHz, CDCl ₃ ) 150.2, 137.1, 136.0 , 132.2, 131.4, 130.1, 129.0, 126.2,

121.8, 120.0, 116.9, 114.9, 73.9, 62.6, 54.2, 52.8, 48.4, 32.9, 28.6 δ; HRMS calcd for C ₂₁ H ₂₃ N ₂ O ₁ Br ₁ Cl 2 = 468.0371, found 418.0363.

Step 3: 1- [2- [4- (3,4-dichlorophenyl) ethyl] -1-piperazinyl] ethyl] isochroman-6-carboxamide (VII)

Following the procedure of Example 40.3. Step with minor variations, it results from 1- (2- (6-bromoisochroman-1-yl) -ethyl] -4- (3,4-dichlorophenyl) -piperazine (VI) 1- (2- (4- (3,4-dichlorophenyl) thyl) ) -1-piperazinyl] ethyl] isochroman-6-carboxamide (VII), R _f = 0.13 (ethyl acetate); NMR (300 MHz, _CDCl3) 7.59 (m, 2H, aromatic H), 7, 24 (2m, 3H, aromatic H), 6.94 and 5.74 (two d, 1H, aromatic), 5.90 (broad d, 2H, PhC (O) NH _2), 4.87 (MH, 1H, J = 6.0 Hz, PhC-H), 4.15 (m, 1H, PhCH ₂ CH-H), 3.77 (m, 1H, PhCH ₂ CH-H), 3.18 (t, 4H, J = 4.8 Hz, four of pip-H), 3.00 (m, 1H, NCH-H), 2.76-2.45 (several m, 7H, four pip-H, two PhCH-H and NCH-H), 2.15 (m, 1H, PhCHCH-H), 2.03 (m, 1H, PhCHCH-H) δ; CMR (75MHz, CDCl ₃ ) 168.3, 152.0, 142.7 , 135.2, 133.0,

130.7, 129.0, 125.0, 117.5, 115.0, 74.8, 63.0, 54.5, 53.0, 48.6, 33.0, 28.8 δ; HRMS calculated for C ₂ H ₂₆ N ₃ FiO ₂ = 433.1324, found 433.1325.

Example 42 1- [2- [4- (4-Fluorophenyl) -1-piperazinyl] ethyl] isochroman-6-carboxamide (VII)

Step 1: 1- [2- (6-bromoisochroman-1-yl) acetyl] -4- (4-fluorophenyl) piperazine (V)

Following the procedure of Example 1,3. step with minor variations it is formed from racemic 6-bromoisochroman-1-yl acetic acid (IV, Example 7, step 1) and 4-fluorophenyl piperazine 1- [2- (6-bromoisochroman-1-yl) acetyl] -4- (4-fluorophenyl) piperazine (V), IR (neat) 1641, 1510, 1482, 1464, 1444, 1278, 1232, 1107, 827, 817 cm ^-1 ; NMR (300 MHz, CDCl ₃ ) 7.32-7.26 (m, 2H, aromatic H), 6.99 (m, 3H, aromatic H), 6.92-6.86 (m, 2H, aromatic H) 5.26 (mt, 1H, J = 9.6 Hz), 4.11 (m, 1H), 3.94 (m, 1H), 3.79-3.60 (m's, 4H), 3 2.88 (m, 4H), 2.99-2.89 (m, 2H), 2.77 (dzd, 1H, J _a = 3.6 Hz, J _b = 14.8 Hz), 2.65 ( d, 1H, J = 10.3 Hz), δ; CMR (75MHz, CDCl ₃ ) 168.0, 147.2,

136.2, 131.7, 129.2 126.2 120.2 118.3 115.6 115.3 73.2 63.3 50.6 50.1 45.2 41.5 39.7 28.5 δ; HRMS calcd for C ₂₁ H 22 N ₂ O ₂ FBr = 432.0843, found 432.0849.

Step 2: 1- [2- (6-bromoisochroman-1-yl) ethyl] -4- (4-fluorophenyl) piperazine (VI)

Following the procedure of Example 1, Step 4, with minor variations, 1- (2- (6-bromoisochroman-1-yl) acetyl) -4- (4-fluorophenyl) piperazine (V) 1- [2- (6-bromoisochroman) is formed. 1-yl) ethyl] -4- (4-fluorophenyl) piperazine (VI), which was purified by flash chromatography on 100 g silica gel using a 40% to 50% gradient of ethyl acetate in hexane, R _f = 0.26 (25% acetate) IR (neat) 2952, 2820, 1510, 1481, 1456, 1379, 1235, 1144, 1109, 817 cm ^-1 ; NMR (300 MHz, CDCl ₃ ), 7.59 (m, 2H, aromatic H), 7.17 (m, 1H, aromatic H), 6.87 (m, 4H, aromatic H), 6.21 (broad s, 2H, PhC (O) NH _2), 4.87 (MH 1 H, J = 6.0 Hz, PhC-H), 4.15 (m, 1H, PhCH ₂ CH-H), 3.77 (m, 1H, PhCH ₂ CH-H), 3.13 (t 4H, J = 4.8 Hz, four of pip-H), 3.00 (m, 1H, NCHH), 2.76-2.45 (several m, 7H, four pip-H, two PhCH-H and NCH-H), 2.15 (m, 1H, PhCHCH-H), 2.03 (m, 1H, PhCHCH-H)), δ; CMR (75MHz, CDCl ₃ ) 158.3, 156.2,

148.2, 137.3, 136.9, 131.7, 129.3, 126.5, 117.8, 117.8, 115.6, 115.4, 74.3, 62.8,

54.6, 53.4, 50.2, 33.2, 28.9 δ; HRMS calculated for C ₂₁ H ₂₄ N ₂ O ₁₀ Br ₁ F ₁ = 418.1056, found 418.1057.

Step 3 1- [2- [4- (4-Fluorophenyl) -1-piperazinyl] ethyl] isochroman-6-carboxamide (VII)

Following the procedure of Example 40, Step 3 with minor variations, 1- (2- (6-bromoisochroman-1-yl) ethyl) -4- (4-fluorophenyl) piperazine (VI) 1- [2- [4- (4- fluorophenyl) -1 piperazinyl] ethyl] isochroman-6-carboxamide (VII), R f = 0.09 (ethyl acetate); NMR (300 MHz, CDCl 3) 7.59 (m, 2H, aromatic H), 7.17 ( m, 1H, atomatic H), 6.87 (m, · · ····

4H, aromatic Η), 6.21 (broad s, 2H, PhC (O) NH ₂ ), 4.87 (wd, 1H, J = 6.0 Hz, PhCH-H), 4.15 (m, 1H , CH ₂ Ph-H), 3.77 (m, 1H, CH ₂ Ph-H), 3.13 (t, 4H, J = 4.8 Hz, four of pip-H), 3.00 (m 1 H, PhCHCH-H), 2.03 (m, 1H, PhCHCH-H) δ; CMR (75MHz, CDCl 3) 169.1, 158.3, 155.5, 147.5, 142.0, 134.4, 131.2, 128.0, 124.9,

124.8, 117.6, 115.4, 115.1, 74.3, 62.7, 54.4, 53.1, 499.9, 32.8, 28.8 δ; HRMS calcd for C ₂₂ H ₂₆ NN ₃ FiO ₂ = 383.2009, found 383.2010.

Example 43 1- [2- [4- (3-ethoxyphenyl) -1-piperazinyl] ethyl] isochroman-6-carboxamide (VII). Step: 1- [2- (6-bromoisochroman-1-yl) acetyl] -4- (3-ethoxyphenyl) piperazine (V)

Following the procedure of Example 1, 3. step with minor variations it is formed from racemic 6-bromoisochroman-1-yl acetic acid (IV, Example 7, step 1) and 3-ethoxyphenylpiperazine 1- [2- (6-bromoisochroman-1-yl) ethyl] -4- (3-ethoxyphenyl) ) piperazine (V) which was purified by flash chromatography on 200 g of silica gel using 25% ethyl acetate in hexane, R _f = 0.28 (50% ethyl acetate in hexanes); IR (neat) 501641, 1501, 1480, 1445, 1241, 1225, 1108, 1040, 1031, 748 cm ^-1 ; NMR (300 MHz, CDCl 3) 7.32-7.26 (m, 2H, aromatic H), 7.03-6.98 (m, 2H, aromatic H), 6.94-6.86 (m, 3H) aromatic H), 5.28 (mt, 1H, J = 7.4 Hz), 4.16-4.05 (m, 4H), 3.98-3.91 (m, 1H), 3.83 -3.65 (m, 4H), 3.08-2.91 (m, 6H), 2.80-2.64 (m, 2H), 1.46 (t, 3H, J = 6.9 Hz) , -CH ₃ ) δ; CMR (75MHz, CDCl ₃ ) 178.5, 152.0, 140.0, 157.0, 156.5,

131.7, 129.4, 126.5, 123.3, 121.0, 120.0, 118.4, 112.5, 73.4, 63.6, 63.5, 60.0, 51, 0,

50.5, 46.4, 42.2, 40.0, 28.8, 14.9 δ; HRMS calcd for C ₂₃ H ₂₇ N ₂ O ₃ Br ₁ = 458.1205, found 458.1215.

Step 2: 1- [2- (6-bromoisochroman-1-yl) ethyl] -4- (3-ethoxyphenyl) piperazine (VI)

Following the procedure of Example 1, Step 4 with minor variations, 1- [2- (6-bromoisochroman-1-yl) ethyl] -4- (3-ethoxyphenyl) piperazine (V) 1- [2- (6-bromoisochroman-1) was formed. yl) ethyl] -4- (3-ethoxyphenyl) piperazine (VI) which was purified by flash chromatography on 100 g of silica gel using 40% to 50% ethyl acetate in hexane, R _f = 0.30 (50% ethyl acetate in hexane); IR (neat) 2816, 1501, 1480, 1448, 1240, 1143, 1124, 1046, 1110, 748 cm ^-1 ; NMR (300 MHz, CDCl ₃ ) 7.31-7.26 (m, 2H, aromatic H), 7.00-6.90 (m, 4H, aromatic H), 6.85-6.83 (m, 1H, aromatic H), 4.78 (mt, J = 5.9 Hz, 1H), 2.69-2.52 (m, 7H), 2.13 (m, 1H), 1.99 (m, 1H), 1.45 (t, 3H, J = 7.0 Hz); CMR (75MHz, CDCl ₃ ) 151.37, 141.19, 137.0, 136.1, 131.5, 129.1, 126.4, 122.5,

120.8, 119.8, 117.9, 112.2, 74.2, 63.4, 62.6, 54.6, 53.5, 50.4, 33.0, 28.7, 14, 8 δ;

HRMS calcd for C ₂₃ H ₂₉ N ₂ O ₂ Br ₁ = 444.1413, found 444.1400.

Step 3: 1- [2- [4- (3-ethoxyphenyl) -1-piperazinyl] ethyl] isochroman-6-carboxamide (VII)

Following the procedure of Example 36 with minor variations, 1- (2- (6-bromoisochroman-1-yl) ethyl) -4- (3-ethoxyphenyl) piperazine (VI) is obtained which is converted to the hydrochloric acid salt using ethereal hydrochloric acid to give 1- [2- [4- (3-ethoxyphenyl) -1-piperazinyl] ethylisochroman-6-carboxamide (VII), m.p. = 208-210 ° C; R _f = 0.14 (10% methanol in ethyl acetate) IR (suspension) 2417, 2365, 1611, 1520, 1489, 1476, 1448, 1260, 1121, 152 cm ^-1 ; NMR (300 MHz, CDCl 3) 7.60 (m, 2H, aromatic H), 7.18 (d, 1H, J = 8.5 Hz, aromatic H), 6.94 (m, 3H, aromatic H), 6.84 (wd, 1H, J = 8.2 Hz, aromatic H), 6.00 (broad d, 2H, PhC (O) NH _2), 4.86 (MH, 1H, J = 6.0 Hz, Ph), 4.13 (m, 1H, CH ₂ Ph-H), 4 06 (q, 2H, 6.9 Hz, _Proc-H2), 3.77 (m, 1H, CH ₂ Ph-H), 3.13 (broad s, 4H, four of pip-H), 3 .00 (m, 1H, NCH-H), 2.76-2.45 (several m, 7H, four pip-H, two PhCH-H and NCH-H), 2.16 (m, 1H, PhCHCH- H), 2.02 (m, 1H, PhCHCH-H), 1.45 (t, 3H, J = 7.0 Hz, PhOCH ₂ CH ₃ ) δ; CMR (75MHz, CDCl ₃ ) 151.2, 142.0, 141.2, 134.1, 131.3,

147.6, 125.0, 124.9, 121.2, 117.9, 112.2, 74.1, 63.0, 62.8, 54.8, 53.3, 50.3, 32, 5,

31.5, 27.2, 22.2, 14.5 δ; HRMS calcd for C ₂₄ H ₃₁ N ₃ O ₃ = 409.2365, found 409.2364.

Example 44 (S) - (-) - 1- [2- [4- (4-methoxyphenyl) -1-piperidinyl] ethyl] -N-methyl isochroman-6-carboxamide (S) - (IX)

Step 1: (S) - (-) - 1- [2- (6-bromoisochroman-1-yl) acetyl] -4- (4-methoxyphenyl) piperidine (S) - (V)

Following the procedure of Example 1, Step 3, with minor variations, 4-methoxyphenylpiperidine (421 mg, 2.2 mmol) was obtained which was purified by LC on 53 g (230-400) silica gel eluting with 40% ethyl acetate / hexane). and formation of (S) - (-) - 1- [2- (6-bromoisochroman-1-yl) acetyl] -4- (4-methoxyphenyl) -piperidine (S) - (V), _Rf = 0.26 (50% ethyl acetate / hexane); [a] ^_D: -86 ° (c = 0.4975, methanol); IR (Liquids) 2933, 1638, 1612, 1513, 1481, 1463, 1446, 1283, 1268, 1247, 1179, 1106, 1036, · · · · · · · · · · · · · · · · «· · · ····································

1005, 830 cm ^-1 ; NMR (300 MHz, CDCl ₃ ) 7.28 (m, 2H, aromatic), 7.11 (dd, 2H, J = 8.6 Hz and J = 3.4 Hz, aromatic), 7.03 (m, 1H, aromatic), 6.85 (d, 2H, J = 8.6 Hz, aromatic), 5.29 (broad s, 1H, O-CH), 4.85 (m, 1H, Ph-CH), 4.10 (m, 2H, OCH _{2 a} and O = CN-CH _{2 a} , N-CO-CH _{2 s} , Ph-CH _{2 b} ), 1.90-1.50 (m, 4H, Ph-C (H) - CH _{2 s} ) δ; CMR (75MHz, CDCl ₃ ) 168.9, 168.8, 158.2, 137.5, 136.8, 136.3, 131.7, 129.4, 127.6,

33.0, 28.9 δ.

Step 2: (S) - (-) - 1- [2- (6-bromoisochroman-1-yl) ethyl] -4- (4-methoxyphenyl) piperidine (S) - (VI)

Following the procedure of Example 1, Step 4, with minor variations, (S) - (-) - 1- [2- (6-bromoisochroman-1-yl) acetyl] -4- (4-methoxyphenyl) -piperidine (S) - (V) crude product which was purified by LC on 47 g (230-400) silica gel eluting with 75% ethyl acetate / hexane to give (S) - (-) - 1- [2- (6-bromoisochroman- 1-yl) ethyl] -4- (4-methoxyphenyl) -piperidine (S) - (VI), R _f = 0.28 (75% ethyl acetate / hexane); [α] _D = -46 ° (c = 0.6677, methanol); IR (liquids) 2932, 2847, 2832, 2805, 1513, 1481, 1466, 1378, 1274, 1247, 1179, 1127, 1109, 1039, 828 cm ^-1 ; NMR (300 MHz, CDCl ₃ ) 7.29 (m, 2H, aromatic), 7.14 (d, 2H, J = 8.6 Hz, aromatic), 6.97 (d, 1H, J = 8.2 Hz, aromatic), 4.10 (m, 1H, OCH _{2 a} ), 3.78 (s, 3HJ, OCH ₃ ), 3.71 (m, 1H, OCH _2b ), 3.04 (m, 2H, NCH _2ab ), 2.95 (m, 1 H, Ph.CH _2a ), 2.70-2.40 (m, 4H, Ph-CH, NCH ₂ Cd, Ph-CH _2b ), 2.04 (m, 4H) , OC (H) -CH _{2 S,} NCH _2ef), 1.79 (m, 4H, Ph-C (H) _-CH2S) δ; CMR (75MHz, CDCl ₃ ) 158.2, 140.3, 137.5, 136.4, 136.2, 131.7, 129.5, 127.7, 126.6, 120.2, 113.9 ,

74.2, 63.1, 55.3, 54.8, 53.9, 41.14, 32.5, 32.0, 28.8) δ; HRMS (EI) calcd for C ₂₃ H ₂₈ BrNO ₂ = 429.1304, found 429.1286.

Step 3: (S) - (-) - 1- [2- [4- (4-methoxyphenyl) -1-piperidinyl] ethyl] -N-methylisochroman-6-carboxamide (S) - (IX)

Following the procedure of Example 5, Step 3, with minor variations, (S) - (-) - 1- [2- (6-bromoisochroman-1-yl) ethyl] -4- (4-methoxyphenyl) -piperidine (S) - (VI, 445 mg, 1.03 mmol) which was purified by LC on 24 g (230-400) silica gel eluting with 75% acetone / hexane to give (S) - (-) - 1- [2]. - [4- (4-methoxyphenyl) -1-piperidinyl] ethyl] -N-methylisochroman-6-carboxamide (S) - (IX), R _f = 0.36 (75% acetone / hexane); IR (liquids) 3291, 2934, 1636, 1612, 1571, 1551, 1514, 1496, 1497,

Q- · ·· ······ ····

O / · · ♦ ♦ * * * · · · · · · · · · · * * *

1315, 1293, 1247, 1179, 1109, 1036 cm ^-1 ; NMR (300 MHz, CDCl ₃ ) 7.54 (m, 2H aromatic), 7.116 (m, 3H, aromatic), 6.84 (d, 2H, J = 8.7 Hz, aromatic), 6.20 (broad) m, 1H, NH), 4.85 (m, 1H, O-CH), 4.13 (m, 1H, OCH _{2 a} ), 3.78 (m, 4H, OCH ₃ and OCH _2b ), 3.00 (m, 6H, Ph-CH _{2 a} , NCH ₃ , Ph-CH _2b , Ph-CH), 2.77-2.40 (m, 4H, N-CH _{2 s} ), 2.10-1.94 (m 4H, N-CH _{2 s} and OC (H) -CH _{2 s} ), 1.80 (m, 4H, Ph-C (H) -CH _{2 s} ) δ; HRMS (EI) calculated for C ₂₅ H ₃₂ N ₂ O ₃ = 408.2413, found 408.2414.

Example 45 (S) - (-) - 1- [2- [4- (4-Trifluoromethylphenyl) -1-piperazinyl] ethyl] -N, N-dimethylisochroman-6-carboxamide (S) - (IX)

Following the procedure of Example 6, Step 4, with minor variations, (S) - (-) - 1- [2- (6-bromoisochroman-1-yl) ethyl] -4- (4-methoxyphenyl) -piperidine (S) - (VI, Example 5, Step 2, 21.17 g, 45.1 mmol) The product was purified by LC on 780 g (230-400) silica gel eluting with 3% to 5% methanol / dichloromethane to afford ( S) - (-) - 1- [2- [4- (4-Trifluoromethylphenyl) -1-piperidinyl] ethyl] -N, N-dimethylisochroman-6-carboxamide (S) - (IX), m.p. = 149-151 °; R _f = 0.34 (5% methanol / dichloromethane); [α] _D = -46 ° (c = 0.988, methanol); IR (suspension) 1627, 1617, 1527, 1414, 1337, 1315, 1294, 1241, 1160, 1152, 1143, 1135, 1107, 1072, 824 cm ^-1 ; NMR (300 MHz, CDCl ₃ ) 7.46 (d, 2H, J = 8.7 aromatic), 7.20 (m, 2H, aromatic), 7.11 (d, 1H, J = 7.9 Hz, aromatic), 6.90 (d, 2H, J = 8.7 Hz, aromatic), 4.85 (broad d, 1H, J = 5.9 Hz, methine), 4.12 (m, 1H, OCH _2a) ), 3.75 (m, 1H, OCH _{2 b),} 3.28 (t, 4H, J = 5.0 Hz, Ph NCH _2s), 3.09 (broad s, 3H, _NCH3); 2.99 (broad s, 4H, NCH ₃ and Ph-CH _2a ), 2.74-2.48 (m, 7H, Ph-NC (H ₂ ), - NCH _{2 s} , Ph-CH _2b ), 2, 12 (m, 1H, C (H) -CH _2a), 2.04 (m, 1H, C (H) -CH _2b) δ; CMR (75MHz, CDCl ₃ ) 171.4, 153.3, 139.5, 134.5, 134.3, 127.7, 126.6, 126.3, (d, J _CF = 4Hz), 126, 2, 124.8, 124.6, 120, .4, (qrt, J _CF = 33 Hz), 114.4, 74.4, 63.0, 54.6, 53.1, 48.0, 39 , 6, 35.4, 33.2, 29.0 δ; MS (EI, m (z) = 461);

Example 46 1- (4-Methoxy-phenyl) -4- [2- [6- (5-methyl-oxazol-2-yl) -isochroman-1-yl) -ethyl] -piperazine (P-2)

Oven-dried 125 ml flask equipped with a stir bar and a condenser was charged with 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl-N-propargylisochroman-6-carboxamide (IX, Example 28, 433 mg, 1.0 mmol) and mercuric acetate and heated to boiling. After 3 hours, the reaction is cooled to 20-25 ° C, the volatiles are removed under reduced pressure and the residue is diluted with 35 ml of sodium hydroxide and extracted twice with 25 ° C. And ethyl acetate (30 ml). The combined organic extracts were washed twice with brine (20 mL), dried over magnesium sulfate, filtered, and concentrated. This material, along with the crude from an identical 0.25 mmol reaction, was purified by LC on 41 g (230400) silica gel eluting with 25% acetone / hexane to give 1- (4-methoxyphenyl) -4- [2 [6- ( 5-methyloxazol-1-yl) isochroman-1-yl) ethyl] piperazine (P-2), which is recrystallized from ethyl acetate / hexane, m.p. = 129-130 ° C; R _f = 0.40 (50% acetone / hexane).

Example 47 1- [2- (6-Amino-isochroman-1-yl) -ethyl] -4- (4-methoxy-phenyl) -piperazine (Z-1) ml oven-dried two-necked flask was charged with 1- [2- (6-Amino-isochroman-1-yl) -ethyl] -4- (4-methoxy-phenyl) -piperazine (VI, 406 mg, 0.94 mmol) in THF (2 mL). The mixture was cooled to -78 ° C and t-butyl lithium (1.7 M in pentane, 1.081 mL, 1.83 mmol) was added dropwise. After stirring at -78 ° C for 15 min, aryllithium was added dropwise via a tube to a solution of diphenylphosphoryl azide (98%, 0.188 mL, 0.85 mmol) in THF (9 mL) at -78 ° C. The reaction mixture is left at -78 ° C for two hours, then warmed to -20 ° C over 40 minutes and then cooled back to -78 ° C. Sodium bis (2-methoxyethoxy) aluminum hydride (3,4) is slowly added with stirring via syringe. M in toluene, 1.11, mL, 3.77 mmol). The reaction was warmed to 0 ° C with nitrogen evolution. The reaction was stirred at 0 ° C for two hours and then at 20-25 ° C for 30 minutes. After cooling to 0 ° C, the reaction is stopped very slowly with water. After the evolution of nitrogen ceased, the crude product was heated to 20-25 ° C, filtered on a glass frit, optionally washed with water and ethyl acetate until the product was evident in the filtrate by TLC. The filtrates were transferred to a separatory funnel, salted out with sodium chloride, shaken and the layers were separated. The organic layer was washed once with 1% aqueous sodium hydroxide and once with brine, dried over sodium sulfate, filtered, and concentrated. After two flame chromatography on 20 g of silica gel eluting with 5% methanol in methylene chloride, 1- (2- (6 aminoisochroman-1-yl) ethyl) -4- (4-methoxyphenyl) piperazine (Z-1) is obtained. _Rf = 0.18 (5% methanol in methylene chloride); IR (neat) 2951, 2828, 1625, 1244, 1104, 1037, 824 cm ^-1; NMR (300 MHz, _CDCl3) 6.85 ( , m, 5H, aromatic H), 6.53 (dzd, 1H, J _a = 2.4 Hz, J _b = 8.2 Hz, aromatic H), 6.43 (d, 1H, J = 2.2 Hz, aromatic H), 4.75 (mt, 1H, J = 5.8 Hz, PhC-H), 4.09 (m, 1H, PhCH ₂ CH-H), 3.76 (s, 3H, OC) -H ₃ ), 3.71 (m, ··· · · · ··· · · · · · · · · · · · ·

1H, PhCH ₂ CH-H), 3.57 (broad s, 2H, NH ₂ and four pip-H), 2.10 (m, 1H, PhCHCH-H), 2.00 (m, 1H, PhCHCH- H) δ; CMR (75MHz, CDCl ₃ ) 153.8, 145.7, 144.6, 134.9, 129.6,

128.2, 125.7, 120.2, 118.2, 115.5, 114.9, 113.6, 74.6, 63.2, 55.6, 54.9, 53.5, 50, 6, 33.3, 29.2 δ; HRMS calcd for C ₂₂ H ₂₉ N ₃ O ₂ = 367.2260, found = 367.2255.

Example 48 (S) - (-) - 1- [2- (6-Amino-isochroman-1-yl) -ethyl] -4- (4-methoxy-phenyl) -piperazine (S) - (Z-1)

Following the procedure of Example 47 with minor variations, (S) - (-) - 1- [2- (6-bromoisochroman-1-yl) ethyl] -4- (4-methoxyphenyl) -piperazine (S) - (VI) (S) is formed. ) - (-) - 1 - [2- (6 aminoizochroman-1-yl) -ethyl] -4- (4-methoxyphenyl) piperazine (S) - (Z-1), R _f = 0.18 (5% methanol methylene chloride); [α] _D = -53 ° (c = 1.04, ethanol); IR (neat) 2951, 28282819, 1625, 1511, 1262, 1244, 1104, 1037, 824 cm ^-1 ; NMR (300 MHz, CDCl ₃ ) 6.85 (m, 5H, aromatic H, 6.53 (dzd, 1H, J _a = 2.4 Hz, J _b = 8.2 Hz, aromatic H), 6.43 (d, 1H, J = 2.2 Hz, aromatic H), 4.75 (MH, 1H, J = 5.8 Hz, PhC-H), 3.57 (bs, 2H, NH _2), 3 11 (t, 4H, J = 4.9 Hz, four pip-H), 2.89 (m, 1H, PhCH-H), 2.60 (m's, 7H, PhCH-H, NC-H ₂ and four pip-H), 2.10 (m, 1H, PhCHCH-H), 2.00 (m, 1H, PhCHCH-H) δ; CMR (75MHz, CDCl ₃ ) 153.8, 145.7, 144, 6, 134.9, 129.6, 128.2,

125.7, 120.2, 118.2, 115.5, 114.9, 11.4, 113.6, 74.6, 63.12, 55.6, 54.9, 53.5, 50, 6, 33.3, 29.2 δ; HRMS calcd for C ₂₂ H ₂₉ N ₃ O ₂ = 367.2260, found = 367.2258.

Example 49 (S) - (-) - N- [Isochroman-1- [2- [4- (4-methoxyphenyl) piperazin-1-yl] ethyl] -6-yl] formamide (S) - (Z-2)

Acetic anhydride (0.32 mL, 3.43 mmol) was cooled to 0 ° C. Addition of 98% formic acid (0.20 mL, 5.2 mmol) dropwise to acetic anhydride gave acetic formic anhydride. The mixture was heated to 55 ° C for 2 hours and then cooled to 0 ° C. THF (1 mL) was added via syringe followed by a solution of (S) - (-) - 1- [2- (6-aminoisochroman-1-yl) ethyl] -4- (methoxyphenyl) piperazine (S) - (Z). -1,

600 mg, 1.63 mmol) in THF (2 mL). The reaction was warmed to 20-25 ° C and stirred for 3 hours. It is then concentrated and purified by flash chromatography to give (S) - (-) - N -isochroman-1- [2- [4- (4-methoxyphenyl) piperazin-1-yl] ethyl] -6-yl] formamide ( S) - (Z-2), R f = 0.20 (5% methanol in methylene chloride); IR (suspension) 1692, 1616, 1539, 1512, 1306, 1292, 1266, 1245, 1107, 825 cm ^-1 ; NMR (300 MHz, CDCl ₃ ) 8.65 (d, 1/2 H (rotometer), J = 11.4 Hz, NC (O) -H), 8.36 (d, 1/2 H (rotometer)) , J = 11.4 Hz, N · ♦ ♦ · · · · · «« «« «« «« «« «« «« «

Η), 7.43 (broad s, 1/2 H (rotometer), NH), 7.24 (m, 1H, aromatic H), 7.07 (dzd, 1H, J _a = 8.4 Hz, J _b = 10.9 Hz, orthomatic H), 6.84 (q, am, 5H, J = 9.2 Hz, aromatic H), 4.80 (wd, 1H, J = 5.8 Hz, PhC-H) ), 4.10 (m, 1H, PhCH ₂ CH-H), 3.76 (s, 3H, OC-H ₃ ), 3.71 (m, 1H, PhCH ₂ CH-H), 3.11 ( t, 4H, J = 4.9 Hz, four pip-H), 2.95 (m, 1H, PhCH-H), 2.60 (m's, 7H, PhCH-H, NC-H ₂ and four pip- H), 2.18 (m, 1H, PhCHCH-H), 2.06 (m, 1H, PhCHCH-H) δ; HRMS calcd for C ₂₃ H ₂₉ N ₃ O ₃ = 395.22.9, found = 395.2210.

