AU9720798A

AU9720798A - Heteroarylpiperidines, pyrrolidines and piperazines and their use as antipsychotics and analgetics

Info

Publication number: AU9720798A
Application number: AU97207/98A
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: 1998-12-18
Publication date: 1999-04-22

Description

Imv I I Mr.' Reguiafion 3.2(2) A USTRA LI A Patents Act 1990

ORIGINAL

COMPLETE SPECIFICATION STANDARD PATENT a. S

I

a., I S 46

II

I- I Application Number: Lodged: 54 a Invention Title: HETEROARYLPIRERIDINES, PYRROLIIJINES AND PIPERAZINES AND THEIR USE AS ANTIPSYCHOTICS AN D ANALGETICS The following statement is a full description of this invention, including the best method of performing it known to us t I

D

I

OI

HETEROARYLPIPERIDINES, PYRROLIDINES AND PIPERAZINES AND THEIR USE AS ANTIPSYCHOTICS AND ANALGETICS CROS-REFERENCE TO RELATED APPI ICATION This application is a continuation-in-part of application Serial No. 08/144,265, filed October 23, 1993, which is a continuation-in-part of 07/969,383, filed October 1992, which is a continuation-in-part of application Serial No. 788,269, filed November 5, 1991, now abandoned, which is a continuation-in-part of application Serial No.

944,705, filed September 5, 1991, now abandoned, which is a continuation of application Serial No. 619,525, filed November 29, 1990, now abandoned, which is a continuation of application Serial No. 456,790, filed December 29, 19S9, now abandoned, which is a continuation-in-part of application Serial No. 354,411, filed May 19, 19S9, now abandoned. The entire disclosure of these applications is relied upon and incorporated by reference herein.

BACKGROUND OF THE INVENTION This invention relates to heteroarylpiperidines, pyrrolidines and piperazines.

More particularly, this invention relates to heteroarylpiperidines, pyrrolidines and piperazines 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. Tnere 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 extra pyramidal 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 s

E

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.

Moreove 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 anaigetics. Nevertheless, the need for safe and effective analgetics has continued to the present day.

SUMMARY OF THE INVENTION This invention aids in fulfilling these needs in the art by providing a compound of the fornula: )p IN wherein X is or RP is selected from the group consisting of lower alkyl, aryl lower alkyl, ary!, 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 selected from the group consisting of: Z N--Y 2 r r o

V

N- Y Ij I I whe-re Z is -CH- or and Y, is selected from the group Consisting of, -(RI)O

N:

in which (R 1 is -CR, 4 Rz(CRR,,),,-CR,,RI,7 where n is 0,1,2, or 3; or

-CHR,,-CH=CH-CHR

4

-CHR,,-C=C-CHR

2 -C H =C H-C RR 2 -CH

-CHR,,-CRR,

4

-CH=CH-CHR,

4

-CHR

24

-C=C-CRY

24 or the -CH=CH- bond being cis or trans; R and m are as defined hereinafter; R, is hydrogen, alkyl, aryl, hydroxy, alkoxy, aryloxy, arylalkyloxy.

aLkanoyloxy, hydroxy lower alkyl, alkoxy lower alkyl, aryloxy lower alkyl, arylatkyl oxy lower alkyl, alkanoyloxy lower alkyl or lo%%tralkycncyI0 (Z where Z, is lower alkyl, -OH, lower aLkoxy, -NHl 2 or halogen; and is hydrogen, alkyl, aryl, hydroxy lower alkyl, aLkoxy lower alkyl, aryloxy lower aLkyl, arylalkoxy lower alikyl, alkanoyloxy lower alkyl or Iowcra&.,yIcncyI (Z where Z, is as previously defined; is hydrogen or and R1 7 taken together with the carbon to which they are attached formr C=O or C=S; and R and m are as defined hereinafter, 3 where R, is as previously defined, and R3 Ls hydrogen or -O)CH,; R4 v.'here R, is as previously defined; and R, is hydFogen, lower alkyl, lower a Lkoxy, hyd roxy, tri(C,-Cdalky'lilyloxy, hydroxy lowver alkyl, alkanoyloxy lowveralkyl, amino, mon or diaLkyvlamino, (C,-C,,)acyl amino, (C,-C,)alkanoyl, triflucormethyl, chlorine, fluor-ine, bromine, nitro, straight or branched chain) alkyl or -C(=O)-aryl; where R, is hydrogen, lower alkyl, low'er alkoxy, hydroxy, chlorine, fluorine, bromine, iodine, lower monoalkylamino, lower dialkylamino, nitro, cyano, trifluoromethyl, trifluoromethoxy; 0a where R, and R, are as previously defined; xy where either one of X, or X, is and the other is and Rg' is hydrogen, lower alkyl, lower alk-oxy, chlorine, fluorine, orbrornine; and R, is as previously defined; 0~ where R, and R, are as previously defined;

U

By where A is

-C(=O)CH

2 -CHCHI-, -CR 2 or

-CR.

5 R,6-; Rz is hydrogen, lower alkyl, hydroxy or alkanoyloxy; R, is hydrogen or lower alkyl; either one of By and B. is CH or N and the other is CH; U is O or q is 1, 2,3 or 4, and R, and R, are as previously defined;

S.

where R, is as previously defined;

R

2 s Rig N' (R4)q R, whereint R 1 R, and q are as defined above; and P, is hydrogen, (C,-C)aky, aryI(C,-C)alkyI, phenyl or substituted phenyl; S. a At..

U

(4 CR4)q wherein R 1 R, and q are as defined above; Ra, and R, are hydrogen, (C,-C,)alkyI, aryl(C,-Cg)alkyl, phenyl or substituted phenyl;

R,

1 and are hydrogen, hydroxy, (C,-CQakyl, ar-yI(CC-C)aLkyl, phenyl, substit-uted phenyl, hydraxymethyl, or CHOR, where R, is (C,-C,,)alkanoyl; or either R, and taken together or R, 1 and R, taken together with the carbon g-roup to which they are attached form a C=O or C=S g-roup; (11) si R, R!3 Rzu whee 1 4 9 R~ ~R 2 and q are as defined above; 1211R R 30 R31 R 3 3 1 where R, R 4 R, R 3 and q are as defined above; (13) wherein R, and R, are previously defined and m is defined hereinafter, (14)

-(R

1 where R, is as previously defined; Q, isS, NH, or and R and m are as defined hereinafter;

OD

0 V where R, is as previously defined; (16) 0 wh-ere and R, are as previously defined and m is as defined hereinafter, (17) 0 Ij(, 0' where R 1 R, are as previously defined and mn is as defined hereinafter; (18) -R 1

-O-RI.

wvhere is selected from thp group consisting of: hydrogen, alIkyl, straight chain or branched) alkyl.

-C(=O)-NR

3 Rw 4 7 and doom 0 0 where is selected from the group consisting of hydrogen and (C,-C,,)alkyl groups; where R, 4 is selected from the group consisting of hydrogen and (C-C~dalkyl groups; where NR 15 R,6 taken together form a ring structure selected from the group consisting of piperidinyl, inorpholinyl and piperazinyl; where R, 7 is selected from the group consisting of lower alkyl and aryl groups; NYhere R.

4 s previously defined and mn is defined hereinafter; (19) -R 1

-NR

1 5

R

1 where R~s and R, 9 are independently selected from the group consisting r hydrogen, 2 straight or branched chain) alkyl, alkyl, -C(=O)-pyridyl or

N'

where NR,,RI 9 taken together forrn a ring structure -selected from the group consisting of piperidinyl, morphol-inyl and piperazinyl; where the piperidinyl or Avsh'Apiperazinyl ring is optionally substituted by where R 1 X, Y, p, R, and R, are as previously defined and mn is defined hereinafter; where R, and R, 2 are as previously defined; (21) r) where R 1 R, and R, 5 are as previously defined; and where R is hydrogen, lower alkyl, loweraIIkoxy, hydroxyl, carboxyl, chlorine, fluorine, bromine, iodine, am-ino, lower mono or diaLkylamnino, nitro, lower alkyl thio, L trifluoromethoxy, cyano, acylarnino, trifluoromethyl, trifluoroacetyl, a rri'nocarbonyl, monoalkyLaminocarbonyl, dialkylarninocarbonyl, formy!, -C(=O)-alkyl, ikyl, ryl, -C(=O)-heteroaryl, -CHCOR,)-atkyl, -C(=W)-alkyl, and -c(=W)-heteroaryl; alk~yl is (C,-C,,)alkyl; :aryl is as previously defined; :heteroaryl is

ILI

Ra is lower alkyl; R, is hydroxy, aikoxy, or -NHR, 1 and is hydrogen, alkyl, (C,-C)acyl, aryl, -C(=O)aryl or -C(=O)heteroaryl, where aryt and heteroaryl are as defined above; and m is 1,2, or 3; vith the proviso that in formula (14)-Z-is not-,N- when Xis Q2 is Y is hydrogen, lower a kyl, lower alkoxy, halogen, hydroxy or trifluoromethyl, and p is] or 2; w-ith the proviso that in formula R, is not H when R, is -(CH2).

5 Z is not ,X is Y is hydrogen, halogen, lower akyl, lower alkoxy, hydroxy or ti-ifluoromethyl, and p is I or 2; with the proviso that in formula (14) Z is not ICH when X is -NH- or Y is hydrogen, halogen, lower alkyl, lower alkoxy, hydroxy or trLfluoromethyl and Q, is with the proviso that in formula (14) Z is not -Cm- when X is Q, is Y is hydrogen, lower alkyl, lower aikoxy, hydroxy or halogen, and p is I or 2: with the proviso that in formnula (14) Z is not _Iwhen X is Q, is-CH,-, Y is hydrogen, halogen, lower alkyl, lower alkoxy or hydroxy, p is I or 2, R is hydrogen, ***and mis 1; *with the proviso that in formula (14) Z is not 4- when X is Q, is R is chlorine, fluorine, bromT-ine, iodine, lowveraifkyl, loweralkoxy, lower alkyl thio, lower mono- or dialkylamino, an-ino, cyano, hydroxy, trifiuoromethyl; R, is ary!; Y is hydrogen, halogen, lower alkyl, lower :Okoxy or hydroxy, p is I or?2; with the proviso that in formula (10 Z is not when X is -NH- or where R, is lower alkyl, aryl lower aLkyl, or phenylsulfonyl, Y is hydrogen, halogen, lower alkyl, lower alkoxy or hydroxy, p is I or 2 and Q2 is with the proviso that Y, is not the moiety ofcfrrnua (8)when ZisCH I i 0, p is 1, and Y is hydrogen, lower alkyl, lower alkoxy, chlorine, fluorine, brom-ine, iodine or a hydroxyl group; a1 with the proviso that in formula Z is not when X isO0 or S, Y is hydrogen, R is hydrogen, )alkyl, chlorine, fluorine, bromine, iodine, cyano,

(C,-C

4 aLkoxy, aryl, -COCR 2 5 s where R2.s is )alkyl; with the proviso thet in for-mula Z is tot N- when X R 1 is R is H, and in 1; wi!Iithe proviso that in formuia R, is not hydrogen when Y is 6-F, X is Z is 'AjH -,and nis 2,3 or 4; with the proviso that in formula (18) R, 2 is not H when Z is Xis- NH- or -N(R 2 where R, is lower aikyl, aryl lower alkyl, or phenyisuifonyl, Y is hydrogen, lower alkyl, lower alkoxy, chlorine, fluorine, bromine, iodine or a hydroxyl group and p is 1 or 2; with the proviso that in formula R, 2 is not H when X is where R, is phenyl, Z is I and Y is hydrogen, lower alkyl, lower alkoxy, chlorine, fluorine, bromine, iodine or a hydroxyl group; with the proviso that in formula R, 3 and R 1 are not lower alkyl when Z-is- X is and R, is aryl and Y is hydrogen, lower alkyl, lower alkoxy, chlorine, fluorine, bromine, iodine or a hydroxyl group; with the proviso that in formula when X is Z is-CH- and Y is hydrogen, lower alkyl, lower alkoxy, chlorine, fluorine, bromine, iodine or a hydroxyl group, RH and are not lower alkyl; with the proviso that in formula R1, and are not hydrogen when R, is S-CH,)2s-, Z is H- X is and Y is 6-F;

CH-

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 acylalion with (C-C, 5 )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 -f atom may alternatively be acylated with a (C,-C,)alkoxy-carbonyl chloride to form a highly lipophilic carbamate derivative of the invention.

The invention also provides for the highly lipophilic compounds which MN 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 12 1 .1 cc S S 4.

c'.

SO 1 0\ comprises administering to a patient a pharmaceutically effective amount of a compound of the invenion.

Further, this invention provides a method of sustained release of a pharmaceutically effective amount of a lipophiic 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.

DFTAll F DF CRIVVION OFTHE PFFFRRFi FBODIMFNlT The con nrnds of this invention are useful as antipsychotic drugs and as analgesic agents. The compounds of the invention can contain a variety of different substiuents and chemical groups. As used herein, when the term "lower- is mentioned in connection with the description of a particular group, the term means that the group it is describing contains from I to 6 carbon atoms.

The term "alkyl" as used herein refers to a straight or branched chain hy'd roca rbon 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.

Te 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 or isopropylene 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

S.

a 0* S. etc.

of a ka noyl groups are formyl, acetyl, propionyl, 22-dimnethy lacetyl, hexanoyl, octanoy), decanoyl, and the like.

The term 'aLkanoic acid" refers to a compound formed by combination of a carboxyl group %0th a hydrogen atom or .1lkyl g-roup. Examples of alkanoic acids are formic acid, acetic acid, propanoic acid, 2.2-iimethylpcetic acid, hexanoic acid, cctanoic acid, decanoic acid, and the like.

The ter-m "an)I lower aikyl" refers to compounds wherein "ary'l" and lowera [kyl- are as defined above- Thne term Iower alkylthio" refers to a monovalent substituent having the fo rm l a l ow.;er alk y I-S-.

TFhe term 'ohenvlsullonyl' refers to a mnonovalen, substituent having the forrnua phenyl-S'O,-.

Ine ter-n *cyl- refers to a substituent having the formula lowr akvlCC=)-or

CF

3 of ivyl-C(=O)- or hetecrrv-C(=O)-.

The term lowver mnonoalkylanito- refers to a monosubstituted derivative of amnmonia, wherein a hydrogen of ammonia is replaced by a lowver alkyl group.

The term "lower dialkylamnino- refers to a disubstit-uted derivative of ammonia, %-,herein two hydrogens of ammonia are replaced by lower a lkyl g-roups.

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

The termn 'dialkylaminocarbonyl- refers to a derivative ofan acid, wherein the hydroxyl group of the acid is replaced by a lower dialkylrnino group.

Thue term "aroyl" refers to a disubstituted carbonyl, wherei at least one substituent is an aryl group, where "aryl" is as previou-sly defined.

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

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

1' E A. (OMPO[ NDSOF THE INJVFNTION The compounds of this invention can be represented by the following for-mula: wherein X. Xis-0-, -N H-,or R, is selected. from the group consisting of lower.,Lk'A. aryl lower alkyl, arylI, cycloalkyl, aroyl, alkanoyi, alkoxycarbonyl and phenylsulfonyl grFOUpS; pis Ior 2; Y is hydrogen, lowver alkyl, hydroxy, chlorine, fluorine, b~ornine, iodine, lowver aikoxy, trifluoromethyl, nitro, or amino; Q, is selected from the group consisting of:- Z/ N

-Y-

and (b)1 where Z is -CH- or anc Y, is selected from the group, consisting of: 0) 0 in which is where n is or 3; or -CHR,,-CH=CH-CH

R,

4

-CHR,

4

-C=C-CHR

2

-CHR

2

,-CH=CH-CRR,,-CHR

2 4

-CHR

2

,CRR,,-CH=CH-CHR,-,

-CHiR 2

,-C=C-CRR

24

-CHR,

4 or -CH-R,i-CRR,,-C=C-CHR,,-, the -CH=CH- bond being cis or trans; R2, is hydrogen, linear alkyl, phenyl, hydroxy, (CC-Cla)alkoxy, aryloxy, aryl(C 2 ,-C~dalky~oxy, (C 1

-C

15 )alka noyloxy, hydroxy(C -Cd)a kyl, ~CC-C,,)alkoxy(C,-C 6 atkyl, phenyl(C 1

-C

6 alkyloxy, ary1(CC-CQ)alkyloxy(C,-Cd)aIkyl or

(C

1 -C,,)a~kanoytnxy(C,-C,)alkyI or Z, is lower alkyl, -OH, lower alkoxy, -NH, or halogen; and RZ,, is hydrogen, linear alkyl, phenyl, hydroxy(C,-Qaikyl, (C,-C,,)alkoxy(C-C,)a~kyI, pheny(C,-CQa1kyloxy, aryl(C,-Cia)alkyloxy(C 1 .Q)alkyI or

(C

1 -C,)alkanoyloxyC 1 -Calkyl or where Z, is as previously defined;is hydrogen or and 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

3 3 Where R, is as previously defined, and R, is hydrogen or -OC H,; (3)

N

where R, is as previously defined; and R, is hydrogen, lower alkyl, lower alkoxy, hydroxy, tri(C 1 -C6a~kyLsilyloxy, hydroxy lower alkyl, al-kanoyloxy lower alkyl, amidno, mnono- or dialkylamino, 3 )acyl amino, (C,-C 18 )alkanoyl, tr-ifluoromethyl, chlorine, fluorine, bromine,

-O-C(=O)C

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

R

where R, is hydrogen, lower alkyl, lower alkoxy, hydroxy, chlorine, fluorine, bromine, iodine, lower monoalkylamino, lower dialkylamino, nitro, cyano, trifluoromethyl, trifluoromethoxy;- -CRR4 ct where R, and R, are as previously defined; where either one of X, or X, is and the other is and R, is hydrogen, lower alkyl, lower alkoxy, chlorine, fluorine, or bromine; and R, is as previously defined; where R, and R, are as previously defined;

U

kA A N I B Il y where A is -CH,CH2r, -CR, 6 or

R,

5 is hydrogen, (C,-C6)alky1, hydroxy or (C,-C,,)alkanoyloxy; is hydrogen or (C,-C 6 )alkyl; either one of B. and B, isCH or N and the other is CH; U isO0 or S; q is 1, 2,3 or 4, and R, and R, are as previously defined;- 0

H.

0 H where~~~~. Ri 9peiosydfnd wherei R, Rindq s ares definedaoe n

R

2 is hydrogen, (C,-C 6 )akyl, aryl(C,-C,)alkyl, phenyl or substituted phenyl: eg 080 Seg R2

R

30 R 31 R3 CR,)q wherein R 1 R, and qare as defined above; and are hydrogen, (CI-C)alkyl, aryI(C,-C,)alkyl, phe nyl or substituted phenyl; R, and are hydrogen, hydroxy, (C-C 6 alkyl, aryl(Cj-CQalkxyl, phenyl, substuted phenyl, hydroxyrnethyl, or CHOR, where is (C,-C,,)alkznoyl; or either R 29 and R~m taken together or Rj, and taken together with the carbon group to which they are attached form a C=O or C=S g-roup; R R 31

R)

2

R

Rn. R, where R 1 R~c, R 32 and q are as defined above; R2R 30

R

31 R2

R

31 7VR 3 2 (R4)q

E

where R 1

R

2

R

2 R, and q are as defined above; wherein R, and R, are previously defined and Mn is defined hereinafter;

-(R

1

)Q

2 CR6n where R, is as previously defined; Q is S, NH, or and R and rm are as defined hereinafter; 0 -RI) 0 where R, is as previously defined; (16) 0 0**where R, and R, are as previously defined and m is defined hereinafter, 0 0 w~ihere R~and R~are as previously defined and m is defined hereinafter, *.:X:wh.ere R, 2 is selected from the group consisting of: W hydrogen, alkyl, 15 straight chain or branched) alkyl, -C(=O)-NR,3R, 7 and 0 where R, is selected from the group consisting of hydrogen and aC-C 5 )ekyl groups; where is selected from the group consisting of hy'drogen and ai-ky: 21 groups; where NR 15

R,

6 taken together formr a ring structure selected from the group consisting of piper-idinyl, morpholinyl and piperazinyl; where is selected from the group consisting of (CC-C 1 )atkyl and aryl g-roups; where R, is previously defined and mn is defined hereinafter; (19) -R,-NR,R 1 ***.*where R, and R 19 are independently selected from the group consisting of:.

hydrogen, straight or branched chain) aLkyl, alkl, -CC-O)-py rid yl; C C (R4m ;and where LNR,,R,, taken together form a ring structure selected from the group consisting of piperidinyl, morpholinyl and piperazinyl; where the piperidin yl or piperazinyt ring is optionaily substituted by where X, Y, p, R 1 R, and R, are as previously defined and mn is defined hereinafter;

-RI-S-R,

where R, and are as previously defined: (21) 0 R28~ 0 where R 1 R, and are as previo(' defined; and where R is hydrogen, lowe,. alkyl.,Iower alkoxy, hydroxyl, carboxyl, chlorine, fluorine, bromine, iodine, amino0, lower mono or dialkylarnino, nitro, lower alkyl thio, t-rifluoromethoxy, cyano, acylarnino, trifluorornethyl, trifluoroacetyl, aminocarbonyl, rronoaLkylan1ocarbontyl, d ialkylamidnocarbonyl, fcu-rnyl, -C(=0)-0-alkyl, -C(=0)-aryl, teroa ryl, -CHCOR,)-alkyl, *CC=W)-alkyl, -C(=W)-aryl, and teroaryl; alkyl is (C,-C 15 )alkyl; aryl is as previously defined; heteroaryl is Q is -CH=N-; W is CH, or CHR, or N-Re; R, is hydrogen. alkyl, or alkanoyl; R. is lower alkyl; R, is hyd roxy. alkoxy, or -NHRO; and.

is hydrogen. lower alkyl, (C,-Cls )acyl. aryl, -C(=0)-ar-ylor -C(=0)-heteroaryl, where aryl and heteroaryl are as defined above; and mis 1,2, or3; with the proviso that in formula (14) Z is not -tN- when X is Q is Y is hydrogen, lower alkyl, lower alkoxy, halogen, hydroxy or trifluoromethyl, and p is 1 or 2; with the proviso that in formula R, is not H when R, is 3 Z is not

I

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

-CH-

Y is hydrogen, halogen, lower alkyl, lower alkoxy, hydroxy or trifluoromethyl and Q is with the proviso that in formula (14) Z is not -CH_ when X is Q is -CHi-, a a-H Y is hydrogen, lower alkyl, loweralkoxy, hydroxy or halogen, and p is 1 or 2; with the proviso that in formula (14) Z is not -CH- when X is Q, is Y is hydrogen, halogen, lower alkyl, lower alkoxy or hydroxy, p is I or 2, R is hydrogen, and m is 1; with the proviso that in formula (14) Z is not when X is -N(R 2 Q2 is R is chlorine, fluorine, bromine, iodine, lower alkyl, lower alkoxy, lower alkyl Sthio, lower mono- or dialkylamino, amino, cyano, hydroxy, trifluoromethyl; R 2 is aryl; Y is hydrogen, halogen, lower alkyl, lower alkoxy or hydroxy, p is I or 2; with the proviso that in formula (14) Z is not -N when X is -NH- or -N(R where R, is lower alkyl, aryl lower alkyl, or phenylsulfonyl, Y is hydrogen, S halogen, lower alkyl, lower alkoxy or hydroxy, p is 1 or 2 and Q, is with the proviso that Y, 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; m with the proviso that in formula Z'is not when Xis O or S, Y is hydrogen, R is hydrogen, )alkyl, chlorine, fluorine, bromine, iodine, cyano, )alkoxy, aryl, -COOR, 2 where R:,is (C,-C,)alkyl; with the proviso that in formula Z is not when X is R, is

-(CH)

25 R is H, and m 1; with the-proviso that in formula R, is not hydrogen when Y is 6-F, X is Z is and n is 2, 3 or 4; with that the proviso that in formula (18) is not H when Z is X is NH- or -N(R 2 where R, is lower alkyl, aryl lower alkyl, or phenylsulfonyl, Y is hydrogen, lower alkyl, lower alkoxy, chlorine, fluorine, bromine, iodine or a hydroxyl group and p is 1 or 2; with the proviso that in formula R,u is not H when X is -N(R 2 where R, is phenyl, Z is -N.and Y is hydrogen, lower aLkyl, lower alkoxy, chlorine, fluorine, bromine, iodine or a hydroxyl group; r with the proviso that in formula and are not lower alkyl when Z is

I

X is and R, is aryl and Y is hydrogen, lower alkyl, lower alkoxy, chlorine, fluorine, bromine, iodine or a hydroxyl group; 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, and are not lower alkyl; with the proviso that in formula and are not hydrogen when R, is Z is -CH-,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: /N (I) where Q, is selected from the group consisting of: (a) -Z N-Y and -Y

I

ir the substituent X in formula is selected from the group consisting of -NH-, or 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 12-benzisothiazole nucleus. When X is -NH- or 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, and The substituent Y is preferably in the 5- or 6-position of the ring. Moreover, in S. 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.

