AU770976B2

AU770976B2 - Heteroarylpiperidines and their use as antipsychotics and analgetics

Info

Publication number: AU770976B2
Application number: AU79385/01A
Authority: AU
Inventors: Yulin Ang; Kenneth J. Bordeau; Edward J. Glamkowski; Grover C. Helsley; Peter A. Nemoto; Joseph Strupczewski; John J Tegeler
Original assignee: Aventis Pharmaceuticals Inc
Current assignee: Aventis Pharmaceuticals Inc
Priority date: 1993-10-28
Filing date: 2001-10-12
Publication date: 2004-03-11
Anticipated expiration: 2014-10-27
Also published as: AU7938501A

Description

P/00/01 128/5/91 Regulation 3.2(2)

AUSTRALIA

Patents Act 1990 COMPLETE SPECIFICATION STANDARD PATENT Applicadion Number: Lodged: Invenfion Title: HETEROARYLPI PERI DINES, PYRROLIDINES AND PIPERAZINES AND THEIR USE AS ANTIPSYCHOTICS AND ANALGETICS The following statement is a full description of this invention, including the best method of performing it known to :-us

HETEROARYLPIPERIDINES

AND THEIR USE AS ANTIPSYCHOTICS AND ANALGETICS BACKGROUND OF THE INVENTION This invention relates to heteroarylpiperidines. More particularly, this invention relates to heteroarylpiperidines having antipsychotic activity and to their use as antipsychotic drugs.

The therapeutic treatment of schizophrenic patients by administration of neuroleptic drugs, such as chlorpromazine, haloperidol, sulpiride, and chemically closely related compounds, is widespread. While control of schizophrenic symptoms has been successful, treatment with these drugs does not cure the psychotic patient, who will almost certainly relapse if medication is discontinued.

There exists a continuing need in the art for antipsychotic drugs for the treatment of psychoses.

Moreover, some of the known neuroleptics produce unwanted side effects.

For example, the side effects of many antipsychotic drugs include the so-called extrapyramidal symptoms, such as rigidity and tremor, continuous restless walking, and tardive dyskinesia which causes facial grimacing, and involuntary movements of the face and extremities. Orthostatic hypotension is also common.

Thus, there also exists a need in the art for antipsychotic drugs that produce fewer or less severe manifestations of these common side effects.

In addition, because of the frequent long term administration of neuroleptics and the problems with patient compliance, there is a further need in the art for long lasting neuroleptics, which can be formulated into sustained release depot preparations, without the side effects previously mentioned.

Moreover, there has been a need for drugs that can produce other biological effects. For example, relief from pain has been an age-old aspiration which has led to the discovery of natural and synthetic analgetics. Nevertheless, the need for safe and effective analgetics has continued to the present day.

.:000o o *oo SUMMARY OF THE INVENTION This invention aids in fulfilling these needs in the art by providing a compound of the formula: (Y)I (I) wherein X is or -N(R 2

R

2 is selected from the group consisting of lower alkyl, aryl lower alkyl, aryl, cycloalkyl, aroyl, alkanoyl, alkoxycarbonyl and phenylsulfonyl groups; p is 1 or 2; Y is hydrogen, lower alkyl, hydroxy, chlorine, fluorine, bromine, iodine, lower alkoxy, trifluoromethyl, nitro, or amino; Q* is where Z is and S*z N--Y o*

Y

2 is selected from the group consisting of:.

(R~n in which CR 1 is -CR 24

R

2 rC(CR23R 2 dn-CR 24 Rv7- where n is 0,1,2, or 3; or

-CHR

24

-CH=CH-CHR

24

-CHR

24

-C=C-CHR

24

CHR

24 -CH=CH-CR23R 24 -CHR2,

-CHR

24 -CR23R 24

-CH=CH-CHR

24

-CHR,

4

-C=C-CR

23

R

24

-CHR

24 or -CH R 24 -CR23R 24 -CM C-CHR 24 the -CH=CH- bond being cis or trans; R and mnare as defined hereinafter; R23 is hydrogen, alkyl, aryl, hydroxy, alkoxy, aryloxy, arylalkyloxy, alkanoyloxy, hydroxy lower alkyl, alkoxy lower alkyl, aryloxy lower alkyl, arylalkyl.

oxy lower alkyl, alkanoyloxy lower alkyl. or lower alkylcneyl-o

(O

where Z, is lower alkyl, -OH, lower alkoxy, -CF 3 -NOV, -NH 2 or halogen; and

RN

4 is hydrogen, alkyl, aryl, hydroxy lower alkyl, alkoxy lower alkyl, aryloxy lower alkyl, arylalkoxy lower alkyl, alkanoyloxy lower alkyl or lowrakyee yI0

(ZOP

where Z, is as previously defined;

R

2 7 is hydrogen or R 24 and R 27 taken together with the carbon to which they are attached form C=O or C=S; and R and m are as defined hereinafter;

(R)O

R

3

NH

where R 1 is as previously defined, and R 3 is hydrogen or-OCH 3 (3)N R4 where R 1 is as previously defined; and

R

4 is selected from hydrogen, lower alkyl, lower alkoxy, hydroxy, tri(C1- C6)-alkylsilyloxy, hydroxy lower alkyl, alkanoyloxy lower alkyl, amino, mono- or dialkylamino, (C1-Cl 8 )acyl amino, (C 1

-C

18 )alkanoyl, trifluoromethyl, chlorine, 10 fluorine, bromine, nitro, 1

-C

18 straight or branched chain) alkyl or -C(=O)-aryl; in which aryl is phenyl or

R

where R5 is hydrogen, lower alkyl, lower alkoxy, hydroxy, chlorine, fluorine, bromine, iodine, lower monoalkylamino, lower dialkylamino, nitro, cyano, trifluoromethyl, trifluoromethoxy; o where R, and R 4 are as previously defined;

(R

1 )O r where either one of or X, is and the other is -CH 2 and d R51 is hydrogen, lower alkyl, lower alkoxy, chlorine, fluorine, or bromn e; and R, is as previously defined; where R, and R, are as previously defined;

U

(RI)-

where A is

-C(=CH

2 -C(0)CH 2

-CH

2

CH

2

-CR

26 or 26 is hydrogen, lower alkyl, hydroxy or alkanoyloxy;

R.

6 is hydrogen or lower alkyl; either one of B~ and B, is CH or N and the other is CH; U Uis 0or S; q is 1, 2,3 or 4, and R, and R 4 are as previously defined; where R, is as previously defined;

R

2 S R, 2 s IR)- (R4)q

R

2 8 R 2 s wherein RI, R 4 and q are as defined above; and

RN

8 is hydrogen, (C 1

-C

6 )alkyl, aryl(C 1 -C6)alkyl, phenyl or substituted phenyl; wherein R 4 and q are as defined above;

R

2 9 and R30 are hydrogen, (C,-C,)alkyI, aryl(CI-C 6 )alkyl, phenyl or substituted phenyl; R3, and R 32 are hydrogen, hydroxy, (C 1

-C

6 )alkyl, aryl(C 1

-C

6 )alkyl, phenyl, substituted phenyl, hydroxymethyl, or CHQR33 where R33 is (Cr-Cls)alkanoyl; or either R 29 and R 3 o taken together or R 3 and R 32 taken together with the carbon group to which they are attached form a C=O or C=S group; 0 1) RR 31

R

32

R

2 9 )q

-(R

1 s R23 R23 where RI, R 4 1 R 28

R

2 9 R30, R 31 R32 and q are as defined above; (12) RR3 31R 32

R

3 1

R

32 (Rr4)q ~:where

R

4

R

2 3, R 2 9 R30, R 31

R

32 and q are as defined above; (13) wherein R, and R 4 are previously defined and m is defined hereinafter; (14) where R, is as previously defined; Q is S, NH, or -CH 2 and R and m are as defined hereinafter;

O

-RI)-C

where R, is as previously defined; (16) where and R 4 are as previously defined and m is as defined hereinafter; (17) 0 V where R 4 are as previously defined and mn is as defined hereinafter; (18) -RI-O-R 2 where R, 2 is selected from the group consisting of: hydrogen, alkyl, 8 straight chain or branched) alkyl, 2

-RI

7 and 0 where RU 3 is selected from the group consisting of hydrogen and (C 2

-C

18 )alkyl groups; where R 14 is selected from the group consisting of hydrogen and (C 1

-C

8 )zalkyl groups; where NRsR 6 taken together form a ring structure selected from the group consisting of piperidinyl, morpholinyl and piperazinyl; where is selected from the group consisting of lower alkyl and aryl groups; where R 4 is previously defined and m is defined hereinafter; (19) -RI-NRaR where R,8 and are independently selected from the group consisting of: hydrogen,

(CI-CI

2 straight or branched chain) alkyl, 8 alkyl, S. 1 alkyl; -C(=O)-pyridyl or

S

R 4 )m

N

28 where NRIaR9, taken together form a ring structure selected from the group consisting of piperidinyl, morpholinyl and piperazinyl; where the piperidinyl or piperazinyl ring is optionally substituted by a

N,

X

where X, Y, p, R 4 and are as previously defined and m is defined hereinafter;

-RI-S-R

1 2 where R, and R 12 are as previously defined; (21)

O

where R 1

R

4 and R 28 are as previously defined; and where oeoo oooo o *o oo

*A

R is selected from hydrogen, lower alkyl, lower alkoxy, hydroxyl, carboxyl, chlorine, fluorine, bromine, iodine, amino, lower mono or dialkylamino, nitro, lower alkyl thio, trifluoromethoxy, cyano, acylamino, trifluoromethyl, trifluoroacetyl, aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, formyl, -C(=O)-alkyl, -C(=O)-O-alkyl, -C(=O)-aryl, -C(=O)-heteroaryl,

-CH(OR

7 )-alkyl, -C(=W)-alkyl, -C(=W)-aryl, and -C(=W)-heteroaryl; 15 alkyl is (Ci-Ci8)alkyl; aryl is as previously defined; heteroaryl is

SQ

3 Q3 is -CH=N-; 20 W is CH 2 or CHR 8 or N-R 9

R

7 is hydrogen, alkyl, or alkanoyl;

R

8 is lower alkyl;

R

9 is hydroxy, alkoxy, or -NHRio; and Ro 0 is hydrogen, alkyl, (C 1

-C

3 )acyl, aryl, -C(=O)aryl or -C(=O)heteroaryl, where aryl and heteroaryl are as defined above; and m is 1, 2, or 3; with the proviso that in formula (14) Z is not -CH- when X is -NH- or

-N(R

2 Y is hydrogen, halogen, lower alkyl, lower alkoxy, hydroxy or trifluoromethyl and Q2 is -CH 2 11 with the proviso that in formula (14) Z is not -CH- when X is Q 2 is

-CH

2 Y is hydrogen, lower alkyl, lower alkoxy, hydroxy or halogen, and p is 1 or 2; with the proviso that in formula (14) Z is not -CH- when X is Q 2 is

-CH

2 Y is hydrogen, halogen, lower alkyl, lower alkoxy or hydroxy, p is 1 or 2, R is hydrogen, and m is 1; with the proviso that Y 2 is not the moiety of formula when Z is X is O, p is 1, and Y is hydrogen, lower alkyl, lower alkoxy, chlorine, fluorine, bromine, iodine or a hydroxyl group; with the proviso that in formula R 4 is not hydrogen when Y is 6-F, X is Z is and n is 2, 3 or 4; with the proviso that in formula when X is Z is and Y is hydrogen, lower alkyl, lower alkoxy, chlorine, fluorine, bromine, iodine or a hydroxyl group, R 18 and R 19 are not lower alkyl; with the proviso that in formula R 18 and R 1 9 are not hydrogen when R 1 is -(CH 2 2 5 Z is X is and Y is 6-F; all geometric, optical and stereoisomers thereof, or a pharmaceutically acceptable acid addition salt thereof.

This invention also provides compounds selected from formula I which are suitable for acylation with (C 4 -C1 8 )carboxylic acids or reactive functional derivatives thereof to form highly lipophilic esters, amides and carbamates, which compounds are also compounds of this invention. Such selected compounds possess a hydroxyl group attached to either an aliphatic or aromatic carbon atom capable of forming the highly lipophilic esters of the invention, a primary or secondary nitrogen atom including the nitrogen at the 1-position of an indazole ring system capable of forming the highly lipophilic amides of the invention. The primary or secondary nitrogen atom may alternatively be acylated with a (C4-

C

18 )alkoxy-carbonyl chloride to form a highly lipophilic carbamate derivative of the invention.

The invention also provides for the highly lipophilic compounds which provide long acting pharmaceutical effects when administered in the form of depot preparations.

This invention also provides a pharmaceutical composition, which comprises a compound of the invention and a pharmaceutically acceptable carrier therefor. In one embodiment of the invention, the pharmaceutical composition is an antipsychotic composition comprising a compound of the invention in an amount sufficient to produce an antipsychotic effect.

In addition, this invention provides a method of treating psychoses, which comprises administering to a patient a pharmaceutically effective amount of a compound of the invention.

Further, this invention provides a method of sustained release of a pharmaceutically effective amount of a lipophilic compound of the invention in the form of a depot preparation.

Finally, this invention provides a method of alleviating pain by administering to a patient a pain-relieving amount of a compound of the invention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT The compounds of this invention are useful as antipsychotic drugs and as analgesic agents. The compounds of the invention can contain a variety of different substituents and chemical groups. As used herein, when the term "lower" is mentioned in connection with the description of a particular group, the term means Sthat the group it is describing contains from 1 to 6 carbon atoms.

S* The term "alkyl" as used herein refers to a straight or branched chain hydrocarbon group having up to 18 carbon atoms and containing no unsaturation, for example, methyl, ethyl, isopropyl, 2-butyl, neopentyl, n-hexyl or pentadecyl.

The term "alkoxy" as used herein refers to a monovalent substituent comprising an alkyl group linked through an ether oxygen having its free valence bond from the ether oxygen, e.g. methoxy, ethoxy, propoxy, butoxy, or pentoxy.

The term "alkylene" as used herein refers to a bivalent radical of a lower branched or unbranched alkyl group having valence bonds on two terminal carbons thereof, for example, ethylene (-CH 2 propylene (-CH 2

CH

2

CH

2 or isopropylene

(-CH(CH

3

)CH

2 The term "cycloalkyl" refers to a saturated hydrocarbon group possessing at least one carbocyclic ring, the ring containing from 3 to 10 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclodecyl and the like.

The term "alkanoyl" refers to the radical formed by removal of the hydroxyl function from an alkanoic acid. More particularly, the term "alkanoyl" as used herein refers to an alkyl carbonyl moiety containing from 2 to 18 carbon atoms, e.g.

CH

3

CH

3 etc.

.Examples of alkanoyl groups are formyl, acetyl, propionyl, 2,2-dimethylacetyl, hexanoyl, octanoyl, decanoyl, and the like.

The term "alkanoic acid" refers to a compound formed by combination of a carboxyl group with a hydrogen atom or alkyl group. Examples of alkanoic adds are formic acid, acetic acid, propanoic acid, 2,2-dimethylacetic acid, hexanoic acid, octanoic acid, decanoic acid, and the like.

The term "aryl lower alkyl" refers to compounds wherein "aryl" and "loweralkyl" are as defined above.

The term "lower alkylthio" refers to a monovalent substituent having the formula lower alkyl-S-.

The term "phenylsulfonyl" refers to a monovalent substituent having the formula phenyl-SO2-.

The term "acyl" refers to a substituent having the formula lower alkyl-C(=O)- or or aryl-C(=O)- or heteroaryl-C(=O)-.

The term "lower monoalkylamino" refers to a monosubstituted derivative of ammonia, wherein a hydrogen of ammonia is replaced by a lower alkyl group.

The term "lower dialkylamino" refers to a disubstituted derivative of ammonia, wherein two hydrogens of ammonia are replaced by lower alkyl groups.

The term "acylamino" refers to a primary or secondary amine, wherein a hydrogen of the amine is replaced by an acyl group, where acyl is as previously defined.

The term "dialkylaminocarbonyl" refers to a derivative of an acid, wherein the hydroxyl group of the acid is replaced by a lower dialkylamino group.

The term "aroyl" refers to a disubstituted carbonyl, wherein at least one substituent is an aryl group, where "aryl" is as previously defined.

Unless otherwise indicated, the term "halogen" as used herein refers to a member of the halogen family selected from the group consisting of fluorine, chlorine, bromine, and iodine.

Unless otherwise indicated, the term "substituted phenyl" as used herein refers to a phenyl group substituted by "lower alkyl (CI-C 3 hydroxy, chlorine, fluorine, bromine, iodine, lower alkoxy, trifluoromethyl, nitro or amino".

Throughout the specification and appended claims, a given chemical formula or name shall encompass all geometric, optical and stereoisomers thereof where such isomers exist.

A. COMPOUNDS OF THE INVENTION The compounds of this invention can be represented by the following formula: f f (I) X/N( wherein X is or

R

2 is selected from the group consisting of lower alkyl, aryl lower alkyl, aryl, cycloalkyl, aroyl, alkanoyl, alkoxycarbonyl and phenylsulfonyl groups; p is 1 or 2; Y is hydrogen, lower alkyl, hydroxy, chlorine, fluorine, bromine, iodine, lower alkoxy, trifluoromethyl, nitro, or amino; Qi is N-Y2 where Z is and

Y

2 is selected from the group consisting of (R)m 5(1) in which (R 1 is -CR 24

R

27

-(CR

23

R

2 4)n-CR 24

R

27 where n is 0, 1, 2, or 3; or -CH R 24 -CH=CH-CH R 2 4-,

-CHR

2 1-CMC-CHR 2

-CHR

24 -CH=CH-CR23R 24

-CHR

2 4

-CHR

24 -CR23R 24

-CH=CH-CHR

24

-CHR

24 -CmC-CR23R 24

-CHR

24 or -CR4C2R4-M-H2the -CH=CH- bond being cis or trans; R23 is hydrogen, (C,-C 18 linear alkyl, phenyl, hydroxy, (C 1

-C

18 )alkoxy, aryloxy, aryl(C 1 -Cldalkyloxy, (C,-C 1 )akanoyloxy, hydroxy(C 1 -Cdalkyl,

(C

1

-C

18 )alkoxy(C 1

-C

6 )alkyl, phenyl(CI-C 6 )alkyloxy, aryl(C 1

-C

1 9)alkyloxy(CI-C 6 )alkyl or

(C,-C

1 )alkanoyloxy(C,-C,)alkyl or :lower lyeel(O where Z, is lower alkyl, -OH, lower alkoxy, -CF 3

-NO

2

-NH

2 or halogen; and

R

2 1 is hydrogen, (C,-C 18 linear alkyl, phenyl, hydroxy(C,-C 6 )alkyl,.

(C,-C,)alkoxy(C 1

-C

6 )alkyl, phenyl(C 1

-C

6 )alkyloxy, aryl(C,-C, 8 )alkyloxy(C,-C 6 )alkyI or 1 )alkanoyloxy(C 1

-C

6 )alkyl or lower alycey Zp ~*:where Z, is as previously defined;

R

2 7 is hydrogen or R 24 and R 2 7 taken together with the carbon to which they are attached form C=O or C=S; and R Rand m are as defined hereinafter;

R)

where R, is as previously defined, and R3 is hydrogen or -OCH 3 17 where R 1 is as previously defined; and

R

4 is selected from hydrogen, lower alkyl, lower alkoxy, hydroxy, tri(C,-

C

6 )alkylsilyloxy, hydroxy lower alkyl, alkanoyloxy lower alkyl, amino, mono- or dialkylamino, (Cl-C18)acyl amino, (Cl-C 18 )alkanoyl, trifluoromethyl, chlorine, fluorine, bromine, -O-C(=O)-(CiC8 straight or branched chain)alkyl or aryl; in which aryl is phenylor where R 5 is hydrogen, lower alkyl, lower alkoxy, hydroxy, chlorine, fluorine, bromine, iodine, lower monoalkylamino, lower dialkylamino, nitro, cyano, trifluoromethyl, or trifluoromethoxy; where R 1 and R 4 are as previously defined;

R'

where either one of Xy or Xz is and the other is -CH 2 and

R'

5 is hydrogen, lower alkyl, lower alkoxy, chlorine, fluorine, or bromine; and R, is as previously defined; EDITORIAL NOTE APPLICATION NUMBER 79385/01 This specification does not contain a page "18"'i

R

2 is hydrogen, (C 1

-C

6 )alkyl, aryI(C 1

-C

6 )alkyl, phenyl or substituted phenyl; (1)R 2 R

R

32

(R

1

)-N

(R4)q wherein RI, R 4 and q are as defined above;

.R

29 and R30 are hydro gen, (C,-C 6 )alkyl, aryl(C 1

-C

6 )alkyl, phenyl or substituted phenyl;

R

3 and R 32 are hydrogen, hydroxy, (C,-C 6 )alkyl, aryl(C,-C 6 )alkyl, phenyl, substituted phenyl, hydroxymethyl, or CHOR33 where R33 is (C,-C 1 )alkanoyl; or either R 29 and R30 taken together or R 3 and R 32 taken together with the carbon group to which they are attached form a C=O or C=S group; 011) R R R 32

-(R

1 (R4) R23. R2S where RI, R 4

RM

8

R

29

R

3 o, R3 1

R

32 and q are as defined above; (12)

R

2 R3 1R 32

R

31

VR

3 2 (R4)q where RI, R 4

R

2

R

2 9 R30, R 3 1 R32 and q are as defined above; (13) wherein R, and R.

4 are previously defined and m is defined hereinafter; te -(Rl)-Qz (R)m .2-a where R, is as previously defined; is S, NH, or -CH 2 and R and m are as defined hereinafter; 0 where R, is as previously defined; (16)0 where R, and R 4 are as previously defined and mn is defined hereinafter; 0 (R4)M where R, and R 4 are as previously defined and mn is defined hereinafter; (18) -R 1

-C)-R

12 where R2 2 is selected from the group consisting of: hydrogen, alkyl, 8 straight chain or branched) alkyl,

-C(=O)-NR

3

R

4 *RsR6 2

-R

1 7 and 0 -N 0 where R, 3 is selected from the group consisting of hydrogen and 8 alkyl groups; where RI, is selected from the group consisting of hydrogen and (C,-C 18 alky', 21 groups; where NR 15

R

16 taken together form a ring structure selected from the group consisting of piperidinyl, morpholinyl and piperazinyl; where R 17 is selected from the group consisting of (Ci-C 1 8 )alkyl and aryl groups; where R 4 as previously defined and m is defined hereinafter; (19) -Ri-NRi8Ri9 0 where R 18 and R 19 are independently selected from the group consisting hydrogen,

(C

1

-C

18 straight or branched chain) alkyl, alkyl, 1

-C

8 alkyl; -pyridyl;

B

B. *B B B B

B

*B

B

B B

B.

(R

4 )m ;and where NR 18

R

19 taken together form a ring structure selected from the group consisting of piperidinyl, morpholinyl and piperazinyl; where the piperidinyl or piperazinyl ring is optionally substituted by where X, Y, p, Ri, R 4 and R 28 are as previously hereinafter; defined and m is defined R-R1 where R, and R 12 are as previously defined; (21) 0 7(RO)M 0 where RI, R 4 and R 28 are as previously defined; and where R is selected from hydrogen, lower alkyl, lower alkoxy, hydroxyl, carboxyl, chlorine, fluorine, bromine, iodine, amino, lower mono or dialkylamino, nitro, lower alkyl thio, trifluoromethoxy, cyano, acylamino, trifluoromethyl, trifluoroacetyl, ::aminocarbonyl, monoalkylaminocarbonyl, dialkytaminocarbonyl, formyl, -C lk l -C(=O)-alkyl, -C(=O)-Oalkyl, -C(=O)-heteroaryl; akli -CW)alkyl,

IN

aryl is as previously defined; heteroaryl is

Q

3

Q

3 is

-CH=N-,

W is CH 2 or CHR 8 or N-Rg;

R

7 is hydrogen, alkyl, or alkanoyl;

R

8 is lower alkyl; Rg is hydroxy, alkoxy, or-NHRio; and Rio is hydrogen, lower alkyl, (Cl-Ci 8 )acyl, aryl, -C(=O)-aryl or heteroaryl, where aryl and heteroaryl are as defined above; and m is 1, 2, or 3; with the proviso that in formula (14) Z is not -CH- when X is -NH- or

-N(R

2 Y is hydrogen, halogen, lower alkyl, lower alkoxy, hydroxy or trifluoromethyl and Q 2 is -CH 2 with the proviso that in formula (14) Z is not -CH- when X is Q 2 is

-CH

2 Y is hydrogen, lower alkyl, lower alkoxy, hydroxy or halogen, and p is 1 or 2; with the proviso that in formula (14) Z is not -CH- when X is Q 2 is 15 -CH 2 Y is hydrogen, halogen, lower alkyl, lower alkoxy or hydroxy, p is 1 or 2, R is hydrogen, and m is 1; with the proviso that Y2 is not the moiety of formula when Z is X is O, p is 1, and Y is hydrogen, lower alkyl, lower alkoxy, chlorine, fluorine, bromine, iodine or a hydroxyl group; with the proviso that in formula R 4 is not hydrogen when Y is 6-F, X is Z is and n is 2, 3 or 4; with the proviso that in formula when X is Z is and Y is hydrogen, lower alkyl, lower alkoxy, chlorine, fluorine, bromine, iodine or a hydroxyl group, R 18 and R 1 9 are not lower alkyl; 25 with the proviso that in formula R 18 and R 19 are not hydrogen when R, is -(CH 2 2 5 Z is X is and Y is 6-F; all geometric, optical and stereoisomers thereof, or a pharmaceutically acceptable acid addition salt thereof.

When the compounds of the invention are represented by the following formula: where Q 1 is -Z N-Y 2 the substituent X is formula is selected from the group consisting of or -N(R 2 When the substituent X is the compounds of the invention contain a 1,2-benzisoxazole nucleus, and when X is the compounds of the invention contain a 1,2-benzisothiazole nucleus. When X is -NH- or -N(R 2 the compounds of the invention contain the indazole nucleus.

When p in formula is 1, the substituent Y is selected from the group consisting of hydrogen, lower alkyl, hydroxyl, halogen, lower alkoxy, -CF 3

-NO

2 and -NH 2 The substituent Y is preferably in the 5- or 6-position of the ring.

Moreover, in the preferred embodiments of the invention, the substituent Y is .:hydrogen, hydroxy, chlorine, bromine, or fluorine, and in the particularly preferred compounds of the invention, Y is fluorine, especially in the 6-position of the ring.

S. 15 When p in formula is 2 and X is each Y substituent can be independently selected from lower alkoxy, hydroxy or halogen groups, preferably methoxy groups.

The value of n in the foregoing formulas can be 2, 3, 4, or 5, and preferably is 2, 3, or 4. In the particularly preferred compounds of the invention n is 2 or 3.

20 When X in the compounds of the invention is -N(R 2 the substituent R 2 is selected from the group consisting of lower alkyl, aryl lower alkyl, aryl, cycloalkyl, aroyl, alkanoyl, alkanoyloxy and phenylsulfonyl groups.

The compounds of the invention can contain one, two, or three Rsubstituents. The substituent R can be hydrogen, lower alkyl, (C 1

-C

18 )alkoxy, hydroxyl, carboxyl, Cl, F, Br, I, amino, (Cl-C 18 )mono or dialkyl amino, -NO 2 lower alkyl thio, -OCF 3 cyano, acylamino, -CF3, trifluoroacetyl -C(=O)-CF 3 aminocarbonyl -C(=O)-NH 2 dialkylaminocarbonyl, formyl, -C(=O)-alkyl, -C(=O)-O-alkyl, -C(=O)-aryl, -C(=O)-heteroaryl, or THE NEXT PAGE IS PAGE 29 -CH(0R 7 )-alkyl, -C(=W)-alkyl, -C(=W)-aryl, or -C(=W)-heteroaryl; aiLkyl is (CI-C 18 alkyl; aryl is phenyl or

R

a (1) where R 5 is hydrogen, lower alkyl, (CI C 6 )alkoxy, hydroxy, 0, F, Br, I, (CI C~dalkylamidno,

-NO

2 -CN, -CF 3 -OCF3; heteroaryl is (2) Q is Er, -CH=N-; W is CH 2 or CHR 8 or N-R,;

R

7 is hydrogen, alkyl, or alkanoyl;

R

8 is lower alkyl; R9 is hydroxy, alkoxy, or -NHR 10 and

R

10 is hydrogen, lower alkyl, (C 1

-C

18 )acyl, aryl, -C(=O)-aryl or C=) heteroaryl, where aryl and heteroaryl are as defined above; and mnis1, 2, or 3 When the compounds of the invention contain two or three R-substituents, :each of the R-substituents can be independently selected from the above substituents.

Preferably, each of the R-substituents is selected from the group consisting of hydrogen,

C

18 alkyl, (C 1

C

15 )alkoxy, hydroxyl, -COCF 3

(C,-C

18 )allcanoyl, Cl, F, Br, 1, (C 1

C

3 )alkylamino,

-NO

2

-CF

3

-OCF

3 -C(=O)-lower alkyl, and -CH(0R 7 )-lower alkyl.

The compounds of the present invention are prepared in the following manner. The substituents R, RI, R 2 R3,, etc., X, Y, and Z and the integers mn, n, and p are as defined above unless indicated otherwise.

B. PREPARATION OF COMPOUNDS OF THE INVENTION The compounds of the invention can generally be prepared by reacting a piperidine of the formula: Z NH (3)

I

where Z is -C-H under alkylating conditions with a compound of the formula: *r ooo op HAL Y 2 (4) where HAL is Cl, Br, or I. The procedures that can be employed for preparing the piperidines and the alkylating agents identified by the above formulas will now be 15 described in detail.

1. Preparation of 3-(1-unsubstituted-4-piperidinyl)-l H-indazoles A compound of the formula: for use in synthesizing the indazole-substituted piperidines of the invention can be prepared using known techniques. For example, suitable techniques are described in substantial detail in U.S. Patent 4, 710, 573.

2. Preparation of 3-(1-unsubstituted-4-piperidinyl)-1,2-benzisoxazoles A compound of the formula: -NH (23) 0^ can be prepared by following the teachings from several sources. For example, U.S. Patent No. 4,355,037 contains a detailed description of compounds of formula (23) and of methods for preparing the compounds. Additional disclosure of methods for preparing the compounds of formula (23) can be found in U.S.

Patent No. 4,327,103 and in Strupczewski et. al., J. Med. Chem., 28:761-769 (1985). The compounds of formula (23) can be employed in the synthesis of the benzisoxazole substituted piperidines of the invention.

3. Preparation of 3-(1-unsubstituted-4-piperidinyl)-1,2-benzisothiazoles Certain 3-(4-piperidinyl)-1,2-benzisothiazoles can be employed in the synthesis of the N-(aryloxyalkyl)heteroaryl piperidines of the invention.

Specifically, a benzisothiazole of the formula: S- NH (24) s can be reacted with the alkylating agent previously described to form the N- (aryloxyalkyl)heteroarylpiperidines of the invention. Compounds of formula (24) and their methods of preparation are described in detail in U.S. Patent No.

4,458,076.

32 4. Preparation of alkylating agents The compounds described in Sections 1-3 above can be reacted with alkylating agents as is known in the art. For example, when Y 2 is as described in formula an alkylating agent of the formula: (R)m

HAL-(CH

2 )nO (4) is reacted to form the N-(aryloxyalkyl)heteroarylpiperidines of the invention. The alkylating agents of formula and methods for preparing the alkylating agents are described in U.S. Patent No. 4,366,162. Additional disclosure can be found in South African publication EA 86 14522. In addition, procedures for making alkylating agents are described in the following Examples. These procedures can be employed to make other alkylating agents for use in this invention.

5. Alkylation of heteroarylpiperidines The heteroarylpiperidines described in Sections 1-3 above can be reacted S. 15 under alkylating conditions with the alkylating agents described in Section 4 to form selected compounds of this invention. The reaction can be carried out by dissolving the reagents in an inert solvent, such as dimethylformamide, acetonitrile, or butanol, and allowing the reagents to react from a temperature of 50 0 C to refluxing of the solvent in the presence of an acid receptor, such as a 20 base. Examples of suitable bases are alkali metal carbonates, such as potassium carbonate, sodium carbonate, or sodium bicarbonate. The reaction can be carried out with or without a catalytic amount of an alkaline iodide, such as potassium iodide or sodium iodide, for a time sufficient to form a compound of formula of the invention. Generally, the alkylation reaction is carried out for about 4 to about 16 hours, depending on reactivity of the reagents. The reaction temperature can vary from about 50 0 C to about 120 0 C. The products can be isolated by treating the reaction product with water, extracting the product into an organic solvent that is immiscible in water, washing, drying, and concentrating the organic solvent to yield the free base, and then, if indicated, converting the resulting compound to an acid addition salt in a conventional manner.

33 In addition, the compounds of formula (19) where R 18

R

19 are both hydrogen may be prepared from the phthalimido compound of formula 7 by treatment with base such as, for example, hydrazine as is known in the art.

More specifically, certain of the compounds of the invention can be synthesized by the following methods: A. Synthesis of Phthalimides The phthalimido compounds of the invention of formula (25) can be synthesized o Z N-(CHR)m N (R4)q x o0 in several ways.

i 1. Alkylation with an N-haloalkylphthalimide S. The heterolarylpiperidines described in Sections 1-3 above are alkylated under known conditions using the appropriate haloalkylphthalimide, preferably an N-bromoalkylphthalimide in a nonprotic 0 S*

HAL-(CH

2 )n N (R4)q (26) 0 organic solvent such as acetonitrile in the presence of a base such as potassium carbonate at a temperature of from about room temperature to about 120 0

C,

preferably from about 800C to about 100C.

2. Reaction with a phthalic anhydride The heteroarylpiperidines described in Sections 1-3 above are first reacted with a haloalkylnitrile to form the corresponding substituted nitrile (27) wherein R is a substituent as defined for R 1 above. The reaction is carried out in a polar, nonprotic organic solvent such as THE NEXT PAGE IS PAGE (27) Z N-(CHR)m-CN (Y)p acetonitrile in the presence of a base such as potassium carbonate at a temperature of from about room temperature to about 120*C, preferably from about 80'C to about 100 0

C.

The nitrile is then reduced, for example with lithium aluminum hydride in an organic solvent such as tetrahydrofuran at a temperature of from about 0"C to about preferably at about room temperature to yield the corresponding primary amine (28).

Z N-(CHR)m-CH 2

NH

2 (Y)p X (28) x The amine(28) is reacted with phthalic anhydride or a substituted phthalic anhydride or the corresponding phthalic acid under known conditions, for example in dichloromethane or dimethylformamide at temperatures of from about 10°C to about !150*C to yield the corresponding phthalimido compound. Preferred conditions for the reaction include dichloromethane at room temperature or dimethylformamide at 135°C.

B. Synthesis of isoindolines The isoindolines of Formula (29) can be prepared by the following routes.

X N-(CHR)m-N2 (R 4 )q (29) IxYN 1. Condensation with an a,a'-dibromo-ortho-xylene The amine (28) is reacted with an a,a'-dibromo-ortho-xylene to obtain the isoindoline. The reaction is carried out in an organic solvent such as acetonitrile in the presence of a base such as potassium carbonate at temperatures of from about room temperature to about 150°C, preferably from about 75'C to about 100°C.

2. Reduction of a phthalimide 41 Alternatively, a phthalimido compound of the invention is reduced, for example with lithium aluminum hydride in an organic solvent such as tetrahydrofuran at a temperature of from about 0°C to about 1000C, preferably from about 700C to about C. Synthesis of tetrahydroquinolines and tetrahydroisoquinolines The tetrahydroquinolines and tetrahydroisoquinolines of the invention can be prepared by alkylating the heteroarylpiperidine with the appropriate 2bromoacetyltetrahydroquinoline or 2-bromoacetyltetrahydroisoquinoline in the presence of a polar organic solvent such as acetonitrile in the presence of a base such as potassium carbonate at temperatures of from about room temperature to about 150 0 C, preferably from about 75 0 C to about 1000C to form the corresponding amide (30, q Z N-(CHR),-C-N o Mp z N-(CHR),-C-N .i X" r c 3 0a) 15 The amide (30, 30a) is reduced, for example with lithium aluminum hydride *in an organic solvent such as tetrahydrofuran at a temperature of from about 00C to about 800C preferably at about room temperature to yield the alkyl compound.

9. Preparation of the "depot" compounds of the invention Selected compounds of the invention posses a hydroxyl group attached to either an aliphatic or aromatic carbon capable of forming the highly lipophilic esters of this invention or possess a primary or secondary nitrogen atom including the nitrogen at the 1-position of an indazole ring system capable of forming the highly lipophilic amides of this invention. The primary or secondary nitrogen atom may alternatively be acylated with a C4-C18 alkoxycarbonyl chloride to form a highly lipophilic carbamate derivative. Representatives of such alcohols and amines and their highly lipophilic derivatives are found in the Examples of this invention.

It is known in the art that long acting derivatives of drugs may be obtained by such transformation. European Patent Publication No. 260,070 discloses the prolonged action of haloperidol decanoate ester. International Publication No.

WO 92/06089 discloses sustained release amide derivatives of sertindole.

Following are typical examples of compounds that can be prepared by following the techniques described above: 1 -[4-[3-[4-(1I,2-benzisoxazol-3-yl)-1 -piperidinyl] propoxy]-3methoxyp henyl] etha none; I -[4--[3-[4-(6-fluoro-1 ,2-benzisoxazol-3-yl -piperid inyl] propoxy]-3methoxyphenyl]-ethanone; I nzisoxazol-3-yi)-1 -p ipe rid inyl] butoxy]-3-methoxyphenyl] 15 ethanone; I -[4-[4-[4-(6-fluoro-1 ,2-benzisoxazol-3-yl)-1 -piperid inyl]butoxy]-3methoxyphenyl]-ethanone; I nzi soxazol-3-yl 1 -p ipe rid i nyl] ethoxy]-3-m ethoxyph enyl] ethanone fumarate; 1 -[4-[2-[4-(6-fluoro-1 ,2-benzisoxazol-3-yl -piperid inyl]ethoxy-3methoxyphenyllethanone; 4-[3-[4-(6-fluoro-1 ,2-benzisoxazol-3-yl)-1 -piperidinyl]propoxy]-3-methoxymethylbenzenemethanol; ,2-benzisothiazol-3-yl)-1 -piperid inyl] propoxy]-3methoxyphenyllethanone; I -[4-[3-[4-(6-fluoro-1, 2-benzisoxazol-3-yl)-1 -p ipe rid i nyl] p ropoxy]-3hyd roxyphenylleth anone; 1 I H-indazol-3-yl)-I -piperidinyl]propoxy]-3-methoxyphenyl]ethanone; I -[4-[3-[4-(6-chloro-1 ,2-benzisoxazol-3-yl)-1 -piperdinyl] propoxy]-3methoxyphenyllethanone; I -[4-[4-[4-(6-chloro-1 ,2-benzisoxazol-3-yl I -pipe rid i nyl] butoxy]-3-methoxyph enyl] ethanone fumarate; 43 I -[4-[3-[4-(5-fluoro-1I,2-benzisoxazol-3-yI -piperid inyl]propoxy]-3methoxyphenyl]ethalofe; 6-fluoro-3-[1 -[3-(2-methoxypheloxy)propyII-4-pi peridinyll-1 ,2-benzisoxazoI furma rate; [4-[3-[4-(6-fluoro-1 ,2-benzisoxazol-3-yI)- I -piperidinyl] propoxyll-3-methoxyphel]l phenylmethanole; 1 H-indazol-3-yI)-l -piperidi1nyI] butoxy]-3-methoxypheflt]ethalnone; I -[4-[2-[4-(6-choro-1 ,2-benzisoxazol-3-yI)-1 -piperid inyl]ethoxy]-3methoxyphenylethalofe; 1 -[3-[3-L4-(6-fluoro-1 ,2-benzisoxazol-3-y)-1 -pipe rid inyI] propoxy~phefl]ethafnonle furma rate; I -[4-[3-[4-(6-fluoro-1 ,2-benzisoxazol-3-yI -piperid inyl]propoxy]-2-methylphelYl] ethanone; I -[2-[3-[4-(6-fluoro-1I,2-benzisoxazo-3-yI -piperid inyl] propoxy]-5-methyl phenyll ethanone; N-[4-[3-[4-(6-fluoro-1 ,2-benzisoxazol-3-yl)-l -piperid inyl] propoxy]-3methoxyphenyllacetamide hemnifumnarate; 6-chloro-3-(1 -piperazinyl)-1 H-indazole; I -[4-[3-[4-(6-fluoro- I H-indazot-3-yI)-1 -pi perid inyl] pro poxy]-3-methoxyphelyl] ethanone; 5: -[4-[3-[4-(6-fluoro-1 ,2-benzisoxazo-3-yI)-1 -piperidinyl]propoxy]-3methylphenyl]ethaflOfe hemnifumnarate; I -[4-[3-[4-(6-fluoro-1 ,2-benzisoxazol-3-yi)-l -pipe rid inyI] propoxy] phel]ethanonle; 4-[3-[4-(6-fluoro-1 ,2-benzisoxazol-3-yl)-1 -piperid inyl] propoxy]-3- 25 'methoxybenzonitrile; I -[4-[4-[4-(6-fluoro-1 H-indazol-3-yI)-1 -piperidinyt]butoxy]-3-methoxyphel] ethanone; 1 ,5-dibromo-4-II3-[4-(6-fluoro-1I,2-benzisoxazol-3-yI)- I -piperid inyl]propoxy] phenyijethanofle; 6-fluoro-3-I1 (3-phenoxypropyl)-4-piperidiyl]t-1 ,2-benzisoxazole; 44 I -[4-[3-[4-(6-fluoro-1 ,2-benzisoxazol-3-y)-1 -piperid inyl]propoxy]-3methylmercaptophenyllethanone; I ,2-benzisothiazol-3-y)-1 -piperidinyllbutoxy]-3-methoxyphenyll ethanone; 1 -[4-[3-14-(6-fluoro-1 ,2-benzisoxazol-3-y)-1 -piperid inyljpropoxy]-3methoxyphenyl]phenylmethanone; I -[3-bromo-4-13-[4-(6-fl uoro-1 ,2-benzisoxazol-3-y)-1 -piperid inyl] propoxyiphenyl] ethanone; 3-[1 I -ethoxyethyl)-2-methoxyphenoxy]propyl]-4-piperid inyl]-6-fluoro- 1,2benzisoxazole hydrochloride; 3-[I I -acetoxyethyl )-2-methoxyphenoxy] propyl]-4-piperid inyI]-6-fluoro-1 ,2benzisoxazole fumarate; I -[4-[3-[4-(6-fluoro-1 ,2-benzisoxazol-3-y)-1 -pipe rid inyl] propoxy]3-methoxyphenyl] penta none; 2-[3-[4-(6-fluoro-1 ,2-benzisoxazol-3-y)-1 -piperidinyl]propoxy]-Nmethylbenzenamine hemnifumnarate; 3-[1 romo-2-methoxyph enoxy)p ropyl]-4-pi perid iyl]-6-fluoro- 1 ,2benzisoxazole; I -[4-[3-[4-(6-fluoro-1I,2-benzisoxazol-3-yl)-1 -piperid inyI]propoxy]-3methoxyphenyl]-propa none; 4-[3-[4-(6-fluoro-1I,2-benzisoxazol-3-yI)- I -piperid inyl]propoxy]-3methoxybenzamide; I -f4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1 -piperid inyl] propoxy]- 3-(methylanmino)phenylle than one; 1 -[4-[3-(4-(6-fluoro-1,2-benzisoxazol-3-yl)-I -piperid inyllpropoxy]- 3-e thoxyphenyijethanone; N-f 2-[3-[4-(6-fluoro-1,2-benzisoxazoI-3-yl)-1 -piperid inyl] propoxy] phenyllacetarnide;.

1 -[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-y)-1 -piperidinyl] propoxyl- 3-dimethylamidnophenyllethanone; 1 -f4-f 3-[4-(6-fluoro-1 ,2-benzisoxazol-3-yl)-1-piperidinyl] propoxy]- 2-rnethoxyphenyliethanone hydrochloride; 14-443f4(6-fluoro- 1,2-benzisoxazol-3-yl)-l -pipe rid in yl] propoxy] -3-me th oxyphenyl]- 2,2,2-trifluoroethanone; 44f3-4-(-fluoro-1 ,2-benzisoxa zol-3-yl)- 1 -pi perid inylI Ipro poxyJI-3-hyd roxy- '1-n-ethylbenzenemethanol; [3-f4-(6-fluoro-1,2-ben.zisoxazol-3 1-pipe rid inyl pro poxy) a nil ine dihydrochioride; N-[5-acetyl-2-[3-(4-(6-fluoro-1 ,2-benzisoxazol-3-yI)- 1 -piperidinyllpropoxylphenyllacetarilde; 3 I -[3-(4-ethyl-3-methoxyphenoxy)propyll-4-piperid inyfl -6-fluoro-1 ,2-benzisoxa zole hydrochloride; 1- f3,5-dinethoxy-4-f 3-[4-(6-fluoro-1 ,2-benzisoxazol-3-ylD- 1 -piperidinyllpropoxylphenyllethanone; N-f 3-f3-[4-(6-fluoro-1 ,2-benxoisoxazol-3-yl)-l-piperid inylipropoxy] phenyllacetamidde hernifurnarate; 3-f 3-f4-(6-fluoro-1 ,2-benzisoxazol-3-yl)-1 -piperidinylipropoxyla niline; 3-f 3-[4-(6-fluoro-1 ,2-benzisoxazol-3-yl)-1 -piperidinyl] propoxyl-4-rnethoxyaniline; 1 4-(6-fluoro-1 ,2-benzisothiazol-3-yI)-1 -piperid inylipropoxy- 3-inethylannophenyll etha none funiarate; N-[3-f3-(4-(6-fluoro-1 ,2-benzisothiazol-3-yl)-1 -piperid inyl Ipropoxy]- 4-methoxyphenyllacetamidde; 1 -f4-[3-f4-(6-fluoro-1,2-benzisothiazol-3-yI)-1 -piperid inyl] propoxy]- .3-rnethoxyphenylethanone hydrochloride; N,N-dirnethyl-4-f3-f 4-(6-fluoro-1,2-benzisoxazol-3-yl)- 1 -pipe rid inyl Ipropoxy-3-meth oxybelza nL1d e; 1 -[4-[3-[4-(6-fluoro-1 ,2-benzisoxazol-3I-yl)-1 -piperidinylipropoxy]- 3-methoxyph enyllethanone oxime; .1 [-3(-6fur-,-ezsxzl3yl--ieiiylrpxlehxpeyl ethanone oxirne 0-methyl ether; 1 -[4-[3-(4-(6-fluoro-1 ,2-benzisoxazol-3-yl)-1-piperidinyl] propoxy]- 3-methoxyphenyl] ethanone hyd razone; 6-fluoro-3-(1 -f3-(2-methoxy-4-(1 -me thylethenyl)phenoxylpropyll-4-piperid inyl]- 1,2-benzisoxazole hydrochloride; MZ-1 44 (4chloro-2-bu tenyl)oxy]-3-me thoxyph efyl e thanonle; -[4-((4-[4-(6-flucoro-1 ,2-benzisoxazol-3I-yI)-I -pipe ridinyl] -2-butenyll oxy]- 3-methoxyphenyijetha none; I [4-(6-fluo ro-1 ,2-be nzisoxa zol-3-y D- I -piperid inyll1-2-bu tenyll oxy]- 4-hydroxyphenyllet ha none hydrochloride; -[3-(14-[4-(6-fluoro-1 ,2-benzisoxazol-3-yl)-1 -piperidinyll-2-butenylloxy]- 4-benzyloxyphenyllethanonle; 6-(3-chloropropoxy)-5-mfethoxyifldole; 6-fluoro-3-[14-3-(5-methoxy-1 H-indol-6-yl)oxy] propyl]-4-piperidinyl]- 1 ,2-benzisoxazole; 6-fluoro-3-[1 H-ind ol-7-yl)oxyl propyl]-4-piperid inyll)-1,2-benzisoxa zole hem-ifuma rate; 6-fluoro-3-[l1-(3-hyd roxypropyl)-4-piperidinyl]-1 ,2-benzisoxazole; 6-fluoro-3-( 1-(2-pyrimiddinoxy)propylJ-4-piperidiflyl]-1 ,2-benzisoxazole fumara te 6-aceto-2-[4-(6-fluoro-l ,2-benzisoxazol-3-yl)-1 -piperid inyllmethyl-l,4-benzodioxan; 2-[4-(6-fluoro-1 ,2-benzisoxazol-3-yl)-1 -piperid inyl~methyl-1 ,4-benzodioxan; 2- flu oro-1 ,2-ben zisoxazol-3-yl)-l -piperid inyl Iethyl-1 ,4-benzod ioxa n; 6-(3-chloropropoxy)-7-me thoxy- 1 -tetra lone; 6- (6-flu oro- 1,2-benzisoxa zol-3-yl)- 1-piperid inyl Ipropoxyl--e th ox y-1 -tetra lone; N-(3-ch loropropyl)-2-belzoxazo inlonle; N-(3-chloropropyl)-6-acetyl-2belzoxa zolinone; N-f 3-[4-(6-fluoro-1 ,2-benzisoxazol-3-yl)-1-pipeidilyllpropyl-6-acetyI- 2-benzoxazolinofle; N-[3-[4-(6-fluoro-1 ,2-benzisoxazol-3-yI)-1 -piperid inyll propyllphthaliride; 1 m inop ropyl)-4-(6-fl uoro- 1,2-benzisoxazol-3-yl)p ipe rid i ne dihydrochioride; cis-2-(3-(4-(6-fluoro-1 ,2-benzisoxazol-3-y)-1 -piperidinyl)propyl)hexahydro-1

H-

isoindole-1 ,3-dione hydrochloride; N-[4-[4-(6-fluoro-1 ,2-benzisoxazol-3-y)-1 -piperid inyl]-butyl]phthatimide; 1 m inobutyl uoro- 1 ,2-benzisoxazol-3-yl)pi pe rid ine d ihydrochioride; cis-2-(4-(4-(6-fluoro-1 ,2-benzisoxazol-3-yl)- I -piperidinyl )butyl)hexahydro-1 Hisoindole-1 ,3-dione hydrochloride; I -[4-[L3-4-(6-fluoro-1I,2-benzisoxazol-3-yI -piperidinyl]propyl]thio]-3methoxyphenyllethaflofe; 4-(6-fluoro-1 ,2-benzisoxazol-3-y)-1 -(2'-methoxyphenyl)butylpiperidifle maleate; 4-(4-bromobutyl)-1 ,3-dithian-2-yI)ethyl benzene; I ithian-2-yI )ethyl]phenyl-4-(6-fluoro-1 ,2-benzisoxazol-3-yI) butylpiperidine; I -[4-(4'-acetophenyl)butyl]-4-(6-fluoro-1 ,2-benzisoxazol-3-yI)piperidine; 1 -[4-[3-[4-(6-fluoro-1 ,2-benzisoxazol-3-y)-1 -piperidinyllpropylamino]-3methoxyp he nylletha none; romo-2-butenyl)oxy]-3-methoxypheflI]ethanonle; 4-(3-chloropropoxy)-3-methoxybezatdehyde; I -[4-[3-L4-(6-fluoro-I ,2-benzisoxazol-3-y)-1 -piperidinyl]propylamino]-3hyd roxyp henyl] etha none; I -[3-acetyla mi no-4-(3-ch lorop ropoxy)pheflyl]ethanonle; N-[2-(3-hyd roxypropoxy)phenyllacetamide; 4-(3-chloropropoxy)-3-methoxybenzaldehyde; -[4-[3-[4-(6-fluoro-1 ,2-benzisoxazol-3-yl)-l -piperidinyl]-2-methylpropoxy]-3- 25 methoxyphenyl] eth anone; -[4-[3-[4-(6-fluoro-I ,2-benzisoxazol-3-yl)-1 -piperidinyl]-2-methylpropoxyl- 3-methoxyph enyl] etha none; -[4-[3-[4-(6-fluoro-1 ,2-benzisoxazol-3-yl -piperid inyl]-2-methyl propoxy]- 3-methoxyp henyl] ethanonle; 1 -[4-[3-[4-[(6-fluoro-I ,2-benzisoxazol-3-yl -piperid inyl]-2 ,2-d imethyl propoxyl-3methoxyphenyl]ethalofe; -[4-[3-[4-(6-fluoro-1I,2-benzisoxazol-3-yl)-I -piperid inyI]-2-phenylpropoxyl- 3 methoxyphenyl] eth afnone; -[4-[3-[4-(6-fluoro-1 ,2-benzisoxazol-3-yI)-l -pipe rid inyl]-2-(3-ch lo rophenyl) propoxy]-3-methoxyphe nyl]eth anone; -[4-[3-[4-(6-fluoro-1 ,2-benzisoxazol-3-y)-l -piperidinyl]-2-(phenylmethyl) propoxy]-3-methoxyphenyl]etha none; -[4-[3-[4-(6-fluoro-1 ,2-benzisoxazol-3-yi)-1 -piperidinyl]-1 -methylpropoxy]-3methoxyp henyijetha none; -[4-[3-[4-(6-fluoro-1 ,2-benzisoxazol-3-yI)- I -pipe rid i nyl]-3-methyl propoxy]-3methoxyph enyl] etha none; ,2-benzisoxazol-3-y)-l -pipe rid inyl]-3-methyl butoxy]-3methoxyphenyl] etha none; -[4-[4-[4-(1I,2-benzisoxazol-3-yI I -piperid inyI]-3-phenylbutoxy]-3methoxyp henylletha none; ,2-benzisoxazol-3-yI)-I -piperidinyl]-2-(2-phenylethyl)butoxy]-3methoxyphenyl]ethanone; 15 (+)-[4-[2-[4-(6-fluoro-1I,2-benzisoxazol-3-y)-1 -piperidinyl]-1 -methylethoxy]-3methoxyph enyl] etha none; I uoro-1I,2-benzisoxazol-3-yI I -piperid inyl]-1 -methyl-2butenyl]oxy]-3-methoxyphenyl]ethanone; I -[4-[[4-[4-(6-fluoro-1 ,2-benzisoxazol-3-yI I -piperid inyl]-3-methyl-2butenyl]oxy]-3-methoxyphenyl] etha none; 1 uo ro- 1,2-benzisoxazol-3-y)- 1 -pipe rid i nyl]- 1 -p ropyl-2butynyl]oxy-3-methoxyphenyl]eth anon e; -[4-[3-[4-(6-fluoro-1 ,2-benzisoxazol-3-yI)-I -piperidinyl]-2-phenylpropoxy]-3methoxyphenyllethanone; and NEXT PAGE IS PAGE 49 S()-6-fluoro-3-(1-[3-(2-methyl-(2-methoxyphenoxy)propyl]-4-piperidinyl]- 1,2-benzisoxazole.

The compounds of the present invention are useful for treating psychoses by virtue of their ability to elicit an antipsychotic response in mammals. Antipsychotic activity is determined in the climbing mice assay by a method similar to those described by P. Protais, et al., Psychopharmacol., 50:1 (1976) and B. Costall, Eur. J.