Example 50 (S) - (-) - N- [Isochroman-1- [2- [4- (4-methoxy-phenyl) -piperazin-1-yl] -ethyl] -6-yl] -acetamide (S) - (Z-2) A 1 ml round-bottom flask was charged with (S) - (-) - 1- [2- (6-aminoisochroman-1-yl) ethyl] -4- (4-methoxyphenyl) piperazine (S) - (Z-1, 200 mg, 0.54 mmol) and 4-dimethylaminopyridine (6.7 mg, 0.054 mmol). Methylene chloride (7 mL) was added via syringe and the reaction vessel was cooled to 0 ° C. Triethylamine (0.114 mL, 0.82 mmol) and acetyl chloride (0.042 mL, 0.60 mmol) were then added via syringe. The ice bath was removed after 15 minutes and the reaction was stirred at 20-25 ° C for 1.5 hours. The reaction was partitioned into 0.5 µl aqueous sodium hydroxide and methylene chloride. The layers were separated and the aqueous layer was extracted once more with methylene chloride. The organics were combined, dried over sodium sulfate, filtered, and concentrated. The concentrate is 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 in methylene chloride); [α] _D = -44 ° (c = 0.93 methanol in methylene chloride); IR (suspension) 1667, 1615, 1599, 1546, 1512, 1421, 1333, 1312, 1247, 1036 cm ^-1 ; NMR (300 MHz, CDCl ₃ ) 7.35, 7.21, 7.15, 7.04, 6.80, 4.80, 4.1.0, 3.76, 3.71, 3.11, 2.95, 2.60, 2.16, 2.10, 2.02 δ; CMR (75MHz, CDCl ₃ ) 168.3, 153.8, 145.7, 136.0, 134.9, 125.3, 120.1,

118.2, 118.0, 114.5, 74.5, 63.1, 55.6, 54.8, 53.5, 50.6, 33.2, 29.2, 24.6 δ; HRMS calcd 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] -6-yl] benzamide (S) - (Z-2)

Following the procedure of Example 50 with minor variations, (S) - (-) - N-isochroman-1- [2- [4- (4-methoxyphenyl) piperazin-1-yl] ethyl] -6-yl] benzamide is obtained from benzoyl chloride. (S) · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ♦ • · · · · · · ·· ·· (Z-2), R _f = 0.30 (5% methanol in methylene chloride); [α] _D = -40 ° (c = 1.0, 50% ethanol in methylene chloride); IR (suspension) 3282, 1651, 1516, 1505, 1339, 1312, 1280, 1244, 1108, 694 cm ^-1 ; NMR (300 MHz, CDCl ₃ ) 7.86 (d, 2H, J = 6.8 Hz, aromatic H), 7.80 (broad s, 1H, PhN-H), 7.50 (m, 4H, aromatic) H), 7.36 (d, 1H, J = 8.3 Hz, aromatic H), 7.10 (d, 1H, J = 8.3 Hz, aromatic H), 6.86 q, 4H, J = 9.2 Hz, aromatic H), 4.84 (mt, 1H, J = 5.8 Hz, PhC-H), 4.13 (m, 1H, PhCH ₂ CH-H), 2.02 (m 1 H, PhCH-H), 3.76 (s, 3H, OC-H ₃ ), 3.76 (m, 1H, PhCH ₂ CH-H), 3.12 (t, 4H, J = 4.6 Hz, four pip-H), 2.99 (m, 1H, PhCH-H), 2.68 (m's, 7H, PhCH-H, NC-H ₂ and four pip-H), 2.10 (m, 1H, PhCHCH-H), 2.02 (m, 1H, PhCHCH-H) δ; HRMS calcd 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] -6-yl] propionamide (S) - (Z-2)

Following the procedure of Example 50 with minor variations, (S) - (-) - N-isochroman-1- [2- [4- (4-methoxyphenyl) piperazin-1-yl] ethyl] -6-yl] propionamide is formed from propionyl chloride (S) - (Z-2), R f = 0.22 (5% methanol in methylene chloride); [α] _D = -44 ° (c = 0.97, 50% ethanol in methylene chloride); IR (suspension) 3306, 1659, 1590, 1515, 1421, 1245, 1214, 1110, 1036, 821 cm ^-1 ; NMR (300 MHz, CDCl ₃ ) 7.76 (s, 1H, aromatic H), 7.36 (broad s, 1H, PhN-H), 7.24 (d, 1H, J = 8.3 Hz, aromatic) H), 7.00 (d, 1H, J = 8.3 Hz, aromatic H), 6.80 (q, 4H, J = 9.2 Hz, aromatic H), 4.77 (wd, 1H, PhCH) ₂ CH-H), 3.07 (t, 4H, J = 4.9 Hz, four pip-H), 3.76 (s, 3H, OC-H ₃ ), 3.71 (m, 1H, PhCH) -H, NC-H ₂ and four pip-H), 2.33 (q, 2H, J = 7.5 Hz, PhNHC (O) CH ₂ CH ₃ ) δ; CMR (75MHz, CDCl ₃ ) 172.5, 153.7, 145.8, 136.3, 134.7, 133.8, 125.2, 120.2, 118.1,

114.5, 74.4, 63.0, 55.6, 54.8, 53.5, 50.6, 33.3, 30.6, 29.2 and 9.8 δ.

Example 53 (S) - (-) - N- [Isochroman-1- [2- [4- (4-methoxyphenyl) piperazin-1-yl] ethyl] -6-yl] acrylamide (S) - (Z-2)

Following the procedure of Example 50 with minor variations, (S) (-) - N-isochroman-1- [2- [4- (4-methoxyphenyl) piperazin-1-yl] ethyl] -6-yl] acrylamide is obtained from acrylic chloride ( S) - (Z 2), R f = 0.22 (5% methanol in methylene chloride); [α] _D = -40 ° (c = 0.79, 50% ethanol in methylene chloride); IR (slurry) 3266, 1661, 1592, 1536, 1512, 1422, 1244, 1218, 1109, 822 cm ^-1 ; NMR (300 MHz, CDCl ₃ ) 7.46 (broad s, 1H, PhN-H), 7.26 (s, 1H), 4 (s, 1H); Aromatic, 7.06 (d, 1H, J = 8.4 Hz, aromatic H), 6.06 (d, 1H, J = 8.4 Hz, aromatic H), 6.06 , 85 (q, 4H, J = 9.2 Hz, aromatic H), 6.43 (dzd, 1H, J _a = 1.3 Hz, J _b = 16.8 Hz, one acrylic-H), 6, 23 (m, 1H, one acrylic-H), 5.76 (dzd, 1H, J _a = 1.3 Hz, J _b = 10 Hz, one acrylic-H), 4.81 (wd, 1H, J = 5.8 Hz, PhC-H), 4.11 (m, 1H, PhCH ₂ CH-H), 3.76 (s, 3H, OC-H ₃ ), 3.75 (m, 1H, PhCH ₂ CH) -H), 3.11 (t, 4H, J = 4.9 H, 2.14 (m, 1H, PhCHCH-H), 2.03 (m, 1H, PhCHCH-H)) δ; CMR (75MHz, CDCl ₃ ) 163.5, 153.8, 145.8, 135.9, 134.9, 134.4,

131.1, 127.9, 125.4, 120.2, 118.2, 118.0, 114.4, 74.5, 63.0, 55.6, 54.8, 53.5, 50.6,

33.2, 29.2 δ; HRMS calculated for C ₅ H 2 * ₃ IN ₃ O ₃ = 421.2365, found = 421.2358.

Example 54 (S) - (-) - N- [Isochroman-1- [2- [4- (4-methoxyphenyl) piperazin-1-yl] ethyl] -6-yl] isobutyramide (S) - (Z-2)

Following the procedure of Example 50 with minor variations, (S) - (-) - N-isochroman-1- [2- [4- (4-methoxyphenyl) piperazin-1-yl] ethyl] -6-yl i-butyryl chloride is formed. ] isobutyramide (S) - (Z-2), R _f = 0.27 (5% methanol in methylene chloride); [α] _D = -42 ° (c = 0.94, 50% ethanol in methylene chloride); IR (suspension) 3289, 1660, 1589, 1524, 1515, 1451, 1422, 1243, 1109, 822 cm ^-1 ; NMR (300 MHz, CDCl ₃ ) 7.43 (s, 1H, aromatic H), 7.23 (d, 1H, J = 8.4 Hz, aromatic H), 7.13 (broad s, 1H, PhN- H), 7.04 (d, 1H, J = 8.3 Hz, aromatic H), 6.84 (q, 4H, J = 9.2 Hz, aromatic H), 4.80 (wd, 1H, J = 5.8 Hz, PhC-H), 4.10 (m, 1H, PhCH ₂ CH-H), 3.76 (s, 3H, OC-H ₃ ), 3.71 (m, 1H, PhCH ₂ CH) -H), 3.10 (t, 4H, J = 4.9 Hz, four pip-H), 2.96 (m, 1H, PhCH-H), 2.60 (m's, 8H, PhCH-H, NC-H ₂ , PhNHC (O) CH) and four pip-H), 2.14 (m, 1H, PhCHCH-H), 2.00 (m, 1H, PhCHCH-H), 1.24 (d, 6H, J = 6.9 Hz, two of PhNHC (O) CHMeC-H ₃ ) δ; CMR (75MHz, CDCl ₃ ) 175.2, 153.8, 145.8, 136.2, 134.9, 125.3, 120.0, 118.2, 117.8, 114.4, 74.5 ,

63.1, 60.8, 55.6, 54.8, 53.5, 50.6, 36.7, 33.2, 29.3, 19.6 2 δ; HRMS calcd for C ₂₆ H 35 N ₃ O ₃ = 437.2678, found = 437.2680.

Example 55 (S) - (-) - 1- [2- (6-ethylaminoisochroman-1-yl) ethyl] -4- (4-methoxyphenyl) piperazine (S) - (Z-4)

Following the procedure of Example 5, Step 2, with minor variations, (S) - (-) - Nizochroman-1- [2- [4- (4-methoxyphenyl) piperazin-1-yl] ethyl] -6-yl] acetamide is obtained. (S) - (Z-2, Example 50) (S) - (-) - 1- [2- (6-ethylaminoisochroman-1-yl) ethyl] -4- (4-methoxyphenyl) piperazine (S) - (Z) -4), R _f = 0.32 (5% methanol in methylene chloride); [α] _D = -46 ° (c = 0.54, 50% ethanol in methylene chloride); IR (pure substances) 2953, 2825, 2819, · · · · · · · · · · · · · · · · · · · · · 1616, 1512, 1268, 1244, 1147, 11104, 824 cm ^-1 ; NMR (300 MHz, CDCl ₃ ) 6.86 (m, 5H, aromatic H), 6.47 (dzd, 1H, J _a = 2.4 Hz, J _b = 8.2 Hz, aromatic H), 6, 34 (d, 1H, J = 2.2Hz, aromatic H), 4.76 (mzd, 1H, J = 8.2Hz, PhC-H), 4.09 (m, 1H, PhCH ₂ CH-H) 3.73 (s, 3H, OC-H ₃ ), 3.71 (m, 1H, PhCH ₂ CH-H), 3.76 (s, 3H, OC-H ₃ ), 3.71 (m 1 H, PhCH ₂ CH-H), 3.13 (taq overlapping, 6H, four pip-H and PhNC-H ₂ ), 2.91 (m, 1H, PhCH-H), 2.62 (m's, 7H, PhCH-H, VN-H ₂ and four pip-H), 2.10 (m, 1H, PhCHCH-H), 2.00 (m, 1H, PhCHCH-H), 1.25 (t, 3H) , J = 7.1 Hz, PhNHCH ₂ CH ₃ ) δ; CMR (75MHz, CDCl ₃ ) 153.8, 146.8, 145.8, 134.8, 126.8, 125.6, 118.2, 114.4, 112.2, 111.6, 74.6 , 63.4, 55.6, 54.9, 53.5, 50.5, 38.6, 33.3, 29.5, 15.0 δ; HRMS calculated for C ₂₄ H ₃₃ N ₃ O ₂ = 395.2573, found = 395.2573.

Example 56 (S) - (-) - 1- [2- (4-Methoxyphenyl) -4- [2- (6-propylaminoisochroman-1-yl) ethyl] piperazine (S) - (Z-4)

Following the procedure of Example 5, Step 2, with minor variations, (S) - (-) - Nizochroman-1- [2- [4- (4-methoxyphenyl) piperazin-1-yl] ethyl] -6-yl] propionamide is formed. (S) - (Z-2, Example 45) (S) - (-) - 1- [2- (4-Methoxyphenyl) -4- [2- (6-propylaminoisochroman-1-yl) ethyl] piperazine (S) - (Z-4), R _f = 0.52 (50% acetone in hexanes); [α] _D = -41 ° (c = 0.69, 50% ethanol in methylene chloride); IR (neat) 2812, 2804, 1614, 1514, 1271, 1254, 1247, 1105, 1034, 830 cm ^-1 ; NMR (300 MHz, CDCl ₃ ) 6.86 (m, 5H, aromatic H), 6.47 (dzd, 1H, J _a = 2.4 Hz, J _b = 8.2 Hz, aromatic H), 6, 34 (d, 1H, J = 2.2Hz, aromatic H), 4.76 (mzd, 1H, J = 5.8Hz, PhC-H), 4.09 (m, 1H, PhCH ₂ CH-H) ), 3.76 (s, 3H, OC-H ₃ ), 3.71 (m, 1H, PhCH ₂ CH-H), 3.54 (broad s, 1H, PhN-H), 3.09 (taq) overlapping, 6H, four pip-H and PhNC-H ₂ ), 2.91 (m, 1H, PhCH-H), 2.62 (m's, 7H, PhCHH, NC-H _2, and four pip-H), 2.10 (m, 1H, PhCHCH-H), 2.00, 1.63, 1.25 δ; HRMS calcd for C ₂₅ H ₃₅ N ₃ O ₂ = 409.2729, found = 409.2722.

Example 57 (S) - (-) - 1- (4-Methoxyphenyl) -4- [2- (6-methylaminoisochroman-1-yl) ethyl] piperazine (S) - (Z-4)

Acetic anhydride (0.32 mL, 3.43 mmol) was cooled to 0 ° C. Addition of 98% formic acid (0.20 mL, 5.2 mmol) dropwise to acetic anhydride gave acetyl formic anhydride. The mixture was heated to 55 ° C for 2 hours and then cooled to -15 ° C in an ethylene glycol / carbon monoxide bath. THF (1 mL) was added via syringe followed by a solution of (S) - (-) - 1- [2- (6-aminoisochroman-1-yl)].

Ethyl] -4- (methoxyphenyl) piperazine (S) - (ZI, Example 48, 1.99 g, 5.41 mmol) in THF (10 mL). The reaction was stirred at -15 ° C for 3 hours. It is then heated to 20-25 ° C and the volatiles are removed under reduced pressure to leave a yellowish oil. A solution of the crude product in THF (30 mL) was placed in a 250 mL round-bottom flask. The mixture was cooled to 0 ° C and boron-methyl sulfide complex (10M, 1.73 mL, 17.3 mmol) was added slowly via syringe. The ice bath was removed as soon as the reaction had calmed down. The mixture was then heated to gentle boiling for 3 hours and then left at 2025 ° C for three days. The reaction was cooled to 0 ° C and methanol (30 mL) was added dropwise (foaming), then stirred at 20-25 ° C for 1 hour and brought to reflux for 2 hours. After cooling to 20-25 ° C, the volatiles were removed under reduced pressure and the aqueous residue was adjusted to pH with aqueous sodium hydroxide solution and extracted with 80 mL of ethyl acetate (three times). The combined organic products were dried over sodium sulfate, filtered and concentrated to give the crude product. The crude material was purified by flash chromatography using 25% acetone in hexane as eluent to give (S) (-) - 1- [2- (4-methoxyphenyl) -4- [2- (6-methylaminoisochroman-1-yl)] -ethyl] piperazine (S) (Z-4), IR (neat) 2933, 2831, 2817, 1616, 1513, 1275, 1246, 1107, 1038, 826 cm ^-1 ; NMR (300 MHz, CDCl ₃ ) 6.86 (m, 5H, atromatic H), 6.47 (dzd, 1H, J _a = 2.4

Hz, J _b = 8.2 Hz, aromatic H), 6.35 (d, 1H, J = 2.2 Hz, aromatic H), 4.76 (wt,

1H, J = 5.8Hz, PhC-H), 4.09 (m, 1H, PhCH ₂ CH-H), 3.76 (s, 3H, OC-H ₃ ), 3.71 (m, 1H (PhCH ₂ CH-H), 3.58 (broad s, 1H, NH), 3.11 (t, 4H, four pip-H), 2.92 (m, 1H, PhCHH), 2.82 (s 3H, NHC-H ₃ ), 2.62 (m's, 7H, PhCH-H, NC-H ₂ and four pip-H), 2.10 (m, 1H, PhCH-H), 2.00 (m , 1H, PhCHCH-H δ; CMR (75MHz, CDCl ₃ ) 153.8, 147.7, 145.8,

131.8, 126.9, 125.5, 118.2, 114.4, 111.3, 74.64, 63.3, 55.6, 54.9, 53.5, 53.4, 50, 6,

33.4, 30.9, 29.5 δ; HRMS calculated for C ₂₃ H ₃ IN ₃ O _2: 381.2416, found = 381.2415.

Example 58 (S) - (-) - 1- (4-Methoxyphenyl) -4- [2- (6-dimethylisochroman-1-yl) ethyl] piperazine (S) - (Z-7)

(S) - (-) - 1- (4-methoxyphenyl) 4- [2- (6-dimethylisochroman-1-yl) ethyl] piperazine (S) - (Z-7) is also isolated from the preparation described in Example 57. _Rf = 0.22 (acetone / hexane 25/75); NMR (300 MHz, CDCl ₃ ) 6.99-6.81 (m's, 5H, aromatic H), 6.62 (dzd, 1H J _a = 2.4 Hz, J _b = 8.2 Hz, aromatic H) 6.46 (d, 1H, J = 2.2 Hz, aromatic H), 4.78 (mzd, 1H, J = 5.8 Hz, PhC-H), 4.10 (m, 1H, PhCH ₂₎ CH-H), 3.76 (s, 3H, OC-H ₃ ), 3.71 (m, 1H, PhCH ₂ CH-H), 3.11 (q, 4H, four pip-H), 2.95 (m, 1H, PhCH-H), 2.92 (s, 6H, two of NC-H ₃ ), 2.62 (m's, 7H, PhCH-H, NC-H ₂ and four pip-H) 1.10 (m, 1H, PhCHCH-H), 2.00 (m, 1H, PhCHCH-H) δ; CMR (75MHz, CDCl ₃ ) 153.8, 149.2, 145.8, 134.6, 126.3, 125.4, 118.1, 114.4, 112.5, 112.4, 111.4 , 74.6, 63.4, 55.6, 55.0, 53.5, 50.6,

46.8, 40.7, 33.4, 29.7 δ.

Example 59 (S) - (-) - 1- [2- (6-ethylmethylaminoisochroman-1-yl) ethyl] -4- (4-methoxyphenyl) piperazine (S) - (Z-7)

(S) - (-) - 1- [2- (6-ethylmethylaminoisochroman-1-yl) ethyl] -4- (4-methoxyphenyl) piperazine (S) - (Z-7) is also isolated from the preparation described in Example 57. _Rf = 0.22 (acetone / hexane 25/75); [α] D = -54 ° (c = 0.83, 50/50 ethanol / methylene chloride); IR (slurry) 2815, 1611, 1515, 1256, 1245, 1236, 1107, 1095, 1037, and 824 cm ^-1 ; NMR (300 MHz, CDCl ₃ ) 6.97-6.81, 6.59, 6.42, 4.77, 4.10, 3.76, 3.71, 3.37, 3.11, 2, 95, 2.88, 2.62, 2.10, 2.00 and 1.11 δ; CMR (75MHz, CDCl ₃ ) 153.8, 147.6, 145.8, 134.6,

125.7, 125.5, 118.1, 114.4, 112.1, 111.0, 74.7, 63.5, 55.6, 55.0, 53.5, 50.6, 46.8,

37.5, 33.5, 29.7 and 11.3 δ.

Example 60 (S) - (-) - N- [Isochroman-1- [2- [4- (4-methoxyphenyl) piperazin-1-yl] ethyl] -6-yl] -N-methylacetamide (S) - (Z) -5)

Following the procedure of Example 50 with slight variation, (S) - (-) - 1- [2- (4-methoxyphenyl) -4- [2- (6-propylaminoisochroman-1-yl) ethyl] piperazine (S) - (Z) is formed. -4), the title compound, _Rf = 0.26 (methanol / methylene chloride 5/95); [α] _D = -38 ° (c = 0.69, 50/50 ethanol / methylene chloride); IR (slurry) 1669, 1661, 1513, 1448, 1445, 1275, 1248, 1109, 1036, and 826 cm ^-1 ; NMR (300 MHz, CDCl ₃ ) 7.13, 6.98, 6.86, 4.83, 4.13, 3.76, 3.76, 3.23, 3.10, 2.97, 2, 61, 2.14, 2.02 and 1.87 δ; CMR (75MHz, CDCl ₃ ) 170.6,

153.8, 145.7, 142.7, 137.8, 135.7, 127.2, 126.1, 124.8, 118.2, 114.4, 74.5, 62.8,

61.2, 55.6, 54.8, 53.5, 50.7, 32.7, 33.3, 29.0 and 22.5 δ.

Example 61 (S) - (-) - N- [Isochroman-1- [2- [4- (4-methoxy-phenyl) -piperazin-1-yl] -ethyl] -6-yl] -N-methyl-isobutyramide (S) - (Z-5)

Following the procedure of Example 54 with minor variations, (S) - (-) - 1- (4-methoxyphenyl) -4- [2- (6-methylaminoisochroman-1-yl) ethyl] piperazine (S) - (Z-4) is formed. (S) - () - N- [Isochroman-1- [2- [4- (4-methoxyphenyl) piperazin-1-yl] ethyl] -6-yl] -N · Methyl isobutyramide (S) · methyl · methyl · methyl methyl methyl methyl iz iz iz iz S iz iz iz iz iz iz iz iz iz iz iz iz iz iz - (Z-5), R _f = 0.33 (5% methanol in methylene chloride); [ _.alpha. ] _D = -34 DEG (c = 0.80, 50% ethanol in methylene chloride); IR (suspension) 2962, 1658, 1512, 1468, 1457, 1386, 1245, 1109, 1038, 825 cm ^-1 ; NMR (300 MHz, CDCl ₃ ) 7.13 (d, 1H, J = 8.2 Hz, aromatic H), 6.98 (d, 1H, J = 8.2 Hz, aromatic H), 6.86 ( mzq, 5H, J = 9.2 Hz, aromatic H), 4.83 (mzd, 1H, J = 5.8 Hz, PgC-H), 4.13 (m, 1H, PhCH ₂ CH-H) 3.76 (s, 3H, OC-H ₃ ), 3.76 (m, 1H, PhCH ₂ CH-H), 3.22 (s, 3H, NC-H ₃ ), 3.10 (t, 4H, J = 4.6 Hz, four pip-H), 2.97 (m, 1H, PhCH-H), 2.61 (m's, 8H, NC (O) CMe ₂ -H, PhCHH, NC-H) ₂ and four pip-H), 2.14 (m, 1H, PhCHCH-H), 2.02 (m, 1H, PhCHCH-H), 1.03 (d, 6H, J = 6.5 Hz, two from NC (O) _CHC-H3) δ; CMR (75MHz, CDCl ₃ ) 177.4, 153.8, 145.7, 142.4, 137.8, 135.7, 127.4, 126.1, 125.0, 118.2, 114.5 , 74.5, 62.8, 55.6, 54.8, 53.5, 50.7, 37.5, 33.3, 31.0, 29.0, 19.8 δ; 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] -N-methanesulfonamide (S) - (Z) -3)

Combine (S) - (-) - 1- [2- (6-aminoisochroman-1-yl) -ethyl] -4- (4-methoxyphenyl) piperazine (S) - (Z-1) (200 mg, 0 , 54 mmol) and 4-dimethylaminopyridine (6.7 mg, 0.054 mmol). Pyridine (2 mL) was added via syringe, the mixture was cooled to 0 ° C and methane sulfonyl chloride (0.045 mL, 0.60 mmol) was added. After 15 minutes, the ice bath was removed and the reaction was stirred at 20-25 ° C for 1.5 hours. The reaction was diluted with water and extracted twice with ethyl acetate. The combined organics were washed once with a saturated aqueous solution of copper sulfate, then with water, dried over magnesium sulfate, filtered and concentrated. The concentrate was chromatographed on 25 g of silica gel using 50% acetone in hexane as eluent to give (S) - (-) - N- [isochroman-1- [2- [4- (4-methoxyphenyl) piperazine-1 -] - yIjethyl] -6-yl] -Nmethansulfonamidu (S) - (Z-3), R _f = 0.21 (5% methanol in methylene chloride); [α] _D = -43 ° (c = 0.89, 50% ethanol in methylene chloride); IR (suspension) 1512, 1339, 1319, 1295, 1244, 1152, 1106, 1037, 973, 826 cm ^-1 ; NMR (300 MHz, CDCl ₃ ) 7.05 (m's, 3H, aromatic H), 6.87 (q, 4H, J = 9.0 Hz, aromatic H), 4.80 (mzd, 1H, J = 5) 8 Hz PhCH), 4.11 (m, 1H, PhCH ₂ CH-H), 3.76 (s, 3H, OC-H ₃ ), 3.71 (m, 1H, PhCH ₂ CH-H), 2.60 (m's, 7H, PhCH-H, NC-H ₂ and four pip-H), 2.11 (m, 1H, PhCHCH-H), 2.01 (m, 1H, PhCHCH-H) δ; CMR (75MHz, CDCI ₃ ) 153.8, 145.7, 135.8, 135.6, 134.8, 1126.1, • · · · · ········ · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

121.2, 119.0, 118.2, 114.5, 74.4, 62.9, 55.6, 54.8, 53.5, 50.6, 39.4, 33.2, 29, 1 δ; HRMS calcd for Ca 4 N 4 Si = 445.2035, found = 445.2031.

Example 63 (S) - (-) - 6-amino-1- [2- [4- (4-methoxyphenyl) piperazin-1-yl] ethyl] -6-yl] -isochroman, methyl urea (S) - (X- 6) (S) - (-) - 1- [2- (6-aminoisochroman-1-yl) -ethyl] -4- (4-methoxyphenyl) -piperazine (S) (Z-1, 376 mg, 1, 0 mmol) was added to acetonitrile (4 mL). Methyl isocyanate (0.091 mL, 1.53 mmol) was then slowly added via syringe, followed by additional acetonitrile (7 mL) and the reaction was stirred at 20-25 ° C for 3 hours. The precipitate was filtered and washed thoroughly with ethyl acetate and hexane to give the crude product, which was purified by flash chromatography using 5% methanol in methylene chloride to give (S) - (-) 6-amino-1- [2- [4- (4) methoxyphenyl) -piperazin-1-yl] ethyl] -6-yl] isochroman, methyl urea (S) - (X-6) R _f = 0.07 (5% methanol in methylene chloride); [α] _D = -43 ° (c = 0.75, 50% ethanol in methylene chloride); IR (suspension) 3312, 1645, 1614, 1597, 1567, 1512, 1421, 1310, 1244, 1109 cm &^lt; -1 &gt;; NMR (300 MHz, CDCl ₃ ) 7.11 (s, 1H, aromatic H), 7.02 (m, 2H, aromatic H), 6.84, (qam, 5H, J = 9.2 Hz, aromatic H ), 5.09 (wd, 1H, J = 5.5 Hz, C (O) NMe-H), 4.77 (wd, 1H, J = 5.8 Hz, PhC-H), 4.07 ( m, 1H, PhCH ₂ CH-H), 3.76 (s, 3H, OC-H ₃ ), 3.71 (m, 1H, PhCH ₂ CH-H), 3.09 (t, 4H, J = 4.9 Hz, four pip-H), 2.90 (m, 1H, PhCH-H), 2.79 (d, 3H, J = 4.7 Hz, C (O (NHC-H ₃ )), 2 60 (m's, 7H, PhCH-H, NC-H ₂ and four pip-H), 2.10 (m, 1H, PhCHCH-H), 2.02 (m, 1H, PhCHCH-H), δ; CMR (75MHz, CDCl ₃ ) 156.8, 153.8, 145.7, 136.8, 135.0, 133.5,

125.5, 121.2119.1, 118.2, 114.5, 74.5, 63.1, 55.6, 54.8, 53.5, 50.6, 33.2, 29.2, 27.0 δ; HRMS calcd for C ₂₄ H ₃₂ N ₄ O ₃ = 424.2474, found = 424.73.