When p in formula-() is 2 and X is each Y substituent can be independently selected from lowdr alkoxy, hydroxy or halogen groups, preferably methoxy groups.

S* When the substituent Y, has the formula (R)m and R, contains unsaturation, R, preferably has the formula e -CH,-CH=CH-CH,-.

When the substituent Y, has the formula

N

the substituent R, is preferably hydrogen or )alkyl carbonyl and n is 3.

When the substitutent Y, has the formula 0 26

I

the 5ubititutent R, is preferably hydrogen or and r is eFerably I or 2.

WVhen the substituent Y, has the formula -o

R

the substituent is preferably -OCH 3 and n is preferably 3.

When the substituent R, has the formula 0 4 the substituent R, is preferably and n is preferably 3.

When the substituent Y, has the formula r a o r ~r r r ix.

'he substituent R, is preferably hydrogen or methyl and n is preferably 2.

'hen the substituent Y, has the formula

H

the value of n is preferably 3 or 4.

When the substituent Y2 has the formula the substituent R, is m-efem-bly when R con,,ains unratu 1r, ton.

\Mrnen the substituent R is

-V

the substituent Q LS preferably -CH=tN; and the substituent W is preferably CH~, the substituent R, in CH-R3 is preferably CH 3 the substit-uent P, in N-P, is preferably hydroxy, lower alkoxy, or and the

R,

0 in NHRO, is preferably hydrogen.

The value of n in the foregoing- formulas can be 2, 3, 4, cr 5, and preferably is 2, 3, or 4. In the particul1arly preferred compounds of the inivention n is 2 or 3.

***When X in the compounds of the invention is the substituent R, is selected from the g-roup consisting of lower alkyl, aryl lower a kyl, aryl, cycloa llyl, aroyl, alkanoyl, alkanoyloxy and phenyisulfonyl groups.

Tne substituent Z can be -CH- in which case the compounmds of the invention are heteroarylpiperidine derivatives, or N in which case the compounds are heteroarylpiperazine derivatives. When the substiruent Q has the formula the compounds of the invention are heteroarylpyr-rolidines. The preferred compounds of the invention are the heteroarylpiperidines, i.e. compounds in which Z is -H The compounds of the invention can contain one, two, or three The substituent R can be hydrogen, lower alkyl, )alkoxy, hydroxyl, carboxyl, Cl, F, Br, 1, amino, )mono or dialkyl amino, -NO, lower alkyl thio, -OCF., cyano, acylarnno, -CF3, trifluoroacetyl -C(=O)-CF 3 amiunocarbonyl (i.e.

d ia kylaminocarbonyl.

formnyl, Ikyl, 0)-a ry V.

-C(=O)-heteroarvl, or 2 j C B. C B 0 .t C -'p -C(=W)-alkv,, -C(=VW)-aryl, or -C(=W-heteroary]; alkyl is aLkyl; aryl is phenyl or where Rs is hydrogen, lower alkyl, C, )aikoxy, hydroxy, Cl, F, Br, 1, C~~)alkylamnino, -CN, -OCF,; heteroaryl i Q03 (2) Qis -CHrN-; W is CH, or CHR, or N-R 5

R

7 is hydrogen, alkyl, or aikanoyl; R, is lower alkyl; R, is hydroxy, alkoxy, or and is hydrogen, lower alkyl, )acyl, aryl, -C(=O)-aryl or C=) heteroaryl, where aryl and heteroaryl are as defined above; and m is 1, 2, or 3.

When the compounds of the invention contain two or three R-substituens, each of the R-substituents can be independently selected from the above Preferably, each of the R-substituents is selected from the group consisting of hydrogen, alkyl, (CI )alkoxy, hydrox)'l, -COCF. (C 1

-C

15 )a knoyl, Cl, F, Br, 1, C 3 )alkylamino, -NO, -OCF,, -C(=O)-loiwer alkyl, and -CH(OR,)-lower aLkyl.

The com pounds of the present invenrtion are prepared in the following manner. The subs tituents R, R 1

R,,.R

3 etc., X, Y, and Z and the integers mn, n, and p are 29 as defined above unless indicated otherwise.

B FRFPA1RATiONOFCOMYPOUNDSOF-F INVFNJTION The compounds of the invention can generally be prepared by reacting a piperidine or-& piperazine of the formula: (YPZ

NH-

XN

or a pyrrolidine of the formula-.

(3A)

NH

under alkylafing conditions with a compound of the formula: HAL -Y 2 0v 0where HAL is CI, Br, or 1. The procedures that can be employed for preparing the piperidines. the piperazines. and the pyrrolidinies and the alkylating agents identified by the above formulas will now be described in detail.

i. Preparatio~n of 3-(1-unsibsriruted-4-piperainvl)-1H-inciaoLe Compounds of the formulae: N NH (Y)P

H

and So. (6) Ro for use in synthesizing the indazoyl-substituted piperazines of the invention can be prepared as follows.

A substituted aryl ester of formula is selected, 0 C- OR, C p 7 M Hal Swhere R, is lower alkyl and Hal is a halogen selected from the group consisting of Cl, Br, and I. The ester of formula is reacted with hydrazine, HNNH,, under standard hydrazide formation conditions. Typically, the reaction is carried out in a nonreactive solvent, e.g. ethanol, methanol, or toluene, at a temperature of ambient temperature to the reflux temperature of the solvent for 4 to 16 hours to form a hydrazide of formula 0

II

C-NH

c-

I

1Hal The hydrazid e of for-mula Ls reacted 1%ith a phenyl sulffonyl halide of the fo rmuLLa 0 IIS-Hal(9) where Hal is a halogen selected from the g-roup con~sisting of Ci and Br, to for-ma compound of the formula 0 II O it 11 N i ~Typically this reaction is carried out in a basic solvent, such as pyridirie or collidine, at a temperature of 0' to 30'C for 2 to 16 hours.

The compound of formula (10) in rumn is reacted neat with thionyl chloride at a temperature of 50* to 79'C (reflux temperature) for 2 to 16 hours to form a compound of formula (11)

C=N

Nli CY~p I NH Compound (11) is reacted with a compound of formula (12), (12) M NRI I where RI, is lower aikyl, under conventional nucleophilic reaction conditions, for example in an inert solvent, such as tetrahydrofuran (THF), toluene, or diethylether, at a temperature of 5' to 50'C for I to 16 hours to form a compound having the formula 4N 0 0 (4 rati he compound of foula 1)04t)nrac with a conenstion ae, such a hacpe, perg.Brne or cIuprunde, ionaoventa ch raso cdirntiyontyallye inaietolete.g ortermethyLw-~xie(NSo at amin emperature o 2't 7' o o1 1 hours to form a crazne unittd phn ufflinaoeo h formula NNR33 N N-Cy The compound of formula (15) is then subjected to reduction by means of a metal hydride, e.g. lithium aluminum hydride (LiAIH,). Typically the reduction is carried out under standard reduction conditions in a solvent, such as tetrahydrofuran or diethyl ether, at a temperature of 350 to 67*C for 6 to 16 hours to form a compound of formula (16): @go *Go~ 06 I 90 *5 0~ 0 *0 we..

SO S x ageb.,

S

ci A compound of formula (16) can be formed in an alIter-ative manner by first reacting a compound of for-mula (14) with a strong base, such as a metal alcoholate, e.g. sodium methoxide, sodium ethoxide, or sodium butoxide, or with KOH- in tetrahvdrofuran to form a compound of formula (Yp IK N iNR (17) This; reaction is typically carried out in a polar solvent, such as for example CHO.H or CHsOH, at a temperatu-re of ambient to 50 0 OC for I to 16 hours.

Alternatively, the compound of for-muLa (17) can be formed by reducing compound (14) with LiAIH, under conditions as previously described.

The compound of formuLda (17) in turn can be reacted with a cyanation reagent, as previously described, to form a cyano substituted piperazine indazole of the formula cc S. a S S S. N~ N O

H

which in turn can be reduced with a metal hydride, as previously described, to form a compound of formul1a (16).

In an alternative embodiment, a compound of formula (18) can be reacted with an aqueous mineral acid, e.g. H,50, or HCI, at a temperature of 5fl to 120*C for 2 to 16 hours to form a compound of formula (16).

2. Preparation oF3-(-tinvtibstititerl-4-pippra'7inv)-1 '-pninxazcnler (i A compound of the formula: ~N NH (Y)p at'\can be prepared according to conventional techniques. Suitable pmocedures are described in J. M'ved. Chem. 1956, 22:359. Compounds of formula (19) are useful for synthesizing the benzisoxazoie substituted piperazines of the invention.

3. Pre.-oratinn of -e'ohals.

A compound of the formula: -M a for use in synthesizing the benzisothiazole substituted piperazines of the invention can be prepared according to the techniques described in J. Med. CherrL 1986, 29:359, United Kingdom Patent (GB) 2 163 432 A and Tetrahedron Letters, Vol 34, No.41, pp6525-6528, 1993.

4. Preparation Qf -(l-uin-Lihstitlit ,i--pjpEridinly)-1H-inia7c'le' A compound of the formula: for use in synthesizing the indazole-substituted piperidines of the Linventionl can be prepared using known techniques. For example, suitable techniques are described in substantial detail in U.S. Patent 4,710,573.

1- 0.1ln,~i -4; A compound of the formula: O 'N(23) can be prepared by following the teachings from several sources. For example, U.S.

Patent No. 4,355,037 contains a dletailed 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. 4,327,1013 and in Strupczewvski et al., J. Mved. Chem., 2-9:761-769 (1985). The compounds of formula (23) can be employed in the synthesis of the benzisoxazole substituted piperidines of the invention.

6. Prepara.tion o -1-r~I~i~t~--i~iiy)1 9 bjzstizje of the N-(arylox alkyl~heteroaryl piperidines of the invention. Specifically, aeti -Ip~ d nl z olazl sc nb m l y di es nhOi benzisothiazole of the formula: S (24) car be reacted with the alkylating agent previously described to form the N-(a ryloxva!kyi)hete.-oa-rylpiperidines of th-: invention. Compowids of formula (24) and their mehods of preparation are described in detail in U.S. patent 4,458,076.

7. prnrpn nf 21lklatina 2aeais I ne coimr-cunds described in Sections 1-6 above can be reacted wYith alky',:ting agents as is known in the art. For example, when Y 2 is as described in formula an alkylating agent of the formula: HA L- (CHJn (4) is reacted to form the N-(aryloxyalkyl)heteroarylpiperidines, piperazines, and pyrrolidines 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 Sinvention.

8. Alkylation of heteroarylpiperidinfe. piperaines. and pyrrolidine, The heteroarylpiperidines, piperazines, and pyrrolidines described in Sections 1-6 above can be reacted under alkylating conditions with the alkylating agents described in Section 7 to form selected compounds of this invention. The reaction can be carried out by dissolving the reagents in an inert solvent, such as r( dimethylformamide, acetonitrile, or butanol, and allowing the reagents to react from a o temperature of 50'C to refluxing of the solvent in the presence of an acid receptor, such as a base. Examples of suitable bases are alkai metal carbonates, such as potassium carbonate, sodium carbonate, or sodium bicarbonate. The reaction can be %W carried out with or without a catalytic amount of an alkaline iodide, such as potassium a 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' to about 120'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.

In addition, the compounds of formula 19 where RR 19 are both hydrogen may be prepared from the phthalimido compounid of formula 7 bv treatment with 'base such as, for example, hydrazine as is know-n in the art.

More specifically, certain of the compounds of the invention can be synthesized by the folow-ing methods: A. Synthesiis of Phthalimides *The phthalimido compounds of the inven tion of formula (25) can be synthesized 0 o N-(CtR' I -(Z4Oq in several ways.

1. Alkylation with an N-haloalkylphthallimide The heterolarylpiperidines, piperazines and pyrrolidines described in Sections 1-6 above are alkylated under known conditions using the appropriate haloalkylphthalimidde, preferably an N-bromoalkylphthaLirnide in a nonproric 0 c~iHAL(CH 2 )n-N1 (R&4)q (26) C4 0 00 organic solvent such as acetonitrile in the presence oF a base such as potassium WOW carbonate at a temperature of from about room temperature to about 120'C, preferably from about &O0C to about ICO'C.

2. Reaction with a phthalic anhydride The heteroarylpiperidines, piperazines and pyrroUdines described in Sections 1-6 above are first reacted with a haloalkylnit rile to form the corresponding substituted nit rile (27) wherein R is a substitute n, as d efin ed for R, above. The reaction is carried out in a polar, nonprotic organic sciven: such as (27) Z iN-CCHR)X,-CN

'-N

acetonit-ile in the presence of a base such as potassium carbonate at a temperature of from about room temperatfre to about 120*C, preferably from about S0 0 C to about 000 *C.

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

z. 'N Z N -CHR)rnCI kNil, (Y)p I @04 N(2S) The arnine(2S) is reacted Iwith phthalic anhydride or a substituted phthalic anhydride or the corresponding phithalic acid under known conditions, for example in dichioromethane or dimethylforrnamide 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 dimethyl forma ridde at 135'C.

B. Svnlhei, of ikoindolinen The isoin dolines of Formula (29) can be prepared by the following routes.

00 I-N ~N (29) L Condensation with an c:,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 lemperature to about 130'C, preferably f-rom abou.' 75*C to about 2. Reduction of a phthalimide Alternatively, a phthaLimiddo compound oi the invention is reduced, for examnple twIth lithiumr aluminun hydride in an organic solvent such as tetrahydrofuran at a temperature of from about O*C to about ICO'C, preferably From about 70'C to about C. SyXntheqic of tetrahvdroguin M'e n ~vrionnline,; The tetrahydroquinoLinies and tetrahydroouLiolnes; of the invention can be pi-epared by atkylating the heteroarylpiperidine, piperazine and pyr-rolidines 3A) wvith the appropriate 2-bromoacetyltetrahydroquin-oline or 2-bromoacetyltetra hyd roisoquinoline in the presence of a polar organic solvent such as acetonitrile in the presence of a base such as potassium carbonate at temperatures olfFrom about room temperature to about 150 0 C, preferably from about 75*C to about 100'C to form the correspondiLng amnide (30, I

~N

xp N Ra x-J 1 The amide (30, 30a) is reduced, for example with l-ithium alumrinumn hydr-ide in an organic solvent such as tetrahydrofuran at a temperat-ure of from about O'C to about SO'C preferably at about room temperature to yield the alkyl compound.

9. Preparation of the "depot" ompoindq oF the" invention Selected compounds of the invention possess a hydroxyl g-roup attached to either an aliphatic or arom-atic carbon capable of forming the highly lipophi-lic esters of this invention or possess a primary or secondary nitrogen atom including the nitrogen at the I -oosition of an indazole ring system capable of forming the highly lipophi-lic anuides of this invention. The primary or secondar-y nitrogen atom may alternatively be acylated wi.th a alkoxycarbonyl chloride to form-a highly I= ohiLic carbarnate dierivative_ Representatives of such alcohols and amnines and thei-r-highly lipophili derivatives are found in the Examples5 of this Livertion.

I t is known in the a rt tha t long acting de riva tives of d rugs mzy b'e obtained by such trans formation. European Patent Pub-fication No. 260,070 discloses the -prolonged actionl of halopiiiidol dlecanoate ester. International Pub~ication, No. WO 92/06089 discloses sustained release arnide derivatives of sertindole.

Foll.in ar ypicaL exaples of compounds of h ento that can be prepared-by Molowing thetechniques described above: 1 H--indazol-a-yl)-l -piperazinyllpoppxyl-3-metho-xyphenyllethanone; I 14(3-(4-G1,2-benzisoxazol-a.-y0-1 -pipe rid iny I Iprooo'xy] metioxy ohen l Ie tha none, 1.(4-[3-[4-(6-fluoro-32?-benzisoxazol -yi)l) peridin) lipropoxy 3methoxyphenylle tha none; (-(4-[4-(1,2-benzL-o~caz6l-3--yD)7I plperidinyl~bulto\yJ retho?.'Vohten' llethanone;- 1-(4-[4-[4-(6-fiuoro- 1,2-bienzisox-azoi_ ayl)- 1-pip rnunvllboutoxyl-3-methoxphenyl].

ethanone; bezs-.az 3y)lpiperidinyllethox-y i-3- ethox< phenylletha none fumarate; 1 H-indazol-3-ylf-l-pipcraziny-llbutoxyI 3- -met oxyphenylletha none fumarate; I -[4-[2-(4-(6-fluoro-1,2-benzisoxazol 3 1 piperidi ny ljehoxy]- 3-methoxyphenyllet ha none; 4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yi)-1 -piperid inyllpropoxyl- 3-mezhoxy-"-methylben zenemethanol; I -[--(3-(4-(1,2-benzisothiazol-3-yl)-I -piperid inyl lpropoxyl- 3-methoxyphenylIe t ha none; I -[4-(3-(4-(6-fluoro-1 .2-benzisoxazol-3-yl)-I -piperidinyll propoxy]- 3-h yc roxyphenyl le tha none; i-4[3-[4-(6-fluoro-1 l--indazol-3-yl)--piperazinvilloro)oxy I- 3-methoxyphenyl~etha none; 1 -k-(4-(4-(6-tluoro-I H-indazol-3-yl)- I -piperazinyllbutxyl- 3met hoxy ohenviletha none.

S0 5 I H-indazol-3-yl)- I pprdrl i oe 1-[4t-[314"-(6-chloro-l,2-benzisoxa zol-3-yi).-I-pit~er-idiny'I1'oro-,-ox-Y>J 3-rnethoxyphenylletha none; *i -[4-[4-(-t-(6-chlo,-o-1,2-benzisoxazol-3-yl)-I -Pper~id iny li butoxy- 3-methoxyphenyl1]etha none fumnarate; 1-(4-(3-(4-(5-fluoro-1,2-benzisoxazol-3-yl)-i -pip~erid; nYl]propox- 3-methoxyphenyllethanone; 6-fluoro-3-(1 -[3-(2-rnethoxyphenoxy)propyl]-4-pi pe ridiayl] -1,2-b enzisoxazole fuma ra te; f4-r3-[4-(6-fluoro-1,2-benzoisoxazol-3-yl)-I -pipel-idinyl Ipropoxy]- 3-methoxyphenvillphenylmethanone; 14-[-1-IH-indazol-3-yl)-1 -pirperidinylibuto.xvl- 1-net hoxyphenylletha none; l-[4-(2-t4-(6-chloro-1,2-benzisoxazol.3-yl)-1-piperd inyilethoxy]- 3-methoxyphenyllethanone; I -[3-[3-(4-(6-fluoro- ,-be-nzisoxazoZ-3-yl)-I -niperid inyl lpropoxyjphenyl]etha none funa ra te; 1 -[4'-(3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)I -piperid inyllpropoxy]- 2-niethyipheny 11 etha none; 14(24(344-(6-fluoro- nzisaxa zoI-3-YI)--pipe rid inyll propox y I S-methylphenyllethanone; N- -3 4(-lur 12-benzisoxazoI-3-yI)-I -piper-id inyijpropoxy]- 3-rnethoxyphenyllaceiamide hemnifumnarate; 6-chloro-3-(1-pipe ra zinyl)-l H-iridazole; 14443-[46.-fuoro-l H-indazol-3-yl)-1 -piperid inylpr'onpoxy) 3-methoxypThenyllethanone; 1-[ 4 6 -fuoro-1,2-benzisoxa zol-3-y)- -pipe rid inyl) propoxyl- 3-methylphenylethanone heiniFumarate4' i-(4-(3-(4-(6-fhioro-1 ,2-benzisoxazol-3-yI)-i Tpiperid inyl I oropo-xylphenyllethanione, 1 -[4-(3-[4-(6-chloro- IH-inidazol-3-y 1)-i -piperazinivil propoxy]- 3-methoxyphenyllethan;-ne; l-[4-[4-[4l-Cl 2-benzisothia zol-3-yI) -l-piDerazinyllbutoxy]-3-rh ethoxyphenyllethanone; proDox v]-3-n .2hoxybenzonitri le; to bo 1-['(444-6-fluoro-1I H-inda Zo ]-pip ei- dInyl Ibutox yl- 3-methoxyph enyl letha none; 1-4-(3-Pr-(1 -be nzoyI-6-fluor-o- I H-ind azol-3-yDI)-o-iperazm Iv] pro pox yj- 3-methoxyphenyllethanone sesquifurrarate; 1 -[4-[4-(4-(6-chloro-1 H-indazol-3-yi)-l-pipera zinyljbu toxy]- 3-ne thoxyphenylletha none; .2-benzisothiazol-3-y)-1 -piperazinyilpropoxy]- 3-methoxyphenyl letha none hernifu-Larate; 1-f3,5-dibromo-4-f3-r4-(6-fluaro-l,2-benzisoxazol-3-yzy I -piperidinyllpropoxyl phenyllethanone; I14 P i~ hizl3y) pprznllthxl--ehxpenlIe oe &-fl uoro-3-f I-( 3 -phe noxyp ropy 1) 4-pipe rid i ny I 1,2- ben zisoxa zole; 14-4-[-4-6-chloro-l F--indazo!-3-yD)-l -piperazinyllethoxyl- 3-rniethoxyphenyl letha none; 14'(3 ,(-ior-,-eno~x o--l-I-ierdi) propoxyl- 3-met hylme rcaptoph enyiletha none; [-,-ezsthizl3y- p ,rd y butoy 3m hxp nlJ hnoe 1 -4-(3-[4-(6-fluoro- 1,2-be nzisoxazol -pipe rid inyli propoxylI- 3- methoxyphe nyliphe n vlmetha none; I -f3-bromo-4-(3-14-(6-fluoro-1 .2-benzisoxazol-3-yl>- I1-piperid inyll propoxylphenyl I etha none; 341 -[3-[4-(-ethoxyerhyl)-2-methoxyphenoxyj propyl]-4t-piperidinyl]-6-Ruoro- 1 ,?-benzisoxa zole hydrochloride; 34 1-f 3-f4'-(1 -acetoxyethyD)-2-rnethoxyphenoxylpropyl--Pip-eridinylI--6-fluorol,2-benzisoxazole fumnarate, 1-[4-(3-(4-(6-fluoro-1 .2-benzisoxazol-3-yI)-i -piperid inyl Ipropoxy- 3-mnethoxyphenyllpenta none; 2-[3-[4-(6-fluoro-1 ,2-bernzisoxa zol-3-yl)-l -piperdi my! Ip)ropcxy]-r'4-rethylbenzenar mine hemifu-rnarate; 3 3 4 -br-oro-2-methoxpheno.xv)propyl]A'pive-:Idinyl-&fluor-1l,2-benzisoxazole; uoro 1 2 -benzisoxa zol -1 )ie rid iny I ro poxy3-me thoxyp henyl I propanone; 4-(3-f-4-(6-Fiuoro-1,2-benzisoxazo-3-yf)l-pipe-r~iivIILooox y]-3-methoxybenzarnide, .v.