Pharmacol., .5:39 (1978).

Subject CK-1 male mice (23-27 grams) are group-housed under standard laboratory conditions. The mice are individually placed in wire mesh stick cages X and are allowed one hour for adaption and exploration of the new environment.

:i Then apomorphine is injected subcutaneously at 1.5 mg/kg, a dose causing climbing in all subjects for 30 minutes. Compounds to be tested for antipsychotic activity are injected intraperitoneally or given oral doses at various time intervals, e.g. 30 minutes, 60 minutes, etc. prior to the apomorphine challenge at a screening dose of 10-60 mg/kg.

For evaluation of climbing, 3 readings are taken at 10, 20, and 30 minutes after apomorphine administration according to the following scale: Climbing Behavior Mice with: Score 4 paws on bottom (no climbing) 0 2 paws on the wall (rearing) 1 4 paws on the wall (full climb) 2 9* 9 9 O•00 Mice consistently climbing before the injection of apomorphine are discarded.

With full-developed apomorphine climbing, the animals are hanging on to the cage walls, rather motionless, over long periods of time. By contrast, climbs due to mere motor stimulation usually only last a few seconds.

The climbing scores are individually totaled (maximal score: 6 per mouse over 3 readings) and the total score of the control group (vehicle intraperitoneallyapomnorphine subcutaneously) is set to 100%. ED 5 0 values with 95% confidence limits, calculated by a linear regression analysis, of some of the compounds of the present invention as well as a standard antipsychotic agent are presented in Table 1.

TABLE 1 CLIMBING MOUSE ASSAY COMPOUND

(ED

5 0 mg/kg, ip) I -[4-[3-[4-(1I,2-benzisoxazol-3-yl 0.67 piperid inyl] propoxy]-3-methoxyphenyl]ethanone I -[4-[3-[4-(6-fluoro-1I,2-benzisoxazol-3-yl)-1 0.095 piperidinyl]propoxy]-3-methoxyphenyl]ethanofle ,2-benzisoxazol-3-yI)-1 1.6 *pipe rid inyl] butoxy]-3-methoxyph enyl]eth anone I -[4-[4-[4-(6-fluoro-1I,2-benzisoxazol-3-y)-1 0.68 piperidinyl]butoxy]-3-methoxyphenyl]ethanone I -[4-[3-[4-(6-fluoro-1 ,2-benzisothiazol-3-y)-1 0.16 *pipe rid inyl] propoxy]-3-methoxyphenyl]etha none ~:hydrochloride 2-[4-(6-fluoro-1 ,2-benzisoxazol-3-yl)-1 0.29 pipe rid inyl] ethyl]- 1,4-benzod ioxa n I -[4-[[4-[4-(6-fluoro-1 ,2-benzisoxazol-3-yl 0.61 pipe rid inyl]-2-butenyl]oxy]-3methoxyphenyllethanone 51 I -[4-(4'acetophenyl)butyl]-4-(6-fluoro-1,2- 0.34 benzisoxazol-3-yI) pipe rid m e 6-fluoro-3-[1 -(3-hydroxypropyl)-4-piperidinyl]-1 4.1 benzisoxazole 4-[4-(6-fluoro-1 ,2-benzisoxazol-3-y)-1 3.31 piperidinyl]butyl decanoate fumarate I -(3-aminopropyl)-4-(6-fluoro-1 ,2-benzisoxazol-3- 22.6 yI)-piperidine dihydrochioride N-[2-[4-(6-fluoro-1 ,2-benzisoxazol-3-yI)- 1- piperid inyl]ethyl]phthalim ide S00 0 S *N-[2-[4-(6-fluoro-1 ,2-benzisoxazol-3-y)-1 0.48 piperidinyl]ethyl]phthalimide hydrochloride -luoro-1-[3-[(oquno--yI nzoxyxpoyl-- 0.172 yl pi riddl]- ,2-enzisoxazothlene esqiumarate1 oneiiy~thlptaiie hydrochloride 2,3-dihydro-2-[2-[4-(6-fluoro-1 ,2-benzisoxazol-3- 1.17 yI)-l -piperidinyl]ethyl]-3-methyl-1 H-isoindol-1 -one hydrochloride N-[2-[4-[(6-fluoro-1 ,2-benzoxazol-3-y)-1 0.097 piperidinyl]ethyl]-4-aminophthalimide fumnarate N-[2-[4-(6-fluoro-1I,2-benzisoxazol-3-yI 1- 1.6 piperidinyl]ethyl]-4-hyd roxyphthalimide hydrochloride 2-[2-[4-[(6-fluoro-1 ,2-benzisoxazol-3-yl 1- 1.9 piperidinyl]ethyl]-2,3-dihydro-1 H-isoindol-1 -one N-[2-[4-(6-fluoro-1 ,2-benzisoxazol-3-y)-1 0.16 piperidinyl]ethyl]-3-methoxyphthalimide 4-(6-fluoro-1 ,2-benzisoxazol-3-yl 0.36 dihydro-1 H-isoindol-2-yI)ethyl]piperidine dihydrochioride 3-12-[4-(6-fluoro-1I,2-benzisoxazol-3-yI 0.61 piperid inyl]ethyl]-2-methyl-3H-quinazolin-4-one *.*N-[3-[4-(6-fluoro-1 ,2-benzisoxazol-3-y)-1 0.7 piperidinyl]-butyl]phthalimide hydrochloride 1 ,2,3,4-tetrahyd ro-1 H-isoquinolin-2-yl)-2-[4-(6- 6.25 fluoro-1 ,2-benzisoxazol-3-y)-1 -piperidinyl]ethanone hydrochloride ethanolate N-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1 0.23 piperidinyl]ethyl-1,2,3,4-tetrahydroisoquinoline difumarate 2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]- 2.33 1-(2,3-dihydro-1 H-isoindol-2-yl)ethanone fumarate 4-(6-fluoro-1 H-indazol-3-yl)-1 -[2-(5-fluoro-2,3- 0.27 dihydro-1 H-isoindol-2-yl)ethyl]piperidine dimaleate N-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1- 1.19 piperidinyl]ethyl]-1,2,3,4-tetrahydroquinoline fumarate N-[2-[4-(6-fluoro-1 H-indazol-3-yl)-1- 0.44 piperidinyl]ethyl]-1,2,3,4-tetrahydroisoquinoline dimaleate Clozapine (standard) 8.1 Antipsychotic response is achieved when the compounds of the present invention are administered to a subject requiring such treatment as an effective oral, parenteral, or intravenous dose of from 0.01 to 50 mg/kg of body weight per 5 day. It is to be understood, however, that for any particular subject, specific dosage regimens should be adjusted according to the individual need and the professional judgment of the person administering or supervising the administration of the aforesaid compound. It is to be further understood that the dosages set forth herein are exemplary only and they do not, to any extent, limit the scope or practice of the invention.

Some of the compounds of the present invention are also useful as analgetics due to their ability to alleviate pain in mammals. The analgetic utility is demonstrated in the phenyl p-quinone writhing assay in mice, a standard assay for analgesia: Proc. Soc. Exptl. Biol. Med., 95:729 (1957). Thus, for instance, the subcutaneous dose effecting an approximately 50% inhibition of writhing

(ED

5 o) in mice produced in this assay is as shown in Table 2.

TABLE 2 INHIBITION OF HENYLQUINONE INDUCED

WRITHING

COMPOUND

ED

50 mg/kg ,sc 1-[4-[3-[4-(1,2-benzisoxazol- 3 0.17 piperidinyl]propoxy]- 3 methoxyphenyl]ethanone 0.03 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol- 3 yl)-1 -piperidinyl]propoxy]- 3 .methoxyphenyl]ethanone Propoxyphene (standard) 3.9 1.3 Pentazocine (standard) 1.3 Analgesia is achieved when the compounds of the present invention are administered to a subject requiring such treatment as an effective oral, parenteral, or intravenous dose of from 0.01 to 100 mg/kg of body weight per day. It is to be 10 understood, however, that for any particular subject, specific dosage regimens should be adjusted according to the individual need and the professional judgment of the person administering or supervising the administration of the aforesaid compound. It is to be further understood that the dosages set forth herein are exemplary only and that they do not, to any extent, limit the scope or practice of the invention.

Effective amounts of the compounds of the present invention can be administered to a subject by any one of several methods, for example, orally as in capsules or tablets, parenterally in the form of sterile solutions or suspensions, and in some cases intravenously in the form of sterile solutions.

The compounds of the present invention, while effective themselves, can be formulated and administered in the form of their pharmaceutically acceptable addition salts for purposes of stability, convenience of crystallization, increased solubility, and the like. Preferred pharmaceutically acceptable addition salts include salts of mineral acids, for example, hydrochloric acid, sulfuric acid, nitric acid, and the like; salts of monobasic carboxylic acids, for example, acetic acid, propionic acid, and the like; salts of dibasic carboxylic acids, for example, maleic acid, fumaric acid, and the like; and salts of tribasic carboxylic acids, such as carboxysuccinic acid, citric acid, and the like.

Effective quantities of the compounds of the invention can be administered orally, for example, with an inert diluent or with an edible carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purposes of oral therapeutic administration, compounds of the invention can be incorporated with an excipient and used in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gums, and the like. These preparations should contain at least 0.5% of active compound of the invention, but can be varied depending upon the particular form and can conveniently be between 4% to about 70% of the weight of the unit. The amount of active compound in such a composition is such that a suitable dosage will be obtained. Preferred compositions and preparations according to the present invention are prepared so that an oral dosage unit form contains between 1.0-300 milligrams of the active compound of the invention.

Tablets, pills, capsules, troches, and the like can also contain the following •ingredients: a binder, such as microcrystalline cellulose, gum tragacanth, or gelatin; an excipient, such as starch or lactose; a disintegrating agent such as alginic acid, Primogel, corn starch, and the like; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; and a sweetening agent such as sucrose; or saccharin, or a flavoring agent, such as peppermint, methyl salicylate, or orange flavoring. When the dosage unit form is a capsule, it can contain, in addition to materials of the above type, a liquid carrier such as a fatty oil. Other dosage unit forms can contain various materials that modify the physical form of the dosage unit, for example, as coatings. Thus, tablets or pills can be coated with sugar, shellac, or other enteric coating agents. A syrup can contain, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, dyes, colorings, and flavors. Materials used in preparing these various compositions should be pharmaceutically pure and non-toxic in the amounts used.

For the purpose of parenteral therapeutic administration, the active compound of the invention can be incorporated into a solution or suspension. These preparations should contain at least 0.1% of active compound, but can be varied between 0.5 and about 50% of the weight thereof. The amount of active compounds in such compositions is such that a suitable dosage will be obtained. Preferred compositions and preparations according to the present invention are prepared so that a parenteral dosage unit contains between 0.5 to 100 milligrams of active compound.

Solutions or suspensions can also include the following components: a sterile diluent, such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol, or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates, or phosphates, and agents for the adjustment of tonicity such as sodium chloride or dextrose. The parenteral preparation can be enclosed in ampules, disposable syringes, or multiple dose vials made of glass or plastic.

The highly lipophilic esters, amides and carbamates of the present invention are capable of sustained release in mammals for a period of several days or from about one to four weeks when formulated and administered as depot preparations, as for example, when injected in a properly selected pharmaceutically acceptable oil.

The preferred oils are of vegetable origin such as sesame oil, cottonseed oil, corn oil, coconut oil, soybean oil, olive oil and the like, or they are synthetic esters of fatty acids and polyfunctional alcohols such as glycerol or propyleneglycol.

The depot compositions of the present invention are prepared by dissolving a highly lipophilic ester, amide or carbamate of the instant invention in a pharmaceutically acceptable oil under sterile conditions. The oil is selected so as to 1' obtain a release of the active ingredient over a desired period of time. The appropriate oil may easily be determined by consulting the prior art, or without undue experimentation by one skilled in the art.

An appropriate dose of a compound in accordance with this embodiment of the invention is from about 0.01 to 10 mg/kg of body weight per injection. Preferably, the depot formulations of this invention are administered as unit dose preparations comprising about 0.5 to 5.0 ml of a 0.1 to 20% weight/weight solution of compound in the oil. It is to be understood that the doses set forth herein are exemplary only and that they do not, to any extent, limit the scope or practice of the invention.

The following examples are for illustrative purposes only and are not to be construed as limiting the invention. All temperatures are given in degrees Centigrade unless indicated otherwise.

**e PAGES 58 TO 62 HAVE

BEEN

LEFT BLANK

INTENTIONALLY

63 EXAMPLE

I

1- 4- 3- 4-(1 ,2-1enzisoxa~zol-3Yl 11-pieidifnl lPrOPOxYV methoxyphenyllethanone A mixture of 3 4 -piperidinyl)1,2benzisoxazole hydrochloride (4.8 g, mmol),

K

2 C03 (5.2 g, 40 mmol), 1l 4 3 -chloropropoxy)3methoxyphenyllethalOfe (5.3 g, 22 mmol), a few crystals of Kl and dimethylformamide ml) was stirred at 90 C for 16 hours. The reaction was poured into water and the aqueous mixture was extracted with ethyl acetate. The extract was washed (water), dried (MgSO4) and concentrated to afford a brown oil. The oil was chromatographed on a Waters Prep 500 utilizing silica gel columns and ethyl actt-iehlmn as eluent. Concentration of the appropriate fractions afforded 3.9 g of product as an off-white solid. Recrystallization from absolute ethyl alcohol afforded 2.6 g of I -14-13-[4-( 1 ,2-benzisoxazol3yl)lpiperjiflnylpropoxy-3methoxyphenylltaoe m.p. 102-104 0 C, as colorless i needles.

ANALYSIS:

Calculated for C 24

H

28 N204: 70.56%C 6.91 %H 6.86%N S Found: 70.73%C 6.93%H 6.85%N EXAMPLE 2 :e 1 4 I4 -(6.Fluoro 1 ,2 -berzisoxazol-,, l) piperidin l1pro Poxy 3 m ethoxY A stirred mixture of 6-loo3(-pprdnl ,2-benzisoxazole hydrochloride (5.1 g, 20 mmol),

K

2 C03 (5.2 g, 40 mmol), 1 -[4-(3-chloropropoxy)- 25 3-ehxpey]ehnn (5.3 g, 22 mmol), and dimethylformamide (60 ml) *.:was heated at 90 for 16 hours. The reaction was poured into water, and the aqueous mixture was extracted with ethyl acetate. The ethyl acetate was washed (water), dried (MgSO4) and concentrated to afford a moist solid. Recrystallization (twice) from ethyl alcohol afforded 5.0 g of I -4I3[4(6fuoro1,2benzisoxazol3yl)lpipeejdfyl]propoxy3methoxyphenyl]ehnn as a beige solid, m.p. 118-120'C.

ANALYSIS:

Calculated for C 24

H

27 FN204: 67.60%C 6.38%H 6.57%N 64 Found: 67.47%C 6.40%H 6.53%N.

EXAMPLE 3 I -(4-[4-[4-(1I,2-BeflzisoxazOl-3-yl)I -PiPerdifnljbutoXYV3 m etho xkhe nllha n one hdohoie(.,1 A mixture of 3-(4-piperidinyl)i ,2-benzisoxazole hdohoie(. ,1 mmol),

K

2 C03 (5.5 g, 40 mmol), and 1-[ 4 (4bromobutoxy)3methoxYphenylllethanofle (5.5 g, 18 mmol), and dimethYlformamide (60 ml) was stirred and heated at 7500 for 16 hours. The reaction was poured into water and was extracted with ethyl acetate. The ethyl acetate was washed (water), dried (MgSO4), and the solvent concentrated to afford 7.2 g of a beige solid.

Recrystallization (twice) from ethyl alcohol yielded 3.3 g of I ,2benzisoxazol-3-Yl) 1 -piperidinylI-butoxy]3methoxyphenyl]ethanoe m.p. =99- 10100.

AN ALYSIS: Calculated for C 25 1-10204: 7 1.11 %C 7.16%H 6.63%N *Found: 70.76%C 7.24%H 6.58%N.

EXAMPLE 4 14 ~[4~4~(6.Flu~O~1 2b~enzisxazo3Yl- I -1piperidinYbtxl A stirred mixture of 6-loo3(_pprdn -,2-benzisoxazole hydrochloride (5.1 g, 0.02 mol),

K

2 003 (5.2 g, 0.04 mol), 1 -[4-(4-bromobutoxy)- 3 0.0 ~66g 2mol), and dimethylformamide (60 ml) was 25 heated at 7500 for 5 hours. The reaction was poured into water, and the aqueous mixture was extracted with ethyl acetate. The ethyl acetate was washed (water), dried (MgSO4), and the solvent was concentrated to yield initially an oil, which solidified upon standing. The solid was triturated with hexane and collected to afford 7.7 g of the product as a waxy solid. The compound was chromatographed on a Waters Prep 500 utilizing silica gel columns and elutin~g with dichloromethane/methan~ol Concentration of the appropriate fractions yielded 5.1 g of off-white solid I 4 -[4 4 .{4(6fuoro.A ,2-benzisoxazol3yl)piperidinyl)-buto yi-3-methoxypheylltaoe which when recrystallized from ethyl alcohol yielded 3.2 g of featherywhite needles, M.P. =88-90C.

ANALYSIS: 0: 6-6C .4H 63% Calculated for C 25

H

29 FN2 0 6 7.96%/C 6.649%H 6.360/N.

Found: 6 .6/C 640O .9N 1 2 4 2 B n i~ a ct 3 i pe rid in jj. Ije th o x vl 3 m e th o x phey~ehanne umarate A mixture of 3 -(4-Piperidinyl)-l ,2-benZisoxazole hydrochloride (4.8 g, mmol),

K

2 C03 (5.2 g, 40 mmol), 900 4 (2-hforeth16) g, 22 mmy~f), andde (90 ml) was heated at 0Cfr1 hours., The reo was pomtured into water and the aqueous mixture was extracte Th reatyl aetate The ethyl acetate was washed (water), dried exrce wigth) andth l soletase cocnrtd to afford an oil. Upon standing, the oil (MSlidid t e afodabiesld h rde solid was recrystallized twice from SOethyl alcohol to afford 5.9 g of an offwht soid Thrsli was isl eey acetate, and fumaric acid (1.2 9, 1.1 equiv.) was addd The ixt hur s. Ate briefly on a steam bath, and then stirred at ambient temperaturfo2hus.A initial green oil settled out and the supernatant solution was decanted. Ether was adde tothedecntate and 4.0 g of a white fumnarate salt was collected. The salt wasrecystlliedtwice from ethanolether to yield 1.7 g Of fumara2-4{ benzisoxazol 3 -yl)Iumrae m.p. 12 7-129 0

C.

25

ANALYSIS*

Calulte fr 23 26 2 04C4H4 0 4: 63 .52%C 5 .92%H .4% Fou td frC2H 63 .00 5.87%H 5.42%N 1-4- 2-4- 6Fluoro-l 3 I ieridinIetX-3 30 ox )henynethanone eii y)1 9 b n i o a o A stirred mixture o 6 lQ 3(5.2perdi),~ ,-4-2-chb e th5O o le) hydrochloride (5.1 g, 20 mmol),

K

2 003(52gIj 4 (.hlreoY) 66 methoxyphenyl]ethanone (5.0 g, 1022 mmol), and dimethylformamide (90 ml) was heated at 90°C for 16 hours. The reaction was poured into water, and the aqueous mixture was extracted with ethyl acetate. The ethyl acetate was washed (water), dried (MgSO4), and concentrated to afford 7.4 g of a yellow solid. The solid was chromatographed on a Waters Prep LC 500 utilizing dichloromethane/methanol as eluent, and subsequent concentration of the appropriate fraction afforded 4.0 g of a yellow solid. The solid was recrystallized from ethyl alcohol to yield 3.1 g of 1.[ 4 -[2-[4-(6-fluoro-1,2-benzisoxazol-3yl)-l-piperidinyl]ethoxy]-3-methoxyphenyl]ethanone, as slightly yellow flakes, m.p.

=132-134 0

C.

ANALYSIS: Calculated for C 2 3

H

25 FN204 66.98%C 6.11%H 6.79%N Found: 66.90%C 6.20%H 6.74%N.

r EXAMPLE 7 15 -e -amethylbenzenemethanol To a stirred mixture of 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazo3-yl)-lpiperidinyl]propoxy-3-methoxy-phenyl]ethanone g, 9.4 mmol) in methanol/tetrahydrofuran (60 ml, was added sodium bohydride (0.4 g, mmol). After an initial evolution of gas, all insolubles went into solution. The reaction was stirred at ambient temperature for 3 hours and TLC at this time showed a very slight amount of starting ketone. Therefor another 0.1 sodium borohydride was added, and stirring was continued for an additional hour. TLC now showed complete disappearance of starting material. The reaction was concentrated to an off-white residue, which was diluted with water and collected to yield 3.4 g of alcohol. This was recrystallized from toluene (twice, with a charcoal treatment) to yield 2.7 g of 4.[3.[4-(6-fluorO-1,2- Sc3thhybehzenemethanol as a white benzisoxazol3yl)-l.piperidinyl3methoxymethylbenzenemethano as a white solid, m.p. 136-138 0

C

ANALYSIS:

A§ 67.27%C 6.82%H 6.54%N Calculated for C 24

H

29 FN204: 67.27%C 6.8%H 6.54%N Found: 67.59%C 6.89%H 6.47%N i

I

67

EXAMLE

etaone A mixture of 3 (4iperidinyly) ,2-benzisothiazoe (3.0 g, 13.7 mmol), potassium carbonate (2.3 9, 16.5 mmol), 1-[4-(3chloropropoxy) 3 methoxyphenYlethanone (4.0 9,16.5 mmol), potassium iodide (200 mg) and methoxyphenyllethanone (4-0 9, rder N2 for 24 hours. Tecoe acetofitrile (100 ml) was stirred at reflux u acetonitrile. The filtrate reaction was filtered and the cake was washed well witha was concentrated to an oily residue, which was partitioned between water and thyl acetate extract was washed well with water, dried with MgS4 and concentrated to yield 6.1 g of a beige oil which solidified upon standing. The product was triturated with diethyl ether and filtered to give 4.2 g of a beige solid. The compound was recrystallized from ethyl alcohol to afford 3.5 g, alchol(utlizngdecolonizing carbn and another recrystallization from ethyl alcohol (utilizingdeiingcron) proid 2.4(41%) of I4-13- 4 2 -benzisothiazol3 1 5 r o v d e 2 g- 9 5 C Sp C3-methoxyphenyllethanone, m.

ANALYSIS: 67.90%C 6.65%H Calculated for C 24

H

28 N203S 5 6 7.89%C 6.61 %H 6.59%N Found6 .i20EXAMPLE9 3 1-4-3-4 6~lu~O-l,2~enz~oxzol- I i eridin I ro ox- -Fluoro '1,2-bernzsoxazo- 3henyI ethanone ij(A) 1-[4-l(3-chlropropoxy)-3-hydroyphenyieethanon To a stirred solution of -[4-(3-chloropropoxy)-3-methoxyphenyethanone To a stired ylenechloride (120 MI old o-0C dyie (10.0 g, 41 mmol) in ethylene chloride (12 methanol) was added, dropwise, IM boron tribromide in methylene chloride (123 ml, 120 mmol). The temperature was kept between -40 0 C and -500C. After complete addition, the reaction was permitted to reach -30oC, and the

TLC

checked (ca. 15 min. after final boron tribromide was added). Saturated NaHCO3 was added, dropwise never allowing the temperature to 90 above

O

0 0 during most of the addition. When sufficient NaHC 0 3 had been added to make the M 68 solution basic, the organic lhe layewas c washed with brine, dried (MgSO4), and concentrated to yield 8.1 g of dark brown oil, which slidified on standing. This was chromatographed on a Waters Prep 500 LC (2 silica columns, 2% methanol-methylene chloride as eluent). Upon concentration of the appropriate fractions, 5.8 g of a brown tacky solid were obtained. This was recrystallized from isopropyl ether (with decanting of the yellow isopropyl ether supernatant from the dark brown oily residue) to give initially 2.5 g of a yellow solid. Concentration of the mother liquor gave an additional 0.5 g, m.p. 110- 1130C.

1 4 3[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-l-piperidinyl]propxyl-3hydroxyphenyl]ethanone isoxazoe (2.8 g, 13 A stirred mixture of 6 fluoro3-(4-piperidinyl)-l ,2benzisxazole (2.8 g, 13 mmol), NaHCOi (1.1 g) several crystals of KI, 3 c h l oropropoxy)-3-hydroxyphenylethanone, and acetonitrile (100 ml) was refluxed for 16 hours. The 15 phenyilethanone, and acetonitrite (100 s extracted with ethyl reaction was poured into water, and the aqueous mixture was extracted with ethyl :::acetate. The organic extract was washed (water), dried (MgSO4), and the solvent acetate. The organic extract wa was a thick yellow oil. The oi was ***was concentrated to afford 5.7 g of a thick yellow oil. Te oil w7a chromatographed on a Waters Prep 500 LC on silica gel, eluting with 7% methanomethene chloride. Concentration of the appropriate fraction afforded 2 a yellow oil, which upon standing yielded 3.5 g of the compound as a pale, yellow solid The solid was recrystallized from ethyl alcohol to afford 2.7 g of 1-[4- 3 -[4-(6-fluoro-1,2-benzisoxazol-3-yl)- piperidinylprpxy3hydrphey ethanone as a pale yellow solid, m.p. 1 2 2124 25 ANALYSIS:H 6.79%N 2N204 66.98%C 6.11%H 6.79%N Calculated for C 23

H

2 FN204 66.9%C 6.6.9%N Found: 66.97%C 6.20%H 6.69%N Found: EXAMPLE 10 -14- 43-4-H-nl

P

IeridinI ro

P

ox -3methoXhen y ethanone A mixture of 3-(4-piperidinyl) indale (3.0 g, 15 mml),

K

2 C3 (1.6 g)

S

1 3 schloropropoxy)3methoxyphenyl]ethanone (5.3 g, 22 mmol), a few crystals of KI and acetonitrile (100 ml) was stirred and refluxed for 16 hours. The I] [l l 1 I 1 .l r II I t t l r t i t 69 reacionwaspoued ntowatr ad a white solid separated from solution. The seo was olleced diedo and aforded 5.1 g of product. Recrystallization from ethanol yielded 3.6 g of the compound whchlon idemeaoraphY (prearativ HPLC on silica gel, eluting with methylene clrd/ehnl.)gv (490/) of an off-white solid. Recrystallization from ethanol afforded the analytically pure j H-indazol-3yl) 1 i -pipeeidinyUlpropoxy- 3 methoxyphenylethanone as a white solid, M.P. M71173oC.

ANALYSIS* .7H Calculated for

C

24

H

29 N303: 70.74%C 7.270/H 10.31%/N Found: 7.2C 72% O4% LL:1--3-4-6Chlr- ,2benzisoxazo[ 3 11 1:-1 ieridin isxzlI' ro o -3- 5 Astirred mixture of 6 chloro3(4Piperidinyl) i,2-benzi5soxazole (4.7 g, mmOI), 1 4 3 -cloropropoxy e v(48 g 20 m o)

K

2 003 (2.8 several crystals of KI and acetonitrile (120 ml) was refluxed for 16 ooo hours. The reaction was filtered and the filtrate was concentrated to yield a solid- Oil mixture. The residue was chromatographed on a Waters Prep 500 utilizing 20slc oun n ltn ith methylene chloride/Methanol Concentration of the desired fractions yielded 3.2 g of a beige solid, which upon recrystallization from ethanol afforded 2.7 g of 14 i~ 4(~hoo ,~f~sxzly~ pipriinylpopoyl3-mthxyhel-ethanone as a beige solid, m.p. =116- 11800.

ANALYSIS:

Calculated for

C

24

H

27 C1N2 0 4: 65 .08%/C 6.14%H 6 .32%N Found: 65.35%C 6.22%/H 6.28%N ~44-6~Cloo- ,~bel~ Jz l I i eriin I butox -3meth fumlitann f arate A stirred mixture of 6 chloro3(4piperidinyl)l 2 benziSO~azoe(. ,2 mmol), j 1 4 4 -bromobutoxy)-3mtoyhnlehnn (6.0 g, 20 mmol), K2C03 (2.8 g) and acetoflitrile (120 ml) was refluxed for 16 hours. The reaction was allowed to cool, filtered, and the filtrate was concentrated to 9.9 g of a brown oil.

The oil was chromatographed on a Waters Prep 500 utilizing silica gel columns and eluting with methylene chloride/methanol Concentration of the appropriate fractions afforded 2.3 g of an off-white solid. The solid was dissolved in ethanol and fumaric acid (0.62 g, 1.1 eq.) was added. Upon concentration of the ethanol, a crude, brown solid was collected, which was taken up in refluxing acetone. Upon cooling, a white Solid Crystallized from solution yielding 2.2 g of 1 4 1 4(6..Chloro- ,2benzisoxazol3yl)I piperidinyllbutoxyV-3 methoxYphenYllethanone fumrarate as a white solid, m.p. 139141C.

ANAL.YSIS:

Calculated for C 25

H

29 CIN 2 04C4H4 0 4: 6078%C 5.80%H 4.89%N Found: 60.69%C 5.74%H 4.85%N EXAMPLE 13 1 4 -I3 -4 (5 Fluoro benzisoxazol3Y 1 -1 p peridinYUpropoxY 3m ethox Y A mixture of 5fluoro3(4-piperidinyl)l ,2benzisoxazole (2.2 g, 10 MMOl), 1-4(-hoorpx)3mtoyhnlehnn (2.4 g, 10 mmol),

K

2 C03 (1.4 20 a few crystals of KI and acetonitrile (100 ml) was stirred and refluxed for 8 hours. The reaction was poured into water and the aqueous mixture was :::extracted with ethyl acetate. The ethyl acetate extract was washed (brine), dried oo o(MgSO4), and concentrated to afford 4.0 g of a white solid. The solid was 0 0 0 chratograPhed on a Waters Prep 500 HPLC utilizing silica gel columns and eluting with methylene chloride/methanol Concentration of the appropriate fractions afforded 2.0 g of lII4-3[4(5ftluoro-I ,2-benzisoxazol3yl)piperidtfylpropoxy3methoxypheyllehn as a white crystalline solid, m.p.

1 03-105 0

C.

ANALYSIS:

Calculated for

C

24

H

27 FN204: 67.59%C 6.38%H 6.57%N Found: 67.50%/C 6.47%H 6.53%N 71 EXAMPLE 14 6-Fluoro-3-l 2 -me-oxiyridin ,2-benzisoale fumarate A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.45 g; 11.1 mmol),

K

2 CO3 (2.0 and 3 -(2-methoxyphenoxy)propyl chloride (3.5 g, 17.4 mmol) in acetonitrile (40 ml) was heated at 900C for 4 hours. At the end of the reaction, the solvent was removed, and the solids were dissolved into dichloromethane (100 ml). The solution was washed with water and brine, then dried over MgSO4. The crude material from the solution was combined with 1.2 g of crude material prepared in the same fashion (using 0.5 g of starting material).

The combined material was purified by flash chromatography on a silica gel column (49 g, eluted with 0.5% diethylamine: 1% methanol:9 8 dichloromethane, 1 The fractions containing the pure product were pooled and concentrated down to a light oil (3.68 This oil was treated with fumaric acid (1.14 g, 9.8 mmol) in ethanol (13 ml). The 6-fuoro-3-[1-[3-( 2 methoxyphenoxy)propyl]-4-piperidinyl]-1,2-benzisoxazole fumarate crystals obtained weighed 4.01 g m.p. 169-170

C.

ANALYSIS:

Calculated for C 22

H

2 5

FN

2 03C4H4 0 4: 62.39%C 5.84%H 5.60%N Found: 62.37%C 5.88%H 5.60%N EXAMPLE ~3[4(6-Fluoro-1 ,2benzisoxazol-3-yl) piperidinro methoxyphenyl]phenylmethanone A stirred mixture of 6-fuoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.01 g; S 9.13 mmol), K2C03 (2.0 and 3 -chloropropoxy)-4-methoxy p henyl p h e n y l methanone (3.93 g; 11.3 mmol) and acetonitrile (50 mi) was heated at reflux for 4 hours. At the end of the reaction, the solvent was evaporated and the residue was partitioned between water (150 ml) and dichloromethane (400 ml). The dichloromethane solution was washed with water and brine (100 ml), dried over MgSO4 then concentrated to an oil. The purification was done by flash chromatography over a silica gel column (SiO 2 40 g eluted with dichloromethane, 300 ml; 1% methanol in dichloromethane, 850 ml). The material thus obtained as a colorless oil solidified on standing. Recrystallization from ethanol (150 ml) gave 1 -[3-[3-[4-(6-fluoro-1 ,2-benzisoxazol-3-y)-1 pipe rid inyl] propoxy-4-meth oxyphenyl]-ph enyl methanon e as white crystals, 3.07 g m.p. 140-141 0C.

ANALYSIS:

Calculated for 0 29

H

29

FN

2 0 4 71 .30%C 5.98%H 5.73%N Found: 71 .09%C 5.98%H 5.73%N EXAMPLE 16 1j-4[4-[4-(1 H-indazol-3-yl)-1 p i e rid i nyll-butoxyl-3methoxyVh enylethanon e A mixture of 3-(4-piperidinyl)-1H-indazole (3.2 g, 16 mmol), 1-[4-(4-bromobutoxy)-3-methoxyphenyl]ethanone (5.0 g, 16 mmol), K 2 00 3 (2.2 g) and acetonitrile (100 ml) was stirred and refluxed for 6 hours. The reaction was poured into water and the resulting yellow solid that formed was collected to .K 15 afford 5.3 g of product. The compound was recrystallized from acetonitrile and then from ethyl acetate to yield 3.0 g of a slightly yellow solid of (1 H-i ndazol-3-yI) -1 -pipe rid inylII-butoxy]-3-meth oxypheflyl]eth anone, m.p. =133- 13500.

ANALYSIS:

Calculated for C 25

H

31

N

3 0 3 71 .23%C 7.41%H 9.97%N Found: 70.85%C 7.61 %H 9.81 %N EXAMPLE 17 00000*1 -f4-r2-r4-(6-Chloro-1 .2-benzisoxazol-3-yl)-1 -pipe rid inylleth oxyl-3 methoxyphenvi- 0 0 25 ethanone 0. 90:A stirred mixture of 6-chloro-3-(4-piperidinyl)-1 ,2 benzisoxazole (4.6 g, 19 mmol), 1-4(-hootoy--mtoyhnlehnn (4.3 g, 19 mmol), K 2 00 3 (2 .8 a few crystals of KI and acetonitrile (120 ml) was refluxed for 16 hours.

The reaction was filtered and the filtrate was concentrated to yield 8.0 g of yellow solid. The solid was chromatographed on a Waters Prep 500 LC (silica columns, eluting with methylene ch lo ride/m ethanol, Concentration of the appropriate fractions yielded 3.2 g of a light yellow solid, which upon recrystallization from ethyl acetate afforded 2.3 g of 1 -[4-[2-14-(6-chloro-1 ,2-benzisoxazol-3-y)-1 73 piperidinyl]ethoxy]-3-methoxyphenyl]ethanone as a pale yellow solid, m.p. 133- 1350C.

ANALYSIS:

Calculated for C 2 3

H

25

CIN

2 04: 64.41%C 5.88%H 6.53%N Found: 64.35%C 5.87%H 6.41 %N EXAMPLE 18 3-( 3 -Bromopropoxy-4-methoxyphenyl)phenylmethanone A solution of 3-hydroxy-4-methoxybenzophenone (4.6 g, 20 mmol) in dimethylformamide (35 ml) was treated with sodium hydride (600 mg, 25 mmol) at 0°C for 20 minutes, then 1,3-dibromopropane (5 g, 24.7 mmol) was added in one portion. The mixture was heated at 90°C for 1 hour, and then stirred at room temperature for 2 hours. At the end of the reaction, the mixture was poured into water (500 ml) and extracted with ethyl acetate (400 ml). The ethyl acetate 15 solution was washed with water, brine and dried over anhydrous MgS04. The Ssolvent was removed and the crude oil was purified by flash chromatography over a silica gel column (SiO 2 85 g; eluted with 3:1 hexane:dichloromethane, 1.6 I; 3:7 hexane: dichloromethane, 1.4 The pure product thus obtained weighed 4.67 g, as an oil. Recrystallization twice from isopropyl ether (500 ml) gave analytically pure 3-(3-bromopropoxy-4-methoxyphenyl)phenylmethanone (2.42 g), 81-83C.

ANALYSIS:

Calculated for C 1 7 H,7BrO 3 58.47%C 4.91%H Found: 58.63%C 4.82%H EXAMPLE 19 1-[3-[3-[4-(6-Fluoro-1,2-benzisoxazol- 3 -piperidinyl1propoxy]phenyl]ethanone fumarate A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride (4.53 g, 20.5 mmol),

K

2 CO3 (4.5 1 -[3-(3-chloropropoxy)phenyl]ethanone (6.4 g, 29 mmol) in acetonitrile (60 ml) was heated at reflux for 5 hours. At the end of the reaction, the solvent was removed and the residue was extracted into dichloromethane (300 ml). The inorganic insolubles were filtered off. The dichloromethane solution was concentrated to a small volume (10 ml) and purified on a flash chromatographic column (SiO 2 75 g, eluted with dichloromethane, 900 ml; and 2% methanol in dichloromethane, 800 ml). The fractions containing the pure product were combined and concentrated to an oil (2.87 g, The oil was dissolved into ethanol and treated with a solution of fumaric acid (841 mg).

Recrystallization (twice) from ethanol afforded 2.53 g of 1-[3-[3-[4-(6-fluoro-1,2benzisoxazol-3-yl)-1-piperidinyl]propoxy]phenyl]ethanone fumarate as white crystals, m.p. 172-174°C.

ANALYSIS:

Calculated for C 22

H

25

FN

2 0 3

OC

4

H

4 0 4 63.27%C 5.70%H 5.47%N Found: 63.00%C 5.63%H 5.43%N EXAMPLE 1 -[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1 -piperidinyl]propoxy]-2-methylphenyl]- 15 ethanone A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride (5.5 g, 21.6 mmol), K2CO3(3.5 1-[4-(3-bromopropoxy)-2methylphenyl]ethanone (4.83 g, 17.8 mmol) in dimethylformamide (25 ml) and S' acetonitrile (75 ml) was heated at 1200C for 5 hours. At the end of the reaction, the solvent was removed and the residue was extracted into dichloromethane (300 ml) and the solution was washed with water and brine. The organic solution was dried and evaporated to a crude oil. The purification was done by flash chromatography over a silica gel column (80 g, eluted with dichloromethane, 1 I; S* 1% methanol: dichloromethane, 1.2 I; 2% methanol:dichloromethane, 1.2 The 25 purest fractions were combined and afforded 2.91 g of solid. Recrystallization 0 from dichloromethane and ethanol gave 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3yl)-1-piperidinyl]propoxy]-2-methyl-phenyl]ethanone as off-white crystals: 2.42 g, m.p. 113-114C.

ANALYSIS:

Calculated for C 24

H

27

FN

2 0 3 70.22%C 6.63%H 6.82%N Found: 70.13%C 6.63%H 6.77%N EXAMPLE 21 I -[2-[3-[4-(6-Fluoro-1 ,2-benzisoxazol-3-yl)-I ethanone A mixture of 6-fluoro-3-(4-piperidinyl)-1 ,2-benzisoxazole hydrochloride (2.87 g, 11.23 mmol), K 2 C0 3 (2.5 1-[2-(3-bromopropoxy)-5methylphenyllethalOfle (3.74 g, 13.8 mmol) in dimethylformamide (10 ml) and acetonitrile (50 ml) was heated at 9500 for 6 hours. At the end of the reaction, the solvent was concentrated and the mixture was extracted into dichloromethane (300 ml). The organic solution was washed with water and brine, dried over MgSO 4 then concentrated down to a crude oil. The purification was done by flash chromatography over a silica gel column (SiO 2 60 eluted with 1

CH

3 OH:dichloromethane: 1.2 1; 3% CH 3 OH:dichloromethale: 600 ml). The material thus obtained was crystallized from a small volume of ether and hexane es to provide 2.13 g of off-white I -[2-[3-[4-(6-fluoro-1 ,2-benzisoxazol-3-yl)-l L 15 piperidinyl]propoxy]-5-methylphenyl]ethalone, m.p. 92-93*C.

::ANALYSIS:

:eCalculated for C 24

H

27

FN

2 0 3 70.22%C 6.63%H 6.82%N *Found: 70.21 %C 6.69%H 6.81 %N Goo EXAMPLE 22 9* N-[3-(3-[4-(6-Fluoro-1 ,2-benzisoxazol-3-yl)- I -piperidinyl] propoxy]-4methoxyphenyllaceta mid e hemnifumarate A mixture of 6-fl uoro-3-(4-pi pe rid inyl)- 1 ,2-be nzisoxazole hydrochloride (3.94 g, 15.4 mmol), K 2 C0 3 (3.67 g, 26.6 mmole), N-[3-(3-bromopropoxy)- 4 SX 25 methoxyphenyllacetamide (5.56 g, 18.6 mmol) in dimethylformamide (75 ml) and 0 acetonitrile (100 ml) was heated at 1000C for 3 hours. At the end of the reaction, the solvent was concentrated and the mixture was extracted into dichloromethane (500 ml). The organic solution was washed with water (500 ml) and brine (400 ml), dried, then concentrated to a crude oil. The purification was effected by flash chromatography over a silica gel column (SiO 2 65 g, eluted with 1%

CH

3 OH:dichloromethafle, 1.2 1; and 3% CH 3 OH:dichloromethane, 500 ml). The material thus obtained weighed 2.33 g as an oil. This material was dissolved in ethanol and treated with a solution of fumaric acid (661 mg) in ethanol. The N-[3-[3-[4-(6-fluoro-1 ,2 benzisoxazol-3-yI)-lI-piperidinyllpropoxyl-4methoxyphenyl]acetamide hemifurmarate was obtained as off-white crystals weighing 2.17 g, m.p. 205-206'C.

ANALYSIS:

Calculated for C 24

H

28

FN

3 0 4 00.5 C 4

H

4 0 4 62.50%C 6.05%H 8.41 %N Found: 62.30%C 6.05%H 8.32%N EXAMPLE 23 I -[4-[3-[4-(6-Fluoro- I H-indazol-3-yl)-1 -piperid inyllpropoxy]-3-methoxyphenyl]ethanone A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1 H-indazole (3.5 g, 16 mmol),

K

2 C0 3 (2.2 1-[4-(3chloropropoxy)-3-methoxyphenyl]ethanone (3.8 g, 16 mmol) and acetonitrile (90 ml) was refluxed for 16 hours. The reaction was poured into water and the resulting white solid, which precipitated from solution, was collected to afford 5.5 g of the desired product. The compound was :.~recrystallized from dimethylformamide (twice) to afford 3.0 g of I (6-fl uoro- 1 H- dao--l-1-iprdinlpooy-ehxpey~tann as a white solid, m.p. 202-204*C.

ANALYSIS:

Calculated for C 24

H

28

FN

3 0 3 67.75%C 6.63%H 9.88%N *:Found: 67.59%C 6.61 %H 9.96%N EXAMPLE 24 uoro- 1, 2-benzisoxazol-3-yl I -pi perid i nyll pro poxy]-3-methyl phenyl]ethanone hemnifumnarate A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1 ,2-benzisoxazole hydrochloride (3.0 g; 11.7 mmol), K 2 C0 3 (3.0 and 1-[4-(3-bromopropoxy)-3methylphenyl]-ethanone (3.19 g) in dimethylformamide (20 ml) and acetonitrile ml) was heated at 95*C for 4 hours. At the end of the reaction, the solvent was concentrated down to about 30 ml, then partitioned between water (200 ml) and dichloromethafle (300 ml). The dichloromethane solution was separated and washed with water and brine, then dried over MgSO 4 The crude product from the evaporated solution was purified by flash chromatography over a silica gel 77 column (SiO 2 60 g, eluted with 1% methanol in dichloromethane, 600 ml; 2% methanol in dichloromethafle, 600 ml). The material thus obtained was a light yellow oil, weight: 2.07 g This oil was dissolved in ethanol and treated with a solution of fumaric acid (585 mg) in ethanol. The 1-14-[3-[4-(6-fluoro-1 ,2benzisoxazol-3-yl)-I 1 pipe rid inyl] propoxy]-3-methyl phenyllethanone hemifu marate crystals formed on cooling at 0 0 C. This was collected and weighed 1.5 g, m.p.

185-1 8700.

ANALYSIS:

Calculated for C 24

H

27

FN

2 0 3 *0.5 C 4 1- 4 0 4 66.65%C 6.24%H 5.98%N Found: 66.69%C 6.23%H 5.95%N EXAMPLE I -[4-[3-[4-(6-Fliioro-1I,2-benzisoxazol-3-yl)- I -pipe rid i nyl] propoxy] phenylletha none A mixture of 6-fluoro-3-(4-piperidinYl)-1 ,2-benzisoxazole (3.27 g, 14.8 mmol), K 2 C0 3 (3 1-4(-rmpoox~hnlehnn (4.5 g, 17.5 mmol) in acetonitrile (60 ml) was heated at reflux for 4 hours. The solvent was removed.

The residue was dissolved in dichloromethafle (300 ml) and washed with water and brine, then dried over MgSO4. The crude product from the evaporated solution was purified by flash chromatography (Si0 2 60 g; eluted with I methanol in dichloromethane, 1 liter). The purest fractions were combined and gave 2.8 g, 48%, of I -[4-[3-[4-(6-fluoro-1 ,2-benzisoxazol-3-yl)-l piperidinyl]propoxy)phenyl~ethanone, m.p. 111-1 12C.

ANALYSIS:

Calculated for C 23

H

25

FN

2 03& 69.68%C 6.36%H 7.07%N Found: 69.80%C 6.38%H 7.07%N EXAMPLE 26 4-[3-[4-(6-Fluoro-1I,2-benzisoxazol-3-yl)-1 pip eridinyllpropoxyl-3-m thoxybenzonitrile A mixture of 6-fluoro-3-(4-piperidirnyl)-1 ,2-benzisoxazole (3.0 g, 13.6 mmol), K 2 00 3 (2.8 4-(3-bromopropoxy)-3-methoxybenzonitrile (4.0 g, 14.8 mmol) in acetonitrile (70 ml) was heated at reflux for 3 hours. At the end of the reaction, the solvent was removed on a rotary evaporator. The organic material 78 was extracted into dichloromethane (250 ml) and the inorganics; were filtered off.

The dichioromethane solution was concentrated to a crude oil. The purification was done by flash chromatography over a silica gel column (SiO 2 55 g; eluted with dichloromethane, 600 ml; 1% methanol in dichloromethane, 600 ml). The material thus obtained was crystallized from a small amount of dichioromethane.

Recrystallization from ethanol (25 ml) provided 3.8 g of 4-[3-[4-(6-fluoro- I ,2-benzisoxazol-3-yl -piperid inyl]-propoxy]-3-methoxybenzonitrile as white crystals, m.p. 107-108'C.

ANALYSIS:

Calculated for C 23

H

24

FN

3 0 3 67.47%C 5.91 %H 1 0.26%N Found: 67.32%C 5.90%H 10.24%N EXAMPLE 27 I -[4-[4-[4-(6-Fluoro- I H-indazol-3-yl)-l -piperid inyllbutoxy]-3-methoxyphenyl]- 15 ethanone A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1 H-indazole (1.9 g, 8.6 mmol), 1*4(-rmbtoy--ehxphnlehnn (2.6 g, 8.6 mmol), K 2 C0 3 (1.2 and acetonitrile (75 ml) was refluxed for 6 hours. The reaction was poured into water and a white solid settled from solution. This was collected, dried and afforded 3.2 g of product. The product was recrystallized from ethanol to yield 2.7 g (71 of I -[4-[4-[4-(6-fluoro-1 H-indazol-3-yl -piperid inyl]butoxy]-3-methoxyphenyl]ethanone as glistening white flakes, m.p. 158-1

ANALYSIS:

o Calculated for C 25

H

3 oFN 3 0 3 68.32%C 6.88%H 9.56%N 25 Found: 68.00%C 6.93%H 9.51 N EXAMPLE 28 1 ,5-Dibromo-4-[3-[4-(6-fluoro-1I,2-benzisoxazol-3-yl)-1 -piperid inyl] propoxy]phenyllethanone A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1 ,2-benzisoxazole (2.0 g, mmol), K 2 C0 3 (1.3 and I 4(-rmorpx)35-irmpenlehnn (2.65 g, 9.0 mmol) and acetonitrile (50 ml) was heated at reflux for 3 hours. At the end of the reaction, the solvent was evaporated and the residue was 79 extracted into dichloromethane (150 ml). The insolubles were filtered off. .The dichloromethane solution was concentrated down to an oil. The purification was done by flash chromatography on a silica gel column (SiO 2 47 g; eluted with dichloromethane, 300 ml; 1 methanol in dichloromethane, 600 ml). The material thus purified as a colorless oil, solidified on standing. Recrystallization from ethanol gave 1 ,5-d ibromo-4-[3-[4-(6-fluoro-1 ,2-benzisoxazol-3-yl)-1 pipe rid inyl] propoxy]-phenyl]etha none as white crystals (2.93 g, m.p. =102- 103 0

C.

ANALYSIS:

Calculated for C 23

H

23 Br 2

FN

2

O

3 49.84%C 4.18%H 5.05%N Found: 49.91 %C 4.11 %H 4.98%N EXAMPLE 29 6-Fluoro-3-[1 -(3-phenoxypropyl)-4-piperidinyll-l ,2-benzisoxazole A mixture of 6-fluoro-3-(4-piperidinyl)-1 ,2-benzisoxazole (4.0 g, 18.2 mmol), K 2 C0 3 (3.0 g, 21.8 mmol), KI (100 mg), 3-chloropropoxybenzefle (3.4 g, *:20.0 mnmol), and acetonitrile was stirred at reflux under nitrogen for 30 hours. The reaction was poured into water and the aqueous mixture was extracted with ethyl acetate. The ethyl acetate extract was washed with brine, dried with MgSO 4 and concentrated to afford 6.2 g of a damp, beige solid. The compound was :recrystallized twice from ethanol to yield of 6-fluoro-3-[1 -(3-phenoxypropyl)- 4-piperidinyl]-1 ,2-benzisoxazole as a light beige solid, m.p. 78-80 C.

ANALYSIS:

*Calculated for C 21

H

23

FN

2

O

2 71.17%C 6.54%H 7.90%N 25 Found: 71.00%C 6.52%H 7.81 %N EXAMPLE I -[4-[3-[4-(6-Fluoro-1 ,2-benzisoxazol-3-y)-1 -piperid inyllpropoxy]-3-fl2ethoxyphenyll-2,2,2-trifluoroethanone A mixture of 6-fluoro-3-(4-piperidinyl)-1 ,2-benzisoxazole (1.5 g, 6.7 mmol), 1 loorpx)3mtoyhnl-,2 ,2-trifl uoroetha none (2.0 g, 6.7 mmol), K 2 00 3 (0.88 KI (0.1 g) and acetonitrile (50 ml) was stirred and refluxed for 16 hours. After cooling, the reaction was poured into water and the aqueous mixture extracted with ethyl acetate. The extract was washed (1- 2 dried (MgSO 4 and the solvent was concentrated to an oil, which upon evacuation at high vacuum afforded 3.2 g of a waxy solid. The solid was chromatographed on a Waters preparative LC (silica columns, eluting with 3% methanoldichloromethane). Concentration of the appropriate fractions gave 1.8 g of I -[4-[3-[4-(6-fluoro-1 ,2-benzisoxazol-3-yl 1 -pipe rid i nyl]-propoxy]-3methoxyph enyl]-2,2,2-trifl uoro-eth anone solid, m.p. 94-96'C.

ANALYSIS:

Calculated for C 24

H

24

F

4

N

2 0 4 60.00%C 5.03%H 5.83%N Found: 60.01 %C 5.06%H 5.68%N EXAMPLE 31 I -[4-[3-[4-(6-Fluoro-1 ,2-benzisoxazol-3-y]- I -piperid inyllpropoxy]-3-methylmerca ptop henyll etha none A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1 ,2-benzisoxazole (1.88 g, mmol), K 2 C0 3 (1.8 g) and 1-[4-(3bromopropoxy)-3-methylmercaptophenyl]ethanone (2.3 g, 7.6 mmol) in acetonitrile (100 ml) was heated at reflux for 4 hours. At the end of the reaction, the solvent was concentrated, then diluted :..with dichloromethane (250 ml). The insolubles were filtered off. The dichloromethane solution was concentrated to dryness as an oil. Purification was effected by flash chromatography on a silica gel column (SiO 2 54 g, eluted with dichloromethane, 500 ml; 1% methanol-dichloromethane, 1.1 The purest fractions were combined to give a colorless oil which solidified to an off-white solid (2.4 Recrystallization from ethanol (100 ml) yielded 1-[4-13-[4-(6-fluoro- 1 ,2-benzoisoxazol-3-yl] -1 -pipe rid i nyl] propoxy]-3methyl mercaptophenyl]etha none as off-white needle crystals, 2.15 g, m.p. 150-152'C.

ANALYSIS:

Calculated for C 24

H

27

FN

2 0 3 S: 65.14%C 6.15%H 6.33%N Found: 65.09%C 6.10O%H 6.25%N EXAMPLE 32 1 romopropoxy)-3-bromophe nyIletha none 81 A stirred mixture of 3-bromo-4-hydroxyacetophenone (4.5 g, 21.2 mmol),

K

2 C0 3 (4 g) and 1,3-dibromopropane (7.6 g) in acetonitrile (200 ml) was heated at reflux for 2 hours. At the end of the reaction, the solvent was removed and the residue was dissolved in dichloromethane (400 ml) and filtered. The dichloromethane solution was concentrated to an oil. The oil was added to isopropyl ether and stirred to cause crystallization (4.1 g; The solid was recrystallized from isopropyl ether to give 3.5 g of 1-[4-(3-bromopropoxy)-3bromophenyl]ethanone as glistening crystals, m.p. 83-84"C.

ANALYSIS:

Calculated for C 1

H

12 Br 2 0 2 39.31%C 3.60%H Found: 39.80%C 3.55%H EXAMPLE 33 1-[4-(3-Bromopropoxy)-3,5-dibromophenyl]ethanone 15 A stirred mixture of 3,5-dibromo-4-hydroxyacetophenone (3.0 g, 10.1 mmol), K 2

CO

3 (2.8 g, 20.3 mmol), 1,3-dibromo- propane (4.0 g, 19.8 mmol) in acetonitrile (100 ml) was heated at reflux for 5 hours. The solvent was removed.

.The crude product was extracted into dichloromethane (150 ml) and the insoluble inorganics were filtered off. The solution was concentrated to dryness again.

Purification was carried out by flash chromatography on silica gel (45 g, SiO 2 eluted with 1:1 hexane:dichloromethane). The material thus obtained (2.8 g) was recrystallized twice from isopropyl ether to give analytically pure bromopropoxy)-3,5-dibromophenyl]ethanone, m.p. 87-88 0

C.