Example 64 (S) - (-) - 6-amino-1- [2- [4- (4-methoxyphenyl) piperazin-1-yl] ethyl] -6-yl] -isochroman, t-butyl carbamate (S) - (X) -6) (S) - (-) - 1- [2- (6-Amino-iso-chroman-1-yl) -ethyl] -4- (4-methoxy-phenyl) -piperazine (S) (Z-1, 200 mg, 0) (54 mmol) was treated with sodium hexamethyldisilazane (200 mg, 1.09 mmol). THF (2 mL) was added via syringe and the reaction was stirred for 15 minutes. Di-t-butylpyrocarbonate (108 mg, 0.50 mmol) was added as a solution in THF (2 mL). The mixture was stirred at 20-25 ° C for 20 hours. The reaction mixture was poured into water (40 mL). The volatiles were removed under reduced pressure, the aqueous residue was extracted with ethyl acetate (2 x 50 mL). The combined organics were dried over sodium sulfate, filtered, and filtered. · ·· ···· · ··· · · · ··· ··· ·· ·· ·· ·· ·· · concentrate. The concentrate was chromatographed on 30 g of silica gel using 5% methane in methylene chloride as eluent to give (S) - (-) - 6 amino-1- [2- [4- (4-methoxyphenyl) piperazin-1-yl] ethyl 6-yl] -isochroman t-butylcarbamate (S) - (X-6) R _f = 0.38 (5% methanol in methylene chloride); [α] _D = -39 ° (c = 0.65, 50% ethanol in methylene chloride); IR (suspension) 1694, 1522, 1515, 1423, 1367, 1286, 1243, 1167, 1109, 1058 cm ^-1 ; NMR (300 MHz, CDCl ₃ ) 7.24 (s, 1H, aromatic H), 7.02 (m, 2H, aromatic H), 6.86 (q, 4H, J = 9.0 Hz, aromatic H) 6.44 (broad s, 1H, NH), 4.79 (mzd, 1H, J = 5.8 Hz, PhC-H), 4.10 (m, 1H, PhCH ₂ CH-H), 3, 76 (s, 3H, OC-H ₃ ), 3.71 (m, 1H, PhCH ₂ CH-H), 3.10 (t, 4H, J = 4.6 Hz, four pip-H), 2, 94 (m, 1H, PhCHCH-H), 2.60 (m's, 7H, PhCH-H, NC-H ₂ and four pip-H), 2.11 (m, 1H, PhCHCH-H), 2.01 (m, 1H, PhCHCH-H), 1.52 (s, 9H, three of _CC-H3) δ; CMR (75MHz, CDCl ₃ ) 153.8, 152.8, 145.8, 136.5, 134.8, 132.8, 125.3, 118.6, 118.2, 116.8, 114.4 , 80.6, 63.1, 61.1, 55.6, 54.8, 53.5, 50.6, 33.3, 29.3, 28.4 δ.

Example 65 1- (4-Methoxyphenyl) -4- [2- (6-methylaminomethylisochroman-1-yl) ethyl] piperazine (BB-2)

Following the procedure of Example 1, Step 4 with minor variations, 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] -N-methyl-isochroman-6-carboxamide (IX, EXAMPLE 37) is obtained from the crude product. . Purify by LC on 13 g (230-400) silica gel eluting with 5% 3M ammonium in methanol / dichloromethane to give 1- (4-methoxyphenyl) -4- [2- (6-ethylaminomethylisochroman-1-yl) ethyl] piperazine (BB-2), m.p. = 74-76 ° C; R f = 0.36 (5% 3M NH ₃ in methanol / dichloromethane); IR (suspension) 2788, 1512, 1291, 1276, 1253, 1232, 1180, 1151, 1132, 1107, 1051, 1035, 1012, 927, 831; NMR (300 MHz, CDCl ₃ ) 7.08 (m, 3H, aromatic), 6.85 (m, 4H, aromatic), 4.85 (broad d, 1H, J = 6.0 Hz, methine), 4 15 (m, 1H, OCH _{2 a} ), 3.77 (m, 4H, OCH ₃ and OCH _2b ), 3.71 (s, 2H, Ph-CH ₂ -N), 3.11 (t, 4H, J = 4.9 Hz, Ph-N-CH _{2 s} ), 2.97 (m, 1H, Ph-CH _{2 a} ), 2.72-2.50 (m, 7H, Ph-NC (H ₂ ) -CH _2s -NCH _{2 s} , Ph-CH _2b ), 2.46 (s, 3H, NCH ₃ ), 2.14 (m, 1H, C (H) -CH _{2 a} ), 2.04 (m, 1H, C ( H) -CH _2b ) δ; CMR (75MHz, CDCl ₃ ) 153.6, 145.6, 137.9, 136.7, 1233.9, 128.5, 126.0, 124.7, 118.0, 114.3, 74.5 , 63.0, 55.6, 55.4, 50.5, 35.9, 33.2, 29.0 δ; HRMS calcd for C ₂₄ H ₃₃ N ₃ O ₂ = 395.2573, found = 395.2573.

Example 66 1- (4-Methoxyphenyl) -4- [2- (6-dimethylaminomethylisochroman-1-yl) ethyl] piperazine (BB-2)

Following the procedure of Example 1, Step 4 with minor variations, 1- (2- (4- (4-methoxyphenyl) -1-piperazinyl) ethyl) -N-methyl-isochroman-6-carboxamide (IX, Example 36) was obtained from crude Purify by LC on 13 g (230-400) silica gel eluting with 100% dichloromethane and gradually increasing in polarity to 5% ammonium in methanol / dichloromethane to give 1- (4-methoxyphenyl) -4- [2- ( 6-dimethylaminomethylisochroman-1-yl) ethyl] piperazine (BB-2), m.p. = 95-98 ° C; R _f = 0.33 (5% 3M NH ₃ in methanol / dichloromethane); IR (suspension) 2809, 2791 , 2770, 2762, 1512, 1442, 1277, 1253, 1232, 1179, 1150, 1107, 1045, 1037, 832 cm ^-1 ; NMR (300 MHz, CDCl ₃ ) 7.07 (m, 3H, aromatic), 6 87 (m, 4H, aromatic), 4.83 (broad d, 1H, J = 6.4 Hz, methine), 4.11 (m, 1H, OCH _2a ) 3.76 (m, 4H, OCH ₃₎ and OCH _{2 b} ), 3.40 (s, 2H, Ph-CH ₂ -N), 3.11 (t, 4H, J = 4.9 Hz, Ph-NCH _{2 s} ), 2.97 (m, 1H, Ph-CH _{2 a} ), 2.65 (m, 7H, Ph-NC (H ₂ ) -CH ₂ -NCH ₂ and Ph-CH _{2 b} ), 2.26 (s, 6H, N CH 5), 2.18 (m, 1H ,

C (H) -CH _2a), 2.05 (m, 1H, C (H) -CH _2b) δ; CMR (75MHz, CDCl ₃ ) 153.8, 145.8, 137.0,

136.6, 133.9, 129.5, 127.1, 124.6, 118.2, 114.4, 74.6, 64.0, 63.2, 55.6, 54.9, 53, 5,

50.6, 45.3, 33.3, 29.1 δ; HRMS (EI) calculated for C ₂₅ H ₃₃ N ₃ O ₂ = 409.2729, found = 409.2733.

Example 67 1- [2- [4- (4-Methoxy-phenyl) -1-piperazinyl] -ethyl] -isochroman-6-carboxylic acid ethyl ester (X)

Oven-dried 10 ml flask equipped with a stir bar, condenser and three-way adapter is charged with 1- [2- (6-bromoisochroman-1-yl) ethyl] -4- (4-methoxyphenyl) -piperazine (VI, Example 24, Step 2, 431 mg, 1.0 mmol), palladium acetate (11 mg, 0.05 mmol), 1,3-bis (diphenylphosphino) propane (25 mg, 0.06 mmol), 2.5 mL dimethylformamide, diisopropylethanolamine (0, 35 mL, 2.0 mmol) and ethanol (1.2 mL, 20 mmol). The resulting mixture was purified six times with carbon monoxide under reduced pressure and then heated to 100 ° C. After 18 hours, cool the mixture to 20-25 ° C, concentrate under high vacuum, dilute with 20 mL of 1 M sodium hydroxide, and extract twice with ethyl acetate (20 mL). The combined organics were washed once with brine (20 mL), dried over magnesium sulfate, filtered and concentrated to give the product. Purify by LC on 22 g (230-400) silica gel with 30% acetone / hexane to give 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] isochroman-6-carboxylic acid ethyl ester (X), m.p. = 117-119 ° C; Rf = 0.45 (35% acetone / hexane); IR (suspension) 1712, 1513, 1422, 1286, 1260, 1246, 1187,

100 ALIGN!

1145, 1140, 1108, 1053, 1037, 1023, 818, 767 cm ^-1 ; NMR (300 MHz, CDCl 3) 7.84 (d,

1H, J = 8.2 Hz, aromatic), 7.80 (s, 1H, aromatic), 7.17 (d, 1H, J = 8.1 Hz, aromatic), 6.85 (m, 4H, aromatic) ), 4.85 (broad d, 1H, J = 6.0 Hz, methine), 4.36 (qrt, 2H, J = 7.1 Hz, _{CO2 CH2),} 4.15 (m, 1H, OCH _2a ), 3.76 (m, 4H, OCH ₃ and OCH _2b ), 3.10 (t,

4H, J = 4.7Hz, Ph-N-CH _{2 s} ), 3.00 (m, 1H, Ph-CH _{2 a} ), 2.79-2.50 (m, 7H, Ph-NC (H ₂ )) CH _{2 s} .NCH _{2 s} , Ph-CH _{2 b} ), 2.15 (m, 1H, C (H) -CH _{2 a} ), 2.06 (m, 1H, C (H) -CH _{2 b} ), 1.69 ( t,

3H, J = 7.1Hz, C (H ₂ ) -CH ₃ δ; CMR (75MHz, CDCl ₃ ) 166.2, 153.5, 145.4, 142.9, .2, 54.3

2,

50.3, 32.8, 28.7, 14.0 δ.

Example 68 6-Acetyl-1- [2- [4- (4-methoxyphenyl) -1-piperazinyl-ethyl] isochroman, hydrochloric acid salt (XXIV)

Oven-dried 10 mL vessel equipped with a stir bar and a condenser was charged with 1- [2- (6-bromoisochroman-1-yl) ethyl] -4- (4-methoxyphenyl) -piperazine (VI, Example 24, Step 2, 431) mg, 1.0 mmol), palladium acetate (11 mg, 0.05 mmol), 1,3-bis (diphenylphosphino) propane (25 mg, 0.06 mmol), thallium acetate, (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) were warmed to 100 ° C and after 20 hours cooled to 20-50 ° C. 25 ° C, hydrochloric acid (1M, 6 ml) was added and stirred for 1 hour, the mixture was concentrated under high vacuum, diluted with 20 ml of 5M sodium hydroxide and extracted twice with ethyl acetate (20 ml). (20 mL), dried over magnesium sulfate, filtered, and concentrated, purified by LC on 27 g (230-400) silica gel with 25% acetone / hexane, then diluted with ethyl acetate / methanol and treated with hydrochloric acid to give a solid which is recrystallized from ethyl acetate / methanol to give 6-acetyl-1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] isochroman, the hydrochloric acid salt ( XXIV), m.p. = 195-197 ° C; R _f = 0.15 (30% acetone / hexane); IR (suspension) 2560, 2516, 2487, 2462, 1675, 1511, 1444, 1425, 1359, 1290, 1265, 1245, 1113, 1035, 837 cm ^-1 ; free base NMR (300 MHz, CDCl ₃ ) 7.78 (d, 1H, J = 8.1 Hz, aromatic), 7.72 (s, 1H, aromatic), 7.20 (d, 1H, 8.1 Hz, aromatic), 6.87 (m, 4H, aromatic), 4.89 (broad d, 1H, J = 6.0 Hz, methine), 4.15 (m, 1H, OCH _2a ), 3.76 (m, 4H, OCH ₃ and OCH _2b ), 3.11 (t, 4H, J = 4.8 Hz, Ph-N-CH _{2 s} ), 3.00 (m, 1H, Ph-CH _{2 a} ), 2, 80-2.55 (m, 10H, Ph-NC (H2 ₎ ) 9

101 ··· ·· CH _{2 s} -NCH _{2 s} , COCH ₃ ), 2.15 (m, 1H, C (H) -CH _{2 a} ), 2.06 (m, 1H, C (H) -CH _2b ) δ ; CMR (75MHz, CDCl ₃ ) 197.8, 153.7, 145.6, 1143.5, 135.2, 134.4, 128.9, 126.1, 125.0,

118.1, 114.3, 74.5, 62.9, 55.5, 54.6, 53.4, 50.5, 33.0, 29.0, 26.5 δ; HRMS (EI) calculated for C ₂₄ H ₃ oN ₂ 0 ₃ = 394.2256, found = 394.2262.

Example 69

6-Formyl-1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] -isochroman (AA-1)

- [2- (6-bromoisochroman-1-yl) ethyl] -4- (4-methoxyphenyl) -piperazine (VI, Example 24, Step 2, 2.80 g, 6.5 mmol) is mixed with fresh distilled tetrahydrofuran (16 mL) and cooled to -78 ° C. To the mixture was added a 1.7 M solution of tert-butyllithium (7.7 mL, 13.0 mmol). After 15 minutes, aryl lithium was mixed with dimethylformamide (1.0 mL, 13 mmol). The mixture was warmed to 20-25 ° C over 1.5 h, 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 the crude product. The material was purified by LC on 160 g (230-400) silica gel with 30% acetone / hexane to give 6-formyl-1- [2- [4- (4-methoxyphenyl) -1-piperazinyl-ethyl] -isochroman (AA-1) Rf _. = 0.28 (30% acetone / hexane); IR (liquids) 2949, 2819, 1698, 1608, 1512, 1464, 1456, 1291, 1285, 1244, 1143, 1124, 1110, 1038, 824 cm ^-1 ; NMR (300 MHz, CDCl ₃ ) 9.97 (s, 1H, CHO), 7.69 (d, 1H, J = 8.0 Hz, aromatic), 7.60 (s, 1H, aromatic), 7, 28 (d, 1H, J = 7.7 Hz, aromatic), 6.85 (m, 4H, aromatic), 4.90 (broad d, 1H, J = 6.0 Hz, methine), 4.16 ( m, 1H, OCH _{2 a} ), 3.76 (m, 4H, OCH ₃ and oCH _2b ), 3.10 (t, 5H, J = 5.0 Hz, Ph-N-CH _{2 s} and Ph-CH _{2 a} ) 2.83-2.50 (m, 7H, Ph-NC (H ₂ ) -CH _{2 s} -NCH _{2 s} , Ph-CH _{2 b} ), 2.16 (m, 1H, C (H) -CH _2a ), 2.07 (m, 1H, C (H) CH _{2 b} ) δ; CMR (75MHz, CDCl ₃ ) 192.0, 153.8, 145.7, 135.0, 134.7, 130.4, 127.4,

125.6, 118.2, 114.4, 74.6, 62.8, 55.6, 54.6, 53.5, 50.6, 33.1, 29.0 δ; HRMS (EI) calculated for C ₂₃ H ₂₈ N ₂ O ₃ = 380.2100, found = 380.2098.

Example 70 2- [Isochroman-1- [2- [4- (4-methoxyphenyl) piperazin-1-yl] ethyl] -6-yl] acetamide (AA-4). Step: 1- [2- (6-hydroxymethylisochroman-1-yl) ethyl ] -4- (4-Methoxyphenyl) piperazine (AA-2)

102

6-Formyl-1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] isochroman (AA-1, Example 71, 2.51 g, 6.6 mmol) was mixed with 25 mL of methanol and cool to 0 ° C. The mixture was then mixed with one portion of boron sodium hydride (500 mg, 13.2 mmol). The reaction was gradually warmed to 20-25 ° C over two hours, 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. The material was purified by LC on 130 g (230-400) silica gel eluting with methanol / dichloromethane (5/95) to give - [2- (6-hydroxymethylisochroman-1-yl) ethyl] -4- (4-methoxyphenyl) piperazine ( AA-2), R _f = 0.15 (35% acetone / hexane); IR (slurry) 1513, 1445, 1428, 14292, 1279, 1248, 1186, 1152, 1140, 1107, 1057, 1034, 1011, 928, 826 cm ^-1 ; NMR (300 MHz, CDCl ₃ ) 7.17 (d, 1H, J = 8.0 Hz, aromatic), 7.09 (m, 2H, aromatic), 6.86 (m, 4H, aromatic), 4, 82 (br d, 1H, J = 6.3 Hz, methine), 4.64 (s, 2H, Ph-CH-O), 4.12 (m, 1H, OCH _2), 3.76 (m, 4H, OCH ₃ and OCH _2b ), 3.10 (t, 4H, J = 4.8 Hz, Ph-N-CH _{2 s} ), 2.97 (m, 1H, Ph-CH _{2 a} ), 2.72- 2.50 (m, 7H, Ph-NC (H ₂ ) -CH ₂ NCH _{2 s} , Ph-CH _{2 b} ), 2.10 (m, 2H, C (H) -CH ₂ S) δ; MS (EI, m / z) = 382;

Step 2: 1- [2- (6-cyanomethylisochroman-1-yl) ethyl] -4- (4-methoxyphenyl) piperazine (AA-3)

1- [2- (6-hydroxymethylisochroman-1-yl) ethyl] -4- (4-methoxyphenyl) -piperazine (AA-2, 2.33 g, 6.1 mmol) was mixed with 61 mL of dichloromethane and triethylamine ( (1.3 mL, 9.1 mmol) and cooled to 0 ° C. The mixture was treated with methanesulfonyl chloride (0.52 mmol, 6.7 mmol). The reaction was warmed to 20-25 ° C over 1.5 hours and concentrated under reduced pressure. The crude methanesulfonate was diluted with 31 mL of dimethylsulfoxide and sodium cyanide (896 mg, 18.3 mmol). The mixture was heated to 60 ° C. After 2 hours the volatiles were removed under high vacuum, the residue was diluted with 100 mL water and extracted twice with ethyl acetate (75 mL). The combined organics were washed once with brine (75 mL), dried over magnesium sulfate, filtered and concentrated. The material was purified by LC on 88 g (230-400) silica gel eluting with 30% acetone / hexane to give 1- [2- (6- (cyanomethylisochroman-1-yl) ethyl] -4- (4-methoxyphenyl) piperazine (AA). -3), mp = 118-119 ° C; R f = 0.36 (35% acetone / hexane); IR (suspension) 2810, 1790, 1512, 1444, 1275, 1253, 1232, 1182, 1151, 1111, 1107, 1058, 1051, 1031 and 831 cm ^-1 ; NMR (300 MHz, CDCl ₃ ) 7.10 (m, 3H, aromatic), 6.87 (m, 4H, aromatic), 4.82 (broad d, 1H, J = 6.3 Hz, methine), 4.14 (m,

103

1H, OCH _{2 a} ), 3.76 (m, 4H, OCH ₃ and OCH _2b ), 3.74 (s, 2H, NC-CH ₂ ), 3.11 (t, 4H, J = 4.8 Hz, Ph-N-CH _{2 s} ), 2.98 (m, 1H, Ph-CH _{2 a} ), 2.04 (m, 1H, C (H) -CH _2b ) δ; CMR (75MHz, CDCl ₃ ) 153.8, 145.8, 138.1, 135.1, 128.4, 127.9, 125.8, 125.6, 118.2, 117.9, 114.3 ,

74.4, 62.9, 55.6, 54.7, 53.5, 50.6, 33.3, 29.0, 23.2 δ; MS (EI, m / z) = 391;

Step 3: 2- [isochroman-1- [2- [4- (4-methoxyphenyl) piperazin-1-yl] ethyl] -6-yl] acetamide (AA-4)

- [2- (6-cyanomethylisochroman-1-yl) ethyl] -4- (4-methoxyphenyl) piperazine (AA-3, 785 mg, 2.0 mmol) is mixed with 5.0 mL dimethylformamide and potassium carbonate ( 39 mg, 0.28 mmol). The mixture was treated with 30% hydrogen peroxide (0.24 mL, 2.3 mmol). After 20 minutes, the reaction was diluted with 100 mL of dichloromethane, washed once with water (20 mL), once with brine (20 mL), dried over magnesium sulfate, filtered, and concentrated. The material was then recrystallized from ethyl acetate / hexane to give 2 [isochroman-1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] -6-yl] acetamide (AA-4), m.p. 159-161 [deg.] C .; R _f = 0.15 (5% methanol / dichloromethane); IR (slurry) 3381, 3208, 2791, 1658, 1633, 1513, 1444, 1293, 1275, 1255, 1231, 1150, 1108, 1032, 833 cm ^-1 ; NMR (300 MHz, CDCl ₃ ) 7.09 (s, 2H, aromatic), 7.02 (s, 1H, aromatic), 6.86 (m, 4H, aromatic), 5.59 (broad s, 1H, NH), 4.81 (broad d, 1H, J = 6.0 Hz, methine), 4.12 (m, 1H, OCH _{2 a} ), 3.76 (m, 4H, OCH ₃ and OCH _2b ), 3 53 (s, 2H, O = _C-CH2), 3.10 (t, 4H, J = 4.9, _Ph-N-CH2s), 2.96 (m, 1H, C (H (- CH _2a ), 2.77 (d, 3H, J = 4.9 Hz, NCH _3i ), 2.732-2.56 (m, 7H, Ph-NC (H ₂ ) -CH ₂ -NCH _{2 s} ) 2.03 (m, 1H, C (H) CH _{2 b} ) δ; CMR (75MHz, CDCl ₃ ) 173.4, 153.8, 145.7, 137.4, 134.7, 132.8, 129.8,

127.2, 125.4, 118.1, 114.4, 74.5, 55.6, 54.8, 53.5, 50.6, 42.8, 33.2, 29.0 δ; MS (EI, m / z) = 409;

Example 71 2- [Isochroman-1- [2- [4- (4-methoxyphenyl) piperazin-1-yl] ethyl] -6-yl] -N-methylacetamide (AA-5)

Following the procedure of Example 3, Step 1, with minor variations, 2 [isochroman-1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] -6-yl] acetamide (AA-4, 446 mg) was formed. , 1.09 mmol) of crude product. Purify by LC on 40 g (230-400) silica gel eluting with 50% ethyl acetate / hexane to give 2- [isochroman-1- [2- [4- (4-methoxyphenyl) piperazin-1-yl] ethyl] -6 yl] -N, N-di-t-butyloxykarbonylacetamid, R _f = 0.45 (60% ethyl acetate / hexane) the substance reacted with methylamine according to the general

104

The procedure of Example 3, Step 2, with minor variations, gave the desired product which was purified by LC on 13 g (230-400) silica gel, eluting 60% acetone / hexane to give 2- [isochroman-1- [2- [4- (4-methoxyphenyl) piperazin-1-yl] ethyl] -6-yl] -N-methylacetamide (AA-5), m.p. 147-148 [deg.] C .; R _f = 0.20 (50% acetone / hexane); IR (suspension) 3309, 1652, 1550, 1515, 1442, 1426, 1412, 1354, 1251, 1228, 1153, 1147, 1114, 1036, 826 cm ^-1 ; NMR (300 MHz, CDCl ₃ ) 7.09 (s, 2H, aromatic), 7.01 (s, 1H, aromatic), 6.87 (rn, 4H, aromatic), 5.45 (broad s, 1H, NH), 4.83 (broad d, 1H, J = 6.0 Hz, methine), 4.15 (m, 1H, OCH _{2 a} ), 3.77 (m, 4H, OCH ₃ and OCH _2b ), 3 53 (s, 2H, O = _C-CH2), 3.12 (t, 4H, J = 4.9, _Ph-N-CH2s), 2.95 (m, 1H, C (H (CH _2a ), 2.77 (d, 3H, J = 4.9Hz, NCH _3i ), 2.732-2.56 (m, 7H, Ph-NC (H ₂ ) -CH ₂ -NCH _{2 s} , Ph-CH _2b ), 2.15 (m, 1H, C (H) -CH _{2 a} ), 2.04 (m, 7.09) s, 2H, aromatic), 7.02 (s, 1H, aromatic), 6.86 (m, 4H, aromatic), 5.59 (broad s, 1Η, NH), 4.81 (broad d, 1H, J = 6.0 Hz, methine), 4.12 (m, 1H, OCH _2a) ), 3.76 (m, 4H, OCH ₃ and OCH _{2 b),} 3.53 (s, 2H, O = _C-CH2), 3.10 (t, 4H, J = 4.9, Ph-N -CH _{2 s} ), 2.96 (m, 1H, C (H (-CH ₂ )), 2.03 (m, 1H, C (H) -CH _2b ) δ; CMR (75MHz, CDCl ₃ ) 171.6 , 153.8, 145.7, 137.4, 134.7, 132.9, 130.0,

127.3, 125.4, 118.2, 114.4, 74.5, 63.0.55.6, 54.9, 53.6, 50.6, 43.3, 33.3, 29, 0.26.5 δ; MS (EI, m / z) = 423;

Example 72 1- [2- [4- (4-Hydroxyphenyl) -1-piperazinyl] ethyl] -isochroman-6-carboxamide (CC-2)

1- [2- [4- (4-Phenylmethoxyphenyl) -1-piperazinyl] ethyl] -isochroman-6-carboxamide (CC-1, Example 9, 0.42 mmol, 200 mg), palladium on carbon (10%, 20 mg), ethanol (5 mL) and methylene chloride (2 mL). After four days, the starting material was worked up. The reaction mixture was filtered through celite beads and washed several times with ethanol, methanol, methylene chloride or ethyl acetate. The combined filtrates were concentrated. The crude material was recrystallized from hot ethanol with a small amount of methanol to give 1- [2- [4- (4-hydroxyphenyl) -1-piperazinyl] ethyl] -isochroman-6-carboxamide (CC-2), IR (suspension) 3300, 3255, 3206, 1672, 1615, 1513, 1444, 1426, 1366, 1256 cm ^-1 ; NMR (300 MHz, DMSO) 7.85 (d, 1H, J = 8.2 Hz, aromatic H), 7.82 (s, 1H, aromatic H), 7.43 (d, 1H, J = 8, 2 Hz, aromatic H), 6.96 (d, 2H, J = 8.8 Hz, aromatic H), 6.81 (d, 2H, J = 8.8 Hz, aromatic H), 5.00 (broad) d, 1H), 4.18 (m, 2H), 3.85 (m, 1H), 3.68 (m, 4H), 3.46-3.0 (several broad m, 6H), 2.86 • • • • •

105 (broad d, 2H, J = 16 Hz), 2.37 (broad m, 1H), δ; HRMS (EI) calcd for C 22 H 27 N 3 O 3 = 382.2131, found = 382.2136.

Example 73 (S) - (-) - 1- [2- [4- (4-Hydroxyphenyl) -1-piperazinyl] ethyl] -N-methylisochroman-6-carboxamide (S) - (CC-2)

A Parr bottle was charged with (S) - (-) - 1- [2- [4- (4-phenylmethoxyphenyl) -1-piperazinyl] ethyl] -N-methylisochroman-6-carboxamide (S) - (CC-1, Example 20). 50 ml of methanol, 25 ml of tetrahydrofuran and 10% palladium on carbon (20 mg). The resulting black suspension was covered with hydrogen at 50 psi and shaken. After 60 hours, the hydrogen pressure was reduced to 186 kPa, the reaction mixture was filtered through celite and concentrated. The concentrate was recrystallized from methanol / ethyl acetate to give (S) - (-) - 1- [2- [4- (4-hydroxyphenyl) -1-piperazinyl] ethyl] -N-methylisochroman-6-carboxamide (CC-2) mp = 154-162 ° C; R _f = 0.11 (5% methanol / ethyl acetate); [α] D = -53 ° (c = 0.9681, 50% methanol); IR (suspension) 3350, 3200, 3174, 2811, 1642, 1173, 1542, 1517, 1300, 1271, 1248, 1243, 1232, 1104, 825 cm ^-1 ; NMR (300 MHz, DMSO- d ₆₎ δ 8.81 (s, 1H, OH), 8.37 (broad d, 1H, J = 4.6 Hz, NH), 7.61 (m, 3H, aromatic 7.27 (d, 1H, J = 8.1 Hz, aromatic), 6.76 (d, 2H, J = 8.9 Hz, aromatic), 6.63 ((d, 2H, J =

8.9 Hz, aromatic), 4.78 (broad d, 1H, J = 6.0 Hz, methine), 4.03 (m, 1H, OCH _{2 a} ), 3.66 (m, 1H, OCH _2b ) 2.93 (m, 4H, Ph-N-CH _{2 s} ), 2.76 (d, 4H, J = 4.5 Hz, N-CH ₃ and PhCH _{2 a} ), 2.49 (m, 6H, Ph -NC (H ₂ -CH ₂ s -NCH ₂ s), 2.35 (m, 1H, Ph-CH _2b ), 2.15 (m, 1H, C (H) -CH _{2 a} ), 1.85 ( m, 1H, C (H) -CH _2b) δ; CMR (75 MHz, _DMSO-d6) 166.4, 150.8, 144.2, 141.2, 133.7, 132.3, 127.5, 124.8, 124.6, 117.6, 115 4, 73.6, 62.2, 54.2, 53.1, 50.0, 32.5, 28.5, 26.2; HRMS (EI) for C ₂₃ vapočtena ₂ H 9 N ₃ O ₃ = 395.2209, found = 395.2212; total water content = 4.28%.