0 0* S

C'

1-(4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-vJ)-I -piperid in YlI proooxyl- 3-(me thylamino) phenyl] et hanone; 1 -[4-[3-(4-(6-fluoro-1 ,2-benzi5oxazol-3-yI)-I -piperici inyl I propoxyl- 3-e thoxyph e-nyile than one; N42-r3-4(6-fluoro-i,2--benzisoxazol-3-yl)-l -pip~er-idinylipropoxylpheny]]acetamidde;.

l-E4-(3..4-(6-fluro-l,2-benzisoxazol-3-yl)-1 -piperidinyl propoxy]- 3-dimethylannophenylle thanone; 1-[4-f3-[4-(6-fluoro-1,2-benzisoxazol-3-ylU-]-piperidinyli propoxyl- 2-rnethoxypheny lethanone hydrochloride; 1-[4-[3-14-(6-fluoro-L,2-benzisoxazol-3-yl)-I -pipe rid inyl] propoxy] -3-mrethoxyphenyl I- 2,2,2-trifluoroe thanon e; 4-[3-[4-(6-fluoro-1 ,2-benzisoxazol-3-yl)-l-piperid inyl]prc.. ooxy]-3-hyd roxy- '-methylbenzeniemethanol; 2-[3-44-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinylipropoxyla niline dihydrochioride; N-[5-acetyl-2-[3-[4-(6-fluoro-1 ,2-benzisoxa zol-3-yl)- I-piperidinylipropoxyiphenyllacetarnide; 3-[l-t3-(4-ethyl-3-methoxyphenoxy)propyl-4-pipe rid inyl]-6-fltioro-1,2-benzisoxa zole hydrochloride,- 1-[3,5-dimethoxy-4-[3-[4-(6-fluoro-l ,2-benzisoxazol-3-yl)- 1-piper-idinyllpropoxylphenyliethanone; N-[3-[3-[4-(6-fluoro-1,2-benxoisoxzol-3-yl)--piperidinyl~propoxylphenyl~acetam-ide hemnifti arate; 3-E3-[4-6-fluoro-L,2-benziscxazol-3-yl- I -pi peridinyllipro poxyla niline; 3-[3-44-(6-fluoro-1,2-benziscoxazol-3-yl)--piperidinylIpropoxy]-4-methoxyaniLine; 1-(4-[3-14-(6-fluoro-1,2-benzisothiazol-3-yl)-1 -piperidinyl ipropoxy- 3-rnethylaminophenyll etha none furnarate; N- [3-13-446- fluoro- 1,2-b enzisoth iazol-3-yl)- I-pipe rid in y I I rop ox y 4-methoxyph enyl lace ta mid e; 1-[4-[3-[4-(6-fluoro-1,2-benzsothiazol-3-yl)-1 -piperid iloropoxyl- 3-methoxyphenylletharnone hydrochloride; N,N-dimethyl4-(3-[4-(6-fluoro-1 ,2-benzisoxazol-3-vl)- Il-pipe rid iny I Ipro poxy] -3 metha xybe n zamid e; l-(4-(3-[4-(6-fluoro-I ,2-benzisoxazol--y1)-I -piperid inyl I propoxy 3-methoxyphenyliEthanone oxime; 1443 -[4-(6-fluoro-1,2-benzisoxazol-3-yl)i-piperid inyllpropoxy] methioxyphenyl]ethanorie oxirne 0-methyl ether; 1-4-3-[4-(6-fluoro-I ,2-be nzisoxazol-3I-y 0-1 -pipe rid inyl I propox y I 3-methoxyphenyllethanone hydrazone; :*6-fluoro-.3- (2-me thoxy-(0 -me thyle the ny1) ph enoxyl propyl1i-A-piper-id inyl]I- 1,2-benzisoxazole hydrochloride; W-I (Z-4-[R4-chloro-2-b-Lteny~xy-3-me thoxyphenyll etha none; V. -[4-[[4-[4-(6-fluoro-I ,2-benzisoxazol-3-ylY] -piper-idinyl]-2-butenylloxy]- 3-methox phenylethanone; -(6-fluoro- 1,2 -benzisoxazol-3-y)- I -pipe rid inylI]I-2-b utenyl Ioxy]- 4-hydiroxyphenylletha none hyvdrochloride; 3-444-(6-fluo ro-1,2-benzisoxazo 1-3-yi)-I -pipe rid i nyljI-2-buteny I Ioxyi 4-benzyloxyphenylletha none; 6-(3--chloropropoxy)-5-rriethoxyindole; 6-fluo)ro-3-t1-f3-1((5-nethoxy- I H-nd oi-6-yl)oxylpropli-4-piperidinyll- L,-benzisoxazole; 6-fluoro-3-f H -indol -T-yDoxylpropyli-4-pipe rid inyl]I-1,2-benzisoxazole hem-iffumarate; 6-fluoro-3- yd roxypropyl0-4-p ipe rid inyI]-l 1,2-b enzisoxazo le; 6- iluoro-3-[l-2-pyrimid io xy) pro pyl-4-pi peridinyl-1,2-ben zisoxazole furnarate, 6-aceto-2-(4-(6-fluoro-I ,2-benzisoxazol-3-yl)-I -pipe rid inyllne thy]-I1,4-benzod ioxa n; 2-4-(6-fluoro-I 9 -be nzisoxa zol-3-yl) -I -pipe rid inyl11 methyl-I ,4-ben zod ioxan; 2-[4-(6-fluoro-l ,2-benzi~ox-azol-3-yl)-I -pipe rid inyl Iethyl-I,4-benzodioxan; &-(3-chloropropoxy)-7-rnethoxy-1 -tetratonle; [4-6-flu oro-l 1,-b enzisoxa zo I-3-y0- 1 -pipe rid in yl I pro poxy]--7-methoxy- I-tetralon e; N-(3-ch loropropyl)-2-benzoxazolinone; N-(3-ch loropro pyl)-6-ace tyl-2-be nzoxazolIin one; N- N3-[4-C6-flu oro-I.2-benzisoxa zo1-3-y)- I -pipe rid in yI Ip ropy I]-6-ace tylI- 2-ben zoxazolinone; N-('3-(4-(6-tluor-o-,,2-benzisoxazcl-3-yl)-l -piperidinvll propyllphthalimide;

V

0 I-(3-a minopropy fluo-,o- 1,2-b enziso xazo I-3-yD'Ip ipe rid in e d ihydrochiorid C; cis-2-(3-(4t-(6-fluoro-1,2-benzisoxazol-3-yl)- I-iiperid invlI)propy-Ihexahydro- I H-isoindole-1,3-dione hydroddoride; N-(4-[4-(6-fiuoro-I 2-benzisoxazol-3-yl) -l-pioeridinvl]-butyijphtha lirniide; .1 -(4-aminobu ty])-4-(6-fluoro- 1,2-benzisoxazol -3-y1) p ipe rid ine dihydrochioride; cis-2-(4-(4-(6-fluoro-1 ,2-benzisoxazol-3-yl)- 1 -pipe ridf inyl) butyl)hexahydro- I H-isoindole-1,3-d jone hydrochloride; 1-[(4-(13-[446-fl uoro-1,2-be nziso xazo1-3-y1) -1 pipe rid in y I propyllthiol- 3-methoxyphenylle tha none; .4-(6-fluoro-1,2-benzisoxazol-3-yl)-1 -(2'-methoxy'phenyl) butylpiperidine rnaleate; 4-(4-bromobutyl)-1 ,3-dithian-2-yI)ethylbenzene; I -[4-(1I2-dithian-2-yI)ethyllphenyl-4-(6-fluoro-1,2-benziso azol-3yl)butylpiperidine; 1-[4-(4-acetophenyI)bu tyl l-4-( 6 -fluoro-,2-benzisoxazol-3-ynpiper-idine; 1-4-[3-4-(6-fluo ro-1,2-benzisexazol-3-yn)-1 -pipe rid inyh propyla minol- 3-methoxyphenyllIetha none; (2,4-difluorophenyl)-[i-phenylmethyl)-3-pyrrolid inylI rnethanone oxalate; 6-tluoro.-3-[1-ph-enylnmethyl)-3-pyrrolid inylJ-1 ,2-benzisoxazole fumnariate; (EM- -f4-[(4-bromo-?-butenyl)oxy]-3-methoxyphenylletha none; 4-(3-chloropropoxy)-3-methoxybenzaldehyde; 6-fluoro-3-C3-pyrrolidinyl)-1,2-benzisoxazole hydrochloride: *-[4-3-[4-(6-fluoro-],2-benzisoxazol-3-yI)-1-piperidinyl] propylarnino)- 3-hydroxyphenylletha none; 1-[3-acetylanmino-4-(3-chloropropoxy)phenyllethanone; N-(2-(3-hydroxypropoxy)phenyllacetarnid e; 4-C3-chloropropoxy)-3-methoxybenzaldehyde; U+ -1-(4-t3-(4-(6-fluoro-1 ,2-benzisoxazol-3-yi)-1 -pi peridinyll-2-methylpropoxyJ- 3-methoxyphenyijethanone; -[4-[3-[4-C6-fluoro-1,2-benizisoxazol-3-yi -I -piperidiny! V--methylpropoxy]- 3-methoxyphenylletha none; (R)-(-)-I4-f34[4-(6-fluoro-1,2-benzisoxazol-3-y l-Diperidinyll-2-mrethylprupox-y)- 3-rnethoxyphenyl letha none; I-f4-(3-(-4-[(6-fluoro-1.2-benzisoxazol-3-yI[)-1 -piporidinvll11-2,2-dimethylpropoxv]- 3-met howp\'h e nviletha none;- -(4-43-[4-(6-fluoro-1 ,2-be.,nzisoxa zo-3-l) -I 1-pipe rid iny1 -2 -phe ropoxy] 3-rnethoxyphenyllethanone; (4-(6-fluoro--1,2-ben zis oxazol-3- y -pipe rid illy II .2-(3-chlorophenyl)propoxy-3-mthoxyp hely I Jet hanone; W±-1 (4-(6-fluoro--12-benzisoxazuI-3-yD1 -pipe rid in y- 2-(phenylnmethyl)propoxy-3-methoxyphenliethalofe; U+ -1 -[4-[3-4-(6-fluoro-1,2-benzisoxazo-3-yD)-I -pipe rid iny -me thyi propoxyl- 3-me thoxyph enylle tha none; 4-13-[4-(6-flu oro-1,2-ben zisoxazo 1-3-y D- I -pipe rid in y i]-3-ne thy Ip ropox y- 3-rnethoxyphenyllethanione; 2-benzisoxazo1- 3-yI)-%-piperidiny1]-3-methylbutoxy]o 3-methoxypheftyllethanorle; tUO -4-(4-[4-1,2-benzisoxazo -3-yO-1 -pipe rid in y1]-3-phe nylbu tox y]- 3-inethoxyphenyliethanone; 3-methoxyphenyll etha none; U-)-(4-{2-(4-6-fluro-1,2-benzisoxazol-3-y)-1 -pi perid inyll-1 -methylethoxyl-.

3-methoxyphenyllethaflone; 3-methoxyphenyliethanone; 0Z-1 -[4-U[4-[4-(6-fluoro-l ,2-benizisoxazol-3-y9)-I -pipe rid inyl) -3-rnehyl-2-butenyl]I oxy]- 3-methoxyphenyllethanone; W44 [4-(4-(6-fluoro-1,2-ben7zisoxazol-3-yi)-I -pipe rid in y 1- 1-propyl-2-butynylloxyl-3methoxypheny]Iethanone; -L4-(3-[4-(6-fluoro-I H-indazol-3-yl)DA -pipe ra zinyl I-2-methyl propoxyl- UQ ~3-methoxyphenylle tha none; (R)+C)-1-tI44-[4-(6-fluoro-I H-indazol-3-yl)-1 -pioerazin vI ]-2-rnethylpropoxy]- 3-methoxyphenylle tha none; 3-rnethoxyphenlylethanone; 3-methoxyphenyllerhanone; and 4S (±)-6-floro-3-[l-(3-(2-methy!-(2-methoxyphenoxy)prop)ylJ-.piperidinyl]- I 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 (i976) and B. Costal, Eur. J.

Pharmnacol., 50:39 (1978).

Subject CK-1 male mice (23-27 grams) are group-housed under standard V. laboratory conditions. The mice are individually placed in wire mesh stick cages X 10") and are allowed one hour for adaption and exploration of the new environment.

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 0 4 paws on the wall (full climb) 2 Mice consistently climbing before the injection of apomorphine are discarded.

SWith full-developed apomorphine climbing, the animals are hanging on to the Scage 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 a 49 i4 3 readings) and the total score of the control group (vehicle int ra peritonealIlyapornor-phine subcutaneously) is set to 10076. values with 95% confidence Lin-its, calculated by a linear reg-ression analysis, of some of the compounds of the present inivention as well as a standard antipsychotic agent are presented in Table 1.

.:TABLEI

*CLIMBING IMOUSE ASSAY COMPOUND mg/kg, ip) :*1-14434[4-(1 H-indazol-3-yl0-I 0.98 phenyl] ethanone 1 -(4-[3-[4-(1,2-benzisoxazol-3-y!) -1-piperidinyll propoxy-3-rethoxy- 1-443- fluloro-1 ,2-benzisoxa zol- 3-yI)-I -piperidinyl lpropoxy-3-nethoxyphenyl letha none 0.095 [4-(1,2-benzisoxazol1-3-yl)-1 piperidinyllbutoxy] -3-methoxyphenyl] ethanone 1.6 i-f -4-[4-4-(6-fluoro-1 .2-benzisoxazol-3-yl)-I pipe ridinyllbutoxy 1-3-met hoxyphenyl let hanlol 0.6S 1 -[4-[3-(4-(6-fluoro-1 ,2-benzisothiazol- 3..v)-1pipeidiyl~p~pOy]-3metOXY ph~enyllethanone hydrchloride 0.16 2-.4-(6&fluoro-1 ,?-benzisoxazol-3-yl)-lpio~eridinyljethylI-1,4-benzcdioxan 0.29 (Z)-i1 (4 -f4-(6-fluoro- I ,2-be nz is o \a zol- 3-v D)-I piperid in yI] .2.bue W. 10XV 1 3.

methoxv'phen yl ]eth3 none 0.61 I -[4-4-acetophenyl)butyl-4-(6-fluoro- .,2-benzisoxazol-3,-yl)piperid joe 0.3-1 6-fluorc-34-0 (-hyd roxy prot) y 1) piperidiriyll,2-benzisoxazole 4. 1 4- (4-(6-fluoro-i ,2-benzisoxa zol-3-ylD- 1-piperidinyilbutyl decanoate furnarate 3.31 1-3-amninopropyl)-4-(6-fluoro- I .2-benzisoxazol-3-YlU- :piperidine dlihydrochloride 2-2.6 **N-(2-[4-(6-fluoro-I 2-benzisoxazol-3-yl)- I-piperidinyliethyljphthatimide iN-[2-[4-(6-fluoro-l ,2-benzisoxa zol-3-yI)- 1-viperidinilfethyljphthalimide hydrochloride .S 6-fluoro-3-(l 4. propyll-4-piperidinyli-I,2-benzisox\azole .44sesqu-ifurnarate 0.172 PIP4 N-(2-(4-(6-.Fluoro-1,2-benzisothiazol-3-y)- 1-piperidinyllethyl Iphthaliide hydrochloride 03 N-[2-[4-C6-fluoro-1 ,2-benzisoxaz-ol-3-yU)l-piperidinvilet hyl]-3,6-di fluorophthal iride 2.9 N-[2-44(6-fluoro-1 H-indazol-3-yI)awf I-piperazinyliethyllphthalimide 1.2 N-2-[4-(6-fluoro-l H-indazol-3-yI)- 00 -piperidinv!Jethyi~lphthalirnide hydrochioride 0.8 2,3-dihydro-2-(?-(4-(6-luoro-I 2-b-enzisoxazol-3-yI)- I -piperidinyllethyl J-3-rethylene-I H-isoindol-1I-one hydrochloride 0.64 2,3-dihydro-2-[2-[4-(6-fluoro-1 ,2-benzisoxazol-3-vi)- I -piperidinivllethyl]-3 -methvl1-I H--isoindol-1 -one h~yd rochloride 1.17 ethvljI-4-amin ophthah'ride~ umarate 0.097 ethylJ-4-hyd roxyphtha [i mid e hydrochloride 1.6 2-(2-(4-(6-fluoro-1 H-indazol-3-Yl -1-piperaziny I Iethyl I- 2,3-dihyd ro-3--hydroxy-1 H-isaindol-I -one hernifurna rate 2.2 2- oro -1,2-benzisox azol-3--y -1 -pipe rid inylIlIE!th y I]- 2,3-dihydro-1 H-isoindol-I -one 1.9 N-[2-4-(6-fluoro- I H-ind azol-3-y0- 1 -pipe razinyl let hyl I 4-methylphthalim-ide dihydrochloride 0.37 N-[2-[4-(6-fluoro-1 ,2-benzisoxazol-3-yl)-1-piperid invilethyl]ses3-mnethoxyphthalirnde 0.16 4-(6-fluoro-1,2-benzisoxazol-3-yl)-1 -(2-(2,3-dihyd ro-IHisoindol-2-yl)ethyll pipe rid ine dihydrochloridle 0.36 3-f 2-(4-(6-fluoro-1,2-benzisoxazo -3-y D- I -pipe rid i nyl1I ethyl)1- 2-methyl-3H--quinazolin-4-one 0.61 4-(6-fluoro-1 H-indazol-3-y1)-i -[2-C2,3-dihydro-1 H -isoind ol- 2 -yl)- *-ethyl Ipi perazine dimnaleate 0.25 ec a. N-f3-[4-(6-fluoro-1 .2-benzisoxazol-3-vl)-lI-piperid inyllbutyllphthalimide hydrochloride 0.7 1]-(123,4-tetra hyd ro-1 H4-isoquiriolin-2-yl)-2f4-(6-fluoro-1,2-benzisoxazo i-3-yl)-l -piperid inyl]ethanone hydrochloride etha nolate 6.25 4-(6-fluoro-1 H-indazol-3-y)-1-2-(5-fluoro-2,3dihydro-1 H-isoindol-?-ylethyl Jpiperazine dimaleate 0.16 4-C6-fluoro-IH-indazol-3-yl)-1 -[3-C2,3-dihydro- 1H-isoindol-2-yl)propylipiperazine dirnaleate 0.46 N\-12-[4-(6-fluoro-1,2-benzisoxazol-3-yD)-I ONOWpiperidinyll ethyl-i ,2,3,4-tetra hyd roisoquinoline difuniarate 0.23 2-4-(6-fl uoro- 1,2-ben zisoxa zol-3-y D-1 -pipe rid; nyl I- 1-2,3-dihydro-i H-isoindol-2-yl)ethanone furnarate 2.33 4-(6--Eiuoro-I H--indazol-3-yl)-l-f ?-(5-fluoro-2,3-dihvd ro- IH-isoindol-2-yl)ethyllpiperidine dirnaleate 0.27 N-f 2-[4-(6-fluoro-1I,2-benzisox a zol-3,-vl)- 1piperidinylIethyil-1,2,3,4'-tetrahydroquinoiint! hirrorate 1.19 4-(6--fluoro-I l--indlazol-3-yl-1 -[2-(2,.3-dihyd I H-isoindol-2-yl)ethyll piperaz-in. difumd rate? 1.17 rnethv1-lH-isoindo[-2-yl)ethyijpiperazine difurnarate 0.35 4-Cl H-indazol-3-yl)-1 ihydro-5-fluoro-I F-fisoindol-2-yl)ethytlpiperazine dimraleate 1.32 N-[2-4-(6-fluoro-] H-indazol-3*yl)-l-piperidinylJ lhyl)- 1,2,3,4-tetrahydroisoquinoline dirnaleate 0.44 Clozapine (standard) 8.1 9* 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 day. Itis to be understood, however, that for any particular subject, specific dosage regimens %ass should be adjusted according to the individual need and the professional judgment of the person admirnistering or supervising the administration of the aforesaid U 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 inetin Some of the compounds of the present invention are also useful as dlue to their ability to alleviate pain in mammals. The aaalgetic utility is demonstratEc: in the phenyl p-quinone writhing assay in mice, a standard assay for analgesia: Proc.

Soc. Exptl. Biol. Med., K-):729 (1957). Thus, for instance, the subcutaneous dose effecting an approximately 50% inhibition of writhing in mice produced in this assay is as shov.n in Table 2.