ANALYSIS:

25 Calculated for C1IHlBr302: 31.84%C 2.67%H Found: 31.97%C 2.63%H EXAMPLE 34 1 -4-[4-[4-(1,2-Benzisothiazol-3-yl)-1 -piperidinyl]butoxyl- 3 methoxyphenyllethanone A stirred mixture of 3-(4-piperidinyl)-1,2-benzisothiazole (2.6 g, 11.9 mmol), 1-[4-(4-bromobutoxy)-3-methoxyphenyl]ethanone (3.9 g, 13.1 mmol), K 2 C0 3 g, 14.3 mmol), KI (200 mg) and acetonitrile (125 ml) was stirred at reflux under nitrogen for 18 hours. The reaction was cooled to ambient temperature and filtered. The filter cake was washed well with fresh acetonitrile and the filtrate was concentrated to yield a wet, brown solid. The residue was diluted with water and the aqueous suspension was extracted with methylene chloride. The organic extract was washed with water, dried with MgSO 4 and concentrated to afford g of a dark oil. The oil was purified by preparative HPLC (Waters Associates prep LC/System 500, utilizing 2 silica gel columns and 5% methanol/methylene chloride) to give 4.5 g of a beige solid. A 3.1 g 7.1 mmol) sample was taken up in absolute ethanol (80 ml) and oxalic acid (0.67 g, 7.4 mmol) was added. The solution was refluxed mildly on a steam bath for 45 minutes and was then stirred at ambient temperature for 1 hour. The resultant suspension was diluted with anhydrous ether (150 ml) and stirred for 5 minutes. The solid was collected and dried to afford 3.1 g of a light, beige solid. The salt was recrystallized from ethanol to yield 2.8 g. The compound was converted back to the free base with 15 NaOH to give 2.4 g, which was immediately recrystallized from ethanol to provide *1.5 g of 1-[4-[4-[4-(1,2-benzisothiazol-3-yl)-1-piperidinyl]-butoxy]-3methoxyphenyl]ethanone as a beige powder, m.p. 78-80°C.

ANALYSIS:

Calculated for C 25

H

30

N

2 0 3 S: 68.46%C 6.91%H 6.39%N Found: 68.34%C 6.85%H 6.33%N EXAMPLE 1 -4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1 -piperidinyl]propoxy]-3methoxyphenyl]-phenylmethanone 25 A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.2 g, 10 mmol),

K

2 C0 3 (2.3 g) and 1-[4-(3-bromopropoxy)-3-methoxyphenyl]phenylmethanone (3.47 g, 10 mmol) in acetonitrile (100 ml) was heated at reflux for 3 hours. At the end of reaction, the acetonitrile was concentrated and the mixture was extracted into dichloromethane (200 ml). The insolubles were filtered off and the solvent was evaporated to an oil. Purification was carried out by flash chromatography over a silica gel column (SiO 2 50 g; eluted with dichloromethane, 600 ml; 1% methanol:dichloromethane, 600 ml; 2% methanol: 98% dichloromethane, 600 ml).

The fractions containing the pure product were combined and concentrated to 83 give 4.24 g of an off-white solid. Recrystallization from ethanol (75 ml) gave 3.9 g of 1 uoro- 1,2-benziosoxazol-3-y I -pipe rid inyl]-propoxy]- 3-methoxyphenyl]phenylmethanone as off-white crystals, m.p. 128-130 0

C.

ANALYSIS:

Calculated for C 29

H

29

FN

2 04: 71 .30%C 5.98%H 5.73%N Found: 71.31 %C 5.99%H 5.75%N EXAMPLE 36 I -[4-[3-(4-(6-Fluoro-1I,2-benziosoxazol-3-yl)-I -piperidinyllpropoxy]- 3 bromophenyllethanf A mixture of 6-fluoro-3-(4-piperidilyl)-1 ,2-benzisoxazole (2.1 g, 9.5 mmol),

K

2 C0 3 (2.0 g) 1-3boo4(-rmprpx~hnlehnn (3.1 g, 9.2 mmol) in acetonitrile (100 ml) was heated at reflux for 3 hours. At the end of reaction, the solvent was concentrated and the mixture was extracted into dichloromethane 15 (200 ml). The insolubles were filtered off. The dichloromethane was concentrated again. The crude residue was purified by flash chromatography over a silica gel column (SiO 2 49 g; eluted with dichlorometharle, 500 ml; 1% methanol:dichloromethane, 600 ml; 3% methanol: 97% dichloromethane, 600 ml).

The material thus obtained (3.26 g, 72%) was recrystallized from ethanol (40 ml) to give I -[4-[3-[4-(6-fluoro-1 ,2-benzisoxazol-3-yl)-l -piperidinyl]-propoxy]- 3 *.:bromophenyllethanone as light yellow crystals (3.0 m.p. =126-128*C.

ANALYSIS:

Calculated for C 23

H

24 BrFN 2 O3: 58.12%C 5.09%H 5.89%N Found: 57.64%C 5.35%H 5.55%N 1.90 EXAMPLE 37 3-[1 E-hxehv)2mtoyhnxlo: 11-piperidnyll-6-fluoro-I ,2benzisoxazole hydrochloride To a mixture of 4-[3-[4-(6-fluoro-1 ,2-benzisoxazol-3-yl)-l -piperidinyl]propoxy]-3-methoxyamethylbenzenemethaIo (3.8 g, 89 mmol) in pyridine ml) was added acetic anhydride (5 ml). The mixture was warmed briefly on the steam bath to effect solution, and then the reaction was allowed to stand at ambient temperature for 16 hours. Most of the pyridine was evaporated under 84 reduced pressure and the resultant oil was diluted with water. The aqueous solution was made basic with dilute NaOH, and subsequently extracted with ethyl acetate. The organic extract was washed (water), dried (MgSO4), and the solvent concentrated to give 3.7 g of the O-acetyl derivative as a colorless oil. The compound was dissolved in diethyl ether and ethereal HCI was added to precipitate a gum-like hydrochloride salt, which upon treatment with refluxing ethyl acetate afforded 3.4 g of a crystalline salt, m.p. 143-145"C. Attempting to recrystallize the salt from ethanol:diethyl ether resulted in displacement of the acetate to afford the ethyl ether. The salt of this product (2.8 g) was recrystallized from ethanol:diethyl ether to yield 2.1 g of 3-[1-[3-[4-(1-ethoxyethyl)-2methoxyphenoxy]propyl]-4-piperidinyl]-6-fluoro-1,2-benzisoxazole hydrochloride, m.p. 139-141°C.

ANALYSIS:

Calculated for C 26

H

33

FN

2 0 4 *HCI: 63.34%C 6.95%H 5.68%N S 15 Found: 63.06%C 6.80%H 5.63%N EXAMPLE 38 -Acetoxyethyl)-2-methoxyphenoxy]propl]-4-piperidinl-6-fluoro-1,2benzisoxazole fumarate A mixture of 4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-l-piperidinyl]-3methoxy-a-methylbenzenemethanol (4.8 g, 11 mmol) in pyridine (45 ml) was warmed briefly to effect solution and then acetic anhydride (6.3 ml) was added.

The reaction stood at ambient temperature for 16 hours, was concentrated in vacuo, and the colorless oil that remained was dissolved in water. The aqueous 25 solution was made basic with saturated K 2 C0 3 solution, and the mixture was extracted with diethyl ether. The extract was washed (water), dried (MgSO4) and concentrated to afford 5.2 g of a thick, colorless oil. The oil (4.8 g) was dissolved in anhydrous diethyl ether and fumaric acid (1.2 g, 0.01 mol) was added. The mixture was stirred at ambient temperature for 4 hours, and then was permitted to stand at ambient temperature for 16 hours. The resultant white, acetoxyethyl)-2-methoxyphenoxy]propyl]-4-piperidinyl]-6-fluoro-1,2-benzisoxazole fumarate was collected and afforded 3.0 g of material. The filtrate was treated with an additional amount of fumaric acid (0.3 g) and 0.9 g more of acetoxyethyl) -2-m ethoxyphenoxy] propyl]-4-p ipe rid inyl]-6-f luoro- 1 ,2-benzisoxazole fumnarate was harvested. The two batches were combined and recrystallized from acetonitrile (twice) to yield 2.3 g of the acetate, mn.p. 150-1520C.

ANALYSIS:

Calculated for 0 26

H

31

FN

2 0 3

*C

4

H

4 0 4 61 .43%C 6.01 %H 4.78%N Found: 61 .06%C 5.87%H 4.73%N EXAMPL E 39 1 -l4-[3-l4-(6-Fluoro-1 .2-benzisoxazol-3-yl)-1 -pigeridinvllproloxyl-3-methoxy- Dhenyllioentanone A mixture of 6-flIuo ro-3-(4-p ipe rid inyl)-1, ,2-benzisoxazole (2.2 g, 10 mnmol),

K

2 00 3 (3 1-[4-(3-bromopropoxy)-3-methoxyphenyl]pentanone (3.7 11.3 mmol) in acetonitrile (140 ml) was heated at reflux for 4 hours. At the end of the reaction, the mixture was cooled and filtered. The filtrate was concentrated to an 15 oil. Purification was performed by flash chromatography over a silica gel column (SiO 2 55 g; eluted with 1% methanol in dichloromethane, 600 ml; 3% methanol: 97% dichloromethane, 400 ml). The fractions containing pure product were pooled and concentrated to a solid (4.3 g, Recrystallization from ethanol (10 ml) gave a powdery solid of 1 -[4-13-[4-(6-fluoro-1 ,2-benzisoxazol-3-yl)-1 pipe rid inyl] propoxy]-3-m eth oxyph enyl] pentanone (3.22 m.p. 79-800C.

ANALYSIS:

*Calculated for 0 27

H

33

FN

2 0 4 69.21 %C 7.10O%H 5.98%N Found: 69.00%C 6.94%H 6.39%N EXAMPLE 2-[3-l4-(6-Fluoro-1 .2-benzisoxazol-3-yl)- 1 -ieridinyllnropoxyl-N-methylbenzenamine hemifumarate A mixture of 6-fluoro-3-(4-piperdinyl)-1 ,2-benzisoxazole (2.5 g, 11 .4 mnmol),

K

2 00 3 (1.8 g, 13.0 mmol), 4-(3-chloropropoxy)-2-methylaminobenzene (2.4 g, 12.0 mmol) and acetonitrile (100 ml) was stirred at reflux for 18 hours. The reaction was cooled to ambient temperature and was poured into water. The aqueous mixture was extracted with ethyl acetate and the ethyl acetate extract was washed with water, dried with MgSO 4 and concentrated to yield 4.1 -g of a 86 brown oil. The oil was purified by preparative HPLC (Waters Associates prep LC/System 500, utilizing 2 silica gel columns and eluting with 4% methanolmethylene chloride). Concentration of appropriate fractions yielded 2.45 g of a beige oil. The product was taken up in ethyl acetate (50 ml) and fumaric acid (0.78 g) was added. The mixture was stirred at mild reflux for 45 minutes and then at ambient temperature for 1.5 hours. The product was isolated by vacuum filtration to provide 2.5 g of a pale yellow solid. Recrystallization from ethanol afforded 2.0 g of 2-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1 piperidinyl]propoxy]-N-methylbenzenamine hemifumarate as beige crystals, m.p.

=180-182°C.

ANALYSIS:

Calculated for C 22

H

26

FN

3 0200.5C 4 H404: 65.28%C 6.40%H 9.52%N Found: 65.08%C 6.35%H 9.45%N 15 EXAMPLE 41 1 -[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1 -piperidinyl]propoxy1-3-methoxyphenyl]propanone S• A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.8 g, 15.2 mmol), K 2 C0 3 (3 1-[4-(3-bromopropoxy)-3-methoxyphenyl]propanone (4.6 g, 18.2 mmol) in acetonitrile (100 ml) was heated at reflux for 2 hours. At the end of the reaction, the mixture was filtered and the solvent was concentrated and the residue was extracted into dichloromethane (300 ml). The dichloromethane was filtered and concentrated again. The crude material (6.4 g) was purified by flash 00 'chromatography over a silica gel column (SiO 2 50 g; eluted with 25 dichloromethane, 700 ml; 1% methanol in dichloromethane, 1.4 The material thus purified (weight: 2.87 g, 51%) was recrystallized from ethanol (25 ml) to give 2.13 g of 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-l-piperidinyl]propoxy]- 3 methoxyphenyl] propanone as beige colored crystals, m.p. 118-119C.

ANALYSIS:

Calculated for C 25

H

29

FN

2 04: 68.16%C 6.64%H 6.36%N Found: 68.32%C 6.63%H 6.29%N 87 EXAMPLE 42 4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1 -piperidinyl]propoxy]-3methoxybenzamide A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.2 g, 10.0 mmol), K 2 C0 3 (2.0 g) and 4-(3-bromopropoxy)-3-methoxybenzamide (2.32 g, mmol) in acetonitrile (80 mi) was heated at reflux for 5 hours. At the end of the reaction the solvent was evaporated. The residue was extracted into dichloromethane. The inorganic insolubles were filtered off. The dichloromethane was concentrated again. The crude residue was purified by flash chromatography over a silica gel column (55 g, SiO 2 eluted with 1% methanol in dichloromethane, 1 I; 2% methanol in dichloromethane, 1 The material thus obtained weighed 2.93 g as white crystals. Recrystallization from hot ethanol (60 ml) gave 2.2 g of 4-[3-[4-(6-fluoro-1 ,2-benzisoxazol-3-yl)-1 -piperidinyl]propoxy]-3methoxybenzamide as white crystals, m.p. 163-164'C.

15 ANALYSIS: Calculated for C 23

H

26

FN

3 0 4 64.62%C 6.13%H 9.83%N Found: 64.20%C 6.06%H 9.71 %N 0 O.

i EXAMPLE 43 1-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1 -piperidinyl]propoxy]- 3 (methylamino)-phenyl]lethanone ~A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.3 g, 10.3 mmol), K 2 C0 3 (1.4 g, 10.3 mmol), 1-[4-(3-chloropropoxy)-3- (methylamino)phenyl]ethanone (2.5 g, 10.3 mmol), KI (0.10 and acetonitrile 25 (100 mi) was stirred at reflux under nitrogen for 23 hours. The reaction was cooled to ambient temperature, poured into water, and the aqueous mixture was extracted with ethyl acetate. The ethyl acetate extract was washed twice with water, dried with MgSO 4 and was concentrated to yield 4.8 g of a damp, brown solid. The compound was isolated by preparative HPLC (Waters Associates prep LC/System 500, utilizing 2 silica gel columns and 4% methanol-methylene chloride as eluent). Concentration of appropriate fractions afforded 2.4 g.

Recrystallization from ethanol gave 2.1 g of 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol- 88 3-yl)-1-piperidinyl]propoxy]-3-(methylamino)phenyl]ethanone as a beige solid, m.p. 151-153°C.

ANALYSIS:

Calculated for C 24

H

28

FN

3 0 3 67.75%C 6.63%H 9.88%N Found: 67.83%C 6.76%H 9.90%N EXAMPLE 44 1 -[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1 -piperidinyl]propoxy]-3-ethoxyphenyl]ethanone A suspension of NaH (0.28 g of a 50% oil dispersion, 5.9 mmol) in dimethylformamide (20 ml) was cooled to 4 0 C in an ice bath. To this was added, dropwise, 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1 -piperidinyl]propoxy]-3hydroxyphenyl]ethanone (2.3 g, 0.0056 mol) dissolved in dimethylformamide ml). After total addition, the mixture was stirred under nitrogen for 1 hour keeping 15 the temperature below 10"C. A solution of bromoethane (1.3 g, 11.8 mmol) dissolved in dimethylformamide (15 ml) was then added, dropwise, to the reaction mixture. Stirring under nitrogen was continued for 3 hours allowing the temperature to slowly rise to ambient temperature. The reaction was cooled in an ice bath, water was added and the aqueous mixture was extracted with ethyl acetate. The ethyl acetate extract was washed with water, dried with MgS0 4 and was concentrated to yield 3.9 g of a damp, beige solid. The solid was triturated with diethyl ether and filtered to yield 1.5 g. This was combined with an additional sample (3.5 g total), and recrystallization from ethanol provided 3.0 g of glistening, beige crystals of 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1 25 piperidinyl]-propoxy]-3-ethoxyphenyl]ethanone, m.p. 112-114C.

ANALYSIS:

Calculated for C 25

H

29

FN

2 0 4 68.16%C 6.64%H 6.36%N Found: 68.10%C 7.03%H 6.35%N EXAMPLE 1-[4-(3-Bromopropoxy)-3-(methylmercapto)phenyl]ethanone A mixture of 1-[4-hydroxy-3-(methylmercapto)phenyl]ethanone (5.4 g; mmol), K 2 C0 3 (4.2 1,3-dibromopropane (8 g, 39 mmol) in acetonitrile (150 ml) 89 was heated at reflux for 3 hours and stirred at room temperature overnight.

Acetonitrile was removed at reduced pressure and the residue was extracted into dichloromethane (250 ml). Insolubles were filtered off. The dichloromethane solution was concentrated. The crude product was purified on a silica gel column (SiO2, 100 g; eluted with 3:2 hexane:dichloromethane, 1.6 The compound crystallized upon concentration, and the product (3.5 g, 39%) was recrystallized from ethanol (40 ml) to yield 1-[4-(3-bromopropoxy)- 3 (methylmercapto)phenyl]ethanone as white needles, 2.0 g; m.p. 120-122 0

C.

ANALYSIS:

Calculated for C 12

H

1 5 BrO2S: 47.53%C 4.99%H Found: 47.74%C 4.91

%H

EXAMPLE 46 4- Bromoro )-3-th benznitrile A mixture of 4-hydroxy-3-methoxybenzonitrile (7.5 g, 50 mmol), K2CO3 mixtureo (7.5 g, 50 mmol),

K

2 C03 (12.5 and 1,3-dibromopropane (15 g, 75 mmol) in acetonitrile (100 ml) was heated at reflux for 3 hours and left standing at room temperature overnight. The solvent of the reaction was removed on a rotary evaporator, and the crude solid was extracted into methylene chloride (500 ml). The insolubles were filtered off.

The dichloromethane solution was concentrated and the material was purified on a flash chromatography column (SiO 2 105 g; eluted with 2:3 dichloromethane:hexane, and then with dichloromethane). The desired product thus purified weighed 7.74 g Recrystallization twice from ethanol gave analytically pure 4-(3-bromopropoxy)-3-methoxybenzonitrile, m.p. 99-101

C.

25 ANALYSIS: Calculated for C 11

H

12 BrNO2: 48.91%C 4.48%H 5.19%N Found: 49.49%C 4.47%H 5.21

%N

EXAMPLE 47 1-64-3-BromorooxK-3-methylhenlth A mixture of 4.hydroxy-3-methylacetophenone (14.5 g, 96 mmol),

K

2 C03 (17.5 g, 144 mmol), and 1,3-dibromopropane (30 g, 144 mmol) in acetonitrile (400 ml) was heated at reflux for 6 hours. At the end of the reaction, the solvent was r~ IT' 1 f r. -T ll.. T. IrT-[ I Il l ru" lrr'l l l'r' 1ni removed on a rotary evaporator, and the crude .solid was extracted into dichloromethane (750 ml). The insoluble inorganlics were filtered off. The dichloromethane solution was concentrated again to a crude oil (34.5 g).

purification was effected by flash ch~rmatography over a silica gel column (SiO2, 15 g; lutd with 7:3 hexane:dichloromethane, 2 I; and dichloromethane 2 The material thus purified weighed 14.6 g an1wsrerstlizd rm tanl Recrystallization again from ethanol gave analytically Pure bromopropoxYy)3methylphenyl]-taoe m 59-61 0OC.

ANALYSIS: 2 315C Calculated for C1 2

HI

5 BrO2 53.35%C 5.52%H Found:

EXAMPLE

48 1 4 3 ~~Qloropoxy)..mehY A mixture of 1 4 hydroxy3mthyheYP mmol),

K

2 C03 (13 g, 92.1 mmol), and 1,-irmpoae(28 (14 86 61.4 i acetonitrile (400 ml) was heated at reflux for 4 hours. The reaction was followed by thin layer chromatography. At the end of the reaction, the inorganics were filtered off and the solvent was removed on a rotary evaporator. The residue was 7 20 purified on a flash ch~rmatographic column (SiO2, 140 g, eluted with 4:1 ***:hexanedichloromethane, 1.2 1) to give a partially solidified material: 15.44 g (7%..ersaliaio.wc from ethanol gave 2.84 g of I 4 (3bromopropOxY)- 3 e h x ph n lp e yl e h n n as w hite crystals M 88-89 C

ANALYSIS:

25 Calculated for

CI

7 Hi 7 BrO3: 58.47%C 4.91%H Found: 59.03%C 4.87%H EXAM PLE 49 N- 2 4 -E46fluoro-i,2-benzis5o, l~aZ,t-'Ol -3YlI kpiperidin I ro oxil phenyq acetmd N-[ 2 3 phenyisufonyypoxyP)phey~ctmd 91 To a solution of N- 2 3 hydroxypropoxY)phenylIlacetmd (Example 1'13) g, 36 mmol) in pyridine (90 ml), cooled to O*C, was added ptoluenesulfonyl chloride (13.6 g, 56 mmol). After the tosyl chloride went into solution, the reaction was then allowed to stand at 5 0 C for 16 hours. The reaction was poured onto ice, and a brown oil settled. The aqueous supernatant was decanted from the oil, and the residual oil taken up in diethyl ether. The diethyl ether was washed with cold (500) 3N HCI and then with brine. The organic layer was dried (MgSO4), and concentrated to afford a thick, brown oil, 5.3 g.

N-[2-[3-[4(6fluoro- 1, 2belzisoxazo-3-y)l piperidilPropoxYJ phenyllacetamide A mixture of 6-fluoro-3-(4piperidinyl)l ,2-benzisoxazole (3.4 g, 16 mmol),

N-[

2 3 .pheylsulfonyloxypropoxY)phenyllctmd (5.3 g, 16 mmol),

K

2 C03 (2.2 and acetonitrile (50 ml) was stirred and refluxed for 5 hours. The reaction was poured into water, and the aqueous suspension was extracted with ethyl acetate.

The ethyl acetate was washed (water and brine), dried (MgSO4) and the solvent was concentrated to afford 6.0 g of a thick, brown oil. The oil was chromatographed on a Waters Prep 500 LC on silica gel. Concentration of the appropriate fractions afforded 3.0 g of a beige solid. This was recrystallized from ethyl acetate to yield (with concentration of the moth er liquors) 2.2g of N- 2 3 -[4-(6-fluoro-1 ,2-enzisoxazol3yl)I -pipeednflypropoxYlphenyllacetmd as a beige solid, m.p. 11B-120oC.

ANALYSIS:

0:Calculated for

C

23

H

26 FN303 6.4C 63% 02% 25 Found: 67.06%C 6.43%H 10.23%N EXAMPLE 0 1 4 3- 4-6-luoro-,2benzisoxazol3-yl)- pipeidinI rO oxv3dimeh aminophen I ethanone To a suspension of sodium hydride (2.3 g, 48.5 mmol of 50% oil dispersion) with dimethylformamide (75 ml), and cooled to 3 0 C in an ice-salt bath and under a stream of nitrogen was added, dropwise, I -(4-hydroxy- 3 92 dimethaminoheny)ethan (87 48.5 mmol) dissolved in dimthylaminophenyethanone (87 70C. After the dimethylformamide (150 ml) so that the temperature did not go over 7 After the addition was over, the bath was rem reaction was stirred at ambient temperature for 45 minutes. The ice bath was rethylformamide (25 ma) was bromo-3-chloropropane (8.4 g, 53.4 mmol) in dimet hlformamide (25 ml) was added dropwise. After the addition was complete, the reaction was stirred for 18 hours at ambient temperature under nitrogen. The reaction was chilled to 7 0 C in an ice bath and water (200 ml) was carefully added. After stirring for 5 minutes, an ice aqueous mixtureth and was extracted wth ethyl acetate (5 x 200 ml). The ethyl the aqueous mixture was extraeddried with MS4, and acetate extract was washed with water (2 x 50 dried with MgSO4, and concentrated to yield 22.2 g of a black oily liquid. The compound was purified by prep HPLC, and combination of appropriate fractions gave 5.0 g of brown oil.

1[4-[3-[4-(6-fluoro-1,2-benzisoxaz-3-y pperdox dimethylaminophenyl]ethanone(2.9 SA mixture of 3 ch l r p r p y -3d im e t h y la m in o p h e n y l l e th a n o n e (2-9 d 2b mixture of 1 3 -chloropropoxy2.5 9, 11.3 o), g, 11.3 mmol), 6-fluoro-3-(4-piperidinyl)i,2-benzisxazole (2.5 g, 11.3 mmol),

K

2 CO3 (1.7 g, 12.2 mmol), KI (200 mg) and acetnil (125 m) was stirred aous reflux for 18 hours. The cooled reaction was poured into water and the aquwus S 20 mixture was extracted with ethyl acetate. The ethyl acetate extract was washed with water, dried with magnesium sulfate and concentrated to yield 5.3 g of an with water, dried with magnesm s u a a ive HPLC (Waters Associates amber oil. The compound was purified by preparative H as ssocat prep LC/Systenm 500 utilizing 2 silica gel columns) and concentration of appropriate fractions provided 1.65 g After combining with two additional appropriate fractions provided 1.65 g m t w t u n e t S* 25 samples, the compound (3.4 g, 7.74 mmol total)was taken up in ethyl acetate and fumaric acid (0.90 g, 7.75 mmol) was added. The mixture was stirred at a mild reflux for 30 minutes and then for hour at ambient temperature The reaction was left to stand overnight andwas then filtered to give 3.6 g. The compound was recrystallized twice from ethanol to provide 2.3 and once from acetonitrile to yield 1.9 g of the compound as a fumarate salt. The compound was converted to the free base by suspending it in dilute NaOH and extracting with dichloromethane. After washing the dichloromethane extract with water and drying with MgSO4, the solvent was removed in vacuo to give 1.4 g of 1-4- 93 [3-[4-(6-fluoro-1 ,2-benzisoxazol-3-yl)-1 -piperidinyl]propoxy]- 3 dimethylamilopheflethanone as a beige solid, m.p. 94-96*C.

ANALYSIS:

Calculated for C 25

H

3 oFN 3 03: 68.32%C 6.88%H 9.56%N Found: 67.74%C 6.74%H 9.40%N EXAMPLE 51 1 -(4[3-[4-(6-Fluoro-I ,2-benzisoxazol-3-yl )-piperidin&LPopoxY- 2 metho)xypheflylle.thann hdrochloride A mixture of 6-fluoro-3-(4-piperidinyl)-I ,2-benzisoxazole (4.4 g, 20 mmol), l-[ 4 3 -chloropropoxy)2methoxyphenyl]ethanone (4.8 g, 20 mmol),

K

2 C03 (2.8 KI (200 mg) and acetonitrile (1 10 ml) was stirred and refluxed for 16 hours.

The reaction was filtered and the filtrate concentrated to afford 9.0 g of a brown oil. The oil was taken up in acetone and fumaric acid (2.5 g, 22 mmol) was added.

The mixture was heated to reflux and then it was stirred at ambient temperature for 1 hour. The resultant fumnarate salt (7.0 g) was collected and then reversed to the free base with aqueous sodium hydroxide to afford 4.6 g of a soft solid. The solid was flash chromatographed on silica gel with dichloromethale-methan~ol as eluent, and after concentration of the appropriate fractions afforded 3.6 g of an off-white solid. The solid was dissolved in anhydrouis ether and ethereal HCI was added to precipitate 3.3 g of the hydrochloride salt. The salt was recrystallized from ethanol to afford 3.3 g of product. Occluded alcohol was .removed to yield 2.8 g of 1 4 3

-I

4 (6fluoro,2benzisoxazol 3 -y)-l pipe rid inyl]propoxy-2methoxyphenylleth anon hydrochloride, m 193-1 25 ANALYSIS: Calculated for C 24

H

28 C1FN204: 62.27%C 6.10%H 6.05%N Found: 61 .88%C 5.90%H 5.96%N EXAMPLE 52 22tilurehnne 4 3 -Chloropropoxy)3methoxybenzoic acid To a stirred suspension under nitrogen of sodium hydride (6.4 g, 130 mmol, of about 50% oil dispersion-ether washed) in tetrahydrofurafi (220 ml) was 94 added pyrazole (4.4 g, 60 mmol) in tetrahydrofuran (60 ml), dropwise. After complete addition, the reaction was stirred for about 15 minutes, and then 4-(3chloropropoxy)-3-methoxybenzaldehyde (24.5 g, 107 mmol) was added. The nitrogen was stopped and air was sparged into the reactor for about 3 hours. The reaction was then allowed to stir at ambient temperature open to the atmosphere for 16 hours. Water was added, the reaction was cooled in an ice bath, and concentrated hydrochloric acid (25 ml) was added dropwise. More water was added and the yellow solid that separated was collected to afford 16.2 g of product. The filtrate was then extracted with ethyl acetate to afford an additional 9.3 g. The samples were combined and recrystallized from acetonitrile to yield 12.6 g of a light, yellow solid, m.p. 154-156 0 C. A 4.0 g sample was recrystallized from acetonitrile to yield 2.6 g of a yellow solid. This was combined with 0.4 g from another sample and recrystallized again from acetonitrile with charcoal treatment to afford 2.0 g of 4 3 -chloropropoxy)-3-methoxybenzoic acid 15 as a yellow solid, m.p. 157-159°C.

ANALYSIS:

Calculated for C 11

H

13 C104: 54.00%C 5.35%H Found: 54.65%C 5.34%H Found: 4 -(3-Chloropropoxy)-3-methoxybenzoyl chloride To a mixture of 4 -(3-chloropropoxy)-3-methoxybenzoic acid (2.4 g, mmol) in dichloromethane (5 ml) was added thionyl chloride (0.9 ml, 12 mmol) dissolved in dichloromethane (5 ml). The reaction was stirred and refluxed for 1 hour, and then the dichloromethane was removed in vacuo to leave a dark oil.

25 The oil was triturated with hexane and the solid that formed while scratching with a glass rod was collected to afford 1.6 g of 4 -(3-chloropropoxy)-3-methoxybenzoyl chloride, m.p. 60-63"C.

1-[4-(3-Chloropropoxy)-3-methoxyphenyl]-2,2,2-trifluoroethanone To a stirred mixture of 4 -(3-chloroproxy)-3-methoxybenzoyl chloride (10.0 g, 38 mmol) in methylene chloride (55 ml) cooled to -70 0 C, there was condensed into a reactor bromotrifluoromethane (70 g, 47 mmol). There was then added to the reactor hexamethylphosphoroustriamide (9.4 g, 41 mmol) dissolved in dichloromethane (7 ml). The first 90% was added quite rapidly, and the remainder at a slower rate. After complete addition, the reaction was stirred at -70 0 C to for an additional hour. The reaction mixture was allowed to come to room temperature. An equal volume of hexane was added and the layers were separated. The lower layer was extracted with hexane and then with diethylether.

The extracts were combined and concentrated to yield 5.6 g of a thick, colorless oil. The oil was chromatographed on a Waters Prep 500 LC utilizing two silica gel columns and eluting with 20% ethyl acetate-hexane. Concentration of appropriate fractions gave 2.7 g of a light oil, which after evacuation at high vacuum solidified to a waxy, white solid (2.4 g) of 1-[4-(3-chloropropoxy)-3-methoxyphenyl]-2,2,2trifluoroethanone.

EXAMPLE 53 4-3-r4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyll ropoxvl-3-hydroxy-- I: i15 methylbenzene methanol 1-[4-(3-chloropropoxy)-3-hydroxyphenyl]ethanone A mixture of 1-[4-(3-chloropropoxy)-3-methoxy-phenyl]ethanone (10.0 g, 41.2 mmol) and concentrated

H

2 SO4 (50 ml) was stirred at 65 0 C for 23 hours. The cooled reaction was poured into 250 g of ice and was stirred vigorously for minutes. The aqueous mixture was extracted with dichloromethane

(CH

2

CI

2 and the resultant dichloromethane extract was washed well with 5% sodium hydroxide. The basic phases were combined and washed with dichloromethane.

The aqueous mixture was cooled in an ice bath and concentrated hydrochloric 25 acid was added until a precipitate formed. The product was isolated by filtration and dried to yield 3.1 g of a light brown solid. This was combined with an additional sample (5.0 g total) and two consecutive recrystallizations from toluene provided 3.4 g of 1-[4-(3-chloropropoxy)-3-hydroxyphenyl]ethanone as a beige solid, m.p. 101-103°C.

ANALYSIS:

Calculated for C 11

H

1 3 CIO3: 57.78%C 5.73%H Found: 58.17%C 5.66%H 96 4 3 -chloropropoxy)-3-hydroxy-a-methylbenzene methanol To a flask charged with sodium borohydride (1.5 g, 39.4 mmol) under nitrogen and chilled to 10 0 C was added, slowly, a solution of chloropropoxy)-3-hydroxyphenyl]ethanone g, 26.2 mmol) dissolved in ethanol-tetrahydrofuran (120 ml, After total addition, the ice bath was removed and the reaction was stirred at ambient temperature for 3 hours. An additional amount of sodium borohydride (0.2 g, 5.3 mmol) was carefully added.

After stirring at ambient temperature for one hour, the solvent was removed in vacuo. The resultant solid residue was diluted with water (100 ml) and left overnight. The product was isolated by vacuum filtration yielding 3.8 g. Two consecutive recrystallizations from toluene provided 3.3 g of 4-(3chloropropoxy)3-hydroxy-a-methylbenzene methanol as a light brown solid, m.p.

107-109°C.

ANALYSIS:

Calculated for C,H1 5 CIO3: 57.27%C 6.55%H Found: 57.60%C 6.43%H 4-[3-4-(6-fluoro-1, 2-benzisoxazol-3-yl) piperidinyl]propoxy]-3-hydroxymethylbenzene methanol 20 A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (4.3 g, 19.5 mmol), 4-(3-chloropropoxy)-3-hydroxy-a-methylbenzenemethanol g, 19.5 mmol), KI (200 mg), NaHCO3 (1.8 g, 21.5 mmol) and CH 3 CN (125 ml) was stirred at reflux under nitrogen for 24 hours. The cooled reaction was filtered and the :filter cake was washed with CH 3 CN. The filtrate was concentrated to afford an oily 25 residue, which was partitioned between water and ethyl acetate. The ethyl acetate extract was washed with water, dried with MgSO4, and concentrated to yield 8.6 g of a dark oil. The oil was purified by preparative HPLC (Waters Associates prep LC/system 500) to yield 5.0 g. The compound was recrystallized twice from ethanol to provide 3.9 g of 4-[3-[4-(6-fluoro-1,2-benzisoxazol3yl)-1-piperidinyl]-propoxy]-3-hydroxy-a-methyl-benzene methanol as a light beige solid, m.p. 142-144C.

ANALYSIS:

Calculated for C 23

H

2 7 FN204: 66.65%C 6.57%H 6.76%N 97

ANALYSIS:

Calculated for C 23

H

27 FN204: 66.65%C 6.57%H 6.76%N Found: 66.68%C 6.35%H 6.72%N EXAMPLE 54 2-_3-[4-(6Fluoro-1 ,2-benzisoxazol- 3 -y)-piperidi n yl1PrOPoXaniline dihydrochloride 2-(3-chloropropoxy) aniline To a stirred suspension of sodium hydride (11.0 g, 230 mmol of a 50% oil dispersion) in dimethylformamide (250 ml), under nitrogen, was added, dropwise, 2-aminophenol (25.0 g, 230 mmol) dissolved in dimethylformamide (125 ml). After complete addition, the reaction was stirred at ambient temperature for 1 hour, and then it was cooled to 5°C (ice bath). 3-Chloro-l-bromopropane (36.2 g, 230 15 mmol) in dimethylformamide (50 ml) was added, dropwise, so that the temperature did not go above 8*C. The reaction was stirred for 4 hours and then permitted to stand at ambient temperature for 16 hours. The reaction was poured into water and extracted with ethyl acetate. The ethyl acetate was washed S(water), dried (MgSO4), and the solvent concentrated to afford 25.4 g of a reddish, dark oil. About 12.0 g of the oil was chromatographed on HPLC columns.

Concentration of the largest fractions gave 5.4 g of 2-(3-chloropropoxy) aniline as an oil.

2-[3-[4-[(6-fluoro-1,2-benzisoxyazol-3-yl) piperidinyl]propoxylaniline dihydrochloride A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (4.8 g, 22 mmol), 2-(3-chloropropoxy)aniline (4.0 g, 22 mmol),

K

2 C03 (4.1 g, 22 mmol), KI (0.2 g), and acetonitrile (100 ml) was stirred and refluxed for 10 hours. The reaction was poured into water and the aqueous mixture was extracted with ethyl acetate. The extract was washed (water), dried (MgSO4), and the solvent was concentrated to afford 9.0 g of a red solid. The solid was triturated with diethyl ether to yield 3.0 g of a beige solid. This sample was combined with a sample (1.1 g) from another run, and a hydrochloride salt was prepared by dissolving the free base in ethanol 98 and then adding ethereal HCI. The resultant salt (3.5 g) was recrystallized twice from methanol-diethyl ether to afford 2.6 g of 2-[3-[4-(6-fluoro-1 ,2benzisoxazol3-Yl)I piperidinyl~prOoxy~aniline dihydrochloride as a brown solid, m.p. 253-255*C.

ANALYSIS'

Calculated for CVlH 24

FN

3 O2o2HCI: 57.02%C 5.92%H 9.50%N Found: 56.68%C 5.71 %H 9.35%N EXAMPLE N-5Aey--3 6fur-,2-benzisoxazol-3-Y10-1 -piveridinyl1prOo2Xylphenyll] acetamide Preparation of 1-[ 3 -acetylamino-4-(3-chloropropoxy)phenyI~ethanone A stirred mixture of 1-[ 3 -acetylamino-4-hydroxyphenylethanone g, mmol),

K

2 C03 (5.7 3chloro1bromopropane (8.9 g, 56 mmol) and acetone (100 ml) was refluxed for 16 hours. The reaction was allowed to cool to ambient temperature and filtered. Concentration of the filtrate yielded 8.5 g of a white solid. The solid was recrystallized from toluene and then from ethanol to afford g of an off-white solid. A 3.3 g sample of this material was flash chromatographed on silica gel with ethyl acetate as eluent. Concentration of the appropriate fractions afforded 2.8 g of a solid. The solid was recrystallized from toluene and then from ethanol-water to yield 2.2 g of a solid, m.p. 124- 126 0

C.

ANALYSIS:

Calculated for C 13 H-1 6 ClNO&: 57.89%C 5.98%H 5.19%N *Found: 57.08%C 5.85%H 5.13%N N-5act12[-[-6fur-1 2-benzisoxazoI- 3 -yi) piperidinyI1propoxYl phenyllacetamide A mixture of 6-loo3(-pprdn -,2-benzisoxazole (4.4 g, 20 mmol), 1-3aeyaio4(-hoorpx~hnlehnn g, 20.5 mmol),

K

2 C03 (2.8 and acetonitrile (70 ml) was stirred and refluxed for 16 hours. The reaction was poured into water and the aqueous mixture was extracted with ethyl 99 acetate. The extract was washed (water), dried (MgSO 4 and then it was concentrated to afford 9.5 g of a brown oil. The oil was taken up in ethyl acetate and ethereal HCI was added until the reaction was acidic. The crude, brown, hydrochloride salt was collected (8.4 and was immediately converted to the free base with NH 4 0H, to afford 5.4 g of the compound as a brown oil. The oil was chromatographed on a Waters Preparative HPLC utilizing silica gel columns.

Concentration of the appropriate fractions yielded 3.5 g of N-[5-acetyl-2-[3-[4-(6fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]phenyl]acetamide as a white solid, m.p. 108-110°C.

ANALYSIS:

Calculated for C 25

H

28

FN

3 0 4 66.21%C 6.22%H 9.27%N Found: 66.12%C 6.25%H 9.27%N EXAMPLE 56 3-[1-[3-(4-Ethyl-3-methoxyphenoxy)propyl-4-piperidinyl-6-fluoro- 1,2-benzisoxazole hydrochloride 4-ethyl-2-methoxyphenol Acetovanillone (Aldrich, 11.0 g, 66 mmol) was dissolved in absolute ethanol (200 ml) and added to 1.5 g of 5% palladium on carbon. A few drops of concentrated hydrochloric acid were added and the mixture hydrogenated on a shaker at 42 psi. The reaction mixture was filtered through Celite, and the filtrate was concentrated to afford 10.3 g of a golden liquid. This was diluted with water, extracted with diethyl ether and the organic phase was washed with water and sodium bicarbonate. The solvent was dried (MgSO 4 and concentrated to afford 9.3 g of a slightly yellow liquid.

4-ethyl-2-methoxy-4-(3-chloropropoxy)benzene A mixture of 4-ethyl-2-methoxyphenol (9.0 g, 59 mmol), 3-chloro-1bromopropane (13.0 g, 83 mmol), K 2 C0 3 (6.2 g) and acetone (200 ml) was stirred and refluxed for 16 hours. The reaction was allowed to cool, and then it was filtered. The filtrate was concentrated to a clear liquid. The liquid was diluted with dilute aqueous NaOH, and the basic mixture was extracted with diethyl ether. The 100 diethyl ether was washed (water), dried (MgSO 4 and the solvent was concentrated to afford 11.9 g of a golden liquid. The liquid was flash chromatographed. This gave a colorless liquid, 9.9 g of 4-ethyl-2-methoxy-4-(3chloropropoxy)benzene.

3-[1-[3-(4-ethyl-2-methoxyphenoxy)propyl]-4-piperidinyl]-6-fluoro-1,2benzisoxazole hydrochloride A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (4.0 g, 18 mmol), KI (0.4 K 2 C0 3 (2.5 4-ethyl-2-methoxy-4-(3-chloropropoxy)benzene (4.4 g, 18 mmol) and acetonitrile was refluxed for 8 hours. The reaction was poured into water, and the aqueous suspension was extracted with ethyl acetate.

The ethyl acetate extract was washed (water) dried (MgSO 4 and the solvent concentrated to afford 7.0 g of a brown oil. The oil was combined with 2.0 g from another sample, and the combined sample was flash chromatographed on silica gel. Concentration of the appropriate fractions yielded 4.4 g of a thick oil, which solidified on standing. The solid was dissolved in ethyl acetate and ethereal HCI was added to precipitate 4.5 g of a white hydrochloride salt. Recrystallization from acetone afforded 3.0 g of 3-[1-[3-(4-ethyl-2-methoxyphenoxy)-propyl]-4piperidinyl]-6-fluoro-1,2-benzisoxazole hydrochloride as a white solid, m.p. 150- 152 0

C.

ANALYSIS:

Calculated for C 24

H

29

FN

2 0 3 *HCI: 64.21%C 6.74%H 6.24%N Found: 64.38%C 6.84%H 6.14%N EXAMPLE 57 S: 1-[3,5-Dimethoxy-4-[3-[4-(6-fluoro-1 2-benzisoxazol-3-yl)--piperidinyl]propoxyphenyl]ethanone 3,5-dimethoxy-4-(3-bromopropoxy)acetophenone To 3,5-dimethoxy-4-hydroxyacetophenone (5.2 g) in dimethylformamide ml) at 0°C under nitrogen, was added sodium hydride (700 mg, 1.1 eq, 98%).

The resulting mixture was stirred for ten minutes until evolution of gas ceased.

Potassium carbonate (4 g) was added, and then 1,3-dibromopropane was added.

101 The mixture was heated at 60 0 C for one hour. When the reaction was complete, the mixture was poured into a water/ice mixture and the resulting solution was extracted with ethyl acetate (600 ml). The ethyl acetate was washed with water, brine, and then concentrated to an oil (9 The product was purified by chromatography on silica gel to yield 3,5-dimethoxy-4-(3bromopropoxy)acetophenone as a light oil, 7.6 g.

1-[3,5-dimethoxy-4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl] propoxy]phenyl]ethanone A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (3.0 g, 13.6 mmol), K 2 C0 3 (2.1 g, 15 mmol), and 3,5-dimethoxy-4-(3-bromopropoxy)acetophenone (4.4 g, 13.8 mmol) in acetonitrile (50 ml) was heated at reflux for 3 hours. At the end of the reaction, the mixture was diluted with dichloromethane 200 ml). The insolubles were filtered. The solution was concentrated to an oil 15 The purification was done by flash chromatography on a silica gel column. The I: product was obtained as a colorless oil (3.85 g, which crystallized from ethanol (400 ml) to give 2.94 g of 1-[3,5-dimethoxy-4-[3-[4-(6-fluoro-1,2benzisoxazol-3-yl)-l-piperidinyl]propoxy]phenyl]ethanone as off-white crystals, o o m.p. 107-108 0

C.

ANALYSIS:

Calculated for C 25

H

29

FN

2 0 5 65.78%C 6.40%H 6.14%N Found: 65.84%C 6.44%H 6.15%N EXAMPLE 58 25 N-[3-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1 S. piperidinyl]propoxylphenyl]acetamide hemifumarate 3-(3-acetamidophenoxy)propyl bromide To 3-acetamidophenol (15.1 g) in dichloromethane (500 ml, dry) was added potassium carbonate (20 g) and then 1,3-dibromopropane (30 The resulting mixture was heated at reflux for 6 hours and then overnight at room temperature. After an additional 24 hours, the reaction was complete. Solids were 102 filtered from the reaction mixture, and the solution was concentrated to an oil, which was purified to yield 3-(3-acetamidophenoxy)propyl bromide, 13.2 g.

N-[3-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)- -piperidinyl]propoxy]phenyl] acetamide hemifumarate A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (9.25 g, 42 mmol), K 2 C0 3 (8 g, 58 mmol) and 3-(3-acetamidophenoxy)propyl bromide (11.4 g, 42 mmol) in acetonitrile (350 ml) was heated at reflux for 3 hours. At the end of the reaction, the reaction was cooled, filtered and the solids washed with dichloromethane (100 ml). The organic solvent was removed on a rotary evaporator to leave a crude oil (18 Purification was by flash chromatography on a silica gel column. The product thus purified was an oil, 12.2 g, Analytically pure sample was prepared by dissolving 3 g of free base in ethanol and treating with fumaric acid solution in ethanol (850 mg:5ml). The fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-propoxy]phenyl]acetamide hemifumarate crystals obtained weighed 2.73 g, m.p. 184-1860C.

SANALYSIS:

Calculated for C 23

H

26

FN

3 0 2 00.5C4H404: 63.95%C 6.01%H 8.94%N Found: 63.47%C 5.94%H 8.78%N EXAMPLE 59 S:3-[3-(4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1 piperidinyl]propoxy]aniline A stirred mixture of N-[3-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1- ;piperidiny]propoxyl]phenyl]acetamide (9.2 g, 22 mmol), prepared as described in the previous example, in 15% hydrochloric acid (110 ml) was heated at 100°C for .00 2.5 hours until a homogeneous solution resulted. The reaction was cooled to 0°C in an ice bath and basified with 50% NaOH. The product was extracted with ethyl acetate (3 x 200 ml). The ethyl acetate solution was washed with water, brine, then dried over Na 2 SO4. The solvent was removed. The crude product was purified on a flash chromatography column. The product thus obtained was a solid: 6.6 g Recrystallization from hot ethanol (50 ml) gave fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]aniline as off-white crystals: 3.46 g, m.p. 115-117°C.

103

ANALYSIS:

Calculated for C 21H 24

FN

3 0 2 68.27%C 6.55%H 11.37%N Found: 68.34%C 6.53%H 11.31%N EXAMPLE 3-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-4-methoxyaniline A mixture of 3-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]- 4-methoxyphenylacetamide (4.2 g, 9.5 mmol), prepared as in Example 26 above, in 15% hydrochloric acid (60 ml) was heated at reflux (110°C) for 2 hours. At the end of the reaction, the solution was cooled to 0°C then basified with 25% NaOH to pH of 10. The product was extracted into ethyl acetate (300 ml). The ethyl acetate solution was washed with water and brine, then dried over Na 2 SO4. The solvent was removed at reduced pressure. The crude oil was purified by flash chromatography on a silica gel column. The product thus purified was an oil, 2.6 g. Crystallization from ethanol (5 ml) and petroleum ether (3 ml) yielded fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-4-methoxyaniline as fine crystals: 1.2 g; m.p. 94-95"C.

ANALYSIS:

Calculated for C 22

H

26

FN

3 0 3 66.15%C 6.56%H 10.52%N Found: 66.16%C 6.54%H 10.44%N EXAMPLE 61 1-[4-[3-[4-(6-Fluoro-1,2-benzisothiazol-3-yl)-l-piperidinyl]propoxy- 3 S* methylamino-phenyl]ethanone fumarate S 1-[(3-N-acetyl-N-methylamino)-4-hydroxyphenyl]ethanone A solution of 2-methoxy(methylamino)benzene (26.0 g, 190 mmol) and 1,2-dichloroethane was cooled to 10-15°C and a solution of acetyl chloride (33.8 g, 430 mmol) dissolved in dichloroethane (50 ml) was dripped in slowly. Following this addition, an additional 100 ml dichloroethane was added. The reaction was cooled to 0°C and aluminum chloride (72.3 g, 540 mmol) was added over the course of 45 minutes so that the temperature did not exceed 10°C. After complete addition, the reaction was heated to reflux and was stirred for 18 hours under

I-

104 nitrogen. The reaction was cooled and was poured into ice. The resulting aqueous phase was extracted further with dichloromethane and the combined extracts were washed with H 2 0, dried with MgSO 4 and concentrated to yield 32.0 g of 1-[(3-N-acetyl-N-methyl-amino)-4-hydroxyphenyl]ethanone as a brown solid, m.p. =168-171°C.

1-(4-hydroxy-3-methylaminophenyl)ethanone A mixture of 1-[(3-N-acetyl-N-methylamino)-4-hydroxyphenyl]ethanone (15.0 g, 72.4 mmol) and concentrated HCI (150 ml) was stirred at reflux for 3 hours. The heat was terminated and the reaction stood overnight. The reaction mixture was transferred to a 1 L beaker and was chilled in an ice-salt bath. Solid sodium bicarbonate was added cautiously until the pH was about 2, and the aqueous mixture was allowed to stand overnight. The reaction mixture was continued to be made basic by the addition of solid sodium bicarbonate. After pH 15 8 was achieved, the reaction mixture was extracted with ethyl acetate. The ethyl V acetate extract was washed with a 200 ml aliquot of water and this was then fed through a bed of Celite. After washing the cake with fresh ethyl acetate the phases were separated. The ethyl acetate extract was washed several more times with water, dried with MgSO 4 and concentrated to yield 10.5 g of a dark solid of 1-(4-hydroxy-3-methylaminophenyl)ethanone.

1-[4-(3-chloropropoxy)-3-methylaminophenyl]ethanone To a stirred suspension of sodium hydride (0.87 g, 18.2 mmol of a 50% oil dispersion) in dimethylformamide (25 ml) under nitrogen and cooled to *0C in an 25 ice-salt bath was added, dropwise, a solution of 1-(4-hydroxy-3-methylaminophenyl)-ethanone (3.0 g, 18.2 mmol) dissolved in dimethylformamide (55 ml) so that the temperature did not rise above 3°C. After the addition was complete, the reaction was stirred for 80 minutes at ambient temperature. The reaction was cooled to 5°C and a solution of 1-bromo-3-chloropropane (3.1 g, 0.0120 mol) in dimethylformamide (20 ml) was added dropwise. After this addition was complete, the ice bath was removed and the reaction was stirred at ambient temperature for hours. Water (75 ml) was carefully added and after stirring vigorously for minutes, the reaction was left to stand overnight. The aqueous mixture was 105 extracted with ethyl acetate and the ethyl acetate extract was washed with water, dried with MgSO 4 and concentrated to yield 3.9 g of a dark solid. The compound was purified by preparative HPLC to afford 2.4 g of a beige solid. This was combined with an additional sample (3.8 g total) and two consecutive recrystallizations from ethanol gave 2.1 g of 1-[4-(3-chloropropoxy)-3methyl-aminophenyl]ethanone as a fluffy, beige solid, m.p. 115-1170C.

ANALYSIS:

Calculated for C 12

H

1 6 CIN0 2 59.63%C 6.67%H 5.79%N Found: 59.49%C 6.64%H 5.79%N 1-[4-[3-[4-(6-fluoro- 1,2-benzisothiazol-3-yl)- 1 -piperidinyl]propxoy-3methylaminophenyl]ethanone fumarate A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisothiazole (1.9 g, 79 mmol), 1-[4-(3-chloropropoxy)-3-methylaminophenyl]ethanone (1.9 g, 79 mmol), 15 K 2

CO

3 (1.1 KI (0.1 and acetonitrile (95 ml) was refluxed for 16 hours. The S reaction was poured into water and the aqueous suspension extracted with ethyl acetate. The extract was washed (water and brine), dried (MgSO 4 and then the solvent was concentrated to afford 3.2 g of a thick, brown oil. The oil was chromatographed on a Waters Prep 500 LC on silica gel columns, and concentration of the appropriate fractions afforded 1.5 g of a brown oil. The oil was dissolved in acetone and fumaric acid (0.4 g, 0.003 mol) was added, and 1.9 g of a white fumarate salt was collected. The salt was recrystallized from oo dimethylformamide to yield 1.1 g of 1-[4-[3-[4-(6-fluoro-1,2-benzisothiazol- 3-yl)-1 -piperidinyl]propoxy-3methylaminophenyl]ethanone fumarate as a white solid, m.p. 198-2000C.

ANALYSIS:

Calculated for C 28

H

32

FN

3 0 6 S: 60.31 %C 5.78%H 7.54%N Found: 60.02%C 5.88%H 7.68%N EXAMPLE 62 N-[3-r3-[4-(6-Fluoro-1,2-benzisothiazol-3-vl)-1 -piperidinvl1proDoxv1-4-methoxyphenyllacetamide 106 N-[3-(3-chloropropoxy)-4-methoxyphenyl]acetamide To a stirred suspension, under nitrogen, of sodium hydride (1.8 g, 38 mmol) in dimethylformamide (60 ml) was added dropwise, N-(3-hydroxy-4methoxy)acetamide (6.1 g, 34 mmol) dissolved in dimethylformamide (23 ml).

After complete addition, the reaction was stirred at ambient temperature for hour, and then 3-chloro-1-bromopropane (5.2 g, 33 mmol) in dimethylformamide ml) was added, dropwise. The reaction was stirred at ambient temperature for 16 hours, and then it was poured into water, and the aqueous mixture was extracted with ethyl acetate. The extract was washed (water), dried (MgSO 4 and the solvent concentrated to afford a purple solid. The solid was triturated with diethyl ether and collected to afford 2.8 g of a purple solid. This sample was combined with a sample (1.2 g) from another run and was recrystallized from toluene twice to yield 2.9 g of an off-white solid. The solid was flash chromatographed on 200 g of silica gel, eluting the column with ethyl acetate, and subsequent concentration of the appropriate fractions afforded 2.4 g of a white S* solid. Recrystallization of the compound from toluene yielded 2.2 g of N-[3- (3-chloropropoxy-4-methoxyphenyl]acetamide, m.p. 112-114°C.