Example 74 (S) - (-) - 1- [2- [4- (4-Trifluoromethanesulfonyloxyphenyl) -1-piperazinyl] ethyl] -N-methyl-isochroman-6-carboxamide (S) - (CC-3)

(S) - (-) - 1- [2- [4- (4-Hydroxyphenyl) -1-piperazinyl] ethyl] -N-methylisochroman-6-carboxamide (CC-2, 959 mg, 2.4 mmol) was mixed with 24 mL of dichloromethane and N-phenyltrifluoromethane sulfonimide (910 mg, 2.5 mmol). The mixture was cooled to 0 ° C and triethylamine (0.51 mL, 3.6 mmol) was added without visible change. After 16 hours, the mixture was diluted with 75 mL of 1M sodium hydroxide and extracted twice with dichloromethane (75 mL). The combined organics were washed twice with brine (50 mL), dried over Na 2 SO 4

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magnesium sulfate, filtered and concentrated. The material was purified by LC on 88 g (230-400) silica gel eluting with 5% methanol / dichloromethane to give (S) - (-) 1- [2- [4- (4-trifluoromethanesulfonyloxyphenyl) -1-piperazinyl] ethyl -N-methyl-isochroman

6-carboxamide (S) - (CC-3) R _f = 0.34 (5% methanol / dichloromethane); [α] _D = -39 ° (c = 0.9447, methanol); IR (suspension) 1641, 1571, 1548, 1505, 1417, 1310, 1297, 1240, 1210, 1209, 1141, 1110, 885, 826, 609 cm ^-1 ; NMR (300 MHz, CDCl ₃ ) 7.55 (m, 2H, aromatic), 7.14 (m, 3H, aromatic), 6.87 (d, 2H, J = 9.4 Hz, aromatic), 6, 18 (broad d, 1H, J = 4.6 Hz, NH), 4.85 (broad D, 1H, J = 5.8 Hz, methine), 4.13 (m, 1H, OCH _2a ), 3, 75 (m, 1H, OCH _{2 b} ), 3.22 (t, 4H, J = 4.9 Hz, Ph-N-CH _{2 s} ), 3.00 (d, 4H, J =

4.9 Hz, N-CH ₃ and Ph-CH _{2 a} ), 2.75-2.49 (m, 7H, Ph-NC (H ₂ ) -CH _{2 s} -NCH _{2 s} and Ph-CH _{2 b} ),

2.15 (m, 1H, C (H) -CH _2a), 2.04 (m, 1H, C (H) -CH _2b) δ; CMR (75MHz, CDCl ₃ ) 168.0,

150.9, 142.1, 141.5, 134.5, 132.7, 127.7, 125.0, 124.5, 121.9, 166.3, 74.4, 63.0,

54.5, 53.2, 48.7, 33.2, 29.1, 26.9; HRMS (FAB) Calcd for C 14 F 15 N 5 O 5 S + H 2 =

528.1780, found = 528.1791.

Example 7 5 (S) - (-) - 1- [2- [4- (4-Acetylphenyl) -1-piperazinyl] ethyl] -N-methylisochroman-6-carboxamide (S) - (IX)

(S) - (-) - 1- [2- [4- (4-Trifluoromethanesulfonyloxyphenyl) -1-piperazinyl] ethyl] -N-methyl-isochroman-6-carboxamide (S) - (CC-3, 527 mg, 1.0 mmol), palladium acetate (11 mg, 0.05 mmol), 1,3-bis (diphenylphosphino) propane (25 mg, 0.06 mmol), 3.5 mL dimethylformamide, triethylamine (0.28 mL, 2.0 mmol) and butyl vinyl ether (0.65 mL, 5.00 mmol). The resulting mixture was heated to 50 ° C. After 16 hours, the reaction was cooled to 20-25 ° C, 8 mL of 1M hydrochloric acid was added and stirred for 1 hour. This acidic mixture was concentrated under reduced pressure, diluted with 15 mL of 1M sodium hydroxide and extracted twice with dichloroethane (25 mL). The combined organics were washed once with brine (15 mL), dried over magnesium sulfate, filtered, and concentrated. The material was purified by LC on 36 g (230-400) silica gel eluting with 50% acetone / hexane to give (S) - (-) - 1- [2- [4- (4-acetylphenyl) -1-piperazinyl] ethyl] -N-methylisochroman-6-carboxamide (S) - (CC-4), which recrystallizes from ethyl acetate / hexane, m.p. = 156-157 ° C; R _f = 0.20 (50% acetone / hexane); [α] D = -41 ° (c = 0.8481, methanol); IR (suspension) 3331, 1662, 1598, 1570, 1550, 1519, 1427, 1415, 1311, 1284, 1239, 1196, 1150, 1107, 609 cm &^lt; -1 &gt;; NMR (300 MHz, CDCl ₃ ) 7.85 (d, 2H, J = 8.9 Hz, aromatic), 7.55 (m, 2H, aromatic),

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7.14 (d, 1H, J = 8.5 Hz, aromatic), 6.84 (d, 2H, J = 8.9 Hz, aromatic), 6.24 (broad d, 1H, J = 4.6) Hz, NH), 4.86 (broad d, 1H, J = 5.8 Hz, methine), 4.12 (m, 1H, OCH _{2 a} ), 3.76 (m, 1H, OCH _2b ), 3, 35 (t, 4H, J = 5.0Hz, Ph-N-CH _{2 s} ), 3.00 (d, 4H, J =

4.9 Hz, N-CH ₃ and Ph-CH _{2 a} ), 2.75-2.53 (m, 7H, Ph-NC (H ₂ ) -CH _{2 s} -NCH _{2 s} and Ph-CH _{2 b} ),

2.50 (s, 3H, O = C-CH _3), 2.16 (m, 1H, C (H) -CH _2a), 2.02 (m, 1H, C (H) -CH _2b); CMR (75MHz, CDCl ₃ ) 196.6, 168.0, 154.2, 141.5, 1234.5, 132.7, 130.4, 127.7, 125.0,

124.5, 113.4, 74.4, 63.0, 54.5, 53.0, 47.3, 33.2, 29.1, 26.9, 26.1 δ HRMS (EI) calculated for C ₂₅ H ₃₁ N ₃ O ₃ = 421.2365, found = 421.2365.

Example 76 (S) - (-) - 3- [Isochroman-1- [2- [4- (4-methoxy-phenyl) -piperazin-1-yl] -ethyl] -6-yl] -1H-dimethylacrylamide (S) - (XVIII)

(S) - (-) - 1- [2- (6-Bromo-iso-chroman-1-yl) -ethyl] - [4- (4-methoxy-phenyl) -piperazine (S) - (VI) (431.4 mg) was added. , 1.0 mmol), palladium acetate (98%, 11.4 mg, 0.05 mmol) and 1,3-bis-diphenylphosphinopropane (97%, 24.7 mg, 0.06 mmol). An ozone atmosphere is prepared. DMF (4.1 mL), dimethylacrylamide (0.72 mL, 7.0 mmol) and diisopropylethylamine (0.35 mL, 2.00 mmol) were introduced via syringe into the reaction vessel. The mixture was heated at 100 ° C for 18 hours. After cooling to 20-25 ° C, the reaction was diluted with aqueous sodium hydroxide solution and extracted three times with ethyl acetate. The organics were collected and concentrated. Excess DMF was removed under high vacuum. The crude material was purified by flash chromatography on 80 g silica gel eluting with 5% methanol in methylene chloride to give a solid which was recrystallized from hot ethyl acetate / hexane to give (S) - (-) - 3- [isochroman- (S) - (XVIII) 1- [2- [4- (4-Methoxy-phenyl) -piperazin-1-yl] -ethyl] -6-yl] -N, N-dimethylacrylamide, m.p. = 120-121 ° C; R _f = 0.30 (5% methanol in methylene chloride); NMR (300 MHz, CDCl ₃ ) 7.62 (d, 1H, J = 15.4 Hz, aromatic H), 7.34 (d, 1H, J = 8.0 Hz, aromatic H), 7.10 ( d, 1H, J = 8.0 Hz, aromatic H), 6.85 (dzdam, 4H and 1H, J _a = 9.1 Hz, J _b = 21.4 Hz, aromatic H), 4.83 (wd) 1 H, J = 6.0 Hz, PhC-H), 4.13 (m, 1H, PhCH ₂ CH-H), 3.75 (m, 1H, PhCH ₂ CH-H), 3.75 (s , 3H, PhOC-H ₃ ), 3.17 (s, 3H, NMeCH ₃ ), 3.10 (tas, 4H and 3H, J = 4.8 Hz, four of pip-H and one of NMe-H ₃ 2.94 (m, 1H, NCH-H), 2.76-2.45 (several m, 7H, four pip-H, two PhCH-H and NCH-H), 2.14 (m, 1H Δ H, PhCHCH-H), 2.02 (m, 1H, PhCHCXH-H), δ; CMR (75MHz, CDCl ₃ ) 166.7, 153.8,

145.7, 142.0, 139.8, 134.5, 133.5, 128.3, 125.5, 118.1, 117.1, 114.4, 74.6, 63.0, 55, 6, 54.8, 53.5, 50.6, 37.4, 35.9, 33.2 and 29.1 δ.

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Example 77

(S) - (-) - 1- (4-Methoxyphenyl) -4- [2- [6- (1,2,4-triazol-3-yl) isochroman-1-yl] ethyl] piperazine (S) - (O-2)

Step 1: (S) - (-) - 1- [2- [4- (4-Methoxyphenyl) -1-piperazinyl] ethyl] -N-dimethylaminomethylene isochroman-6-carboxamide (S) - (O-1)

Mix (S) - (-) - 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] -Nisochroman-6-carboxamide (S) - (VII, 395.5, mg, 1 mmol) with N, N-dimethylformamide dimethyl acetal (94%, 0.34 mL, 2.4 mmol) and toluene (1 mL). The reaction mixture was heated to 90 ° C for 1.5 hours. After cooling to 20-25 ° C, the volatiles are removed under reduced pressure. Purification of the crude material by flash chromatography on 90 g of silica gel using 5% methanol in methylene chloride as eluent gave (S) - (-) - 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] N-dimethylaminomethylene isochroman-6-carboxamide (S) - (O-1), m.p. = 134-135.5 ° C; R _f = 0.28 (5% methanol in methylene chloride); [α] _D = -47 ° (c = 0.96, 50% methylene chloride in ethanol); IR (suspension) 1647, 1608, 1593, 1515, 1446, 1417, 1329, 1259, 1247, 1108 cm ^-1 ; NMR (300 MHz, CDCl ₃ ) 8.63 (s, 1H, NMe ₂ CH), 8.07 (d, 1H, J = 8.1 Hz, aromatic H), 8.02 (s, 1H, aromatic H) 7.14 (d, 1H, J = 8.1 Hz, aromatic H), 6.85 (dzd, 4H, J _a = 9.2 Hz, J _b = 21.6 Hz, aromatic H), 4 88 (mzd, 1H, J = 5.1Hz, PhC-H), 4.13 (m, 1H, PhCH ₂ CH-H), 3.76 (m, 1H, PhCH ₂ CH-H), 3 75 (s, 3H, OC H _3), 3.21 (s, 3H, NMeCH _3), 3.18 (s, 3H, NMeCH _3), 3.10 (t, 4H, J = 4 9 Hz, four pip-H), 2.98 (m, 1H, PhCH-H), 2.76 (mzd, 1H, J = 16 Hz, PhCHCH-H), 2.60 (m's, 6H, NC -H ₂ and four pip-H), 2.15 (m, 1H, PhCHCH-H), 2.05 (m, 1H, PhCHCH-H) δ; CMR (75MHz, CDCl ₃ ) 177.6, 160.8, 153.7, 145.8, 142.0,

134.9, 133.7, 130.3, 127.6, 124.5, 118.1, 114.4, 74.8, 63.1, 55.6, 54.7, 53.5, 50, 6, 41.4, 35.3, 33.2 and 29.2 δ.

Step 2: (S) - (-) - 1- (4-methoxyphenyl) -4- [2- [6- (1,2,4-triazol-3-yl) isochroman-1-yl] ethyl] piperazine (S) - ( O-2)

(S) - (-) - 1- [2- [4- (4-Methoxyphenyl) -1-piperazinyl] ethyl] -N-dimethylaminomethylene isochroman-6-carboxamide (S) - (O-1, 208 mg, 0) , 46 mmol) with glacial acetic acid (1 mL) under argon. With vigorous stirring, hydrazine monohydrate (0.045 mL, 0.92 mmol) was added dropwise via syringe. The reaction was stirred at 20-25 ° C for 24 hours. The reaction mixture is diluted with water and

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The reaction mixture was partitioned between saturated aqueous sodium bicarbonate and methylene chloride. The combined organics were dried over sodium sulfate, filtered and capped. Purification of the crude by flash chromatography on 6 g of silica gel using 5% methanol in methylene chloride as eluent gave (S) - (-) 1- (4-methoxyphenyl) -4- (2- (6- (1)) 2,4-triazol-3-yl] isochroman-1-ylmethyl-piperazine (S) - (O2), m.p. = 195.5-196 ° C; R _f = 0.17 (5% methanol in methylene chloride); NMR (300 MHz, CDCl ₃ ) 8.04, 7.47, 7.46, 7.24, 6.85, 4.89, 4.16, 3.99, 3.80, 3.75, 3, 10, 2.98, 2.77, 2.67-2.59, 2.18 δ; CMR (75MHz, CDCl ₃ ) 159.4, 153.9, 146.9, 145.6,

139.8, 134.7, 127.3, 127.0, 125.3, 124.2, 118.2, 114.5, 63.1, 55.6, 54.7, 53.4, 50, 6, 33.0, 29.0 δ.

Example 78 (S) - (-) - 1- (4-Methoxy-phenyl) -4- (2- [6- (2-methyl-1,2,4-triazol-3-yl) -isochroman-1-yl-ethyl) -piperazine (S) - (O-2)

Following the procedure of Example 77, Step 2, with minor variations, methyl hydrazine (S) - (-) - 1- (4-methoxyphenyl) -4- [2- [6- (2-methyl-1,2,4- triazol-3-yl] isochroman-1-yl-ethyl] -piperazine (S) - (O-2), R f = 0.17 (5% methanol in methylene chloride) NMR (300 MHz, CDCl ₃ ) 8.04, 7.47, 7 , 46, 7.24, 6.85, 4.89, 4.16, 3.99, 3.80, 3.75, 3.10, 2.98, 2.77, 2.67-2.59 , 2.18, 2.07 δ; CMR (75MHz, CDCl ₃ ) 154.4,

153.8, 150.7, 145.7, 140.4, 134.9, 129.3, 126.2, 125.9, 125.3, 118.2, 114.4, 74.5.1,

62.9, 55.6, 54.7, 53.5, 50.6, 37.0, 33.2, 29.0 δ.

Example 79 (S) - (-) - 1- (4-Methoxyphenyl) -4- [2- [6- (2-phenylmethyl-1,2,4-triazol-3-yl) isochroman-1-yl] ethyl] piperazine (S) - (O-2)

Following the procedure of Example 77, Step 2 with minor variations, (S) - (-) - 1- (4-methoxyphenyl) -4- [2- [6- (2-phenylmethyl-1,2,4- triazol-3-yl] isochroman-1-yl] ethyl] piperazine (s) - (O-3), R _f = 0.28 (5% methanol in methylene chloride); NMR (300 MHz, CDCl3) 8.01 (s 1 H, triazole (C-H), 7.37-7.30 (m's, 5H, aromatic H), 5.43 (s, 2H, PhC-H ₂ ) 4.87 (wt, 1H, J = 5.1 Hz, PhC-H), 4.14 (m, 1H, PhCH ₂ cH-H), 3.79 (m, 1H, PhCH ₂ cH-H), 3.78 (s, 3H, OC-H ₃ ) (3.10) t, 4H, J = 4.9 Hz, four pip-H), 2.97 (m, 1H, PhCHCH-H), 2.73-2.52 (several m, 7H, PhCHCH-) H, NC-H ₂ and four pip-H), 2.16 (m, 1H, PhCHCH-H), 2.05 (m, 1H, PhCHCH-H) δ; CMR (75MHz, CDCl3) 155.0, 153.8, 151.3, 145.7, 140.5, 135.9, 134.9, 129.4, 129.0, 128.1, 126.9,

110

δ.

Example 80 (S) - (-) - 1- (4-Methoxyphenyl) -4- [2- [6- (1,2,4-oxadiazol-5-yl) isochroman-1-yl] ethyl] piperazine (S) - (O-2)

Mix hydroxylamine hydrochloride (83.4 mg, 1.2 mmol) with 5N aqueous sodium hydroxide solution (0.24 mL, 1.2 mmol), 70% acetic acid (1.2 mL) and immediately add (S) - (-) - 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] -N-dimethylaminomethylene isochroman-6-carboxamide (S) - (O-1, Example 77, Step 1, 450.6 mg, 1.0 mmol). The mixture was stirred at 20-25 ° C for 70 minutes. Dilute the reaction with water and raise the pH to 8.0 with saturated aqueous sodium bicarbonate. The aqueous mixture was extracted twice with methylene chloride. The combined organics were dried over sodium sulfate, filtered and concentrated. This material (R _f = 0.18 (5% methanol in methylene chloride)) is dissolved in anhydrous acetic acid (2 mL) and anhydrous p-dioxane (2 mL). An argon atmosphere was formed and the reaction was heated to 90 ° C for 2 hours. After cooling to 20-25 ° C, it is diluted with water and the pH is raised to 8.0 with saturated aqueous sodium bicarbonate. The aqueous mixture was extracted twice with methylene chloride. The combined organics were dried over sodium sulfate, filtered and concentrated. Purification of the crude by flash chromatography on 50 g of silica gel using 4% methanol in methylene chloride as eluent afforded (S) - (-) - 1- (4-methoxyphenyl) -4- [2- [6- ( 2-phenylmethyl-1,2,4-triazol-3-yl] isochroman-1-yl] ethyl] piperazine (S) - (O-2), mp = 126, -127 ° C; R _f = 0.36 ( 5% methanol in methylene chloride) NMR (300 MHz, CDCl ₃ ) 8.47 (s, 1H, oxadiazole C-H), 7.95 (d, 1H, J = 8.1 Hz, aromatic H), 7, 92 (s, 1H, aromatic H), 7.28 (d, 1H, J = 8.1 Hz, aromatic H), 6.86 (dzd, 4H, J a = 9.1 Hz, J _b = 21.2) Hz, aromatic H), 4.90 (wt, 1H, J = 5.1 Hz, PhC-H), 2.66-2.51 (several m, 6H, NC-H ₂ and four pipH), 2, 18 (m, 1H, PhCHCH-H), 2.07 (m, 1H, PhCHCH-H), δ; CMR (75MHz, CDCl ₃ ) 175.3, 157.8, 153.8, 145.7, 143 , 6, 153.3, 128.7, 125.8, 125.7, 122.0, 118.2, 114.4,

74.5, 62.8, 55.6, 54.6, 53.5, 50.6, 33.1, 29.0 δ.

Example 81 (S) - (-) - N-Methyl-1- [2- [4- (4-propionylphenyl) -1-piperazinyl] ethyl] isochroman-6-carboxamide (S) - (IX)

Step 1: (S) - (-) - 6-bromo-1- (2-hydroxyethyl) isochroman (S) - (S-1) · * ····

111

Mix (S) - (-) - (6-bromoisochroiman-1-yl) acetic acid (S) - (XI, Example 1,

Step 2, 16.27g, 60 mmol) with 100 mL tetrahydrofuran. A 10 M solution of boron methyl sulfide (18.0 mL, 0.18 mol) was added at 20-25 ° C and in a water bath. After one hour, the mixture was cooled to 0 ° C and 160 mL of methanol was slowly added. Caution: Hydrogen is evolved rapidly after about 1-2 minutes. The mixture is warmed to 20-25 ° C and the volatiles are removed under reduced pressure. The resulting mixture was diluted with 1M sodium hydroxide (150 mL) and extracted three times with ethyl acetate (100 mL). The combined organics were washed once with brine (100 mL), dried over sodium sulfate, filtered, and concentrated. The mixture is recrystallized from ethyl acetate / hexane to give (S) - (-) - 6-bromo-1- (2-hydroxyethyl) -isochroman (S) - (S-1), m.p. = 95-96 ° C; R _f = 0.28 (30% acetone / hexane); [α] D = -107 ° (c = 0.4069, methanol); IR (suspension) 3237, 3022, 1482, 1422, 1326, 1277, 1114, 1053, 1026, 972, 905, 894, 880, 816, 788 cm ^-1 ; NMR (300 MHz, CDCl ₃ ) 7.28 (m, 2H, aromatic), 6.92 (d, 1H, J = 8.2 Hz, aromatic), 4.92 (broad d, 1H, J-6, 8 Hz, methine, 4.15 (m, 1H, OCH _{2 a} ), 3.81 (t, 2H, J = 5.5 Hz, HO-CH ₂ ) 3.74 (m, 1H, OCH _2b ), 3.00 (m, 1H, Ph-CH _{2 a} ), 2.66 (dt, 1H, J = 16.4 Hz and J = 3.1 Hz, Ph-CH _2b ), 2.45 (broad s, 1H 1 H, 2.18 (m, 1H, C (H) -CH _{2 a} ), 2.02 (m, 1H, C (H) -CH _2b ) δ; CMR (75MHz, CDCl ₃ ) 136.5, 136.1, 131.8, 129.4, 126.3,

120.2, 75.9, 63.4, 60.8, 37.5, 28.8 δ; MS (EI, m / z) = 256;

Step 2: (S) - (-) - 1- (2-hydroxymethyl) isochroman-6-carboxylic acid, (S) - (S-2) methyl ester

Combine (S) - (-) - 6-bromo-1- (2-hydroxyethyl) isochroman (S) - (S-1, 5.14 g, 20.0 mmol), palladium acetate (225 mg, 1, 0 mmol), 1,3-bis (diphenylphosphino) propane (495 mg, 1.2 mmol) and 40.0 mL of dimethylformamide with diisopropylethanolamine (10.5 mL, 60.0 mmol) and methanol (16 mL, 0.40) mmol). The resulting mixture was purified six times with carbon monooxide under reduced pressure and rapidly heated to 75 ° C. The reaction mixture was stirred for 19 hours. The mixture was cooled to 20-25 ° C, diluted with 200 mL of water and extracted twice with dichloromethane (200 mL). The combined organics were washed once with water (100 mL), once with brine (100 mL), dried over magnesium sulfate, filtered, and concentrated. Purification of the crude by LC on 300 g (230400) silica gel eluting with 50% ethyl acetate / hexane gave (S) - (-) - 1- (2-hydroxymethyl) isochroman-6-carboxylic acid methyl ester (S). - (S-2), m.p. = 56-58 ° C; R _f = 0.23 (50% ethyl acetate / hexane); [ _.alpha. ] _D = -114 DEG (c =

112 ··· ·

0.8773, methanol); IR (suspension) 3407, 3336, 1718, 1434, 1418, 1296, 1274, 1261, 1250, 1195, 1112, 1055, 1022, 997, 754 cm ^-1 ; NMR (300 MHz, CDCl ₃ ) 7.79 (m, 2H, aromatic), 7.11 (d, 1H, J = 8.0 Hz, aromatic), 4.97 (broad d, 1H, J = 6, 8 Hz, methine, 4.15 (m, 1H, OCH _{2 a} ), 3.88 (s, 3H, CH ₃ ), 3.82 (t, 2H, J = 5.0 Hz, HO-CH ₂ ) 3.75 (m, 1H, OCH _{2 a} ), 3.01 (m, 1H, Ph-CH _{2 a} ), 2.71 (dt, 2H, J = 16.8 Hz and J = 3.3 Hz,

Ph-CH _2b and HO), 2.21 (m, 1H, C (H) -CH _{2 a} ), 2.03 (m, 1H, C (H) -CH _{2 b} )) δ; CMR (75MHz,

CDCI ₃ ) 166.9, 142.8, 134.1, 130.3, 128.3, 127.4, 124.8, 75.8, 63.4, 60.6, 52.1, 37.6 ,

28,9 δ.

Step 3: (S) - (-) - 1- (2-hydroxyethyl) -N-methylisochroman-6-carboxamide (S) - (S-3)

Mix (S) - (-) - 1- (2-hydroxyethyl) isochroman-6-carboxylic acid, (S) - (S-2, 473 mg, 2.0 mmol) methyl ester and 8.0 mL of 6M methylamine in methanol. The reaction vessel was sealed with a Teflon screw cap and the mixture was heated to 75 ° C. After 20 hours, the reaction mixture is cooled to 20-25 ° C, concentrated under reduced pressure and triturated with hexane to give (S) - (-) - 1- (2-hydroxyethyl) -N-methylisochroman-6-carboxamide (S) - (S). -3), m.p. = 90-101 ° C; R _f = 0.20 (5% methanol / dichloromethane); [α] _D = -119 ° (c = 0.8674, methanol); IR (suspension) 3350, 3274, 1648, 1514, 1572, 1564, 1422, 1336, 1320, 1156, 1107, 1078, 1058, 1045, 718 cm &^lt; -1 &gt;; NMR (300 MHz, CDCl ₃ ) 7.53 (m, 2H, aromatic), 7.08 (d, 1H, J = 8.7 Hz, aromatic), 6.32 (broad s, 1H, NH), 4 97 (broad d, 1H, J = 6.7 Hz, methine), 4.16 (m, 1H, OCH _2a ) 3.82 (t, 2H, J = 5.4 Hz, HO-CH ₂ ), 3.74 (m, 1H, OCH _{2 b),} 3.02 (d, 4H, J =

4.9 Hz, NCH ₃ and Ph-CH _{2 a} ), 2.71 (dt, 2H, J = 16.4 Hz and J = 3.2 Hz, Ph-CH _2b and HO), 2.21 (m, 1 H, C (H) -CH _{2 a} ), 2.03 (m, 1H, C (H) -CH _{2 b} ) δ.

Step 4: (S) - (-) - 1- (2-methanesulfonyloxyethyl) -N-methylisochroman-6-carboxamide (S) - (T-2) (S) - (-) - 1- (2-hydroxyethyl) - N-methylisochroman-6-carboxamide (S) - (S-3, 383 mg, 1.6 mmol) was mixed with dichloromethane and triethylamine (0.34 mL, 2.4 mmol) and cooled to 0 ° C. Methanesulfonyl chloride (0.15 mL, 1.95 mmol) was then added. After 15 minutes, the reaction is diluted with 10 mL of dichloromethane, washed once with 15 mL of water and once with 15 mL of brine, dried over magnesium sulfate, filtered and concentrated to give (S) - (-) - 1- (2-methanesulfonyloxyethyl) -N-methyl -isochroman-6-carboxamide

113 • 9 • (S) - (T-2), R _f = 0.35 (60% acetone / hexane); NMR (300 MHz, CDCl ₃ ) 7.53 (m, 2H, aromatic), 7.11 (d, 1H, J = 7.9 Hz, aromatic), 6.23 (broad s, 1H, NH), 4 90 (broad d, 1H, J = 7.4 Hz, methine), 4.46 (m, 1H, OCH _{2 a} ), 4.34 (m, 1H, M 5 O-CH _{2 a} ), 4.12 (m, 1H, MsO-CH _2b), 3.76 (m, 1H, OCH _{2 b),} 3.00 (m, 7H, NCH _3, CH ₃ S-, Ph-CH _2a), 2.73 (dt, 1H, J = 16.1 Hz and J = 3.2 Hz, Ph-CH _2b ), 2.42 (m, 1H, C (H) -CH _2a ), 2.14 (m, 1H, C (H) CH) _2b ) δ.