53I TAB3LE 2 INI-BITION OF PHENYLQUINONE INDUCED WRITHING CO&IPOUND ED-rn/. g m 1 H-indlazol-3-yl)-l -pipe razinylOpropox y I- 0.06 3-me thoxy-phenylle thanone ,2-benzisoxazol-3-yl)-1 -piperidinylpropoxyl- 0.17 3-methoxyphenyllIetha none 1-(4-[3-[4-(6-fluoro -],2-benzisoxazol-3-yl)- 0.03 log.~ 1-piperidlinyljI propoxyl-3-rnethoxyphenyl let ha none S..Propoxyphene (standard) 3.9 Penrazocine (standard) 1.3 case o Analaesia 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. I, is to be (4 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 d=00 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 susoensions, and in some cases intravenously in the form of sterile Solutions.

The comnounds of the present invention, while effective themnselves, can be formulated and administered in the form of their pharrmaceutically 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 ike; 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 S1.0-300 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, g-m 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 q -rI a LIPB---4 I milei

E

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 pharmnceutically 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

*V

should contain at least 0.1% of active compound, but can be varied between 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 Sdosage unit contains between 0.5 to 1CO 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, polyeltnlene 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 ethylenediaminetetrancetic 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 muliple 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 obtain a release of the active ingr-edient over a desired period of time. The appropriate oil may easily be determiined by consulting the prior art, or %without undue experim-entation by one skilled in the a rt.

An appropriate dose of a compound in accorda nce with this; embodiment of the invention is from about 0.01 to 10 mg/kg of body wveight per injection. Preferably, the depot formulations of this invention are administered as unit dose 'preparations comprisina about 0.5 to 5.0 nl of a 0.1 to 20% weight/weight solution of compound in tha oil. It is to be understood that the doses s et forth heren are exe-rp lary only a'nd F that they do not, to any extent, limit the scope or practice of the inventinn.

Trhe following examples are for illustrative purposes only and are not to be construed as limiting the invention. Alt temperatures are giveii ndegrees Centigrade unless indicated otherwvise.

S

EXAMPLE I 1-[4-f3-r4-c1 H-Indazol-3-vl)-I-y ierazinvi I ro ooxvl-3-mn e thoxyr hen v IlIe than one.

2-Brornobenzoic acid 2-pheriyisuifortylhydiazide To a soludon of 2-brornobenzoic acid hydrazide (132 g) in pyridline (1.2 L) V. cooled to about 10 C with an ice bath, was added beozensulfonyl chloride (78.3 ird). After complete addition, the reaction was stirred at ambient temperature for four hours, and then poured into ice-hydroch-loric acid to precipitate a yellow solid, 135 g. The material was recrystallized from isopropanol to yield 125 g of 2-bromobenzoic acid 2-phenylsulfonyihydrazide, m.p. 154-156C.

a-Chloro-2-bronwoberiwt~dehyde phenylisuifoniy~hydra~orre A midxture of 2-bromobenzoic acid phenylsulfonyihydrazide (125 g, 350 mr-nol) and thionyl chloride (265 ml) was stirred and refluxed for 2 hours. After about minutes of reflux, the solid went into solution. The reaction was permitted to coand then it was poured into hexane. The resultant white solid was collected to afford 124 g of a-chloro-2-bromobenzaldehvde phenyLsulfonylhydrazone, m-p.

120-1 22*C- I -[(PhenylsulifonyIhydraz-onol4(2-brorriophe-nyl)methyUj- 4-rnehylpiperazirie 0 To a stir-red solution, under nitrogen, of a-chloro-2-bromobenzaldehyde phenylsulfonylhydrazone (271.1 g; 720 mrnol) in tetrahydrofuran (TI-F; 2 was added dropwise N-methylpiperazine (159.7 g; 1600 MMOl)_ The reaction was stirred at ambient temperature for three hours, and then permitted to stand at ambient temperature for 16 hours. The reaction was chilled in ail ice bath, and then filtered to remove the piperazine hydrochloride that was formed. The filtrate was concentrated to vield a brown gum. The gum was triturated with hot acetonitr-ile, the mixture was cooled in an ice bath, and wvhen cold, was fltered to remove unwanted side product. The filtrate w-.as then concentrated to afford 392.9 a of a brown gum of crude i-[t(phenyLsulfon-y'i)hydrazonoi- (2-bromophenyl)methyl-4-methylpiperazLnC.

3 -(4-Mvftthy1-l -pfperazi'riyl)-l -plhery/sulfontyl-7H-fndaczcIe A midxture of 1 -[[(phenylsulfonyl)hyd razono]-(2-bromo phenyl)methyli- 4-methylpiperazine (31.0 g, 80 mnmol), copper bronze (3.1 KC,C0 (1.5 and dirnethyLformnamide (500 ml), was stirred and refluxed for 1.5 hours. T1he reaction :was poured into water and the aqueous suspension was stir-red vigorously with ethyl acetate. The biphasic mixture was filtered through Celite, and subsequently the layers were separated. The aqueous portion was extracted with another portion of ethyl acetate, and the combined extracts were washed and dried (MgSO,). Concentration of the extract afforded a solid, which upon trituration with ether gave 19.7 g of solid. The solid was recrystallized from isopropanol to afford 17.7 g of product, m.p. 158-161'C. An analytical sample was obtained by another recrystallization from isopropanol (with charcoal treatment) to afford colorless crystals of the indlazole, 3-(4-methvl-1-piperaziny)--phenyL.suLfoflyl-I H-i niazole, m.p. =160-161*C.

Calculated for C!AH,,N,0&S 60.66%C 5.66%H 15.720/N Found: 60.45%C 5.62%H 15.61% N 4-!11-(PhernylsulfonyI)-l H-indazol-3 -yIJ- I-piperuzin ecarbonit rile To a stirred mixture of 3-(4-methyl-1-pip~era-zinyl)-l-phenylsulfonyl- IH-indazole (237 g, 0.67 mole), K 2 CO3 (102 g, 0.74 mole) and dimethylsulfoxide CDMSO, 2000 ml), under nitrogen, was added cyanogen bromide (72 g, 0.68 mmol) dissolved in DM50 (523 ml). The reaction was stirred at ambient temperature for '5.3 hours and w~as then roedinto H,O (7 The solid, which precipitated from solution, was collected by filtration and was v.ashed well with H.,O affording 168 g of product. A 5.2 g sample was recrystallized twice from ethanol-HO yielding 4.0 g of 4--(phenylsulfonyl)-H-indazol-3-y, j-l-piperazinecarbonitrile, m.p. 178-180C.

ANALYSIS:

Calculated for CIsH, 7

N

s OS' 58.85%C 4.66%H 19.06%N Found: 59.01%C 4.f63%H 19.09%N 3-(7-Piperazinyl)-1 H-indazole To a stirred mixture of 4-[1-(phenylsulfonyl)- H-indazol-3-yl]- -piperazinecarbonitrile (163 g, 0.44 mol) in tetrahydrofuran (2.0 1) was added, dropwise, lithium aluminum hydride (880 ml; 0.88 mol of a 1 M lithium aluminum hydride solution in tetrahydrofuran). After complete addition, the reaction was heated to reflux and stirred for 6 hours, stirred at ambient temperature for one hour and allowed to sit at room temperature overnight. The reaction was quenched by the Se careful dropwise addition of water. After no more hydrogen could be observed to evolve, the reaction was filtered and the lithium salt filter cake was washed well with tetrahydrofuran. The filtrate was combined with the filtrate of another run (all together the starting material totaled 300 g, i.e. 820 mmol) and the combined filtrates were concentrated to afford 372 g of a yellow solid suspended in water.

An attempt was made to partition the product between water and dichloromethane, but the product proved to be only slightly soluble in dichloromethane. Therefore, the biphasic product suspension was filtered through a course sintered funnel and the white product which was collected was dried to Safford 121 g. The two phases of the filtrate were separated and the water was Sextracted again with dichloromethane. All of the dichloromethane phases were combined, washed twice with water, dried with magnesium sulfate, and concentrated to afford 41 g of a brown residue. The residue was triturated with diethvl ether and filtered to afford 10 g of a beige solid, m.p. 139-150'C. The NMR and MS spectra were consistent with the structure. Recrystallization of 10 g from toluene afforded 7.5 g of 3-(1-piperazinyl)-lH-indazole, m.p. 153-155"C.

C

o 00 A stirred mnixture of 3-(4-rnethyl-l -piperazinyl)- 1-phenylsulfonyl-l H-i ndazole (13.5 g, 38 rnmol), methanol (150 mld) and 25% CHONa in methanol (15.3 ml) was stirred and refluxed for 2.5 hours. The reaction was concentrated to about one-tenth its volume, and water was added to the rixture, resulting in a red solution. The solution was extracted with dichioromethane, the extract washed dried (MgSO l. and the solvent was concentrated to afford 6.6 g of a rose-colored solid. Two recrystallizations from toluene-hexane afforded 4.3 c, of 3-(4-methyl-1-piperazinyl)-IH-ildazole as an off-white solid, m.p. 111-113,C.

ANALYSIS:

Calculated for 66.645/C 7.4 6% H 25.91 %N Found: 66.83%C 7.4 2%coH 25.69%~N 4-0 H-indazol-3-yU)-1-pipern zicnarbon itnice To a stirred mixture of cyanogen bromide (5.3 g, 0.05 moIX, KC0 3 (7.1 g) and dimethylsulfoxide (40 nil) was added, dropwise, 3-(4-methyl-I -piperazinyl)-l H-indazole (11.0 g, 0.051 mol) dissolved in dime thylsu Ifoxid e (60 ml). The reaction was stirred at ambient temperature for I hour, and then it was poured into water. The aqueous suspension was extracted with ethyl acetate, the ethyl acetate was washed dried (MgSO 4 and concentrated to afford 7.8 g of a yellow solid. This sample was combined with another and recrystallized twice from toluene to afford analytically pure 4-(1 H-indazol1-3-yl)-1 -piperazinecarbonitrile as a white solid, m.p. 1012C

ANALYSIS:

Calculated for 63.A2%C 5.76%H Found: 63.04%C 5.84%H 3 *0 -Piperaziny)-1 H-indazole S. S S

S

C'

A mixture of -1-CH-indazol-3-yl)--piperazinecarbonitrile (8.0 g, 40 mmol) and 25% HSO, (100 ml) was stirred at reflu-x for 4.5 hours. The reaction was cooled in an ice bath and made basic by the dropwise addition of 50% NaOH.

The basic solution was extracted with ethyl acetate. The ethyl acetate was washed with H),O dried with MgSO, and concentrated to afford 5.2 g (73% of the drsired compound, as a solid. The solid was recrystallized twice from toluene to afford g of 3-(1-piperaziyl)-1H-indazole, m.p. 153-155C.

ANALYSIS:

Calculated for C 1 65.32%C 6.98%H 27.70 %N Found: 65.21 %C 6.99%H 27.80%N ff3 1444344-0 H-Tidoazol-3-!-2 -piptrazinyIlproporJ-3-nicthoxyphleriylIdo zorie A mixture of 3-(0-piperazinyl)-11H-indazole (4.0 g, 20 mmol), K,CO, (3.0 g, 22 rrmnol), 1-4-(3-chloropropoxy)-3-methoxypheny lIeth none (5.3 g, 22 mmol), a few crystals of KI, and dimethylformamide (60 ml) was stirred at 90 C for 5 hours.

The reaction was poured into water, and the aqueous mixture was extracted with ethyl acetate. The extract was washed (brine), dried (iMgSOd, and the solvent was concentrated to afford a white solid, which was triturated with diethyl ether and collected to yield 7.0 g of product. Two recrystallizations from absolute ethyl alcohol yielded 5.3 g of analytically pure 1-[4-[3-[4-(lH-indazol-3-yl)-1-piperazinyllpropoxy)-3methoxvphenyllethanone, m.p. 155-157 0

C,

ANALYSIS:

Calculated for C,H,,NO 1 Found: 67.62%C 67.457cC 6.9 1/.H 6.7 4H 13.7276%N 13.56%N .4 dj A *e S a Osat m EXAMPLE 2 1-F4-f3-f4-(,2-Benzisoxazol-3-yl)-l-piperid invillropoxvl,-3-methoxvphenvflethanone A mixture of pipe rid inylD- 1,2-benzisaxa zole hydrochloride (4.8 g, m-mol), K2CO3 (5.2 g, 40 rnmol), 1-[4-(3-chloropropoxy)-3-me thoxyphenyilethanone (5.3 g& 22 mmol), a few crystals of 1(1 and dimethyl-formamide ml) was stir-red at 90 C for 16 hours. The reaction was poured into water and the aqueous mi~xture was extracted with ethyl acetate. The extract was washed (wvater), dried (tMgSO,) and concentrated to afford a br, in oil. The oil was chromatographed on a Waters Prep 500 utiliing silica gel columns znd ethyl acetate-diethylamine 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 ,2-benzisoxazol-3-y D-1 -piperidi nyl] propoxyJ methoxyphenylletha none, m.p. 102-104'C, as colorless needles.

ANALYSIS:

Calculat ed for 70.56%C 6.91l%H 6.8617N Found: 70.73%C 6,93%H 6.85%N EXAMPLE 3 1-[4-f 3-f 4-(6-Fluoro I2-be-nzisoxazol-3-yl)-l-pi pen d i vropoxvl-3m ethoxy-p2henyllethanone A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2 benzisoxazole hydrochloride (5.1 g, 20 rnmol), KCO, (5.

2 40O mmol), I -[4-(3-chloropropoxy)-3-methoxyphenyllethanione (5.3 g, 22 mmol), and dirnethylfor-mamide (60 ml) wa5 heated at 90'C for 16 hours. The reaction wvas poured into wvater, and the aqueous mixture was ext-racted with ethyl acetate. The ethyl acetate was washed (water), dried (MgSO,) and concentrated to afford a moist solid. RecrvsLillization (twice) from ethy;l alcohol afforded 5.0 g (58'7r) of 1 -[-f34.(.florol,2bensoxzol3-v)-i-p ipeid inyvib.

propoxyl-3-methoxyphenyl 1-,2tha none as a beige solid, mi.p.- I 1S-12O'"Z.

ANALYSIS:

Calculated for 67.60%oC 6.3S%H 6.57%N otu.67.47%/C 6.407cH 6.53%oN.

EXAMPLE 4 1-f4-f44[4-(1.2-ilenziso~xazoh-3-yvU-l-p ineridinvllbutoyVI 3-rne tho.Kn hen vi eth anon e A mnixture of 3-(4-pip erid inyl)-1,2-benzisoxa zo le hydrochloride (4.3 g, IS mmol), KCO, (5.5 g, 40 nimol), and 1-[4'-(4-bromobutoxy)-3-methoxyphenyllethanone (5.5 g, 18 miunol), and dirnethyLfornmanide (60 ml) was stirred and heated at 75*C for 16 hours. The reaction was poured into water and was extracted with ethyl acetate. The ethyl acetate was washed (water), dried (MgSO 4 and the solvent cot-:;Q-ntrated to afford 7.2 g of a beige solid. Recrystallzation (twice) from ethyl alcohol yielded 3.3 g oF 1 ,2-benzisoxa zol-3-yl)-1 piperidinylj-butoxvl-3-methoxyphenyllIet hanone, M.P. 99-101'C.

A NAL YS IS: Calculated for 2

O

4 71 .11 %C 7.16%H 6.63%N dffpFound: 70.76%7C 7.24 %H 6.58%N.

EXAMPLE 4-[4 -6F uoro4.2?-b enzisoxazo 1-3-y D-1 -pipe rid invlb u toxyl- 3-me thoxyph envile thanon e A -stirred mixture of 6-flucro-3-(4-piper-idinyl)-1 ,2-benzisoxazole hydrochloride (5.1 g.0.02 rnol), K.C0 3 (5.2 g, 0.04 nnol), 1[4(-bromobutoxv)-3 -methoxyphenylietha none (6.6 g, 22 mmol). and 0~ St S 4 4 a.

4 Se

S

I

dimneth ylformamide (60 ml1) was heated at 75'C for 5 hours. The reiction was poured into water, and the aqueous mixture was extracted w.ith ethyl acetate. The ethyl acetate was washed (w-ater), dried (MgSO 4 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 a of the product as a waxy solid. The compound was chrornatographed on a Waters Prep 500 utilizing silica gel columns and eluting with dichlorornethn ne/methanol Concentration of the appropriate fractions yielded 5.1 g of off-white solid l-[4-[4-(4-(6-fluoro-1,2benzisoxazol-3-yl)-1-pi peridinylJ-butoxy] 7 -3-methoxyphenyllethanone, which when recrystaUlized from ethyl alcohol yielded 3.2 g (367o) of feathery-white needles, M.P. =88-90*C.

ANALYSIS:

Calculated for CH, 6S8.16 %,oC 6.647oH 6.36%N Found: 67.96%7C 6.49%H- 6.29%N.

Aft

EXAMPLE

1-f4.[2-[4-(2-Benisoxazol-3-yvl)4-piperidi nvllethoxyl-3-melhoxyphenyllethanione fumnarate A mixture of 3-(4-piperidinyl)-1,2-benzls-oxa Izole h5ydrochloridle (4.8 g mmol), K 2 C0 3 (5.2 g, 40 mmol), I hoxy)-314 tiethoxyphenyllethanone (5.0 g, 22 nirol), and climethyformaicf' (90 ml) heated at 90'C for 16 hours. The reaction was poured into water and the aqu -eo -usm xture was extracted with ethyl acetate. The ethyl acetate was washed dried (MgSO).

and the solvent was concentrated to afford an oil. Upon standing; tIj- oil solidified to afford a beige solid. The crude solid was recrystallizedtwice -fromn ethyl alcohol to afford 5.9 g of an off-white solid. The solid was disso ted-. rn ethy"l acetate, and fumaric acid (1.2 gI.1 equiv.) wvas added. The mixture was heata'-d briefly on a steam bath, and then stirred at ambient temperature for 2'hours \'.kn initial green oil settled out and the supermtant solution wvas decanted. Ether was added to the decantate and 4.0 g of a white iurnarate salt w,.as collected. The salt.

was recrvstallized twice from ethanol-ether to yield 1.7 g of 1-141(214-Cl ,2-bernzisoxalzol- 3 -yl)-I -pipprid inyvl I tho:.v 1 3- methoxv phenyI1IOthalnone fumarate, m~p. 127-129-C.

Calculated for C,,H, 6

N

2

O

4 .Cd-lO,: 63.52%C 5.92%H11- 5.49%N Found: 63.00%C 5.87%H 5.42%N EXAMPLE 7 I-[4-f4-r4-(I H-lndazol-3-yI)-l-pipera.i n vflbu toxvl-3-me tho.)vphenyllethauione fumarale a A stirred nmixture of 3-(1 -piperazinyl)-1 H-indazole g, 20 rnmol), KCO, (5.3 g, 40 mmcol), I-[-4booutx)3mtoyhnllthnn (6.6 g, 22 rmol), and dimethylforrnmide (60 mli) was heated at 75'C for 6 hou'rs. The reaction was poured into water, and a white solid precipitated from solution- The -solid was colected and dried to afford T72g of the crude product. The crude solid a. was recrystal-lized twice from ethyl alcohol to yield 4.1 g of the free base, which was converted to its fun-orate salt by the addition of fumnaric acid (1.1 g) to the compound dissolved in refluxing acetone. The resulting fuma rate salt (5.0 g) wyas recrystallized from ethyl alcohol to afford 3.8 g (357c) of I 1444[4-0 H-indazol-3-yl)-1 -piperazinyll-butoxyI-3-imetloxyphenyl~etha none furnarate, as a white solid, mn.p. 163-165C.

ANALYSIS:

Calculated for C,H,,NO.CF1 4 62.4 4 %C 6.367%H 10.40%N Found: 62.287cC 6.62%H 10.34%M.

EXAMPLE 8 1 1 jetgMphenyll-etha none A stirred mixt-ure of 6-fluoro-3-(4-piperidilyl)-l.2 benzisoxazale hydrochloride (5.1 g, 20 mmal), KCO, (5.2 l-[4-(2-chloroet hoxy)- 3.rnethoxyphenyllethaflore (5.0 g, 1022 rmcl), and dimethvlformamnide (90 ml) was heated at 90*C for 16 hours. The reaction was poured into wvater, and the aqueous mixture was extracted with ethvl acetate- The ethvi acetate was washed (water), dried (MgSO 4 X, and concentrated to afford 7.4 g of a yellow solid. The solid was chron-Ltographed on a Waters Prep LC 500 utiiing dichloromethane/methanol as eluent, and subsequent concentration of the appropriate fraction afforded 4.0 g of a yellow solid. The solid was recn'ystallized from ethyl alcohol to yield 3.1 g (38%6) of 1-[4-[2-[4-(6-luoro-1,2-benzisoxazol-3-yl)- I -piperidinylethoxy-3-ethoxyphelI ethaone,~ as slightly yellow flakes, M.P.

132-1 34'C.

ANALYSIS:

Calculated for CHFNQ 4 6.8C 6.11 %H 6.79%N Found: 66.90%C 6.20%H 6.74%N.

EXAMPLE 9 4 4[34-(6-Fl uoro-1,2-b enzisoxazol-3-Vl--pip erid i ny I propoxV1,- 3-methoxv-(x-methvlbenzenemethanoI To a stirred mixture of 1-[4-(3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1pi Peridinyl I-propoxy-3-met hoxy-phel lJet ha none g, 9.4 mmol) in methanol/tetrahydrofuran (60 ml, was added sodium horohydride (0.4 g, rnmol)- 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. Therefore, another 0.1 g of 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.[31[4-(6-fluoro-1,2-benzisox-,azol- 3.yl)-l.piperidinvl.3methoxy-re-mthlbenzeflnmethaloI as a white solid, m.p.

136-13S'C

ANALYSIS;

Calculated for C,,HFN,0 4 67.27%C 6.82 H 6.5 Found: 67.59%C 6.89%1- 6.4 7 %N EXAMPLE V. 1-f4-r3-r4-(l .2-Benzisothiazol-3-vl)-l-piperidillpropoxl3me th oxvheny I-e th anon e A mixture of 3-4-pip Prid iny- 1,2-belziso th ia zoe (3.0 g, 13.7 mmuol), potassium carbonate (2.3 g, 16.5 mmol), 1-[4-(3-chloro- :propoxv)-3-nmethox<yphenvl]ethiafone (4.0 g, 16.5 mmol), potassium iodide (200 mg) and acetonitrile (100 nil) was stirred at reflu. under N, for 24 hours. The cooled reaction was filtered and the cake was wvashed well with acetonitrile. The filtrate as concentrated to an oily residue, which wvas partitioned between water and ethyl acetate. The ethyl acetate extract was washed well with water, dried with MgSO, and concentrated to yield 6.1 g of a beige oil wvhich solidified upon standing. The product was triturated wich diethyl ether and filtered to give 4.2 g of a beige solid. The compound wvas recrystallized fromn ethyl alcohol to afford g, and another recrystallization from ethyl alcohol (utlizing decolonizing carbon) provided 2.4 g (41%7) of 1.[-13-[4-O,2-henzisothiazol- 3-vllpiperidinyllpropoxyJ-3mrethoxypheyllthnone, m.p. 93-95'C.