ANALYSIS:

Calculated for C 12

H

16

CINO

3 55.93%C 6.26%H 5.44%N Found: 56.25%C 6.29%H 5.44%N N-[3-[3-[4-(6-fluoro-1,2-benzisothiazol-3-yl)- -piperidinyl]propoxy]- 4 methoxyphenyl]acetamide A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisothiazole (4.0 g, 17 mmol), N-[3-(3-chloropropoxy)-4-methoxyphenyl]acetamide (4.3 g, 17 mmol),

K

2 C0 3 (2.3 KI (0.2 g) and acetonitrile (200 ml) was refluxed for 10 hours. The cooled reaction mixture was filtered and the filtrate was concentrated to yield a dark oil. The oil was dissolved in acetone, and ethereal HCI was added to yield 5.7 g of a yellow hydrochloride salt. The salt was reversed to the free base and the resultant oil (5.2 g) was chromatographed on a Waters Associates Prep LC utilizing silica gel columns. Concentration of the appropriate fractions yielded 4.7 g of an oil, which was converted to a hydrochloride salt. The salt was converted to its free base yielding 2.8 g of a brown oil. The oil was stirred vigorously with ether 1 111~1- 107 to yield 1.4 g of N-[3-[3-114-(6-fluoro-1 ,2-benzisothiazol-3-YI)-1 piperidinyl]propoxy]-4-methoxypheny]acetamide as a white solid, 1.4 g, m.p.

109-111loc.

ANALYSIS:

Calculated for C 24

H

28

FN

3 0 3 S: 63.00%C 6.17%H 9.18%N Found: 62.80%C 6.17%H 8.86%N EXAMPLE 63 I -[4-[3-[4-(6-Fluoro-1 ,2-benzisothiazol-3-yl)- I -piperidinyllpropoxyl- 3-methoxy-phelyllethanonle hydrochloride A stirred mixture of 6-fluoro-3-(4-piperidiflyl)-1 ,2-benzisothiazOle (4.0 g, 17 mmol), I 4(-hoorooy--ehxyhnlehnn (4.1 g, 17 mmol),

K

2 C0 3 (2.3 KI (0.2 and acetonitrile (100 ml) was refluxed for 9 hours. The reaction was poured into water, and the aqueous mixture was extracted with ethyl 15 acetate. The extract was washed (water), dried (MgSO4), and the solvent was concentrated to afford 8.0 g of a brown oil. The oil was chromatographed on a Waters Prep 500 HPLC on silica gel columns. Concentration of the appropriate S. fractions afforded a gum-like residue, which upon trituration with isopropyl ether *.*.afforded 1.9 g of a white solid. The solid was dissolved in absolute ethanol, and ethereal HCI was added to precipitate 1.7 g of a hydrochloride salt. Concentration of the isopropyl ether filtrate, and similar treatment of the residue, afforded an S additional 0.5 g of the salt. The samples were combined and recrystallized from absolute ethanol to yield 1.7 g (21 of I -[4-[3-[4-(6-fluoro-1 ,2-benzisothiazol-3yl -pipe rid inyl] propoxy]-3-methoxyphenyl]ethanone hydrochloride as a white 25 solid, m.p. 221-223 0

C.

:ANALYSIS:

Calculated for C 24

H

27

FN

2

O

3 S*HCI: 60.18%C 5.89%H 5.85%N Found: 60.01 %C 5.97%H 5.79%N EXAMPLE 64 N, N-Dimethyl-4-[3-[4-(6-fluoro-l ,2-benzisoxazol-3-yl)-I -piperidinl propoxyl-3-methoxybenzamlide 108 NN-dimethy-4-bromfopropoxy-3methoxybenzamide To N,-iehl4hdoy3mtoyezmd (5.64 g, 28.7 mmol) in acetonitrile (450 ml) was added potassium carbonate (7.9 g) followed by 1,3dibromopropafle (11.6 The resulting reaction mixture was refluxed for 3 hours and stirred at room temperature for 12 hours. The mixture was filtered and concentrated to an oil. Following purification by column chromatography,

N,N-

dimethyl-4-bromlopropoxy3methoxybenzamide as a colorless oil (7.6 g) was obtained.

NN-dimethyl-4-[3-[4-(6-fluoro- 1, 2-benzisoxazol-3-y)- 1piperidiny~propoxy-3-mfethoxybeflzamide A stirred mixture of 6-fluoro-3-(4-piperidilyl)-1 ,2-benzisoxazole (3.9 g! 17.7 mmol), N,-iehl4boorpoy3mtoyezmd (5.54 g, 17.5 mmol) H: and K 2 C0 3 (3 g) in acetonitrile (250 ml) was heated at reflux for one hour. At the end of the reaction, the insolubles were filtered and washed with dichloromethane. The solvent was removed on a rotary evaporator. The residue was purified by flash chromatography over a silica gel column. The product thus obtained as an oil weighed 7 g. Crystallization from hot ethanol (45 ml) afforded analytically pure N, N-dimethyl-4-[3-[4-(6-fluoro-l ,2-benzisoxazol-3-yl)-l piperid inyl] propoxy]-3-methoxybelza mid e, 3.95 g, 50%, as light yellow crystals, m.p. 126-127*C.

ANALYSIS:

Calculated for C 25

H

3 oFN 3 0 4 65.92%C 6.64%H 9.22%N Found: 65.76%C 6.64%H 9.14%N EXAMPLE I -[4-[3-[4-(6-Fluoro-1I,2-benzisoxazol-3-yl)-l -piperid inylipropoxy]- 3-methoxy-phenyllethar'one oxime A mixture of I -L4-[3-[4-(6-fluoro-1 ,2-benzisoxazol- 3 -yl)-l pi perid inyl] propoxy]-3-methoxyphenyl]etha none (4.3 g, 10 mmol), prepared as in Example 3 above, hydroxylamine hydrochloride (1.3 g, 18 mmol), ammonium acetate (1.7 g, 22 mmol) and ethanol-H20 was stirred and refluxed for 16 hours.

The reaction was poured into water, and the mixture was cooled in an ice bath for 109 2 hours. The resultant, white solid was collected, washed with water and dried to yield 4.6 g of hydrochloride salt of the oxime, m.p. 216-218"C. The compound was dispersed in water and ammonium hydroxide was added until the suspension was decidedly basic. The basic suspension was then extracted with dichloromethane, and after washing with water, drying (MgSO 4 and concentrating the extract, 3.0 g of white solid melting at 168-170 0 C were harvested. The compound was recrystallized from dimethylformamide to yield 2.3 g of 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]- 3 methoxyphenyl]ethanone oxime as a white solid, m.p. 168-170C.

ANALYSIS:

Calculated for C 24

H

28

FN

3 0 4 65.29%C 6.39%H 9.52%N Found: 65.27%C 6.44%H 9.46%N EXAMPLE 66 15 1-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-l-piperidinylpropox methoxyphenyl]ethanone oxime O-methyl ether A solution of 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]methoxyphenyl]ethanone (4.3 g, 10 mmol), prepared as in Example 3 above, methoxylamine hydrochloride (0.93 g, 10 mmol) in pyridine (75 ml)/ethanol (75 ml) was refluxed for 16 hours. Most of the solvent was evaporated under i reduced pressure, and the residue was diluted with water to precipitate 1.6 g of a white solid, m.p. 200-201°C. The aqueous filtrate upon standing deposited another crop of white crystals, which yielded 1.2 g of a pale, yellow solid with a m.p. of 70-72°C. The initial crop of crystals was converted to its free base with aqueous NaOH. After extractive workup with ethyl acetate, 1.2 g of the free base was obtained. The two samples were combined and recrystallized from isopropyl ether to afford 2.0 g of 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1piperidinyl]propoxy]methoxyphenyl]ethanone oxime 0-methyl ether as colorless crystals, m.p. 97-99"C.

ANALYSIS:

Calculated for C 25

H

30

FN

3 04: 65.92%C 6.64%H 9.22%N Found: 65.89%C 6.86%H 9.15%N 110 EXAMPLE 67 1 -[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1 -piperidinyl]propoxyl-3-methoxyphenyl]ethanone hydrazone A stirred mixture of 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1 piperidinyl]propoxy]-3-methoxyphenyl]ethanone (4.3 g, 10 mmol), prepared as in Example 3 above, hydrazine (0.8 g, 2.5 mmol), and ethanol (40 ml) was refluxed for 16 hours. The cooled solution was concentrated to yield an oily residue. The residue was triturated with water and the resultant solid was collected to afford 4.2 g of 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1 -piperidinyl]propoxy]-3methoxyphenyl]ethanone hydrazone as a yellow solid. The compound was recrystallized from isopropanol and then from toluene to afford 1.7 g m.p.

106-1080C.

ANALYSIS:

Calculated for C 24

H

29

FN

4 0 3 65.44%C 6.64%H 12.72%N 15 Found: 65.38%C 6.55%H 12.55%N EXAMPLE 68 6-Fluoro-3-[1-[3-[2-methoxy-4-(1-methylethenyl)phenoxy]propyl]-4-piperidinyl]- 1,2-benzisoxazole hvdrochloride A solution of butyllithium (4.7 ml of a 2.3 M solution in hexanes, 10.7 i mmol) in tetrahydrofuran (65 ml) was stirred under nitrogen and cooled to in an isopropyl alcohol-dry ice bath. Methyltriphenylphosphonium bromide (3.8 g, 10.6 mmol) was added portionwise over the course of 10 minutes. After complete addition, the reaction was stirred at -650C for one hour and was then allowed to J 25 gradually warm up to ambient temperature, where it was stirred for an additional hours. The reaction was cooled to 0°C, and a solution of 1-[4-[3-[4-(6-fluoro- 1,2-benzisoxazol-3-yl)- 1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone prepared as in Example 3 above (4.7 g, 0.0110 mol) dissolved in tetrahydrofuran ml) was added, dropwise, over the course of 30 minutes. After the addition was complete, the reaction was stirred at ambient temperature for 19 hours. The reaction was poured into water and the aqueous mixture was extracted with diethyl ether. The diethyl ether extract was washed several times with water, dried with MgSO4 and concentrated to yield 7.0 g of a light orange solid.

111 Recrystallization from toluene-hexane provided 1.4 g of triphenylphosphine oxide and concentration of the filtrate afforded 5.5 g of a glassy, beige solid. This was combined with an additional sample (6.5 g total) and purification by preparative HPLC (Water's Associates prep LC/System 500) gave 5.2 g of a beige solid, which remained contaminated by triphenylphosphine oxide. The compound was taken up in anhydrous ethanol (300 ml) and methanol (5 drops) and ethereal HCI was added to precipitate 4.0 g of a pale, white solid, m.p. 192-1940C.

ANALYSIS:

Calculated for C 25

H

3 oCIFN 2 0 3 65.14%C 6.56%H 6.08%N Found: 64.95%C 6.62%H 6.04%N EXAMPLE 81 -r4-[[4-r4-(6-Fluoro-1.2-benzisoxazol-3-yl)-1 -piperidinyll-2-butenvlloxv]- 3-methoxyvhenvllethanone A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.2 g, 10 mmol), K2CO3 (2 (E)-4-[(4-bromo-2-butenyl)oxy]-3-methoxyacetophenone (4.0 g, 1.3 eq) in acetonitrile (100 ml) was heated at reflux for 2 hours. At the end of the reaction, the solvent was removed on the rotary evaporator. The residue was extracted into dichloromethane (300 ml). The insolubles were filtered off. The dichloromethane was concentrated. The crude product was purified on a flash chromatography column. The product eluted as an oil, weight 2.87 g Recrystallization from ethanol:hexane (20 ml:5 ml) gave (E)-1-[4-[[4-(6-fluoro-1,2benzisoxazol-3-yl)- -piperidinyl]-2-butenyl]oxy]-3-methoxy-phenyl]ethanone as off-white crystals: 2.46 g; m.p. 91-93 C.

25 ANALYSIS: Calculated for C 25

H

27

FN

2 0 4 68.48%C 6.21%H 6.39%N Found: 68.28%C 6.12%H 6.27%N EXAMPLE -[4-[(4-Chloro-2-butenvl)oxvy-3-methoxyphenyl]ethanone A stirred mixture of 4-hydroxy-3-methoxyacetophenone (16.6 g, mmole), K 2 C0 3 (14 g, 100 mmol) and cis-1,4-dichloro-2-butene (Aldrich, 15 g, 120 mmol) in acetonitrile (250 ml) was heated at reflux for 2.5 hours. The mixture 112 was filtered and concentrated to an oil. Purification was by flash chromatography.

The fractions containing the purest product were combined and concentrated to give white crystals, 7.7 g, 30%. This was recrystallized from ether to give analytical pure 1 -[+-hor--uey~x]--ehxpey~tann (2.72 m.p. 64-66*C.

ANALYSIS:

Calculated for C 13

H

5 CI0 3 61 .30%C 5.94%H Found: 61.28%C 5.94%H EXAMPLE 71 -[4-[[4-[4-(6-Fluoro-1 ,2-benzisoxazol-3-yl)-1 -piperid inyl]- 2-butenylloxy]-3-methoxyphenyllethanone A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1 ,2-benzisoxazole (2.2 g, mmol), K 2 C0 3 (1.8 g, 13 mmol) and 4[4clro2btnlox]3mtoy phenyljethanone (3.43 g, 9.7 mmol) in acetonitrile (100 ml) was heated at reflux ::for 1-1/2 hours. At the end of the reaction, the solvent was removed and the inorganics were filtered after addition of dichloromethane (250 ml). The dichloromethane solvent was removed again. The crude oil was purified on two flash chromatography columns to give a colorless oil (2.78 The oil was solidified by vigorously drying on a vacuum pump. Recrystallization from ethanol ml) and hexane (2 ml) gave analytically pure -[4-[[4-[4-(6-fluoro-1 ,2benzisoxazol-3-y)-1 -piperidinl -uey~oy--ehx-pey~taoe 1.83 g, m.p. 57-59*C.

ANALYSIS:

25 Calculated for C 25

H

27

FN

2 0 4 68.48%C 6.21 %H 6.39%N *Found: 68.26%C 6.18%H 6.32%N EXAMPLE 72 -[3-[[4-[4-(6-Fluoro-1 ,2-benzisoxazol-3-yl)-l -piperidinyl-2butenyl]oxy]-4-hyd roxyphenylletha none hydrochloride The mixture of -[3-[[4-[4-(6-fluoro-1 ,2-benzisoxazol-3-y)-1 -piperid inyl]- 2-butenyl]oxy]-4-benzyloxyphenyi]ethanofle (5.5 g, 10.7 mmol), acetic acid ml), and hydrochloric acid (6 ml) was heated at 7500 for 2 hours. At the end of 113 reaction, the solvent was reduced to about 20 ml on a rotary evaporator. The solution was poured into ice water (350 ml) and extracted with dichloromethane (3 x 250 ml). The dichloromethane solution was washed with brine and dried over Na 2

SO

4 A solid formed on concentration of the solvent. This was collected by filtration (3.4 Recrystallization from hot methanol (40 ml) gave 1.82 g of [3-[[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1 -piperidinyl]-2-butenyl]oxy]-4hydroxyphenyl]ethanone hydrochloride as white crystals, 37.5%, m.p. 208- 210 0

C.

ANALYSIS:

Calculated for C 24

HFN

2 0 4 *HCI: 62.54%C 5.69%H 6.08%N Found: 62.40%C 5.60%H 6.04%N EXAMPLE 73 -[3-[[4-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2butenyl]oxy]-4-benzyloxyphenyllethanone '-bromo-2'-butenyl)oxy]-4-benzyloxyacetophenone To 4-benzyloxy-3-hydroxyacetophenone (17.6 g) in acetonitrile (200 ml) was added potassium carbonate (10 followed by the addition of dibromobutene (19 The resulting mixture was heated at reflux for 3 hours. The mixture was concentrated, extracted into dichloromethane, and the potassium salt was removed by filtration. Solvent was removed, and the resulting material was V purified by flash chromatography to yield 20.5 g of butenyl)oxy]-4-benzyloxy-acetophenone as white crystals.

2-benzisoxazol-3-yl)-I-piperidinyl]-2-buteny]oxy]- 4-benzyloxyphenyl]ethanone A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (5.62 g, 25.5 mmol), K 2 C0 3 (4 g, 29 mmol), and (E)-3-[(4'-bromo-2'-butenyl)oxy]-4-benzyloxy acetophenone (10 g, 26.6 mmol) in acetonitrile (125 ml) was heated at reflux for hours. The mixture was cooled and concentrated to a crude solid. The residue was extracted into dichloromethane (300 mi) and insolubles were filtered. The crude material from the dichloromethane solution was purified on a flash 114 chromatography column. The product thus purified weighed 8 g as a pale white solid. Recrystallization from hot ethanol gave 7.11 g of 1,2-benzisoxazol-3-yl)-1 -piperidinyl]-2-butenyl]oxy]-4-benzyloxyphenyl]ethanone as off-white crystals, m.p. 124-1250C.

ANALYSIS:

Calculated for C31 H 31

FN

2 0 4 72.36%C 6.07%H 5.44%N Found: 72.23%C 6.04%H 5.04%N EXAMPLE 74 6-Fluoro-3-1 -3-(5-methoxv-1 H-indol-6-yl)oxylproDvll-4-Diperidinvll- 1,2-benzisoxazole 6-(3-Chloropropoxy)-5-methoxyindole To a stirred suspension of sodium hydride (0.94 g, 19.6 mmol of a 50% oil 15 dispersion) in dimethylformamide (20 ml) under nitrogen and cooled to -50C was added, dropwise, 5-methoxy-6-hydroxyindole (3.2 g, 19.6 mmol) dissolved in dimethylformamide (60 ml) so that the temperature did not exceed After Scomplete addition, the reaction was stirred for 45 minutes at 0°C. While maintaining the reaction temperature between -50C and 0°C, a solution of 1bromo-3-chloropropane (3.1 g, 19.6 mmol) dissolved in dimethylformamide ml) was slowly added. The mixture was stirred at ambient temperature under nitrogen for 21 hours. The reaction was cooled in an ice bath, and water was added to destroy the excess sodium hydride, and the aqueous mixture was oo* extracted with ethyl acetate. The ethyl acetate extract was washed with water, 25 dried with MgS04 and concentrated to yield 5.3 g of a dark, oily liquid. This was 0. combined with an additional sample, for a total of 10.0 g, and purification by preparative HPLC (Waters Associates prep LC/System 500) provided 5.1 g of a brown solid. A 2.5 g sample was recrystallized from isopropyl alcohol to yield 1.1 g of 6-(3-chloropropoxy)-5-methoxyindole as beige crystals, m.p. 73- 750C.

ANALYSIS:

Calculated for C 12

H

14 CIN0 2 60.13%C 5.89%H 5.84%N Found: 60.26%C 5.86%H 5.77%N 115 6-Fluoro-3-[1-[3-[(5-methoxy- H-indol-6-yl)oxy]propyl]-4-piperidinyl]- 1,2-benzisoxazole A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.5 g, 11.5 mmol), 6-(3-chloropropoxy)-5-methoxyindole (2.5 g, 10.4 mmol), K 2 C0 3 (1.6 g, 11.5 mmol), KI (200 mg) and acetonitrile (100 ml) was stirred at reflux under nitrogen for 40 hours. The cooled reaction was poured into water and extracted with ethyl acetate. The ethyl acetate extract was washed with water, washed with brine, dried with MgSO 4 and concentrated to yield 4.0 g of a solid. The compound was recrystallized from ethanol to afford 3.3 g. Another recrystallization from ethanol (utilizing a charcoal treatment) provided 2.9 g of 6-fluoro-3-[1-[3- [(5-methoxy-H-indol-6-yl)oxy]propyl]-4-piperidinyl]-1,2-benzisoxazole as a beige solid, m.p. 156-1580C.

ANALYSIS:

Calculated for C 24

H

26

FN

3 0 3 68.07%C 6.19%H 9.92%N 15 Found: 67.89%C 6.07%H 9.91%N S. EXAMPLE 6-Fluoro-3-[1-[3-[(1 H-indol-7-yl)oxy]propyl]-4-piperidinyl]-1,2- S" benzisoxazole hemifumarate j 7-(3-Chloropropoxy)indole To a stirred suspension of sodium hydride (0.8 g, 17 mmol of a 50% oil i* dispersion) in dimethylformamide (20 ml), under nitrogen, was added dropwise 7- 'hydroxyindole (2.1 g, 15.7 mmol) in dimethylformamide (20 ml). After complete 25 addition, the reaction was stirred at ambient temperature for 0.5 hour and then cooled to 15C. To this cooled solution was added, dropwise, 1-bromo-3chloropropane (2.5 g, 15.7 mmol) in dimethylformamide (5 ml). The reaction was then stirred at ambient temperature for 16 hours. The reaction was poured into water, and the aqueous suspension extracted with ethyl acetate. The ethyl acetate was washed with water, dried (MgSO 4 and the solvent was concentrated to afford a dark brown oil. Following flash chromatography on silica gel, 7-(3chloropropoxy)indole was obtained as a colorless oil, 1.0 g.

ANALYSIS:

116 Calculated for C 11

H

12 CINO: 63.01%C 5.77%H 6.68%N Found: 63.25%C 5.61 %H 6.65%N 6-Fluoro-3-[1-[3-[(1H-indol-7-yl)oxy]propyl]-4-piperidinyl]- 1,2-benzisoxazole hemifumarate A stirred mixture of 7-(3-chloropropoxy)-1 H-indole (3.5 g, 17 mmol), 6fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (3.5 g, 17 mmol), K 2 C0 3 (2.3 g) and acetonitrile (60 ml) was refluxed for 11 hours. The reaction was poured into water, and the aqueous mixture was extracted with ethyl acetate. The ethyl acetate was washed with water, dried (MgSO4), and the solvent was concentrated to afford a dark oil. The oil was flash chromatographed on silica gel. Upon concentration of the appropriate fractions, 3.0 g of a white, foamy substance was obtained. The substance was dissolved in ethyl acetate (75 ml) and fumaric acid (0.97 g, 83 mmol) was added. The mixture was briefly heated to reflux, and then stirred at 15 ambient temperature for 1.5 hours. The resultant insoluble white fumarate salt was collected and afforded 4.2 g of product. Recrystallization of the salt from dimethylformamide yielded 3.1 g of 6-fluoro-3-[1-[3-[(1H-indol-7yl)oxy]propyl]-4-piperidinyl]1,2-benzisoxazole hemifumarate as a white solid, m.p.

i =213-215°C.

ANALYSIS:

Calculated for C 25

H

26

FN

3 0 4 66.50%C 5.80%H 9.31%N Found: 66.23%C 6.14%H 9.39%N EXAMPLE 76 25 6-Fluoro-3-[1 -(3-hydroxypropyl)-4-piperidinyl]- 1,2-benzisoxazole A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (10.0 g, mmol), K 2 CO3 (10.0 3-bromo-l-propanol (7.3 g, 46 mmol) and acetonitrile (200 ml) was refluxed for 3 hours. The reaction was poured into H 2 0 and 7.1 g of a beige solid was collected. The filtrate was extracted with dichloromethane, and after concentration an additional 6.7 g of crude solid was harvested. The solids were combined and triturated with refluxing ethyl acetate to afford 8.0 g of 6fluoro-3-[1-(3-hydroxypropyl)-4-piperidinyl]-1,2-benzisoxazole as an off-white 117 solid. A sample (4.0 g) was recrystallized from ethanol-water (with charcoal treatment) to yield 2.4 g of the alcohol as a white solid, m.p. 140-1420C.

ANALYSIS:

Calculated for C 15

H

19

FN

2 0 2 64.73%C 6.88%H 10.06%N Found: 64.79%C 6.97%H 10.03%N EXAMPLE 77 6-Fluoro-3-[1-(2-pyrimidinoxv)propvll-4-piperidinyll-1,2-benzisoxazole fumarate To a stirred suspension of 6-fluoro-3-[1-(3-hydroxypropyl)-4-piperidinyl]- 1,2-benzisoxazole (3.6 g, 13 mmol) in tetrahydrofuran (50 ml) was added dropwise, potassium bistrimethylsilylamide (2.6 g, 13 mmol) dissolved in tetrahydrofuran (20 ml). After complete addition, the reaction was stirred at ambient temperature for 5 min, and then 2-chloropyrimidine (1.6 g, 14 mmol) was added. The reaction was stirred at ambient temperature for 4 hours, and TLC at 15 this time indicated an incomplete reaction. An additional quantity of the base g) was added, and the reaction was allowed to proceed at ambient temperature for 14 additional hours. The reaction was poured into water and the aqueous 00 mixture was extracted with dichloromethane. The extract was washed (H 2 0), dried (K 2

CO

3 and the solvent was concentrated to afford a wet solid. The solid was triturated with diethyl ether and the product that separated was collected to yield 1.0 g of the starting alcohol. The filtrate was then concentrated to afford 3.8 g of a waxy, yellow solid. This material was combined with 2.6 g from another run and the combined sample flash chromatographed on silica gel, eluting first with ethyl acetate and then with 8% diethylamine-ethyl acetate. Concentration of the 25 appropriate fractions afforded 3.0 g of the desired compound as a yellow solid.

The solid was converted to a fumarate salt with fumaric acid in acetone, and then reversed to its free base. It was combined with another sample and the combined sample (3.8 g) chromatographed on silica gel on HPLC methanoldichloromethane as eluent). Concentration of the appropriate fractions yielded 1.6 g of a yellow solid. A fumarate salt was prepared to yield 2.1 g of 6-fluoro- 3-[1-[(2-pyrimidinoxy)-propyl]-4-piperidinyl]-1,2-benzisoxazole fumarate, m.p. 184-186 0

C.

ANALYSIS:

1 18 calculated for

C

23

H

25 FN4 0 6.

Found: 58.47%/C 58.52%/C .33%Ho 5.34%H0 J 1.86%N i 1.80%/N EXAMPLE78 idBijmt 6-Aceto- 2 -4 6-fluoro- 1 2 :-ben~ziSo azoI-1-ieii e" J- 1 4 -benzodioxan *9 0 6 aceto-2-mesyloxymty 4 beflzodioxan (.9g 6. ml a (A A e o 2 hy r y m t 4 benzodioxan (3 3 g,2 3 m mo) w asade t dis~~e6i trichlOromethane (100 ml). Triethylamine (2.oguw s ade oo mesdissolved e 9,13 q)a The mixture was stirred for 2ho r at o m tempratre. The mixture was then diluted, washed with an ice/dilute hydriolr acd ixure (150 ml), washed with sodium biaboaehnremdredoerh ageim slaeancoentrated to yield 5.6 g. ollowing joymtorah on a SiO2 column, 3.64 g 700yel)o 4 benZOdioxan were obtain ed. 2b ni~ a -i eiiyi ehl14 (B 6 aceto 24 (6 -fuOro ,z l 2 (3f-0Oaz I3 9pp rdilme 13 .6 benzodioxan 4-ieiiy)i2bnsX 2 0A s t ir r e d m ix tu r e o f 6 A M -2 m e y l b~ e h ylo'a 4 ben(3 .0 i o xa3 2 0 m m O 1 (2 0 0 3 (2 1 4 .5 m m o l) a n d 6 -a e f or 0 2 .m y y h oubrn.o d tota n g, 12 mmol) in acetonitrile (100 ml) was heated at reflux for 3orsidte end f te racton the solvent was removed on a rotary evaporator.Thredu was ofexreact itdchrmethane (350 ml) and the insoluble 5 were filtered off.

s Textadit dichlorom sutowacncentrated and the crude oil was purified by flash chromatography. The product thus obaie w e o3.3 zg (590/)- Rerytallization from ethanol gave 6 aceto24 (6-tuoroi 12en2-xz l3 l i piperidinyllImethyl- 4 benzodio xan as light yellow crystals (3.2 m-P. 12 12300. 68% AN A L -YSIS: 2 H 2F 2 4 67.31% C .65% H 6 75%/ N Calculated for 2

H

3

N

0 67.24%C 5 .50%/H Found* 119 EXAMAPLE 79 2-[4-(6-Fuoro-1 .2-benzisoxazol- 3 -yl)-l :ieridinyl~eth fll ,4-benzodioxafl A stirred mixture of 6-fluoro-3-(4-piperidiflyl)-l ,2-benzisoxazole (3.0 g, 13.6 mmol),

K

2 C03 (2.45 g, 17.7 mmol), 2-methanesulfoflloxymethyl-l ,4-benzodioxan (3.35 g, 13.7 mmole) in acetonitrile (100 ml) was heated at reflux for 12 hours. At the end of the reaction, the insolubles were filtered and rinsed with dichioromethane. The organic solution was concentrated. The crude oil was purified by flash chromatography on a silica gel column. The fractions containing the pure product were pooled and concentrated to a light yellow oil (3.94 g, 74%).

Crystallization from ethanol and petroleum ether gave 2-[4-(6-fluorol ,2benzisoxazol-3-yl) 1 -piperidinyl]methyll ,4-benzodioxan as off-white crystals, 2.22 g, m.p. 86-870C.

AN.ALYSIS:

Calculated for C 21

H-

21

FN

2 03: 68.47%C 5.75%H 7.60%N i Found: 68.33%C 5.75%H 7.51%N EXAMPLE 244 4-6-Fluoro- 1 2-benzisoxaZggl- 3 -yVl-1 -pipe rid inyllethyll 1 .4-benzodioxan 2-mesyIoxyethy-1, 4benzodioxan To the compound 2-hydroxyethyl-1 ,4-benzodioxan (11.96 g) in dichloromethane (450 ml) was added triethylamine (0.12 mol, 10 ml).

Mesylchloride (9.2 g) was then added dropwise and the reaction mixture was stirred for one hour at room temperature. After completion of the reaction, the solution was washed with water, brine, and concentrated to an oil, which was purified by chromatography on silica gel to yield 2-mesyloxyethyll ,4benzodioxan, 17.08 g.

2-[4-(6-fIuoro- 1,2-benzisoxazoI- 3 -Y)l-piperidinyllethyll 1 ,4-benzodioxafl A mixture of 6-fluoro-3-(4-piperidinyl)l ,2-benzisoxazole (4.7 g, 21 mmot),

K

2 003 (3.5 g, 25.4 mmol) and 2-mesyloxyethyl-1 ,4-benzodioxan (5.5 g, 21.3 mmol) in acetonitrile (250 ml) was heated at ref lux for 3.5 hours. At the end of the reaction, insolubles were filtered. The solid was washed with dichloromethafle 120 (200 ml). The solutions were combined and evaporated to an oil. This crude oil was purified by flash chromatography on a silica gel column. The material thus obtained was crystallized from ethanol. The 2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)- 1-piperidinyl]ethyl]-1,4-benzodioxan crystals were collected and weighed 3.8 g, 48%, m.p. =112-113 0

C.

ANALYSIS:

Calculated for C 22

H

2 3

FN

2 0 3 69.09%C 6.06%H 7.32%N Found: 69.17%C 6.02%H 7.31%N EXAMPLE 81 6-3-[4-(6-Fluoro-1.2-benzisoxazol-3-vl)-1 -iDeridinvllpropoxv- 7 methoxy-1-tetralone 6 -(3-chloropropoxy)-7-methoxy-1-tetralone 15 A mixture of 6-hydroxy-7-methoxy-1-tetralone Org. Chem., 1985, S 4937) (1.5 g, 7.8 mmol), K 2

CO

3 (1.7 g, 12.3 mmol), and acetone (30 ml) was stirred at reflux under nitrogen for 45 minutes. The reaction was cooled to ambient temperature and a solution of 1-bromo-3-chloropropane (1.9 g, 12.1 mmol) dissolved in 8 ml acetone was dripped into the mixture. After total addition, 20 the reaction was heated to reflux and stirred under nitrogen for 21 hours. The reaction was cooled to ambient temperature and filtered. The filter cake was washed well with acetone and the filtrate was concentrated to yield 2.0 g 6-(3chloropropoxy)-7-methoxy- -tetralone as an amber oil.

9 9 *0 25 6[3-[4-(6-fluoro-1,2-benzisoxazol-3-y)- -piperidinyl]propoxy-7-methoxytetralone A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (0.78 g, 3.6 mmol), K 2 CO3 (0.60 g, 4.1 mmol), KI (100 mg), 6-(3-chloropropoxy)-7-methoxy-1tetralone (0.87 g, 3.2 mmol), and acetonitrile (50 ml) was stirred at reflux under nitrogen for 17 hours. The cooled reaction was poured into 100 ml of water and the aqueous mixture was extracted with ethyl acetate. The ethyl acetate extract was washed with brine, dried with MgS04 and concentrated to yield 1.7 g of a brown oil. The oil was purified by preparative HPLC (Waters Associates Prep 121 LC/system 500) to afford 1.0 g of a light brown solid. This was combined with an additional sample (2.3 g total) and recrystallization from ethanol yielded 1.7 g. A subsequent recrystallization from ethanol gave 1.25 g of 6-[3-[4-(6-fluoro- 1,2-benzisoxazol- 3 -yl)-1-piperidinyl]propoxy]-7-methoxy- -tetralone as a beige powder, m.p. 129-131

C.

ANALYSIS:

Calculated for C 26

H

29

FN

2 04: 69.01%C 6.46%H 6.19%N Found: 68.77%C 6.43%H 6.16%N EXAMPLE 82 N-3-4-(6-Fluoro-1 .2-benzisoxazol-3- vl-1-pieridinvl propil-6-acetl-2benzoxazolinone N-(3-chloropropyl)-2-benzoxazolinone 15 To a stirred suspension of sodium hydride (7.8 g, 160 mmol, etherwashed) in dimethylformamide (75 ml) was added dropwise under nitrogen, 2benzoxazolinone (20.0 g, 150 mmol) dissolved in dimethylformamide (150 ml).

After complete addition the reaction was stirred at ambient temperature for min, and then it was cooled to -5°C with an ice-acetone bath. A solution of 3- 20 chloro-1-bromopropane (46.6 g, 300 mmol) in dimethylformamide (50 ml) was added dropwise (temperature never exceeded The reaction was allowed to reach ambient temperature and was stirred for 16 hours. The reaction was poured into water, and the aqueous mixture was extracted with ethyl acetate. The ethyl acetate was washed with water, dried (MgSO4), and the extract 25 concentrated to afford 21.9 g of a brown solid. The solid was recrystallized from toluene-hexane to afford

N-(

3 -chloropropyl)-2-benzoxazolinone as large needles, 15.6 g, m.p. 264-2660C.

N-(

3 -chloropropyl)-6-acetyl-2-benzoxazolinone A mixture of N-( 3 -chloropropyl)-2-benzoxazolinone (8.5 g, 40 mmol), polyphosphoric acid (100 and acetic acid (2.4 g, 2.3 ml, 40 mmol), was stirred and heated at 1000C for 2 hours. The hot solution was poured into ice-water to deposit a yellow gum. The mixture was extracted with dichloromethane, and -r 111~-~ _111 _1.-~II 122 insolubles were filtered. The dichloromethafle extract was washed with water, dried (K 2 00 3 and concentrated to afford 6.4 g of a slightly green solid. This was recrystallized from ethanol to yield N-(3-chloropropyl)-6-acetyl-2benzoxazolirlone as a brown solid, 3.5 g, m.p. 100-1 0300.

N-[3-[4-(6-fluoro- 1,2-benzisoxazol-3-y)-l1-piperidinyl]propyl-6-acetyI- 2 benzoxazolinofle A mixture of 6-f luoro-3- (4-pi perid inyI)-1, ,2-benzisoxazole (2.0 g, 9 mmol), N-3clrpoy)6aey--ezxzlnn (2.4 g, 9 mmol), K 2 00 3 (3.6 a few crystals of KI, and acetonitrile (50 ml) was stirred and refluxed for 13 hours.

The reaction was poured into water, and a dark, brown solid that separated was collected to afford 3.3 g of crude product. The solid was chromatographed on a Waters Prep 500 HPLC. Concentration of appropriate fractions afforded 2.3 g of a yellow solid, and recrystallization from ethyl acetate yielded 1.2 g (31 of N-[3- [4-(6-fluoro-1 ,2-benzisoxazol-3-yl)-l -piperidinyl]propyl]-6-acetyl- 2 benzoxazolinone, m.p. 152-1 5400.

ANALYSIS:

Calculated for C 24

H

24

FN

3 0 4 65.89%C 5.53%H 9.61 %N Found: 65.67%C 5.48%H 9.52%N EXAMPLE 83 N-[3-r4-(6-fluoro- 1 2-benzisoxazol-3-yl)- 1 -Di~eridinvllpropyl1~hthalimide A mixture of 6-f Iuoro-3-(4-pi pe rid inyl)-1, ,2-benzisoxazole (6.44 g, 29.1 mmole), K 2 C0 3 (6.4 g, 46 mmol), N-(3-bromopropyl)phthalimide (8.4 g, 31 mmol) in acetonitrile (150 ml) was heated at reflux for 3.5 hours. The insolubles were filtered. The solvent was removed at reduced pressure and the residue was purified by silica gel column chromatography to give N-[3-[4-(6-fluoro-1 ,2benzisoxazol-3-yl)-l -piperidinyl]propyl]phthalimide as a white solid.

Recrystallization from ethanol yielded 9.8 g of off-white crystals, m.p.= 129-130 0

C.

ANALYSIS:

Calculated for C 23

H

22

FN

3 0 3 67.89%C 5.44%H 10.31%N Found: 67.49%C 5.38%H 10.13%N 123 EXAMPLE 84 Amin)opPi)-4-(6-fluoro-l ,2-benzisoxazol-3-yl)piperidine dihvdrochloride A mixture of N-[3-II4-(6-f1uoro-1 ,2-benzisoxazol- 3 I -piperidinyl]propyllphthalimide (8.5 g, 21 mmol), hydrazine monohydrate (1.5 g, 30 mmol) in methanol (60 ml) was heated at reflux for 2 hours. At the end of the reaction, methanol was removed to leave a crude solid. To this was added water (60 ml), then the mixture was acidified with HCl to pH 1. The insolubles were filtered with the aid of a pad of Celite. The aqueous solution was basified with 50% NaOH, (pH 13), then extracted with dichloromethafle. The combined dichloromethane solution was washed with brine, then dried to a colorless oil (4.5 The analytical sample (1.5 g) was prepared by treating the oil with HCI in ethanol at 0 0 C. The 1- (3-aminopropyl)-4-(6- 4 Iuoro-12bnioxz 3y~pprdn dihydrochloride was obtained as white crystals, 2.03 g, m.p. 231-234*C.

ANALYSIS:

Calculated for C 15

H

2 oFN 3 002HCI: 51.44%C 6.33%H 12.00%N Found: 51 .35%C 6.49%H 11 EXAMPLE cis-2-[3-[4-(6-Fl jorol ,2-benzisoxazol-3-y)l I pip e.ridinyl]pro pylhexahydJro

H-

isoindole-1 ,3-dione hdrochloride A mixture of I -(3-aminopropyl)-4-(6-41uoro12bnioxzl y~pprdn (3.01 g, 10.8 mmol) and cis- 1,2-cyclohexane-d icarboxylic anhydride (1.9 g, 12.3 mmol) in dry pyridine (30 ml) was heated at reflux for 16 hours. The dark brown solution was concentrated to dryness on a rotary evaporator. The crude residue was purified twice by flash chromatography over a silica gel column. The pure product thus obtained weighed 2.5 g This was converted to the hydrochloride salt by treatment with HCI in ethanol (50 ml). The cis-2-13-[ 4 6 fluoro-1 ,2-benzisoxazol- 3 -yl)l -piperidinylpropyl]-hexahyd ro-1 H-isoindole-l ,3dione hydrochloride crystals so obtained weighed 3.0 g, m.p. 242-245'C.

ANALYSIS:

Calculated for C 23

H

28

FN

3 0 3 9HCI: 61 .14%C 6.50%H 9.34%N Found: 61 .32%C 6.32%H 9.27%N 124 EXAMPLE 86 N-4-[4-(6-Fluoro-1,2-benzisoxazol- 3 )-lpieridinybtylhthalimide A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (5.5 g, 25 mmol), 4-bromobutylphthalimide (8.0 g, 28.3 mmol, 1.13 eq), K 2 CO3 (4.55 g, 32 mmol) in acetonitrile (100 ml) was heated at reflux for 3 hours. At the end of the reaction, the mixture was filtered. The insolubles were washed with dichloromethane (200 ml). The organic solution was concentrated gradually to allow cystallization. The crude crystals (5.9 g) were collected. The mother liquor was concentrated to a solid (5.5 Purification was by flash chromatography over a silica gel column.

The product (3.8 g) thus purified was recrystallized from ethanol (70 ml) to give 2.48 g of N-[4-[4-(6-fluoro-1,2-benzisoxazol- 3 -yl)-1-piperidinyl]butyl]phthalimide as white crystals, m.p. 144-146*C.

ANALYSIS:

Calculated for C 24

H

2 4 FN303: 68.39%C 5.74%H 997%N Found: 68.34%C 5.74%H 9.84%N EXAMPLE 87 1-(4-Aminobutyl)4-(6fluoro-1 ,2-benzisoxazol-3 piperidihydrochloride A mixture of N-[4-[4-(6-fluoro-1,2-benzisoxazol-3- 20 yl)piperidinyl]butyl]phthalimide (6.9 g, 16.4 mmol) and hydrazine monohydrate (1.64 g, 32.8 mmol) in methanol (70 ml) was heated at reflux for 3 hours. At the end of the reaction, methanol was removed to leave a crude solid. This was dissolved in water and acidified with HCI to pH 2. The insolubles were filtered.

The aqueous solution was basified with 50% NaOH, and then extracted with S 25 dichloromethane. The dichloromethane solution was washed with water and brine, and then dried over MgSO4. The solvent was removed to a colorless oil: 4.48 g. This oil was treated with 2.5 equivalents of HCI in ethanol. The solid was collected. Recrystallization from ethanol (65 ml) and methanol (20 ml) gave 2.0 g of 1-(4-aminobutyl)-4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine dihydrochloride as white crystals, m.p. 234-237"C.

ANALYSIS:

Calculated for C16H 22

FN

3 03.2HCI: 52.75%C 6.64%H 11.53%N Found: 52.37%C 6.59%H 11.07%N 125 EXAMPLE 88 cis-2-[4-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1 -piperidinyl]butyl]hexahydro-1

H-

isoindole-1,3-dione hydrochloride A mixture of 1-(4-aminobutyl)-4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (4.7 g, 16.1 mmol) and cis-1,2-cyclohexanedicarboxylic anhydride (3.23 g, 21 mmol) in pyridine (45 ml) was heated at reflux for 8 hours. At the end of the reaction, pyridine was removed to dryness. The crude product was purified on a silica gel column. The material thus obtained weighed 3.18 g as a clear oil.

This oil was dissolved in ethanol (15 ml), then was treated with HCI in ethanol ml). Crystallization took place upon cooling. The crystals were collected, 3.2 g, m.p. 229-231

C.

ANALYSIS:

Calculated for C 24

H

30

FN

3 0 3 .HCI: 62.13%C 6.73%H 9.06%N Found: 61.79%C 6.68%H 8.92%N S. EXAMPLE 89 1 -[4-[3-[4-(6-Fluoro-1,2-benzisoxazol- 3 -yl)-1 -piperidinyl]propyl]thil-3methoxyphenyl]ethanone 20 1-[4-[(3-chloropropyl)thio]-3-methoxyphenyl]ethanone 'A mixture of 1-(4-thio-3-methoxyphenyl)ethanone (10.0 g, 54.9 mmol), potassium carbonate (9.0 g, 65.1 mmol), and acetone (100 ml) was stirred at reflux under nitrogen for 30 minutes. The reaction was cooled to ambient temperature and a solution of 1-bromo-3-chloropropane (6.5 ml, 9.5 g, 60.4 25 mmol) dissolved in acetone (25 ml) was dripped into the reaction. After complete addition, the reaction was heated to reflux and stirred under nitrogen for 17 hours.

After the reaction was carried to substantial completion, the reaction mixture was filtered and the resulting filter cake was washed with acetone. The filtrate was concentrated to provide an amber oil. A small sample was solidified by trituration with hot cyclohexane to provide 1-[4-[(3-chloropropyl)thio]-3methoxyphenyl]ethanone as a yellow solid, 11.7 g, m.p. 53-55 0

C.

126 1 1,2-benzisoxazol-3-yl)- 1 -piperidinyl]propyl]thio]-3methoxyphenyl]ethanone A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (3.0 g, 13.6 mmol), 1-[4-[(3-chloropropyl)-thio]-3-methoxyphenyl]ethanone (3.5 g, 13.6 mmol),

K

2 C0 3 (2.3 g, 16.6 mmol), KI (200 mg) and CH 3 CN (100 ml) was stirred at reflux under nitrogen for 7.5 hours and then was left at ambient temperature for hours. The reaction was poured into water and the aqueous mixture was extracted with ethyl acetate. The ethyl acetate extract was washed twice with water, once with brine and dried over MgSO 4 The solvent was removed in vacuo to afford 6.8 g of a light brown oil. The sample was purified by flash chromatography. Concentration of appropriate fractions yielded 3.0 g.

Recrystallization from ethanol provided 2.4 g of 1-[4-[3-[4-(6-fluoro-1,2benzisoxazol-3-yl)-1 -piperidinyl]propyl]thio]-3-methoxyphenyl]ethanone as a S: beige solid, m.p. 93-95°C.

15 ANALYSIS: Calculated for C 24

H

27

FN

2 0 3 S: 65.14%C 6.15%H 6.33%N Found: 64.66%C 6.17%H 6.26%N EXAMPLE 20 4-(6-Fluoro-1.2-benzisoxazol-3-yl)-1 -(2'-methoxvphenyl)butvlDiperidine maleate 2-(4-bromobutyl)anisole 2-Bromoanisole (2.0 g, 1.07 mmol) in tetrahydrofuran (20 ml) was cooled to -78 0 C under nitrogen and secondary butyllithium (1.3 M, 10 ml, 1.3 eq) was 25 charged into the resulting solution for two hours. The solution was quenched with 1,4-dibromobutane (3.2 g) and allowed to stir at ambient temperature overnight.

The mixture was diluted with ethyl acetate, washed with water and brine, and concentrated to an oil. Following chromatography on a SiO 2 column, 2.4 g of 2-(4bromobutyl)anisole were obtained.

4-(6-fluoro- 1,2-benzisoxazol-3-yl)- 1-(2'-methoxyphenyl)butyl-piperidine maleate 127 A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.36 g, 10.7 mmole), K2C0 3 (2 g, 14.5 mmol) and 2-(4-bromobutyl)anisole (2.4 g, 10 mmol) in acetonitrile (100 ml) was heated at reflux for 2.5 hours. At the end of reaction, the solvent was removed. The residue was extracted into dichloromethane (200 ml) and filtered. The dichloromethane solution was concentrated. The crude oil obtained was purified on a flash chromatography column. The material thus purified was a light yellow oil (2.73 g, This oil was dissolved in ethanol and treated with maleic acid (607 mg, 1.0 eq) in ethanol. The 4-(6-fluoro-1,2benzisoxazol-3-yl)-1-(2'-methoxyphenyl)butylpiperidine maleate crystals formed on concentration and subsequent cooling to 0°C. These were collected and dried to yield 2.05 g, m.p. 132-1330C.

ANALYSIS:

Calculated for C 23

H

27

FN

2 02OC 4 H404: 65.05%C 6.27%H 5.62%N Found: 65.25%C 6.30%H 5.70%N EXAMPLE 91 1 -4-(1,3-Dithian-2-vlethvllphenvl-4-(6-fluoro-1.2-benzisoxazol-3-vl Sbutylpiperidine 20 4-bromo-1-(1,3-dithian-2-yl)ethylbenzene *To the compound p-bromoacetophenone (36.85 g, 185 mmol) in trichloromethane (300 ml) was added 1,3-propanedithiol (25 g, 230 mmol) and boron trifluoride etherate (3 ml). The resulting mixture was stirred at room temperature for 48 hours. The mixture was diluted with dichloromethane (500 ml), 25 washed twice with 10% sodium hydroxide (200 ml), water, and brine, and then dried (Na 2 SO4). The product was concentrated to an oil. A portion was stirred with ether (100 ml) and a crystalline product was formed. The crystalline product was recovered by filtration and purified by recrystallization to yield 4-bromo-1-(1,3dithian-2-yl)ethylbenzene.

4-(4-bromobutyl)-1-(1,3-dithian-2-yl)ethylbenzene A solution of 4-bromo-1-(1,3-dithian-2-yl)ethylbenzene (27.2 g, 94 mmol) in tetrahydrofuran (200 ml) was charged with sec-butyllithium (99 ml, 1.3 M in 128 cyclohexane, 0.13 mole) dropwise at -78°C under nitrogen. The mixture was stirred at ambient temperature for 1.5 hours, and then quenched with 1,4dibromobutane (42 g, 0.2 mole). After being stirred for 3 hours, the mixture was poured into ethyl acetate, and then washed with water and brine. The organic solution was then dried (Na20S 4 and concentrated to an oil. The crude product was purified by flash chromatography over a silica gel column. The 4-(4bromobutyl)-1-(1,3-dithian-2-yl)ethylbenzene thus purified was a light oil, 22.3 g.

ANALYSIS:

Calculated for C 15

H

21 BrS 2 52.17%C 6.13%H Found: 52.60%C 6.25%H 1-[4-(1,3-dithian-2-yl)ethyl]phenyl-4-(6-fluoro-1,2-benzisoxazol-3yl)butylpiperidine A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (5.4 g, 24.5 mmol), K 2

CO

3 (4.2 g, 30 mmol), 4-(4-bromobutyl)-1-(1,3-dithian-2-yl)ethylbenzene g, 24.6 mmol) in acetonitrile (200 ml) was heated at reflux for 2.5 hours. At the end of the reaction, the mixture was filtered and the solvent was concentrated. The crude (13 g) was purified by flash chromatography over a silica gel column. The material thus purified (8.67 g; 72%) was recrystallized from 20 ethanol (50 ml) and hexane (100 ml) to afford 6.6 g of 1-[4-(1,3-dithian-2yl)ethyl]phenyl-4-(6-fluoro-1,2-benzisoxazol-3-yl)butylpiperidine as light yellow crystals, m.p. 108-110°C.

ANALYSIS:

Calculated for: C 27

H

33

FN

2 0S 2 66.91%C 6.86%H 5.78%N 25 Found: 66.72%C 6.76%H 5.71 %N EXAMPLE 92 1-[4-(4'-AcetoDhenvl)butvyl-4-(6-fluoro-1.2-benzisoxazol-3-vl)piperidine A solution of 1-[4-(1,3-dithian-2-yl)ethylphenyl]butyl-4-(6-fluoro-1,2benzisoxazol-3-yl)piperidine (5.6 g, 11.6 mmol), water (5 ml), and methanol ml), in acetone (50 ml), was treated with mercury (II) perchlorate trihydrate (5 g, 1.1 eq.) at room temperature. After 30 minutes, the reaction was completed. The solids were filtered, and the solvent was removed on a rotary evaporator. The 129 crude product was dissolved in ethyl acetate (500 ml) and washed with water, brine, then dried over Na 2 SO4. The solvent was removed to give a crude oil. The purification was by flash chromatography over a silica gel column. The oil thus obtained (2.67 g, 50%) was combined with 1.1 g of oil prepared in the same fashion. Crystallization from ethanol (10 ml) and hexane (20 ml) yielded acetophenyl)butyl]-4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine as off-white crystals, 2.32 g, m.p. 85-860C.

ANALYSIS:

Calculated for C 24

H

2 7

FN

2 0 2 73.07%C 6.90%H 7.10%N Found: 72.68%C 7.05%H 7.09%N EXAMPLE 93 1 -[4-f3-4-(6-Fluoro-1,2-benzisoxazol-3-vli-1 -iperidinvlDrovylaminol- 3 methoxyphenvllethanone To a stirred suspension of sodium hydride (0.37 g, 7 mmol of a 50% oil dispersion) in dimethylformamide (20 ml) was added, dropwise, fluoro-1,2-benzisoxazol-3-yl)-1 -piperidinyl]propylamino]-3-hydroxyphenyl] ethanone (2.9 g, 7 mmol) dissolved in dimethylformamide (25 ml). The reaction was stirred at ambient temperature for 15 minutes, and then it was cooled with an 20 ice bath to about 5 0 C, whereupon methyl iodide (1.0 g, 7 mmol) in dimethylformamide (1 ml) was added dropwise. The reaction was stirred at ambient temperature for 30 min, and then water was added. The resulting aqueous mixture was extracted with ethyl acetate, the extract washed with water, dried (MgS04), and the solvent was concentrated to afford 4.9 g of a brown oil, which solidified on standing. The solid was flash chromatographed on silica gel.

The appropriate fractions were concentrated to yield 2.7 g of product as a yellow solid. Recrystallization from toluene-hexane yielded 2.0 g of analytically pure 1 -[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1 -piperidinyl]propylamino]-3methoxyphenyl]ethanone as a yellow solid, m.p. 96-98 0

C.

ANALYSIS:

Calculated for C 24

H

28

FN

3 03: 67.75%C 6.63%H 9.88%N Found: 67.93%C 6.72%H 9.80%N 130 EXAMPLE 94 (E)-1-[4-(4-bromo-2-butenyl)oxy]-3-methoxyphenylethanone A mixture of 4-hydroxy-3-methoxyacetophenone (10 g, 59 mmol), K 2 C03 g, 1.2 q) and 1,4-dibromo-2-butene trans, Aldrich, 18 g, 1.2 eq) in acetone (500 ml) was heated at 55°C for 3 hours. At the end of the reaction, the solvent was concentrated. The crude product was extracted into dichloromethane (750 ml) and the insolubles were filtered; then the solution was concentrated again to an oil. Purification on a silica gel column (SiO 2 100 g, eluted with dichloromethane) yielded 7.25 g of white solid. Recrystallization from ether gave analytically pure (E)-1-[4-[(4-bromo-2-butenyl)oxy]-3methoxyphenyl]ethanone (3.91 m.p. 71-72*C.

ANALYSIS:

Calculated for C 13 Hs 5 BrO 3 52.19%C 5.50%H Found: 52.12%C 4.94%H EXAMPLE 4-(3-Chloropropoxy)-3-methoxybenzaldehyde A mixture of vanillin (30.4 g, 200 mmol), K 2 C03 (27.6 g) and acetone (150 ml) was stirred and refluxed for 0.5 hours. Heating was removed, and 1-bromo-3- 20 chloropropane (40.8 g, 260 mmol) in acetone was added dropwise. The reaction was stirred and refluxed for 16 hours, and then it was poured into water. The aqueous mixture was extracted with diethyl ether, the extract was dried (MgSO4), and the solution was concentrated to afford an oil, which upon evacuation solidified to a white solid (50.2 An 8.0 g sample was flash chromatographed S."i 25 on silica gel with 50% ethyl acetatehexane as eluent. Concentration of appropriate fractions gave 2.7 g of 4-(3-chloropropoxy)- 3 methoxybenzaldehyde as a white solid, m.p. 53-55°C.