Step 5: (S) - (-) - N-Methyl-1- [2- [4- (4-propionylphenyl) -1-piperazinyl] ethyl] -isochroman-6-carboxamide (S) - (IX)

A mixture of (S) - (T-2, 509 mg, 1.5 mmol), 4'-piperazinopropiophenone (S) - (-) - 1- (2-methanesulfonyloxyethyl) -N-methyl-isochroman-6-carboxamide ( 393 mg, 1.8 mmol) and potassium carbonate (622 mg, 4.5 mmol) in acetonitrile was heated to 50 ° overnight and then brought to reflux for an additional 5 hours. The reaction mixture was then cooled to 20-25 ° C and concentrated to a residue which was partitioned between water and dichloromethane. The aqueous layer was extracted twice with dichloromethane and the combined organic layers were washed once in water, once in brine, dried over magnesium sulfate, filtered and concentrated to give (S) - (-) - N-methyl-1- [2- [4- (4-Propionylphenyl) -1-piperazinyl] ethyl] isochroman-6-carboxamide (S) - (IX), m.p. = 160-161 ° C; R _f = 0.20 (60% acetone / hexane); IR (suspension) 3274, 1669, 1640, 1607, 1543, 1522, 1415, 1407, 1315, 1233, 1200, 1156, 1142, 1111, 798 cm ^-1 ; NMR (300 MHz, CDCl ₃ ) 7.87 (d, 2H, J = 9.0 Hz, aromatic), 7.55 (m, 2H, aromatic), 7.14 (d, 1H, J = 8.6) Hz, aromatic), 6.85 (d, 2H, J = 9.0 Hz, aromatic), 6.24 (broad d, 1H, J = 4.6 Hz, NH), 4.86 (broad d, 1H J = 5.7 Hz, methine, 4.13 (m, 1H, OCH _{2 a} ), 3.76 (m, 1H, OCH _2b ), 3.34 (t, 4H, J = 7.4 Hz, O = C-CH ₂ ), 2.75-2.46 (m, 7H, Ph-NC (H ₂ ) -CH ₂ -NCH _{2 s} and Ph-CH _{2 b} ), 2.14 (m, 1H, C ( H-CH ₂ ), 2.02 (m, C (H) -CH _2b ), 1.19 (t, 3H, J = 7.4 Hz, C (H ₂ ) -CH ₃ ) δ; CMR (75MHz, CDCl ₃ ) 199.3, 168.0, 154.1, 141.5, 134.5, 132.7, 130.0, 127.7, 127.3, 125.0, 124.5 , 113.5, 74.4, 63.0, 54.5, 53.0, 47.4, 33.2, 31.2, 29.1, 26.8,

8.9 δ; MS (EI, m / z) 435.

Example 82 (S) (-) - 1- [2- [4- (4-Trifluoroacetylphenyl) -1-piperazinyl] ethyl] -N-methyl isochroman-6-carboxamide (S) - (IX)

Following the procedure of Example 81, Step 5, with minor variations, 4'-piperazinotrifluoromethylphenone (504 mg, 1.95 mmol) gave the crude product. This will clean up • ·

114

LC on 59 g (230-400) silica gel eluting with 50% acetone / hexane to give (S) - (-) - 1- [2- [4- (4-trifluoroacetylphenyl) -1-piperazinyl] ethyl] - N-methylisochroman-6-carboxamide (S) - (IX); Rf ₌ 0.20 (60% acetone / hexane).

Example 83 1 - 1- [2- [4- (4-Methoxy-phenyl) -1-piperazinyl] -ethyl] -isochroman-6-yl] -carbonyl-pyrrolidine (IX)

Following the procedure of Example 30 with minor variations, the crude product was obtained from pyrrolidine (1.26 mL, 15.0 mmol). This was purified by flash chromatography on 100 g of silica gel using a gradient of 5-10% methanol in methylene chloride and hexane to give 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] -isochroman- 6yl] carbonyl] pyrrolidine (IX), m.p. = 156.0-156.5 ° C; R _f = 0.35 (10% methanol in ethyl acetate); IR (suspension) 1615, 1609, 1563, 1514, 1441, 1254, 1234, 1154, 1106, 825 cm ^-1 ; NMR (300 MHz, CDCl ₃ ) 7.32 (d, 1H, J = 8.0 Hz, aromatic H). 7.29 (s, 1H, aromatic H), 7.12 (d, 1H, J = 7.9 Hz, aromatic H), 6.85 (q, 4H, J = 9.2 Hz, aromatic H), 4.85 (mt, 1H, J = 5.8 Hz, PhC-H), 4.17-4.10 (m, 1H), 33.80-3.72 (m, 1H), 3.76 ( s, 3H, PhOC-H ₃ ), 3.64 (t, 2H, J = 6.7 Hz, C (O) NC-H ₂ ), 3.11 (t, 2H, J = 6.6 Hz C (O) NC-H ₂ ), 3.11 (t, 4H, J = 4.8 Hz, four of pip-H), 2.99 (m, 1H), 2.73 (wt, 1H, J = 16.4 Hz), 2.66-2.49 (m's, 6H), 2.15 (m, 1H, pipCH-H), 2.04 (m, 1H, pipCH-H), 1.99-1.85 (two slightly overlapping quintets, 4H, J = 7.0 Hz, two of C (O) NCH ₂ CH ₂ ) δ; CMR (75MHz, CDCl ₃ ) 169.4, 153.6, 145.6, 139.7, 135.2, 134.0, 127.7, 124.7,

24.3 δ.

Example 84 (+/-) - 1- [2- (4-Phenyl-1-piperidinyl) ethyl] isochroman-6-carboxamide

Step 1 (+/-) -2- (6-bromoisochroman-1-yl) acetic acid

A mixture of ethyl (+/-) - 2- (6-bromoisochroman-1-yl) acetate (III, Example 1.1 step; 0.77 g, 2.58 mmol), sodium hydroxide (2N, 1.9 mL) ) and ethanol (5 mL) was stirred under reduced pressure for 75 minutes. To the residue were added a few ml of water and enough hydrochloric acid (4N) to bring the pH of the mixture to 2. Extract with ether and dry the organic layers over magnesium sulfate, filter, concentrate to give (+/-) -2- (6-bromoisochroman-). 1-yl) acetic acid (IV), NMR (CDCl ₃ ) 2.69-2.97, 3.83, 4.16, 5.18, 6.94 and 7.32 δ.

• · · ·

115

Step 2: (+/-) - 2- (6-bromoisochroman-1-yl) ethyl alcohol

To (+/-) -2- (6-bromoisochroman-1-yl) acetic acid (IV, Step 1; 0.82 g, 3.0 mmol) in dry THF (20 mL) was added boron methyl sulfide (0). , 86 g, 9.1 mmol). After stirring for 2.5 hours, methanol was added and the mixture was concentrated under reduced pressure. Again methanol is added and the mixture is concentrated twice. The residue was then partitioned between dichloromethane and aqueous sodium carbonate and the organic layers dried over sodium sulfate and concentrated to give (+/-) - 2- (6-bromoisochroman-1-yl) ethyl alcohol (S-1), 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, 7.28 δ.

Step 3: (+/-) - [2- (6-bromoisochroman-1-yl) ethyl] -4-phenylpiperidine

Methanesulfonyl chloride (0.22 mL, 2.84 mmol) was added to a mixture of (+/-) - 2- (6-bromoisochroman-1-yl) ethyl alcohol (S-1, Step 2; 0.599 g, 2.33 mmol), 4-dimethylaminopyridine (0.016 g, 0.131 mmol), diisopropylethylamine (0.49 mL, 2.81 mmol) and dry THF (7.5 mL) in an ice bath. Remove the ice bath and warm to 20-25 ° C. Once the methanesulfonate formation was complete (by TLC), ethylene glycol (2.4 mL), diisopropylethylamine (1.0 mL, 5.7 mmol) and phenylpiperidine (0.452 g, 2.80 mmol) were added and the mixture was heated at 80 ° C overnight. After cooling, the mixture was poured into water and extracted with dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue is chromatographed (silica gel; methanol / dichloromethane, 2/98) to give (+/-) - 1- (2- (6-bromoisochroman-1-yl) ethyl] -4-phenylpiperidine (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 7.17-7.32 δ.

Step 4: (+/-) - 1- [2- (4-phenyl-1-piperidinyl) ethyl] isochroman-6-carboxamide

A mixture of (+/-) - 1- [2- (6-bromoisochroman-1-yl) ethyl] -4-phenylpiperidine (VI, Step 1; 0.422 g, 1.05 mmol), DMF (2.7 mL) , 1,1,1,3,3,3-hexamethyldisilazane (Aldrich; 1.6 mL, 7.58 mmol), diisopropylethylamine (0.38 mL, 2.18 mmol), palladium acetate (0.012 g, 0.053 mmol) and 1,3-bis (diphenylphosphino) propane (0.026 g, 0.064 mmol) was degassed six times under reduced pressure and carbon monoxide was removed each time. The mixture was heated to 90 ° C overnight, then the cooled mixture was poured into hydrochloric acid (1N, 11 mL) and extracted with ether. The pH of the aqueous layer was adjusted to 12 using

116 · · · · · ** ♦ ** ** ♦ ** ♦ ♦ _• ♦ ** ♦ * ♦ * * * * * * * * * * * * Aqueous sodium hydroxide. The aqueous layer was then extracted three times with ethyl acetate and the combined organic layers were washed with salt, dried over magnesium sulfate, and concentrated under reduced pressure. The residue is chromatographed (silica gel; methanol / dichloromethane, 2/98) to give (+/-) - 1- [2- (4-phenyl-1 piperidinyl) ethyl] isochroman-6-carboxamide (VII), NMR (CDCl 3). ₃ ) 1.83, 1.99-2.22, 2.51-2.62, 2.74-2.79, 2.97-3.08, 3.78, 4.14, 4.78, 5.63, 6.05, 7.19-7.33 and 7.59 δ.

Example 85 N-Methyl-1- [2- (4-phenyl-1-piperidinyl) ethyl] isochroman-6-carboxamide, maleic acid salt Step: (+/-) - N-Bis (tert-butyloxycarbonyl) -1 - [ 2- (4-phenyl-1 piperidinyl) ethyl] isochroman-6-carboxamide

Following the procedure of Example 3, Step 1, with slight variation, (+/-) - 1- [2- (4-phenyl-1-piperidinyl) ethyl] isochroman-6-carboxamide (VII, Example 84, 0.231 g, 0.634 mmol) was formed. ) after chromatography (silica gel; methanol / dichloromethane, 2/98) (+/-) - Nbis (tert-butyloxycarbonyl) -1- [2- (4-phenyl-1-piperidinyl) ethyl] isochroman-6-carboxamide (VIII) 1 H, 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 7.60-7.65 δ.

Step 2: N-methyl-1- [2- (4-phenyl-1-piperidinyl) ethyl] isochroman-6-carboxamide, maleic acid salt

The methyl amine gas condenses in a high pressure reaction on a glass reaction vessel cooled to -78 ° C (under argon atmosphere) containing a mixture of (+/-) - N-bis (tert-butyloxycarbonyl) -1- [2- (4- phenyl-1-piperidinyl) ethylisochroman-6-carboxamide (VIIIe, Step 1, 0.2818 g, 0.499 mmol) and dichloromethane (4 mL). After a few ml of liquid condensed methylamine, the reaction vessel was sealed, warmed to 20-25 ° C and stirred overnight. The vessel was then cooled again to 78 ° C and the cap removed. After reheating to 20-25 ° C, the mixture was concentrated under reduced pressure and the 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). TO

N-methyl-1- [2- (4-phenyl-1-piperidinyl) ethyl] isochroman-6-carboxamide was added maleic acid (0.0360 g, 0.310 mmol) in dichloromethane / methanol to give N-methyl-1. - [2- (4-Phenyl-1-piperidiryl) ethyl] isochroman-6-carboxamide, salts

117

Maleic acid (B-IX), NMR (CDCl ₃ ) 1.84, 2.05-2.20, 2.54.2.66, 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 δ.

Example 86 (+/-) - 1- [2- [4- (2,4-dichlorophenyl-1-piperazinyl) ethyl] isochroman-6-carboxamide

Step 1: 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) was warmed to 165 ° C for 6.8 hours, then cooled and partitioned between dichloromethane and aqueous sodium carbonate. The organic layers were dried over sodium sulfate, concentrated under high vacuum to give 1- (2,4-dichlorophenyl) piperazine (Q-3) which was pure enough for use in the second step without further purification.

Step 2: (+/-) - 1- [2- (6-bromoisochroman-1-yl) ethyl] -4- (2,4-dichlorophenyl) piperazine

Following the procedure of Example 84, Step 3, with minor variations of (+/-) -2- (6-bromoisochroman-1-yl) ethyl alcohol (S-1) (Example 84, Step 2; 0.60 g, 2.31 mmol) ), 4-dimethylaminopyridine (0.018 g, 0.147 mmol), diisopropylethyleneamine (0.49 mL, 2.81 mmol), methanesulfonyl chloride (0.22 mL, 2.84 mmol) and dry THF (7.5 mL) are converted to methanesulfonate ( T-1). Methanesulfonate is reacted with diisopropylethyleneamine (1.0 mL, 5.7 mmol), 1- (2,4-dichlorophenyl) piperazine (Q-3, Step 1; 0.65 g, 2.82 mmol) and ethylene glycol, after chromatography (silica gel; methanol / dichloromethane, 2/98) affords (+/-) - 1- [2- (6-bromoisochroman-1-yl) ethyl] -4- (2,4-dichlorophenyl) 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, 26-7,36 δ.

Step 3: (+/-) - 1- [2- [4- (2,4-dichlorophenyl-1-piperazinyl) ethyl] isochroman-

6-carboxamide

Following the procedure of Example 84, Step 4, with minor variations, (+/-) - 1- [2- (6-bromoisochroman-1-yl) ethyl] -4- (2,4-dichlorophenyl) piperazine (VI, 1) was formed. step; 0.373 g, 0.794 mmol) after chromatography (silica gel; methanol / dichloromethane, 2/98) 0.095 g of (+) - 1- [2- [4- (2,4-dichlorophenyl-1-piperazinyl) ethyl] isochroman -6-carboxamide (VII), NMR (CDCl ₃ ) 2.05, 2.15, 2.50-2.80, 3.05, 3.78, 4.15, 4.78, 5.62, 6.04, 6.96, 7.19, 7.35 and 7.60 δ.

• · · · ·

118

Example 87 (+/-) - N-Methyl-1- (2- (4- (2,4-dichlorophenyl-1-piperazinyl) ethyl) isochroman-6-carboxamide

Step 1: (+/-) - N-bis (tert-butyloxycarbonyl) -1- (2- (4- (2,4-dichlorophenyl-1-piperazinyl) ethyl) isochroman-6-carboxamide

Following the procedure of Example 3, Step 1, with minor variations, (+/-) -1- (2- (6-bromoisochroman-1-yl) ethyl) -4- (2,4-dichlorophenyl) piperazine (VI, Example) was formed. Step 3; 0.0854 g, 0.198 mmol), 4-dimethylaminopyridine (0.0046 g, 0.0377 mmol) and di-tert-butyl dicarbonate (0.0982 g, 0.450 mmol) after chromatography (silica gel) methanol / dichloromethane, 2/98) (+/-) - N-bis (tert-butyloxycarbonyl) -1- (2- (4- (2,4-dichlorophenyl-1-piperazinyl) ethyl) isochroman-6-carboxamide ( (MH +), 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 δ.

Step 2: (+/-) - N-Methyl-1- (2- (4- (2,4-dichlorophenyl-1 piperazinyl) ethyl) isochroman-6-carboxamide

Following the procedure of Example 85, Step 2 with minor variations, (+/-) - Nbis (tert-butyloxycarbonyl) -1- (2- (4- (2,4-dichlorophenyl-1-piperazinyl) ethyl) isochroman-6-carboxamide) (VIIIa, Step 1; 0.104 g, 0.164 mmol) after solid phase chromatography (silica gel; methanol / dichloromethane, 1.5 / 98.5 to 3/97 to 5/95). This material was recrystallized from acetonitrile / hexane to give formation of (+/-) - N-methyl-1- (2- (4- (2,4-dichlorophenyl-1-piperazinyl) ethyl) isochroman-6-carboxamide (IX), MS (m / z) = 447; mineral oil; highest 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 7.54 δ.

Example 88 1- [2- [4- (3-Chloro-4-methoxy-phenyl) -1-piperazinyl) -ethyl] -isochroman-6-carboxamide

Step 1: 1- (3-chloro-4-methoxyphenyl) piperazine

A mixture of 3-chloro-p-anisidine (R-2, 0.633 g, 4.00 mmol), bis (2-chloroethyl) amine hydrochloride (0.860 g, 4.80 mmol), potassium carbonate (1.11 g, 8, 00 mmol) and dimethylacetamide (6 ml) were stirred at 100 ° C for 18 hours and then cooled. The mixture was partitioned between dichloromethane, water and aqueous sodium carbonate and the organic layers were dried over sodium sulfate and concentrated. The rest is analyzed by chrome

119 (silica gel; methanol / dichloromethane, 8/92) to give 1- (3-chloro-4-methoxyphenyl) piperazine (R-3), NMR (CDCl ₃ ) 3.05, 3.86, 6.80, 6, 87 and 6.99 δ.

Step 2: (+/-) - 1- [2- (6-bromoisochroman-1-yl) ethyl] -4- (3-dichloro-4-methoxyphenyl) piperazine

Following the procedure of Example 84, Step 3, (+/-) - 2- (6-bromoisochroman-1-yl) ethyl alcohol (S-1, Example 84, Step 3, 0.450 g, 1.75 mmol), 4 -dimethylaminopyridine (0.012 g, 0.090 mmol), diisopropylethylamine (0.32 mL, 1.84 mmol), methanesulfonyl chloride (0.14 mL, 1.81 mmol) and dry THF (5.6 mL) are converted to methanesulfonate . Diisopropylethylamine (0.18 mL, 1.03 mmol) and magnesium chloride (0.08 mL, 1.03 mmol) were added to form the complete methanesulfonate. Diisopropylethylamine (0.65 mL, 4.26 mmol), 1- (3-chloro-4-methoxyphenyl) piperazine (Step 1; 0.398 g, 1.75 mmol) and ethylene glycol (1.8 mL) were then added to the methanesulfonate. ). The mixture was then stirred at 80 ° C for 3 hours. Additional 1- (3-chloro-4-methoxyphenyl) piperazine (0.0443 g, 0.195 mmol) was added and the mixture was heated for an additional 3 hours. After cooling, the mixture was partitioned between dichloromethane and aqueous sodium carbonate. The organic layers were dried over sodium sulfate and concentrated. The residue is chromatographed (silica gel; methanol / dichloromethane, 8/92) to give (+/-) - 1- [2- (6-bromoisochroman-1-yl) ethyl] -4- (3-dichloro-4-methoxyphenyl) 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 , 77-6.78, 6.98 and 7.29 δ.

Step 3: (+/-) - 1- [2- [4- (3-chloro-4-methoxyphenyl) -1 piperazinyl) ethyl] isochroman-6-carboxamide

Following the procedure of Example 84, Step 4, with minor variations, (+/-) - 1- (2- (6-bromoisochroman-1-yl) ethyl) -4- (3-dichloro-4-methoxyphenyl) piperazine (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), diisopropylethylamine (0.34 mL) , 1.95 mmol), palladium acetate (0.0110 g, 0.049 mmol) and 1,3-bis (diphenylphosphino) propane (0.024 g, 0.0575 mmol) after chromatography (silica gel; methanol / dichloromethane, 2/98) 1- [2- [4- (3-chloro-4-methoxyphenyl) -1-piperazinyl) ethyl] isochroman-6-carboxamide (VII). 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 δ.

• · · ·

120

Example 89 (+/-) 1- [2- [4- (3-Chloro-4-methoxyphenyl) -1-piperazinyl) ethyl] -N-methylisochroman-6-carboxamide Step: (+/-) - N-bis ( tert-butyloxycarbonyl) -1- [2- [4- (3-chloro-4-methoxyphenyl) -1-piperazinyl) ethyl] -N-methylisochroman-6-carboxamide

Following the procedure of Example 3, Step 1, with minor variations, 1- [2- [4- (3-chloro-4-methoxyphenyl) -1-piperazinyl) ethyl] isochroman-6-carboxamide (VII, Example 3, Step 1) 0.153 g, 0.355 mmol), 4-diethylaminopyridine (0.0086 g, 0.0704 mmol) and di-tert-butyl dicarbonate (0.186 g, 0.853 mmol) after chromatography (silica gel; methanol / dichloromethane, 2/98) (+ T-N-bis (tert-butyloxycarbonyl) -1 [2- [4- (3-chloro-4-methoxyphenyl) -1-piperazinyl) ethyl] -N-methylisochroman-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 δ.

Step 2: (+/-) - N-Methyl-1- [2- [4- (3-chloro-4-methoxyphenyl) -1-piperazinyl) ethyl] isochroman-6-carboxamide

Following the procedure of Example 85, Step 2, with minor variations, (+/-) - Nbis (tert-butyloxycarbonyl) -1- [2- [4- (3-chloro-4-methoxyphenyl) -1-piperazinyl) ethyl] is formed. isochroman-6-carboxamide (VII, Step 1; 0.183 g, 0.290 mmol) after chromatography (silica gel; methanol / dichloromethane, 2/98) 0.118 g of product. The product crystallized from ethyl acetate / methanol / hexane and then from methyl acetate / dichloromethane to give (+/-) - 1- [2- [4- (3-chloro-4-methoxyphenyl) -1-piperazinyl) ethyl] -N methyl isochroman-6-carboxamide (IX), MS (m / z) 443; IR (mineral oil, highest peaks) 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 7.54 δ.

Example 90 N- (2-hydroxyethyl) -1- [2- [4- (4-methoxyphenyl) -1-piperazinyl) ethyl] -N-methylisochroman-6-carboxamide

Step 1: (+/-) -1- 2- (6-bromoisochroman-1-yl) acetyl 1-4- (4-methoxyphenyl) piperazine •

121

A mixture of (+/-) - 2- (6-bromoisochroman-1-yl) acetic acid (IV, Example 84, Step 1; 4.66 g, 0.0172 mol), dichloromethane (18 mL), DMF (18 ml), diethylcyanophosphonate (3.4 ml, 0.022 mol), 1- (4-methoxyphenyl) piperazine hydrochloride (R-3) (Aldrich; 4.78 g, 0.0.21 mol) and triethylamine (6.5 ml) (0.0.47 mol) was stirred at 20-25 ° C for 2.5 hours. Saturated sodium bicarbonate (100 mL) was added to the mixture, the mixture was stirred for an additional 20 minutes and finally extracted with dichloromethane. The organic layers were dried over magnesium sulfate and concentrated under reduced pressure. The residue was washed twice with hexane (discarded) and concentrated again under reduced pressure. It is then chromatographed (silica gel; ethyl acetate / hexane 50/50) to give (+/-) -1- 2- (6-bromoisochroman-1-yl) acetyl-4- (4-methoxyphenyl) 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, 7.31 δ.

Step 2: (+/-) - 1- [2- (6-bromoisochroman-1-yl) ethyl] -4-methoxyphenylpiperazine

Following the procedure of Example 1, Step 4, using borane methyl sulfide (14 mL) instead of borane-THF, and (+/-) - 1-2- (6-bromoisochroman-1-yl) acetyl-4- (4-methoxyphenyl) piperazine (V, Step 1; 5.83 g, 0.013 mol) 4.33 g (+/-) - 1- (2- (6-bromoisochroman-1-yl) ethyl) -4-methoxyphenylpiperazine (VI), NMR ( CDCI ₃ ) 2.00, 2.12, 2.46-2.71, 2.95, 3.10, 3.75, 4.11, 4.78, 6.87, 6.97 and 7.29 δ.

Step 3: (+/-) - 1- [2- [4- (4-Methoxyphenyl) -1-piperazinyl-ethyl] -isochroman-

6-carboxamide

Following the procedure of Example 84, Step 4, starting from (+/-) -1- [2- (6-bromoisochroman-1-yl) ethyl] -4- (methoxyphenyl) piperazine (VI, Step 2; 4.29 g, 9). , 95 mmol) (+/-) - 1- (2- (4- (4-methoxyphenyl) -1-piperazinyl] ethyl) isochroman-6-carboxamide (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 7.59 δ.

Step 4: (+/-) - N-bis (tert-butyloxycarbonyl) -1- [2- [4- (methoxyphenyl) -1 piperazinyl) ethyl] isochroman-6-carboxamide

Following the procedure of Example 3, Step 1, (+/-) - 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] isochroman-6-carboxamide (VII, Step 3; 1.97 g) was formed. , 4.97 mmol), 4-dimethylaminopyridine (0.0816 g, 0.668 mmol) and di-tert-butyl bicarbonate (2.56 g, 0.0117 mol) (+/-) - N-bis (terobutyloxycarbonyl) -1 - [2- [4- (methoxyphenyl) -1122 · perazinyl) ethyl] isochroman-6-carboxamide (VIII), NMR (CDCl ₃ ) 1.39, 2.03, 2.15, 2.532.78, 2, 99, 3.11, 3.77, 4.13, 4.88, 6.85, 7.21 and 7.63 δ.

Step 5: N- (2-hydroxyethyl) -1- [2-4- [4- (methoxyphenyl) -1 piperazinyl) ethyl] isochromanyl-6-carboxamide

A mixture of (+/-) - N -bis (tert-butyloxycarbonyl) -1- [2- [4- (methoxyphenyl) -1-piperazinyl) ethyl] isochroman-6-carboxamide (VIIIa, Step 4; 0.216 g, 0.362 mmol) ), dichloromethane (7 mL) and ethanolamine (0.2 mL, 3.31 mmol) were stirred overnight at 20-25 ° C. The mixture was then partitioned between water and dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue is chromatographed (silica gel; methanol / dichloromethane (4/96)) to give a product which crystallizes from dichloromethane / hexane / ethyl acetate to give 0.090 g of N- (2-hydroxyethyl) -1- [2-4- [4- ( methoxyphenyl) -1-piperazinyl) ethyl] isochroman-6-carboxamide (IX), MS (m / z) 439; IR (mineral oil) (highest peak) 1514, 1631, 1554, 1031, 3293, 1249, and 1613 cm ^-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 δ.

Example 91 1- [2- [4- (4-Methoxyphenyl) -1-piperazinyl] ethyl] -N (phenylmethoxy) isochroman-6-carboxamide

A mixture of (+/-) - N-bis (tert-butyloxycarbonyl) -1- [2- [4- (methoxyphenyl) -1-piperazinyl) ethyl] isochroman-6-carboxamide (VIII, EXA ret 7, step 4); 0.206 g, 0.345 mmol), THF (7 mL), O-benzylhydroxylamine hydrochloride (0.0645 g, 0.4041 mmol) and diisopropylethylamine (0.12 mL, 0.689 mmol) were heated and boiled for 7 hours. The mixture was then stirred at 20-25 ° C for two days, to the end was added additional O-benzylhydroxylamine hydrochloride (0.323 g, 2.03 mmol) and diisopropylethylamine (0.35 mL, 2.01 mmol). After stirring overnight at 85-90 ° C, THF was removed by concentration under reduced pressure and the residue partitioned between dichloromethane and water. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give the crude product. This material was chromatographed (silica gel; methanol dichloromethane (4/96)) to give a product which was recrystallized from hexane / ethyl acetate / dichloromethane / methanol to give the title compound. MS (m / z) 501; NMR (CDCl3) 2, 03, 2.12, 2.48-2.75, 3.10, 3.77, 4.11, 4.84, 5.05, 6.86, 7.14 and 8.43 δ.

• ♦ · · · ·

123: · · · * ·· ::: *::. : · ·· ::

• ·· ·· · · ··., ,,

Example 92 (+/-) - 1- [1- [2- [4- (4-Methoxy-phenyl) -1-piperazinyl] -ethyl] -isochroman-6-yl] -4-methyl-piperazine

(+/-) - N-Bis (tert-butyloxycarbonyl) -1- [2- [4- (4-methoxyphenyl) -1-piperazinyl) ethyl] isochroman-6-carboxamide (VII, EXA ret 7, Step 4) 0.211 g, 0.355 mmol), THF (11 mL), diisopropylethylamine (0.6 mL, 3.4 mmol) and 1-methylpiperazine (0.4 mL, 3.6 mmol) were stirred at 20-25 ° for 2 days. The THF was then removed under reduced pressure and the residue partitioned between dichloromethane and water. The combined organic layers were dried over sodium sulfate, concentrated under reduced pressure to give the crude product. This material was analyzed by chromatography (silica gel; methanol / dichloromethane, 2/98 to 4/96). The product precipitates from ethyl acetate and hexane to give the title compound and then 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. , 18 δ.

Example 93 (+/-) - N-Hydroxy-1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] -N-methylisochroman-6-carboxamide

(+/-) - N-bis (tert-butyloxycarbonyl) -1- [2- [4- (methoxyphenyl) -1-piperazinyl) ethyl] isochroman-6-carboxamide (VIII, EXA ret 7, step 4); 0.205 g, 0.344 mmol), dichloromethane (7 mL), N-methylhydroxylamine hydrochloride (0.271 g, 3.25 mmol) and diisopropylethylamine (0.60 mL, 3.44 mmol) were stirred at 20-25 ° C overnight. The mixture was partitioned between dichloromethane and water. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue is chromatographed (silica gel; methanol dichloromethane, 2/98 to 4/96) to give the desired product which is recrystallized from hexane / methanol / dichloromethane / ethyl acetate to give 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 7.33 δ.