ANALYSIS:

Calculated for C,,H, 3 N,OS: 67.9076C 6.63 6.60%N Found: 67.89%C 6.61%H 6.5 9 %oN EXAMPLE 11 1-4(-4(-loo12bezsxz -,v)ipperid invllpropo.xVl-3hvdroyvphenvllethinone -ch loroproproxvw)-3-hyvdro.variiI lethq rofl To a stirred solution of 1- (4--hlrp oy- -nt o-yp n tanE (10.0 g, 41 mmCl) in mnethylene chloridie (120 ml) cooled to -50'C (dr-y ice-miethanol) was added, dro-pwise, INI boron tribrornide in niethylene chloride (123 mld, 120 mmol). The tei-perature was kept between -40 0 C and -50'C. After complete addition, the reaction was permitted to reach *30'C, and the TLC checked (ca. 15 min. after final boron tribromnide was added). Saturated NaHCO, was added, drop~wise, never allowing the temperature to go above 0'C during most Of the addition. When sufficient NaHCO, had been added to make the solution basic, the organic layer was collected. The layer was w .ashed with brine, dried (MgSO, 4 X and concentrated to Yield 8.1 g of dark brown oil, which solidified on 5.standing. This was chrom-atographed 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, 110-113'C.

(B)I-t4l-!3-f 4'-(5-Fl,,oro-l 2-ben z isoxaz:o!-3- "-yf--pipeninvirilplropoLyi-3hydroxyphenylkethainone A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2- benzisoxazole (2.8 g.

13 rnmol NaH-C0 3 (1.1 several crystals of KIT, 1-t4-(3-chloropropoxy)- 3-hydroxy-phenyijethanone, and acetonitrile (100 ml) was reftLxed for 16 hours.

The reaction was poured into water, and the aqueous mixtue was extracted with ethyl acetate. The organic extract was washed (water), dried (N-gSO), and the solvent was concentrated to afford 5.7 g of a thick yellow oil. The oil was chromatographed on a Waters Prep 5~)LC .on silica gel, eluting with 7% miethanol/methylene chloride. Concentration of the appropriate fraction afforded a yellow oil, which upon standing yielded 3.3 g of the compound as a pale, yeliow solid. The solid was recry'stallized from ethyl alcohol to afford 2.7 g (50%7) of 1 -[4-131[4-(6-fluoro-1 .2-benzisoxazol-3-yll)-l -pi peridinyll- ?:ropoxvl-3hdro\Yvohen l lethion e as a pale vellow solid, m p. 122-124*C.

ANALYSIS:

Calculated for 66.98 %C 6.11 %CH 6.71%.N Found: 66.97%C 6.20 -3H 6.69%N EXAMPLE 12 methonvphenyll-ethanone A stirred mixture of 6-fluoro-3-(l-piperazinyl)-IH-ind.nzole (2.3 100 -ru mmol), K,CO, 15g 1-[4-(3-chloropropoxy)-3-methoxyphenyllethanone (2.8 g, 11 mmol), several crvstals of K! and dirnethylformarnide (60 ml) was heated at for 16 hours. The reaction was poured into H,0, and the aqueous suspension w.as eytracted with ethvl acetate. The ethyl acetate was washed 2 dried (Mg5O 4 and concentrated to afford 5.0 g of a yel low, oil. The oil was chroma-tographed on aWaters Prep 500 utilizing silica gel columns and eluting with methylene chloride/ methanol Concentration of thle desired fractions yielded 2.0 g (46%) *of an off-white solid. This sample was combined wvith 1.0 g of a previous sample, and this was recrystallized from toluene to afford 2.6 g of cI(pro poxyl-3-methoxypheny letha none as a white soiid,m.p. 135-1'17'C.

Calculated for CH, 7

FN,

4 Q: 64.779%C 6.35%7H 13.14%N Found: 64-66%C 6.2l-%H 13.02%N EXAMPLE 13 1-f 444-r4-(6-Fluoro4IH-indazol-3-yl)-l-pipe razinvllbutoxvl-3- Methoxyphenyll-ethanone A stirred mixture of 6-fluoro-3-01-piperazinyl)-I H-indlazole hydrochloride g.19 mmol), KCO, (5-S 0 and I 4-(4-brornobuto\ v)-3-niethoxvphenyijetnanor-e (6.3 a, 21 mmrol) and dimethvlformamnide ',50 ml) was heated at for 6 hours. The reaction was poured Lnto wvater, and an off-w hite solid orefrmsito.The solid was collected and dried to yield .13 g of crude product. The compound was recrystalized from ethanol (3 times) to afford 3.0 g of an off-white solid. The solid was chromatographed. on a Waters Prep 500 utilizing silica gel columns and eluting with methylene chloride/methanol Concentration of the appropriate fractions afford 2-3 g of an off-white solid, which when recrystallized from ethanol yielded 1.9 g (2617) of analytically pure B too so#* oro- I H-inda zol1-3-ylD-1 -pip era zinylIlI-Du t oxy]-3methoxyphenyl] etharone, m.p. =156-158 0

C.

*OOCalculated for C,,H-,,FNQ 3 6 5.44% C 6.64%9'H 12.72%N Found: 6 3.3 S9% C 6.49%cH 12.60%N a. BEXAMPLE 14 A mixture of 3-(4-piperidinyl)-IH-indazole (3.0 g, 15 mmol), KC0 3 (1.6 g), Ike' 1-[4-(3-choropropoxy)-3-methoxyphenyliethan-one (5.3 g, 22 mmol'X a few crystals of KI and acetonitrile (100 ml) was stirred and refluxed for 16 hours. The reaction was poured into water and a white solid separated from solution., The solid was dwai collected, dried and afforded 5-1 g of product. Recrystallization from ethanol yielded 3.6 g of the compound, which upon chromatography (preparative HPLC on silica gel, eluting with methylene chloride/ met ha nol-9: 1) gave 3.0 g of an off-white solid. Recrystallization from ethanol afforded the analytically pure 1 H-inda zol-3-Y)- I -p iperidinyll -pro paxyl-3-me thoxyp henylIe t hano ne as a white solid,m.p- 171-173'C-

ANALYSIS:

Calculated for 70.74%C 7.17 %H 10-31L7%N Found: 70.527cC 7.27 %H 10.429oN EXAMPLE 1-r4-[3-r4-(6-Chlcoro-l .2-bernzisoxazol-3-vl)-l-n i peridinyl lpropoxv]-3me tho xvphen vilet h anone A stirred mixture of 6 -chloroa-3-(4-piperidiinyl)-1,2-benzisozazole (4.7 g, rrnol), 1-[4-(3-chloropropoxy)-3-rnethoxyphenyljethanone 20 mmol), 2 C0 3 (2.8 several crystaLs of KI and acetonit-l 10m)ws elxdfr1 hours. The reaction was filtered and the Niltrate was concentrated4 to yield a solid-oil mixture. The residue was chromatographed on a Waters Prep 500 utilizing silica columns and eluting with methylene chloridle/methanol Concentration of the desired fractions yielded 3.2 g of a beige solid, which upon recrystallization from ethanol afforded 2.7 g of I -[4-t3-[4-(6-chloro-1,2-benzisoxazol-3-y)- -piperidinyllpropoxyl- 3-methoxy-phenylJ-ethanone as a beig7e solid, mn.p. =116-1 18'C.

ANALYSIS:

*Calculated for C 24

H,

7 CIIN-,: 65.08%C 6.14%H 6.3 2 N Found: 65.35%C 6-22%H 6.26oNI EXAMPLE. 16 1-r4-4-f4--(6-Ch loro-1,2-benzisoxazol-3-vi)l-12pi eridinvllbu toxyl-3methoxyphenyllethanorle fumarate -A stirred mixture of 6 -c hloro-3-(4-pipe rid in vl) 1,2-benz isoxazole (4.7 g, mrmol), ro mbu toxy)-3-methoxy phenylIIet ha none (6.0 a, 20 rnmol), K,C0 3 (2-8 g) and acetonitrile (120 ml) was refluxed for 16 hours. The reaction was allowed to cool, filtered, and the Niltrate was concentrated to 9.9 g of a brown oil. The oil was chromatographed on a Waters Prep 5090 utilizing sili ca gel columns and eluting with methylene chloride/methanot (557). Concentration of the appropriate fractions afforded 2.3 g of an off-w-.hite solid, The solid was dissolved in ethanol and fumnaric acid (0.62 g, eq.) was added- Upon concentration of the elhanol, a crude, brown soli' was coilected, which was taken up in refluxing acetone. Upon cooling, a white soiid cF -stallized fromn solution yieldingr 2.2 g of -(6-chloro-b2-benzisoxazol1-3-vl)l-p--iperidinvi]butoxy]-3-methox-y-phenyl]ethflnfle furnarate as a white solid, imp. 1 39-].41 'C.

A NALYS IS: Calculated for CH,Ch\,O,.CHO,: 60.78%/C 3.80%-aH 4.89rN Found: 60.69%C 5.74%H 4.85%N EXAMPLE 17 1-[4-[3-f4-(--Fluoro-1,2-benzisoxazol-3-y)-I-p iperid in yl ipropoxyl- -3-methoxvy-phen yl e th anon e A mixture of 5-fluoro-3-(4-piperidiny!)-1,2-benzisoxazole (2.2 g, 10 mmol), 1.[4-(3-chloropropoxy)-3-metho~xyphenyljethanone (2.4 g, 10 mrnol), K-C0 3 g), a few crystals of KI and acetonitrile (100 rl) was stirred and refluxed for S hours.

The reaction was poured into water and the aqueous mixture extracted with ethyl acetate. The ethyl acetate extract was washed (brine), dried (MgSO, and concentrated to afford 4.0 g of a white solid. The solid was chromatographed on a Waters Prep 500 HPLC utilizing silica gel columns and eluting with methylene chloride/m ethanol Concentration of the appropriate fractions afforded of 1-[4-[3-[4-(5-fluoro-l ,2)-benzisoxazol-3-yl -piperidiny'l]propoxy I- 3-rnethoxypheniyll-etha none as a white crystalline solid, rn.p. 103-105C.

ANALYSIS:

Calculated for C,H, 7 FN,0 4 67.59%C 6.38%H 6.57%N Found: 67.50%C 6-47%H 6.53% N EXAMPLE 118 6-Fl uoro-3-fl13-(2-me th oxvh gnox-0propyl 1-4 -p ip erid invl-1,2benzisoxazole furnarate A stirred mixture of 6-fluoro-J--(4-piperidinyl)-i,2-benzisoxazole (2.45 g;- 111mrol), K,CO, (2.0 and 3-(2-methoxyphertoxy~prc Qyl chloride (3.3 g, 17.4 romol) in acetonitrile (40 ml) was heated at 90'C for 4 hours. At the end of the reaction, the solvent was removed, and the solidis ,-,ere dissolved ito dichlorornethane (100 ml). The solution was .;ashed wvith water and brine, then died over IMgSO,. 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 st-irdn material).

The combined material was purified by flash chromatography on a silica gel column (49 g, eluted with diethylamine: IF. methanol:9S.5% dichloromethane, -I L) The fractions containing the pure produIct were pooled and concentrated *down to a light oil (3.68 This oil was treated with fumaric acid (1.14 g, 9.8 rmal) in ethanol (13 The 6-fluoro-3-[1-t3-(2-methoxyphenoxy)proPY1P.4..piperidinyli.2-benzisoxazole funa rate crystals obtained weighed 4.0 1 g

:ANALYSIS:

Calculated for 3

-C

4 62.39%C 5.84% H 5.60 76N Found: 6 2.3 7 %C 5 557H !1 560 -o N EXAMPLE 19 1-f3-[3-T4-(6-FI uoro-7t.2-benzisoxazol-3-vl)-1-piperidi nvllpropoxv-4z rnethoxvphenyll~h envimethanone A stirred mixture of 6-fluoro-3-(4-piperid inv)- 1,2 benzisoxazole (2.01 g; 9.13 mmol), KCO, (2.0 and 1-[3-(3-chloroprop I xy)-4-methoxy-phenyllphenylmethanone (3.93 g; 11.3 mmol) and acetonitrile (50 ml) 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 rrD The dichloromethane solution was washed with wa ter-and. brine (100 ml), dried over LMgSO, then concentrated to an oil. The pur-ification was done by flash chromatography over a silica gel column (SiO 2 40 g: eluted with dichloromethane, 300 ml; 1% methanol in dlichloromethane. 850 ml). The material thus obtained as a colorless oil solidified on standing. Recrystallization from ethanoi (150 ml) gave 1-[3-[3-14-(6-fluoro-1 ,2-benzisoxazol-3-vl)-1 .pi peridin-illjpropoxyl)-4-methoxy-phenij.il phenvlmethanone as white cry'stalIs, 3.07 g mop. 140-141 'C.

AMNALYS IS: Calculated for C,H,,FN,O,: Found: 71.3076C 71 .09%C 5.93C70H 5.98%H 3.73% NT

C

CS

C:

6.

EXAMPLE 1-f 444444(IH-i nd azol-3-yl) -1-pipe rid invil-bu toxvl-3-m e th oxvph enyll]eth anon e A mixture of 3-(4-piperidinyl)-IH-indazole (3.2 g, 16 mmol), 1-[4-(4-bromobutoxy)-3-methoxyphenylietha none (5.0 g, 16 mrnol), K-CQJ (2.2 g) and acetonitrile (100 mld) was stirred and refluxed for 6 hours. The. reaction was poured into water and the resulting yelow solid that formed was collected to afford 5.3 g of product.

The compound- was recrystallized from acetonitbile and then from ethyl acetate to yield 3.0 g(45%o) of a-slightly yellow solid of l-[4-[4-[4-(1H-indazol-3-yI)-1piperidinylI-buto~y]-3-methoxyphenyljetha none, mn.p. =133-135 C.

ANALYSIS:

Calculated for 71.2-37%C 7.41 %H 9.9 7 c.N Found: 70.S5%C 7.61 %H 9.81%L~N EXCANPLE 21 1-f4-f2-[4-(6-Chloro-12-benzisoxazol-3-vi)-l-ioeridinyllethowbyl3methoxyphenyll-ethingnC A stirred mixture of 6-chloro-3-(4-piperidinyl)-1,2 benzisoxazole (4.6 g, 19 mmol), l-[4-(2-ch loroethoxy)-3- methoxyphenyllethanone (4.3 g, 19 mnmol), KCO, (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 methvlene chloride/metha nol. Concentration of the appropriate fractions yielded 3.?2 of a light ve[Lw solid, which upon recrystallization from ethyl acetate afforded 2.3 6f 1-[4-[2-(4-(6-chloro-l,2-beaisox-azolI-3-ylD- I-pipe riciinvl! jeth a y- 3-meth oxyphenyll etha none as a pale yellow,. solid, mn D. =133-135'C.

ANALYSIS:

Calculated for CHC\,OA: 64. 'I1I7%C 5.88%H 6.53%"!N Found: 64.35%cC 5.87%oH 6.41%N EX-AMPLE 22 .*-3-(3-Brom oproporv-4-mnethoxyphen yl)ph en yl e t hanone' A solution of 3-hLydroxy-4-methoxybenzophenorie (4z6 g, 20 mmol) in dirnethylforrnamide (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 stir-red 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 solution was washed with water, brine and dried over anhydrous MgSO,. The solvent was removed and the crude oil was purified by flash chromatography over a silica gel column (SiO,, 85 g; eluted with 3:1 hexane:dichloromethane, 1.61f 1.37 hexane:a,dichloromethane, 11.4 The pure product thus obtained v./eighed 4 6 7 g, as an oil. Recrystallization twice from isopropyl ether (500 ml) gave analytically pure 3-(3-bromopropoxy- 4-methoxyphenyl)phenylmethanone (2.42 rn.p. 81S-83'C.

ANALYSIS:

Calculated for C,,H, 17 BrO,: 58.47%C 4.91%H Found: 58.63%C 4.82%H EXAMPLE 23 14334-(46-Fl uoro-1,2-b enzisoxazol1-3-0l-1-p ile rid in vl 11propoxvlphenyllethanone fumarate A mixture of 6-fluoro-3-(4-pip~eridinyl)-1,2-benizisoxazole hydrochloride .(4.53 g, 20.5 rnmol), KC0 3 (4-5 1-(3-(3-chloroirouoxy)phenylletha none (6.4 g-.

29 mrnol) in acetoztitrile (60 ml) was heated reflux for 5 howrs. At the end of the, reaction, the solvent wvas removed and the residue wsextracted into dichioromethane (300 rnl). The inorganic irnsclubles w-,ere filtered off. T he dichioromethane solution was concentrated to a small volume (10 ml) and purified on a flash chromatographic column (SiO, 75 g, eluted with dlichloromethane, 900 ml; and 2% methanol in dichloromethane, 800 mnd). The fractions containing the pure product were combined and concentrated to an oil (2.87 gl; The oil was *..dissoved into ethanol and treated with a solution of fumraric acid (841 mg).

.Recrystallization, (twice) from ethanol afforded 2.53 gyof 1-(3I[ 3 -[4-(6-fluoro-1,2bezsxzol3yl--iei inlpooypevjtann frimarate as White Crystals; rn.p. 172-174'C.

ANALYSIS.

Calculated for C.,H--FtNSO, C H 63.27%C 5.70%H 5.47%N! Found: 63.00%C 5. 6 5.43 %7N EXAMPLE 24 1-T 4 -f3-4-(6-Fuoro1,2benzisoxazo 3yIL)Tpiperi din yllpropoxyl- 2 C methviphenvil-ethanone A stirred mixture of 6 -fluoro-3-(4-piPerid iniyl-1 ,2 benzi-soxazole ____hydrochloride (5.5 g, 21.6 mmol), K,CO,(3.5 1-[47(3-bromopropoxy)-2methylphenyll-ethanone (4.83 g, 17.8 mmol) in dimethylformrnide (25 ml) and 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 evaoorated to a crude oil. The'purification was done by flash chromatography over a silica gel column (80 g,'eluted With dichioromethane, 1 1; 1% methanol.- dichloromiethane, 1.2 1; 2% methanol- -hioromethane, 1.2 The purest fractions Were combined and afforded 2.5 of solid. Recrystallization from dichlorornethane and ethanol gave l-4[ 6 -fluoro-1,2-benzisoxazol-3-v!) l-piendnyilropxyl2-mehvlen~4e~h- 2as off-white crystals: 2.42 g, rn p.

S1l3-114'C.

CalcC ulated for C, 4

HFO

3 70.22%C 6.3% .3% Found: 70.13rC 6.63 %H 6-77 9cN EXAMPLE 1-f2-r3-r4-(6-Fluoro-2 ,2-benizikrrazol-3-yi)-1-p iperid inyl lpropoxvl- A mixture of 6-fiuoro-3-(4-piperidinyl)-1 ,2-benzisoxazole hydrochloride (2.S7 g, 11.23 mmol), KCO, (2.5 1-[2-(3-bromopropoxy)- (3.74 g, 13-8 mmoi) in dimethylformamide (10 ml) and acetonitrile (50 ml) was heated at 95C for 6 hours. At the end of the reaction, the solvent as concentrated and ~the mixture was extracted into dichloromethane (300 ml). The organic solution ;vas washed with water and brine, dried over MgSO, then concentrated down to a crude oil. The purification was done by flash chromatography over a silica gel column (SiO, 60 0, el uted with I% CHOH:dichloromethane: 1. 1;P 3% CHOH:dichloi-rethane: 600 mnl). The material thus obtained was crystallized from a small volumne of eiher and hexane to provide 2-13 a of off-white 1-[2-[3-[4-(6-fluoro-1,2-benzi-soxazol-3-yl)-i -pipcridinyl]propoxy]-5.-me th\'lphenyl letha none, m.p. 92-93'C.

ANALYSIS:

Calculated for C, 4 HFIN,0 3 70.22%C 6.63 %H 6.82%N Found: 70.21%TC 6.6 9 74-I 6. 81% N EXAMPLE 26 N-r3-r3-r4-(6-Fluoro-1,2-benzisoxazol-3-x'l)-1 -pi peridinvllpropoxvl 4-methnayphenvlacetamide hemifumarate A mixt-ure of 6-fluoro-3-(4-piper-idiny)-1,2-ben-zisoxazole hydrochloride (3.94 z, 15.4 mmol), KCO, (3.67 g, 26.6 mrnol). iN13-(S-bromopropoxNv)-4methoxvphenvljacetamidc (5.56 g, 1S.6 nmcl in dimethylfor-mamide (75 ml) and acetonitrile (100 rrl) was heated at ICO 'C for 3 hours, At the end of the reaction, the solvent was concentrated and the mixtnure wvas extracted into dichioromethane (500 mod) -The organic solution was washed with water (500 ml) and brine (400 rrl), dried, then concenrated to a crude oil. The purification was effected by flash M chromatography over a silicIa gel column (SiO,, 65 g, eluted with I% CHOH:dichloromethane, 1.2 1; and 3% CHOH:dichlorrniethane, 500 ml The material thus obtained wveighed 2.33 g (34.37%) as an oil. This material was dissolved in ethanol and treated with a solution of fujmaric acid (661 mug) in :.:-ethanol. The N-f3-[3-[4-(6-fluoro-1,2 benz- E isoxazol-3-yl)-l -piperidinyllpropoxy-4-methoxyv-pheiyllaceta mid e hemnifurna rate *was o btained as of f-white cryistals weighing 2.17 g, m.p. 205-206'C.

ANALYSIS:

Calculated for C, 4

H,,FN

3 0,.0.5 CHO,: 62.50%C 6_03%H &4l %N Found: 62.30%C 6.03%Hf 8.32%N" EXANIPLE 27 6-Chloro -3-(l-piverazinvl)-I H-indazole To a stirred suspension of 4-(6-chloro-1-phenyLsulfonyl[-1H-indazol-3-yl)-lpiperazinecarbonitrile (192.5 g, 479 mmol) in dry tetrahvdrofuran (3.5 1) under N, was added, dropwise, LiAIH, (958 ml of a M solution of lithium aluminum hydride in tetra hydro furan; 958 mmol). After complete addition-, the reaction was heated to reflux and stirred under N, for 4 hours. The reaction w~as cooled to 4o in an ice-salt bath and the excess lithium alum-inumn hydride was destroyed by the careful, dropwise addition of HO. The mixtuic was stirred vigorously for an additional 30 minutes and was then filtered through a coarse sintered glass funnel.