ANALYSIS:

Calculated for C 11

H

13 CI03: 57.78%C 5.73%H Found: 57.21 %C 5.52%H EXAMPLE 96 -~11 11~ 131 1-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)- -piperidinyl]propylamino]- 3 -hydrox phenyllethanone A mixture of N-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propyl]- 6 acetyl-2-benzoxazolinone (6.0 g, 14 mmol) and 10% aqueous sodium hydroxide (50 ml) was stirred and refluxed for 40 minutes. Water was added and the reaction was made acidic with 5% hydrochloric acid. Saturated Na 2

CO

3 was added until effervescence ceased. The aqueous mixture was extracted with dichloromethane. The dichloromethane extract was washed (water), dried

(K

2 C0 3 and concentrated to afford 2.6 g of a tacky solid. The crude solid was treated with saturated NaHCO3, and extracted into dichloromethane. The dichloromethane was washed (brine and then water), and dried (MgS04). The organic extract was then concentrated to yield 2.4 g of a brown solid, which was combined with another sample to yield 5.0 g. This sample was flash chromatographed on silica. A small sample (0.25 g) was recrystallized from 15 toluene to yield 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1 piperidinyl]propylamino]-3-hydroxyphenyl] ethanone as a brownish solid, 0.15 g, m.p. 150-152°C.

ANALYSIS:

Calculated for C 23

H

26

FN

3 03: 67.14%C 6.37%H 10.21%N 20 Found: 67.54%C 6.58%H 9.95%N EXAMPLE 97 S1-[3-Acetylamino-4-(3-chloropropoxy)phenylethanone A stirred mixture of 1-[3-acetylamino-4-hydroxyphenyl]ethanone (7.7 g, S 25 mmol), K 2

CO

3 (5.7 3-chloro-1-bromopropane (8.9 g, 56 mmol), and acetone (100 ml) was refluxed for 16 hours. The reaction was allowed to cool to ambient temperature, and filtered. Concentration of the filtrate yielded 8.5 g of a white solid. The solid was recrystallized from toluene and then from ethanol to afford g of an off-white solid. A 3.3 g sample of this material was flash chromatographed on silica gel. Concentration of the appropriate fractions afforded 2.8 g of a white solid. The solid was recrystallized from toluene and then from ethanol-water to yield 2.2 g of 1-[3-acetylamino- 4 3 chloropropoxy)phenyl]ethanone as a white solid, m.p. 124-126°C.

132

ANALYSIS:

Calculated for C 1 3

H

1 6 CIN0 3 57.89%C 5.98%H 5.19%N Found: 57.08%C 5.85%H 5.13%N EXAMPLE 98 N-[2-(3-hyd roxypropoxy)phefllacetamide A stirred mixture of 2-hydroxyphenylacetaflide (10.0 g, 66 mmol), K 2 00 3 (6.9 3-bromopropaflol (12.8 g, 12 mmol), and acetone (250 ml) was refluxed for 16 hours. The reaction mixture was allowed to cool, and then it was filtered.

The filtrate was concentrated to yield 19.0 g of a thick, brown oil. The oil was distilled with a Kugelrohr apparatus and 11.2 g of a viscous, orange oil was collected. The oil solidified upon standing. An analytical sample was obtained by recrystallization from ethyl acetate to afford the alcohol as an off-white solid, m.p.

=78-80*C.

ANALYSIS:

Calculated for CjjH1l 5 NO3: 63.14%C 7.23%H 6.69%N Found: 63.10%C 7.32%H 6.64%N EXAMPLE 99 20 4-[4-(6-Fluoro-1 ,2-benzisoxazol-3-yl)-l -piperid inylibutyI bromide 000*00A mixture of 6-fluoro-3-(4-piperidiflyl)-1 ,2-benzisoxazole (12 g, 55 mmol),

K

2 C0 3 (13 g) and I ,4-dibromobutane (20 g, 9.3 mmol, 1.7 eq) in acetonitrile (300 0000 ml) was stirred at room temperature overnight. The inorganic material was 10 0: S. filtered. The solution was concentrated to -80 ml, when crystals crashed out. The 25 product was filtered to yield 14.16 g mn.p. =243-245 0

C.

ANALYSIS:

Calculated for C 16

H

20 BrFN 2 O: 54.09%C 5.67%H 7.89%N Found: 54.13%C 5.52%H 7.83%N EXAMPLE 100 2-[4-(6-Fluoro-1 ,2-benzisoxaz--Yl -pprdiythyl acetate fu marate A mixture of 6-fluoro-3-(4-piperidinyl)l ,2-benzisoxazole (3.0 g, 13.6 mmol),

K

2 003 (3.5 g, 25 mmol), 2-bromoethyl acetate (4 g, 26.5 mmol) in 133 acetonitrile (50 ml) was heated at reflux for 4 hours. After cooling to room temperature, the inorganic salts were filtered and washed with DCM (dichloromethane 50 ml). The organic solvent was removed on a rotary evaporator to give an oil. The oily product was purified on a flash chromatography column (60 g of SiO 2 eluted with MeOH in DCM). The pure product thus obtained weighed 4.43 g. This oil was dissolved in ethanol and treated with a solution of fumaric acid (1.2 g) in ethanol. The salt crystallized out at room temperature to yield 3.44 g m.p. 154-155°C.

ANALYSIS:

Calculated for C 16 Hi9FN 2 03=C 4

H

4 04: 56.86%C 5.49%H 6.63%N Found: 56.75%C 5.41 %H 6.54%N EXAMPLE 101 N-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]morpholine 15 A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (3.0 g, 13.6 mmol), 2-chloroethyl morpholine hydrochloride (4.46 g, 29.7 mmol) and K 2 C0 3 (7.3 g, 2.2 eq) in acetonitrile (60 ml) was heated at reflux for 24 hours. The crude mixture was diluted with DCM and filtered. The solvent was concentrated to an oil Purification on a silica gel column (55 g, SiO 2 eluted with MeOH:DCM) 20 yielded a solid product weighing 4 g. Recrystallization from hot ethanol yielded 2.1 g m.p. 131-132 0

C.

ANALYSIS:

Calculated for C 18

H

24

FN

3 0 2 64.84%C 7.26%H 12.60%N Found: 64.80%C 7.09%H 12.77%N EXAMPLE 102 N-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]phthalimide A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (5.15 g, 23.4 mmol), K 2 C0 3 (4.2 g, 30.4 mmol) and 2-bromoethyl phthalimide (7.13 g, 28 mmol) in acetonitrile (250 ml) was heated at reflux for 3.5 hours. The solids and solvent were removed. The residue was purified by flash chromatography (SiO 2 110 g, eluted with 2-4% CH 3 0H:DCM). The product thus obtained weighed 7.8 g 134 Part of the material was recrystallized to give 2.35 g of off white crystals, m.p. 148-1490C.

ANALYSIS:

Calculated for C 22

H

20 FN303: 67.17%C 5.12%H 10.68%N Found: 67.01 %C 5.20%H 10.76%N N-[2-[4-(6-Fluoro- 1,2-benzisoxazol-3-yl) -piperidinyl]ethyl]phthalimide hydrochloride To a solution of 8.0 g of N-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1piperidinyl]ethyl]phthalimide in dichloromethane/ethanol (150 ml) was added 1M HCI in ether. The salt crystallized out rapidly. It was filtered off, washed with ethanol and dried to afford 8.15 g with m.p. 257-259°C, dec. Recrystallization provided 7.20 g of pure white salt, with m.p. unchanged.

ANALYSIS:

Calculated for C 22

H

20

FN

3 0 3 .HCI: 61.47%C 4.92%H 9.77%N Found: 61.12%C 5.21%H 9.58%N SEXAMPLE 103 2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1 -piperidinylethyl methyl ether fumarate 20 A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (3.75 g, 17 mmol), S' K 2 C0 3 (3 g, 21.7 mmol), bromoethyl methyl ether (2.84 g, 20.4 mmol) in acetonitrile (150 ml) was heated at reflux for 3.5 hours. The reaction was cooled.

The inorganics were filtered and rinsed with DCM. The organic solution was concentrated down to an oil (7 Purification on a flash chromatography column S 25 (SiO 2 45 g; eluted with methanol/DCM) gave a light yellow oil as product (4 g, This oil was dissolved into ethanol and treated with a solution of fumaric acid (1.67 g) in ethanol (20 ml). White crystals (5.15 g) were collected, m.p. 157-158 0

C.

ANALYSIS:

Calculated for C 15

H

19

FN

2 0 2 oC4H404: 57.86%C 5.88%H 7.10%N Found: 57.53%C 5.94%H 6.94%N EXAMPLE 104 135 4-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]butyl acetate fumarate A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (9.5 g, 41 mmol),

K

2

CO

3 (7.2 g, 51 mmol), and 4-bromobutyl acetate (10 g, 51 mmol) in acetonitrile (200 ml) was heated at reflux for 3.5 hours. At the end of the reaction, the solution was cooled and filtered. The inorganic salt was washed with DCM (50 ml). The organic solvent was removed. The residue was purified on a flash chromatography column (packed with Sorbsil C30 silica gel, 100 g, eluted with DCM, 1 liter, increasing methanol from 2 to 2.51). The material thus purified weighed 12.92 g A small sample (1.67 g) was dissolved in ethanol and treated with 1 equivalent of fumaric acid (580 mg) in ethanol to yield white crystals: 1.8 g, m.p. 142-143°C.

ANALYSIS:

Calculated for Ci8H 2 3

FN

2 0 3

*C

4

H

4 0 4 58.66%C 6.04%H 6.22%N :i Found: 58.56%C 6.02%H 6.13%N EXAMPLE 105 4-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]butanol fumarate A mixture of 4-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]butyl acetate (11.5 g, 34.4 mmol), 15% NaOH (100 ml) and ethanol (100 ml) was heated at 20 reflux for 4 hours. After cooling to room temperature, the base was neutralized with HCI to pH 7. The solution was concentrated down to a small volume ml), then extracted with DCM. The DCM solution was washed with brine and dried over MgS04. The solvent was concentrated to give ~10 g of crude oil. Purification by flash chromatography (Sorbsil C-30, 100 g, eluted with MeOH:DCM, 3 liters) S 25 yielded 9.8 g of white solid. The sample for testing was prepared by treatment of the free base (2.0 g) with fumaric acid (780 mg. 1.0 eq) in ethanol. The crystals were collected and dried: 1.5 g, m.p. 131-132 0

C.

ANALYSIS:

Calculated for C 16

H

21

FN

2 0 2

*C

4

H

4 0 4 58.82%C 6.17%H 6.86%N Found: 58.81%C 6.37%H 6.66%N EXAMPLE 106 4-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]butyl decanoate fumarate 136 To a solution of 4-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]butanol g, 6.84 mmol), triethylamine (1,0 g, 10 mmol) in DCM (70 ml) decanoyl chloride (1.7 g, 8.9 mmol) was added dropwise at room temperature. The mixture was stirred for 1 hour, then was concentrated to a crude solid. The solid was extracted into ethyl acetate, and the insoluble salts were filtered. The solvents were removed. The crude product was purified by flash chromatography (Sorbsil 30 g, eluted with a mixture of MeOH in DCM). The oil thus obtained (2.5 g, 81%) was converted to a fumarate salt with fumaric acid (650 mg, 1.0 eq) in ethanol. Crystals were collected: 1.48 g, m.p. 109-110°C.

ANALYSIS:

Calculated for C 2 6

H

39

FN

2 03SC 4

H

4 04: 64.04%C 7.70%H 4.98%N Found: 64.30%C 7.86%H 4.78%N .EXAMPLE 107 S: 15 3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propyl decanoate fumarate To a solution 3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-l-piperidinyl]propanol (1.81 g, 6.5 mmol) triethylamine (0.9 g, 9.0 mmol) in DCM (45 ml) was added decanoyl chloride (1.5 g, 7.8 mmol) dropwise at room temperature. The mixture was stirred for 20 minutes, then concentrated down to a crude solid. The solid 20 was extracted into EtOAc (20 ml), and the insoluble salts were filtered. The EtOAc was removed. The crude oil was purified by flash choursomatography (Sorbsil C-30, 30 g; eluted with MeOH:DCM). The oil thus obtained (2.54 g, was converted to a fumarate salt with fumaric acid (670 mg) in ethanol. The crystals collected weighed 1.61 g, m.p. 100-102°C.

S" 25 ANALYSIS: Calculated for C 25

H

27

FN

2 03C4H404: 63.52%C 7.54%H 5.11%N Found: 63.63%C 7.74%H 5.03%N EXAMPLE 108 N,N-Diethyl-4-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-l-piperidinylbutyl carbamate fumarate To a mixture of 4-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-l-piperidinyl]butanol (1.55 g, 5.3 mmol) potassium t-butoxide (750 mg, 6.7 mmol) in THF (100 ml), 137 diethylcarbamyl chloride (900 mg, 6.63 mmol) was added dropwise at room temperature. The mixture was stirred for 2 hours, then the solvent was removed.

The residue was extracted into DCM. The DCM solution was washed with brine and dried over MgSO4. The solution was concentrated. The product was purified on a flash chromatography column (SiO 2 14 g, eluted with 2% MeOH in DCM), to yield 1.84 g of oil. This oil was dissolved into ethanol ml) and treated with a solution of fumaric acid (850 mg, 1.0 eq) in ethanol. Crystallization was induced with a small volume of isopropyl ether to produce 2.09 g, m.p. 152-153 0

C.

ANALYSIS:

Calculated for C 21

H

30

FN

3 03*C 4

H

4 04: 59.16%C 6.75%H 8.28%N Found: 59.17%C 6.84%H 8.16%N EXAMPLE 109 1 N-Methyl-4-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1 -piperidinyl]butyl carbamate 15 fumarate To a mixture of 4-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]butanol (1.84 g, 6.3 mmol), K 2 C0 3 (850 mg) in chloroform, methyl isocyanate (448 mg, 7.7 mmol and 360 mg, 6.2 mmol) was added dropwise in two portions. The mixture was filtered and concentrated to a crude oil. Purification was done on a S: 20 flash chromatography column (SiO 2 11 g, eluted with 2% CH30H in DCM) to yield a light yellow oil (2.05 g, This oil was dissolved into ethanol and treated with a solution of fumaric acid (800 mg, 1.0 eq). Crystallization was induced with drops of isopropyl ether. Weight: 1.36 g, m.p. 96-98 0

C.

ANALYSIS:

Calculated for C 18

H

24

FN

3 03OC 4 H404: 56.76%C 6.06%H 9.02%N Found: 56.27%C 6.03%H 8.86%N EXAMPLE 110 2-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-1,3-dioxane fumarate A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.0 g, 9.1 mmol),

K

2 C0 3 (1.5 g, 10.9 mmol) and bromoethyl-1,3-dioxane (2.1 g, 10.7 mmol) in acetonitrile (50 ml) was heated at reflux for 3 hours. At the end, the insolubles were filtered and rinsed with DCM and the filtrate was evaporated down. The 138 crude mixture was purified by flash chromatography over a silica gel column (Sorbsil C-30, 25 g; eluted with DCM and MeOH in DCM). The fractions containing the pure product were combined and concentrated to give 3.13 g of oil.

The oil was treated with a fumaric acid (1.0 g) ethanol solution. The crystals were collected: 3.98 g m.p. 161-162 0

C.

ANALYSIS:

Calculated for C 8

H

23

FN

2 0 3 oC 4

H

4 0 4 58.66%C 6.04%H 6.22%N Found: 58.69%C 5.96%H 6 6.20%N EXAMPLE 111 2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl-1 -piperidinyl]ethanol hemifumarate.

2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-I -piperidinyl]ethyl acetate 2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl acetate was 15 prepared according to Example 115.

S 2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl-1-piperidinyl]ethanol hemifumarate 2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-l-piperidinyl]ethyl acetate (10.58 g, 34.6 mmol), 15% NaOH (100 ml) and ethanol (100 ml) was heated at reflux for 4 20 hours. The solution was cooled and neutralized with HCI to pH-7. The ethanol was removed under reduced pressure. The aqueous solution was basified with NaHCO 3 and extracted with DCM (2 x 200 ml). The DCM solution was washed with brine and dried over MgSO 4 and evaporated to give a white solid: 6.88 g A sample (2.03 g) was dissolved in ethanol and treated with 25 fumaric acid (660 mg, 1.0 eq). Crystallization was induced with drops of isopropyl ether to yield off-white crystals: 1.43 g, m.p. 159-161 C.

ANALYSIS:

Calculated for C14H17FN 2 02*0.5C 4

H

4 0 4 59.62%C 5.94%H 8.69%N Found: 59.55%C 5.95%H 8.53%N EXAMPLE 112 2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl decanoate fumarate 139 A mixture of 2 -[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl alcohol (1.6 g, 5 mmol) and triethylamine (800 mg, 8 mmol) in chloroform (100 ml) was treated with decanoyl chloride (1.3 g, 7.2 mmol) dropwise at room temperature.

The mixture was stirred for 4 hours. The solvent was removed to leave a crude solid. The solid was dissolved into a small amount of DCM (15 ml), then was filtered. The solution was concentrated. The purification was done by flash chromatography over a silica gel column (Sorbsil C-30, 30 g; eluted with MeOH: DCM). The purified oil (2.45 g, 95%) was treated with a fumaric acid (660 mg, eq)/ethanol solution (15 ml). Crystallization was induced by adding drops of ether; yield: 1.97 g, m.p. 109-110oC.

ANALYSIS:

Calculated for C24H 35

FN

2 0 3 SC4H 4 0 4 62.90%C 7.35%H 5.24%N Found: 62.93%C 7.30%H 5.14%N EXAMPLE 113 N,N-Diethyl-2-[4-(6-fluoro-1, 2 -benzisoxazol-3-vl)- 1 -iperidinyllethvl carbamate fumarate To a mixture of 2 -[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1 -piperidinyl]ethanol (1.6 g, 6 mmol) and potassium t-butoxide (850 mg, 7.6 mmol) in THF (100 ml) diethyl carbamyl chloride (1.03 g, 7.5 mmol) was added dropwise at room temperature. The mixture was stirred for 4 hours. The reaction mixture was S: concentrated to a crude solid. The solid was dissolved in DCM and purified on a flash chromatography column (Sorbsil C-30, 27 g; eluted with a MeOH:

DCM

mixture). The product thus purified as a light oil (2.2 g, 91%) was dissolved into 25 ethanol and treated with a fumaric acid (690 mg, 1.0 eq)/ethanol solution (15 ml).

Crystallization on cooling yielded 2.15 g of white crystals, m.p. 133-135oC.

ANALYSIS:

Calculated for Ci9H 26 FN30 3

.C

4 H404: 57.61%C 6.31%H 8.76%N Found: 57.49%C 6.25%H 8.54%N EXAMPLE 114 2-[4-[(6-Fluoro-1,2-benzisoxazol-3-yl)-1 -iDeridinyllethyllamine hemifumarate ;i

I'

140 N-[4-(6-fluoro- 1,2-benzisoxazol-3-yl)-1 -piperidinyl]ethyl phthalimide N-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl phthalimide was prepared according to Example 117.

2-[4-[(6-Fluoro- 1,2-benzisoxazol-3-yl)-1 -piperidinyl]ethylamine hemifumarate A mixture of 2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl phthalimide (4.6 g, 11.7 mmol) and hydrazine monohydrate (1.17 g, 23.4 mmol) in methanol (50 ml) was heated at reflux overnight. At the end of the reaction, methanol was removed to leave a crude solid. This was stirred with water (150 ml) and acidified with HCI to pH 2. The insolubles were filtered. The aqueous solution was basified with 50% NaOH then extracted with DCM (2 x 250 ml). The DCM solution was washed with brine and dried over MgSO 4 The solvent was removed to produce a colorless oil: 2.12 g. This oil was treated with a solution of 15 fumaric.acid (935 mg, 1.0 eq) in ethanol. The salt crystallized out: 0.99 g, m.p. 203-205°C. A second crop of 0.73 g 198-200°C) was collected later.

ANALYSIS:

Calculated for C 1 4

H

1 8

FN

3 00.5C 4

H

4 0 4 59.80%C 6.27%H 13.07%N Found: 59.51 %C 6.35%H 13.31 %N EXAMPLE 115 :4 2-[4-(6-Fluoro-1,2-benzisoxazol-3-vl)-1-piDeridinvllethl decanamide fumarate To a mixture of 2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl] ethylamine (1.49 g, 5.5 mmol) and triethylamine (1.0 g, 10 mmol) in chloroform (50 ml) decanoyl chloride (1.26 g, 6.6 mmol) was added at room temperature.

The mixture was stirred for 3 hours at room temperature. The solvent was stripped down to a crude mixture. This crude mixture was purified by flash chromatography over a silica gel column (SiO 2 20 g; eluted with a solution of MeOH in DCM). The fractions containing the pure product were pooled and concentrated to give 2.3 g of oil. This oil was converted to a fumarate salt by treatment with fumaric acid (655 mg) in ethanol. The ethanol was concentrated down to a small volume and 3 volumes of isopropyl ether was added. This 141 mixture was stirred overnight to cause crystallization. The solids were collected, weighed: 1.83 g m.p. 108-110°C.

ANALYSIS:

Calculated for C 24

H

36

FN

3 0 2

*C

4

H

4 0 4 63.02%C 7.56%H 7.87%N Found: 62.42%C 7.58%H 7.66%N EXAMPLE 116 2-f4-(6-Fluoro-1,2-benzisoxazol-3-vl)-1-piDeridinvllethyl acetamide fumarate A mixture of 2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl] ethylamine (2.56 g, 9.7 mmol) and triethylamine (1.45 g, 14.5 mmol) in DCM (50 ml) was treated with dropwise addition of acetyl chloride (1.0 g, 12.7 mmol) at room temperature. The mixture was stirred for 4 hours at room temperature. The i reaction mixture was diluted with DCM and washed with brine. The organic solution was dried over MgSO 4 and concentrated to a crude oil. The crude oil was 15 purified by flash chromatography over a silica gel column (SiO 2 20 g; eluted with

CH

3 OH in DCM). The pure product thus obtained weighed 1.36 g It was converted to a fumarate salt by treatment with fumaric acid (517 mg) in ethanol. Recrystallization from ethanol gave white crystals; weight: 1.53 g, m.p. S 132-1330C.

20 ANALYSIS: Calculated for C 16

H

20

FN

3 0 2

C

4

H

4 0 4 57.00%C 5.74%H 9.97%N Found: 57.05%C 5.85%H 9.95%N o* EXAMPLE 117 2-[[2-[4-(6-Fluoro-1,2-benzisoxazol-3-vl)-1 -Dieridinvllethyllaminolethyl acetate fumarate A mixture of 2-[4-[(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]amine g, 7.6 mmol), K2C0 3 (1.38 g, 10 mmol) and bromoethyl acetate (1.40 g, 8.3 mmol) in acetonitrile (50 ml) was heated at reflux for 4 hours. At the end, the insolubles were filtered off and rinsed with DCM. The solvent was evaporated down. The crude mixture was purified by flash chromatography over a silica gel column (Sorbsil C-30, 30 g; eluted with 2% CH 3 OH in DCM, 800 ml). The oil (1.15 g) thus obtained was treated with a solution of fumaric acid (358 mg) in ethanol.

142 Crystallization was induced by adding drops of ethyl ether, yield: 1.09 g, m.p. 116-118"C.

ANALYSIS:

Calculated for C 18

H

24

FN

3 0 3

C

4

H

4 0 4 56.77%C 6.06%H 9.03%N Found: 56.32%C 5.97%H 8.94%N EXAMPLE 118 Methyl 2-[4-[(6-fluoro-1.2-benzisoxazol-3-vl)-1-piDeridinvllethyl carbamate fumarate A mixture of 2-[4-[(6-fluoro-1,2-benzisoxazol-3-yl)-1 -piperidinyl]ethyl]amine g, 7.6 mmol) and triethylamine (1.0 g, 10 mmol) in DCM (50 ml) was treated with methyl chloroformate (860 mg, 9.12 mmol) dropwise at room temperature.

The mixture was stirred for 1 hour. The reaction mixture was diluted with DCM and washed with brine. The organic solution was dried over MgSO 4 and 15 concentrated to a crude oil. The purification was done by flash chromatography over a silica gel column (28 g of Sorbsil C-30, eluted with DCM and MeOH/DCM).

The pure oil thus obtained weighed 2.34 g. It was converted to a fumarate salt by treatment with fumaric acid (840 mg, 1.0 eq) in ethanol. Crystallization was induced by adding drops of isopropyl ether, yield: 2.31 g, m.p. 163-1650C.

20 ANALYSIS: Calculated for C 16

H

20

FN

3 0 3

C

4

H

4 0 4 54.92%C 5.53%H 9.61%N Found: 54.49%C 5.45%H 9.24%N EXAMPLE 119 Z-2-[2-[4-(6-Fluoro-1.2-benzisoxazol-3-vl)-1 -piDeridinvllethvllhexahvdro-1

H-

isoindole-1,3-dione fumarate A mixture of I -(2-aminoethyl)-4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (3.77 g, 14.3 mmol) and cis-1,2-cyclohexane-dicarboxylic anhydride (2.82 g, 18.2 mmol, 1.25 eq) in dry pyridine (50 ml) was heated at 65 0 C for 48 hours. The dark brown solution was concentrated to dryness on a rotary evaporator. The crude residue was purified twice by flash chromatography over a silica gel column (SiO 2 45 g and 50 g, eluted with DCM and 1% CH 3 OH in DCM). The pure product thus obtained 2.35 g was converted to the fumarate salt by 143 treatment with fumaric acid (660 mg) in ethanol. The crystals after two recrystallizations weighed 1.37 g, m.p. 172-173°C.

ANALYSIS:

Calculated for C 22

H

26

FN

3 03*C 4

H

4 04: 60.57%C 5.87%H 8.15%N Found: 60.40%C 5.55%H 7.82%N EXAMPLE 120 (S)-(+)-3-[4-(6-Fluoro-1,2-benzisoxazol-3-vl)-1 -piperidinvll-2-methl- 1-propanol fumarate A mixture of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (7.2 g, 32.7 mmol), (S)-(+)-3-bromo-2-methyl-1-propanol (5.0 g, 32.6 mmol), K 2 C0 3 (7.19 g, 52 mmol) in acetonitrile (250 ml) was heated at reflux overnight. The insolubles were filtered off. The solvent was removed at reduced pressure and the crude residue S: was purified by silica gel chromatography (SiO 2 84 g, eluted with 21 of 1% 15 CH 3 OH in DCM) to give the target compound as an off-white solid (8.83 g, 94%).

A sample of 1.7 g was converted to the fumarate salt by treatment with fumaric Sacid (710 mg) in ethanol. Recrystallization from ethanol yielded 1.74 g of white crystals, m.p. 119-121°C.

ANALYSIS:

Calculated for C 20

H

25

FN

2 0 6 58.82%C 6.17%H 6.86%N Found: 58.81 %C 6.24%H 6.76%N EXAMPLE 121 4-(6-Fluoro-1.2-benzisoxazol-3-vl)--1[3-(1-piperidinvl)roDvllpiperidine difumarate A mixture of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (3.0 g, 13.6 mmol), N-(3-chloropropyl)piperidine hydrochloride (4.05 g, 20.4 mmol), K 2

CO

3 (6 g, 43.4 mmol), tetrabutylammonium hydrogen sulfate (phase transfer catalyst, 2.3 g) in acetonitrile (100 ml) and water (15 ml) was heated at reflux for 16 hours. The mixture was washed with brine and the layers were separated. The organic solution was concentrated. The crude product (6.4 g) was purified by flash chromatography over a silica gel column (55 g, sorbsil C-30; eluted with 2% CH30H:0.5% DEA in DCM, 1.41). The oil thus purified (4.5 g) was treated with fumaric acid (1.6 g) in ethanol. The solid was collected: weight 3.1 g, m.p.178- 144 181 C. Recrystallization from ethanol yielded 2.28 g of white crystals, m.p. 190- 192 0

C.

ANALYSIS:

Calculated for C 2 0H 24

FN

3 02oC 4

H

4 04: 58.22%C 6.28%H 7.27%N Found: 58.39%C 6.36%H 7.34%N EXAMPLE 122 1-(3-Dimethylaminopropyl)-4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine difumarate A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (3.05 g, 13.8 mmol), 3-dimethylaminopropyl chloride hydrochloride (3.4 g, 21 mmol), K 2 C0 3 (6.2 g, 45 mmol), tetrabutylammonium hydrogen sulfate (phase transfer catalyst, g) in acetonitrile (100 ml) and water (50 ml) was heated at 60 0 C overnight.

The aqueous phase was separated, and acetonitrile was removed at reduced pressure. The residue was extracted into DCM. The organic solution was washed 15 with H 2 0 and brine, then dried with MgSO 4 The solvent was removed and the crude product (4.3 g) was treated with fumaric acid (1.58 g, 1.0 eq) in dilute ethanol. The crystals were collected (2.53 m.p. 192-194"C. Recrystallization from ethanol yielded 2.08 g of white crystals, mp 194-195°C.

ANALYSIS:

20 Calculated for C 17

H

24

FN

3 0 2 oC 4 H404: 55.86%C 6.00%H 7.82%N Found: 56.11%C 5.94%H 7.86%N EXAMPLE 123 (R)-(-)-3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1 -piperidinyl]-2-methyl-1 -propanol fumarate A mixture of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (14.5 g, 65 mmol),

K

2 CO3 (10 g, 72 mmol). (R)-(-)-3-bromo-2-methyl-1-propanol (10 g, 65.3 mmol), tetrabutylammonium hydrogen sulfate (1.27 g, phase transfer catalyst) in acetonitrile (300 ml) and H 2 0 (5 ml) was heated at reflux for 6 hours. The mixture was cooled and the solvent was removed on rotary evaporator. The residue was extracted into methylene chloride (DCM), and the insolubles were filtered. After concentration of the extract, the crude product was purified by flash chromatography over a silica gel column (SiO 2 150 g; eluted with DCM, 1 I; 2% 145

CH

3 OH in DCM, 1.61). The material thus purified weighed 17 g The sample for testing was prepared by treatment of a sample (2.28 g) with fumaric acid (953 mg) in ethanol. The crystals formed slowly upon addition of isopropyl ether. These were collected and dried: weight 1.84 g, m.p. 114-115°C.

ANALYSIS:

Calculated for C 16

H

2 1

FN

2 0 2 oC 4

H

4 0 4 58.82%C 6.17%H 6.86%N Found: 58.48%C 6.08%H 6.57%N EXAMPLE 124 -Methoxyethyl)-2-hydroxyphenoxyl propyl]-4-piperidinyl]-6-fluoro-1,2benzisoxazole A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (5.7 g, 26.0 mmol), 4-(3-chloropropoxy)-3-hydroxy-a-methylbenzenemethanol (6.0 g, 26.0 mmol), NaHCO 3 (2.4 g, 28.6 mmol), KI(200 mg) and CH 3 CN (150 ml) was stirred 15 at reflux under N 2 for 17 hours. A TLC showed a trace of the alkylating side chain, therefore additional 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (0.6 g, 2.7 mmol) and NaHCO 3 (0.22 g, 2.6 mmol) was added and the reaction was refluxed 3 hours longer. The cooled reaction was concentrated and the residue was partitioned between EtOAc and H 2 0. The EtOAc extract was washed with H 2 0 20 then brine and after drying with MgSO 4 the extract was concentrated to yield 11.9 g of a beige oil. The sample was purified by preparative HPLC (Water's Associates Prep LC/System 500 utilizing 2 silica gel columns and eluting with MeOH-CH 2 Cl 2 Concentration of later fractions afforded 4.2 g of 4-[3-[4-(6-fluoro- 1,2-benzisoxazol-3-yl)-l-piperidinyl]propoxy]-3-hydroxy-amethylbenzenemethanol. Concentration of earlier fractions gave 4.0 g of a mixture of 4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3hydroxy-a-methylbenzenemethanol and -methoxyethyl)-2-hydroxyphenoxy]propyl]-4-piperidinyl]-6-fluoro-1,2-benzisoxazole (the latter was apparently formed by the reaction of the former with MeOH on silica gel). The mixture was dissolved in anhydrous Et20 (330 ml) and anhydrous MeOH (100 ml) and ethereal HCI was added. After stirring 1.5 hours, anhydrous Et20 was added and the resultant solid was collected and dried to yield 2.9 g of a mixture of the respective HCI salts. The solid was suspended in H 2 0 and was basified with

NH

4 0H. The aqueous mixture was extracted with CH 2

CI

2 and the extract was washed with H 2 0, dried with MgSO 4 and concentrated to yield 2.7 g of a light beige oil. The oil was purified by preparative HPLC (Water's Associates Prep LC/System 500 using 2 silica gel columns and 3% MeOH-CH 2

CI

2 as eluent).

Concentration of later fractions yielded 0.5 g of 4-[3-[4-(6-fluoro-1,2-benzisoxazol- 3-yl)-1-piperidinyl]-propoxy]-3-hydroxy-a-methylbenzenemethanol. Concentration of earlier fractions gave an oil that solidified upon standing. The product was triturated with heptane and filtered to yield 1.2 g of a white powder. The compound was recrystallized from EtOH to provide 1.1 g of methoxyethyl)-2-hydroxyphenoxy]propyl]-4-piperidinyl]-6-fluoro-1,2-benzisoxazole as clean white crystals m.p. 98-1000C.

ANALYSIS:

Calculated for C 24

H

29

FN

2 0 4 67.27%C 6.82%H 6.54%N Found: 67.18%C 6.84%H 6.54%N EXAMPLE 125 6-Fluoro-3-1-[3-1(1 H-indol-5-vl)oxylDroDvil-4-piperidinvll 1 2-benzole A mixture of 6-fluoro-3-(4-piperidinyl)-l,2-benzisoxazole (2.6 g, 11.8 !20 mmol), K 2 C0 3 (1.6 g, 11.6 mmol), KI (200 mg), 5-(3-chloropropoxy)indole (2.2 g, 10.5 mmol) and CH3CN (100 ml) was stirred at reflux under N2 for 18 hours. The cooled reaction was poured into H 2 0 and the aqueous mixture was extracted with EtOAc. The EtOAc extract was washed 2 times with H 2 0, 2 times with brine and after drying with MgSO 4 the solvent was removed in vacuo to yield 5.1 g of a dark oil. The oil was purified by preparative HPLC (Water's Associates Prep LC/System 500, using 2 silica gel columns and 4% MeOH-CH 2 Cl2 as eluent) to afford 2.65 g of a beige solid. Recrystallization from ethanol gave 2.2 g of a beige powder, m.p. 118-121

C.

ANALYSIS:

Calculated for C 23

H

24

FN

3 0 2 70.21%C 6.15%H 10.68%N Found: 69.80%C 6.21 %H 10.78%N _1 1--11 147 EXAMPLE 126 6-Fluoro-3-1 -[3-(isoauinol-5-vloxvloropyll-4-DiDeridinvll-1,2-benzisoxazole sesquifumarate A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.8 g, 13 mmol), 5-(3-chloropropoxy)isoquinoline (2.8 g, 13 mmol), K 2

CO

3 (1.7 g) and

CH

3 CN (50 ml) was refluxed for 16 hours. The reaction was filtered and the filtrate was concentrated to an oil. The filter cake was treated with H 2 0, and the aqueous suspension was extracted with CH 2

CI

2 The filtrate was also extracted with

CH

2

CI

2 and the extracts were combined, washed (H 2 dried (K 2 CO) and concentrated to yield 5.4 g of a brown oil. The oil was purified by HPLC on silica gel columns, eluting with CH 2

CI

2 /MeOH to afford 2.3 g of a yellow oil. The oil was dissolved in EtOAc and fumaric acid (0.66 g, 1 eq) was added. The mixture was refluxed briefly, and then stirred at ambient temperature for 16 hours.

The resulting white solid was collected to afford 2.2 g of the fumarate salt. The 15 compound was recrystallized from DMF to yield 1.4 g of the isoquinoline as a sesquifumarate, m.p. 213-2150C.

S ANALYSIS: Calculated for C 3 0

H

3 0

FN

3 0O: 62.17%C 5.22%H 7.25%N Found: 62.01%C 5.11%H 7.28%N EXAMPLE 127 e. f6-Fluoro-3-1 H-indol-4-vl)oxyloropvl-4-Diperidinvl-1,2-benzisoxazole A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (3.5 g, 16 mmol),

K

2 C0 3 (2.2 g, 16 mmol), KI (200 mg), 4-(3-chloropropoxy)indole (3.0 g, 14 mmol) and CH 3 CN (100 ml) was stirred at reflux under N 2 for 7 hours and then at ambient temperature for 68 hours. Reflux was resumed for an additional 6 hours whereupon a TLC revealed incomplete reaction. K 2 C0 3 (0.5 g, 4 mmol) was added and the reaction was stirred at reflux for 17 hours. The cooled reaction was poured into H 2 0 and the aqueous mixture was extracted with EtOAc. The organic extract was washed with H 2 0 and saturated NaCI and after drying over MgSO 4 the solvent was removed to afford 5.7 g of a beige solid. The product was purified by preparative HPLC (Water's Associates Prep LC/System 500 using 2 silica gel columns and 4% MeOH-CH 2 CI2 as eluent) to yield 3.4 g of a beige solid.

148 Two consecutive recrystallizations from EtOH provided 2.3 g of a white powder, m.p. 129-131*C.

ANALYSIS:

Calculated for C 23

H

24

FN

3 0 2 70.21%C 6.15%H 10.68%N Found: 69.90%C 6.15%H 10.65%N EXAMPLE 128 6-Fluoro-3-[1-[3-[(6-methoxy-1 H-indol-5-yl)oxy]propyl]-4-piperidinyl]-1,2benzisoxazole hemifumarate A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (3.0 g, 14 mmol), 5-(3-chloropropoxy)-6-methoxyindole (3.0 g, 13 mmol), K 2

CO

3 (2.1 g, 14 mmol), KI (200 mg) and CH 3 CN (150 ml) was stirred at reflux under N 2 for 48 hours. The cooled reaction was poured into H 2 0 and the aqueous mixture was extracted with EtOAc. The EtOAc extract was washed with H 2 0 and brine and was dried with 15 MgSO 4 Removal of the solvent in vacuo gave 5.6 g of a dark oil. The oil was purified by preparative HPLC (Water's Associates Prep LC/System 500 using 2 silica gel columns and 2% Et 2 NH-EtOAC as eluent) to yield 2.5 g of a beige solid. Recrystallization from EtOH afforded 2.0 g of an off white powder. A 1.8 g (4 mmol) sample was dissolved in warm EtOAc and fumaric acid (0.5 g, 4 mmol) S 20 was added. The reaction was stirred at ca 40 0 C for 30 minutes and was then allowed to gradually cool to ambient temperature. The resultant hemifumarate salt was collected and dried to yield 2.0 g. The product was recrystallized from EtOH to provide 1.5 g of a light beige powder m.p. 186-188 0

C.

ANALYSIS:

Calculated for C 26

H

28

FN

3 0 5 64.84%C 5.87%H 8.73%N Found: 64.22%C 5.85%H 8.55%N EXAMPLE 129 1 -[4-[3-[4-(6-Fluoro-1,2-benzisothiazol-3-yl)-1 -piperidinyl]propoxy]-3hydroxyphenyl]ethanone A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisothiazole (2.4 g, 10.1 mmol), 1-[4-(3-chloropropoxy)-3-hydroxyphenyl]ethanone (2.5 g, 11.1 mmol), NaHCO 3 (0.94 g, 11.1 mmol), KI (100 mg) and CH 3 CN (100 ml) was stirred at 149 reflux under N 2 for 65 hours. The cooled reaction was poured into H 2 0 and the aqueous mixture was extracted with EtOAc. The EtOAc extract was washed with

H

2 0 (Ix) and brine (3x) and after drying with MgSO 4 the solvent was evaporated to give 4.2 g of a dark solid. Three consecutive recrystallizations from EtOH provided 2.1 g of glittery beige crystals m.p. 135-1370C.

ANALYSIS:

Calculated for C 23

H

25

FN

2 0 3 S: 64.47%C 5.88%H 6.54%N Found: 64.44%C 5.69%H 6.29%N EXAMPLE 130 4-r3-4-(6-Fluoro-1.2-benzisothiazol-3-yl)-1 -pDieridinvllpropoxy-3-methoxy-amethylbenzenemethanol To a stirred solution of 1-[4-[3-[4-(6-fluoro-1,2-benzisothiazol-3-yl)-l- S0:0: piperidinyl]propoxy]-3-methoxyphenyl]ethanone (4.1 g, 9.3 mmol) in 60 ml MeOH- 15 THF under N 2 at ambient temperature, NaBH 4 (0.386 g, 10.2 mmol) was added portionwise. After complete addition, the reaction was stirred for 3.5 hours and was concentrated to yield a white gum. This was triturated with H 2 0 (2x) and the aqueous fraction was decanted away. Residual water was removed under high vacuum to afford 5.0 g of a white powder. The compound was taken up in 20 boiling toluene and the insolubles were filtered away. Concentration of the toluene filtrate afforded 3.8 g of a beige solid. Purification via preparative

HPLC

(Water's Associates prep LC/System 500, using 2 silica gel columns and 2% Et 2 NH-EtOAc) provided 2.7 g of a light beige solid. The product was recrystallized 0 from EtOAc to afford 1.7 g of a pure white powder, m.p. 113-115°C.

ANALYSIS:

Calculated for C 24

H

29

FN

2 0 3 S: 64.84%C 6.58%H 6.30%N Found: 64.85%C 6.44%H 6.19%N EXAMPLE 131 (R)-(-)-3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1 -piperidinyl]-2-methyl-1 -propyl acetate fumarate To a mixture of (R)-(-)-3-[4-(6-fluoro-l,2-benzisoxazol-3-yl)-l-piperidinyl]-2methyl-1-propanol (3.2 g, 11 mmol), triethylamine (3.2 g, 11 mmol) in DCM (100 150 mi), acetyl chloride (890 mg, 11.3 mmol) was added dropwise at 0"C. The mixture was stirred at room temperature for 4.5 hours. The solvent was removed on a rotary evaporator. The triethylamine HCI salt was filtered off using a small amount of DCM. The crude product was dissolved in DCM was purified by flash chromatography over a silica gel column (SiO 2 30 g; eluted with DCM and 1%

CH

3 0H in DCM). The oil, thus purified, weighed 2.11 g This oil was treated with a solution of fumaric acid (695 mg, 1.0 eq.) in ethanol to give the fumarate salt. Recrystallization from ethanol and isopropyl ether again yielded white crystals, 2.09 g, m.p. 118-120 0

C.

ANALYSIS:

Calculated for C 18

H

23

FN

2 03OC4H404: 58.66%C 6.04%H 6.22%N Found: 58.53%C 5.76%H 8.91%N EXAMPLE 132 15 ,2-benzisoxazol-3-yl)- 1 piperidinyl2-methyl-l-propoxy- 3-methoxyphenyl]ethanone fumarate 2-benzisoxazol-3-yl)- -piperidinyl]-2-methyl- -propyl methanesulfonate 20 To a mixture of (R)-(-)-3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1 -piperidinyl]-2methyl-1-propanol (7.26 g, 24.8 mmol), triethylamine (3 ml, 30 mmol) in methylene chloride (DCM, 120 mi), methanesulfonyl chloride (3.13g, 27.3 mmol) ~was added dropwise at 0CC. The mixture was stirred at room temperature for 1 hour, then concentrated down to a crude mixture. Triethylamine hydrochloride salt was removed by filtration with DCM/ether as solvent. The crude oily mixture was purified with a flash chromatography column (SiO 2 90 g; eluted with DCM). The colorless oil, which is the methanesulfonate ester, weighed 6.48 g and was used directly in the following step.

2-benzisoxazol-3-yl)-1-piperidinyl]-2methylproproxy]-3-methoxyphenyl]ethanone fumarate A solution of the above methanesulfonate (6.48 g, 175 mmol) in DMF mi) was added in one portion to an aged (hour) cold mixture of acetovanillone (4.13 g, 24.9 mmol) and sodium hydride (670 mg, 26.5 mmol) in DMF (40 ml) at 0°C. The resulting mixture was warmed to -50OC briefly and stirred at room temperature for 16 hours. The mixture was extracted into DCM (500 ml) and washed twice with water, then brine. The organic solution was dried over MgSO4 and concentrated to an oil. This crude mixture was purified twice by flash chromatography over a silica gel column. The material thus purified weighed 5.37 g. The fumarate salt was prepared by treatment of purified oil with fumaric acid eq.) in ethanol and ether. Slightly off-white crystals were collected: 3.76 g m.p. 141-1420C.

ANALYSIS:

Calculated for C 25

H

29

FN

2 04OC 4

H

4 04: 62.58%C 5.98%H 5.03%N Found: 62.52%C 5.75%H 4.96%N EXAMPLE 133 i 15 3-[4-(6-Fluoro-1 2-benzisoxazol-3-vl)-1 -piperidinvll-2,2-dimethyl-1 -propanol fumarate A mixture of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (3.0 g, 13.6 mmol), K 2

CO

3 (12.5 g, 17.5 mmol), 3-bromo-2,2-dimethyl-1-propanol (3 g, 21 mmol, 1.5 tetra-butylammonium hydrogen sulfate (1 g, phase transfer 20 catalyst) in water (5 ml) and acetonitrile (150 ml) was heated at reflux for 43 days.

TLC showed a small spot for the expected product. The mixture was diluted with EtOAc (400 ml) and washed with brine. The organic solution was dried and concentrated to a dark brown mixture. The crude mixture was purified carefully by flash chromatography (SiO2, 95 g to afford the dried pure product; 260 mg, as an oil. This oil was converted to the fumarate salt by treatment with fumaric acid (98.5 mg, 1.0 eq.) in ethanol. Recrystallization from ethanol:ether yielded 210 mg of white crystals, m.p. 144-1450C.

ANALYSIS:

Calculated for C 17

H

23

FN

2 02OC4H404: 59.70%C 6.44%H 6.63%N Found: 59.52%C 6.38%H 6.52%N 152 EXAMPLE 134 1 -(S)-(+)-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1 -piperidinyl]-2-methyl- 1propoxyl]-3-methoxyphenyl]ethanone fumarate (S)-(+)-3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-methyl-1propyl methanesulfonate To a mixture of (S)-(+)-3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1 -piperidinyl]- 2-methyl-1-propanol (8.8 g, 30 mmol), triethylamine (3.2 g, 32 mmol) in dichloromethane (DCM, 150 ml), methanesulfonyl chloride (4 g, 35 mmol) was added dropwise at OC over 10 minutes. The mixture was stirred at room temperature for 1 hour, then concentrated. Triethylamine HCI salt was filtered off with a little DCM as solvent. The crude oil was purified with a flash chromatography column (SiO 2 90 g; eluted with DCM). The colorless oil thus purified weighed 5.28 g was used immediately in the following step.

S 2-benzisoxazol-3-yl)-1-piperidinyl]-2-methyl- Vo00&proproxy]-3-methoxyphenyl]ethanone fumarate A solution of (S)-(+)-3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1 -piperidinyl]-2methyl-1-propyl methanesulfonate (5.28 g, 14.27 mmol) in dimethylformamide 20 (DMF, 10 ml) was added in one portion to an aged (1 hour) cold mixture of acetovanillone (3.55 g, 33.1 mmol) and sodium hydride (530 mg, 22 mmol) in DMF (35 mi) at 0 0 C under N 2 The reaction was stirred overnight (16 hours.) at room temperature. The mixture was diluted with EtOAc and washed with H 2 0 (2 times) and brine. The organic solution was dried and concentrated to an oil (9.4 The crude oil mixture was purified by flash chromatography (SiO 2 60 The oil thus purified weighed 4.3 g, and was converted to the fumarate salt (fumaric acid, 1.13 g) in ethanol. Recrystallization from ethanol gave 1.36 g of white crystals, m.p. 163-165*C.

ANALYSIS:

Calculated for C 25

H

29

FN

2 0 4

OC

4

H

4 0 4 62.58%C 5.98%H 5.03%N Found: 62.40%C 5.84%H 4.92%N 153 EXAMPLE 135 2-[4-(6-Fluoro-1,2-benzisoxazol- 3 -yl)-l-piperidinyllethyl thioacetate fumarate To a stirred solution of 0°C of triphenlyphosphine (13.3 g, 50 mmol) in THF (150 ml), diisopropylazodicarboxylate (10.2 ml, 50 mmol) was added dropwise.

After stirring at 0°C for 0.5 hour, a solution of 6-fluoro-3-[1-(2-hydroxyethyl)- 4 piperidinyl]-1,2-benzisoxazole (8.5 g, 32 mmol) and thioacetic acid (10.2 ml, 0.14 mol) in DMF (35 ml) was added dropwise. The reaction was then stirred at ambient temperature for 16 h, and then it was concentrated at 60 0 C, under vacuum, to yield a red oil. The oil was triturated with H 2 0, and then it was flash chromatographed on silica gel, eluting first with CH 2

CI

2 and then with 10% MeOH-

CH

2 CI2. The appropriate fractions were concentrated to yield 16.5 g of an oil. The oil was triturated with Et20 and the solid (reaction by-products) that formed was removed by filtration. The filtrate was treated with fumaric acid (4.3 and 7.2 g of the fumarate salt of the desired product was obtained as an off white solid. The salt was recrystallized from EtOAc and then twice from EtOH to afford 1.0 g of the thioacetate as an off white solid, m.p. 118-120C.

EXAMPLE 136 SN-2-4-(6-Fluoro-1,2-benzisoxazol- 3 -l)-I-piperidinyleth- 4 20 dichlorophthalimide A mixture of 2-[4-[(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]amine (2.83 g, 10.7 mmol) and 4,5-dichlorophthalic anhydride (2.56 g, 11.93 mmol, 1.1 eq) in methylene chloride (100 ml, DCM) was stirred for 2 h, white solids precipitated and the TLC showed disappearance of the starting material. The solvent was removed, and the crude solid was loaded onto a flash chromatography column (28 g, SiO 2 sorbsil C-30, eluted with 1% MeOH in DCM; of NH 4 0H was added towards the end of elution). The material thus purified weighed 2.26 g as white crystals. Recrystallization twice from a large volume of hot ethanol (400 ml) yielded 1.57 g of white shining crystals, m.p. 132-134*C.

ANALYSIS:

Calculated for C 22

H

18 CI2FN303: 57.16%C 3.92%H 9.09%N Found: 57.13%C 3.63%H 8.93%N 154 EXAMPLE 137 N-[2-[4-(6-Fluoro-1,2-benzisothiazol-3-yl)-1-piperidinyl]ethyl]phthalimide hydrochloride A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisothiazole (3.3 g, 14 mmol), 2-bromoethylphthalimide (3.7 g, 14.7 mmol), K 2 C0 3 (2.0 g) and CH 3 CN (85 ml) was stirred and refluxed for 2.5 hours. The reaction was poured into H 2 0 and a white precipitate resulted, which was collected to afford 2.0 g of product. The aqueous filtrate was extracted with CHCI 3 the extract washed

(H

2 dried (MgSO4) and was concentrated to afford 3.5 g of an off-white solid. Upon trituration of this solid with acetone, an additional 2.0 g of product was realized.

The two samples were combined and suspended in MeOH (50 ml), and ethereal HCI was added until the reaction mixture was acidic. After stirring for 1 hour at ambient temperature, Et20 (50 ml) was added to afford 3.7 g of the hydrochloride salt. The salt was recrystallized from MeOH-Et2O to yield 2.3 g of the 15 compound as a white solid, m.p 271=273"C.

i E o

ANALYSIS:

Calculated for C 22

H

20 FN30 2 SoHCI: 59.25%C 4.75%H 9.42%N Found: 58.99%C 4.60%H 9.33%N 20 EXAMPLE 138 N-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-l-piperidinylethy- 3 ,6 dichlorophthalimide A mixture of 2-[4-[(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl] amine (2.44 g, 9.24 mmol) and 3,6-dichlorophthalic anhydride (2.01 g; 9.27 mmol) in 25 dichloromethane (DCM, 50 ml) was stirred at room temperature for 1 hour. White precipitates formed and the TLC of the reaction mixture showed that there was no starting amine remaining. The solvent was stripped down and the white solids which were poorly soluble in DCM were loaded onto a flash chromatography column, (SiO 2 30 g) and the column was eluted with a solution of 1% CH 3 OH in DCM. The desired product thus obtained weighed 2.29 g Recrystallization from hot ethanol yielded 2.15 g of white crystals, m.p. 163-164°C.

ANALYSIS:

Calculated for C 2 2

H

1 8CI 2 FN303: 57.16%C 3.92%H 9.09%N 155 Found: 57.16%C 3.64%H 9.13%N EXAMPLE 139 N-[2-[4-(6-Fuoro-1 ,2-benzisoxazol-3-yI)-l -piperidinylle thyl]-4-chlorophthalimide A mixture of 2-[4-[(6-fluoro-1 ,2-benzisoxazol-3-yl)-I -piperidinyl~ethyl]amifle (2.13 g, 8.07 mmol), 4-chlorophthalic acid monosodium salt (2.2 g, 10 mmol) and dicyclohexylcarbodiimide (DCC, 4.25 g, 20.6 mmol) in acetonitrile (150 ml) was stirred at room temperature for 24 hours. The cloudy mixture was filtered, then the solvent was stripped down. The residue was partitioned between water and dichloromethane (0CM). The DCM solution was washed with brine and dried over MgSO4. The solvent was removed. The crude product was purified on a flash chromatography column (Si02, 35 g; eluted with DCM, and 1% CH 3 0H in DCM).

The desired product thus obtained weighed 1.3 g. Recrystallization from ethanol yielded 590 mg as white crystals, m.p. 170-171*C.

ANALYSIS:

Calculated for C 22

H-

19

FN

3 0 3 61 .76%C 4.48%H 9.82%N Found: 61 .87%C 4.39%H 9.89%N 006* EXAMPLE 140 0# 20 N-I24-(6-Fluoro-1 ,2-benzisoxazol-3-yl)-l -piperidinyllethyl]-3-flUOrOphthalimide o o *A mixture of 2-[4-[(6-fluoro-1 ,2-benzisoxazol-3-yl)-l -piperidinyl]ethyl] amine V (2.37 g, 8.98 mmol), 3-fluorophthalic acid (1.82 g, 9.9 mmol) and 0900 dicyclohexylcarbodiimide (DCC, 5.5 g, 26.7 mmol, 2.6 eq) in dichloromethane 000.(DCM, 250 ml) was stirred at room temperature for 18 hours. The solids were 0 25 filtered off. The organic solution was concentrated down. The residue was purified on a flash chromatography column (SiO 2 50 g; eluted with 1.4 liter; 2-6%

CH

3 OH:DCM, 1 liter). The desired product th us obtained weighed 2.64 g (71%) as an off-white solid. Recrystallization from hot ethanol gave 1.41 g of white crystals, m.p. 142-143*C.