Example 94 (S) - (-) - 1- [2- [4- [4- (tert-Butyloxycarbonyl) phenyl] -1-piperazinyl] ethyl] -N-methylisochroman-6-carboxamide (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 was heated at 40 ° C for 1 hour, then the cooled mixture was poured into ethyl ether (1300 mL) and washed with chloro acid.

124: ·. . ::

• Hydrogen (10%, 250 ml), followed by water (250 ml) and then carbonate potassium (10%, 250 mL). The ether layer was dried over sodium sulfate and concentrated under reduced pressure. The residue is 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 7.99 δ.

Step 2: 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 (121 mL) was heated to 155 ° C for 160 minutes. After cooling, the solid was removed by filtration and washed with hexane. The combined filtrates were dried over sodium sulfate, concentrated under high vacuum, and the residue partitioned between dichloromethane and water. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The slightly wet solids from the solvent precipitated in hexane, the solid was collected and washed with hexane. It was then dried at 20-25 ° C under reduced pressure to give t-butyl 4- (piperazin-1-yl) benzoate. Additional product was obtained by concentrating the filtrate and chromatography (silica gel; methanol / dichloromethane / ammonium hydroxide, 3.5 / 96.5 / 0.5 to 7/93 / 0.5) to give 4- (piperazin-1-yl) benzoic acid, t-butyl ester (Q-3); MS (m / z) 262; NMR (CDCl ₃ ) 1.57, 3.01, 3.25, 6.84 and 7.87 δ.

Step 3: (S) - (-) - 4- [4- [2- (6-bromoisochroman-1-yl) ethyl] -1-piperazinyl] benzoic acid, tert-butyl ester (V-1)

Following the procedure of Example 84, Step 3, with minor variations, (S) - (-) 2- (6-bromoisochroman-1-yl) ethyl alcohol (S-1) was formed (Example 6, Step 1; 4.95 g). , 0.0193 mol) and 4- (piperazin-1-yl) benzoic acid, t-butyl ester (Q-3) (Step 2; 5.42 g, 0.0206 mol) of the title compound, MS (m / m) (z) 500; NMR (CDCl ₃ ) 1.57, 2.02, 2.12, 2.502.70, 2.95, 3.32, 3.73, 4.10, 4.79, 6.85, 6.97, 7 , 29 and 7.86 δ.

Step 4: (S) - (-) - 1- [2- [4- [4- (tert-Butyloxycarbonyl) phenyl] -1-piperazinyl] ethyl] -N-methylisochroman-6-carboxamide

To a mixture of (S) - (-) - 4- [4- [2- (6-bromoisochroman-1-yl) ethyl] -1-piperazinyl] benzoic acid, tert-butyl ester (V-1) (Step 3) 2.63 g (5.25 mmol) in dimethylacetamide (45 mL) which was degassed was added palladium (II) acetate under an argon atmosphere.

125 (0.0616 g, 0.274 mmol), 1.3 bis (diphenylphosphino) propane (0.164 g, 0.396 mmol) and diisopropylerthylamine (1.8 mL, 0.0103 mol). The mixture is degassed a second time under an artgon atmosphere. It is then heated to 60-65 ° C with bubbling carbon monoxide. After a few minutes, methylamine also starts to bubble out of the mixture. After heating at 60-65 ° C for 6.5 hours, the mixture was stored in a refrigerator overnight. Then, filter through silica and add a further portion of palladium acetate (0.065 g, 0.290 mmol), 1,3bis (diphenylphosphino) propane (0.162 g, 0.329 mmol) and diisopropylethyleneamine (1.8 mL, 0.0103 mol) and heat to the filtrate and heat. 4 hours at 60 ° C with the addition of carbon monoxide and methylamine gases, then the mixture is cooled and concentrated under reduced pressure. The residue was partitioned between dichloromethane and water. The combined organic layers were washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure. The residue is analyzed by chromatography (silica gel; methanol / dichloromethane, 2/98 to 4/96). The combined impure fractions were 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 (+/-) - 1- [2- [4- [4- (Methoxyphenyl) -1-piperazinyl-ethyl] -isochroman-6-ol, methylcarbamate ester (X-6)

Step 1: (+/-) - 2- (6-hydroxyisochroman-1-yl) acetic acid, ethyl ester

To an ice-cooled mixture of 3-hydroxyphenyl alcohol (X-1) (2.9 g, 21 mmol) and ethyl 3,3-diethoxypropionate (4.75 g, 25 mmol) in nitromethane (5 mL) was added boron ether trifluoride (3). , 44 mL). After addition of all components (about 5 minutes), the reaction is stirred for an additional 60 minutes. The mixture was then partitioned between dichloromethane and aqueous ammonium chloride. The organic layers were dried over sodium sulfate and concentrated. The residue is chromatographed (silica gel; ethyl acetate / hexane 10/90 to 30/70) to give (+/-) - 2- (6-hydroxyisochroman-1-yl) acetic acid, ethyl ester (X-2), NMR (CDCl ₃ ) 1.28, 2.6-3.0, 3.79, 4.09, 4.21, 5.07, 5.19, 6.60 and 6.91 δ.

Step 2: (+/-) - 2- (6-hydroxyisochroman-1-) acetic acid

To (6-hydroxyisochroman-1-) acetic acid, ethyl ester (X-2) (Step 1; 2.38 g, 10.1 mmol) in ethanol (10-15 mL) is added sodium hydroxide (2N, 10 ml). The mixture was stirred overnight and the ethanol was then removed under reduced pressure. The resulting aqueous mixture was then diluted with a few mL of salt and acidified with hydrochloric acid (3N).

126 was extracted with ethyl ester and concentrated. To remove excess starting material, the residue was partitioned between aqueous sodium carbonate and dichloromethane. The organic phase was removed and the aqueous phase was acidified with concentrated hydrochloric acid and then extracted with ether. The ether layer was dried over magnesium sulfate and concentrated. The concentrate crystallized from THF / hexane / dichloromethane to give (+/-) - 2- (6-hydroxyisochroman-1-yl) acetic acid (X-3), NMR (CDCl ₃ ) 2.1-3.0, 3.81 , 4.15, 5.2, 6.59, 6.68 and 6.90.

Step 3: (+/-) -1- 2- (6-hydroxyisochroman-1-yl) acetyl-4- (4-methoxyphenyl) piperazine

To a mixture of (+/-) - 2- (6-hydroxyisochroman-1-yl) acetic acid (X-3) (Step 2; 0.361 g, 1.76 mmol), 1- (4-methoxyphenyl) piperazine dihydrochloride ( 0.458 g, 1.73 mmol), dichloromethane (5 mL) and DMF (0.5 mL) were added triethylamine (0.80 mL, 5.72 mmol) then diethyl cyanophosphonate (0.29 mL, 1.91 mmol). . After stirring for 50 minutes, water was added to the mixture and stirred for 1 hour. The mixture was then extracted with dichloromethane and the organic layers were separated, mixed and washed with aqueous sodium carbonate. The organic layers were dried over sodium sulfate and concentrated. The residue was crystallized from ethyl acetate-dichloromethane-methanol to give (+/-) - 1-2- (6-hydroxyisochroman-1-yl) acetyl-4- (4-methoxyphenyl) piperazine (X-4), 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 δ.

Step 4: (+/-) - 1- [2- [4- [4- (methoxyphenyl) -1-piperazinyl] ethyl] isochroman-6-ol

(+/-) -1- 2- (6-hydroxyisochroman-1-yl) acetyl-4- (4-methoxyphenyl) piperazine (X-4) (Step 3; 0.375 g, 0. 98 mmol), boron methyl sulfide (0.28 mL, 2.9 mmol) and THF (15 mL) were stirred overnight at 20-25 ° C and then at 80 ° C for two hours. After cooling, the mixture was treated with methanol and concentrated under reduced pressure. Methanol addition and concentration was repeated two more times and the residue was then stirred for 3 hours in hydrochloric acid / acetone (4N, 1/9, 5 mL). The acetone is then removed under reduced pressure and the residue is partitioned between dichloromethane and aqueous sodium carbonate. The organic layers were dried over sodium sulfate and concentrated. The residue was crystallized from dichloromethane / hexane to give (+/-) - 1- [2- [4- [4- (methoxyphenyl) -1-piperazinyl] ethyl] -isochroman-6- ol (X-5), NMR (CDCl 3) 2.05, 2.21, 2.5-2.7, 2.94, 3.13, 3.70, 3.76, 4.10, 4.82 , 6,41,6,57 and 6,80-6,91 δ.

Step 5: (+/-) - 1- [2- [4- [4- (methoxyphenyl) -1-piperazinyl-ethyl] -isochroman-6-ol, methyl carbamate ester (X-6)

To (S) - (-) - 1- [2- [4- [4- (methoxyphenyl) -1-piperazinyl] ethyl] -isochroman-6-ol (X-5) (Step 4; 0.064 g, 0.17 mmol) and DBU (0.032 g, 0.21 mmol) in dichloromethane (2 mL) were added methyl isocyanate (0.31 mL; 0.52 mmol). After stirring for 1.5 hours, the mixture was partitioned between dichloromethane and dilute sodium hydroxide. The organic layers were dried over sodium sulfate and concentrated. The residue is chromatographed (silica gel; methanol / dichloromethane 2/98) to give (+/-) - 1- [2- [4- [4- (methoxyphenyl) -1-piperazinyl] ethyl] -isochroman-6-ol, methyl ester carbamate (X-6), which crystallizes from ether / hexane. MS (m / z) at 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 7.08 δ.

Example 96 (+/-) - 1- [2- [4- [4- (Aminocarbonyl) phenyl] -1-piperazinyl] ethyl] -N-methylisochromanyl-6-carboxamide

Step 1: (+/-) - 1- (2-chloroethyl) isochroman-6-ol

To a mixture of 3-hydroxyphenyl 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 was added and the mixture was partitioned between dichloromethane, water and salt. The organic layers were dried over sodium sulfate and concentrated. The residue is chromatographed (silica gel; ethyl acetate / hexane 10/90) to give (+/-) - 1- (2-chloroethyl) isochroman-6-ol (Y-2) containing a small amount of (+/-) - 1- (2-ethoxyethyl) isochroman-6-ol as an impurity. The material was used without further purification in 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 6.95 δ.

Step 2: (+/-) - 1- (2-chloroethyl) isochroman-6-ol, sulfuric acid trifluoromethane ester

To a mixture of (+/-) - 1- (2-chloroethyl) isochroman-6-ol (Y-2.1 step; 0.079 g, 0.371 mmol), triethylamine (0.0413 g, 0.408 mmol), 4-dimethylaminopzridine (0.0009 g, 0.0074 mmol) and dichloromethane (1 mL) cooled to -78 ° C were added anhydride

128 Sulfuric trifluoromethane acid (0.069 g, 0.408 mmol) was added. Remove the cooling bath and slowly warm the mixture to 20-25 ° C. After stirring for 60 minutes, the mixture was partitioned between dichloromethane and aqueous ammonium chloride. The organic layers were dried over sodium sulfate and concentrated. The residue is chromatographed (silica gel; ethyl acetate / hexane 10/90) to give (+/-) - 1- (2-chloroethyl) isochroman-6-ol, sulfuric acid trifluoromethane ester (Y-3), NMR (CDCl 3). ₃ ) 2.24, 2.31, 2.73, 2.78, 3.00, 3.67, 3.80, 4.12, 4.94 and 7.05-7.18 δ.

Step 3: (+/-) - 1- (2-chloroethyl) -N-methylisochroman-6-carboxamide

(+/-) - 1- (2-chloroethyl) isochroman-6-ol, sulfuric acid trifluoromethane ester) Y-3, Step 2; 0.291 g, 0.844 mmol) in DMF (1.5 mL) was degassed under reduced pressure over five minutes and then palladium acetate (0.018 g, 0.084 mmol) and 1,3bis (diphenylphosphino) propane (0.52g, 0.127 mmol) were added. ). After addition of diisopropylethylamine (0.29 mL, 1.69 mmol), carbon monoxide boils. Methylamine is then boiled and the bath temperature is raised to 50 ° C. Methylamine gas and carbon monoxide gas were added again over 1 hour, and finally palladium acetate (0.010 g) and 1,3-bis (diphenylphosphino) propane (0.025 g) were added at the end. After four hours the mixture was cooled and then partitioned between ether, aqueous ammonium chloride, ammonium chloride-brine and brine. The organic layers were dried over magnesium sulfate and concentrated. The remaining material is chromatographed (silica gel; methanol / dichloromethane 2/98) to give (+/-) - 1- (2-chloroethyl) -N-methylisochroman-6-carboxamide (Y-4), 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 7.56 δ.

Step 4: (+/-) - 1- [2- [4- [4- (aminocarbonyl) phenyl] -1-piperazinyl] ethyl] -N-methylisochromanyl-6-carboxamide

A mixture of (+/-) - 1- (2-chloroethyl) -N-methylisochroman-6-carboxamide (Y-4, step 3; 0.0937 g, 0.369 mmol) of 4- (piperazin-1-yl) benzamide (Q-3, Preparation 1, 0.114 g, 0.554 mmol), diisopropylethylamine (0.0716 g, 0.554 mmol), sodium iodide (0.007 g) and ethylene glycol (2 mL) were heated at 100 ° C for 6.5 hours and then an additional 0.056 g of 4- (piperazin-1-yl) benzamide was added. After stirring at 100 ° C for 24 hours, the mixture can be cooled (stirring). Water was then added and the mixture was extracted with dichloromethane. The organic layers were concentrated and mixed with a sticky residue (from which the aqueous layer was removed by decantation). The mixed raw product is analyzed for chromium129 * and · · • *

chromatography (silica gel; methanol / dichloromethane 6/94) to give (+/-) - 1- [2- [4- [4 (aminocarbonyl) phenyl] -1-piperazinyl] ethyl] -N-methylisochromanyl-6-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 δ.

Example 97 (R) - (+) - 1- [2- [4- [4- (Aminocarbonyl) phenyl] -1-piperazinyl] ethyl] -N-methylisochromoranyl-6-carboxamide

Separation of (+/-) - 1- [2- [4- [4- (aminocarbonyl) phenyl] -1-piperazinyl] ethyl] -N-methylisochromanyl-6-carboxamide (Y-5, Example 96) into its plus and minus enantiomers This was achieved by chiral phase column chromatography using a 4: 1 / 0.08 (v / v) ethyl alcohol / isopropyl alcohol / triethylamine solvent mixture and detection at 295 nM. The first peak is (S) - (+) - 1- [2- [4- [4- (aminocarbonyl) phenyl] -1-piperazinyl] ethyl] -N-methylisochromanyl-6-carboxamide (Example 6), the second represents (R). 1 - (+) - 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-6-carboxamide

Step 1 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 boiled at 100 ° C for 85 minutes and then cooled . Water (5-10 ml) was added and the mixture was partitioned between ethyl acetate, aqueous sodium carbonate and brine-aqueous sodium carbonate. The organic layers were dried over magnesium sulfate and concentrated to give 1- (4-cyanophenyl) piperazine, NMR (CDCl 3) 1.77, 3.02, 3.28, 6.85, and 7.49 δ.

Step 2: (S) - (-) - 2- (6-bromoisochroman-1-yl) ethyl alcohol

Borane-methyl sulfide (3.1 mL, 33.2 mmol) was added to a mixture of (S) - (-) - 2- (6-bromoisochroman-1-yl) acetic acid (XI, Example 1, Step 2; 0 g, 11 mmol) and THF (40 mL). An exothermic reaction occurs and gas evolution occurs. After stirring for 2.5 hours, methanol is slowly added to quench excess borane-methyl sulfide. The mixture was then concentrated under reduced pressure and methanol was added to the residue. After the total addition of methanol, the residue was partitioned between dichloromethane, aqueous hydrochloric acid and

130 <, ··· ····················· · Aqueous sodium bicarbonate. The organic layers were dried over sodium sulfate and concentrated. The residue was chromatographed (silica gel; methanol / dichloromethane 4/96) to give (S) - (-) - 2- (6-bromoisochroman-1-yl) ethyl alcohol (S-1), NMR (CDCl 3) 2.03 , 2.20, 2.60-2.70, 3.02, 3.70-3.85, 4.16, 4.93, 6.93 and 7.29 δ.

Step 3: (S) - (-) - 6-bromo-1- (2-bromoethyl) isochroman

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 due to the exothermic reaction occurring after (S) - (-) - 2- (6-bromoisochroman-1-yl) ethyl alcohol (S-1, Step 2; 2.35 g, 9.1 mmol) in dichloromethane (25 mL) was added over 10 min. ml). Remove the cooling bath, stir the mixture for 40 minutes, and add hexane dropwise to the end until the liquid becomes clear. The mixture was left in the refrigerator overnight and then the solids were removed by filtration. The solid phase is washed with ether, the combined filtrates are concentrated and the residue is chromatographed (silica gel; ethyl acetate / hexane, 10/90) to give (S) - (-) - 6-bromo-1- (2-bromoethyl) isochroman ( 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. , 29 δ.

Step 4: (S) - (-) - 4- [4- [2- (6-bromoisochroman-1-yl) ethyl] -1-piperazinyl] benzonitrile

A mixture of (S) - (-) - 6-bromo-1- (2-bromoethyl) isochroman (T-1, step 3, 1.53 g, 4.79 mmol) of 1- (4-cyanophenyl) piperazine ( Q-3, Step 1, 0.987 g, 5.27 mmol), diisopropylethylamine (0.681 g, 5.27 mmol) and ethylene glycol (5 mL) were heated at 95 ° C for 4 hours and then overnight at 20 ° C. Deň: 22 ° C. The mixture was partitioned between dichloromethane and water and the organic layers were dried over sodium sulfate and concentrated. The residue is chromatographed (silica gel; methanol / dichloromethane 2/98) to give (S) - () - 4- [4- [2- (6-bromoisochroman-1-yl) ethyl] -1-piperazinyl] benzonitrile ( VI) NMR (CDCl3) 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 δ.

Step 5: (S) - (-) - 1- [2- [4- (4-Cyanophenyl) -1-piperazinylyl) ethyl] -N-methylisochroman-6-carboxamide

Following the procedure of Example 6, Step 4, with minor variations of (S) - (-) - 4- [4- [2- (6-Bromoisochroman-1-yl) ethyl] -1-piperazinyl] benzonitrile (VI, Step 4, 1 61 g) is transformed into (S) - (-) - 1- [2- [4- (4-cyanophenyl) -1-piperazinylyl) ethyl] -N-methylisoquinoline. 9-carboxamide (IX), MS (m / z) at 404 ; IR (mineral oil, peak 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 7.54 δ.

Example 99 (S) - (-) - 1- [2- [4- (4-Aminocarbonyl) phenyl] -1-piperazinylyl-ethyl] -Nmethyl-N- (phenylmethoxy) isochroman-6-carboxamide

Step 1: (S) - (-) - 1- [2 - [(tetrahydropyran-2-yl) oxy] isochroman-6-carboxylic acid methyl ester

A mixture of (S) - (-) - 1- (hydroxyethyl) isochroman-6-carboxylic acid, methyl ester (S-2, Example 81, Step 2, 1.36 g, 5.76 mmol), dichloromethane (10 mL) ), p-toluene sulfonic acid monohydrate (0.0142 g, 0.0747 mmol) and 3,4-dihydro-2H-pyran (1.6 mL, 0.0175 mol) were stirred at 20-25 ° C for 45 min. . The mixture was then partitioned between aqueous sodium carbonate and dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue is chromatographed (silica gel; ethyl acetate / hexane 5/95 to 15/85) to give (S) - (-) - 1- [2 [(tetrahydropyran-2-yl) oxy] isochroman-6-carboxylic acid, 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 δ.

Step 2: (S) - (-) - 1- [2 - [(tetrahydropyran-2-yl) oxy] ethyl] isochroman-6-carboxylic acid

A mixture of (S) - (-) - 1- [2 - [(tetrahydropyran-2-yl) oxyjethyl] isochroman-6-carboxylic acid methyl ester (W-2, Step 1, 1.55 g, 4.85) mmol), ethanol (12 mL), sodium hydroxide (2N, 3.6 mL, 7.2 mmol) and water (1 mL) were stirred at 2025 ° C for 6.5 hours. The mixture was then left in the refrigerator overnight. It was then stirred for an additional 2.5 hours at 2025 ° C and concentrated under reduced pressure. Water (6 mL) was added and the remaining mixture was cooled in an ice bath. The pH of the mixture was adjusted to pH 5 with 4 N hydrochloric acid, and the resulting suspension was extracted with dichloromethane. The combined organic layers were dried over magnesium sulfate, concentrated under reduced pressure to give (S) - (-) - 1- [2 - [(tetrahydropyran-2-yl) oxy] ethyl] isochroman-6-carboxylic acid (W-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 7.88 δ.

·

132 • ·

Step 3: (S) - (-) - N-Methyl-N- (phenylmethoxy) -1- [2 - [(tetrahydropyran-2-yl) oxy] ethyl] isochroman-6-carboxamide

1,1'-Carbonyldiimidazole (0.064 g, 0.39 mmol) was added to (S) - (-) - 1- [2 [(tetrahydropyran-2-yl) oxy] ethyl] isochroman-6-carboxylic acid (W). -3.2 step (0.109 g, 0.356 mmol) and THF (2 mL). The mixture was stirred at 20-25 ° C for 2 hours and then N-methyl, O-benzylhydroxylamine (Tetrahedron Letters, 30, 31-34 (1989), 0.054 g, 0.39 mmol) was added, the mixture was stirred overnight at 60 ° C. It was then concentrated and the residue was partitioned between dichloromethane, water and aqueous sodium carbonate. The organic layers were dried over sodium sulfate and concentrated. The residue is chromatographed (silica gel; methanol / dichloromethane, 2/98) to give (S) - (-) - N-methyl-N (phenylmethoxy) -1- [2 - [(tetrahydropyran-2-yl) oxy] ethyl ] -6-carboxamide isochroman (VI), NMR (CDCl3) 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 δ.

Step 4: (S) - (-) - 1- (2-hydroxyethyl) -N-methyl-N-phenylmethoxy iso chroman-6-carboxamide (S) - (-) - N-methyl-N- (phenylmethoxy) -1- [2 - [(tetrahydropyran-2-yl) oxy] ethyl] isochroman-6-carboxamide (W-4, step 3; 0.131 g, 0.308 mmol) was stirred at 20-25 ° C for 2 h acetic acid / THF / water (4/2/1, 5 mL), then 4 hours at 60 ° C, and left in the refrigerator overnight. The solvents were removed and the resulting mixture was partitioned between dichloromethane and water. The organic layers were dried over sodium sulfate, concentrated and the residue analyzed by chromatography (silica gel; methanol / dichloromethane, 2/98) to give the crude product. In addition, NMR of this material indicated the presence of tetrahydropyranyl (THP) -like protons, methanol (2 mL) and p-toluenesulfonic acid hydrate (0.006 g). The mixture was stirred overnight. The solvent was removed under reduced pressure and the residue was partitioned between dichloromethane and aqueous sodium carbonate. The organic layers were dried over sodium sulfate and concentrated to give (S) - (-) - 1- (2-hydroxyethyl) -N-methyl-N-phenylmethoxy isochroman-6-carboxamide (W-5), 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 7.46 δ.

Step 5: (S) - (-) - 1- [2- [4- (4-Aminocarbonyl) phenyl] -1-piperazinylyl) ethyl] -N-methyl-N- (phenylmethoxy) isochroman-6-carboxamide • ·

133

• *

To an ice-cooled mixture of (S) - (-) - 1- (2-hydroxyethyl) -N-methyl-N-phenylmethoxyisochroman-6-carboxamide (W-5, step 4; 0.099 g, 0.290 mmol), diisopropylethylamine (0.049 g, 0.377 mmol) and 4-dimethylaminopyridine (0.0018 g, 0.014 mmol) in dichloromethane (1.5 mL) were added methanesulfonyl chloride (0.043 g, 0.377 mmol) in dichloromethane (0.5 mL). The mixture was stirred for 1.5 hours and then partitioned between dichloromethane and aqueous sodium carbonate. The organic layers were dried over sodium sulfate and concentrated to give the methanesulfonate (W-6). To the methanesulfonate was added 4- (piperazin-1-yl) benzamide) (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 was used to wash the vessel walls. The mixture was heated at 85 ° C for 2.5 hours and then cooled. Water was added and the mixture was left in the refrigerator overnight. The supernatant is then decanted and the residue analyzed by chromatography (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 δ.

Example 100 (S) - (-) - 1- [2- [4- [4-Aminocarbonyl) phenyl] -1-piperazinyl] ethyl] -N-hydroxy-N-methylisochroman-6-carboxamide

(S) - (-) - 1- [2- [4- [4-Aminocarbonyl) phenyl] -1-piperazinyl) ethyl] -N-methyl-N (phenylmethoxy) isochroman-6-carboxamide (W-7, Example 99, Step 5, 0.067 G, 0.13 mmol), palladium on charcoal (10%, 0.0068 G) and methanol (3 mL) was stirred for 1 hour under about one atmosphere of hydrogen, then ethyl acetate was added. (1 mL) to dissolve the remaining starting material. Stirring was continued under a hydrogen atmosphere and after 8 hours additional palladium on charcoal (10%, 0.0068 g) was added. When the starting material is consumed (about 28 hours), the palladium on charcoal is filtered off and the filtrate is concentrated. The residue is chromatographed (silica gel; methanol / dichloromethane, 8/92 to 15/85) to give (S) - (-) - 1- [2- [4- [4-aminocarbonyl) phenyl] -1-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 δ.

Example 101 (+/-) - 1- [2- [4- (4-Aminosulfonyl) phenyl] -1-piperazinyl] ethyl] -N-methylisochroman-6-carboxamide

134 «· · · · ·

Step 1: 4- (piperazin-1-yl) benzenesulfonamide

A mixture of 4-fluorobenzenesulfonamide (Q-2, 6.95 g) and piperazine (17.1 g) in water (30 mL) was heated at 100 ° C overnight. The solid was collected, washed with water and toluene, dried under reduced pressure to give 4- (piperazin-1-yl) benzenesulfonamide (Q-3), MS (m / z) = 241; IR (mineral oil, peak 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 δ.

Step 2: (+/-) - 1- [2- [4- [4-Aminosulfonyl) phenyl] -1-piperazinyl] ethyl] -N-methyl isochroman-6-carboxamide

Following the procedure of Example 96 with minor variations, (+/-) - 1- (2-chloroethyl) -N-methylisochroman-6-carboxamide (Y-4, Example 96, Step 3, 0.024 g, 0.095 mmol) and 4- ( piperazinyl-1-yl) benzenesulfonamide (Q-3, Step 1) (+/-) - 1- [2- [4- [4aminosulfonyl) phenyl] -1-piperazinyl] ethyl] -N-methylisochroman-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 7.76 δ.