The filter cake was washed well with tetrahydrofuran (3 x 500 ml) and then with methanol (2 x 500 ml) and the filtrate was concentrated to yield 151.0Ogof a beige gurm. Trituration with diethyl ether afforded a solid, which was collected and dried to give 75.0 g (66%6) of the desired indlazole. A 4.0 g sam ple was recr-vstallized from toluene to YielId 3.2 g, which was recr-ystallized again from toluene (utilizing decolonizing carbon) to Provid-e 2.1 of a beige, 6-chloro-3-(l-piperazinvll)-1 H-indazole solid. 135-137C.

ANALYSIS:---

Calculated frOr C,,H, 3 ClN,: 55.82%C 5-54%H 3.6% Found: 5 5.91%'-rC 5.5 %HIL 23.41% N EXAMIPLE 28 X. -f4-f3-[4-(6-Fluoro-TH-indazol-3-v)--piperidinvllpropox-<vl-3m ethoxph en XI he than one A stirred mixture of 6-fluoro-3-(4-piper-idiny-l)-1H- indazole (3.5 g, 16 rnmol), K.C0 3 (2.2 1 I4-(3-chloropropoxy)-3-methoxypthenyJetha none 3 8 g, 16 mmol) and acetonitrile (90 ml) was refluxed for 16 hours. Th-e reaction was poured into wvater and the resulting white solid, w~hich precipitated from solution, collected to afford 5.;g of the desired produICt. The comipound was recrystallized from dimethylfor-mamide (twvice) to afford 3.0 g of 1-44344 -(6-flu o-o- I H-ind.-zol-3'vyDI)--piperid inyll proDoxyl met hox vphenyllethanoneas a white solid, rn-p. =202-204'C

ANALYSIS.

Calculated for C, 4

HF

3

FNO

2 67.757%C .3H 9S% Fo und: 6 7-5 9 5CC 6 -61 9.9 6 %N EXAMPLE 29 1-[44[3-F4- (6-Flu joro-l,2-b enzisoxazo I-3-vl)-l-pipe rid invl pro poxvl-3methylphenyll-ethanone hemifumarate A stirred mixture of 6-fluoro-3)-(4f-piperidinyl)-1.2-benzisoxazole hyd rochlo ride (3.0 g; 11.7 mmol), KC,C0 (3.0 and l-[4-(3-bromoproooxy)-3-methylphenyl]-ethanone (3.19 gr) in dimethylfor-mamide ml) and acetonitrile (30 ml) was heated at 95'C for 4 hours. At the end of the reaction, the solvent was concentrated down tc. about 343 mnl, then partitioned between water (200 ml) and dichloromethane (300 nil). The dichioromnethane solution was separated and washed with %-,ater and brine, then dried over %IgSO,- The crude product from the evapcratE-d solution vwas purifie-d rlash chromatogr-aphy over a silica gel column (SiO,, 60 gel!uted with I. methanol in dichloromethane, 600 ml; 27. methanol in dichlomorethane, 600 ml). The material thus obtained was a light Yellow oil, weight: IN7 g (43'c) This oil was dissolved in ethanol and treated w~ith a~ solution of fumaric acid (355 mg) in ethanol. -The I -t44-3-[4-(6-fluoro-1 ,2-b-enzisoxazol-3-v- l)-1 -piperid invi I propoxvl-3-methylphenyljethanone hemifumarate crvstals for-med on cooling at 0 C. This was collected and weighed 1.5 g, m.p. 1SS-187'C.

S a a ANALYS1S: Calculated for C,,HI 7 CH,1 4 0: 66.635%C Found- 6 6.699c C 6.24%H 6.23 %H .5.98%1N 5.95%7,N

OP.

EXANTPLE 1-f4-f3-r4-(6-FRuoro-1,2-berL.isoxazol1-3-y Q -I-piperi din v I propoxylphenl ]eth an Cwie A mixture of 6-fluoro-3-(4-piper-idinvl)-L?2-benzisoxazole (3.27 g, 14.8 mmol), K,CO, (3 1W4-(3-bromnopropdxy)phenyl,.)ethanone (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 dichloromethane (300 ml) and washed with water and brine, then dried over MgSO,. The crudle product from the evaporated solution w~as purified by Rlash chromatography (SiO, 60 g; eluted with 1% methanol in dichioromethane, I liter). The purest fractions were com bined and gave 2.8 g, 48%, of l-[4-[S-[4-(6-fluoro-1,2-benziso-azol---Yl)- 1-piperidinyllprogoxv)phenyljethanone, rn.p. 111-1 12'C.

ANALYSIS:

Calculated for CH.,FN.O 3 69.63'7C 6.36% H 7.077%N Found. 69.SOcC 6 3 S cH 7.077a N EXAMPLE 31 1 -4-[3-r4-(6-Ch I ore-I H-intl azol-3-v D -I -piperazinv I Ivropoxvl-3meth oxyph en vi l-e th a none A rnixtui-e of 6-chioro-3-(l-piperazinyl)-1 H-indazole C3.4 g, 14 mmnol), K-CO, g, IS mmnol), hloropropoxy)-3-methoxyp nenyl let ha none (3.8 g.16 rnimoD, 'KI (200 ma), and acetonitrile (125 ml) was stirred at reflux under N, for hours. After stand ing at room temperature for 40 hours, the reaction was filtered and the filler cake \vas washed well with acetonitrile. The filtrate was concen- *:trated to an oily solid, which was partitioned between water and ethyl acetate.

The ethyl aceta te extract was washed with water, dried with MLVgSO, and concentrated to yield 6.9 g of a dark oil, which solidified after 2 days under vacuum. The product was purified by preparative HPLC (Waters Associates Prep LC/system 500 utilizing 2 silica gel columns and 6% mnethanol/metnvlene chloride as eluent) to yield 4.2 g The Material wvas recrystallized from ethanol to yield 3.4 g of glistening, beige, I-[4-[3-(4-(6-chloro-I H-inciazol-3-yl)- I -piperazinyllpronoxy-3-methcxy-phenyl-eharnone crystals, m.p. 132-134'C-

ANALYSIS-

Calculated for CH.

7 ClN~rO,: 62.37%cC 6i14%aH 12. 65% N Found: 62_49%C 6.16 %cH 12.60%cNr EX-AMPLE 32 1-F4-f4-[4-U.,2-Benzisothiazol-3-vl)--piperazinvllbutoxyl]- 3-methoxyphenyllethanone A mixture of 3-C-~ioerazinyl)-1,2-benzisothiazole (4.0 g, 18.2 mmol), I -[4-(4-bromobutox<y)-3-methoxvphen Yl I]etha none (6.0 g, 20.0 mmol), K,.CO, g, 21.8 mmol), KI (200 Mg7) and acetonitrile (123 ml) was stirred at reflux under N, hours. tMost of the solvent was removed i'1 uacuo and the resultant gummy residue was partitioned bet-.een ethyl acetate and water. The organic extract was washed with water, dried with %,gSO 4 and concenitrated to yield 7.Sg.

Purification by preparative2 HPLC (Waters Associates Prep LC/System 500, utilizinu,0 2 silica gel columns and 47c methanol-nethvlene chloride as eluent) afforded 6.5 g of a damnp, off-w-.hite solid. The product ecrystalliz-ed twice frIom toluene to provide 3.1 g(39%) of 1--f-44-(12-benzisothiazol-3-yl)-l-piperazinyllbutoxyl-3-methoxyphenyl ,letha nione a wvhite sohd, Imp. 114-i 16*C.

ANALY515: Calculated for C, 4

H-,NO

3 S: 65.58%C 6.6 5%crH 9.5 6 %N Found: 6 5.74%caC 6.66%H 9.54 N EXAMPLE 33 4- [3-4(6-Fl u oro-1,2-benz isoxazol-3-y Q-1-p i Peri d in v I I rop oxvl- 3-methox-v-benzonitrile A mixture of 6-fl uoro-3-( I-p ipe rid inyl)- 1,2-b enz isoxazo le (3-0 g.13.6 rnmol).

S. *KC0 3 (2.8 4-(3-bromopropoxy)-3-methoxybenzonitrile (4.0ga, 14.8 mmol) in acetonitrile (70 ml) was heated at reflux for 3 hours. At the end of the reactioTI, the solvent was removed on a rotary evaporator. The organic material w~as extracted into 0 ichlororn ethane (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 columnn (SiO,. 55 g; eluted with dichloromnethane, 600 ml; 1% methanol in dichloromethane, 600 ml). The material thus obtained was crystallized from a small amount of dichloromethane.

Recrys tallization from ethanol (25 ml) provided 3.8 g (68%i) of 4-[3-[4-(6-fluoro-l,2-benzisoxazol-3-yl)-1-pipeu-idinivll-prupoxy -3-methioxybenzo- No nitffle as white crystals, mn.p. l07-IOS*C.

ANALYSIS:-

Calculated for CIH- 2 IF1N 3

O

3 67.47%C 3. 91 %H 10-26%N Found: 67.32aC 5. 9 05CH 10.24%-,N EXAMP4P LE 34 1-[4-[444-(6-Fl uo ro-1 H-indaza 1-3-vl)-l-p iperid inv Ilb Utowl-3 m ethoxvh env H-ethanon e A stifred mixtu-re of 6-fluoro-3-(4-piperidinyl)-]H- indazole (1.9 g, 8.6 rornol), Il-,[4-(4-brornobutoxy)-3-methoxypheny 11et ha none (2.6 g, 8.6 mmol), KZ0 3 (1.2 and acetonitrile (75 ml) was refluxed for 6 hours. The reaction was poued.

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%17) of 1 '4-[4-[4-(6-fluoro-iH-indazol-3-yl -piperidinylibutoxyl- 3-methoxy-phenyljethanone as gflistening white flakes, m.Q. =158-160'C.

ANALYSTS:

Calculated for C,,HFNO,.- 68.32%C 6.88%H 9.56%N Found: 68.00%C 6.93% H 9.51 %N -EXAMPLE 1-4(3 -(-enzovl-6-fluoro-1 H-indazo l-3-yl)-1-piperazin vI propoxvj- 3-methoxv-phenvllethanone sesquifumnarate A mixture of I -[4-[3-[4-(6-fluoro-1 H-inda zol-3-yl)-1 -piperazinyl ipropoxyl- 3-methoxyphenylletha none (3.2 g, 7.5 mmol) and benzoyl chloride (15 ml) was heated on a steam bath for 15 minutes. The reaction was allowed to cool and ether was added. The insoluble. off-white compound was harvested to yield 4.4 g of the product as a hydrochloride salt. The salt was converted to free base with aqueous ammonium hydroxide, and after extractive w.orkup with methylene chloride, 3.0 g of the free base wa's isolated as a while solid. The free base-was dissolved in ethyl acetate and fumnaric acid (0.72 g, 1.1 eq.) was added and the mixture heated on the steam bath for 15 min. After standing, at ambient temperature for 4 days, 2.0 g of an off-white fuma rate salt was collected, while concentration oF the filtrate afforded an additional 1.0 gof-the salt.

Recrystallization, first -from ethyl acetate, and then fromn ethanol Yield ed1.4 g of 11-4-[3-[f4-(1-bernzovl-6-fluoro-1 H -indazol-3-vl).l -pi pera zinyJ propoxy)-3-methoxypheny'llethanone sesquifuma rate, m. p. =138-1

ANALYSIS:

Calculated for C,.,H3,FNO,.1.3 C 4 HjO 4 61.355%C 5.29%H 7.93%N Found: 6l.68%/cC 3.31%H 8125%N EXAMPLE 36 1-[4-[4-f4-(6-Chi oro-lH-indazol-3-v)-TI-piperazinylibu toxyl-3- .~methoxyphenvll-elhanone mixture of 6-chloro-(3-GI-pioerazinyI)I-lH-indazole K 4 O g, 17 n-ol), K,C0 3 (2-8 g, 20 mmol), 1-t4-(4-bromobutoxy)-3-methoxyphenylletha none (5.

7 g, 19 n-tmol), KI (100 mg) and ac~tonitrile (125.ml) was stirred at reflux under nitrogen for 18 hours. The cooled rea'ction-was poured into water and the resultant *.off-white solid was collected, by filtration.-and dried to yield 7.0 g. The compound was recrystallized twice from toluene to yield 6 2 g. Further purification by preparative HPLC (Waters Ass~oci ates Prep LC/System 500, utilizing rnethanol/rnethylene chlor-ide as eluent and 2 silica gel columns) afforded 5.3 g of -listening, beige crystas whch were recrvstallized four times from toluene to yield.3.1 g of a white solid.'Analytically pure material Was obtained by a CA_ subsequent recrystallization from dimethylformamide to afford 2.5 g of 1 -L4--(4-4(6-chloro-1 H-indazol-3-Yl)-1 -piperazinyllbutoxy]-3- CO methoxyphenyll etha none as an-ff-white powder, 189-191 'C.

ANALYSIS:

Calculated for C 24 H,,C1N,0 3 63.08%C 6.40%H 12.26%N Found: 62-86%C 6.57%H 12.49%N EXAMPLE 37 1-f4-f3-f44(1,2-Bernzisoth iazol-3-vl)-1 -p iperazi nvl Ipzopoxyl-3methoxyph enyll-etha none hernifumarate A mixture of 3-(1-piperazinyl)-1,2-benzisothiazole (4.0 g, 18.2 mmal), KC2O, g, 21.8 mmol), KI (200 mg), 1-[4-(3-chloropropoxv)-3-miethoxvphenylletha none (5.3 g, 20.0 mmol), and acetonitrile (123 ml) was stirredi at reflux under N, for 26 hoa-rs. The cooled reaction was filtered and the filter cake was washed well with acetonitrile. The filtrate was concentrated to afford 10.7 g of an oily residue, which was extracted with ethyl acetate. The ethyl acetate extract was washed with water, dried with MgSO, and concentrated to yield 8.0 g of a dark oil. The oil was puified by preparative HPLC (WVaters Associates Prep UC/Systemn 500, utiliing 2 silica gel columns and 3% methanol/rnethylene chloride as eluent). Concentration of appropriate fractions provided .4.6 g of a red oil, which solidified upon standing.

.A3.4 g sample was taken up in ethyl acetate (100 ml) and fumaric acid (0.95 g) :.was added. The mixture was stir-red at a mild reflux for I hour and then at ambient for 1.5 hours. The resultant beige solid was collected by filtration and dried to Yield 4.0 g. The product was recrystallized twvice from ethanol to provide 2.7 g (27V%) of 1 [3-14-CI.2-benzi-sothiazol-3-yl)-i -p ipera zi nyl ]pro poxy]- 3-e~hoxyphenyljethanone hemniftimarate as a beige powvder, mn-p. 186-188~

ANALYSIS:

Calculated for CH,, 3 S0.5CHO 4 62.09%rcC 6.06%H 8-69%N Found: 62.017%C 6.06% 1-1 8.68%N EXAM4PLE 38 1-[3,5-D ibromo-4-f3-[4-(6-fluoro-1,2-benzisoxazol-3-y11piperidinvlpropoxyl-phenvllethanone A stir-red mixture of 6-fluoro-3-(4-piperidinyl)-l,2- benzisoxazole (2.0 g d~ 9.0 mmol), K.C0 1 (1.3 and 1-14-(3-bro mopropoxy)-3,5-dibromophenyl] etha none (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 wyas 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 (Si0 2 47 eluted with dichloromethane, 300 ml; 1%7 methanol in dichloromethane, 600 ml). The material thus purified as a colorless oil, solidified on standing. Recrystal1iza-ion irom, ethanol gave S6 1-[3,5-dibromo-4-[3-14-(6-fluoro-1,2- benzisoxazol-3-vl)-1-pipeidinyllpropoxylphenyljethanone as white crystals (2.93 g, m.p. 102-103'C.

ANALYSIS:

Calculated for CHBrFN,O: 49.84%C 4.S%H 5.05%N Found: 49.91%C 4.11%H 4.93%N EXAMPLE 39 .1-f4-f2-[4-(1,2-Benzisothiazol-3-yll-1-piperaznvilethoxvl-3methoxvphenvil-ethanne A mixture of 3-(1-piperazinyl)-1,2-benzisothiazole (4.0 g, 18.2 mmol), [4-(2-chloroethoxy)-3-methoxyphenyll-ethanone (4.3 g, 20.0 mmol), KCO, (3.0 g, 21.8 mmol), acetonitrile (125 mi) and a catalytic amount of KI was heated to reflux and stirred under nitrogen for 24 hours. At this point, an additional amount of

KCO

3 (1.0 g, 7.2 mmol) and alkylating agent (0.4 g, 1.7 mmol) was added to the reaction mixture and heating at reflux was resumed for 24 hours. The reaction was cooled to ambient temperature and filtered. The filter cake was washed with acetonitrile and the filtrate was concentrated to afford a dark oil. The oil was extracted with methylene chloride, and the organic extract was washed with water, dried with MgSO, and concentrated to yield 9.2 g of an oil.,- Purification by preparative HPLC (Waters Associates Prep LC/System 500 utilizing 2 silica gel columns and 3% methanol/methylene chloride as eluent) provided 3.8 g of a soft, beige gum, which readily solidified. The compound was recrystallized twice from ethanol to give 2.1 g of 1-[4-(2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyliethoxy]-3-methoxyphenyl]ethanone as a beige solid, m.p. 98-100*C.

ANALYSIS:

Calculated for C,HN 3 ,OQS: 64.21%C 6.12%H 10.21%N Found: 64.05%C 6.09%H 10.12%N EXAM~PLE 6-Fluoro-3-fl-(3-yhencxvvropvl)-4-piperidinvll-1,2-benzisoxazole A mixture of 6-fluoro-3-(4-piperidinyl)-,2-benz5oxazole (4.0 18.2 rnmol), KC0 3 (3.0 g, 21.8 mmol), KI (100 mg), 3-chloropropoxyben-zene (3.4 g, 20.0 mmol), and Pcetonitrile was stirred at reflux under nitrogen for 30 hours. The reaction was poured into water and the aqueous mixture was exL-acted with ethyl acetate.

**The ethyl acetate extract was washed with brie did itMgSO, n-ocn trated to afford 6.2 g of a damp, beige solid. The compound was recrystallized twice from ethanol to yield of 6 -fluoro-3-[l-(3-phenoxvpropyl)- *4-piperidinyl1-1,2-ben-ziso ,zole as a light beige solid, m.p. =78-801C.

ANALYSIS:

Calculated for 71.17%C 6.5 4 %SH 7.9 0% N Found: 7 1. 0 0 6.52%oH .8%Nr EXAMPLE 41 1A44[2-14-(6-Chio-oH-indazol-3-V)-l-piperazinvllethoxyl-3 methoxyphenvll-ethanone f~bA n-ixture of 6-chloro-f3-(1-piperaziny])1-1H-indazole (2.1 8.9 mmol), KCO, (1.5 g, 10.7 rnmol), KI (100 mg), 1-[4-(2-chloroethoxy)l-3-methoxy- JIL J&phenyllethanone (2.2 g, 9.8 minI) and ac etonitrile (70 ml) Was stirr-ed at reflux for 48 hours under The cooled reaction was poured into water and the aqueous mixture was extracted with ethyl acetate. The organic extract was washed with water, dried with MgSQ, and concentrated to yield 6.0. of a light yellow oil. The oil was purified by preparative HPLC MWaters Associates prep LC/System 500, employing 2 silica gel columns and 5.5%a methanol/methylene chloride as eluent).

Concentration of later fractions provided 1.6 g of an off-white solid. This was combined with an additional sample (3.4 g total) ,nd Iwo consecutive recrvsta lLiza tions from ethanol yielded 2.1 g of H-indazol3-y)-1 -piperazinvi Jethoxvl-3-methoxyphenryliethanone as an off-white solid, rn.p. =154-,156'C.

ANALYSIS:

Calculated for C-,F{ClN,,O: 61.61 %C Foun d: 61.665'C 5.88% H 5-8757cH 13.06%N 13.06%N a 06 s* 03 09 a EXAMPLE 42 I-f4-f3-[4-(6-Fl u oro-1,2-b ez is oxazo -3-vD -1-p i perid in nyl IProp ox-vl- 3-m ethoxv-P henvl -2,2,2-tri fluo roe th anone A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (1.5 g, 6.7 mmol), 1-r4-(3-chloropropoxy)-3-methoxyphenyl]-2.?,2-trifluoroetha none (2.0 g, 6.7 rnmol), K,C0 3 (0-88 KI (0.1 g) and acetonitrile (50 nil) was stirred and refluxed for .16 hours. Aft er cooling, the reaction was poured into water and the aqueous mrixture extracted with ethyl-acetate. T he extract was washed dried (MgSO,),,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 Water, preparative LC (silica columns, eluting wvith 3% rnetha noil-dichlorometha ne). Concentration of the appropriat~e fractions gave 1.8 g of 1 -[4-43-[4-(6-fluoro-1,2-benzisoxazol -3-yl)- 1 piper idinyll-pro poxy]-3-methoxyphenyl -222-trifluo ro-etha none solid, =94-96'C.

A NA LYS IS: Calculated for FN,0 4 60.00%C 5.03%H- 5.83 %tN Found.: -60.01 %C 50 6 %H 5.68%N EXAMPLIE 43 [4-(6-Fu oro-12-benzi soxazol -3-vI 1-1 -p iperid in vi Iproloxl- 3-m ethv I-m ercaptophe n yl I eth anon e A stirred mixture of 6-flujoro-3-(4-piocrid invl)-i.2-benzi-soxa zole (0.88 g, mmol). K,C0 3 (l.S g)and 1-[4-(3-bromopro~oxvY)-3-Tmethvlmercaptophenyllethanone (2-3 g, 7.6 mmol) in acetonitrile (100 ml) ,vas heated at reflux for 4 hours. At the end of the reaction, the solvent was concentr ated, then diluted with dlichloromethane (250 ml). The insolubles were filtered off. The dichioromethane 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 colorless oil whch solidified to an off-white see, solid (2.4 Recrystallization from ethanol (100 nil) yielded 1 :r4-[34[4-(6-fluoro-1,2-benzoisoxazol-3-yll-i -piperid inyllpropoxyj-3-methylrnercapt ophenyll etha none as off-white ne edle crystals, 2.15 g, m.p. =130-152C.

5" ANALYSIS: a. ~Calculated for FN,OIS: 65.14%C 6.15%H 6.33%N Found: 6.9C 6.10%H 6.25 %cN EXAMPLIE 44'.

1-r4-(3-Bromopropoxy)-3-bromobhenyllethanone A stirred mixture of 3-bromo-4-hydroxyacetophenone (4.3 g, 21.2 mnmol), KCO, (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 issolved in dichloromethane (400 ml) anid fiiered. The dichloromethane solution was concentrated to an oil. The oil was added to -SN isopropyl ether and stir-red to cause crystallization (4.1 g; 58%. The solid was recrystallized from isopropyl ether to give 3-5 g of ]-[4-(3-bromopropoxy)- 3-bromophenylletha none as glistening crystals, m.p- 83-84 0

C.