ANALYSIS:

Calculated for C 22

H-

19 FAN03: 64.22%C 4.66%H 10.21 %N Found: 64.11 %C 4.70%H 10.14%N 156 EXAMPLE 141 N-[2-[4-(6-Fluoro-1 ,2-benzisoxazol-3-yI I -piperidinyl]ethyl]-4-fluorophthalimide A mixture of 2-14-[(6-fl uoro- 1,2-benzisoxazol-3-y)-1I -pipe rid inyllethylla mine (3.2 g, 12 mmol), 4-fluorophthalic anhydride (freshly prepared according to the procedure of Markezich, U.S. Patent 3,956,321, 1976; 2.0 g, 12 mmol) and dicyclohexylcarbodiimide (DCC, 2.48 g, 12 mmol) in chloroform (100 ml) was stirred at room temperature for 18 hours. The insolubles were filtered off. The solution was loaded onto a flash chromatography column (SiO 2 45 g) then was eluted with a solution of 2% methanol in methylene chloride. The fractions containing the desired product were pooled and concentrated to yield 2.9 g of white solid. The material was converted to a hydrochloride salt by treatment with a solution of hydrochloride in ethanol. Recrystallization from ethanol gave the pure sample, 1.01 g, m.p. 253-255 0

C.

ANALYSIS:

15 Calculated for C22H 19

FN

3

O

3 9HCI: 59.00%C 4.50%H 9.38%N Found: 58.81 %C 4.38%H 9.48%N EXAMPLE 142 N-[2-[4-(6-Fluoro-1 ,2-benzisoxazol-3-y)-1 -piperidinyl]ethyll-4-methylphthalimide A mixture of 2-[4-([6-fluoro-1 ,2-benzisoxazol-3-y)-1 -piperid inyl]ethyl]amine (2.44 g, 9.24 mmol), 4-methylphthalic anhydride (1.76 g, 10.8 mmol) and dicyclohexylcarbodlimide (2.1 g, 1.0 mmol) in dichloromethane (DCM, 100 ml) was stirred at room temperature for 2 hours. The insolubles were filtered off. The ~*:DCM solution was concentrated to a crude solid. This was purified on a flash chromatography column (35 g, Si0 2 Sorbsil-C-30; eluted with 1 CH 3 0H in 99% DCM). The material thus purified weighed 1.0 g as a white solid.

Recrystallization from hot ethanol gave 665 mg of crystals, m.p. 138-140*C.

ANALYSIS:

Calculated for C 23

H

22

FN

3 03: 67.80%C 5.44%H 10.31 %N Found: 67.67%C 5.48%H 10.30%N EXAMPLE 143 N-[2-[4-(6-Fluoro-1 ,2-benzisoxazol-3-yl)-1 -piperidinyllethyll-4-methoxyphthalimide 157 A stirred mixture of 2-[4-[(6-fluoro-1,2-benzisoxazol-3-yl)-1piperidinyl]ethyl]amine (2.63 g, 10 mmol) and 4-methoxyphthalic anhydride (1.78 g, 10 mmol) in dichloromethane (100 mi) is stirred at room temperature for 3 hours. The solvent is then removed under reduced pressure and the residual material is purified by flash chromatography. The product is purified further by recrystallization to give N-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1 piperidinyl]ethyl]-4-methoxy-phthalimide.

EXAMPLE 144 N-[2-[4-(6-Fluoro- ,2-benzisoxazol-3-y)-1 -piperidinyl]ethyl]-4-nitrophthalimide hvdrochloride A mixture of 2-[4-[(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]amine (2.9 g, 11 mmol), 4-nitrophthalic anhydride (2.33 g, 12.1 mmol) and dicyclohexylcarbodiimide (2.25 g, 11 mmol) in dichloromethane (DCM, 150 mi) S 15 was stirred at room temperature for 16 hours. The mixture was filtered. The brownish solution was loaded onto a flash chromatography column, (SiO 2 35 g; eluted with DCM, then 2% CH 3 OH in DCM). The desired product thus obtained weighed 2.35 g as a pale white solid, m.p. 191-193"C. This solid was converted to the hydrochloride salt by treatment with an HCI solution in ethanol to yield 1.54 g, m.p. 250-253"C dec.

0:

ANALYSIS:

Calculated for C 22 Hi 9

FN

4 0 5 *HCI 55.64%C 4.25%H 11.90%N Found: 55.81%C 4.08%H 11.67%N EXAMPLE 145 4-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1 -piperidinyl]-2-methyl-2-hydroxybutane fumarate To a solution of ethyl 3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1 piperidinyl]propionate (3.21 g, 10 mmol) in tetrahydrofuran (THF, 100 mi), was added methylmagnesium bromide (10 ml, 30 mmol, 3M solution in ether) dropwise over 15 minutes at room temperature under N 2 The resulting mixture was stirred for 16 hours. The mixture was slowly hydrolyzed with aqueous NH 4

CI

solution. The THF solution was diluted with EtOAc (300 ml), then was washed 158 with water and brine. The organic solution was separated and dried over MgSO4.

After removal of solvent, the crude product was purified by flash chromatography g, SiO 2 eluted with 1 CH 3 0H:99 DCM). The material thus purified weighed 2.36 g as white crystals. This was converted to the fumarate salt by treatment with fumaric acid (895 mg) in ethanol. Recrystallization from ethanol yielded white crystals, 2.47 g, m.p. 156-158 0

C.

ANALYSIS:

Calculated for C17H 23

FN

2 02*C4H404: 59.70%C 6.44%H 6.63%N Found: 59.40%C 6.27%H 6.28%N EXAMPLE 146 Ethyl 3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propionate fumarate A mixture of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (5 g, 22.7 mmol),

K

2 C0 3 (3.8 g, 27.5 mmol) and ethyl bromopropionate (5 g, 27.6 mmol, 1.2 eq) in 15 acetonitrile (200 ml) was heated at reflux for 16 hours. The mixture was cooled and filtered. The solvent was removed, and the residue was purified on a flash chromatography column (60 g, SiO 2 eluted with DCM). The material thus purified S'weighed 7.27 g The fumarate salt was prepared by treatment of the free base (2.17 g) with fumaric acid (820 mg, 1.0 eq) in ethanol. Recrystallization from 20 ethanol yielded 2.49 g of white crystals, m.p. 135-136 0

C.

ANALYSIS:

Calculated for C 17

H

2 1FN 2 0 3 oC 4 H404: 57.79%C 5.77%H 6.42%N Found: 57.86%C 5.67%H 6.30%N 25 EXAMPLE 147 2,3-dihydro-2-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1 -piperidinyl]ethyl]-3-hydroxy- 1 H-isoindol-1-one To a suspension of N-[2-[4-(6-fluoro-1,2-benzisoxazol- 3 -yl)-1 piperidinyl]ethyl]phthalimide (7.8 g, 19.8 mmol) in methanol (250 ml) and DCM (30 ml) was added NaBH4 (1.7 g, 45.5 mmol) at room temperature under nitrogen. After stirring for 0.5 hours the homogeneous reaction mixture was concentrated. The remaining solid was purified on a flash chromatography column (SiO 2 1:1 EtOAc/DCM, increased to 10% MeOH) to give 7.0 g of 159 the desired product as a solid which was recrystallized from EtOAc, m.p. 172- 173"C.

ANALYSIS:

Calculated for C 22 H22FN 3 0 3 66.82%C 5.61%H 10.63%N Found: 66.63%C 5.52%H 10.51%N EXAMPLE 148 2,3-dihydro-2-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1 -piperidinyl]ethyl]-1 Hisoindol-1-one To 2-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-2,3-dihydro- 3-hydroxy-1H-isoindol-1-one (2.2 g, 5.6 mmol) was added a solution of trifluoroacetic acid (11.0 ml) in dichloromethane (30 ml) at room temperature, under nitrogen. Triethylsilane (1.5 ml) was then added and the reaction mixture was allowed to stir for 18 hours at which time it was poured into a NaHCO 3 (sat.).

15 The layers were separated and the aqueous phase was extracted with DCM (3X).

The combined organics were washed with brine and dried (Na 2

SO

4 Filtration and concentration gave the crude product as a solid which was recrystallized from EtOAc to give 1.6 g of the desired product as a white solid, m.p. 166-168°C.

20 ANALYSIS: 'Calculated for C 22

H

22

FN

3 0 2 69.64%C 5.84%H 11.07%N Found: 69.37%C 5.70%H 11.00%N EXAMPLE 149 25 (S)-3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1 -piperidinyl]-2-methylpropyl-methyl carbamate To a solution of 2-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]- 2,3-dihydro-3-hydroxy-1H-isoindol-1-one (3.1 g, 10.6 mmol) in dry THF (120 ml) was added methyl isocyanate (0.66 ml, 11.1 mmol) followed by milled K 2 CO3 (2.2 g, 15.9 mmol) at room temperature, under nitrogen. The reaction mixture was stirred for 3 days at which time it was filtered through a pad of Celite and the solids washed with EtOAc. The combined filtrates were concentrated to give the crude product which was purified via flash column chromatography (silica gel, 2% 160 Et 3 N/EtOAc). The product containing fractions were concentrated to give 2.7 g of the desired product as an oil which solidified on standing.

Recrystallization from EtOAc/pet.ether gave the product as a solid, m.p. 72- 74 0

C.

ANALYSIS:

Calculated for C18H 24

FN

3 03: 61.88%C 6.92%H 12.03%N Found: 61.82%C 7.02%H 11.77%N EXAMPLE 150 (S)-3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-l-piperidinyl]-2-methylpropyl decanoate fumarate To a solution of 2-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]- 2,3-dihydro-3-hydroxy-1H-isoindol-1-one (3.2 g, 10.9 mmol) in DCM (110 ml) was added decanoyl chloride (2.3 ml, 10.9 mmol) at 0°C, under nitrogen. The reaction 15 mixture was stirred for 1.25 hours at which time it was poured into NaHCO3 The layers were separated and the aqueous phase was extracted with DCM The combined organics were dried, filtered and concentrated to give •the crude product which was purified via flash column chromatography (silica gel, EtOAc/DCM). The product containing fractions were concentrated to give 20 3.4 g of the desired product as a yellow oil. The fumarate salt was prepared in ethanol with fumaric acid (1.05 The white salt was filtered and washed with isopropyl ether, m.p. 110-112 0

C.

SANALYSIS:

Calculated for C 26

H

39

FN

2 03*C 4 H404: 64.04%C 7.70%H 4.98%N 25 Found: 64.07%C 7.75%H 4.90%N EXAMPLE 151 (S)-6-Fluoro-3-[1-(3-methoxyphenyl-2-methylpropyl)-4-piperidinl]-12benzisoxazole To a solution of 2-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)- -piperidinyl]ethyl]- 2,3-dihydro-3-hydroxy-1H-isoindol-1-one (3.3 g, 11.3 mmol) in dry THF (120 ml) was added potassium tert-butoxide (1.9 g, 16.9 mmol) followed by dimethyl sulfate (1.2 ml, 11.9 mmol) at room temperature, under nitrogen. The reaction 161 mixture was stirred for 21 hours at which time it was filtered through a pad of Celite and the solids washed with EtOAc. The combined filtrates were concentrated to give the crude product. Purification via flash column chromatography (silica gel, 0-20% acetone/DCM) afforded 1.6 g of the desired product as a solid, m.p. 40-42 0

C.

ANALYSIS:

Calculated for C 17

H

2 3

FN

2 0 2 66.65%C 7.57%H 9.14%N Found: 66.49%C 7.48%H 9.12%N EXAMPLE 152 (+)-6-Fluoro-3-1 -(3-hyd roxybutyl)-4-piperidinyll-1.2-benzisoxazole Racemic 3-hydroxybutyl tosylate was prepared in a manner described by Ferreira et al., Tetrahedron, 46 pp. 6311-6318, (1990). To a solution of the :i racemic tosylate (9.2 g, 37.7 mmol) in acetonitrile (190 ml) was added 6-fluoro-3- (4-piperidinyl)-1,2-benzisoxazole (8.3 g, 37.7 mmol) followed by milled potassium carbonate (7.8 g, 56.6 mmol) at room temperature under nitrogen. The reaction mixture was warmed to reflux for 4.5 hours and allowed to cool to room temperature. The solids were removed via filtration through a pad of Celite and were washed with EtOAc. The combined filtrates were concentrated to give the 20 crude product. Purification via preparative HPLC (silica gel, 10% MeOH/EtOAc) afforded 6.3 g 100-102*C.

ANALYSIS:

Calculated for C 16

H

21

FN

2 0 2 65.73%C 7.24%H 9.58%N Found: 65.59%C 7.30%H 9.52%N EXAMPLE 153 (S)-6-Fluoro-3-[1-(3-hydroxy-2-methylpropyl)-4-piperidinyl]-1,2-benzisothiazole fumarate A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisothiazole (4.6 g, 20 mmol), (R)-(-)-3-bromo-2-methyl-1-propanol (3.0 g, 20 mmol), K 2

CO

3 (2.7 g, 20 mmol), tetrabutylammonium sulfate (0.058 CH 3 CN (95 ml) and H 2 0 (19 ml) was stirred and refluxed for 4.5 hours. After standing at ambient temperature for 16 hours, the reaction was poured into H 2 0, and subsequent extractive workup of 162 the aqueous with EtOAc yielded 6.8 g of a partially solidified oil. The product was purified by flash chromatography on silica gel, eluting the column with CH 2

C

2 then 2% MeOH-CH 2 Cl2 and finally 5% MeOH-CH 2 Cl2. Concentration of the appropriate fractions yielded 5.2 g of a waxy solid. The solid was dissolved in acetone and fumaric acid (1.9 g, 1.0 eq) was added and the reaction briefly heated at reflux. The resultant fumarate salt precipitated from solution yielding 4.8 g of white solid. The compound was recrystallized from acetonitrile to yield 3.1 g of the alcohol as a white solid, m.p. 151-153*C.

ANALYSIS:

Calculated for Ci 6

H

21

FN

2 0SoC 4 H404: 56.59%C 5.94%H 6.60%N Found: 56.31 %C 5.96%H 6.48%N EXAMPLE 154 N-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-3,6difluorophthalimide A mixture of 2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]amine (1.53 g, 5.8 mmol), 3,6-difluorophthalic anhydride (1.0 g, 5.43 mmol) and dicyclohexylcarbodiimide (DCC, 1.84 g, 8.9 mmol) in methylene chloride (DCM, 100 ml) was stirred for 6 hours, and then left standing overnight at room 20 temperature. The solids were filtered off. The solution was loaded onto a silica gel column (35 g, Sorbsil C-30), then eluted with a mixture of methanol and DCM The fractions containing the desired product were pooled and concentrated to give 1.23 g of white solid. Recrystallization from DCM and hot ethanol yielded 1.03 g of white crystals, m.p. 144-145°C.

25 ANALYSIS: Calculated for C 22

H

18

F

3

N

3 03: 61.54%C 4.23%H 9.79%N Found: 61.63%C 3.83%H 9.77%N EXAMPLE 155 N-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-1,2,3,4 tetrahydroisoquinoline-1,3-dione A mixture of 2-[4-[(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]amine (2.45 g, 9.28 mmol), homophthalic anhydride (1.78 g, 10.9 mmol) and DCC (2.2 163 g, 10.7 mmol) in CHCI 3 (100 ml) was stirred at room temperature for 3.5 hours.

The insolubles were filtered off. The solution was loaded onto a flash chromatography column (Sorbsil C-30, 40 eluted with DCM (1.5 2% CH 3

OH

in DCM (1 then washed with 20% CH 3 OH in DCM. The fractions containing the front spot were pooled and concentrated to give 500 mg of yellow solid. This solid was recrystallized again from ethanol to provide 340 mg of crystals, m.p.

148-150°C.

ANALYSIS:

Calculated for C 23

H

22

FN

3 0 3 67.80%C 5.44%H 10.31%N Found: 67.54%C 5.31%H 10.17%N EXAMPLE 156 2-[4-[(6-Fluoro-1,2-benzisothiazol-3-yl)-1-piperidinyl]ethyl]amine sesquifumarate i: To a stirred solution of N-[2-[4-(6-fluoro-1,2-benzisothiazol-3-yl)-1- S: 15 piperidinyl]ethyl]phthalimide (17.0 g, 42 mmol) and MeOH (200 ml) under N 2 was added, dropwise, hydrazine monohydrate (4.2 g, 83 mmol). After complete addition, the reaction was stirred at reflux for 17 hours. The reaction mixture was concentrated and the resultant residue was dissolved in H 2 0. The aqueous solution was acidified to pH ~2 with concentrated HCI and the precipitate was 20 filtered. The filtrate was basified with 50% NaOH and the product was extracted into CH 2

CI

2 The CH 2

CI

2 extract was washed with H 2 0, dried with MgSO 4 and concentrated to yield 6.0 g of a beige oil. A 5.8 g sample of the oil (21 mmol) was warmed in EtOH (100 ml) and fumaric acid (2.7 g, 23 mmol) was added. The solution was refluxed gently for 15 minutes and was stirred at 25 ambient temperature for 1.5 hours. Anhydrous Et 2 0 (400 ml) was added and the product collected to yield 7.1 g of an off-white powder. A portion (3.0 g) was recrystallized from MeOH-Et20 to provide 1.7 g of the sesquifumarate salt as a white powder m.p. 169-171°C.

ANALYSIS:

Calculated for C14H18FN3S*1.5C 4

H

4 0 4 52.97%C 5.35%H 9.27%N Found: 52.96%C 5.44%H 9.39%N 164 EXAMPLE 157 (S)-6-Fluoro-3-[1-(3-hydroxybutyl)-4-piperidinyl]-1,2-benzisoxazole (S)-Hydroxybutyl tosylate was prepared in a manner described by Ferreira et al., Tetrahedron, 46, pp. 6311-6318, (1990). To a solution of the tosylate (6.8 g, 28.0 mmol) in acetonitrile (150 ml) was added 6-fluoro-3-(4-piperidinyl)-1,2benzisoxazole (6.2 g, 28.0 mmol) followed by milled potassium carbonate (5.8 g, 42.0 mmol) at room temperature under nitrogen. The reaction mixture was warmed to reflux for 3 hours and allowed to cool to room temperature. The solids were removed via filtration through a pad of Celite and were washed with EtOAc.

The combined filtrates were concentrated to give the crude product. Purification via flash column chromatography (silica gel, 0-10% MeOH/EtOAc) afforded 5.5 g of the desired product as an oil which solidified on standing, m.p. 84- 86°C

ANALYSIS:

15 Calculated for C 16

H

2 1

FN

2 02: 65.73%C 7.24%H 9.58%N Found: 65.58%C 6.83%H 9.50%N EXAMPLE 158 (R)-6-Fluoro-3-[1-(3-hydroxybutyl)-4-piperidinyl-1,2-benzisoxazole 20 (R)-Hydroxybutyl tosylate was prepared in a manner described by Ferreira et al., Tetrahedron, 46 pp. 6311-6318, (1990). To a solution of the tosylate (8.4 g, 34.2 mmol) in acetonitrile (120 ml) was added 6-fluoro-3-(4-piperidinyl)-1,2- 0* benzisoxazole (7.5 g, 34.2 mmol) followed by milled potassium carbonate (7.1 g, 51.3 mmol) at room temperature under nitrogen. The reaction mixture was warmed to reflux for 2 hours and allowed to cool to room temperature. The solids were removed via filtration through a pad of Celite and were washed with EtOAc.

The combined filtrates were concentrated to give the crude product. Purification via flash column chromatography (silica gel, 10% MeOH/EtOAc) afforded 6.0 g of the desired product as an oil which solidified on standing, m.p. 82- 84 0

C.

ANALYSIS:

Calculated for C1 6

H

2 1FN202: 65.73%C 7.24%H 9.58%N Found: 65.66%C 7.13%H 9.53%N 165 EXAMPLE 159 Ethyl 3-[4-(6-Fluoro-1,2-benzisothiazol-3-yl)-l-piperidinyl]propionate hydrochloride A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisothiazole (6.0 g, 25 mmol), ethyl 3-bromopropionate (4.5 g, 25 mmol), K 2 C0 3 (3.5 g) and CH 3 CN (100 ml) was stirred and refluxed for 16 hours. The reaction was poured into H 2 0, and after extractive workup with EtOAc, 6.0 g of an orange oil was realized. The oil was dissolved in Et20 and ethereal HCI was added to precipitate 6.3 g of a white hydrochloride salt. The salt was recrystallized from CH 3 CN to yield 6.0 g of the desired compound. An analytical sample was obtained by recrystallization of a 1.0 g sample from EtOH-Et 2 0 to yield 0.8 g of a white solid, m.p. 197-1990C.

ANALYSIS:

Calculated for C 17

H

2 1

FN

2 0 2 S.HCI: 54.76%C 5.95%H 7.51%N Found: 54.77%C 5.99%H 7.28%N Ii EXAMPLE 160 4-[4-(6-Fluoro-1,2-benzisothiazol-3-yl)- -piperidinyl]-2-methyl-2-hydroxybutane hemifumarate To a stirred solution, under N 2 of ethyl 3-[4-(6-fluoro-1,2-benzisothiazol-3- 20 yl)-l-piperidinyl]propionate (3.1 g, 9 mmol), in THF (100 ml) was added, dropwise, methylmagnesium bromide (9.0 ml, 27 mmol of a 3 M solution in ether). The reaction was stirred at ambient temperature for 16 hours and then a saturated solution

NH

4 CI was added dropwise, with cooling. The reaction was further diluted with H 2 0, and after extractive workup of the aqueous mixture with EtOAc, 2.8 g of a waxy solid resulted. The solid was dissolved in EtOAc and 3.0 g of fumaric acid was added, and 5.0 g of a fumarate salt was collected, which was contaminated with unreacted fumaric acid. The crude salt was recrystallized from and then from DMF to afford 1.6 g of the desired compound as a hemifumarate, m.p. 237-239"C.

ANALYSIS:

Calculated for C 17

H

23

FN

2 0S*C 4 H404: 59.98%C 6.64%H 7.36%N Found: 59.75%C 6.65%H 7.39%N 166 EXAMPLE 161 N-[2-[4-(6-Fluoro-1 ,2-benzisoxazol- 3 -yi)-I -piperidinyllethyl]-3-hyd roxyphthalimide hydrochloride A mixture of 2-[4-[(6-fluoro-1 ,2-benzisoxazol-3-YI)-l -piperidinyl]ethyl]amifle (2.48 g, 9.3 mmol), 3-hydroxyphthalic anhydride (1.8 g, 10.9 mmol) and dicyclohexylcarbodiimide (2.2 g, 10.7 mmol) in chloroform (100 ml) was stirred at room temperature for 48 hours. The mixture was filtered. The yellow solution was loaded onto a flash chromatography column (SiO 2 40 g; eluted with DCM, 1 1; and 2% CH 3 0H in DCM, 1 The desired product thus obtained as a light yellow solid weighed 2.12 g m.p. 156-157 0 C. This material was converted to the hydrochloride salt by treatment with a solution of hydrochloric acid in ethanol.

The off-white crystals were collected: 1.97 g, m.p. 270-272*C dec.

ANALYSIS:

Calculated for C 2 2

H

20

FN

3

O

4 *HCI: 59.26%C 4.75%H 9.42%N 15 Found: 59.34%C 4.70%H 9.19%N EXAMPLE 162 N-[2-[4-(6-Fluoro-1I,2-benzisoxazol-3-yl)-l -,piperidiinyllethyl]-4 fluorophthalimide A solution of 2-[4-[(6-fluoro-1 ,2-benzisothiazol-3-yl)-l -piperidinyllethyl] 20 amine (2.7 g, 10 mmol), 4-fluorophthalic anhydride (1.6 g, 10 mmol) and DMF ml) was stirred under N 2 at ambient temperature for 1 hour and then at 70 0 C for 2 hours. Most of the DMF was removed in vacuo to afford 4.6 g of a damp, beige 9solid. The compound was dissolved in anhydro us Et 2 O (100 ml) and MeOH ml) and the insolubles were filtered off. The filtrate was made acidic with ethereal HCI to precipitate the HCI salt. Additional anhydrous Et 2 O (500 ml) was added and the salt was collected to give 3.5 g of a beige solid. Recrystallization from EtOH provided 2.0 g of an off-white powder, m.p. 269-271*C.

ANALYSIS:

Calculated for C 22 Hi 9

F

2

N

3 0 2 S*HCI: 56.96%C 4.35%H 9.06%N Found: 57.33%C 4.33%H 9.11 %N EXAMPLE 163 6-FlorO3-[ roy-3-ethylpentyl) 4-pipeid inyl]-1 ,2-benzisoxazole 167 To a solution of ethyl 3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1 piperidinyl]propionate (3.9 g, 12.0 mmol) in THF (100 ml) was added ethylmagnesium bromide (12.0 ml, 36.0 mmol, 3.0 M in ether) at room temperature under nitrogen (mild exotherm). The reaction mixture was stirred for 17 hours at which time it was carefully quenched with NH 4 CI (sat., 20 ml). The precipitated salts were dissolved into water (25 ml) and the layers were separated. The aqueous phase was extracted with EtOAc (2X) and the combined organics were washed with brine and dried (Na20 4 Filtration and concentration gave the crude product which was purified via flash column chromatography (silica gel, 1% MeOH/DCM) to give 2.4 g of the desired product as an oil which solidified on standing, m.p. 50-53°C.

ANALYSIS:

Calculated for C 19

H

27

FN

2 0 2 68.24%C 8.14%H 8.38%N Found: 67.99%C 8.11%H 8.48%N EXAMPLE 164 Decanoic acid 2-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-l-piperidinyl]ethyl-3-oxo- 2,3-dihydro-lH-isoindol-1-yl ester To a solution of 2-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl- 20 2,3-dihydro-3-hydroxy-1 H-isoindol-1-one (1.4 g, 3.5 mmol) in DCM (30 ml) was added Et 3 N (1.2 ml, 8.8 mmol) followed by decanoyl chloride at 0° under nitrogen.

After stirring for 1h in the cooling bath, the solvent was removed using a stream of nitrogen. The remaining residue was diluted with EtOAc and the precipitated triethylamine hydrochloride was filtered off. The filtrate was concentrated and the remaining oil was flushed through alumina with ether to give 1.6 g of the desired product as a yellow oil.

ANALYSIS:

Calculated for C 32

H

40 FN304: 69.92%C 7.33%H 7.64%N Found: 69.70%C 7.39%H 7.56%N EXAMPLE 165 6-Chloro-2-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1 -piperidinyl]ethyl]-1

H-

benz[de]isoquinoline-1,3(2H)-dione 168 A mixture of 2-[4-[(6-fluoro-1,2-benzisoxazol-3-yl)-l-piperidinyl]ethyl]amine (2.32 g, 8.8 mmol) and 4-chloro-1,8-naphthalic anhydride (2.45 g, 10.5 mmol, 1.25 eq) in chloroform (120 ml) was stirred at room temperature overnight. To the mixture was added 5 ml of methanol and the solution was concentrated down to 20 ml. The resulting mixture was loaded onto a flash chromatography column (SiO 2 50 g; eluted with dichloromethane, DCM, 1 I, and 2% CH 3 OH in DCM, 1 I).

The product thus obtained as a light yellow solid weighed 2.61 g. Recrystallization from CH 2

CI

2 /ethanol gave 2.5 g of pale white crystals, m.p. 207-209"C.

ANALYSIS:

Calculated for C 2 6

H

21

CIFN

3 0 3 65.34%C 4.43%H 8.79%N Found: 64.87%C 4.32%H 8.67%N EXAMPLE 166 SN-(2-4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidiny]ethyl-4-terttylphthamid 15 fumarate

S..

A mixture of 2-[4-[(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]amine (2.0 g, 7.57 mmol) and 4-(t-butyl)phthalic anhydride (1.62 g, 7.94 mmol) in dimethylformamide (DMF, 20 ml) was heated at 135°C for 3 hours. The solvent was removed on a rotary evaporator under vacuum, and further dried on a 20 vacuum pump. The residue was purified by flash chromatography over a silica gel column (SiO 2 35 g; eluted with DCM, and 1-2% of methanol in DCM). The product thus obtained as an oil was triturated with isopropyl ether and dried to a waxy solid. This solid was converted to the fumarate salt by treatment with a solution of fumaric acid (778 mg) in ethanol. The crystals were collected and weighed: 3.03 g; m.p. 198-199°C.

ANALYSIS:

Calculated for C 26

H

2 8

FN

3 0 3 oC4H404: 63.71 %C 5.70%H 7.43%N Found: 63.46%C 6.05%H 7.27%N EXAMPLE 167 N-[2-[4-(6-Fluoro-1 H-indazol-3-yl)-l-piperidinyl]ethyl]phthalimide hydrochloride A mixture of 6-fluoro-3-(4-piperidinyl)-1H-indazole (2.5 g, 11 mmol), 2bromoethylphthalimide (3.0 g, 10 mmol), NaHCO3 (1.0 g) and DMF (30 ml) was 169 stirred and heated at 60 0 C for 2.5 hours. The reaction was poured into H 2 0, and after extractive workup with EtOAc there remained 4.0 g of a golden oil. The oil was dissolved in EtOAc and ethereal HCI was added to yield 1.9 g of the hydrochloride salt as a white solid. The solid was recrystallized from MeOH-Et 2 0 and then from DMF to afford 0.54 g of the compound as a white solid, m.p.

270-272*C.

ANALYSIS:

Calculated for C 22

H

21

FN

4 0 2 HCI: 61.61%C 5.17%H 13.06%N Found: 61.50%C 5.05%H 12.86%N EXAMPLE 168 2-[2-[4-(6-Fluoro-1,2-benzisothiazol-3-yl)-1 -piperidinyl]-2,3-dihydro-3-hydroxy-1

H-

isoindol-1-one hydrochloride To a stirred solution of the N-[2-[4-(6-fluoro-1,2-benzisothiazol-3-yl)-1piperidinyl]ethyl]phthalimide (2.5 g, 6 mmol) in MeOH (50 ml)-CH 2 CI2 (20 ml) was added NaBH 4 (0.8 g, 21 mmol). The reaction was stirred at ambient temperature :for 2 hours, and then the solvent was evaporated. The residue was diluted with

H

2 0, and extractive workup of the aqueous with CH 2 C12 afforded 2.2 g of a beige solid. The solid was combined with a sample from a prior run, and the combined S. 20 sample (3.2 g) was chromatographed on a Waters Prep 500 LC, eluting with EtOAc-Et 2 NH Concentration of the appropriate fractions afforded 2.2 g of a white solid. The solid was dissolved in EtOAc and ethereal HCI was added to yield 2.0 g of a hydrochloride salt. The salt was recrystallized first from EtOH and then from DMF to yield 1.2 g of a white solid, m.p. 210-212°C.

ANALYSIS:

Calculated for C 22

H

2 2

FN

3 0 2 SeHCI: 58.99%C 5.18%H 9.38%N Found: 58.89%C 5.23%H 9.16%N EXAMPLE 169 N-[2-[4-(6-Fluoro-1,2-benzisthiazol-3-yl)-l-piperidin yl]-4methylphthalimide hvdrochloride A mixture of 2-[4-[(6-fluoro-1,2-benzisothiazol- 3 -yl)-1 piperidinyl]ethyl]amine (3.4 g, 12 mmol), 4-methylphthalic anhydride (2.0 g, 12 170 mmol) and DMF (75 ml) was stirred at 70 0 C under N 2 for 3.5 hours. Most of the DMF was removed in vacuo, and the oily residue was diluted with H 2 0. EtOAc was added to the aqueous mixture and the biphase was filtered through Celite to remove an insoluble yellow solid. The solid was scraped away from the Celite and was dissolved in CH 2

CI

2 The solution was filtered through the original Celite cake, and the CH 2

CI

2 filtrate was washed with H 2 0, dried with MgSO 4 and concentrated to yield 0.5 g of an off-white solid. The phases of the EtOAc/H 2 0 filtrate were separated and the aqueous was further extracted with EtOAc. The EtOAc extract was washed with H 2 0, dried with MgSO 4 and concentrated to afford 3.5 g of an off-white solid. The two samples were combined and recrystallized from EtOH to give 2.2 g of a white powder. The product was dissolved in anhydrous ether (200 ml) and methanol (100 ml) and the solution was made acidic with ethereal HCI. After ca. 30 minutes of stirring the I: salt began to precipitate. Additional anhydrous ether (400 ml) was added over 2 15 hours and the resultant white solid was collected to yield 2.2 g. Recrystallization from MeOH-ether provided 1.7 g of a white powder, m.p. 268-271 C.

ANALYSIS:

Calculated for C 23

H

22

FN

3 0 2 S.HCI: 60.06%C 5.04%H 9.14%N Found: 60.01 %C 5.00%H 9.12%N EXAMPLE 170 6-Fluoro-3-[1-(3-hydroxy-3-propylhexyl)-4-piperidinyl]-1,2-benzisoxazole hydrochloride To a solution of ethyl 3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]- 25 propionate (4.5 g, 14.0 mmol) in THF (120 ml) was added propylmagnesium chloride (21.1 ml, 42.0 mmol, 2.0 M in ether) at room temperature under nitrogen (mild exotherm). The reaction mixture was stirred for 17 hours at which time it was carefully quenched with NH 4 CI (sat., 30 ml). The layers were separated and the aqueous phase was extracted with EtOAc The combined organics were washed with brine and dried (Na 2

SO

4 Filtration and concentration gave the crude product which was purified via flash column chromatography (silica gel, 2% Et 3 N/ether). After flushing the product through alumina with ether, the hydrochloride salt was prepared in ether/EtOAc 40 ml, 1 drop IPA) with 171 ethereal HCI to give 2.5 g of the desired product as a white solid, m.p. 163-164C.

ANALYSIS:

Calculated for C 21

H

31

FN

2 0 2 .HCI: 63.22%C 8.08%H 7.02%N Found: 62.97%C 7.95%H 7.01 %N EXAMPLE 171 N-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1 -piperidinyl]ethyl]-3-nitrophthalimide fumarate A mixture of 2-[4-[(6-fluoro-1 ,2-benzisoxazol-3-yl)-1 -piperidinyl]ethyllamine (2.09 g, 7.9 mmol) and 3-nitrophthalic anhydride (1.6 g, 8.3 mmol, 1.05 eq) in dimethylformamide (DMF, 20 ml) was heated at 135C for 3 hours. The solvent was removed on a rotary evaporator under vacuum and further dried on a vacuum pump. The residue was purified by flash chromatography over a silica gel column (SiO 2 35 g; eluted with dichloromethane, 300 ml, and 3% CH 3 0H in DCM, 300 ml). The product thus obtained 2.01 g, was dissolved into DCM (15 mi) and ethanol (5 ml) and was treated with a solution of fumaric acid (530 mg, eq) in ethanol (15 ml). The crystals were collected and weighed: 2.03 g, m.p. 237-239aC.

S 20 ANALYSIS: *Calculated for C 22

H

19

FN

4 0 5

*C

4

H

4 0 4 56.32%C 4.18%H 10.10%N Found: 55.94%C 4.23%H 9.87%N EXAMPLE 172 25 N-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1 -piperidinyl]ethyl]-4-hydroxyphthalimide hydrochloride A mixture of 2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1 -piperidinyl]ethyl]amine g, 18.9 mmol), 4-hydroxyphthalic acid (4.14 g, 1.2 eq), and dicyclohexylcarbodiimide (DCC, 8.61 g, 4.18 mmol) in dimethylformamide (50 ml, DMF) was stirred and heated at 75 0 C for 18 hours. The mixture was cooled, and the solids (DCU) were filtered and rinsed with dichloromethane (DCM). The solution was concentrated down to dryness. The residue was dissolved into dichloromethane (100 mi) and the insolubles, which contained the product also, 172 were filtered and collected. The solution was concentrated down to 50 ml and loaded onto a flash chromatography column (SiO2 50 g; eluted with OM, and methanol:DCM mixture). The desired product was c ethanol with an HCi 1.71 g. This solid was converted to the hydrochloride salt in in ether solution (IM, 5 ml). The crystals were collected and dried; weight: 1.2 g; m.p. 2 72-275'C dec.

ANALYSIS:

Calculated for C 2 2

H

2 oFN3 04OHCI 5 9.26%C 4.75%H 9.42%N Found: 59.08%C 4.60%H 9.34%N uorio- 3 di ridin I -1 2-benzisothiazole hcdrochloride A mixture of 6-fluoro-3-(4-Piperidinyl)-1, 2 benzisothiazole (3.9 9, 17 mmol),

K

2 C03 (2.3 g, 17 mmol, ()-3-hydroxybutyl tosylate (4.0 9, 16 mmol) and CH 3

CN

(100 ml) was stirred at reflux under

N

2 for 5 hours. The cooled reaction was filtered through Celite and the cake was rinsed with EtOAc. The filtrate was concentrated to afford 67 g of a red oil. Purification via preparative

PLC

(Water's Associates Prep CISystem 500, using 2 silica gel columns and MeOH-CH2CI2) provided 2.5 g of a beige solid. The product was dissolved in anhydrous Et 2 O and a minimal amount of MeOM and the solution was acidified V 0 with ethereal CI. Additional Et 2 O wasadded to precipitate 1.9 g of the HCI salt.

o fm e -Et2O gave 1.7 g and a second recrystallization from 00Recrystalization from MeOH-EOSv 12140 CH 3 CN yielded 1.0 g of a light beige powder, m.p. 8 2184 0

C.

ANALYSIS:

Calculated for Ci 6 H2,FN 2 OSoHCI: 5 5.72%C 6.43%H 8.12%N Found: 5 5.83%C 6.54%H 8.19%N EXAMPLE 174 Decnoc ci 11-det 13-4-6-fluor-,-bz-soxazo-3Y\ yI perld-in propyl ester hydrochlorideeridiny-1,2- To a solution of 6-fluoro-3-[.( 3 -hydroxy-3-ethylpentl)pp benzisoxazole (2.5 g, 7.48 mmol) in 0CM (100 ml) was added decanoyl chloride ml, 7.48 mmoI) at 0CC, under nitrogen. The reaction mixture was stirred for 4 173 days at which time it was poured into NaHCO3 (sat., 50 mi). The layers were sepraedand the aqueous phase was extracted with DOM The combined organics Were died filtered and concentrated ogv h rd rdc hc waspurfie vi fashcolmn ~~matography (silica gel, 20-40% EtOAcIDCM)- The product containing fractions were concetaed to givn30yg(8%)ouh desired product as a yellow oil. The hydrochloride salt was prepar red nyru ether (60 ml) and isopropanol (I MI) with ethereal HCI. The white salt was filtere and washed with anhydrous ether, M.P. 159-161-C.

ANALYSIS: 0JHI 63% .3H 53% Calculated for C 29

H

45 FN23 l 6 6.45%C 8.83%H 53i3%N Found: 6 .5C 90% .1 0 0 EXML 175 N 6FlurOI,2~en~5Oxz 3 I 1 rdnIeth I2,-nahthalimide N -L2 154 A 1 m FIur _o f 244(~ l~ o n iS Cx a 3 yl) -i p p rid in y leth Y a m in e (.g,7.58 mmol), and 2 3 naphthalenedicarboxv nyrde(.8g in (0mD )waheted at 150 0 C for 2 hours. At the end, the mixture was cooled and the solvent wareodtorys.Th residue was purified by flash chr 0 matography over silica gel column (60 g Of SiO2 eluted with dichloromethane (DCM), and 1.5% CH- 3 0H in DCM) h rdc crsalized out on concentration; weight' 1.6 g RecrystalliZation from **.ochloroform ethanol gave 1.38 g of off-white crytalsm p. 121 3C *ANALYSIS'.4% Calclate fr C 26

H~

2 2 FN33: 7042%C 5.o0%H 94% aFoutd 6 9.85%C 4.59%H 9.27%N 2,3-ih dro2 24-(6-fluoro-l,2-benzisoxazol I liperidin vIeth I-3-h drox yd ro 2 L2 3 -m eth I-i H- isoind o llI -o n e fumarate z l 3 y i i e i i yl 30 To the solution of N _[2_[4(6fluoro-l 2 -beflZsoxazo~ l appr d ded ethyllphthalimide (6.2 15.87 MMOl) inle 8 yd~u (TM,.5F, 802 ml) wasthe ade dropwise a solution of metylmagneium bromide (3M, 6. mlurs 12e ieThea room temperature under N. The mixture was stirred at 55 0 Cfo16husTe 174 reaction mixture was treated with NH 4 CI solution (10 ml) and partitioned between brine and ethyl acetate. The EtOAc solution was washed with brine and dried.

Filtration and concentration gave a crude product (3.9 This crude product was purified on a flash chromatography column (40 g, SiO 2 eluted with 0.5% CH 3

OH

in DCM). The pure product (1.75 g, 27%) thus obtained was treated with fumaric acid (500 m, 1.0 eq) in ethanol to yield 1.8 g, m.p. 167-168 0

C.

ANALYSIS:

Calculated for C 23

H

24

FN

3 0 3 *C4H404: 61.71%C 5.37%H 8.00%N Found: 61.47%C 5.67%H 7.82%N EXAMPLE 177 2,3-Dihydro-2-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-3methylene-1 H-isoindol-1-one hydrochloride 1 To the solution of 2,3-dihydro-2-[2-[4-(6-fluoro-l,2-benzisoxazol- 3 -yl)-1piperidinyl]ethyl]-3-hydroxy-3-methyl-1H-isoindol-1-one (4.88 g, 11.9 mmol) in chloroform (50 ml) was added HCI.ether (1M, 20 ml) solution. A precipitate formed. This mixture was stirred for 18 hours at room temperature. The mixture was basified with triethylamine and washed with brine. The organic solution was dried and concentrated to a crude material. The purification was done by flash 20 chromatography over silica gel column (SiO 2 60 g; eluted with DCM). The pure product thus obtained weighed 3.28 g Treatment with HCI*ether solution in ethanol gave 1.52 g of white crystals, m.p. 261-263°C.

ANALYSIS:

S. Calculated for C 23

H

20

FN

3 0*HCI: 64.56%C 5.42%H 9.82%N Found: 64.47%C 5.51%H 9.72%N EXAMPLE 178 -[2-[4-(6-Fluoro-1,2-benzisoxazol- 3 -yl-1 -piperidinylethyl]cyclohexanol hydrochloride To pentamethylene bis(magnesium bromide) (35.0 ml, 17.5 mmol, 0.5 M in THF) was added a solution of ethyl 3-[4-(6-fluoro-1,2-benzisoxazol- 3 -yl)-1piperidinyl]propionate (5.6 g, 17.5 mmol) in THF (100 ml) at 0°C, under nitrogenmild exotherm. The reaction mixture was warmed to room temperature and stirred 175 for 17 hours at which time it was carefully quenched with NH 4 CI (sat., 50 ml). The precipitated salts were dissolved into water (25 ml) and the layers were separated. The aqueous phase was extracted with EtOAc (2X) and the combined organics were then dried (Na 2 SO4). Filtration and concentration gave the crude product which was purified via flash column chromatography (silica gel, EtOAc/DCM then 100% EtOAc) to give 2.8 g of the desired product as a white solid. The hydrochloride salt was prepared in anhydrous ether (125 ml) and methanol (15 ml) with ethereal HCI, m.p. 210°C (dec.).

ANALYSIS:

Calculated for C 20

H

27

FN

2 0 2 .HCI: 62.74%C 7.37%H 7.32%N Found: 62.85%C 7.53%H 7.14%N EXAMPLE 179 5-(4-(6-Fluoro-12-benzisothiazol-3-yl)-1-piperidinyl-3-ethyl-3-hydroxypentane 15 hydrochloride To a stirred solution, under N 2 of ethyl 3-[4-(6-fluoro-1,2-benzisoxazol-3yl)-l-piperidinyl]propionate (5.3 g, 16 mmol) in THF (200 ml), was added dropwise, ethyl magnesium bromide (15.7 ml of a 3.0 M solution in Et 2 The reaction was stirred at ambient temperature for 16 hours and then following 20 cooling in an ice bath, a saturated solution of NH 4 CI was added dropwise. The aqueous mixture was extracted with EtOAc, and the extract was washed (H 2 0), dried (MgSO 4 and the solvent was concentrated to afford 5.8 g of a yellow oil.

The oil was chromatographed on a preparative HPLC, upon a silica gel column, .:eluting with 6% MeOH/CH 2 Cl 2 Concentration of the appropriate fractions yielded S 25 3.7 g of a yellow oil. The oil was dissolved in Et20 and ethereal HCI was added to precipitate 4.0 g of a white salt. The salt was recrystallized twice from EtOH-Et 2 0 to afford 1.4 g of the alcohol as a white solid, m.p. 207-209°C.

ANALYSIS:

Calculated for C 1 9

H

27

FN

2 0S.HCI: 58.98%C 7.29%H 7.24%N Found: 58.95%C 7.63%H 7.11%N 176 EXAMPLE 180 4-(6-Fluro-,2benzisoxazol- 3 -yl)-1-piperidinyl]-2-methylbutyl decanoate fumarate To a mixture of 4-[4-(6-fluoro-1,2-benzisoxazol- 3 -yl)-1-piperidinyl]- 2 methyl-2-butanol (4.68 g, 15.3 mmol) and triethylamine (2.23 g, 22.3 mmol) in chloroform (20 ml) was added decanoyl chloride (3.5 g, 18.4 mmol, 1.2 eq) dropwise at 0°C. The reaction was stirred at ambient temperature for 4 hours.

The solvent was removed. The residue was purified by flash chromatography over a silica gel column (SiO 2 65 g, eluted with DCM, 1 I, 1% CH 3 OH in DCM, 1 The product thus purified weighed 5.7 g as an oil. This oily product was converted to the fumarate salt in ethanol with fumaric acid (1.51 g, 1.0 eq) to yield 3.34 g, m.p. 133-1340C.

ANALYSIS:

Calculated for C 27

H

41

FN

2 0 3 "C4H404: 64.56%C 7.87%H 4.86%N Found: 64.42%C 7.74%H 4.78%N EXAMPLE 181 S[ 4(6-Fluoro-1 ,2benzisoxazol-3-yl)-piperidinylethyl]-?,3-dihydro-3-methyl- I H-isoindol-1-one hydrochloride 20 A mixture of 2-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]- 2 3 dihydro-3-hydroxy-3-methyl-1H-isoindol-1-one (3.96 g, 9.7 mmol) and lithium aluminum hydride (1.1 g, 50% in oil, 1.5 eq) in tetrahydrofuran (50 ml) was stirred at room temperature for 16 hours. The mixture was quenched carefully with a small amount of ice, then was diluted with ethyl acetate (200 ml). The mixture was stirred for 20 minutes. The insolubles were filtered. The organic solution was dried over MgSO4 and concentrated down to a yellow oil (4.5 This oil was purified by flash chromatography over silica gel column (SiO 2 58 g; eluted with DCM, 1 I, and 1% CH 3 OH in DCM). Only 1.91 g of desired product was obtained.

This material was treated with HCI (1M HCI in ether, 6 ml) in ethanol followed by isopropyl ether to yield 1.48 g m.p. 213-215 0

C.

ANALYSIS:

Calculated for C 23

H

24

FN

3 02.HCl: 64.25%C 5.86%H 9.77%N Found: 63.88%C 5.74%H 9.44%N 177 EXAMPLE 182 1-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1 -piperidinyl]ethyl]cyclopentanol hydrochloride In a flame-dried 500 ml round-bottom flask, equipped with addition funnel and condenser, was placed magnesium metal (3.4 g, 140 mmol) and anhydrous ether (20 ml). A solution of 1,4-dibromobutane (4.4 ml, 36.5 mmol) in anhydrous ether (10 ml) was then syringed into the addition funnel and added dropwise to the magnesium metal. Initially no reaction took place, but with the addition of a few crystals of iodine and gentle heating the Grignard reagent began to form. The rate of addition was such that a gentle reflux was maintained. Upon complete addition, the Grignard was stirred for 0.5 hours. A solution of 3-[4-(6-fluoro-1,2benzisoxazol-3-yl)-1-piperidinyl]propionate (9.0 g, 28.1 mmol) in THF (75 ml) was then added (dropwise, exothermic) at room temperature and stirred for 21.5 hours. The reaction mixture was carefully quenched with NH 4 CI (sat., 100 ml) and S. 15 the precipitated magnesium salts were dissolved into water (50 ml). The layers were separated and the aqueous phase was extracted with EtOAc The combined organics were dried (Na 2

SO

4 filtered and concentrated to give the crude product. Purification via flash column chromatography (silica gel, EtOAc/DCM) gave 6.2 g of the desired product as a white solid. The 20 hydrochloride salt was prepared in EtOAc (50 ml), ether (40 ml), and methanol 'ml) with ethereal HCI, m.p. 185-188 0

C.

ANALYSIS:

Calculated for C 19

H

25

FN

2 0 2 .HCI: 61.87%C 7.10%H 7.59%N Found: 61.79%C 7.09%H 7.53%N EXAMPLE 183 N-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-4-aminophthalimide fumarate A solution containing 2-[4-[(6-fluoro-1,2-benzisoxazol- 3 -yl)-1piperidinyl]ethyl]amine (6.8 g, 25.7 mmol), dicyclohexyl carbodiimide (DCC, 8.2 g, 39 mmol) and 4-aminophthalic acid (4.57 g, 25.2 mmol) in dimethylformamide (DMF, 100 ml) was heated at 110°C for 5 hours and kept at 65°C for 18 hours. At the end of the reaction, the solids (DCU) were filtered and the solvent was 178 removed on a rotary evaporator using a vacuum pump. The resulting crude product was purified by flash chromatography (SiO 2 130 g) and provided 7.5 g of the desired product. It was converted to the fumarate salt which was recrystallized from ethanol and isopropyl ether: 7.1 g, m.p. 229-230aC.

ANALYSIS:

Calculated for C 22

H

2 1 FN403oC 4 H404: 59.54%C 4.80%H 10.68%N Found: 58.99%C 4.79%H 10.37%N EXAMPLE 184 N-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl-6-pyrrolo- 3 ,4- 6]pyridine-5,7-dione fumarate A solution of 2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethylamine (4.14 g, 15.7 mmole) and 3,4-pyridinedicarboxylic anhydride (2.64 g, 17.7 mmol) in dimethylformamide (DMF, 100 ml) was heated at 130oC for 18 hours. The solvent was removed on the rotary evaporator with a vacuum pump. The residue was dissolved into ethanol (250 ml) and the insolubles were filtered. To the ethanol solution was added fumaric acid (1.82 g, 1.0 eq), then the solution was concentrated to 120 ml. Isopropyl ether (120 ml) was added and the mixture was stirred overnight. The white crystals (3.1 g, m.p. 203-206 0 C, were 20 collected and recrystallized again from ethanol to give 2.34 g of pure product, m.p. 208-209"C.

ANALYSIS:

Calculated for C 21

H

19

N

4 03*C 4 H404: 58.82%C 4.54%H 10.98%N S.Found: 58.59%C 4.67%H 10.71%N EXAMPLE 185 N-[2,3-Epoxypropyl)-4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidine fumarate A mixture of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (11 g, 50 mmol),

K

2 C0 3 (7.5 g, 54 mmol) and epibromohydrin (9 g, 54 mmol) in acetonitrile (150 ml) was heated at reflux for 16 hours. The mixture was filtered and concentrated to dryness. The crude product was purified by flash chromatography (Si0 2 180 g, eluted with methylene chloride (DCM), and 1-2% CH 3 OH in DCM). The material thus purified as off-white solids weighed 8.7 g This material (3 g) was 179 converted to fumnarate salt in ethanol and isopropyl ether to give 3.27 g of white crystals, m.p. =145-147*C.

ANALYSIS:

Calculated for C 15

H

1 7

FN

2 0 2 *04H404: 58.16%C 5.39%H 7.14%N Found: 57.93%C 5.35%H 7.02%N EXAMPLE 186 4-[3-f4-(6-Fluoro-1 ,2-benzisoxazol-3-yl)-1 -pprdiy]2hdoy1 -propoxy]phefnl methyl ether A mixture of 4-(6-fluoro-1,2bnioxzl3y~pprdn (4.4 g, 20 mmol) and 2,3-epoxypropyl-4-methoxyphenyl ether (3.7 g, 20.5 mmol) in isopropyl alcohol (80 ml) was heated to reflux for 2 hours. The mixture was cooled and the crystals were collected to yield 6.81 g m.p. 134-135 0

C.

for C 22

H

25

FN

2 0 4 65.99%C 6.29%H 7.00%N *Found: 66.11 %C 6.31 %H 6.84%N EXAMPLE 187 3-[4-(6-Fluoro-1 ,2-benzisoxazol-3-y)l piperidinyl]-2-hvdroxy -propyI phthalimide 20 A mixture of 4-(6-fluoro-1 ,2-benzisoxazol-3-yl)piperidine (5.5 g, 25 mmol) and N-(2,3-epoxypropyl)phthalimide (5.1 g, 25.5 mmol) in isopropanol (100 ml) was heated at reflux for 4 hours and stirred at 65'C for 18 hours. The reaction was cooled and the solvent was removed on a rotary evaporator. The white solids were dissolved in methylene chloride and purified on a silica gel column (110 g, eluted with 1% CH 3 0H in 0CM, 1.5 The pure product thus obtained weighed 7.91 g, 75%. Recrystallization from DCM and isopropyl ether yielded 4.0 g, m.p.

162-1 6300.

ANALYSIS:

Calculated for C 23

H

22

FN

3 04: 65.24%C 5.24%H 9.92%N Found: 65.00%C 5.05%H 9.77%N 180 EXAMPLE 188 1-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1 -piperidinyl]-3-phthalimido-2-propyl decanoate fumarate To a solution of 3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2hydroxy-1-propylphthalimide (6.26 g, 14.5 mmol), triethylamine (2.0 g, 20 mmol) in chloroform (200 ml) was charged with decanoyl chloride (3.6 g, 18.9 mmol, 1.26 equivalent) dropwise at room temperature. The mixture was stirred overnight. The mixture was concentrated and the crude product was purified on a flash chromatography column. The product thus obtained as an oil (4.96 g, 59%).

This oil was converted to fumarate salt in a dilute ethanol solution to yield 2.0 g, m.p. 138-140*C.

ANALYSIS:

Calculated for C 33

H

4 0

FN

3 0*C 4

H

4 04: 64.06%C 6.39%H 6.06%N Found: 63.90%C 6.39%H 5.88%N EXAMPLE 189 N-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-4-(1-decanoyl) aminophthalimide To a solution of 2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-4- 20 aminophthalimide (1.5 g, 3.67 mmol), triethylamine (0.46 mg, 4.6 mmol) in chloroform (30 ml) was charged with decanoyl chloride (0.8 mg, 4.2 mmol) dropwise at room temperature. The mixture was stirred for 1 hour. An additional portion of decanoyl chloride (0.1 mg, 0.52 mmol) was added to complete the reaction. The mixture was concentrated down, and the crude product was purified 25 on a flash chromatography column (30 g of silica gel; eluted with dichloromethane (DCM) and 1% CH 3 OH in DCM). The oily product was dissolved in ethanol and treated with ether to yield white crystals 1.04 g m.p. 159-160°C.

ANALYSIS:

Calculated for C 32

H

39

N

4 0 4 68.31%C 6.99%H 9.96%N Found: 68.47%C 7.27%H 9.95%N 181 EXAMPLE 190 N-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1 -piperidinyl]ethyl]-4-(1 decanoyl)oxyphthalimide fumarate To a mixture of 2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-l-piperidinyl]ethyl]-4hydroxyphthalimide (5.1 g, 12.5 mmol), triethylamine (2.09 g, 1.67 equiv) in chloroform (150 ml) was charged decanoyl chloride (3.8 g, 20 mmol) dropwise at room temperature. The mixture was stirred at room temperature overnight (16 hours). The solution was diluted with methylene chloride (DCM, 150 ml) and washed with brine. The organic solution was dried and concentrated to a crude mixture. Purification on a flash chromatography column (Si02, 100 g, eluted with DCM and 1% CH 3 OH in DCM) yielded a colorless oil (5.0 g, This product was treated with fumaric acid (1.0 g) in ethanol (30 ml) and isopropyl ether ml) to give 3.1 g of white crystals, m.p. 108-110°C.