Following the procedure of Example 94 (Scheme 5) with minor variations, using the reactants for the corresponding products, the compounds of Example 102-104 were obtained:

Example 102 (S) - (-) - N-Methyl-1- [2- [4- [4- (methylaminocarbonyl) phenyl] -1-piperazinyl] ethyl] isochroman-6-carboxamide

Example 103 (S) - (-) - N-Methyl-1- [2- [4- [4- (dimethylaminocarbonyl) phenyl] -1-piperazinyl] ethyl] isochroman-6-carboxamide

Example 104 (S) - (-) - N-Methyl-1- [2- [4- [4- (n-propylaminocarbonyl) phenyl] -1-piperazinyl] ethyl] isochroman-6-carboxamide

Following the procedure of Example 100 with minor variations, using the reactants for the corresponding products, the compounds of Example 105-108 were obtained: Example 105 (S) - (-) - N-hydroxy-N-methyl-1- [2- [4- [4- (trifluoromethyl) phenyl] -1-piperazinyl] ethyl] isochroman-6-carboxamide

Example 106 (S) - (-) - 1- [2- [4- [4- (Chlorophenyl) -1-piperazinyl] ethyl] -N-hydroxy-N-methylisochroman-6-carboxamide

Example 107 (S) - (-) - 1- [2- [4- (4-Cyanophenyl) -1-piperazinyl] ethyl] -N-hydroxy-N-methylisochroman-6-carboxamide

135

Example 108 (S) - (-) - N-Hydroxy-N-methyl-1- [2- [4- [4- (methylcarbonyl) phenyl] -1-piperazinyl] ethyl] isochroman-6-carboxamide

Minor variations known to those skilled in the art follow Scheme DD to provide compounds of Examples 109-120. Example 109 (S) -4- [4- [2- [6- (1,2,4-triazol-3-yl)] 1-Isochroman-1-yl-ethyl] -1-piperazinyl-benzamide

Example 110 (S) -4- [4- [2- [6- (2-Methyl-1,2,4-triazol-3-yl) -isochroman-1-yl-ethyl] -1-piperazinyl] -benzamide

Example 111 (S) -4- [4- [2- [6- (1,2,4-Oxadiazol-5-yl) -isochroman-1-yl] ethyl] -1-piperazinyl] -benzamide

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-1,2,2,4-triazol-3-yl) -isochroman-1-yl] ethyl-4- [4-trifluoromethyl-phenyl] -piperazine

Example 114 (S) -1- [2- [6- (1,2,4-Oxadiazol-5-yl) -isochroman-1-yl] ethyl-4- [4-trifluoromethyl-phenyl] -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-3yl) isochroman-1-yl] ethyl] piperazine

Example 117 (S) -1- [4-Acetylphenyl] -4- [2- [6- (1,2,4-oxadiazol-5-yl) isochroman-1-yl] ethyl] piperazine

Example 118 3- [1- [2- [4- (4-Aminocarbonyl-phenyl) -piperazin-1-yl-ethyl] -isochroman-6-yl] -N, N-dimethyl-acrylamide

Example 119 3- [1- [2- [4- (4-Trifluoromethyl-phenyl) -piperazin-1-yl-ethyl] -isochroman-6-yl] -N, N-dimethyl-acrylamide

Example 120 3- [1- [2- [4- (4-Acetyl-phenyl) -piperazin-1-yl] -ethyl] -isochroman-6-yl] -N, N-dimethyl-acrylamide

136 • ·

Formulas to Examples (E-No)

and ₃ / Ά

N N (+) - enantiomer

(-) - enantiomer

(-) - enantiomer

• ·

137

E-14

H _and C

O II C

N

AND

H

• ·

138

O

II

O

139

O

II

o II

\ //

• 2 HCl

141 o o

II η

The (-) enantiomer e-45

E-47

142

E-55

143 • · · * ········

E-61

E-63

144

145 • · · ·

146

····· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

147

O

E-95

148

R - (+) - enantiomer <N

O

II c-nh ₂

E-98

E-97

149

SCHEME

(Π)

(III)

(IV)

(VI)

150

(VII) (VIII) (VI) (IX) (X)

151

SCHEME C

co ₂ c ₂ h ₅

(II)

IN

152

SCHEME D (CH 3 J 8 Si 1)

VI (XIII)

(XIV)

(XV)

153

SCHEME E

O

(VI) (XVI) (XVIII) (XVIII) (XIX)

154

SCHEME F * «· · • ·

(XXIII)

155

SCHEME G

(XXIV)

156

SCHEME H / \

· (VI) (XXVI) (XXVII) (XXVIII) (XXIX)

157

SCHEME I

(XXXIII)

158

SCHEME J

(XXXII)

* 1

_R2 (XXXV)

(XXXVI) \ II

(XXXVII)

159

SCHÉMAK

(XXXII)

(XXXVIII)

160

SCHEME L

(XXXIX)

(XL)

... »

161

SCHEME Μ

(ΧΧΧΠ) (ΧΙΑ) (ΧΙΑΙ)

Qv5, 0

(XLIW

• · »

• · ·

162

SCHEME N

(XLI)

(XLIV)

163

SCHEME O

N-0

··

• (VII) (0-1) (0-2) (0-3) • • * *

164

SCHEME P

(P-2) (P-2)

165

SCHEME Q

166 SCHEME R • · · • · · · • · · < • · · · < • · · <1 • · · · · ° ^Z ^ 2C I (R-1) 1 (R-2) and (R-3)

167

SCHEME S

OH

O

• ·

(S-1) (S-2)

168

SCHEME T

(Χ -Br, OMs) (T-1)

(IX) · · IX IX IX IX IX IX IX IX IX IX IX IX IX IX IX IX IX IX IX IX IX • · · ·······················

169

SCHEME U

(U-1) (U-2) (U-3) (U-4)

OH

170

SCHEME V

(C ^ Cg alkyl)

(V-4) (V-4)

171 • ·

SCHÉMAW

(W-1) (W-2) (W-3) (W-4) (W-5) (W-6) (W-7) (W-8)

172 • ······························ ··· · ♦ · · ·· · ·

SCHÉMAX

(X-1) (X-2) (X-3) (X-4) (X-5) (X-6)

173 • ·· ·

SCHÉMAZ

174

SCHEME AA

(vi) (AA-1) (AA-2) (AA-3) (AA-4) (AA-5)

175

SCHEME BB

O

(BB-2)

176

SCHEME CC

(CC-1)

O

(CC-2)

(CC-3)

O

(IX)

177

SCHEME DD

178

Claims (38)