ANALYSIS:

Calculated for C, 1 39.31 %C 3.6 0 'oH Found: 39.80%C 3.55%H EXAMPLE 1A[4-(3-Bromopropoxv)-3.5-dibromophenvllethanone be A stirred mnixture of 3,5-dibromo-4-hydroxvacetophe-ncne (3 .0 g, 10.1 rmcl), K,CO, (2.8 g, 20.3 mmol), 1,3-dibromo- propane 4 19.8 rniol) in acetonitrile (100 ml) was heated at reflux fo- 5 hours. The solvent was removed.

The crude product wvas extracted into dichloromethane (150 -rd) and the insolulV inorganics were filtered off. The solution was concentrated to dryness again Purification was carried'oP lt by flash chromatography on silica gel (45 g, eluted with 1:1 hexane:dichloromethane). The material thus obtained (~was recrystaffized twice from isopropyl ether to give analytically pure 1 -(4-(3-bro mopropoxy)-3,5-d ibromophenyl] etharion-e, m. p. 87-88'C.

AiN!ALI-YSIS Ca) .ed for 31-84%/C 2.67%,'H Found: 31.97%C 2.63%H E'XAMPLE 46 1-r4-f4-[4-(1,2-Benzisothiazol--yl)4-piperidinvllbu toNXv-3-methoxvvhienyllethanone -A stirred m.-ixture of 3-(4-piperidinyl)-1,2-bernzisothiazole 2 .6 g, 11.9 mmnol), 1-[4-(4-bromobutoxy)-3-rnethoxyphenyllethanone (3.9 g, 13.1 n-u-nl), K.C0 3 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 temperaiture 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 NMgSO, and concentrated to afford 6.5 g of a dark oil. The oil was purified by preparative HPLC (Waters Associates prep LC/System 500, utilizing 2 silica gel columns and 37c m-ethanol/methylene chloride) to give 4.5 g ofl a beige solid. A 3.1 g mmol) sample was taken up in absolute ethanol (80 ml) and oxalic acid (0.67 a, 7.4 rnmol) was added. The solution was reFluxed mildly on a steam bath for 45 m inutes and was then stirrE-d at ambient temperature for I 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. Tnhe salt was recrystallized. from ethanol to yield 2.8 g. The compound was converted back to the free base with NaOH to give 2.4 which was immediately recrystallized from ethanol to provide 1.5 g of ,2-benzlsothiazol-3-y)-1 -piper-idinyllbu toxyl-3-methoxyphenyl Ie tha.none as a beige powder, m.p. =78-80C.

AN~ALYSIS:

Calculated for C2,HN,O 3 S: 68.46%7C 6.91 %H .6.39%N Found- 6S834%C 6.85%Hl- 6.33%N 0 0*e *0a~ EXAMPLE 47 6-Fluo ro-1 .2-befiz isoxazo 1-3-v 1)-l-p iperid in vllpropoxv 1- 3-metli oxyph etiyll-ph en lm ethan one A mixture of 6-fluoro-3-(4 -piperidinyl)-1,2-benzisoxazole (2.2 g, 10 mmol), KC0 3 (2.3 g) and 1- [4 -(3-bromopropoxy)-3-methoxyphenylIl phenylmetha none (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 mixtujre 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 aver a silica gel column (SiO 2 50 g: eluted with dichloromethane, 600 ml; 1% methanol:dichlor-omethane, 600 nml; 2% methanol: 98%7- dichloromethane, 600 ml).

The fractions containing the pure product were combined and concentrated to give 4.24 g of an off-white solid. Recryst-allization f-rom ethanol (75 ml]) gave 3.9 g of I -[4-13-f 4-(6-fluoro-l,2-berziosoxazol-3-yl)-1 -p iperidinyl]-propoxyj-3methoxvphenylj phenylmetha none as off-white crystals, r p. 128-130'C.

AN ALYS IS: Calculated for C,l-N,O,: -Found: 7i.30i'aC 71.317oC 5.99%H 5.73 7a N 5.75%N EXAMPLE 48 l-f4-3-f4-(6-Fluoro-12-benziosxazol-3-v)--piperidinvflp]ropoxcv-3bromophenvilethanone A n-ixture of 6-fluoro-3-(4i-piperidinyl)-1,2-benzisoxazole (2.1 g& 9.5 mmcl), IKCO, (2.0 g) 1-[3-bromo-4-3-btomopropoxy)ph enyfletha none (3.1 g, 9.2 mmol) in acetonitrile (100 ml) was heated at reflux for 3 hours. At the end of reaction, thee solvent was concentrated and the mixture was extracted into dichioromethane (200 ml). The insolubles were filtered off. The dichioromethane was concentrated again. The crude residlue was purified by flash chromatography over a silica gel column (Si0 2 49 g; eluted with dichloromethane, 500 ml; 17% methanoo:dichloromethane, 600 ml; 3% methanol: 97% dichloromethane, 600 ml). The material thus obtained (3-26 g. 7-27) 1was recrystallized from ethanol (40 nil) to give fluoro-1,2-benzisoxa zol-3-y)-I -piperid inyl ]-pro Doxyl -3-bromophenyliethanone as light yellow crystals (3.0 m.p. =126-128'C.

ANALYSIS:

Calculated for C, H, B rFN,0 3 58.12.%'C 5.09%-H 5.89%N Found: 57.E4'.C 5.3 5 caH 555%tN EXAMPLE 49 (-Et hoxve th y 1)-2-m e thoxyp hen oxy112ro pv y1-4piperidinvll--6-fluoro-l.2-benzisoxaLzole hydrochloride To a mixture of 4-[3-j4-(6-fluoro-1,2-ben7zisoxazol-3-yl -piperidinyllpropoxyJ-3-methoxy-a-methlbenzenemethanoI (3.8 g, 89 mmol) in pyridine ml) was added acetic anhydride (G ml). The mixture was warmed briefly on the steam bath to effect solution, and then the reaction wvas allowed to stand at ambient ternoerature for 16 hours. Most of the pyridine w~as eveaorated under reduced pressure and the resultant oil was diluted with water.Thaqeu solution was made basic with dilute NaOH, and subsequently extracted with ethyl acetate. The organic extract was washed (water), dried (.%MgSO and the solvent concentrated to give 3.7 g of the 0-acetyl derivative as a colorless oil. The compound was dissolved in diethyl ether and ethereal H-CI was added to precipitate a gumn-like hydrochloride salt, which upon tree tnent with refluxing ethyl acetate afforded 3.4 gof a crystalline salt, mp. 143-145C. 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 (487G) of 3-[P-[34[4-0 -et hoxyethyl)-2-methoxyphenoxy]I pro py I I -p ipe rid invl11-6-fluo ro-1,2benzisoxazole hydrochloride, =J39-14VC.

ANALYSIS

Calculated for C,,HFN,O,.HCI: 63.34%7C 6 95%7cH 5-68%N Found: 63.06%C 6.807 0 H 5-63%N EXAMPLE 3-fl-r3-r4-(-Acetowethyl)-2-methoxvphenoxvlproov1-4- 1piperidinvl-6-fluor-1Z-benzisoxazole fumarate A m-ixture of 4-[3-[4-C6-fluoro-1,2-benzisoxa zol-3-yl)-1 -piperidinylj- 3-methoxy-a-methylbenzenemethanoI (4.8 g, IlI 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 wa ter. The aqueous solution was made basic with saturated KzC0 3 solution, and the mixture was extracted with diethyl ether. The extract was washed (w.ater), dried (IMgCSO) and concentrated to afford 5.2 g of a thick, colorless oil. The oil (4.8 g) was dissolved in anhvdrous diethyl ether and fumaric acid (1.2 g, 0.01 moll was added. The mnixture was stir-red at ambient temperature for 4 hours, and then was permitted to stand at ambient temperature for 16 hours. The resultant white, 3-f -a ce .oxvethvl)-2-me ho\xvphen oxv .orocv ,i- 4-pipeidinyl1]-6-fqluoro-1,2-benZi3-OO' hlnl Marte W23 d afford d, 3.0 c, of material. The filtrate was treated with an additional amourat ol r ina.-c acid (0a and 0.9 g more of -1f--(actxeh-2mho-pnoyrplJ 4-piperidinyll-6-fluoro-1,2--b-2nzisoxazole fim-arate was harvested. The two batches were combinedl and ret-Ty-stallizecl from acetoni-ile (twice) to yield 2.3 -g of the acetate, m.p. 151,1-152'C.

A NALYSIS: Calculated for C,,H 3 6 1.435-C 6.X11%H 4.78%7;N Eou nd: 61.06cC 5.-S7% oH 4.73%M **EX.AMPLE 51 01-(4 -f3-f4-(-Fl uoro-12-benisoxazol-3-Y D--p ipe rid in yl I p ropnxvl- Z 3-methoxx'-phenyllpentanone A mixture of 6-fluor o-3-(4-piperidinvlt)-1,2-benzisoxazole (2.2 g, 10 mm ol), *-K,C0 3 (3 -brornopropoxy)-3-miethoxvp~henyllpenitaione (3.7 g, 11.3 m mol) in acetonitrile (10 ml) w.as heated at ro-flux for -4 hours. At the end of the reaction, the mixture wvas cooled and filtered. The filtrate was concentrated to an oil. Purification was performed by flash chromatography over a silica gel column 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, 91 Recrystallization from ethanol (10 ml) gave a powdery solid of 1 u o ro- 1,2-benz Ls oxa zo1-3- y I -p ip erid inl YIIP ro p-xy 1-3 -ne th oxy phe ny I pentanone (3.22 m.p. =79-80'C.

ANALYSIS:

Calculated for C,-HFNOO: 6 9.21 SaC 7-10%H 5.98%N Found: 69.00%cC 6.94%H 6.39WN EXAMPLE 52 N-mnethvl-benzenamnine herniifurnarate A rr&xture of 6-f-iuoro-3-(4-piperdiinyD)-1,2-benzi-soxazole (2-5 g, 11-4 rnimol), KC0 3 (1.8 g, 13.0 m mol), 4t-(3-chloropropoxy)-2-methyla rn-inobenz-ene (211 g, 12.0 minmol) and acetonitri-le (100 ml) was stirred at reflUx for IS hours. The reaction was cooled to ambient temperature and was poured into w atpr. The aqueous mixture wvas extracted with ethyl acetate and the ethyl acetate extract was washed with water, dried with M1,gSO 4 and concentrated to yield 4.1 c, of a brown oil The oil1 was purified by preparative HPLC (Waters Associates prep LC/System 500, utilizing 2 silica gel columns and eluting with 47o methanol-methylene chloride).

Concentration of appropriate fractions yielded 2,15 a of a beige oil. The product was taken up in ethyl acetate (50 ml) and fumaric- acid (0.78 g) w-as added. The mixture was stirred at mild reflux for 45 mnutes and then at ambient temperature for 1.5 hours- The product was isolated by vacuum filtrat-ion 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-pioe-id iI prop~oxyi-N-methylbenz-ena rrun e hemnifumarate as beige crvstals, m.D. 180-182'C.

ANALYSIS:

Calculated for C. ,,,FiNO,0.5CHO 4 65.28%C/ 6.40%H 9.52%N Found: 65.03c%7C 6.35%H 9.45%N EXAM'vPLE 53 1-f4-r3-r4-(6-Fluoro-l.2-benzisoxazol-3-vl)-l-viperidinyllpropox ,l- 3-methoxy-phenyllprop~anone A mixture of 6-tluoro-3-(4-piperildinvi1)-l,2-heni7soXaZole (2.8 g, 15.2 mnmol), K.CO, (3 g0. l-[4-(3-hromop~ropoxy)-3-methoxy-pheny'llpropanone (4.6 g, 18.2 mmol) in acetonitrile (100 ml) heated at reflux fir 2' hou-s. At the end of the reaction, the mixture wvas filtered and the solvent was concentrated and the residue wvas extracted into dichioromethane (300) rllY_ Th d rethane was filtered and concentrated again. TFhe crude na-erial (6,4 ;v as bYne. Evtash chromatography over a silica gel column (SiO 2 50 g; elute-ci with dicliloromethane, 700 nil; 1% methanol in dichioromethane, 1.4 The mteria t'hus pur-fed (weight: 2.87 g, 51%o) was reci-sta~lized from ethanol (25 zml) to give 2.13 g of I -[4t-[3-[4-(6-fluoro-I..2-benz7isoxazol-3'-yl)-1 -piperid nyl I pro uox ]-3-rmet hox yvhen yl] propanone as beige colored crystals, m.p. =118-1 19'C.

ANALYSIS:

Calculated for CH,,FN,0,: 68.16%C 6.6 4 ,cH 6.36%N Found: 6S.32%C. 6.63%H 6.2 9%c-oN EXAMPLE 54 4-I3-[4-(6-Fluoro-1,2-benzisoxazol-3-v'1)-l-p iperid in vl]PropoxCVl-3methoxvbenizam ide A mixture of 6-fiuoro-3-(4-piperidinyfl-1.2-benzisoxazole (2.2 g. 10.0 mmol).

K,C0 3 (2.0 g) and 4-(3-bromo pro poxy)-3-me th oxybenza mid e (2.32 g.8.0 mmol) in acetonitrile (80 ml) was heated at reflux for 5 hours. -At the end of the reaction the solvent was evaporated. The residue was extracted into dichlorornethane. The inorganic insolubles were filtered off. The dichloromethane was concent-rated again. The crude residue was purified by flash chromatography' over a silica gel column (35g SiO,; eluted with 1% methanol in dichloromethane, 1 1; 2% methanol in dichtoromethane, 1 l).-The material thus obtained weighed 2.93 g as white crystal Recrystallization from hot ethanol (60 ml) gave 2.2 g of uoro-1,2-benzisoxazol-3-yl)-l-piper-idinyll propoxy]I.3-me thoxvbenzamid e as white crystals, m.p. =163-1 6-4 C.

Calculated for CH, 6

FN

3 6 4.6 2 %C -6.13%H 9.83%N Found: 64.20%C 6_065%H 4971%N 97 EXAMNfP LE 5 1444[3-446-17l1unro-1 .2-benzisoxazo 1-3-v D -i-p iperid in v I Ipropoxvl- -kLIttIV ~t V L ICi Ld 1tjIlt: *4* 5 0 A mixture of 6-fluoro-3-(4t-piperidilnyl)-1,2-benzLsoxazole (2.3 g, 10.3 mrnol), KC0 2 (1.4 g& 10.3 mmol), I -[4-(3-chlorop ropoxy)-3-(methyiarnino)phenyljetha none g, 10.3 mmcit), KI (0.10 and acetonitrile (100 ml) 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, and was concentrated to yield 4.8 g of a damp, browin solid. T he compound was isolated by preparative HPLC MVaters Associates prep LC/System 500, utilizing 2 silica gel columns and 4% me thanol-methylene chloride as eluent). Concentration of appropriate fractions afforded 2.4 g. Recrystalliza Lion rom ethanol gave 2.1 g of I -f4-f3-f4-(6-fluoro-i ,2-ben~zisoxazol-3-yl)-] -piperidiinyl] propoxyi'-3'-(methylamino)ph enyljethanone as a beige solid, rn.p. 15-53C

ANALYSIS:

Calculated for C, 4

,FN

3 O1: 67.75%7C 6.63%H 9.88%iN Found: 67.83%C 6 76%H 9 9fl%/N EXAMPLE 56 I-r4-[3-[4-(6-Fluoro-l .2-benzisoxazo l-3-vl)-l-p iperid inyl ]propoxvl,- 3-ethoxvphenyl l-e thin one A suspension of NaH (0.28 a of--a 5017 oil dispersion, 5.9 rnmol) in dimethylforrnamide (20 ml) was cooled to 4oC in an ice bath. To this was added, diropwise. 1 -t4-r3-[4-(6-fluoro-1 ,2-benziLSox~zol-3-yl)- -piperidinylipropoxy]- 3-hyd roxyphenyllIet ha none (2.3 g, 0.0056 mol) dissolved in dlimethylformamidle ml). After total additiol"t the mixture w.as stirred under nitrogen for 1 hour.

keeping the tem'perature below 10*C. A solution of bromoethane (0.3 g, 11.8 mnio!) dissolved in dimne? hyforrnamid e (15 ml) was thenadded, dropwise, to the reaction -mixt-ure. Stirring under nitrogen was continued for43 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 MgSO,, and was concentrated to yield 3.9 g of a damp, beige solid. The solid was tritura ted with diethyl ether and filtered to yield 1.5 g. This was combined with an additional sample (3.5g total), and recrystallization from ethanol provided 3.0 g of glistening,b beige crystals of 1 -[4--[3-14-(6-fluoro-1 ,2-benzisoxa zol-3-yl)-l -pipe rid inyl1] -propoxyl 3-ethoxyphenylletha non~e, r.p. =112-114'C.

ANALYSIS:

.Calcualated for C,.H 2

FNO-

4 68.16%C 6.64%H 6.36% N Found- 68.10%C 7.03%H 6.35%N .*.EXAMPLE 57 I-[4-(3-Bromoprc1oxoy)-3-(methvlmercapto)phenyllethanone A mixture-oF 1 -[4-hydrox-y-3-(methylmercapto)phenylj-ethancne (5.4 g; 30 mmol), K.C0 3 1,3-dibromopropane (8 g, 39.mmol) in acetonitrile (150-m) was heated at reflux for 3 hours and stirred at room temperature overnight. -Acetonitrile was removed at reduced pressure and the residue was S.extracted into dichloromethane (250 mld). Insolubles were filtered off. The 'NI dichioromethane solution was concentrated. The crude product was purified on a silica gel column (SiO 2 100 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-(methyl merca pto)phenyl e tha noneas white needles, 2.0 g; m.p. =120-1IW)C.

ANALYSIS:

Calculated for C,,H~sBrO,5: 47-53%C 4.99%H Found: 47.74%C 4.91 %H EXAMIPLE 58 4-(3-Brornopropox-v-3-methoxvbenzoniblile A mixture of 4-hydroxy-3-methoxybenzonitrile (7.5 g, 50 mmnoD, KZCO, (12.5 and L31-dibrornopropane (15 g, 75 mmiol) in acetonitrile (100 mld) 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 dichlorornethane solution was concentrated and the material was purified on a flash chromatog-raphy column (SiO 2 105 g; eluted with 2:3 dichloromethane:hexane, and then with dichioromethane). The desired product thus purified weighed 7.74 g RecrystaUlzation twice from ethanol gave analytically pure 4-(3-bromopropoxy)-3-methoxybenzonitrl e, m.p. =99-101 'C.

ANALYSIS:

Calculated for C,,H,BrNO 2 48.91 %C 4.48%H 5.19%N .*:Found: 49.49%C 4.47%H 5.21 %N EXAMPLE 59 1-4-(3-Bromopropoxv)-3-m ethylphenvile than one A mixture of 4-hydroxy-3-methylacetophenone (14.5 g, 96 mmol), K,CO, (17.5ga, 144 mmol), and 1,3-ibromopropane (30 g, 144 rnmol) in acetonitrle (400 n-d) was heated at reflux for 6 hours. At the end of the reaction, the-solvent was removed on a rotary evaporator, and the crude solid was extracted into ct dichloromethane (750 ml). The insoluble inorganics were filtered off. The dichioromethane solution was concentrated again to a crude oil (34.5 g).

Purification was effected by flash chromatography over a silica gel column (SiO 2 150 g; eluted with 7.3 hexane:dichloromethane, 2 1; and dichlorornethane 2 Thematerial thus purified weighed 14.6 g and was recrystallized from ethanol Recrystallization again from ethanol gave analytically pure 1-[4-(3-bromopropoxy)-3-methylphenyvi]-ethanone mnp- 59-61'C- A NALY Calculated for Cj-d-1 1 BrQi 53.15%C 5.5S7%H Found: 53.35%C 5.52%H EXAMPLE 1-f4(3--Bromopropoxy)-3-rn ethoxyphenyl] ph e nvlme th an one A mixture of I -(4-hydroxy-3I-methoxyphenyl)pheryl-mnetha none (14 g, 61.4 mmol), K 2 ,C0 3 (13 g, 92.1 ruroiX and 1,3-cibromopropane (28 g, 86 mmol) in ~*acetonitrile (400 ird) 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 ev'aporator. The residue wa's purified on a flash chromatographic colun (5102, 140-g, eluted with 4:1 hexane:dichloromethane, 1.2 1) to give a partially solidified material: 15.44 g Recrystallization twice from ethanol gaye 2-84 g of 1-[4i(3bromopropoxy)- 3-methoxypheriyll phenylmetha none as white crystals. imp 88-89 0

C.

ANALYSIS:

Calculated for C,.

7 H,,BrO,: 58.47%C 4.91 %H Found: 59.039,C 4.87%7aH EXAMPLE 61 N-F2-[3-f4-(6-fluoro-,2-benzisoxazol-3-v I)- 1-piperidinyllpropoxylphenyl Iace tam ide N4(2-(3-phenylsuloniyloxypropoxy)phenyllacetam ide To a solution of N-[2-(3-h.-droxypropoxy) phen y 11-aceta mid e (Example 113) g.36 mmnmol) in pyridine (90 rM, cooled to O'C, was added p-toluenesulfonyl chloride (13.6 g, 56 mmol). After the tosyl chloride went into solution, the reaction was then allowed to stand at 5'C for 16 hours. The reaction was poured onto ice, C S and a brown oil settled. The aqueous 5upernatant wa5 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 (MgSO 4 and concentrated to afford a thick, brown oil, 5.3 g.

N-12-[3-14-(6-ftuoro-l ,2-benzisoxa-zoi-3-yl)- 1-piper-idinyllpropoxyJphenyfjacetam~e A midxture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (3.4 16 rnnol), N-[2-(3-phenylsulfonyloxypropoxy)phenyllacetamide (5.3 g, 16 mmol), 1( 2 C0 3 (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 (MgSO 1 and the solvent was concentrated to afford 6.0 g of a thick, brown oil. The oil was chrornatographed on a Waters Prep 500 LC on silica gel. Concer'fration of the appropriate fractions afforded 3.0 g of a beige solid. This was rec, -stallized from ethyl acetate to yield (with concentration of the mother liquors) 2.2 g of N-(2-[3-[4-(6-fluoro-1 ,2-benzisoxa zol-3-yl -l -piperid inyllpropoxylphenyljacetarmid e as a beige solid, m.p. 118-120'C.

ANIALYSIS:

Calculated for FN 3 67.14%C 6.37%H 10.21 %N Found: 67.06%C 6.437H 10l.23%N EXAMPLE 62 1-r4-f3-4-(6-Fluoro-,2-beiisoxazol-3-yl)-l-piperidinvlpropoL(1- 3-dimethyl-aminophenyllethanone l-14-(3-Chloropropoxy)-3-dimethylkmincphertylleihanone To a suspension Of sodium hydride (2.3 g, 48.5 mmol of 50% oil disp ersion) with dimet hyformiamidle (75 ml), and cooled to YC in an ice-s-alt bath and undler a stream of nitrogen was added, dropwise, 1-(4-hydroxy-3-dimethylarminophenyl)ethanone (8.7 g, 48.5 mmol) dissolved in dLmethylformamide (i50 ml) so that the temperature did not go over 7'C. After the addition was over, the bath was removed and the reaction was stirred at ambient temperature for 45 minutes.