ANALYSIS:

S 15 Calculated for C 32

H

38

FN

3 0 5

*C

4

H

4 04: 63.61%C 6.23%H 6.18%N SFound: 63.71 %C 6.30%H 6.25%N i EXAMPLE 191 4-[3-[4-(6-Fluoro- 1,2-benzisoxazol-3-yl)-1 -piperid inyl]-2-hyd roxy-1 -propoxyl-3- 20 methoxyphenyl methanone A stirred mixture of 4-(2,3-epoxypropoxy)-3-methoxyphenyl methanone (4.5 g, 22.5 mmol) and 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (5.36 g, 24.3 mmol) in isopropyl alcohol (150 ml) was heated at 55°C for 16 hours. The mixture "was cooled and the solvent was removed on a rotary evaporator. The residue 25 was purified by flash chromatography over a silica gel column (SiO 2 80 g; eluted with dichloromethane, DCM, and 1% CH 3 OH in DCM). The oil thus obtained solidified quickly, weight: 9.47 g. Recrystallization from ethanol and isopropyl ether, then toluene provided 8.6 g of white crystals, m.p. 107-1080C.

ANALYSIS:

Calculated for C 24

H

27

FN

2 0 5 65.15%C 6.15%H 6.33%N Found: 65.35%C 6.04%H 6.05%N 182 EXAMPLE 192 1 -[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-propanone hydrochloride A mixture of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (7.45 g, 33.4 mmol), K 2 C0 3 (5.5 g) and bromo-2,2-dimethoxypropane (6.84 g, 37.6 mmol) in acetonitrile (200 ml) was heated and stirred at reflux for 4 hours. An additional charge of bromo-2,2-dimethoxypropane (5.1 g, 28 mmol) was added and the mixture was refluxed overnight. After being cooled to room temperature, the mixture was filtered, and the solvent was removed on a rotary evaporator. The residue was purified by flash chromatography over a silica gel column (SiO 2 100 g; eluted with dichloromethane, DCM, and 1% CH 3 OH in DCM). The oil product thus obtained weighed 2.2 g The oil product was dissolved into ethanol ml) then was treated with HCI in ether solution (1M, 9 ml) at room temperature. The crystals were collected, 2.08 g, m.p. 220-223 0 C dec.

ANALYSIS:

15 Calculated for C 15

H

1 7

FN

2 0 2 *HCI: 57.60%C 5.80%H 8.96%N .Found: 57.49%C 5.97%H 8.67%N EXAMPLE 193 1 -[(4-Aceto-2-methoxy)phenoxy]-3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1 20 piperidinyl]-2-propyl decanoate fumarate To a stirred mixture of 4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1piperidinyl]-2-hydroxy-1-propoxy]-3-methoxyphenyl methanone (3.64 g, 8.23 mmol), triethylamine (1.6 g, 16 mmol) in chloroform (150 ml) was added decanoyl chloride (2.35 g, 12.4 mmole, 1.5 eq) dropwise at room temperature. The mixture 25 was then heated at reflux for 1 hour. The mixture was cooled and diluted with methylene chloride (DCM) and washed with water and brine. The organic solution was dried and concentrated to a crude mixture. Purification on a flash chromatography column (SiO 2 65 g; eluted with DCM, 0.4 I and 1% CH 3 OH in DCM, 0.6 I) yielded a colorless oil: 3.29 g This product was treated with fumaric acid (623 mg) in ethanol (10 ml) and isopropyl ether (50 ml) to give 2.64 g of a white solid, m.p. 109-110°C.

ANALYSIS:

Calculated for C34H 45 FN206*C 4

H

4 0 4 64.03%C 6.93%H 3.93%N 183 Found: 63.86%C 6.88%H 3.74%N EXAMPLE 194 N-[2-[4-(6-Fluoro-1I,2-benzisoxazol-3-yt)- I -piperid inyllethyllth iaphthalimide A mixture of N uoro-1, ,2-benzisoxazol-3-yI)- 1 -pipe rid inyllethyl]phthalimide (3.93 g, 10 mmol) and 2,4-bis(4-methoxyphelyl)-1 ,3,2,4dithiadephosphetane-2,4-disulflde (2.02 g, 5 mmol, 1 equiv. Lawesson's Reagent) is stirred and heated in anhydrous tetrahydrofuran for 3 hours at 600C. The reaction mixture is evaporated on silica gel and purified by chromatography on a silica gel column. The product is further purified by recrystallization to afford N-[2fluoro-1 ,2-benzisoxazol-3-yl)-l -piperidinyl] ethyllthiaphthalimide.

EXAMPLE 195 By using substantially the same procedure as described in Example 194 15 except that 10 mmol (2 equiv.) of Lawesson's Reagent is used and the reaction time at 6000 is extended to 5 hours there is obtained N-12-[4-(6-fluoro-1 ,2benzisoxazol-3yl)-1 -piperidinyl]ethyl-1 ,3-bis-thiaphthalimide.

EXAMPLE 196 20 2-[2-[6-Fluoro-1,2bnioao -l--pprdnlpoylmn dihydrochioride hernihyd rate 2-[4-[6-Fluoro- 1, 2-benzisoxazol-3-yI) 1 -piperidinyl~propioflit rile A mixture of 4-(6-fluoro-1 ,2-benzisoxazol-3-yl)-1-piperidine (10 g, 45.4 mmol); 2-chloropropionitril (10 g, 112 mmol), K 2 00 3 (9.4 g, 1.5 eq) in acetonitrile (100 ml) was stirred and heated at 8000 for 16 hours. The mixture was filtered and concentrated to dryness. The crude solids were purified by flash chromatography (SiO 2 160 g; eluted with methylene chloride, (DOM) 1.5 1; and 1% CH 3 0H in 0CM, 1 The white solid material thus obtained weighed 10.1 g and was recrystallized from ethanol and isopropyl ether to yield 5.1 g, m.p. 133- 1340C.

ANALYSIS:

Calculated for C 15

HI

6

FN

3 0: 65.92%C 5.90%H 1 5.37%N 184 Found: 65.92%C 5.85%H 15.52%N 2-[4-(6-Fluoro-1, 2-benzisoxazol-3-yl)- 1-piperidinyl]propyl]amine dihydrochloride hemihydrate To a solution of 2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1 piperidinyl]propionitrile (6.7 g, 24.5 mmol) in THF (200 ml) was added lithium aluminum hydride (3.6 g, 50% in oil, 2 eq) in portions under N 2 at room temperature for 3.5 hours. At the end of the reaction, the excess of LAH was carefully hydrolyzed with ice-chips (7 ml) under N 2 A solution of 15% NaOH (2 ml) was added, then the mixture was stirred for 30 minutes. The insolubles were filtered and the organic solution was concentrated down to a pale oil (7.6 g) which partially solidified. A sample (1.5 g) of this mixture was dissolved into ethanol and was treated with HCI (6 ml, 1 M in ether). The white solid which precipitated was collected and recrystallized from ethanol to give 708 mg, m.p. 215-217 0 C of the 15 dihydrochloride hemihydrate.

S

ANALYSIS:

Calculated for C 15

H

20

FN

3 Oo2HCI0.5H 2 0: 50.14%C 6.45%H 11.69%N 2.50%H 2 0 Found: 49.94%C 6.17%H 11.11%N 2.12%H 2 0 20 EXAMPLE 197 N-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1 -piperidinyl]propyl]phthalimide hydrochloride To a stirred mixture of 2-[4-[(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propyl]amine 2.56 g, 9.2 mmol) and triethylamine (1.35 g, 13.5 mmol) in 25 chloroform (150 ml) was added phthalic anhydride (1.61 g, 10.9 mmol). The mixture was stirred at room temperature for 4 hours. At the end of the reaction the solvent was evaporated on a rotary evaporator and the crude residue was dried in vacuo. The purification was done by flash chromatography over a silica gel column (40 g, SiO 2 eluted with methylene chloride, then increase the MeOH concentration to The pure product thus obtained (2.18 g) was combined with another batch of same quality material (1.53 g) and then was converted to the hydrochloride salt with HCI in ether solution. The white solid was recrystallized from methanol to give 3.12 g, m.p. 275-277°C.

185

ANALYSIS:

Calculated for C 23

H

22

FN

3 0 3 HCI: 62.23%C 5.22%H 9.47%N Found: 61.93%C 5.32%H 9.46%N EXAMPLE 198 N-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1 -piperidinyl]ethyl]-3methoxyphthalimide hydrochloride A mixture of 2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-l-piperidinyl]ethyl]-3hydroxyphthalimide hydrochloride (4.36 g, 10.33 mmol) and K 2 C0 3 (3.6 g, 26 mmol) in methanol was stirred for 15 minutes. Then dimethylsulfate (4.0 g, 3.17 mmol) was added, followed by potassium t-butoxide (1.1 g, 10 mmol) and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated and the residue was extracted with DCM (400 ml). The organic layer was filtered and concentrated and the resulting residue was 15 chromatographed on silical gel (47 g SiO 2 eluting with DCM and MeOH:DCM S: mixture. The resulting product (1.4 g) was converted to the hydrochloride salt in ethanol with 1N-HCI in ether. The resulting white solid was recrystallized from methanol to give 1.12 g, mp 247-250°C.

ANALYSIS:

Calculated for C 23

H

22

FN

3 0 4 *HCI: 60.07%C 5.04%H 9.14%N Found: 59.79%C 5.05%H 8.98%N EXAMPLE 199 6-Fluoro-3-[1-[3-(2,5-dimethoxyphenoxy)propyl]-4-piperidinyl]-1,2-benzisoxazole *i 25 hydrochloride 2-(3-Chloropropoxy)-1,4-dimethoxybenzene A mixture of 2,5-dimethoxyphenol (29 g, 0.19 mol), K 2 C0 3 (35 3chlorobromopropane (38.5 g, 0.25 mol) and acetone (250 ml) was stirred and refluxed for 6 hours, and then stirred at ambient temperature for 16 hours. The reaction was filtered, and the filtrate was concentrated to an orange liquid. The liquid was taken up into Et20, and the organic layer washed with 1N NaOH, H 2 0, dried (MgSO 4 and was concentrated to yield 37.8 g of an orange solid. An 11.7 g 186 sample of this solid was flash chromatographed on silica gel (180 g) with EtOAc/CH 2

CI

2 as eluent. Concentration of similar fractions gave 7.2 g of white, waxy solid, which was recrystallized from petroleum ether to afford a white solid, m.p. 48-50°C.

ANALYSIS:

Calculated for C 11

H

15 CI0 3 57.27%C 6.55%H Found: 57.19%C 6.52%H 6-Fluoro-3-[1-[3-(2,5-dimethoxyphenoxy)propyl]-4-piperidinyl]-1,2benzisoxazole hydrochloride A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (3.0 g, 14.0 mmol), 2-(3-chloropropoxy)-1,4-dimethoxybenzene,

K

2 C0 3 (2.1 g) and acetonitrile mL) was stirred and refluxed for 24 hours. The reaction was filtered and the *i filtrate was concentrated to 5.0 g of an oil. The oil was chromatographed on a preparative HPLC on a silica gel column with 5% MeOH-CH 2 Cl 2 as eluent.

Concentration of the appropriate fractions afforded 4.6 g of an oil, which, with ethereal HCI, was converted to 4.0 g of a white hydrochloride salt. The salt was recrystallized twice from EtOH to yield 2.9 g of product as a white solid, m.p. 186- 188 0

C.

ANALYSIS:

Calculated for C 23

H

27

FN

2 0 4 oHCI: 61.26%C 6.26%H 6.21%N Found: 61.14%C 6.38%H 6.15%N EXAMPLE 200 25 4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-2-hydroxy-5methoxy-alpha-methylbenzenemethanol 1-[4-(3-Chloropropoxy)-2-hydroxy-5-methoxyphenyl]ethanone A mixture of 2,4-dihydroxy-5-methoxyacetophenone (1.4 g, 7.7 mmol),

K

2 C0 3 (1.4 g, 10.0 mmol), 3-chlorobromopropane (1.6 g, 10.0 mmol) and acetone mL) was stirred and refluxed under N 2 for 16 hours. The reaction was poured into H 2 0, and the aqueous suspension was extracted with ethyl acetate. The extract was washed (H 2 0, brine) dried (MgSO 4 and concentrated to yield 1.4 g of 187 an offwhite solid. Recrystallization twice from ethanol afforded 0.4 g of the alkylated phenol as a solid, m.p. 99-101 C.

ANALYSIS:

Calculated for C 12

H

1 5 CI0 4 55.71%C 5.84%H Found: 55.61%C 5.92%H 1-[4-[3-[4-(6-Fluoro- 1,2-benzisoxazol-3-yl)-1-piperidinylipropoxy]-2- A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (4.2 g, 19 mmol), 1-[4 (3-chloropropoxy)-2-hydroxy-5-methoxyphenyl]ethanone (5.0 g, 19 mmol), NaHCO3 (1.8 g, 20 mmol) and acetonitrile (120 mL) was stirred and refluxed for 16 hours. The reaction was filtered and the filtrate was concentrated to a dark oil.

The oil was taken up in anhydrous ether and ethereal HCI was added to ii: precipitate 8.7 g of art off-white hydrochloride salt. A 2.0 g sample of the salt was 15 converted to its free base and chromatographed by preparative HPLC (silica gel with 5% MeOH/CH 2 Cl 2 as eluent). Concentration of the desired fractions gave 1.1 g of a white solid, which was recrystallized from EtOH to yield 0.85 g of the product, m.p. 122-124"C.

ANALYSIS:

Calculated for C 24

H

27

FN

2 0 5 65.15%C 6.15%H 6.33%N Found: 64.93%C 6.23%H 6.20%N 4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)--piperidinyl]propoxy]-2-hydroxymethoxy-alpha-methylbenzenemethanol 25 To a stirred solution of 4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1- (3.0 g, 6.8 mmol) in tetrahydrofuran/ethanol (70 ml, 4:3) was added sodium borohydride (0.26 g, 6.8 mmol). The reaction was stirred at ambient temperature for 0.75 hours, and then concentrated to afford a thick oil. The oil was triturated with H 2 0 and the aqueous suspension was extracted with CH 2

CI

2 The extract was washed with H 2 0, dried (MgSO 4 and concentrated to afford 3.4 g of a white solid. The solid was recrystallized from MeOH and then from EtOH to yield 0.80 g of solid, m.p. 156- 1580C.

188

ANALYSIS:

Calculated for C 24

H

29

FN

2 0 5 64.85%C 6.58%H 6.30%N Found: 64.73%C 6.58%H 6.13%N EXAMPLE 201 N-[2-[4-(6-Fluoro-1 ,2-benzisoxazol-3-y)-1 -piperidinyllethyl]phthalimide fumnarate A solution of fumaric acid (448 mg, 3.86 mmol) in ethanol was added to a hot solution of 2-[4-(6-fluoro-1 ,2-benzisoxazol-3-yl)-1 -piperidinyl]ethyl]phthalimide (1.52 g, 3.86 mmol) in ethanol. The solution was cooled and the crystals were collected to yield 1.9 g. Recrystallization once from ethanol yielded 1.15 g of the fumarate salt, m.p. 231-232'C.

ANALYSIS:

Calculated for C 22

H

2 oFN 3 0 3

*C

4

H

4 0 4 61 .29%C 4.75%H 8.25%N Found: 61.03%C 4.68%H 8.38%N EXAMPLE 202 N-[2-[4-(6-Fluoro-1 ,2-benzisoxazol-3-yl)-1 -piperidinyllbutyllphthalimide I -[2-(6-Fluoro-I, 2-benzisoxazol-3-y)- I-piperidinylJ-2-hydroxybutane A stirred mixture of 4-(6-fluoro-1 ,2-benzisoxazol-3-yl)piperidine (5.5 g, mmol) and 1,2-expoxybutane (1.89 g, 26.3 mmol) in isopropyl alcohol (100 ml) was heated at 65 0 C for 2 days. This mixture was cooled and the solvent was removed to leave a brown oil which was purified by flash chromatography over a silica gel column (SiO 2 70 g; eluted with DCM, 1 I and MeOH:DCM 98%) to 25 give an off-white solid weighing 6.3 g. Recrystallization from hot ethanol yielded 1.96 g of fine crystals, m.p. 87-88*C.

ANALYSIS:

Calculated for C 16

H-

21

FN

2 0 2 65.73%C 7.24%H 9.58%N Found: 65.83%C 7.12%H 9.54%N N-[2-[4-(6-Fluoro-I, 2-benzisoxazol-3-y)- I-piperidinyl~butyl]phthalimide A solution of diethyl azodicarboxylate (DEAD, 4.9 g, 28.3 mmol) in THF ml) was added dropwise to a solution of 2-[4-(6-fiuoro-1 ,2-benzisoxazol-3-y)-1- 189 piperidinyl]butanol (6.9 g, 23.6 mmol), phthalimide (4.16 g, 1.2 eq), and triphenylphosphine (7.4 g, 28.3 mmol) in TMF (200 ml) at room temperature. The solution was stirred at room temperature for 24 hours. After the reaction, the solvent was stripped to dryness. The residue was stirred in ether (200 ml) and the insolubles were removed by filtration. The oily residue from concentration of the ether solution was purified by two flash chromatography (SiO 2 75 g, eluted with dichloromethane, DCM, and 1-2% CH 3 OH in DCM) and (100 g of SiO 2 eluted with DCM, 1 I, and 1% CH 3 OH in DCM, 1.2 Two close compounds were separated and the top compound on TLC (1.6 g) was recrystallized from isopropyl ether to yield 0.76 g of white crystals, m.p. 86-88 0

C.

ANALYSIS:

Calculated for C 24

H

24

FN

3 0 3 68.39%C 5.74%H 9.97%N Found: 68.47%C 5.67%H 9.97%N 15 EXAMPLE 203 N-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]butyl]phthalimide hydrochloride .0 A solution of diethyl azodicarboxylate (DEAD, 4.9 g, 28.3 mmol) in THF ml) was added dropwise to a solution of 2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1piperidinyl]butanol (6.9 g, 23.6 mmol), phthalimide (4.16 gm, 1.2 eq), and triphenylphosphine (7.4 g, 28.3 mmol) in THF (200 ml) at room temperature. The solution was stirred at room temperature for 24 hours. After the reaction, the solvent was stripped and the residue was stirred in ether (200 ml). The insolubles .1 were removed by filtration. The oily residue from concentration of the ether S: 25 solution was purified by two flash chromatography (SiO 2 75 g; eluted with dichloromethane, DCM, and 1-2% CH 3 OH in DCM) and (SiO 2 100g; eluted with DCM, 1 I; and 1% CH 3 OH in DCM, 1.2 Two close compounds were separated.

The lower compound on TLC 3.66 g was treated with HCI/ether in ethanol, and the solid salt was precipitated with hexane. Recrystallization from ethanol and isopropyl ether yielded white crystals 3.26 g, m.p. 210-214 0 C dec.

ANALYSIS:

Calculated for C 24

H

24

FN

3 03*HCI: 62.95%C 5.50%H 9.18%N Found: 62.70%C 5.58%H 9.13%N 190 EXAMPLE 204 4-Fluoro-N-[2-[4-(6-fluoro-1 H-indazol-3-yl)-1 -piperidinyl]ethyl]phthalimide maleate -Benzoyl-6-fluoro-3-(1-phenoxycarbonyl-4-piperidinyl) -1H-indazole To a solution of 1-benzoyl-6-fluoro-3-(1-methyl-4-piperidinyl)-1H-indazole g, 5.93 mmol) in dichloromethane (100 ml) was added phenyl chloroformate (3.9 ml, 29.65 mmol) at room temperature. The reaction mixture was stirred at room temperature for 24 hours, refluxed for an additional 0.5 hours and subsequently concentrated. The remaining residue was dissolved into dichloromethane and washed with 10% HCI The organic phase was dried (MgSO4), filtered, and concentrated to give an oil which was purified via flash column chromatography (silica gel, 20% DCM/EtOAc). Concentration of the product-containing fractions gave an oil which solidified on standing. The white solid was washed with EtOAc, leaving 0.47 g of the desired product, m.p. 137- 15 139 0

C.

ANALYSIS:

SCalculated for C 26

H

22

FN

3 0 3 70.42%C 5.00%H 9.48%N Found: 70.38%C 4.81 %H 9.42%N [4-(6-Fluoro- 1H-indazol-3-yl) -piperidinyl]acetonitrile 00 To a suspension of 1-benzoyl-6-fluoro-3-(1 -phenoxycarbonyl-4-piperidinyl)- 1H-indazole (31.6 g, 71.3 mmol) in ethanol (500 ml) was added 50% KOH(aq.) (100 g of KOH in 100 g H 2 0) at room temperature. The reaction mixture was warmed to reflux for 4 hours and cooled to room temperature. After adjusting the 25 pH to about one (to litmus) using HCI (con., 110 ml), the volatiles were removed under reduced pressure. The remaining wet solid was diluted with water and collected via filtration. The solid material was dissolved into hot water to which NaOH(aq.) was added (pH was about 10, to litmus). The precipitated 4-(6fluoro 1H-indazol-3-yl)piperidine (10.7 g) was filtered and used without further purification.

To a stirred suspension of 4-(6-fluoro-IH-indazol-3-yl)piperidine (4.95 g, 22.6 mmol) and NaHCO 3 (2.1 g, 24.9 mmol) in dry acetonitrile (110 ml) was added chloroacetonitrile (1.6 ml, 24.9 mmol) at room temperature, under nitrogen.

191 The suspension was warmed to reflux for 22.5 hours, cooled to room temperature, and subsequently filtered. The remaining solids were washed with DCM and the combined filtrates were concentrated. The resulting brown oil was dissolved into EtOAc and washed with water. The organic phase was dried (MgS04), filtered and concentrated to give a brown solid which was re-dissolved into DCM/EtOAc and flushed through alumina with DCM. The eluent was concentrated to give 5.2 g of the desired product as a solid, m.p. 149-151 C.

ANALYSIS:

Calculated for C 14

H

15

FN

4 65.10%C 5.85%H 21.69%N Found: 64.84%C 5.90%H 21.74%N 2-[4-(6-Fluoro-1 H-indazol-3-yl)-1 -piperidinyl]ethylamine To a solution of [4-(6-fluoro-1H-indazol-3-yl)-1-piperidinyl]acetonitrile (6.1 g, 23.6 mmol) in dry THF (235 ml) was added (dropwise) lithium aluminum hydride (LAH) (28.4 mmol, 1.0 M in THF) at room temperature, under nitrogen.

Upon complete addition, the reaction mixture was warmed to reflux for 3 hours.

After cooling to 0°C in an ice bath, the reaction was carefully quenched with water (4.0 ml). The solids were removed via filtration and washed with THF. The o combined filtrates were concentrated to give 5.6 g of the desired product. This material was suspended in DCM and filtered to give the product as an off-white solid, m.p. 125-128 0

C.

ANALYSIS:

Calculated for C14H19FN4: 64.10%C 7.30%H 21.36%N Found: 63.60%C 7.10%H 21.03%N e 4-Fluoro-N-[2-[4-(6-fluoro- 1H-indazol-3-yl) -1-piperidinyl]ethyl]phthalimide maleate To a solution of 2-[4-(6-fluoro-IH-3-indazolyl)-1-piperidinyl]ethylamine (6.1 g, 23.3 mmol) in DMF (230 ml) was added 4-fluorophthalic anhydride (4.2 g, 25.5 mmol) at room temperature under nitrogen. The reaction mixture was warmed to 0 C for 2.5 hours at which time it was allowed to cool to room temperature. The DMF was removed under reduced pressure to give a brown oil which was dissolved into DCM/MeOH. Purification via flash column chromatography (silica 192 gel, 2% MeOH/DCM) afforded 3.6 g of the desired product as a white solid. The maleate salt was prepared in methanol (75 ml) using maleic acid (2.1 The precipitated salt was collected via filtration and recrystallized from acetonitrile to give a white solid, m.p. 193-195C.

ANALYSIS:

Calculated for C 22

H

2 0

F

2

N

4 0 2

*C

4

H

4 0 4 59.31%C 4.59%H 10.64%N Found: 59.15%C 4.80%H 10.80%N EXAMPLE 205 3-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1 -piperidinyl]ethyl]-2-methyl-3Hquinazolin-4-one A stirred mixture of 3-(4-piperidinyl)-6-fluorobenzisoxazole (4 g, 18.2 mmol), K 2

CO

3 (3.76 g, 27.2 mmol) and 3-(2-chloroethyl)-2-methyl-3H-4quinazolinone (6.0 g, 27 mmol) in acetonitrile (300 ml) was heated at reflux for 16 15 hours. The reaction was complete as judged by TLC. The solids were filtered and the solvent was evaporated. The residue was purified over a flash chromatography column (SiO2,,75 gm, eluted with dichloromethane and MeOH in dichloromethane). The pure product thus obtained weighed 6.5 gm.

Recrystallization from ethanol yielded white crystals, 3.94 gm m.p. 164- 1650C. This material appeared pure by TLC over silica gel plates.

ANALYSIS:

Calculated for C 23

H

23

FN

4 0 2 67.97%C 5.70%H 13.78%N Found: 67.66%C 5.66%H 13.60%N 25 EXAMPLE 206 4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1 -[3-(2,3-dihydro-1 H-isoindol-2yl)propyl]piperidine difumarate A stirred mixture of 3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1 piperidinyl]propyl amine (3.46 g, 12.5 mmol), K 2

CO

3 (4 g, 29 mmol) and a,adibromo-o-xylene (3.3 g, 12.5 mmol) in acetonitrile (300 ml) was heated at reflux for 3.5 hours. The mixture was cooled and the insolubles were filtered. The dark red solution was concentrated down to a dark oil. This oil was purified by flash chromatography over a silica gel column (SiO 2 45 g; eluted with dichloromethane 193 and MeOH in dichloromethane). The product thus obtained weighed 1.95 g as an oil. This oil was dissolved in ethanol and was treated with a solution of fumaric acid (600 mg) in ethanol. The resulting crystals were collected as an off white solid and weighed 1.44 gm, m.p. 206-209 0

C.

ANALYSIS:

Calculated for C 23

H

26

FN

3 0*2C 4

H

4 0 4 60.88%C 5.60%H 6.87%N Found: 60.47%C 5.81%H 6.84%N EXAMPLE 207 4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1 -[2-(2,3-dihydro-1 H-isoindol-2-yl)ethyl]piperidine dihydrochloride A mixture of 2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethylamine (2.67 g, 10.1 mmol), a,a-dibromo-o-xylene (2.76 g, 10.4 mmol) and K 2 C0 3 (3.2 g, 23 mmol) in acetonitrile (300 ml) was heated at reflux for 1 hour. The mixture 15 turned pinkish and reaction was complete. The mixture was cooled, then filtered.

The solution was concentrated down to a foam. Extraction with ether yielded 1.13 g of off-white solids. This material was dissolved into methanol with another batch (1.15 prepared in a similar way, and was treated with ethereal HCI-ether ml, 1 The crystals which formed weighed 2.35 g, with m.p. =259-262°C.

ANALYSIS:

Calculated for C 22

H

24

FN

3 0 2 o2HCI: 60.28%C 5.98%H 9.59%N Found: 59.98%C 5.83%H 9.48%N EXAMPLE 208 25 4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1 -[2-(5-fluoro-2,3-dihydro-1 H-isoindol-2yl)ethyl]piperidine difumarate To a solution of 2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl-4fluorophthalimide (4.5 g, 10.9 mmol) in tetrahydrofuran (120 ml) was charged with a solution of lithium aluminum hydride (35 ml, 35 mmol, 1M in ether) dropwise under N 2 at room temperature. The mixture was stirred at room temperature for 24 hours. The excess of hydride was quenched carefully with ice chips and 5 ml of 20% NaOH. The mixture was stirred for 1 hour, diluted with EtOA (200 ml) then filtered. The organic solution was concentrated to dryness. The residue was 194 purified by flash chromatography over a silica gel column (SiO2, 70 gm; eluted with 1% CH30H: 99% dichloromethane). The product thus obtained (weighed g) was dissolved into ethanol and treated with a solution of fumaric acid (918 mg) in ethanol. The crystals formed were collected to yield 2.25 g of white crystals, m.p. 228-229"C.

ANALYSIS:

Calculated for C 22

H

23

F

2

N

3 0*2C 4

H

4 0 4 58.53%C 5.08%H 6.83%N Found: 58.48%C 4.98%H 6.78%N EXAMPLE 209 4-(6-Fluoro-1 2-berzisoxazol-3-yl)-1-(2,3-dihydro-l H-isoindol-2yl)propyl]piperidine fumarate A stirred mixture of 2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1 piperidinyl]propylamine (2.92 g, 10.5 mmol), cc-a-dibromo-o-xylene (3.0 g, 11.03 15 mmol) and K2C0 3 (3.5 g, 25.3 mmol) in aceotnitrile (150 ml) was heated at reflux for 6 hours. The insolubles were filtered off. The solvent was removed on a rotary evaporator. The residue was purified twice by flash chromatography over a silica gel column (40 g and 45 g of silica gel). The product after purification weighed 1.15 g. This oil was treated with a solution of fumaric acid (490 mg) in ethanol.

The off white crystals were collected to yield 680 mg,m.p. 164-165*C.

ANALYSIS:

Calculated for C 23

H

26

FN

3 0C 4

H

4 0 4 65.44%C 6.10%H 8.48%N Found: 64.83%C 6.01 %H 8.08%N 25 EXAMPLE 210 N-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1 -piperidinyl]-2-hydroxy-1 -propyl]-2,3dihydro-1 H-isoindole dihydrochloride To a stirred mixture of 1-(3-amino-2-hydroxypropyl-4-(6-fluoro-1,2benzisoxazol-3-yl)piperidine (2.24 g, 7.6 mmol), K 2 C0 3 (1.61 g, 11.7 mmol) in acetonitrile (100 ml) was added a,a-dibromo-o-xylene (1.54 g, 6.1 mmol). The mixture was heated at reflux for 4 hours then cooled. The insolubles were filtered.

The dark red solution was concentrated down. The residue was purified by flash chromatography over a silica gel column (SiO2, 30 g; eluted with 1% CH 3 OH in 195 dichloromethafle). The product so obtained weighed 940 mg as an oil. This oil was dissolved in ethanol and was treated wit acoltiond ofcrHtie ethain 18 mg of AcCI in ethanol). The dark solids werecolteanrcysllzdginn ethanol to yield off-white crystals (1 .01 m.p. 240-2430C.

ANALYS-IS:

Calculated for

C

23

H

26

FN

3 02oHCI: 58-98%C 6.03%H 8.97%N Found: 58.72%C 6.16%H 8.94%N EXAMPLE 211 N2-4- 6-Fluoro-l ,22- benzzisoxazol-3-YL)-i pe (triiso orpylsilyl oxy-1 H-isoindole difuarate A mixture of 2-[4-(6-fluoro-l ,2-benzisoxazol-3-yl)-l-pprdiylthlmn (1 52 acet3mol,1,-ibo oitrile (300 mill)x-y was (2.4 g, 5.7 mmol) and 1(2003 (1.8 9, 13 mmOl) in aeoirl(30m)wsstirred overnight (18 i hours) at room temperature. The mixture was filtered and the solvent was stripped. The residue was purified by flash chromatography over a silica gel 0.*.colmn gmof iO 2 ;elued ith 1-3%

CH

3 0H in dichloromethane. The product thus purified (weight: 900 mg) was convre totefm re a leytedatmnt with fumaric acid (194 mg) in hot ethanol. The crystals wercoltean weighed 590 mg, m.p. 208-21 000.

ANALYSIS:

*..*Calculated for

C

31

H

44

FN

3 02Si92C4H4 0 4: 60.84%C 6.81%H 5.46%N Found: 60.41%C 6.87%H 5.35%N EXAMPLE 212 N~I~4-6-HuOro -1,2 -benzisoxazol3Yl 1 -pp rdfl le l 2 ,3 dih ydroxy-A H-isoindole fumarat hyre To a stirred solution of N-I2-[4(6fluoro-1,2-benzisoxazol3yi)) pieiiyltyl23dhdo5(eiorpliy)x- H-isoirndole (11.5 g, 21.5 mmol) in tetrahydrofuran (50 ml) was added a solution of tetrabutyfl ammonlium fluoride (1 M in tetrahydrofuran, 24 ml, 24 mmol) in portions at room temperature.

The mixture was stirred for 2 hours, then diluted with methylene chloride (200 ml).

The organlics was washed with H-20 and brine, dried with anhydrous MgSO4- The 196 solvents were removed and the residue was purified by flash chromatography over a silica gel column (90 g of SiO2; eluted with 1-4% of CH 3 OH in methylene chloride). The desired fractions were combined and concentrated to give 1.5 g of free base. This solid was recrystallized from ethanol to yield 570 mg of off white crystals. The crystals were converted to fumarate salt in hot ethanol and water to give pinkish crystals, 560 mg, m.p. 191-193°C.

ANALYSIS:

Calculated for C 2 2

H

24

FN

3 0 2 *C4H404H2 0 60.57%C 5.87%H 8.15%N Found: 60.20%C 5.73%H 8.04%N Found: EXAMPLE 213 4(6-Fluoro H-indazol-3-yl -2-(2,3-dihyd r 1 H-isoindol-2-yl)eth !I oH Tndazol 4- y dimaleate To a solution of N-[2-4-(6-fluoro-H-indazol-3-yl)-1-piperidinyl]ethyl] phthalimide hydrochloride (Example 167) (3.1 g, 7.91 mmol) in TEIF (100 ml) was c "solution in THF, 16.6 mmol) added lithium aluminum hydride (16.6 ml of a 1.0 M solution in THF, 16.6 mmol) o at room temperature, under nitrogen. The reaction mixture was warmed to reflux for 6.5 hours and cooled to room temperature. The reaction was quenched with water (1.5 ml, dropwise) and the precipitated salts were removed via filtration.

20 The solids were washed with DCM and the combined filtrates concentrated to give 2.5 g of the crude product as a solid. The dimaleate salt was prepared in methanol using 3.5 g of maleic acid. The light green precipitate was collected via filtration and washed with methanol. Recrystallization from methanol gave 2.1 g of the desired product as an off-white solid, m.p. 196-199 25 ANALYSIS: 9.

Calculated for C 22

H

25

FN

4 2C4H4 0 4: 60.40%C 5.58%H 9.39%N Found: 60.33%C 5.42%H 9.42%N EXAMPLE 214 S2 -6-Fluoro- 2 ben z is o'piperidi n -mid 6 fluoro 1 2 benzis o xaz o l3 yl l pi peridinylacetam ide 197 The mixture of 4-(6fluoro-1, 2 -benzisoxazol3-yl)piperidine (6.77 g, 30.7 mmol), K2C03 (5 g, 36.2 mmol) and 2-bromoacetamide (4.46 g, 32.3 mmol) in acetonitrile (250 mi) was heated to reflux for 4 hours. The insolubles were filtered and rinsed with dichloromethane (DCM). The solvents were removed. The residual solid was dissolved in DCM and upon concentration of this solution, 2.3 g of product crystallized out and was collected when the volume was reduced to about 50 mi. The rest of the product in DCM was purified by flash chromatography over a silica gel column (80 gm, SiO 2 eluted with DCM and 1

CH

3 OH in DCM). The total product (4.2 g) thus purified was recrystallized from ethanol to yield 2.82 g of white crystals, m.p. 170-1720 C dec.

ANALYSIS 582%H 15.15%N Calculated for C1 4 H1 6 FN302: 60.64%C 5.82%H 15.15%N Found: 60.66%C 5.87%H 15.10%N 15 2-[4-(6-Fluoro-1,2-benzisoxazol-3-yi)--piperidinyl]-l-(2,3-dihydro-1Hisoindol-2-yI)-ethanone Ssoo-2-y xture of 2 -4-(6-floro-1 ,2-benzisoxazol-3-yl)-1piperidinyl]acetamide (2.56 g, 9.2 mmol) in DMF (40 ml) was chipped in sodium hydride (770 mg, 60% in oil, 20.1 mmol) at room temperature under

N

2 The 20 mixture was heated to 65C for 3 hours. a,a-dibromoxylene (2.43 g, 9.2 mmol) was added and the resulting mixture was heated at 700C for 4 hours, then left standing overnight for 16 hours. The DMF mixture was poured into H 2 0 (400 ml) and the organics were extracted into ethyl acetate (250 ml). The ethyl acetate solution was washed with brine and dried over MgSO4. The solvent was removed and the residue was purified by flash chromatography over a silica gel column (SiO 2 45 gm; eluted with 1% CH 3 OH: 99% DCM). The product thus purified as a white solid weighed 1.73 g. Recrystallization from a small amount of ethanol yielded white crystals: 1.65 g, m.p. 184-1850C.

ANALYSIS: 1107%N Calculated for C22H 2 2FN302 69.64%C 5.84%H 11.07%N Found: 69.48%C 5.67%H 11.05%N 198 EXAMPLE 215 2-[4-(6-Fluoro-1 ,2-benzisoxazol- 3 -yl)-1 -piperidinyl]-1 -(2,3-dihydro-1 H-isoindol- 2-yl)ethanone fumarate Free base (1 g, Example 215B) of 2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1piperidinyl]-1-(2,3-dihydro-1H-isoindol-2-yl)ethanone dissolved in hot ethanol ml) was treated with a solution of fumaric acid (306 mg) in hot ethanol. The mixture was cooled and the product collected, 1.2 gm, m.p. 223-225

C.

ANALYSIS:

Calculated for C 22

H

22

FN

3 0 2 .C4H404: 63.02%C 5.29%H 8.48%N Found: 62.86%C 5.03%H 8.39%N EXAMPLE 216 4-6-Fluoro-1H -indazol-3yI)-l-piperidinyl]- -[2-(5-fluoro-2,3-dihydro-1

H-

isoindol-2-yl)ethyl1piperidine dimaleate 5 To a solution consisting of 2-[4-(6-fluoro-1H-indazol-3-yl)-1piperidinyl]ethylamine (6.1 g, 23.2 mmol) in DMF (230 ml) was added 4fluorophthalic anhydride (4.2 g, 25.5 mmol) at room temperature, under nitrogen.

SThe reaction mixture was warmed to 80 0 C for 2.5 hours at which time it was allowed to cool to room temperature. The DMF was removed under reduced 20 pressure mmHg, 55 0 C) to give a brown oil which was dissolved into DCM/MeOH. Purification via flash column chromatography (silica gel, 2% MeOH/DCM) afforded 3.6 g of 4-fluoro-N-[2-[4-(6-fluoro-lH-indazol-3-yl- Spiperidinyl]ethyl]phthalimide. To a solution of the latter compound (3.6 g 8.8 mmol) in anhydrous THF (100 ml) was added LAH (18.4 ml of a 1.0 M solution in 25 THF, 18.4 mmol) at room temperature, under nitrogen. The reaction mixture was warmed to reflux for 4 hours. Upon cooling to room temperature, the reaction was quenched with water (1.5 ml, dropwise). The precipitated salts were removed via filtration and washed with DCM. The combined filtrates were concentrated to give a solid which was purified via flash column chromatography (silica gel, 0-8% MeOH/DCM). The product containing fractions were concentrated to give 2.4 g product as an off-white solid. The dimaleate salt was prepared in methanol using 2.4 eq. of maleic acid. The white precipitate was collected via filtration and washed with methanol, m.p. 186-188 0

C.

199 ANkALYSIS:.

Calculated for C 22

H

24

FN

4 2C4H4 0 4. 58.63%C 525%H 9.07%N Found:584% 5.9H g7N EXAMPLE 217 J-4~6Fluoro-1 zl3 ,2 benZisoxazol-3-yl)-l -piperidiflyl-I ,33dihydroifldoI- A stirred mixture of 4-(6-fluoro-l 2 -benzisoxazol3-yl)piperidine g, 45.4 mmol),

K

2 C03 (7.2 g, 52.5 mmol) and N-(2-bromoacetyl)indoline (12 g, 50 mmol) in acetonitrile (300 ml) was heated at reflux for 4 hours. The mixture was cooled and filtered. The solution was concentrated down until solid appeared. The crystals were collected: weight 12.68 g. The mother liquor was concentrated to :00dryness. The residues were purified further by flash chromatography to yield an additional 1.35 g. Total yield was 14.03 g. A 2 g sample was dissolved in 15 ethanol/methylene chloride and was treated with a solution of fumaric acid (612 00 mg) in ethanol to yield 2.58 g, m.p. 226-227 0

C.

ANALYSIS:

*Calculated for C 22

H

22

FN

3 02 0 C4H4 0 4: 63.02%C 5.29%H 8.48%N 000Found: 62.79%C 5.30%H 8.40%N 20 EXAMPLE 218 1-1,,3 ,4-Tetrahydro-l -isoguinl0 in2yIL)244(6-fluOro-- 1 ,-enzisoxzol3yl

J-

piperidinyIlethann ydrochloride ethanolate 00. :A mixture of 4-(6-fluioro-1,2-(4.3 g, 19.

0 0 25 mmol),

K

2 003 (3.45 g, 25 mmol, 1.25 eq) and 2bromoacetyl-1,2,3,4terhdosounln (5 g, 20 mmol) in acetonitrile (200 ml) was heated at reflux for 2 hours. The reaction was cooled and the insolubles were filtered. The solvent was removed and the crude oil was purified by flash chromnatography over a silica gel column (90 g Of SiO 2 eluted with DCM and 1% CH- 3 0H in 0CM). The oil thus purified weighed 6.41 g. A 3 g sample was dissolved into ethanol (20 ml) and was treated with I MHCl-ether solution (10 ml). The cr ystals were collected and recrystallized twice from ethanol to yield 2.43 g of white crystals as the hydrochloride ethanolate, m.p. 206-208*C.

200 ANAL.YSIS:.% .6H 88% Calculated for C 23

H

24 FN0 2 HCIC2H6O: 63.08 6.562%H 8.89%N Found: 63.24%c 662H 89% EXAMPLE 219 N~[~[~(Floro-l ,2berizisoxazol3-Ylv pip eridin~yleth yl-l ,2,3 A- S d f m r te o 3 p p r d n l To a solution of 2-[4-(6-fluoro-l ,2-benzisoxazl3Yl -ppei iny) (1 2 ,3,4tetrahydro-l H-i 5 qunolin-2yl)ethanone (2.36 g, 6 mmol) in THF was charged lithium aluminum hydride (15 ml, 1iM in ether) dropwise under

N

2 at room temperature. The mixture was stirred for 3 hours at room temperature. At the end, the excess of hydride was quenched with ice chips and 2 ml of NaOH. The mixture was diluted with EtOAc and filtered. The solvents were removed to dryness. The residue was purified by flash chromatography over a i silica gel column (SiO2 18 g; eluted with I%

CH

3 0H in DCM). The product thus obtained weighed 1.62 g. This material was dissolved into hot ethanol and was treated with a solution of fumaric acid (490 mg) in ethanol. The mixture was cooled and the crystals were collected to yield 1.15 g, m.p. 2 18-220 0

C.

ANALYSIS:

20 Calculated for

C

23

H

26

FN

3 0.204H4 0 4: 60.88%C 5.60%H 6.87%N **Found: 61 .00%C 5.50%H 6.64%N EXAMPLE 220 ,2 ,3,4 Tetrahydr~ogl Hnisog-uinolin-2Yl I 4 1 1,2-renz~ piperidinyI ethanone uart l( 2 ChIoroacetyl)4-(6fuoro-1, 2 benzisoxazo3-yI)PiPeridine A solution of 4(6fluoro1,2b niox zl3y~pp rd (4.4 g, 20 mmol), triethylamine (2.1 g, 21 mmol) in chloroform (50 ml) was added to a solution of chloroacetyl chloride (2.5 g, 22 mmol) in chloroform (100 ml) dropwise at room temperature. The mixture was stirred for 2 hours. The solution was diluted with dichloromethane (DCM9 100 ml) and then washed with

H

2 0 and brine. The solvent was removed and the oily product was purified by flash chromatography 201 (Si02, 50 g; eluted with DCM and I CH 3 0H in 0CM). The pure product was obtained as an oil, 4.2 g. Crystallization from ethanol yielded 2.2 g of white crystals, m.p. 101-102'C.

ANALYSIS:

Calculated for C 14 Hl1 4 CIFN2O2: 56.67%C 4.76%H 9.44%N Found: 56.70%C 4.75%H 9.46%N 4-Tetrahydro-lIH-iso quinolin- 2 I-[4-(6-fluoro-I, 2-benzisoxazoI- 3-yI)-lI piperidinyI~etha none fumarate A mixture of 4-(6-fluoro-1 ,2-benzisoxazol-3-yl)-l -piperidinyl-2chloroacetamide (3.0 g, 10.8 mmol),

K

2 C0 3 (1.5 gin, 10.8 mmol) and 1,2,3,4tetrahydroisoquinoline (1.4 g, 10.5 mmol) in acetonitrile (90 ml) was heated at reflux for 4 hours. The reaction was cooled and filtered. The solvent was removed, and the residue was purified by flash chromatography over a silica gel column (50 g Of SiO 2 eluted with DCM and 1 CH 3 0H in 0CM). The light yellow oil (3.28 g) thus obtained was dissolved in ethanol and treated with a solution of fumaric acid (968 mg) in ethanol. The solid crystals were collected and recrystallized again to give 3.18 g of off-white crystals, m.p. 188-189*C

ANALYSIS:

*:20 Calculated for C 23

H

24

FN

3 0 2 SC4H404: 63.65%C 5.54%H 8.25%N Found: 63.42%C 5.33%H 8.16%N 0 94 0EXAMPLE 221 (6-Fluoro-1 ,2-benzisoxazol-3-yl)-l -piperidinyl]-2-hydrOxy-l -propyl]-l ,2,3,4tetrahydroisoquinolifle difumarate A mixture of ,3-epoxy)propyl]-4-(6-fluoro-1l,2-benzisoxazol- 3 yl)piperidine (3.56 g, 12.9 mmol) and 1,2,3,4-tetrahydroisoquinoline (2.06 g, 15.4 inmol) in isopropyl alcohol (150 ml) was heated at reflux for 4 hours. At the end of the reaction, the solvent was removed. The residual oil was purified by flash chromatography over a silica gel column (SiO 2 45 g, eluted with 1% CH 3 0H: 99% methylene chloride). The product thus purified as a light oil, weighed 4.15 g.

The oil was treated with a solution of fumaric acid (1.98 gin, 17 mmol) in ethanol.

202 The white crystals so obtained were recrystallized in a large volume of hot ethanol (-150 ml). The recrystallized crystals weighed 2.75 g, m.p. 179-181 0

C.

ANALYSIS:

Calculated for C 24

H

28

FN

3 0 2 92C4H404: 59.90%C 5.66%H 6.55%N Found: 60.06%C 5.77%H 6.36%N EXAMPLE 222 6 ,7-Dimethoxy-2-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yi)-I -piper-idinyl]-2-hvd roxv-1 propyl]-1 ,2,3,4-tetrahydroisoguinoline A stirred mixture of I -(2,3-epoxypropyl)-4-(6-fluoro-l ,2-benzisoxazol-3yl)piperidine (3.2 g, 11.6 mmol),

K

2 C0 3 (2 gin, 1.25 eq) and 6,7-dimethoxy- I ,2,3,4-tetrahydroisoquinoline hydrochloride (3.3 g, 1.25 eq) in isopropyl alcohol (200 ml) was heated at reflux for 6 hours. The mixture was cooled and filtered.

The solvent was removed to about 50 ml and the solution was allowed to stand 15 overnight. Crystals (0.6 g) formed and were collected. The mother liquor was concentrated to a white solid. Recrystallization twice from ethanol yielded the product (1.95 m.p. 153-1 54C.

ANALYSIS:

Calculated for C 26

H

32

FN

3 04: 66.51 %C 6.87%H 8.95%N eg 20 Found: 66.51 %C 7.05%H 8.83%N CC EXAMPLE 223 H-indazol-3-yI)-1 -piperidinyllethyl]1,2,3,4- ~:tetrahydroisoguinoline dimaleate C 25 To a solution of 4-(6-fluoro-1 H-indazol-3-yl)piperidine (4.8 g, 18.9 mmol) in

CH

3 CN (200 ml) was added 2-bromo-1 ,2,3,4-tetrahydroisoquinolin- 2 yl)ethanone (4.8 g, 18.9 mmol) and sodium bicarbonate (1.9 g, 22.7 mmol) at room temperature. The reaction mixture was warmed to reflux (4 hours), cooled to room temperature and filtered through a pad of celite. The solids were washed with 0CM and the combined filtrates were concentrated. The remaining residue was purified via preparative HPLC (silica gel, 5-10% MeOH/DCM) to give 4.1 g of 1 ,2 ,3,4-tetrahyd roisoquinolin-2-yl)2[ 4 6 fluoro-1 H-indazol-3-yl)-l -piperidinylI ethanone which was used without further purification. To a suspension of the 203 latter (3.7 g, 9.4 mmol) in THF (100 ml) was added (dropwise) lithium aluminum hydride (11.3 ml of 1.0 M solution in THF, 11.3 mmol) at room temperature, under nitrogen. The reaction mixture was warmed to reflux (5 hours), cooled to room temperature and carefully quenched with water (10 ml). The precipitated salts were removed via filtration and washed with 1:1 EtOAc/DCM. The combined filtrates were concentrated and the remaining oil was purified via flash column chromatography (silica gel, 10% MeOH/DCM) to give 2.2 g of the product. The dimaleate salt was prepared in methanol (30 ml) with maleic acid (3.0 m.p.

185-187 0

C.

ANALYSIS:

Calculated for C 23

H

27

FN

4 e2C 4

H

4 0 4 60.98%C 5.78%H 9.18%N Found: 60.85%C 5.75%H 9.09%N EXAMPLE 224 15 1-(1,2,3,4-Tetrahydro-1 H-quinolin-1 -yl)-2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1 m piperidinyl]ethanone furmarate SA stirred mixture of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (4.7 g, 21.4 mmol), K 2

CO

3 (3.6 g, 25.6 mmol) and N-(2-bromoacetyl)-1,2,3,4tetrahydroquinoline (6 g, 23.6 mmol) in acetonitrile (200 ml) was heated at reflux for 1.5 hours. The mixture was cooled and the solids were filtered off. The solvent was stripped to dryness. The residue was purified by flash chromatography (SiO 2 100 gm; eluted with methylene chloride (DCM) and 1% CH 3 OH in DCM). The product thus purified weighed 7.75 g. A sample of 1.88 g in ethanol was treated with a solution of fumaric acid (550 mg, 1.0 eq) in ethanol to yield the fumaric salt, 25 2.15 g, m.p. 162-163"C.

ANALYSIS:

Calculated for C 23

H

24

FN

3 0 2

OC

4

H

4 0 4 63.65%C 5.54%H 8.25%N Found: 63.52%C 5.46%H 8.17%N EXAMPLE 225 N-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1 -piperidinyl]ethyl]-1,2,3,4tetrahydroquinoline fumarate 204 To a stirred solution of 2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]- 1-(1,2,3,4-tetrahydroquinolin-1-yl)ethanone (5.5 g, 14 mmol) in THF (50 ml) was charged with lithium aluminum hydride (17 ml, 17 mmol, 1 M in ether) dropwise under N 2 at room temperature. The mixture was stirred for 8 hours at room temperature. At the end of this period the excess of hydride was quenched with ice chips and 3 ml of 20% NaOH. The mixture was diluted with EtOAc (150 ml) and stirred for 1 hour. The EtOAc was dried with MgSO4 and filtered. The solvent was removed to dryness. The residue was purified by flash chromatography over a silica gel column (SiO 2 55 g; eluted with 1-3% CH 3 0H:DCM). The product thus obtained weighed 1.83 g. This material was dissolved into hot ethanol and was treated with a solution of fumaric acid (700 mg) in ethanol. The crystals were collected and weighed 1.85 g, m.p. 192-1930C.

ANALYSIS:

Calculated for C 23

H

26

FN

3 0.C 4

H

4 0 4 65.44%C 6.10%H 8.48%N EXAMiPLE 226 N-[3-[4-(6-Fluoro-1,2-benzisoxaz3-yl)-1 -piperidinyl)-2-hydroxy-1 -propy]- 1,2,3,4-tetrAdrg uinoline hemifumarate A stirred mixture of N2, -epoxypropyl)-4-(6-fluoro-1,2-benzisoxazol-3yl)piperidine (2.41 g, 8.73 mmol), 1,2,3,4-tetrahydroquinoline (1.33 g, 10 mmol, in isopropyl alcohol (50 ml) was heated at reflux for 6 hours. The solution was cooled and the solvent was removed on a rotary evaporator. The crude solid was 0'0 purified by flash chromatography over a silica gel column (SiO 2 40 g, eluted with 25 methylene chloride DCM, and 1-3% MeOH in DCM). The product thus purified weighed 2.0 g. This material was dissolved in ethanol and was treated with a solution of fumaric acid (567 mg, 1.0 eq) in ethanol. The solids collected were recrystallized again from ethanol (50 ml) to yield 1.0 g of white crystals, as a hemifumarate, m.p. 170-171C.

ANALYSIS:

Calculated for C 24

H

28

FN

3 0 2 *0.5*C 4 H404: 66.79%C 6.47%H 8.99%N Found: 66.27%C 6.54%H 8.86%N 205 EXAMPLE 227 N-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1 -piperidinyl]acetyl]-10,11 dibenz[b,f]azepine fumarate A stirred mixture of 2-chloroacetyl-10,11-dihydro-5H-dibenz[b,f]azepine (6.6 g, 24.3 mmol), 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (5 g, 22.7 mmol) and K 2

CO

3 (3.5 g, 40 mmol) in acetonitrile (300 ml) was heated at reflux for 4 hours. The insolubles were filtered, and the solvent was removed on a rotary evaporator. The crude product was purified by flash chromatography over a silica gel column (100 g of SiO 2 eluted with dichloromethane (DCM) and 1-2% CH 3

OH

in DCM). The product thus obtained weighed 8.7 g as a yellow oil. A sample g) of this material was dissolved in ethanol and was treated with a solution of fumaric acid in ethanol (360 mg/3 ml). The solids collected were recrystallized from acetonitrile to yield 890 mg of white crystals, m.p. 182-183 0

C.

ANALYSIS:

15 Calculated for C 28

H

26

FN

3 0 2

SC

4

H

4 0 4 67.24%C 5.29%H 7.35%N Found: 66.66%C 5.17%H 7.33%N EXAMPLE 228 o- N-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-ethoxyphthalimide hemihydrate A mixture of 3-(4-piperidinyl)-6-fluorobenzisoxazole (3.42 g, 15 mmol), N- (2-bromoethoxy)-phthalimide (4.3 g, 16 mmol) and K 2 C0 3 (26 g, 18 mmol) in acetonitrile (150 ml) was heated at reflux for 2 hours. The solids were removed and the solvent was evaporated. The residue was purified over a flash 25 chromatography column (packed with SiO 2 60 g; eluted with dichloromethane (DCM) and 1% CH 3 OH in DCM). The pure product thus obtained, weighing 6.8 g was crystallized from DCM:ethanol. Recrystallization from ethanol and i-propyl ether yielded white crystals (2.4 g, m.p. 125-127 0 C) as the hemihydrate.