PATENT CLAIMS 1- [2- [4- (3-chloro-4-methoxyphenyl) -1-piperazinyl] ethyl] isochroman-6-carboxamide. 1- [2- [4- (4-hydroxyphenyl) -1-piperazinyl] ethyl] isochroman-6-carboxamide, (+/-) - 1- [2- (4-phenyl-1-piperidinyl) ethyl] isochroman- 6-carboxamide • 9 216 (+/-) - 1- [2- [4- (2,4-dichlorophenyl) -1-piperazinyl] ethyl] isochroman-6-carboxamide, 1- [2- [4-phenylpiperazinyl] ethyl] isochroman-6-carboxamide 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] isochroman-6-carboxamide, 1- [2- [4- (3-Trifluoromethylphenyl) -1-piperazinyl] ethyl] isochroman-6-carboxamide, (S) - (-) - 1- [2- [4- (4-Trifluoromethylphenyl) -1-piperazinyl] ethyl] isochroman-6-carboxamide, 1- [2- [4- (4-Diethylaminophenyl) -1-piperazinyl] ethyl] isochroman-6-carboxamide 1- [2- (6-Amino-isochroman-1-yl) -ethyl] -4- (4-methoxy-phenyl) -piperazine, (S) - (-) - 1-2- (6-Amino-isochroman-1-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-1-yl) ethyl] piperazine, (S) - (-) - 1- (4-methoxyphenyl) -4- [2- (6) (S) - (-) - 1- (4-methoxyphenyl) -4- [2- (6-dimethylaminoisochroman-1-yl) ethyl] piperazine and (S) - (-) -methylaminoisochroman-1-yl) ethyl] piperazine; -1- 2- (6-ethylmethylaminoisochroman-1-yl) ethyl] -4- (4-methoxyphenyl) piperazine. 1- [2- [4- (4-chlorophenyl) -1-piperazinyl] -N-N, N-dimethylisochroman-6-carboxamide and (S) - (-) - 1- [2- [4- (4-trifluoromethylphenyl)] -1-piperazinyl] ethyl] -N, N-dimethylisochroman-6-carboxamide. 1- [2- [4- (4-chlorophenyl) -1-piperazinyl] ethyl] -N-methylisochroman-6-carboxamide, (S) - (-) - 1- [2- [4- (4-methoxyphenyl)] -1-piperidinyl] ethyl] -N-methylisochroman-6-carboxamide, (S) - (-) - 1- [2- [4- (4-hydroxyphenyl) -1-piperazinyl] ethyl] -N-methylisochroman-6-carboxamide, ( S) - (-) - 1- [2- [4- (4-Trifluoromethanesulfonyloxyphenyl) -1-piperazinyl] ethyl] -N-methyl-isochroman-6-carboxamide, (S) - (-) 1- [2- [4] - (4-acetylphenyl) -1-piperazinyl] ethyl] -N-methylisochroman-6-carboxamide, (S) - (-) - N-methyl-1- [2- [4- (4-propionylphenyl) -1-piperazinyl] ethyl] isochroman-6-carboxamide, 213 N-methyl-1- [2- (4-phenyl) -1-piperidinyl] ethyl] isochroman-6-carboxamide, (+/-) - N-methyl-1- [2- [4- (2,4- dichlorophenyl) -1-piperazinyl] ethyl] isochroman-6-carboxamide, (+/-) - 1- [2- [4- (3-chloro-4-methoxyphenyl) -1-piperazinyl] -N-methylisochroman-6- (S) - (-) - 1- [2- [4- [4- (tert-butyloxycarbonyl) phenyl] -1-piperazinyl] ethyl] -N-methylisochroman-6-carboxamide, (+/-) - 1 - [2- [4- [4- (aminocarbonyl) phenyl] -1-piperazinyl] ethyl] -N-methylisochromanyl-6-carboxamide, (R) - (+) - 1- [2- [4- [4- (aminocarbonyl)] phenyl] -1-piperazinyl-ethyl] -Nmethylisochromanyl-6-carboxamide, (+/-) - 1- [2- [4- [4- (aminosulfonyl) phenyl] -1-piperazinyl] ethyl] -Nmethylisochroman-6-carboxamide, (S) - (-) - N-methyl-1- [2- [4- [4- (methylaminocarbonyl) phenyl] -1-piperazinyl] ethyl] isochroman-6-carboxamide, (S) - (-) - N- methyl 1- [2- [4- [4- (dimethylaminocarbonyl) phenyl] -1 piperazinyl-ethyl] isochroman-6-carboxamide, (S) - (-) - N-methyl-1- [2- [4- [4] - (n-propylaminocarbonyl) phenyl] -1-piperazinyl] ethyl] isochroman-6-carboxamide. 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] -N-butylisochroman-6-carboxamide, 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] -N-ethylisochroman-6-carboxamide, 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] -N-propylisochroman-6-carboxamide, 1- [2- [4- (3-Trifluoromethylphenyl) -1-piperazinyl] ethyl] -N-methylisochroman-6-carboxamide, 1- [2- [4- (4-Propoxyphenyl) -1-piperazinyl] ethyl] -N-methylisochroman-6-carboxamide, (S) - (-) - 1- [2- [4- (4-ethylphenyl) -1] -piperazinyl] ethyl] -N-methylisochroman-6-carboxamide, 212 • • • • (S) - (-) - 1- [2] - [4- (4-ethoxyphenyl) -1-piperazinyl] ethyl] -N-methylisochroman-6-carboxamide, (S) - (-) - 1- [2- [4- (4-phenylmethyloxyphenyl) -1-piperazinyl] ethyl (R) - (+) - 1- [2- [4- (4-ethoxyphenyl) -1-piperazinyl] ethyl] -N-methylisochroman-6-carboxamide, 1- [2- [4- (4-ethoxyphenyl) -1-piperazinyl] ethyl] -N-methylisochroman-6-carboxamide, (1) -CF ₃ ; (2) C- -C ₈ alkyl, (3) -O-R 1. _3a , wherein R 1 is as defined above, (4) -NR 1. _3A RI ₃ b where Ri. _{3A, 3B} and Ri are as defined above, (J) -CO -rm wherein R m is as defined above; (IV) R ₂ is identical to R _1; R ₂ may be the same or different from R 1; and pharmaceutically acceptable salts thereof. (1) -H, (2) C 1 -C ₈ alkyl, (3) -CF (4) -SO ₂ -CF ₃ , (5) - (CH ₂ ) n _{2 -} , wherein n ₂ is 0 to 4 (G) -N (Ri.i) _2> wherein Rm are the same or different and are defined above, (H) -CO-N (R _{1.1) 2,} where R m are identical or different and are defined above, (I ) -SO ₂ -R _1-3 , where R _b3 is: (1) -H, 208 (1) C! -C ₈ alkyl, (3) C ₂ -C ₈ alkenyl containing 1 to 3 double bonds (=), (4) C ₂ -C ₈ alkynyl containing 1 or 2 triple bonds (=), (5) - (CH ₂₎ ) _n7 -φ, wherein n ₇ is 0 to 4, and wherein -φ is optionally substituted with one or two (a) -F, -Cl, -Br, -I, (b) -C = N, (c) - CF ₃ , (d) C 1 -C ₃ alkyl, (e) -O-Qma, wherein Q m _A is -H, C 1 -C ₆ alkyl, -CF ₃ or (CH) ₂ -φ, (f) -NQ 1 -; i _A Qi-ib, wherein Qma and Qi-ib are the same or different, and wherein Qi-ib is -H, C 1 -C ₆ alkyl, -CF ₃ or -CH ₂ -φ, and wherein Qi-ib is as defined above, ( g) -CO-NQma Qmb where Qma and Qmb are as defined above, (h) -SO ₂ -NQma Qmb wherein Qma and Qm _B are as defined above, (i) -NQma -SO ₂ -Qmb wherein Qma and Qmb are as defined above, (j) -no ₂ , (k) -O -SO ₂ -CF ₃ , and wherein Q _{V 2} is: 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] -N- (phenylmethoxy) isochroman-6-carboxamide, (+/-) - N-hydroxy-1- [2- [4- (4 -methoxyphenyl) -1-piperazinylmethyl-N-methylisochroman-6-carboxamide 206 ······ · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · (S) - (-) - 1- [2- [4- (4-Aminocarbonyl) phenyl] -1-piperazinyl] ethyl] -N-methyl-N (phenylmethoxy) isochroman-6-carboxamide, (S) - (-) - 1- [2- [4- (4-aminocarbonyl) phenyl] -1-piperazinylethyl] -N-methyl-N-methylisochroman-6-carboxamide, (S) - (-) N-hydroxy-N- methyl 1- [2- [4- (4-trifluoromethyl) phenyl] -1-piperazinyl] ethyl] isochroman-6-carboxamide, (S) - (-) - 1- [2- [4- (4-chlorophenyl) - 1-piperazinyl-ethyl-N-hydroxy-N-methylisochroman-6-carboxamide, (S) - (-) - 1- [2- [4- (4-cyanophenyl) -1-piperazinyl] ethyl] -N-hydroxy-N-methylisochroman-6-carboxamide (S) - (-) - N-hydroxy-N-methyl-1- [2- [4- [4- (methylcarbonyl) phenyl] -1-piperazinyl] ethyl] isochroman-6-carboxamide, (S) -4- [ 4- [2- [6- (1,2,4-triazol-3-yl) isochroman-1-yl] ethyl] -1-piperazinyl] benzamide, (S) -4- [4- [2- [6- (2) (S) -4- [4- [2- [6- (1,2,4-Oxadiazole) -methyl-1,2,4-triazol-3-yl] isochroman-1-yl] ethyl] -1-piperazinyl] -benzamide 5-yl) isochroman-1-yl-ethyl (S) -1- [2- [6- (1,2,4-triazol-3-yl) isochroman-1-yl] ethyl] -4- [4-trifluoromethylphenyl] piperazine, (S) -1- [2]] -1-piperazinyl-benzamide - [6- (2-methyl-1,2,4-triazol-3-yl) isochroman-1-yl] ethyl] -4- [4-trifluoromethylphenyl] 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-triazole) -3-yl) isochroman-1-yl-ethyl-piperazine, 207 (S) -1- [4-acetylphenyl] -4- [2- [6- (2-methyl-1,2,4-triazol-3-yl) isochroman-1-yl] ethyl] piperazine, (S) -1- [4-acetylphenyl] -4- [2- [6- (1,2,4-oxadiazol-5-yl) isochroman-1-yl] 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-6-carboxamide, 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] isochroman-6-ethyl carboxylic acid ester, 1- (4-methoxyphenyl) -4- [2- (6-dimethylaminomethylisochroman-1-yl) ethyl] piperazine, 205 1- (4-methoxyphenyl) -4- [2- (6-methylaminomethylisochroman-1-yl) ethyl] piperazine, 1- (4-Methoxyphenyl) -4- [2- [6- (5-methyloxazol-2-yl) isochroman-1-yl) ethyl] piperazine, (S) - (-) - N- [Isochroman-1- [ 2- [4- (4-methoxyphenyl) piperazin-1-yl] ethyl] -6-yl] methanesulfonamide; 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] -N-phenylmethyl-N-methylisochroman-6-carboxamide, 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] -N-phenylisochroman-6-carboxamide, 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] -N - [(S) -α-methylphenylmethyl] isochroman-6-carboxamide, 1- [2- [4- (4-Methoxyphenyl) -1-piperazinyl] ethyl] -N - [(R) -α-methylphenylmethyl] isochroman-6-carboxamide, 1- [2- [4- (4-Methoxyphenyl) -1-piperazinyl] ethyl] -N-phenylmethylisochroman-6-carboxamide, 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] -N- (4-methoxyphenylmethyl) isochroman-6-carboxamide, 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] -N-propargylisochroman-6-carboxamide, 1- [2- [4- (4-Methoxyphenyl) -1-piperazinyl] ethyl] -N-allylisochroman-6-carboxamide, 1- [2- [4- (4-methylsulfonylphenyl) -1-piperazinyl] ethyl] -N-methylisochroman-6-carboxamide, 1- [2- [4- (4-methylsulfonylphenyl) -1-piperazinyl] ethyl] isochroman-6-carboxamide, (S) - (-) - 1- [2- [4- (4-trifluoromethoxyphenyl) -1-piperazinyl] ethyl] -N-methylisochroman-6-carboxamide, 1 · ·············· (iii) -CF ₃ , (iv) C 1 -C ₃ alkyl (v) -O-Q 1-2 E> wherein Q 1-2E is -H, C 1 -C 6 alkyl, -CF _3, or -CH ₂ - (vi) -NQ 1. _2E Q1-2F where Qi- _Qi-2 ea 2Fjsou same or different, and wherein Q. _2F is -H, C 1 -C ₃ alkyl, -CF _3, or -ΟΗ ₂ -φ, and wherein Q 1. _2E is as defined above, (vii) -CO ^- NQ-2e Q1-2F where Qi- ₂ ea Qi- f ₂ are as defined above, (viii) -SO ₂ -NQ1.2E Q1-2F and Q1-2F are as defined above, (ix) -SO ₂ -NQ1-2E Qi-2f where Q1-2E and Qi. _2F are as defined above, (x) -NO 2, (xi) -O-SO ₂ -CF ₃ , and wherein Q 1 ... _{2 C} is identical to Q 1. _2D a Q1-2C and Q1-2D can be the same or different, (B) _-SO2 -NQm Qi- ₂ wherein Q and _W are as defined above, Ch.2, (C) -CO-O -Q. ₃ , where Ο _Ί . ₃ je: (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 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 ) _n 7 -φ, where n? is 0 to 4 and wherein -φ is optionally substituted with one or two (a) -F, -Cl, -Br, -I, (b) -CsN, (c) -CF ₃ , (d) C 1 -C ₃ alkyl , (e) -O-Qma, wherein Qma is -H, C 1 -C ₆ alkyl, -CF _3, or -CH ₂ -Φ> (f) -NQma Qmb, wherein Qma _and Qmb are the same or different, and wherein Qmb is -H, C 1 -C ₆ alkyl, -CF _3, or -CH ₂ -φ, and wherein Qma is as defined above, (g) -CO -NQma Qmb, where Qma and Qmb are defined above, (h) -SO ₂ -NQma Qmb, where Ql-1A and Qmb are defined above, (i) -NQma-S0 ₂ Qmb, where Ql-1A and Qmb are defined above, O) -no ₂ , (k) -O -SO ₂ -CF ₃ , and wherein Q m is: 1QA · · · · · · · · · · · · · · · (1) -H, (2 ) _Cl-C8 alkyl, (3) C ₂ -C ₈ alkenyl containing 1-3 double bonds (=), (4) C ₂ -C ₈ alkenyl containing 1 or 2 triple bonds (=), (5) C _{3 C8} cycloalkyl, (6) -C -C ₃ alkyl, -C ₃ -C ₈ cycloalkyl, (7) -CF (8) - (CH _{2) n2} -φ, where n ₂ is defined above, and is -φ optionally substituted with one or two (a) -F, -Cl, -Br, -I, (b) -C 1 N, (c) -CF (d) C 1 -C ₆ alkyl, (e) -O-Q 1 - ₂ a, where Q ₁ A is: (i) -H, (ii) _Ci-C6 alkyl, (iii) -CF (iv) - (CH ₂ H, (9) - (CH _{2) n9} -Qi- ₂ B _(CH2) nio -Q1 -2C, wherein n ₉ and n ₁₀ are the same or different and are 0 to 4, wherein, Q 1, _2B is -O- or -NCh-ar, wherein Q 1d is: (a) -H, (b) C 1 -C ₈ alkyl, (c) C ₂ -C ₈ alkenyl having 1 to 3 double bonds, (d) C ₂ -C ₈ alkynyl having 1 or 2 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 ) n n -φ, where nu is 0 to 4, and -φ is optionally substituted with one or two (i) F, -Cl, -Br, -I, (ii) -C = N, • ········ 1QC ·············· (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 1 or 2 triple bonds ( s), (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, where n ₂ is 0 to 4, and where -φ is optionally substituted with one or two (a) -F, -Cl, -Br, -I, (b) -C = N, (c) -CF ₃ . (D) C 1 -C ₃ alkyl, (e) -O-R 1 -ia, wherein R f. _1A is -H, C 1 -C ₆ alkyl, -CF _3, or -CH ₂ -φ, (f) -NR 1. _1A R _mb , wherein R 1i _A and R 1i. _1B are the same or different and wherein R 1 -B is -H, C 1 -C ₈ alkyl, -CF _3, or -ΟΗ- ₂ -φ, and wherein R 11a are as defined above, (g) -CO-NR 1 _-A 1 R 1-ib, where Ri-ia a Rmb are as defined above, (h) -SO ₂ -NR 1 _{-A A} R 1-ib, where Ri-ia a Rmb are as defined above, (i) -NR ₁ -I _A -SO ₂ -R 1-ib. where Rma a Rmb are as defined above, O) -NO ₂ , (k) -O-SO ₂ -CF ₃ , (L) -N (R m), wherein R 1 may be the same or different and is as defined above, (M) -CO-N (R 1 -). i) ₂ , wherein R m can be the same or different and is as defined above, (N) -SO ₂ -R _{1 -} , 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 1 or 2 triple bonds (=), (6) C _{3 C8} cycloalkyl, (7) C * -C ₃ alkyl, -C ₃ -C ₈ cycloalkyl, (8) - (CH _{2) n2} -φ, where n ₂ is as defined above and the -φ is optionally substituted with one or two ( a) -F, -Cl, -Br, -I, (b) -CsN, (c) -CF ₃ , (d) C 1 -C ₃ alkyl, 192 (e) -O-Ri-3a, where Ri. ₃ is -H, _Ci-C6 alkyl, _-CF3 or ΟΗ ₂ -φ, (f) -NR ^ and Ri ₃ b, ₃ e where RI Rub are identical or different and wherein Rv is -H _3B , -C 1 -C ₆ alkyl, -CF _3, or -CH ₂ -φ, and wherein R 1 is C 1 -C ₆ alkyl; _3A is as defined above, (g) -CO-NR ₃ b and Ri where Ri. _3A and R 1. _3B are as defined above, (h) -SO ₂ -NR 1. _{3A, 3B} wherein RI Ri_ _3A and _3B Ri_ are as defined above, (i) -NR ₂ -R _3A -SO. _3B wherein R 1_ _3A and R 1. _3B are as defined above, (j) -NO ₂ , (k) -O-SO ₂ -CF ₃ , (9) -O-R 1 _-A , wherein R 1. _3A and R 1. _3B are as defined above, (10) -NR _V3A R 3b, wherein R 3B R-θ 3a-3b are as defined above, (O) _-NR-SO2-i -Ri- ₃ wherein Rm and Ri _3, be the same or different as defined above, (P) ^- (CH ₂ ) n ₂ -φ, wherein n ₂ is as defined above, and wherein -φ is optionally substituted with one or two (1) -F, -Cl, -Br, -I, (2) -C =N, (3) -CF ₃ , (4) C 1 -C ₆ alkyl, (5) -O-Rvi, wherein R 1-1 is as defined above, (6) -N (R 2) _{( 1} ) ₂ , wherein R _V1 are the same or different and are as defined above, (7) -CO -N (R ₁ .i) ₂ , wherein R _V1 are the same or different and are as defined above, (8) -SO ₂ -N (R ₁ , ₁ ) ₂ , wherein R m are the same or different and are as defined above, (9) -NR _1, -SO ₂ -R m, wherein R m are the same or different and are as defined above, 193 · ··· ············ (10) -no ₂ , (11) -0 -SO ₂ -CF ₃ ; (IV) R ₂ is identical to Ri, R ₂ may be the same or different Rf; (V) Qije: (A) -CO -NQmQm, wherein Qm 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 1 or 2 triple bonds (=) • 186 · · · · · · · · • ···· ···· · »····· ·· ·· · · · · · · (6) C ₃ -C ₈ cycloalkyl, (7) -C 1 -C ₃ alkyl -C ₃ -C ₈ cycloalkyl, (8) -NO (9) -ON, (10) -CF (11) -O-5A, wherein Ch-sA is: (a) -H, (b) O, -C ₈ alkyl, (c) C ₂ -C ₈ alkenyl having 1 to 3 double bonds, (d) C ₂ -C ₈ alkynyl having 1 to 2 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) - (CH ₂ ) _n7 -φ wherein n ₇ is 0 thru 4, (12) -NQV5AQ1-5D wherein Qi- ₅ a is as defined above, d is Qi- _5: (a) -H, (b) C 1 -C ₈ alkyl, (c) C ₂ -C ₈ alkenyl having 1 to 3 double bonds, (d) C ₂ -C ₈ alkynyl having 1 to 2 triple bonds (=), ( e) C ₃ -C ₈ cycloalkyl, 187 (f) -C 1 -C 3 alkyl - C ₃ -C ₆ cycloalkyl, (g) -cf ₃ . (h) - _{(CH2) n7} -Φ wherein n ₇ is as defined above, (13) -CO-SD -NQi_5a Qi wherein Qi. ₅ aa Qi. _5D are as defined above, (14) -SO ₂ -Q1-5K wherein Q-SK is (a) -H, (b) -CF _3, (c) C 1 -CE alkyl, (d) C ₂ -alkenyl -CE containing 1 to 3 double bonds (=), (e) C ₂ -C ₈ alkynyl containing 1 or 2 triple bonds (=), (f) C ₃ -C ₆ cycloalkyl, (g) -C 1 -C ₃ alkyl -C _{3 C8} cycloalkyl, (h) - _(CH2) n7 -φ wherein n ₇ is as defined above, (15) -SO ₂ -Q -NQvsa-sk where aa Qi- Qi_ ₅ to ₅ can be identical or different, and are as defined above, (16) - _{(CH2) n7} -φ wherein n ₇ is as defined above and where the -φ is optionally substituted with one or two (a) -F, -Cl, -Br, -I, (b ) -C = N, (c) -CF _3i (d) C 1 -C ₆ alkyl, 188 (e) -O-Qi-5a, wherein Qi. _5A is as defined above, (f) -NQi-5A Qi-5d, wherein Q1-5A 3 Qi-sd are as defined above, (g) -CO -NQ1.5A Qi-sd, wherein Qi. ₅ aa Qi. ₅ d are as defined above, (h) -SO ₂ -NQf -5aQi-5d, where Qi and Qi-sa-sd defined above, (i) -SO ₂ -NQ1.5A -Q1.5D where Qi. ₅ and a Qi-sd are as defined above, O) -no ₂ , (k) -O-SO ₂ -CF ₃ ; (K) 3-Oxadiazole optionally substituted with one Q 1 _-S , wherein Q 1. ₅ is as defined above, (L) triazole optionally substituted with one or two CUs, which may be the same or different, wherein Q 1. ₅ is as defined above, (M) 5-thiadiazole optionally substituted with one Q 1. ₅ , wherein Q 1 -s is as defined above, (N) 3-thiadiazole optionally substituted with one Q 1. ₅ , where Qi. ₅ is as defined above, (O) 2-oxazole optionally substituted with one or two Q 1. ₅ , which may be the same or different, wherein Q 1. ₅ is as defined above, (P) 2-thiazole optionally substituted with one or two Qi- _5, which may be identical or different, wherein Qi_ ₅ is as defined above, (Q) 2-imidazole optionally substituted with one, two or three Qi_ ₅ which may be the same or different, wherein Q 1. ₅ is defined above, (R) 1-imidazole substituted with one, two or three Q1-5, which may be the same or different, wherein Q1.5 is as defined above, (S) tetrazole optionally substituted with one Q1-5, wherein Q1. 5 is as defined above • • · · (T) cyclobutenedione optionally substituted with one Qm and one Qi- ₅ wherein Q1.1 and CH-s are as defined above, (U) 1-pyrimidinyl optionally substituted with one Qi_ ₅ wherein Qi. _s is as defined above, (V) 2-pyridinyl optionally substituted with one Q1-5, wherein Q1.5 is as defined above, (W) 3-pyridinyl optionally substituted with one Q1.5, wherein Q1-s is as defined above, (X) 4 pyridinyl optionally substituted with one Q1-5, where Q1-5 is as defined above, (Y) -Z 1 -Z ₂ -CO ₂ -Qi- wherein Qi- ₂ is as defined above and Z is -O-or -Nqm, wherein Qm is as defined above, wherein Z ₂ is -O- or -Nqm, where Qm is as defined above, with the proviso that if Χ _Ί is - (CH ₂ ) _n i -, where nf is 0 and Q1 is: -CO -NQm Qi- ₂ , -SO ₂ -NQm Q- ₂ or -NQm Q1-2, -NQm ₂ -CO-Qi- then Qm and Qf. ₂ , both cannot be selected from -H, -C 1 -C 6 alkyl, -C ₃ -C ₇ cycloalkyl, -C 1 -C ₃ alkyl - (C ₃ -C ₇ ) cycloalkyl and pharmaceutically acceptable salts thereof. 190 · e 4 e 4 4 4 «« «« «« «« «« (1) -F, -Cl, -Br, -I, (2) -C =N, (3) -CF ₃ , (4) C 1 -C ₆ alkyl, 181 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ··· · (5) -O-Rm, where Rm is as defined above, (6) -N (Ri-i) ₂ , where Rm are identical or different and are as defined above, (7) -CO -N (R m) ₂ , wherein R m are identical or different and are as defined above, (8) -SO ₂ -N (R m) ₂ , wherein R m are identical or different and are as defined above, (9) -NR m -SO ₂ -R m, wherein R m are the same or different and are as defined above, (10) -NO ₂ , (11) -O-SO ₂ -CF ₃ ; (Q) -CO-R m, where R m is as defined above, (R) -CO-O-Q 1. ₂ , wherein Q _{1 - 2} is defined below, (IV) R ₂ is identical to R 1, R ₂ may be the same or different from R f; (V) Qi is: (A) -CO -NQmQm wherein Qm 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 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 ) n ₇ -Φ, wherein n ₇ is 0 to 4 and wherein -φ is optionally substituted with one or two (a) -F, -Cl, -Br, - I, (b) -C 1-4 N, (c) -CF ₃ , (d) C 1 -C ₃ alkyl, 182 (e) -O-Q 1 -ia, wherein Q 1 _{-A A} is -H, C 1 -C ₆ alkyl, -CF _3, or -CH ₂ -Φ> (f) -NQmaQi-ib, wherein Q 1 -A 1 and Q 1 -B are the same or different, and wherein Q 1 -B is -H, C 1 -C 6 alkyl, -CF _3, or -CH ₂ -φ, and wherein Qvia is as defined above, (g) -CO -NQma Qi-ib, wherein Qma and Qmb are as defined above, (h) -SO ₂ -NQma Qi-ib, wherein Qma and Qmb are as defined above, (i) -NQma -SO ₂ -Qi- ib, wherein Q _MA and Qmb are as defined above, (j) -no ₂₁ (k) -O-SO ₂ -CF ₃ , and wherein Ch-2 is (1) -H, (2) C 1 -C ₈ alkyl, (3) C ₂ -C ₈ alkenyl having 1 to 3 double bonds (=), (4) C ₂ -C ₈ alkynyl containing 1 or 2 triple bonds (=), (5) C ₃ -C ₈ cycloalkyl, (6) ) -C -C ₃ alkyl, -C ₃ -C ₈ cycloalkyl, (7) -CF (8) - (CH _{2) n2} -φ, where n ₂ is defined above, and the -φ is optionally substituted with one or two (and ) -F, -Cl, -Br, -I, (b) -C = N, (c) -CF (d) C 1 -C ₆ alkyl, (e) -O-Q 1 -α, wherein Q 1-2A is (') -H, (ii) C 1 -C ₆ alkyl, (iii) -CF ₃ , (iv) - (CH ₂ H, 183 (9) - (CH ₂₎ n -Q-2B _{(CH2) n10} -Q1-2C wherein n ₉ n ₁₀ are the same or different and are from 0 to 4, where Q _{1 <2B} is -O- or - NQi. _2D - where Qi. ₂ d is: (a) -H, (b) C 1 -C ₈ alkyl, (c) C ₂ -C ₈ alkenyl having 1 to 3 double bonds, (d) C ₂ -C ₈ alkynyl having 1 or 2 triple bonds, (e) C ₃ -C ₈ cycloalkyl, (f) -C 1 -C ₃ alkyl -C ₃ -C ₈ cycloalkyl, (9) -cf ₃ , (h) ^- (CH ₂ ) n -ii, wherein nu is 0 to 4, and -φ is optionally substituted with one or two (i) F, -Cl, -Br, -I, (ii) -C = N, (iii) -CF ₃ , (iv) C 1 -C ₃ alkyl, (v) - O -Qi. ₂ e, wherein Q _{1 2} e is -H, C 1 -C ₈ alkyl, -CF ₃ or -CH ₂ -f, (vi) -NQ 12 _E Q 1-2 F, wherein Q 1. _2E and Qmf are the same or different, and wherein Q ₁ f is -H, C 1 -C ₈ alkyl, -CF _3, or -CH ₂ -φ, and wherein Q 1 _-2E is as defined above, (vii) -CO -NQ 1. ₂ e Q 1 -f, wherein Q ₁ -f and Q ₁ -f are defined above, (viii) -SO ₂ -NQ ₁ _ _2E Q ₁ -f, where Q ₁ -f is as defined above, (ix) -NQ 1 -f ₂ e -SO ₂ -Q _{1 - 2} f, wherein Q _{1 - 2} and Q _{1 - 2} f are as defined above, (x) -no ₂ , (xi) -O -SO ₂ -CF ₃ , and wherein Q 1. _2C is identical to Qi. _2D and • · · · 184 · A · A · A · · · · · · · Q1-2C and Q1-2D can be the same or different, and wherein Q _V1 Qi- ₂ together with the nitrogen atom a five or six membered ring which may contain further nitrogen or oxygen atom; (B) -SO ₂ -NQm Q1-2, wherein Q1.1 and Q1.2 are as defined above, (C) -CO -O -Qi-3, wherein Q1.3 is (1) -H, (2) -CF _3i (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 1 or 2 triple bonds (s), ( 6) C ₃ -C ₈ cycloalkyl, (7) -C 1 -C ₃ alkyl -C ₃ -C ₈ cycloalkyl, (8) - (CH ₂ ) n ₇ -φ, wherein n ₇ is as defined above and -φ is optionally substituted one or two (a) -F, -Cl, -Br, -I, (b) -C = N, (c) -CF ₃ , (d) C 1 -C ₃ alkyl, (e) -O-Q 1 - 3A where Qi. _3A is -H, C 1 -C ₆ alkyl, -CF _3, or - CH2 -φ, (f) -NQi- Q1-3B _3A wherein _3A and Qi- Q ^ b are identical or different, wherein Q ^ is -H, C 1 -C ₆ alkyl, -CF _3, or -CH ₂ - φ, and where Q1.3A is as defined above, 185 (g) -CO -NQ1.3A Q1-3B, wherein a Qi. _3B are as defined above, (h) -SO ₂ -NQi- _3A Q1-3B, wherein Q1-3A and Q1-3B are as defined above, (i) -NQ1.3A -SO ₂ -Q1-3B, wherein Q1-3A and Qi. _3B are as defined above, (j) -NO 2, (k) -O-SO ₂ -CF ₃ , (D) -CO-Q1.3, where Ον ₃ is as defined above, (E) -CO-imidazole, (F) -NQmQi.2, wherein Qm and Qi. ₂ are as defined above, (F ') -CO -NQvt -Qi- ₂ wherein Qvi and Ch 2 are as defined above, (G) -C (Q _1/3) = N -O -Qm. wherein it is identical to Q1.3 and Ch.3 is as defined above, Qva and may be the same or different, (H) -SO ₂ -Qv3, wherein Qv3 is as defined above, (I) -N (Qi.i) -SO _2- Q1.3, wherein Qm and Q1.3 are as defined above, (J) 5-oxadiazole optionally substituted with one Q1.5, wherein Q1.5 is: (1) -H, (2) -CF ₃ , (3) -C 1 -C ₈ alkyl, (4) C ₂ -C ₈ alkenyl containing 1 to 3 double bonds (=), 180 1. A 1,6-disubstituted isochroman of formula (I) wherein: (I) W 1 is a nitrogen (-N-) or carbon atom (-CH-); (II) X 1 is: (A) - _{(CH2) n1} -wherein n is 0-3, (B) -CH = CH-; (III) Ri 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 (I) -C = N, (J) -cf (K) -O-Rvi, wherein R m is (1) -H (2) C 1 -C ₈ alkyl, (3) C ₂ -C ₈ alkenyl containing 1 to 3 double bonds (=), (4) _C2-C8 alkynyl containing 1 or 2 triple bonds (=), • · · · 179 ······························· (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, where n ₂ is 0 to 4, and where -φ is optionally substituted with one or two (a) -F, -Cl, -Br, -I, (b) -C = N, (c) -CF ₃ , (d) C 1 -C ₃ alkyl, (e) -O-R 1 -ia, wherein Rma is -H, C 1 -C ₈ alkyl, -CF _3, or -CH ₂ -φ, (f) -NRma Rmb, where Rma and R 1. _1B are the same or different and wherein R 1 _-B is -H, C 1 -C ₆ alkyl, -CF ₃ or -CH ₂ -φ and wherein R 1. _1A is as defined above, (g) -CO-NR m R mb, wherein R1-1A and Rmb are as defined above, (h) -SO ₂ wherein -NRmaRmb Ri-1A and Rmb are as defined above, (i) -NRma-SO ₂ -Rmb, wherein Ri-1A and Rmb are as defined above, O) -no ₂ , (k) -O-SO ₂ -CF ₃ , (L) -N (R m), wherein R m can be the same or different as defined above, (M) -CO -N (R m) ₂ wherein R m are the same or different as defined above, (N) -SO ₂ -R m, wherein R 1. ₃ je: 2- [isochroman-1- [2- [4- (4-methoxyphenyl) piperazin-1-yl] ethyl] -6-yl] -N-methylacetamide, (S) - (-) - 3- [isochroman-1- [ 2- [4- (4-methoxyphenyl) piperazin-1-yl] ethyl] -6-yl] -N, N-dimethylacrylamide, (S) - (-) - 1- (4-methoxyphenyl) -4- [2- [6- ( 1,2,4-Triazol-3-yl) -isochroman-1-yl-ethyl-piperazine, (S) - (-) - 1- (4-methoxyphenyl) -4- [2- [6- (2-methyl-1,2) (S) - (-) - 1- (4-Methoxyphenyl) -4- [2- [6- (2-phenylmethyl-1,2,4-triazole)], (4-triazol-3-yl) -isochroman-1-ylmethyl] piperazine -3-yl) isochroman-1-yl-ethyl-piperazine, (S) - (-) - 1- (4-methoxyphenyl) -4- [2- [6- (1,2,4-oxadiazol-5-yl) -isochroman] -1-yl-ethyl-piperazine, 2- [isochroman-1- [2- [4- (4-methoxyphenyl) piperazin-1-yl] ethyl] -6-yl] acetamide, (2) -CF ₃₁ 2.1,6-disubstituted isochroman (I) according to claim 1, wherein (I) W 1 is a nitrogen (-N-) or carbon atom (-CH-); (II) Xi is: (A) - (CH _{2) n1} - where n is 0-3, (B) -CH = CH-; (III) Ri 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 (I) -CN, (J) -CF (K) -O-R 1 -I, wherein R _M is: 3- [1- [2- [4- (4-Acetyl-phenyl) -piperazin-1-yl] -ethyl] -isochroman-6-yl] -N, N-dimethyl-acrylamide. 3- [1- [2- [4- (4-Trifluoromethyl-phenyl) -piperazin-1-yl] -ethyl] -isochroman-6-yl] -N, N-dimethyl-acrylamide, 3- [1- [2- [4- (4-Amino-carbonyl-phenyl) -piperazin-1-yl] -ethyl] -isochroman-6-yl} - N, N-dimethylacrylamide, The 1,6-disubstituted isochroman (I) according to claim 1, wherein W 1 is a nitrogen atom. (3) C 1 -C ₈ alkyl, The 1,6-disubstituted isochroman (I) of claim 1, wherein W 1 is a carbon atom. (4) C ₂ -C ₈ alkenyl containing 1-3 double bonds (=), The 1,6-disubstituted isochroman (I) of claim 1, wherein X 1 is - (CH ₂ ) _n 1 -. (5) C 2 -C ₈ alkynyl containing 1 or 2 triple bonds (=), (6) C ₃ -C ₈ cycloalkyl 196 (7) -C -C ₃ alkyl, -C ₃ -C ₈ cycloalkyl, (8), ^_ (CH ₂₎ n7 -φ wherein n ₇ is as defined above and the -φ is optionally substituted with one or two (a) -F , -Cl, -Br, -I, (b) -CsN, (c) -CF ₃ , (d) C 1 -C ₃ alkyl, (e) -O-Q- _3A , wherein Q- _3A is -H, Ci -C ₆ alkyl, -CF ₃ or -CH ₂ -φ, (f) -NQksa Qvsb wherein Qi- _3A and are identical or different and wherein Qi. _3B is -H, C 1 -C 6 alkyl, -CF _3, or -CH ₂ -φ, and wherein Q 1. _3A is as defined above, (g) -CO -NQi. _3a Qf. _3B , where a Qi. _3B are as defined above, (h) -SO ₂ -NQ 1. _3A Qi. _3B , wherein Qi. _3A and are as defined above, (i) -NQi. _3A -SO ₂ -Q. _3B , wherein Q _V3A and 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) -NQ1.1Q1.2, wherein Qm and Q1. ₂ are defined above, • V · · · · 197 (G) -C (Q _1/3) = N-O-4 -Q, wherein Q ^ is equal to ₃ and Q Qi_. ₃ is as defined above, Q _{1 -} and may be the same or different, (H) -SO ₂ -Q _{1 -} , wherein Q _{1 - 3} is as defined above, (I) -N (Q _{1 1} ) -SO ₂ -Q _{1 -} , wherein Qm and Q1.3 are as defined above, (J) 5-oxadiazole optionally substituted with one Q1. _5i wherein Q 1.5 is (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 1 or 2 triple bonds (ξ), (6) C ₃ -C ₈ cycloalkyl, (7) -C 1 -C ₃ alkyl -C ₃ -C ₈ cycloalkyl, (8) -NO (9) -C = N, (10) -CF (11) -O-Q1.5A, wherein Q1-sa is: (a) -H, (b) C 1 -C ₈ alkyl, (c) C ₂ -C ₈ alkenyl having 1 to 3 double bonds, (d) C ₂ -C ₈ alkynyl having 1 to 2 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) - (CH ₂ ) n ₇ -Φ, wherein n ₇ is 0 to 4, (12) -NQ1.5A Qi-5d, wherein Qi. ₅ and is defined above, Qi. _5D is: (a) -H, (b) C 1 -C ₈ alkyl, (c) C ₂ -C ₈ alkenyl having 1 to 3 double bonds, (d) C ₂ -C ₈ alkynyl having 1 to 2 triple bonds (=), (e) C ₃ -C ₈ cycloalkyl, (f) -C 1 -C ₃ alkyl, - C ₃ -C ₈ cycloalkyl, (g) -CF (h) - ₍₂ 0Η) _{η7 -φ} wherein n ₇ is as defined above , (13) -CO--NQí was Q1-5D where Qi_ ₅ aa Qi- _5D are as defined above, (14) -SO ₂ -Q-5K, wherein Q-5kje (a) -H, (b) -CF (c) C 1 -C ₈ alkyl, (d) C ₂ -C ₈ alkenyl having 1 to 3 double bonds (=), (e) C ₂ -C ₈ alkynyl containing 1 or 2 triple bonds (=), (f) C ₃ -C ₈ cycloalkyl, 199 · · 9 9 • • • • • • • • • • 199 • • • 9 • • 9 9 9 9 9 (G) -C 1 -C ₃ alkyl -C ₃ -C ₈ cycloalkyl, (h) - (CH ₂ ) _n 7 -Φ, where n ₇ is as defined above, (15) -NQvsa -SO ₂ - Qi-sk, where Qi. ₅ aa Qi. _{The 5Ks} may be the same or different and are as defined above, (16) ^- (CH ₂ ) n ₇ -φ, where n ₇ is as defined above and wherein -φ is optionally substituted with one or two (a) -F, -Cl, -Br , -I, (b) -CSN (c) -CF _3, (d) _Ci-C6 alkyl, (e) -O-5a -Q, wherein Q. ₅ and is as defined above, (f) -NQvsa Qi-5d, where ΟνδΑ and Qi. ₅ d are as defined above, (g) -CO -NQvsa Q1.5D. wherein Q1 and Q1. ₅ d are as defined above, (h) -SO ₂ -NQi-5 _A-5D Qi wherein Qi and Qi-sa. _5D are as defined above, (i) -NQi- ₅ and -SO ₂ -Q-5d, where Qi. _5A and Qi-sd are defined above, O) -NO ₂ , (k) -O -SO ₂ -CF ₃ ; (K) 3-oxadiazole optionally substituted with one Qi_ ₅ wherein Qi. ₅ is as defined above; e 200 (L) triazole optionally substituted with one or two compounds (200). Q ₁₅ , which may be the same or different, wherein Q 15 is as defined above, (M) 5-thiadiazole optionally substituted with one Q 1. ₅ , wherein Q1.5 is as defined above, (N) 3-thiadiazole optionally substituted with one Q1.5, wherein Q1.5 is as defined above, (O) 2-oxazole optionally substituted with one or two Q1.5 which may be identical or different, wherein Q1.5 is as defined above, (P) 2-thiazole optionally substituted with one or two Q1.5, which may be the same or different, wherein Q1.5 is as defined above, (Q) 2-imidazole optionally substituted with one , two or three Q1.5, which may be identical or different, wherein Q1.5 is as defined above, (R) 1-imidazole substituted with one, two or three Q1.5, which may be identical or different, wherein Q1.5 is defined above, (S) tetrazole optionally substituted with one Q15, where Q1.5 is as defined above, (T) cyclobutenedion optionally substituted with one Qm and one Q1.5, where Qvi and Ο _ν5 are as defined above, (U) 1-pyrimidinyl optionally substituted with one as defined above, Q1-5 where Q1-5 Yippee (V) 2-pyridinyl as defined above, optional substituted one Q1-5, where Q1-5 Yippee (W) 3-pyridinyl as defined above, optional substituted one Q1-5, where Q1-5 Yippee (X) 4-pyridinyl as defined above, optional substituted one Q1-5, where Q1-5 Yippee 201 (Y) -Z, -CO-Z ₂ -Q1-2 wherein Qi- ₂ is as defined above and Z is -O- or -N _q ii, wherein Q f.f is as defined above, wherein Z ₂ is -O- or -N _q1 _i, where Q _V1 is as defined above with the proviso that if Xi is - (CH ₂ ) _n i where m and Qi is: -CO -NQm Qi-2 -SO ₂ -NQm Q- ₂ or -NQi-i Q1-2 -NQm -CO-Q1.2 then Q1.1 and Qi. ₂ , both cannot be selected from -H, -C 1 -C ₆ alkyl, -C3- _C7 cycloalkyl, -C 1 -C 3 alkyl - (C ₃ -C ₇ ) cycloalkyl and pharmaceutically acceptable salts thereof. (5) C ₂ -C ₈ alkynyl containing 1 or 2 triple bonds (=), (6) C ₃ -C ₈ cycloalkyl, (7) -C 1 -C ₃ alkyl -C ₃ -C ₈ cycloalkyl, (8) - (CH ₂ ) n ₂ -φ, wherein n ₂ is as defined above and -φ is optionally substituted by one or two: (a) -F, -Cl, -Br, -I, (b) -CSN (c) -CF _3, (d) C, -C ₃ alkyl, (e) -0 -Ri- _3A wherein Ri_ ₃ and is -H, C 1 -C ₆ alkyl, -CF _3, or - ΟΗ ₂ -φ, (f) -NR v R 1. _3B , wherein R 1. _3A and R 1. _3B are identical or different and wherein R 1. _3A is as defined above, (g) -CO -NRvsa _3B RI wherein RI and R _3A are defined above, (h) -SO ₂ -NR 6 and R 1. _3B wherein R 1. _3A and R 6 are defined above, (i) -NR @ ₂ and -SO -Ri- _3B wherein R₁ and R1-3B are as defined above, O) -no ₂ , (k) -O-SO ₂ -CF ₃ , (9) -O-R a where R 1. _3A and R 1. _3B are as defined above, (10) -NR 1 and R _3B , wherein _3B R 1. _3A and RI- _3B are as defined above, (O) ₂ -Ri- -NRm -SO _3, where R m and R _V3 can be identical or different, as defined above, (p) - _{(CH2) n2} -φ, where n ₂ is as defined above and where -φ is optionally substituted with one or two: (6) C 1 -C ₈ alkyl; 209 (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 ) _{n 2} -φ wherein n ₂ is as defined above and -φ is optionally substituted with one or two: (a) -F, -Cl, -Br, -I, (b) -C =N, (c) -CF ₃ , (d) C 1 -C ₆ alkyl, (e) -O-Q ₁₂ a, wherein Q 1-2a is (I) -H, (ii) C 1 -C ₈ alkyl, (iii) -CF ₃ , (iv) - (CH ₂ ) -φ, (B) -SO ₂ -NQm C 6 wherein Qi . <and Qi. ₂ are as defined above, (C) -NQi-i Q1. _2i wherein Qm and Qi- ₂ are as defined above, (D) -CO -NQm -Qi- _2, wherein Qi and Qm. ₂ are defined above, (III) R 1 is: (A) -H, (B) -F, -Cl, -Br, -I, (C) C 1 -C ₈ alkyl, (D) -C = N 210 (E) -CF (F) -O-R 1 -I, wherein R m is: 6-formyl-1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] isochroman, 6-acetyl-1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] isochroman, The 1,6-disubstituted isochroman (I) according to claim 5, wherein m is 0 or 1. A disubstituted isochroman (I) according to claim 1, wherein X 1 is -CH = CH-. A disubstituted isochroman (I) according to claim 1, wherein R 1 is -O-R m, -CF ₃ , -CO-N (R 11) 2, and -CO-R m. 202 9 · · · 204 The 1,6-disubstituted isochroman (I) of claim 7, wherein R m is C 1 -C ₃ alkyl. The 1,6-disubstituted isochroman (I) of claim 1, wherein R ₂ is -H. The 11,1,6-disubstituted isochroman (I) of claim 1, wherein Q 1 is selected from the group consisting of -CO-NQ m Q 1. _2, SO ₂ - NQ-iQi- _2, and -NQmQi. ₂ . The 1,6-disubstituted isochroman (I) of claim 10, wherein Ch is -CO-NQ1. 1Q1-2 · The 1,6-disubstituted isochroman (I) of claim 11, wherein the pharmaceutically acceptable salt anion is selected from the group consisting of methanesulfonic acid, hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, benzoic, citric, tartaric, fumaric, maleic anions. CH ₃ - (CH ₂ ) _n -COOH, wherein n is 0 to 4, HOOC - (CH ₂ ) _n -COOH, wherein n is as defined above. 14.1,6-Disubstituted isochroman (I) according to claim 1, wherein R f is (Q) -CO-R 11 or -CO-O-Q ₁₂ . The 1,6-disubstituted isochroman (I) according to claim 14, wherein the 1,6-disubstituted isochroman is (S) - (-) - 1- [2- [4- (4-trifluoroacetylphenyl) -1-piperazinyl] ethyl -Nmethylisochroman-6-carboxamide. The 1,6-disubstituted isochroman (I) of claim 1, wherein Q 1 is (Y) -Z 1 -CO ₂ -Q ₁ - The 1,6-disubstituted isochroman (I) of claim 16, wherein the 1,6-disubstituted isochroman is selected from the group consisting of (S) - (-) - 6-amino-1- [2- [4- (4- (S) - (-) - 6-amino-1- [2- [4- (4-methoxyphenyl) piperazin-1-yl] ethyl] isochroman t-butylcarbamate; · · · · · 203 • · ······························ (+/-) 1- [2- [4- (4-Methoxyphenyl) -1-piperazinyl] ethyl] isochroman-6-ol methyl carbamate ester. The 1,6-disubstituted isochroman (I) of claim 1, wherein Q 1 is (F ') -NQm CO-Q _{1 - 2} . The 1,6-disubstituted isochroman (I) of claim 18, wherein the 1,6-disubstituted isochroman is selected from the group consisting of: (S) - (-) - N- [Isochroman-1- [2- [4- (4-methoxyphenyl) piperazin-1-yl] ethyl] -6-yl] benzamide; and (S) - (-) - N- [Isochroman- 1- [2- [4- (4-Methoxy-phenyl) -piperazin-1-yl] -ethyl] -6-yl-acrylamide. The 1,6-disubstituted isochroman (I) according to claim 1, wherein Qf and Qi. ₂ , together with the attached nitrogen atom, form a 5 and 6 membered ring. The 1,6-disubstituted isochroman (I) of claim 20, wherein the 5 and 6 membered ring is selected from the group consisting of pyrrolidine, piperidine, piperazine, and morpholine. 22.1,6-Disubstituted isochroman (I) according to claim 20 which is (+/-) - 1- [2- [4- (4-methoxyphenyl) -1-piperazinylyl] ethyl] isochroman-6-yl] -4-methylpiperazine. The 1,6-disubstituted isochroman (I) of claim 1, which is selected from the group consisting of: An aromatic bicyclic amine of formula (ABA) ^R ₁ ^R 2 (ABA) wherein (I) W 1 is a nitrogen (-N-) or carbon (-CH-) atom; (II) Xf is - (CH ₂ ) ni and η _Ί is 0, (III) Q 1 is (A) -CO -NQm Q ₁ - ₂ , where Q m is ^- . The aromatic bicyclic amine (ABA) of claim 24, wherein N 1 is (-N-). The aromatic bicyclic amine (ABA) of claim 24, wherein one of R 1 and R ₂ is -H. 211 • «· The aromatic bicyclic amine (ABA) of claim 24, wherein Ch is (A) -CO- NQm Ql-2 · The aromatic bicyclic amine (ABA) of claim 27, wherein Q m is -H. The aromatic bicyclic amine (ABA) of claim 27, wherein Q 1. ₂ is -CH ₃ . The aromatic bicyclic amine (ABA) of claim 27, wherein the pharmaceutically acceptable salt anion is selected from the group consisting of methanesulfonic, hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, benzoic, citric, tertaric, fumaric, maleic anionic anions CH ₃ ( CH ₂ ) _n -COOH, wherein n is 0 to 4, HOOC - (CH ₂ ) _n -COOH, wherein n is as defined above. Aromatic bicyclic amines (ABA) according to claim 27, wherein the substituted amino compounds are selected from the group consisting of (S) - (-) - 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] - N-methylisochroman-6-carboxamide, (R) - (+) - 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] -N-methylisochroman-6-carboxamide, (S) - (-) 1- [2- [4- (4-Trifluoromethylphenyl) -1-piperazinyl] ethyl] -N-methylisochroman-6-carboxamide, (S) - (-) 1- [2- [4- (4- (aminocarbonyl) phenyl) -1] -piperazinyl] ethyl] -N-methylisochroman-6-carboxamide, The aromatic bicyclic amine (ABA) of claim 31, wherein the substituted amino compound is (S) - (-) - 1- [2- [4- [4- (trifluoromethylphenyl) -1-piperazinyl] ethyl] -Nmethylisochroman-6- carboxamide and (S) - (-) - 1- [2- [4- [4- (aminocarbonyl) phenyl] -1-piperazinyl-ethyl] -N-methylisochroman-6-carboxamide. 214 • · · ♦ ················· The aromatic bicyclic amine (ABA) of claim 27, wherein the substituted amino compound is selected from the group consisting of: The aromatic bicyclic amine (ABA) of claim 24, wherein the substituted amino compound is selected from the group consisting of: The aromatic bicyclic amine (ABA) of claim 24, wherein the substituted amino compound is selected from the group consisting of (S) - (-) - N- [isochroman-1- [2- [4- (4-methoxyphenyl) piperazine-1]. (S) - (-) - N- [Isochroman-1- [2- [4- (4-methoxy-phenyl) -piperazin-1-yl] -ethyl] -6-yl] -acetamide (S) - (-) - N- [Isochroman-1- [2- [4- (4-methoxyphenyl) piperazin-1-yl] ethyl] -6-yl] propionamide, (S) - (-) - N- [Isochroman -1- [2- [4- (4-methoxyphenyl) piperazin-1-yl] ethyl] -6-ylisobutyramide, (S) - (-) - N- [isochroman-1- [2- [4- (4-methoxyphenyl)] (piperazin-1-yl) ethyl] -6-yl] -N-methylacetamide; and (S) - (-) - N- [isochroman-1- [2- [4- (4-methoxyphenyl) piperazin-1-yl] ethyl] ethyl. 6-yl] -N-methylisobutyramide. 36. The aromatic bicyclic amine is selected from the group consisting of (S) - (-) - 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] isochroman-6-carboxamide, (R) - (+) -1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] isochroman-6-carboxamide, The aromatic bicyclic amine of claim 36 which is (S) - (-) - 1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] isochroman-6-carboxamide, (R) - (+) -1- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] isochroman-6-carboxamide. The aromatic bicyclic amine of claim 36, wherein the pharmaceutically acceptable salt anion is selected from the group consisting of methanesulfonic, hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, benzoic, citric, tartaric, fumaric, maleic anionic anions CH ₃ - (CH ₂₎ ) _n COOH, wherein n is 0 to 4, HOOC- (CH ₂ ) _n -COOH, wherein n is as defined above.