ANALYSIS:

Calculated for C 22

H

20

FN

3 0 4 *0.5.H 2 0: 63.15%C 5.05%H 10.04%N 2.15%H 2 0 Found: 63.20%C 5.16%H 9.80%N 2.32%H 2 0 206 EXAMPLE 229 3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1 -piperidinyl]-2-hydroxy-l -propylamine hvdrochloride hydrate A stirred mixture of 3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-l-piperidinyl]-2hydroxy-1-propylphthalimide (6.2 g, 14.6 mmol) and hydrazine hydrate (1.4 g, 28 mmol) in methanol (300 ml) was heated at reflux for 4 hours, then at 65 0 C for 16 hours. The mixture was cooled and the solvent was stripped to dryness. The white residue was stirred with H 2 0 (40 ml) and acidified with HCI to pH=3. The milky white solids were filtered with the aid of Celite. The light yellow solution was basified with 50% NaOH to pH=9, then extracted with methylene chloride

(DCM,

3x180 ml). The DCM solution was washed with brine, dried and stripped to give an oil (2.93 g) which solidified slowly. A 1 gm sample of this solid was treated with a HCI/MeOH solution to precipitate out a hydrochloride salt. This salt was recrystallized from ethanol

H

2 0 to yield 0.52 g of white crystals, m.p. 150- 15 152 0

C.

ANALYSIS:

Calculated for C1 5

H

2 0FN 3 02*HCI*H20: 51.80%C 6.67%H 12.08%N Foun 51.74%C 6.32%H 12.05%N Found: EXAMPLE 230 N-(2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl-3-pyridinecarboxamide dihydrochloride hydrate To a mixture of 2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl] ethylamine (1.17 g, 4.34 mmol) and triethylamine (1.08 g, 10.8 mmol) in 25 chloroform (30 ml) was added nicotinoyl chloride hydrochloride (0.96 g, 5.4 mmol) in one portion. The mixture was stirred for 1 hour at room temperature. The solution was diluted with methylene chloride (DCM) and washed with brine and dried over anhydrous MgSO4. The solution was concentrated and the crude product was purified by flash chromatography over a silica gel column (SiO 2 g; eluted with DCM and 13% MeOH in DCM). The free base thus purified weighed 1.7 g. This product was treated with 1 M. HCI in ethanol and recrystallized twice from methanol:isiproply ether to yield white crystals, 1.19 g, m.p. 243-245 0 C as a dihydrochloride hydrate.

207

ANALYSIS:

Calculated for C 20

H

21

FN

4 0 2 .2HCIoH 2 0: 52.30%C 5.49%H 12.20%N 3.92%H 2 0 Found: 52.34%C 5.39%H 12.11%N 3.68%H 2 0 EXAMPLE 231 1,2-bis-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethane difumarate To a stirred mixture of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (2.2 g, mmol) and K 2

CO

3 (1.47 g, 11 mmol) in acetonitrile (50 ml) was added 1,2dibromoethane (1 g, 5.4 mmol) dropwise at room temperature. The mixture was stirred at room temperature for 16 hours. The reaction mixture was filtered and the solvent was removed on a rotary evaporator. The crude solid was purified by flash chromatography (SiO 2 30 g; eluted with methylene chloride, DCM, and MeOH in DCM). The product thus purified, weighed 513 mg. This solid was treated with fumaric acid (270 mg, 2 eq) in ethanol. The crystals collected were I:l: 15 recrystallized from ethanol:H 2 0 to yield 630 mg of white crystals, m.p. 246- 247 0

C.

ANALYSIS:

Calculated for C 26

H

28

F

2

N

4 0 2 58.45%C 5.19%H 8.02%N S* Found: 58.36%C 5.22%H 7.92%N EXAMPLE 232 1,3-Bis-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1 -piperidinyl]-2-hydroxypropane dihydrochloride A stirred mixture of 1-(2,3-epoxypropyl)-4-(6-fluoro-1,2-benzisoxazol-3yl)piperidine (1.19 g, 4.3 mmol) and 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (0.95 g, 4.3 mmol) in isopropyl alcohol (50 ml) was heated at reflux for 1 hour, then stirred at 65 0 C for 16 hours. The solvent was removed on a rotary evaporator. The solid residues were purified by flash chromatography over a silica gel column (SiO 2 35 g; eluted with methylene chloride, DCM, and CH 3 OH in DCM). The product thus obtained, weighed 2.55 g. This material was dissolved in ethanol and was treated with a solution of HCI (1 M in ether). The salt collected weighed 2.35 g, m.p.>270 0 C dec.

ANALYSIS:

208 Calculated for C 27

H

30

F

2

N

4 03*2HCI: 56.95%C 5.66%H 9.84%N Found: 56.55%C 5.68%H 9.51 %N EXAMPLE 233 2-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-y)-1 -piperidinyl]ethyl]-2-phenyl-1,3indandione A mixture of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (2.2 g, 10 mmol),

K

2 C0 3 (1.6 g, 11.6 mmol) and 2-toluenesulfonyl-2-phenyl-1,3-indandione (4.2 g, mmol) in acetonitrile (50 ml) was heated at reflux for 3 hours. The mixture was cooled and the insolubles were filtered. The solvent was removed on a rotary evaporator. The residue was purified twice using a flash chromatography column (SiO2, 45 g and 40 g; eluted with DCM). The product thus purified was recrystallized from ethanol (30 ml) and isopropyl ether, yield: 2.8 g, m.p. 149- 150 0

C.

15 ANALYSIS: Calculated for C 2 9

H

25

FN

2 03: 74.34%C 5.38%H 5.98%N Found: 74.24%C 5.50%H 5.87%N EXAMPLE 234 2-[4-(6-Fluoro-1,2-benzisoxazol3-yl)--piperidinylacetonitrile A mixture of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (11 g, 50 mmol), V 60

K

2 C0 3 (8.5 g, 61.6 mmol) and 2-chloroacetonitrile (5.5 g, 73 mmol) in acetonitrile (250 ml) was heated at reflux for 24 hours. The insolubles were filtered off and rinsed with methylene chloride (DCM). During concentration of the solvents on 25 the rotary evaporator, crystals appeared. The crystals were collected and weighed 5.79 g. The product in the mother liquor was further purified by flash chromatography over a silica gel column (SiO 2 70 g; eluted with DCM, and 1%

CH

3 OH in DCM). The second crop of product thus obtained weighed 5.2 g. The total yield was 10.9 g. The sample was recrystallized once more from ethanol, m.p. 130-132 0

C.

ANALYSIS:

Calculated for C 1 4

H

1 4 FN30: 64.85%C 5.44%H 16.21%N Found: 64.68%C 5.32%H 16.26%N 209 EXAMPLE 235 3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propionitrile A mixture of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (11 g, 50 mmol),

K

2 C0 3 (8.5 g, 74 mmol) and 3-bromopropionitrile (8.2 g, 1.2 eq) in acetonitrile (300 ml) was heated at reflux for 24 hours. The mixture was cooled and the insolubles were filtered. The solvent was removed on a rotary evaporator and the crude product was purified by flash chromatography over a silica gel column (SiO 2 120 The product thus purified weighed 8.94 g. Recrystallization from ethanol yielded the nitrile as white crystals 4.3 g, m.p. 100-101 C.

ANALYSIS:

Calculated for C 1 sHi6FN 3 0: 65.92%C 5.90%H 15.37%N Found: 65.87%C 5.87%H 15.37%N EXAMPLE 236 15 1 -Phenoxycarbonyl-3-(1-phenoxycarbonyl-4-piperidinyl)-1H-indazole To a suspension of 3-(1-methyl-4-piperidinyl)-1H-indazole (5.0 g, 23.2 mmol) in DCM (100 ml) was added potassium carbonate (8.0 g, 58.0 mmol) followed by the dropwise addition of phenyl chloroformate (6.9 ml, 51.0 mmol) at room temperature. After stirring for five days, the reaction was filtered through a pad of celite and the solids were washed with DCM. The combined filtrates were concentrated and the remaining solid was purified via flash column chromatography (silica gel, 10% methanol/DCM) to give 6.7 g of the 1phenoxycarbonyl-3-(1-methyl-4-piperidinyl)-1 H-indazole as the hydrochloride salt.

**le The free amine of the latter compound was prepared in Na 2 C0 3 (sat.) and 25 extracted into EtOAc. Concentration of the organic layer afforded 4.7 g of the free amine which was used without further purification. To a solution of 1phenoxycarbonyl-3-(1-methyl-4-piperidinyl)-1H-indazole) (4.7 g, 14.0 mmol) in DCM (100 ml) was added potassium carbonate (0.85 g, 6.2 mmol) followed by phenyl chloroformate (2.1 ml, 15.4 mmol) at room temperature, under nitrogen.

After stirring for 2 days, the reaction mixture was filtered through a pad of celite and the solids were washed with DCM. The remaining oil was purified via flash column chromatography (silica gel, DCM) to give another oil which solidified from 210 EtOAc/pet. ether. The white solid (4.2 g) was collected via filtration and washed with pet ether, m.p. 113-116°C.

ANALYSIS:

Calculated for C 26

H

23

N

3 0 4 70.74%C 5.25%H 9.52%N Found: 70.47%C 5.17%H 9.38%N EXAMPLE 237 1-[4-(3-Chloropropoxy)-3-methoxyphenyl]-2-hydroxyethanone A solution of 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (4.3 g, 17.7 mmol), [bis[trifluoroacetoxy)iodo]benzene (15.6 g, 36.2 mmol), H 2 0 (18 ml),

CF

3

CO

2 H (2.8 ml) and CH 3 CN (90 ml) was refluxed for 3 hours. The CH 3 CN was removed under reduced pressure and the resulting yellow liquid was partitioned between H 2 0 and CH 2

CI

2 The biphasic mixture was filtered, the organic phase collected, washed with saturated NaHCO3 solution and concentrated to afford :O 15 g of an amorphous brown solid. The solid was flash chromatographed on silica gel, eluting the column with 5% EtOAc/CH 2 CI2. Concentration of similar fractions afforded 0.7 g of the compound as a pale yellow solid, m.p. 99-101 C.

s EXAMPLE 238 1 -[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1 -piperidinyl]propoxy]- 3 methoxyphenyl]-2-hydroxyethanone A mixture of 3-(4-piperidinyl)-6-fluoro-1,2-benzisoxazole (1.3 g, 5.8 mmol), .[4-(3-chloropropoxy)-3-methoxyphenyl]-2-hydroxyethanone (1.5 g, 5.8 mmol), I"s" NaHCO3 (1.5 g) and 1-methyl-2-pyrrolidinone (50 ml) was stirred under N 2 at S 25 100 0 C for 6 hours. The reaction was poured into H 2 0, and the aqueous suspension was extracted with EtOAc. The extract was washed

(H

2 dried (MgSO4) and concentrated to afford the product. This invention thus provides a group of chemical compounds that are capable of producing antipsychotic effects and may be capable of affecting negative symptoms of schizophrenia in a beneficial manner. In addition, many of the compounds may also have reduced tendencies to produce extrapyramidal side effects in mammals.

Claims

1. A compound of the formula: (Y) P I Q1 wherein X is or -N(R 2 R 2 is selected from the group consisting of lower alkyl, aryl lower alkyl, aryl, cycloalkyl, aroyl, alkanoyl, and phenylsulfonyl groups, and aryl is defined hereinafter; p is 1 or 2; Y is hydrogen, lower alkyl, hydroxy, chlorine, fluorine, bromine, iodine, lower alkoxy, trifluoromethyl, nitro, or amino; Q1 is -z N- Y 2 where Z is and Y 2 is selected from the group consisting of: (3) *in which (R 1 is -CR 24 R 27 -(CR 23 R 2 4)-CR 24 R 27 where n is 0, 1, 2, or 3; or 212 -CHR 24 -CH=CH-CHR 24 -CHR 24 -C=-C-C.HR 24 -OH R 24 -CH=CH-CR 23 R 24 -CH R 2 4 -OH R 24 -CR 23 R 24 -CH=CH-CH R 24 -CHR 2 4 -C=C-CR 23 R 24 -CHR 24 or -CHR 24 -0R 23 R 24 -C=EC-CHR 24 the -CH=CH- bond being cis or trans; R 23 is hydrogen, (0-018) linear alkyl, phenyl, hydroxy, (C 1 -C 1 )alkoxy, aryloxy, aryl(Oi -Ci a)alkyloxy, (Ci 8 )alkanoyloxy, hydroxy(Ci -C 6 )alkyl, (CI -C 18 )alkoxy (Ci-C 6 )alkyl, aryl(Ci -Cl 8 )alkyloxy(Ol-C 6 )alkyI, (Cl- C, 8 )alkanoyloxy(Ci -C 6 )alkyl or lower alkyleneyl (ZO/ where Z, is lower alkyl, -OH, lower alkoxy, -OF 3 -NO 2 -NH 2 or halogen; and R 24 is hydrogen, (01-018) linear alkyl, phenyl, hydroxy(C,-C 6 )alkyl, (CI-Ci 8 )alkoxy(C, -06) alkyl, phenyl(Cl,-C 6 )alkyloxy, aryl(C, -CI8)alkyloxy(Cl- C 6 )alkyl, (C 1 -Cl 8 )alkanoyloxy (0 1 -C 6 )alkyl or lower alkyleneyl ZO where Z, is as previously defined; 213 R 27 is hydrogen or R 24 and R 27 taken tog ether with the carbon. to which they are attached form 0=0. or C=S; and R' 4 is selected from: tri(CI-0 6 )alkylsilyloxy, hydroxy lower alkyl, alkanoyloxy lower alkyl, (0 4 -018)acyl amino, (0 7 -0 18 )alkanoyl, or -0-C(=0)-(Cl3-Cl8 straight or branched chain) alkyl; where R, and R' 4 are as previously defined; where R 1 and R' 4 are as previously defined; U :(R4)q r A Bz where A is -C(=CH 2 -C(=0)0H 2 -CH 2 CH 2 -0R 26 =N- or -0R 25 R 2 6 R 25 is hydrogen, (C-C 6 )alkyl, hydroxy or (C-C 18 )alkanoyloxy; R 2 6 is hydrogen or (Cj-0 6 )alkyl; 214 either one of By and Bz is CH or N and the other is CH; U is OorS; q is 1, 2, 3 or 4, and R 1 is as previously defined; R 4 is hydrogen, lower alkyl, lower alkoxy, hydroxy, tri(Ci-C 6 )alkylsilyloxy, hydroxy lower alkyl, alkanoyloxy lower alkyl, amino, mono- or dialkylamino, (Ci-Ca 8 )acyl amino, (C-Cis)alkanoyl, trifluoromethyl, chlorine, fluorine, bromine, -O-C(=O)-(C1-Ci8 straight or branched chain) alkyl or -C(=O)-aryl; in which aryl is phenyl or where R 5 is hydrogen, lower alkyl, lower alkoxy, hydroxy, chlorine, fluorine, bromine, iodine, lower monoalkylamino, lower dialkylamino, nitro, cyano, trifluoromethyl, trifluoromethoxy; excluding compounds where U is O, A is and By and Bz are both CH; -(R 1 N(R 4 )q R 28 R 2 8 wherein Ri, R 4 and q are as defined above; and i: R 28 is hydrogen, (C 1 -C 6 )alkyl, aryl(Ci-C 6 )alkyl, phenyl or substituted phenyl; 215 R 2 R 30 R 31 4 R 3 2 (R4 )q wherein R 1 R 4 and q are as defined above; R 29 and R 30 are hydrogen, (Cl-C 6 )alkyl, aryl(0 1 -0 6 )alkyl, phenyl or substituted phenyl; R 31 and R 32 are hydrogen, hydroxy, (C 1 -0 6 )alkyl, aryl(C 1 -C6)al kyl, phenyl, substituted phenyl, hydroxymethyl, or CH0R 33 where R 33 is (CI-0 18 )alkanoyl; or either R 29 and R 30 taken together or R 31 and R 32 taken together with the carbon group to which they are attached form a 0=0 or C=S group; N 4 )q (11)2 R 8 R 28 216 where R 1 R 4 R 28 R 29 R 3 0 R 3 1 R 32 and q are as defined above; R2 RP 30 R 31 R3 R 2 R 3 1 V 32 (R4)q (12) where R 1 R 4 R 29 R 3 0 R 31 R 32 and q are as defined above; (13) (R4)m wherein R, and R 4 are as defined above, and m is defined hereinafter; 0 (R 4 )m a a. a. (16) where R, and R 4 are as defined above, and m is defined hereinafter; 0 (Rt)m 0 (17) .*too: 0.00.. 217 where R, and R 4 are as defined above; and mn is defined hereinafter; (18) -R 1 -O-R' 12 where R' 1 2 is selected from the group consisting of: alkyl, C(=O)-(013-0IB straight or branched chain) alkyl, -0(=O)-NR 1 3 Rl 4 where R1 3 is a (013-018) alkyl group and R 14 is a (013-018) alkyl group, or 2 -Rl 7 where R 1 7 is (0 7 -0 1 8 )alkyl and m is defined hereinafter; (19) -R 1 -NR 1 8 R 19 where R 18 and R 19 are independently selected from the group consisting of: hydrogen,. -0(=O)-pyridyl, -(013-018 straight or branched chain) alkyl, -0(=O)-O-(013-018) alkyl, -0(=O)-(013-018) alkyl, and R 28 where NR 18 R 19 taken together form a ring structure selected from the group consisting of piperidinyl and piperazinyl, where the piperidinyl or piperazinyl ring is substituted by *lose 00 218 x>L where X, Y, p, R 1 R 4 and R 28 are as previously defined, and m is defined hereinafter, with the proviso that only one of R 18 and R 1 9 is hydrogen; -Ri-S-R'12 where R 1 and R' 12 are as previously defined; 4)m 2 o (21) where R 1 R 4 and R 28 are as previously defined; and m is 1, 2, or 3; and, any hydroxyl group attached to an aliphatic or aromatic carbon atom, or any primary or secondary nitrogen atom may be acylated with a (C4- Cl 8 )alkanoyl group; in addition, any nitrogen atom may alternatively be acylated with a (C4-C18)alkoxycarbonyl group; all geometric, optical and stereoisomers thereof, or a pharmaceutically acceptable acid addition salt thereof. ee 219

2. The compound of claim 1 having the formula: Z NY

3. The compound of claim 2 wherein Y 2 is \A BZ

4. Te cmpond f caim3 weren Ais CH(H)- ByandBz re H, ndy *i 0. 4. The compound of claim 3 wherein A is -CHO),0-adB.aeOH n

6. The compound of claim 5 which is selected from: 2-[2-[4-(6-fluoro-1 ,2- benzisoxazol-3-yl)-1 -pipe rid inyl]ethyl]-2,3-d ihyd ro-3-hyd roxy-1 H-isoindol-1 -one, decanoic acid 2-[2-14-(6-fluoro- 1,2-benzisoxazol-3-yl)- 1 -pipe rid inyl]ethyl-3-oxo- 2,3-dihydro-1 H-isoindol-1 -yl ester, and the pharmaceutically acceptable acid addition salts of the aforesaid compounds.

7. The compound of claim 4 wherein X is 220

8. The compound of claim 7 which is selected from: 2-[2-[4-(6-fluoro-1,2- benzisothiazol-3-yl)-1 -piperidinyl]ethyl]-2,3-dihydro-3-hydroxy-1 H-isoindol-1 -one and its pharmaceutically acceptable acid addition salts.

9. The compound of claim 4 wherein X is -NH-. The compound of claim 3 wherein A is By and Bz are CH, and U is 0.

11. The compound of claim 10 wherein X is a. S a a a aaa a. SSS a.. a.

12. The compound of claim 11 which is selected from: N-[2-[4-(6-fluoro-1,2- benzisoxazol-3-yl)-l-piperidinyl]ethyl]thiaphthalimide and its pharmaceutically acceptable acid addition salts.

13. The compound of claim 3 wherein A is By and Bz are CH, and U is S.

14. The compound of claim 13 wherein X is The compound of claim 14 which is selected from: N-[2-[4-(6-fluoro-1,2- benzisoxazol-3-yl)-1-piperidinyl]ethyl]-1,3-bis-thiaphthalimide and its pharmaceutically acceptable acid addition salts. 221

16. The compound of claim 3 wherein A is -C(0H 3 By and Bzare OH, and U isO0.

17. The compound of claim 16 wherein X is

18. The compound of claim 17 which is selected from: 2,3-dihydro-2-[2-[4-(6- fluoro-1 ,2-benzisoxazol-3-yi)-1 -pipe rid inyl]ethyl]-3-hyd roxy-3-m ethyl- 1 H-isoindol- 1 -one and its pharmaceutically acceptable acid addition salts.

19. The compound of claim 3 wherein A is -CH(0H 3 By and Bz are OH, and U is 0. S S S S eSO S *S 0 0 S S S0 S. S S 55 SSSS S S. S 05 0 S S 55 0@SS S *055 00 5556 S 5* S S S OS 0 55 0*

20. The compound of claim 19 wherein X is

21. The compound of claim 20 which is selected from: 2-[2-[4-(6-fluoro-1 ,2 benzisoxazol-3-yl)-1 -p ipe rid inyl]ethyl]-2,3-d ihyd ro-3-methyl- 1H-isoindol-1 -one and its pharmaceutically acceptable acid addition salts.

22. The compound of claim 3 wherein A is -C(=0H 2 By and Bz are OH, and U is 0.

23. The compound of claim 22 wherein X is 222

24. The compound of claim 23 which is selected from: 2,3-dihydro-2-[2-[4-(6- fluoro-1,2-benzisoxazol-3-yl)-1 -piperidinyl]ethyl]-3-methylene-1 H-isoindol-1-one and its pharmaceutically acceptable acid addition salts. The compound of claim 3 wherein A is -CH 2 By and Bz are CH, and U is 0.

26. The compound of claim 25 wherein X is

27. The compound of claim 26 which is selected from: 2-[2-[4-(6-fluoro-1,2- benzisoxazol-3-yl)-1-piperidinyl]ethyl]-2,3-dihydro-1 H-isoindol-1-one and its pharmaceutically acceptable acid addition salts.

28. The compound of claim 3 wherein A is -C(=O)CH 2 By and Bz are CH, and U is O. *0 The compound of claim 29 which is selected from: N-[2-[4-(6-fluoro-1,2- benzisoxazol-3-yl)-l-piperidinyl]ethyl]-1,2,3,4-tetrahydroisoquinolin-1,3-dione and its pharmaceutically acceptable acid addition salts.

31. The compound of claim 3 wherein A is By is CH, Bz is N, and U is 223

32. The compound of claim 31 wherein X is

33. The compound of claim 32 which is selected from N-[2-[4-(6-fluoro-1 ,2- benzisoxazol-3-yl)-I -piperidinyl]ethyl]-6-pyrrolo[3 pyridine-5,7-dione and its pharmaceutically acceptable acid addition salts.

34. The compound of claim 3 wherein A is -CR 26 By and B, are CH, and U is 0. The compound of claim 34 wherein X is

36. The compound of claim 35 which is selected from: 3-[2-[4-(6-fluoro-1 ,2- benzisoxazOl-3-yl)-lI-piperid inyl]ethyl]-2-methyl-3H-quinazolin4one and its pharmaceutically acceptable acid addition salts.

37. The compound of claim 2 wherein Y 2 is 2R 2 R 28 ~N (R4)q *R 28 R 28

38. The compound of claim 37 wherein X is

39. The compound of claim 38 which is selected from: 4-(6-fluoro-1 ,2- benzisoxazol-3-yi)l ,3-d ihyd ro-1 H-isoindol-2-yI )propyl] piperidine, 4-(6-fluoro- I ,2-benzisoxazol-3-yi)-l ,3-d ihyd ro- I H-isoindol-2-yl)ethyl] piperidime, 4-(6-fluoro- 224 1 ,2-benzisoxazol-3-y)-1 luoro-2,3-dihydro- 1 H-isoi ndol-2-yl)ethyl]pipe rid ine, 4-(6-fluoro- 1,2-benzisoxazol-3-y)-1 -[2-(2,3-dihydro-1 H-isoindol-2- yl)propyllpiperidine, N -[3-[4-(6-flIuo ro-1, ,2-benzisoxazo1-3-yl) -1 -pipe rid inyl]-2- hydroxy-l1-propyl]-2,3-dihydro-l1H-isoindole, N-[2-[4-(6-fluoro-1 ,2-benzisoxazol-3- yI)-l -pi pe rid inyl]ethyl]-2,3-d ihyd ro-5- (tri isop rOpysilyl)OXy- 1H-isoindole, flIuo ro- 1,2-benzisoxazol-3-y)- 1.-pi pe rid inyl]ethyll-2,3-d ihyd ro-5-hyd roxy- 1 H- isoindole, 2-[4-(6-fluoro- 1,2-benzisoxazol-3-yl)-1 -piperidinyl]-1 -(2,3-dihydro-1 H- isoindol1-2-yl)ethan one, and the pharmaceutically acceptable acid addition salts of the aforesaid compounds. The compound of claim 37 wherein X is -NH-.

41. The compound of claim 40 which is selected from: 4-(6-fluoro-1 H-indazol- 3-yl)-l -[2-(2,3-dihydro-1 H-isoindol-2-yl)ethyl]piperidine, 4-(6-fluoro-1 H-indazol-3- yl)-l -[2-(5-fluoro-2,3-dihydro-1 H-iso indol-2-yl)ethyl]pipe rid ine, and the pharmaceutically acceptable acid addition salts of the aforesaid compounds.

42. The compound of claim 2 wherein Y2 is .100*

43. The compound of claim 42 wherein X is 225

44. The compound of claim 43 which is selected from: 2-[4-(6-fluoro-1 ,2- benzisoxazol-3-yl)-1 -piperidinyl]-1 -(2,3-dihydroindol-1 -yl)ethanone and its pharmaceutically acceptable acid addition salts. The compound of claim 2 wherein Y 2 is R 31 P 32 R 3 R 8 R 28

46. The compound of claim 45 wherein X is

47. The compound of claim 46 which is selected from: 1-Cl ,2,3,4-tetrahydro- 1 H-isoquinolin-2-yl)-2-[4-(6-fluoro-l ,2-benzisoxazol-3-y)-1 -piperid inyletha none, N-[2-[4-(6-fluoro-1 ,2-benzisoxazol-3-yI)-1 -piperidinyl]ethyl]-(1 ,2,3 ,4- tetrahydroisoquinoline, 2-(1 ,2,3,4-tetrahydro-1 H-isoquinolin-2-y)-l -[4-(6-fluoro- I ,2-benzisoxazol-3-y)-1 -pi perid inylletha none, N-[3-[4-(6-fluoro-1 ,2-benzisoxazol- 3-yl)-I -piperidinyl]-2-hydroxy-1 -propyl]-l ,2,3,4-tetrahydroisoquinoline, 6,7- d imethoxy-2-[3-[4-(6-fluoro-1 ,2-benzisoxazol-3-yl)-1 -piperidinyll-2-hyd roxy-1 propyl]-1 ,2,3,4-tetrahydrosoquinoline and the pharmaceutically acceptable acid addition salts of the aforesaid compounds.

48. The compound of claim 45 wherein X is -NH. 226

49. The compound of claim 48 which is selected from: N-[2-[4-(6-fluoro-1 H- indazol-3-yl)-1 -pipe rid inyl]ethyl]- 1 ,2,3,4-tetrahyd roisoq uinol ine and its pharmaceutically acceptable acid addition salts. The compound of claim 2 wherein Y 2 is R29R3 R 32 S(R4)q :51. The compound of claim 50 wherein X is

52. The compound of claim 51 which is selected from: 1-(1 ,2,3,4-tetrahydro- 1 H-quinolin-1 -yl)-2-[4-(6-fluoro-1 ,2-benzisoxazo-3-y)-1 -piperidinyllethanone, N- [2-[4-(6-fluoro-1 ,2-benzisoxazol-3-yI)-1 -pipe rid inyl]ethyl]- 1,2,3,4- tetrahydroquinoline, N-[3-[4-(6-fluoro-1 ,2-benzisoxazol-3-yl)-1 -piperidinyl)-2- hydroxy-1 -propyl]-1 ,2,3,4-tetrahydroquinoline, and the pharmaceutically acceptable acid addition salts of the aforesaid compounds.

53. The compound of claim 2 wherein Y 2 is 227 N R4.

54. The compound of clai m 53 which is selected from: N-[2-[4-(6-fluoro-1 ,2- benzisoxazol-3-yI)-l1-piperidinyllacetyl]-1 0,1 1-dihydro-5H-dibenz[b,f]azepine and its pharmaceutically acceptable acid addition salts.

55. The compound of claim 2 wherein Y 2 is 0 (R 4 )M :0.:0

56. The compound of claim 55 wherein R, is -CH 2 -0H 2 0.0.0 0, 57. The compound of claim 56 which is selected from: 6-chloro-2-[2-[4-(6- fluoro-1 ,2-benzisoxazol-3-yl)-1 -piperidinyl]ethyl]-1 H-benz[de]isoquinoline-1 ,3(2H)- dione and its pharmaceutically acceptable acid addition salts.

58. The compound of claim 2 wherein Y 2 is 228 R)-I (R4)m 0

59. The compound of claim 58 wherein R, is -CH 2 -CH 2 The compound of claim 59 which is selected from: N-2-[2-[4-(6-fluoro-1,2- benzisoxazol-3-yl)-l-piperidinyl]ethyl]-2,3-naphthalimide and its pharmaceutically acceptable acid addition salts.

61. The compound of claim 2 wherein Y2 is -R 1 -O-R' 12

62. The compound of claim 61 which is selected from: N-[2-[4-(6-fluoro-1,2- benzisoxazol-3-yl)-1-piperidinyl]ethoxyphthalimide and its pharmaceutically acceptable acid addition salts.

63. The compound of claim 2 wherein Y2 is -RiNR 18 R 1 9

64. The compound of claim 64 wherein R 18 is hydrogen and R 19 is pyridyl. *o 6.Tecmon o li hrinY sRNiR9 *.i 229 The compound of claim 64 which is selected from: N-[2-[4-(6-fluoro-1,2- benzisoxazol-3-yl)-1-piperidinyl]ethyl]-3-pyridinecarboxamide and its pharmaceutically acceptable acid addition salts.

66. The compound of claim 63 wherein NR 18 R 1 9 forms a ring structure selected from the group consisting of piperidinyl and piperazinyl, where the piperidinyl or piperazinyl ring is substituted by and where X, Y, and p are as previously defined.

67. The compound of claim 66 which is selected from: 1,2-bis-[4-(6-fluoro-1,2- benzisoxazol-3-yl)-l-piperidinyl]ethane, 1,2-bis-[4-(6-fluoro-1,2-benzisoxazol-3- yl)-1-piperidinyl]-2-hydroxypropane, and the pharmaceutically acceptable acid addition salts of the aforesaid compounds. S68. The compound of claim 63 wherein R 18 is hydrogen and R 19 is 0 69. The compound of claim 2 where Y2 is _hreaR9 O" *RR4 8 230 The compound of claim 69 which is selected from: 2-[2-[4-(6-fluoro-1,2- benzisoxazol-3-yl)-1-piperidinyl]ethyl]-2-phenyl-1,3-indandione and its pharmaceutically acceptable acid addition salts.

71. A compound of the formula: Q1 (Y)P Q1I NN wherein X is or -N(R 2 R 2 is selected from the group consisting of lower alkyl, aryl lower alkyl, aryl, cycloalkyl, aroyl, alkanoyl, and phenylsulfonyl groups, and aryl is defined hereinafter; p is 1 or 2; Y is hydrogen, lower alkyl, hydroxy, chlorine, fluorine, bromine, iodine, lower alkoxy, trifluoromethyl, nitro, or amino; -z Q- is S -Z N-Y2 I where Z is and Y2 is selected from the group consisting of: 231 in which (Ri) is -CR 24 R 27 -(CR 23 R 24 )n-CR 24 R 27 where n is 0, 1, 2, or 3; or -CHR 24 -CH=CH-CHR 24 -OH R 24 -05-C-CHR 24 -CHR 24 -CH=CH-CR 23 R 24 -CHR 24 -CHR 24 -CR 23 R 24 -CH=CH-CHR 24 -OH R 24 -C=-C-CR 23 R 24 -CHR 24 or -OH R 24 -CR 23 R 24 -C=-C-CHR 24 the -OH =CH- bond being cis or trans; R 23 is hydrogen, (Cl-C18) linear alkyl, phenyl, hydroxy, (C 1 -C, 8 )alkoxy, aryloxy, aryl(Cl-C18)alkyloxy, (C.-C 18 )alkanoyloxy, hydroxy(Cl-0 6 )alkyl, (C1-C18)alkoxy(Cj-C6) alkyl, aryl(Cl-0 1 8 )alkyloxy(Cl-C 6 )alkyl, (Cl- C,8a)aI kanoyloxy(Ci -C 6 )alkyl or lower alkyleneyl where Z, is lower alkyl, -OH, lower alkoxy, -OF 3 -NO 2 -NH 2 or halogen; and R 24 is hydrogen, (Cl-Cia) linear alkyl, phenyl, hydroxy(Cl-C6)alkyl, (0 1 -C 18 )alkoxy(Cj-C6) alkyl, phenyl(0 1 -C6)alkyloxy, aryl(C 1 -C1a)alkyloxy(Cj- C 6 )alkyl, (Cl-Ci 8 )alkanoyloxy (Cl-C 6 )alkyl or lower alkyleneyl 232 where Z, is as previously defined; R 2 7 is hydrogen or R 2 4 and R 27 taken together with the carbon to which they are attached form C=O or C=S; and R and m are as defined hereinafter; with the proviso that R 23 is not hydrogen, (Cl-C 6 )Iinear alkyl, phenyl, or lower alkyleneyl when R 2 7 is hydrogen and R 24 is hydrogen, (C 1 -C 6 )inear alkyl, phenyl, or S. loe alkleSy wit th prvs htR4i o yrgn C-6lna lypeyo AP lower alkyleneyl 233 R3 where R 1 is as previously defined, and R 3 is hydrogen or -OCH 3 (3) where R 1 is as previously defined; and R" 4 is selected from hydrogen, lower alkyl, lower alkoxy, hydroxy, amino, mono- or dialkylamino, (C 1 -C 3 )acylamino, (Ci-C 6 )alkanoyl, trifluoromethyl, chlorine, fluorine, bromine, or -O-C(=O)-(C1-C12 straight or branched chain) alkyl or -C(=O)aryl; in which aryl is phenyl or where R 5 is hydrogen, lower alkyl, lower alkoxy, hydroxy, chlorine, fluorine, bromine, iodine, lower monoalkylamino, lower dialkylamino, nitro, cyano, trifluoromethyl, trifluoromethoxy; (R, 4 (4) where R 1 and R" 4 are as previously defined; b io 234 R XY where either one of Xy or Xz is and the other is -CH 2 and R' 5 is hydrogen, lower alkyl, lower alkoxy, chlorine, fluorine, or bromine; and R 1 is as previously defined; 0 Jf :a R"4 N (6) where R 1 and R" 4 are as previously defined; U -(R4)q A B A where A is By and Bz are both CH; U isO; q is 1, 2, 3 or 4, and R 1 are as previously defined; R 4 is hydrogen, lower alkyl, lower alkoxy, hydroxy, tri(C-C 6 )alkylsilyloxy, hydroxy lower alkyl, alkanoyloxy lower alkyl, amino, mono- or dialkylamino, 235 (Ci-C 1 s)acyl amino, (Ci-Cl 8 )alkanoyl, trifluoromethyl, chlorine, fluorine, bromine, straight or branched chain) alkyl or -C(=O)-aryl; in which aryl is phenyl or where Rs is hydrogen, lower alkyl, lower alkoxy, hydroxy, chlorine, fluorine, bromine, iodine, lower monoalkylamino, lower dialkylamino, nitro, cyano, trifluoromethyl, trifluoromethoxy; -(Rl)-N O H where R 1 is as previously defined, and with the proviso that none of R 23 R 24 and R 27 are hydroxy; R(R) (14) where Rl is as previously defined; Q 2 is or -CH 2 and SR and m are as defined hereinafter; 236 R1 K where R 1 is as previously defined; (18) -Ri-O-R"12 where R" 12 is selected from the group consisting of: hydrogen, -C(=O)-(C1-C12 straight or branched chain) alkyl, -C(=O)-NR13RI4, -C(=O)-NR 1 5 R 1 6 and -S(=0)2-R17, where R 13 is selected from the group consisting of hydrogen and (Ci-C12) alkyl groups; where R 14 is selected from the group consisting of hydrogen and (C1-Ci2) Salkyl groups; where NR 15 R 16 taken together form a ring structure selected from the group consisting of piperidinyl, morpholinyl and piperazinyl; where R 1 7 is selected from the group consisting of (C-C 6 )alkyl and aryl groups; where R, is as previously defined; (19) -R1-NR 1 sR 1 9 where R 1 8 and R 19 are independently selected from the group consisting of: hydrogen, 237 (0-012 straight or branched chain) alkyl, alkyl, and alkyl; where NR1 8 R 19 taken together form a ring structure selected from the group consisting of piperidinyl, morpholinyl and piperazinyl; and R, is as p reviously defined; ,-SR1 w here R, and R" 1 2 are as previously defined; and where R is hydrogen, lower alkyl, lower alkoxy, hydroxyl, carboxyl, chlorine, fluorine, bromine, iodine, amino, lower mono or dialkylamino, nitro, lower alkyl thio, trifluoromethoxy, cyano, acylamino, trifluoromethyl, trifluoroacetyl, aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, formyl, .*lyl -C(=O)-O-alkyl, -C(=O)-aryl, -C(=O)-heteroaryl, -CH(0R 7 )-alkyl, -C(=W)-alkyl, -C(=W)-aryl, and -C(=W)-heteroaryl; alkyl is (0 1 -C 18 )alkyl; aryl is as previously defined; 238 heteroaryl is Q3 is -CH=N-; W is CH 2 or CHR 8 or N-R 9 R 7 is hydrogen, alkyl, or alkanoyl; R 8 is lower alkyl; R 9 is hydroxy, alkoxy, or -NHRio; and R 10 is hydrogen, lower alkyl, (C 1 -C 18 )acyl, aryl, -C(=0)-aryl or -C(=0)-heteroaryl, where aryl and heteroaryl are as defined above; and m is 1, 2, or 3; and, any hydroxyl group attached to an aliphatic or aromatic carbon atom, or any primary or secondary nitrogen atom may be acylated with a (C4- C 18 )alkanoyl group; in addition, any nitrogen atom may alternatively be acylated with a (C 4 -C 8 )alkoxycarbonyl group; all geometric, optical and stereoisomers thereof, or a pharmaceutically acceptable acid addition salt thereof.

72. The compound of claim 71 having the formula: ZI Y N 239

73. The compound of claim 72 wherein Y 2 is (R)m

74. The compound of claim 73 wherein R, is -CH 2 CH(OH)0H 2 or -CH 2 CH[OC(=O)(0 1 -Cl 8 )alkyl]CH 2 The compound of claim 74 wherein R is independently selected from hydrogen, (0-C 6 )alkoxy or (C 1 -Cl 8 )alkanoyl and m is 1 or 2.

76. The compound of claim 75 wherein X is and Z is -OH-.

77. The compound of claim 76 which is selected from: 4-[3-[4-(6-fluoro-1.,2- be nzisoxazol-3-y)-pi1pe rid inyl]-2-hyd roxy- 1 -propoxylphenyl methyl ether, 4-13-L4- (6-flIuo ro- 1, 2-benzisoxazol-3-yl) -pipe rid i nyl]-2-hyd roxy- 1 -propoxy]-3- methoxyphenylmethanone, 1 -[(4-aceto-2-methoxy) phenoxy]-3-[4-(6-fluoro-1,2- benzisoxazol-3-yl)-1 -pipe ridinyl]-2-propyl decanoate, and the pharmaceutically acceptable acid addition salts of the aforesaid compounds.

78. The compound of claim 72 wherein Y2 is U 0 where A is By and B. are both CH; 240 U is 0; and R, is -CH 2 CH(OH)0H 2 or -CH 2 CH[0C(=0)(C-Cl 8 )alkylICH 2

79. The compound of claim 78 wherein X is and Z is -OH-. The compound of claim 79 which is selected from: N-[3-[4-(6-fluoro-1 ,2- be nzisoxazol-3-y)- 1 -pipe rid inyl]-2-hyd roxy- 1 -p ropyl] phthal im ide, 1 -[4-(6-fluoro- 1 ,2-benzisoxazol-3-yl)-l1-piperidinyl]-3-phthalimido-2-propy decanoate, and the pharmaceutically acceptable acid addition salts of the aforesaid compounds.

81. The compound of claim 71 which is selected from: N-[2-14-(6-fluoro-1 ,2- benzisoxazol-3-yl)- 1 -piperidinyl]ethyl]- 4-(1 -decanoyl)ami nophthalimide, flIuo ro-1, ,2-benzisoxazol-3-yi)- 1 -pi perid inyl]ethyl]-4- (1 -decanoyl) oxyphthal imide and the pharmaceutically acceptable acid addition salts of the aforesaid compounds.

82. The compound of claim 72 wherein Y2 is -R 1 -0-R" 12 *83. The compound of claim 82 wherein R" 1 2 is hydrogen.

84. The compound of claim 83 wherein X is The compound which is selected from: 1 -[2-[4-(6-fluoro-1 ,2-benzisoxazol- 3-yl)-1 -pipe rid inyl]ethyl]cyclohexanol and its pharmaceutically acceptable acid addition salts. 241

86. The compound which is selected from: 1 -[2-[4-(6-fluoro-1 ,2-benzisoxazol- 3- yl)-1 -piperidinyl]ethyl]cyclopentano and its pharmaceutically acceptable acid addition salts.

87. The compound of claim 72 wherein Y 2 is -R 1 NR 1 8 R 19

88. The compound of claim 87 wherein R 1 8 and Rig are both hydrogen.

89. The compound of claim 88 which is selected from: 3-[4-(6-fluoro-1 ,2- benzisoxazol-3-yl)- 1 -pipe rid inyl]-2-hyd roxy- 1 -p ropylamni ne, and its pharmaceutically acceptable acid addition salts. A compound which is selected from: ethyl 3-[4-(6-fluoro-1 ,2-benzisothiazol- 3-yl)-l1-piperidinyl]propionate, 2-[4-(6-fluoro-1 ,2-benzisoxazol-3-yl)-1 piperidinyl]acetonitrile, 3-[4-(6-fluoro-1 ,2-benzisoxazol-3-y)-1 piperidinyllpropionitrile, 1 -[4-(3-chloropropoxy)-3-methoxyphenyl]-2- hydroxyethanone, and the pharmaceutically acceptable acid addition salts of the aforesaid compounds.

91. A compound which is selected from: (S)-6-fluoro-3-[1 -(3-methoxyphenyl-2- methyl propyl) -4-pi pe rid inyl]- 1 ,2-benzisoxazole and its pharmaceutically acceptable acid addition salts. 242

92. A compound which is selected from: N-(2,3-epoxypropyl)-4-(6-fluoro-1 ,2- benzisoxazol-3-yI)piperidine and its pharmaceutically acceptable acid addition salts.

93. A compound which is selected from: 1 -[4-(6-fluoro-1 ,2-benzisoxazol-3-yl)- 1 -piperidinyl)-2-propanone and its pharmaceutically acceptable acid addition salts.

94. A compound which i s selected from: phenoxycarbonyl-3-(1- phenoxycarbonyl-4-piperidinyl)-1 H-indazole and its pharmaceutically acceptable acid addition salts. A compound which is selected from: 1 -[4-[3-[4-(6-fluoro-1 ,2-benzisoxazol1- 3-yl)-l1-p ipe rid inyl] propoxy]-3-methoxyphenyl]-2-hyd roxyethanone and its pharmaceutically acceptable acid addition salts. :96. The compound N-[2-[4-(6-fluoro-1 ,2-benzisoxazol-3-yl)- piperidinyl]ethyl]phthalimide hydrochloride.

97. A compound of the formula: Q1 Y) 0 wherein X is -N(R 2 243 R 2 is alkoxycarbofl; pis 1 or 2; Y is hydrogen, lower alkyl, hydroxy, chlorine, fluorine, bromine, iodine, lower alkoxy, trifluoromethyl, nitro, or amino; Q, is where Z is and Y 2 is selected from the group consisting of: (1)I in which (RI) is -CR 24 R 27 -(CR 2 3R 24 )n-CR24R27- where n is 0, 1, 2, or 3; or -CHR 24 -CH=CH-CHR24-, -CHR 24 -C=-C-CHR24-, -CHR 24 CH=CH-CR 23 R24CHR24-, -CHR 24 CR 23 R 24 CHCHCHR24-, CHR 24 -C=-C-CR 23 R 24 CHR24-, or -OH R 24 -CR 23 R24-C-C-C HR 2 4 the -CH=CH- bond being cis or trans; R 23 is hydrogen, (CI-C18) linear alkyl, phenyl, hydroxy, (CI-C. 18 )alkoxy, aryloxy, aryl(C,-Ci 8 )alkyloxy, (C 1 -C 18 )alkanoyloxy, hydroxy(CI-C6)alkyl, 244 (C 1 -C1~ 8 )alkoxy(C 1 -0 6 )alkyl, aryl(C 1 -C, 8 )alkyloxy(Cl-0 6 )alkyl, (Cr. C 18 )alkanoyloxy (Cl-C 6 )alkyl or lower alkyleneyl (ZO/ where Z, is lower alkyl, lower alkoxy, -CE 3 -NO 2 -NH 2 Or halogen; and R 24 is hydrogen, (Cl-C 18 linear alkyl, phenyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 18 )alkoxy(C 1 -C6)alkyl, phenyl(Cl-C 6 )alkyloxy, aryl(C 1 8 )alkyloxy(C 1 C6)alkyl, (Ci a)alkanoyloxy(C 1 -C6)alkyl or (Z 1 lower alkyleneyl where Z, is as previously defined; R 27 is hydrogen or R 24 and R 27 taken together with the carbon to which they are attached form 0=0 or C=S; and .~and m are as defined hereinafter; es.RI) R: (2 3 wher Ri*speiul dfnd n 3i hdoe r-C .R4 0000 7Q) 245 where R 1 is as previously defined; and R 4 is hydrogen, lower alkyl, lower alkoxy, hydroxy, tri(CI-C 6 )alkylsilyloxy, hydroxy lower alkyl, alkanoyloxy lower alkyl, amino, mono- or dialkylamino, (C 1 -C 18 )acyl amino, (C 1 -C 8 s)alkanoyl, trifluoromethyl, chlorine, fluorine, bromine, 1 -C 18 straight or branched chain) alkyl or -C(=O)-aryl; in which aryl is phenyl or where R 5 is hydrogen, lower alkyl, lower alkoxy, hydroxy, chlorine, fluorine, bromine, iodine, lower monoalkylamino, lower dialkylamino, nitro, cyano, trifluoromethyl, or trifluoromethoxy; c R4 (4) where R 1 and R 4 are as previously defined; where either one of Xy or Xz is and the other is -CH 2 and R' 5 is hydrogen, lower alkyl, lower alkoxy, chlorine, fluorine, or bromine; and o 246 R, is as previously defined; aR4 where R, and R 4 are as previously defined; -R 1 (R4)q where. A is -C(=CH 2 -C(=O)CH 2 -0H 2 0H 2 -CR 26 =N- or -CR 25 R 26 R 2 5 is hydrogen, (C 1 -C 6 )alkyl, hydroxy or (Cl-C 18 )alkanoyloxy; R 2 6 is hydrogen or (C 1 -C 6 )alkyl; either one of By and Bz is CH or N and the other is CH; U is 0 or S; q is 1, 2, 3 or 4, and R, and R 4 are as previously defined; 0 H (8) where R, is as previously defined; 247 P2 B 2 8 2 8 R 2 8 (9) wherein R 1 R 4 and q are as previously defined; and R 2 8 is hydrogen, (C-C 6 )alkyl, aryl(0 1 -C 6 )alkyl, phenyl or substituted phenyl; R 2 30 31 R 32 (R 4 )q wherein R 1 R 4 and q are as defined above, R 29 and R30 are hydrogen, (Cl- C 6 )alkyl, aryl(Cl-C 6 )alkyl, phenyl or substituted phenyl; R 3 1 and R 32 are hydrogen, hydroxy, (Cl-C 6 )alkyl, aryl(Cl-C6)alkyl, phenyl, substituted phenyl, hydroxymethyl, or CHOR33where R 33 is (Cl-Cl 8 )alkanoyl; or either R 29 and R 30 taken together or R 31 and R 3 2 taken together with the carbon group to which they are attached form a C=O or C=S group; *R 31 32 R31. (R4)q (11) R 2 8 R 28 where R 1 R 4 R 28 R 29 9 R 3 0 9 R 31 R 3 2 and q are as defined above; 248 (12) (4) where R 1 R 4 R 29 R 30 R 31 R 32 and q are as defined above; (13) ()m wherein R 1 and R 4 are previously defined, and m is defined hereinafter; (14) where R 1 is as previously defined; Q2 is or -CH 2 and R and m are as defined hereinafter; where R, is as previously defined; 249 O0 0 4 (16) where R 1 and R 4 are as previously defined, and m is defined hereinafter; R1 K^-N (R O o (17) where R 1 and R 4 are as previously defined, and m is defined hereinafter; (18) -R1-O-R12 where R 12 is selected from the group consisting of: hydrogen, alkyl, 1 -C 18 straight chain or branched) alkyl, -C(=0)-NR13RI4, -C(=O)-NR 5 R 6 o"o 2 -R 1 7 and o- 250 0 N where R 13 is selected from the group consisting of hydrogen and (Ci-C 18 alkyl groups; where Ri 4 is selected from the group consisting of hydrogen and (Ci-C 18 alkyl groups; where NR 1 5 R 16 taken together form a ring structure selected from the group consisting of piperidinyl, morpholinyl and piperazinyl; where R 17 is selected from the group consisting of (Ci-C 8 i)alkyl and aryl groups; where R 1 and R 4 are as previously defined, and m is defined hereinafter; -R,-NRi8R,1 where R 18 and Rig are independently selected from the group consisting of: hydrogen, (Ci-C 18 straight or branched chain) alkyl, 8 alkyl, -C(=O)-(Ci-Ci 8 alkyl; -C(=O)-pyridyl; R d ;and 2 8 R 251 where NR 18 R 1 i taken together form a ring structure selected from the group consisting of piperidinyl, morpholinyl and piperazinyl; where the piperidinyl or piperazinyl ring is optionally substituted by where X, Y, p, R 1 R 4 and R 28 are as previously defined; and m is defined hereinafter; -R 1 -S-R 1 2 where R 1 and R 1 2 are as previously defined; 0 o (21) where R 1 R 4 and R 28 are as previously defined; and where R is hydrogen, lower alkyl, lower alkoxy, hydroxyl, carboxyl, chlorine, fluorine, bromine, iodine, amino, lower mono or dialkylamino, nitro, lower alkyl thio, trifluoromethoxy, cyano, acylamino, trifluoromethyl, 252 trifluoroacetyl, aminocarbonyl, monoalkylaminocarbonyl, dial kylamninocarbonyl, formyl, -C(=O)-alkyl, -C(=O)-O-alkyl, -C(=O)-aryl, -C(=O)-heteroaryl, -OH (0R 7 )-alkyl, -C(=W)-alkyt, -C(=W)-aryl, and -C(=W)-heteroaryl; S alkyl is (0-C 18 )alkyl; aryl is as previously defined; heteroaryl is 0000 '00, 0 3 is -CH=N-; W is OH 2 or CHR 8 or N-R 9 R 7 is hydrogen, alkyl, or alkanoyl; R 8 is lower alkyl; R 9 is hydroxy, alkoxy, or -NHRjO; and RIO is hydrogen, lower alkyl, (0 1 -C, 8 )acyl, aryl, -C(=0)-aryl or -C(=0)-heteroaryl, where aryl and heteroaryl are as defined above; and 253 mis 1,2, or 3; and, any hydroxyl group attached to an aliphatic or aromatic carbon atom, or any primary or secondary nitrogen atom may be acylated with a (C4- C1 8 )alkanoyl group; in addition, any nitrogen atom may alternatively be acylated with a (C4-C18)alkoxycarbonyl group; all geometric, optical and stereoisomers thereof, or a pharmaceutically acceptable acid addition salt thereof.

98. A pharmaceutical composition comprising a compound of any one of claims 1, 71, and 97 and a pharmaceutically acceptable carrier.

99. An antipsychotic composition which comprises the compound of any one of claims 1, 71, and 97 in an amount sufficient to produce an antipsychotic effect and a pharmaceutically acceptable carrier.

100. Use of the compound of any one of claims 1, 71, 97, 98, and 99 for the manufacture of a medicament for the treatment of psychoses.

101. An analgesic composition which comprises a compound of any one of claims 1, 71, or 97 in an amount sufficient to produce a pain-relieving effect and a pharmaceutically acceptable carrier.

102. A method of alleviating pain which comprises administering to a mammal a pain-relieving amount of the compound of any one of claims 1, 71, or 97. 254

103. A method of treating psychoses which comprises administering to a mammal a psychoses-treating amount of the compound of any one of claims 1, 71, or 97.

104. Use of the compound of any one of claims 1, 71, or 97 for the manufacture of a medicament for the relief of pain.

105. A depot pharmaceutical composition which comprises a pharmaceutically acceptable carrier and a therapeutically effective amount of the compound of any one of claims 1, 71, or 97 wherein the compound contains a hydroxy group, an amino group or a nitrogen at the 1-position of an indazole ring which has been acylated.

106. The depot pharmaceutical composition of claim 105 wherein the hydroxy group or amino group is acylated with a (C 4 -C 18 )alkanoyl group or a (C4- C0 18 )alkoxycarbonyl group.

107. The composition of claim 105 or claim 106 which contains a pharmaceutically acceptable oil.

101089. The composition of claim 107 wherein the oil is selected from the group consisting of coconut oil, peanut oil, sesame oil, cotton seed oil, corn oil, soybean oil, olive oil and esters of fatty acids and polyfunctional alcohols. 00 oooo3 255 109. A depot pharmaceutical composition which comprises a pharmaceutically acceptable carrier and a therapeutically effective amount of the compound of any one of claims 6, 77, 80 or 81. 110. A method for providing a long lasting antipsychotic effect which comprises injecting into a mammal an amount of the composition of any one of claims 107, 108, and 109 sufficient to produce a long lasting antipsychotic effect. 111. Use of the composition of any one of claims 105, 106, and 109 for the manufacture of a medicament providing a long-acting antipsychotic effect. DATED this 24 th day of November 2003 AVENTIS PHARMACEUTICALS INC WATERMARK PATENT TRADE MARK ATTORNEYS 290 BURWOOD ROAD HAWTHORN VICTORIA 3122 AUSTRALIA P14825AU02 KMH/RES C *o