The ice bath was reapplied and a solution of l-bromo-3-chloropropane (8.4 g, 53.4 mmol) in dimethylformamide (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 7C in an ice bath and water (200 ml) was carefully added. After stirring for 5 minutes, the aqueous mixture was extracted with ethyl acetate (5 x 200 ml). The ethyl acetate extract was washed with water (2,x 50 ml), dried with MgSO, and concentrated to yield 212 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.

S i) 7-4-[3-[4-(6-fluoro-2 -benzisoxazol-3-y )--piperidirnylpropoxyl-3dimethylaminophenyl]ethartone a- A mixture of 1-[4-(3-chloropropoxy)-3-dimethylaminophenyl]ethanone (2.9 g, 11.3 mmol), 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.5 g, 11.3 mmol), K,CO3 (1.7 g, 122 mmol); KI (200 mg) and acetonitrile (125 ml) was stirred at reflux for 18 hours. The cooled reaction was poured into water and the aqueous mixture A 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 amber oil. The compound was purified by preparative HPLC (Waters Associates prep LC/System 0 :500 utilizing 2 silica gel columns) and concentration of appropriate fractions provided 1.65 g After combining with two additional 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 minutes and then for 1 hour at ambient temperature. The reaction was left to stand overnight and was then filtered to give 3.6 g. The compound was recrystallized twice from ethanol to provide 2.3 g 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 103 dichioromethiane. After washing the dichioromethane extract with w"ater and drying with M gSO 4 the solvent was removed in vacuo to give I g (]4%7)of I ,-benzisoxazol3-yl)-1 -piperidinyllpropoxv 1-3-dirnethylamrinophenyllethanone as a beige solid, mn.p. 94-96*C.

ANALYSIS:

Calculated for CH 3

.,FN

3 0 3 68.32%C 6.88 %H 9.56%N Found: 67.74%C 6.74 %H 9.4076N

S

p

S

~0* U. 4 .11.

EXAMPLE 63 1-W f3-446-Flu oro-1 .2-benzisoxazo 1-3-y -1-12i 1 eri d inyl Iprop oL(Yl- 2-methoxypThenyllethanone hydrochloride A mixture of 6-fluoro-3-(4-piper-idinyl)-1,2-benzisoxazole (4.4 g, 20 mrnol), 1-[4-(3-chloropropoxy)-2-me.thoxyphenyljetha none (4.8 g, 20 rnmol), K, (2.8 g), 1(1 (200 mg) and acetonidtrile (110-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 furnaric acid (2.5 g, 22 mmol) was added.

The mixture was heated to reflux and 'then it was stirred at ambient temperature for I hour. -The resultant fumarate salt (7.0 g) was collected ancr 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 dicliloromethane-methanol as eluent, and after concentration of the appropriate fractions afforded 3.6 g of an off-white solid. The solid was dissolved in anhydrous ether and ethereal MCI 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--r3-[4-(6-fluoro-1 ,2-benzisoxazol-3-yl)- I -pi perid inylI pro poxyl-2-m ethoxyp henyJ ethanone hydrochloride, m.p. 193-195'C

ANALYSIS:

Calculated for 62.27%C 6.1017H 6.0 5 coN Found: 61.88%C 5.9017C 3-96 %N EXAMPLE 64 144-(3-ChloroproOxy)-3-m ethoxv-phenvll-2,2,2-tri f Iuoroe tha none 41-(3-Chloropropoxy)-3-methoxybenzoic acidi 0 00 To a stirred suspension under onitrogen of sodium hydride (6.4 g, 130 rnmol, of about 5076 oil dispersioni-ether washied) in tetrahydrofuran (220 mld) was added pyrazole (4.4 60 rnmol) in tetrali~drofuran- (60 ml), dropwise. After complete addition, the reaction was stirred~for about 15 minutes, and then, 4-(3-chloropropoxy)-3l.--nethoxybenzaldehyde (24.5 g, 107 mmnol) was added. The nitrogen was stopped and,.air was sparged into the reactor for about 3 hours. The reaction was then allowe to stir at ambient temperature open to the atmosphere for 16 hours_,-'Water was added, the reaction was cooled in an ice bath, and concentrzated hydrochloric acid (25 mld) was added dropwise. More water was added and the yellodv solid that separated was collected -to afford 16.2 g of produict. 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~ighe. yellow solid, m.p. =154-156*C. A 4.0 g sample was recrystal-lized from acetonitrile to. yield 2.6 g of a yellow solid. This was combined with 0.4g from another sample and recrystallized again from acetonitrile with charcoal treatment to afford 2.0 g of 4-(3-chloropropoxy)- 3-methoxybenzoic acid as a yellow solid, m.p. 157-159C.

ANALYSIS:

Calculated for C,,H,,C10 4 Found: 54.00%C 514.65%C 5-35%H 5.34%H 44~3-Ch torop ropoxy)-3 -met hoxybe n zoyl chloride To a mixture of 4-(3-ch loro pro poxy)-3-m ethoxybenzoic acid (2.4 g, mmol) in dichloromethane (5 ml) was added thionyl chloride (0.9 ml, 12 mmol) dissolved in dlichloromethane (5 ml). The reaction was stirred and refluxed fcr 1.

hour, and then the dichloromethane was removed ir: L:;c'o to leave a dark oil. The oil was triturated with- hexane and the sobd that formed while scratching with a glass rod was collected to afford 1.6 g of 4- (3-chlIoreopro poxy)-3- methoxybenzoyl chloride, m.p. 60-63'C.

1 -(4-(3-Chloroprapoxy)-3-me-Ihorjphenyl-2.22-trifluaroethanone To a stirred mixture of 4-(3-chloroproxy)-3-methoxybenzoyl chloride (10.0 g, 38 mrhol) in methylene chloride (55 ml) cooled to -7OoC, there was condensed into a reactor bromotrifluoromethane (70 g, 47 mmol). There was then added to the .~..reactor hexamethylphosphoroustriarnide (9.4 gr, 41 mmol) dissolved in dichlorornethane (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'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- 2,2,2-trifluoroetha none.

EXAMPLE 4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yvH-1-piperid invllpropoxyl- '3-hvdroxy-a-m ethyl benze .ne methanol -ch loropropoxy)-3-hydror-rphenyet.an one *A mixture of 1-[4-3-chloropropox)-3-methoxv-phenyllethanone (10.0 g, 41.2 mrnol) and-concentrate d H-SO, (50 il) was stir-red at 65C for 23 hIoUs. The cooled reaction was poured into 250 g of ice and wvas stirred vigorously for 106 minutes. T-he aqueous mixture was extracted with dichlorornethane (CH-CI: and the resultant dichioromethane extract w.as washedwl with sodium hydroxide. The basic phases were combined and washed with dichlorom-ethane.

The aqueous mixture was cooled in an ice bath and concentrated hydrochloric acid was added until a precipitate formed. The product w.as 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 re--crytallizations from toluene provided 3.4 v C22%o) of l-[4-3-chloropropoxy)-3-hvdroxyphenyl) etha none as a beige solid, rn.p. l01-103*C.

ANALYSIS:

Calculatied for C, 1 H,,C10 3 57.787oC 5.73%H Found: 5&.17%C 5.66%TH 4-(3-chlorop ropoxy)-3-hydroxry- a-rnehylbenz7ene methanzol To a flask charged with sodium borohydride (1.5 g, 39.4 minmol) under nitrogen and chilled to 10 0 C was added, slowly, a solution of 1-[4-(3-chloropropoxy)-3-hydroxyphenyljetha none (6.0 g, 26.2 mmol) dissolved in *y*y -ethanol-tetrahydrofura-n (120 md, 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 rnmol) 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 in]) and left overnight. The product was isolated by vacuu-m filtration yielding 3.8 g. Two consecutive recrystallizations from toluene provided 3.3 g of 4-(3-chloropropoxy)-3-hydroxy-a-methylben~zene methanol as a light brown solid, m.p. 107-109*C.

ANALYSIS

Calculated for C,,H, 5 C10 3 37.27%C 6.557%H Found: 57.60%C 6.4 3%- UC -43 -(-6fYr-12bnzsxiz!3y) I-Pcilr6rapoxyJ-3 hydroxy~- c-mt-4n1benzene mehzneU.r2 A rnLxture of 6-fluoro-3-(4l-piperidinyl)-1 2-beazisoxazole (4.3 19.5 rnmol), 4-(3-cHoropropoxy)-3-hvdroxy-c-rnethvlbenzenemethanoI (4.5 g, 19.5 mmol), KI (200 mg), NaHCO, (1.8 21.5 rnm-ol) and CHCN (125 ril) was stirred at reflux under nitrogen for 24 hours. The cooled reaction was filtered and the filter cake was washed with CH-1CN. The filtrate was concentrated to afford an oily residue, which was partitioned between water and ethyl acetate. The ethyl acetate extract was washed with water, dried with MgSO 4 and concentrated to yield 8.6 g of a darkoil. The oil was purified by preparative FIPLC (Waters Associates prep ***LC/system 500) to yield 5.0 g. The compound was recrystallized twice from ethanol to provide 3.9 g (49%7) of 4-t3-[4-(6-fluoro-1, 7 -benziso-xazol-3-yl)- I -piperid inyl I-pro poxyJ-3-hydroxy- a-ne thy I-benzene methanol as a light beige .solid, m.p. =142-144'C.

en. ANALYSIS: Calculated for C:,H,,FN,O 4 66.65%C 6.5 7%coH 6.76%N Found: 6 6.68 5'0C 6.3596H 6.72%N X* EXAMPLE 66 2-r3-[4-(6-Flu oro-1,2-benzisoxazol-3-vl)-[-piperid inylipropoxylaniline dihvdrachloride 2-(3-chloropropoxy.)anffine To a stirred suspension of sodium hydride (11.0 g, 230 mmol of a 5076 oil dispersion) in dimethylformnamide (250 ml), under nitrogen, was added, dropwise, 2-arninophenol (25.0 g, 230 mmol) dissolved int dimethylforrnamide (125 ml). After complete addition, the reaction was stirred at ambient temperature for 1 hour, and then it was cooled to Soc (ice bath). 3-Chloro-I -bromno propane (36.2 g, 230 mmol) in dimethylformamide (50 ml) was added, dropwise, so that the temperature did not go above 8'C, The reaction was st-irred for 4 hours and then permitted to stand at ambient temperaur for 16 hours; The reaction was poured into water and extracted with ethyl acetate. The ethyl acetate was washed (water), dried-' (MgSO,), -and the solvent concentrated to afford 25.4 g of a reddish, dark oil.

About 12.0 a of the oil was chromatographed on HPLC colurms. Concentration of the largest fractions gave 5.4 g of 2-(3--chloropropoxy) aniine as an oil.

2-43-f4-(6-fl uoro-1 ,2 -ben zisoxazo 1-3 -vy)-1 -pipe ridin Wilpropoxylan ilin e dihydrochia ride A mixture of 6 -fluoro--3-(4-piperidinyl)-1,2-bezsoxazole (4.8 g, 22 mmol), 2 -(3-chloropropoxy)aniline (4.0 g, 22 mmrol), K,C0 3 (4.1 g, 22 mmol), KI (0.2 and .3.acetonitrile (100 ml) was stirred and refluxed for 10 hours. The reaction was .000 poured into water and the aqueous mixture was extracted with ethyl acetate. The .11. extract was washed (water), dried (MgSO 4 and the solvent was concentrated to 'Gas afford 9.0 g of a red solid. The solid was triturated with diethyl ether to yield 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 and then adding ethereal HI. The resultant salt (3.5 a) was recrystallized twice from methanol-diethyl ether to afford 2.6 g of 2-[3-1 4-(6-fluorol, 2 -benzisoxazol-3-y)-i-piperidinyliprTopoxyloniline dihydrochioride as a brown solid, m.p. )53-255'C.

ANALYSIS:

Calculated for C,,H 2

FN,

3 0 2 2HCI: 57.02%/,C 5.92%H 9.50%N,', Found: 56.68%C 5.71 %H 9.35%N N-B-A ce tyl -24l3-f 4-(6-f Iubo-1,2-benzisox azo]73-vI)1..p iperid inyl I Prepa ration of I -f 3 -acet!,lrninoa--(3-chlor-opropory~phenyIe-anone A stirred mixture of 1-l3-acetylamino-4-hvdrokyphenv'1l ethanone (7.7 g, mrnol), K 2 CO, (5.7 3-chloro-1-bromnopropane (3.9 56 mmol) and acetone (100 nl) was refluxed for 16 hours. The reaction was allow.ed to cool to ambient temperature and filtered. Concentration of the filtrate yieldedl S.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-wa ter to yield 2.2 g (5176') of a solid, m.p.

124-126*C.

ANALYSIS:

Calculated for C,,H,,C1N0 3 57.89%C 598%H 5.19%N ~Found: 57.08%C 5.85%H 5.13 %oN a 41 N-[5-acetyl-2-!3-14-(6-fiuoro-1 .2-beniiisox~zo!-3-y 1-I -piperidinylltega propoxylphenyllacetamnide A-iixture of 6-fluor6-l3-(4-pipe rid inyl)-1,2-benzisoxa zole (4.4 g, 20 inmol), 1-f 3-acetylamino 47(3-chloropropoxy)phenyl Jethanone (5.5 g, 20.5 mnmo]), K 2 C0 3 (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 acetate.

The extract was washed (water), dried (MgSO 4 and then it was concentrated to afford 9.5 g of a brown oi(liThe oil was ta-ken-up in ethyl acetate and ethereal HCI was added until the reaction was acidic. The nide, brown, hydrochloride salt was collected (8.4 and was immediately converted to the free base with NHOH, to afford 5.4 g of the compound as a brown oil. The oil was chroma tog-raphed on a awarbWaters Preparative HPLC utilizing silica gel columns. Concentration of the appropriate fractions yielded 3.5 g of N-(5-ace tyl-2- flu oro-1 ,2-benzisoxazol- 3.yl)-1-piperidinyllpropoxy]-phenyllacetarnide as a white solid, m.p. 108-110o2.

ANALYSIS:

Calculated for CnH, FNO,: 66.21 %C 6.22%71- 9.27%N Found- 66.12%C 6.2-5%H -9.27%N EXAMPLE 68 3-fl-[3-(4-Ethv 1-3-meth onzyhenoxv~propv] J-4-pi E)Erid 1 nNA-6-flIuoro- 1,2-benzisoxazole hydrochloride 4-dyl-2-methoxyphenol Acetovanillone (Aldrich, 11.0 g, 66 mrnol) was dissolved in absolute ethanol (200 mld) and added to 1.5 a of 5% palladium on carbon. A few drops of concentrated hydrochloric acid were added and the mix~ture 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 see* f* sedium bicarbonate. The solvent was dried (MgSO 4 and concentrated to afford *j9.3 g of a slightly yellow liquid.

A midxture of 4-ethyl-2-methoxy phenol (9.0 g, 59 mmnol), 3-chloro-l-bromopropane (13.0 g, 83 mmol), KCO, and acetone (200 rmd) was stir-red 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 diethyl ether Was washed (water), dried (MgSO), and the solvent was concentrated to afford 11.9 g of a golden liquid. The liquid was flasgh chromnatographed. This gave a colorless liquid, 9.9 g of 4-ethyl-2-methoxy-4-(3-chloropropoxy)benzene.

3-(l -[3-(4-ethyl-2-mnethoxyphenoxy)propyI1.4-piperidinylj-6-fiuoro-I,2benzisoxazole hydrochloride A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (4.0 g, IS rorol), I (0.4 KCO, (2.5 4-ethyl-2-mnethoxy-4-(3-chlorooropox-y)benzene (4-4 g, 18 mmol) and acetonitrile .wa$ refluxed for 8 hours. The recilction was poured into water, and the aqueous suspension was extracted with ethyl aCetate.

T'ne ethyl acetate extract was washed (water) dried (MgSO) 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 flash chrLornatographed on silica gel. 'Concentration of the appropriate fr-actions 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 310 g of 34[143-(4-e thyl-2-methoxyphenoxy)-propy 1j,- 4-piperidinylj-6-fluoro-1,2-benzisoxazole hydrochloride as a white solid, nip.

ANALYSIS:

Calculated for C, 4

HFN,O

3 .HCl: 64.217%C 6.74%H 6.24%N Found: 64.38%C 6.84%H 6.14%N 0* EXAMPLE 69 1-f3,5-Dimethoxv-4-r3-r4-(6-fluor)-.1.2-benzisoxazol-3-vl)-l- 1)i perid inllprovoxy1-ph env lethan one 3,5-dirnethorj-4-(3-bromopropox)acetophenione To 3,5-dimethoxy-4-hydroxyacetophenone (5.2 g) in dirnethylforrnmide ml) at 0'C under nitrogen, was added sodium hydride (700 mg, 1.1 eq. 98%o).

The resulting n-ixture was stirred for ten minutes until evolution of gas ceased.

Potassium carbonate (4 g) was added, and- then' 1,3-dibromopropane was added- The mixture was heated at 60*C for one hour. When the reaction was complete, -the mixture was poured into a water/ice miixture 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 imethoxy--4-(3-bromopropoxy)acetophe none as a light oil, 7.6 g.

1-f3,5-dime-thoxvw4-!3 -i4-(6-fiuoro-1,2-bernziso:,-zoI-3 -tl)-I 7.,--ridinv1ip ropoxylph eny I e-tha r ore A stirred mixture of 6-fluoro-3-C4-piperidinyl)-i,2-benzisoxazole 13.6 mmol), KC0 3 (2.1 g, 15 mmol), and 3-cldimethoxy--4-(3-bromopropoxy)acetophenione (4.4 g, 13.8 rnmol) in acetonitrile (50 m.1) was heated at reflux for 3 hours. At the end of the reaction, the rniure was diluted with dlichloromethane 200 ml). The insolubies were filtered. The solution was concentrated to an oil The purification was donE by flash chromatography on a silica gel column.

The product was obtained as a colorless oil (3.85 g, 61 which crystallized from ethanol (400 ml) to give 2.94 g of l-[3,5-dirnethoxy-4-[3-[4-(6-fluorol,2-benzisoxazol-3-yl)-l-piperidinyll-propoxylphenyllethanone as off-white crystals, m.p. 107-108*C.

AN~ALYSIS:

Calculated for C,-fH Fi\JQ: 578%C 6.40%H- 6.14%N Found: 65.847%C 6.44 %H 6.15%N 31 '4 EXAMPLE N-f3-3-[ 4-(6-Fl u oro-t.2-benzisoxazo 1-3-0l-1 -pip eri di nyl I ropo~aL phenyllacetamide hemnifumarate 3-(3-acdoamidophenonjy)propqlI bromide To 3-acetarnidophenol (15.1.g) in dichloromethane, (500 dry) was added potassium carborate (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 filtered from the reaction~ mixture, and the solution Was concentrated to an oil, which was purfied to yield 3-(3-acetamidopheno y)propyl bromide, 13.2 g.

U-t3-[3-14-(6-fl uoro-1, benr :isaxazoi-3 1 -piperidirylipropoxrylphervy1lccetcnmze hernifurarate A stirred mixture of 6-fluoro-3-(4-piperidinvl)-1,2-b-enzisoxazole (9.25 g, 42 inmol), KCQ, (8 g, 58 mrnol) and 3-(3-acetaridcophenoxy)propyl bromide (11.4 g, 42 mmol) in acetonitrile (350 m.1) 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 chrbmatography 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 fumnaric acid solution in ethanol (850 mg:5m1d)- The N-[3-[3-[4-(6-fluoro-1 ,2-benzisoxazol-3-yl)-I -piper-idinyljpropoxyiphenyllacetamide hemifu-marate crystals obtained weighed 2.73 g, m.p. 184-1S6*C.

ANALYSIS:

Calculated for C,,H,O,s0.5CHO,: 63.95%C 6.01 %H 8.94%N Foun d: 63.47%C 5.94%H- 8.78%N EXAMPLE 71 \:.3-r3-[4-(6-Fluoro-12-benzisoxazol-3-vl)-- iperidiny lipropoxvylanilin e A stirred mixture of N-[3-[3-[4-(6-fluoro-1 ,2-benzisoxazol-3-yl)-1 piperidinylpropoxvllphenyllacetamide (9.2 g, 22 mmol), prepared as described in the previous example, in 15% hydrochloric acid,(110 mld).was heated at 100*C for hours until a homogeneous. solu tion resulted. The reaction was cooled to 0O'C in an ice bath and basified with 50%7 NaOH-. The product was extracted with ethyl acetate (3 x 200 nil). The ethyl acetate solution was washed with water, brine, then dried over Na-SO 4 The solvent was removed. The crude product was purified on a flash chromatography column. The product thus obtained was a solid: 6.6 g (805c). Recrystallization from hot ethanol (30 mil) gave 3-[3-[4-(6-fluoro-1 ,2-benzisoxazol-3-yl)-1-piperid inwllpropoxy]-aniline as of(f-white cr-ystals: 3.46 g, rn.p. 115-1 17'C.

ANALYSLS:

Calculated for H, 4

FN\

3

C,:

Found: 68.277%C 68.34 %C 6. 5 5 %cH 6.53 %H 1 1.37%1\ 11.31%N

C.

C* C S

C

EXAMPLE 72 3-13-4(6-Fl uoro-1,2-be nzisoxazo 1-3-YI) pi2 er- d in vl]2ropo.".14-meth oxva nil ine A mixture of -fluo ro- I ,2-benzisoxa zo I-3-yl- I -pipe rid inyl I pro poxy]- 4-methoxyphenylacetamide (4.2 g, 9.5 mmnol), prepared as in Example 26 above, in 15% hydrochloric acid (60 ml) was heated at reflux (1 10'C) for 2 hours. At the end of the reaction, the solution was cooled to O'C then basified with 25% NaOH topH 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-SO 4 The solvent w.as 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 3-f 3-f 4-(6-fluoro-1,2-benzisoxazol-3yl)-l-pi -eridinyli-propoxyl-4-methoxyaniline as fine crvstals 1.2 g; mn.p. =94-95*C.

AN ALYSIS: Calculated for C_,,FN, 3 0- 66.1517C 6.56% H 10.52%N Found: 66.16%,YC 6.54%H 10.44%N 00 EXAMPLE 73 1-f 4 -3-[4-(6-Flu oro-L,2-be nyiso th iazol-3-yl) -1-pipe rid in yflpropo xy-3methylamnino-phenriletha none fumnarate I -lt3-N-acetyl-N-rnethiyfn ninzo)--hvidroxyphzeny.Ilethinone A solution of. 2-methoxy(methylamio)b-erizene k26.0 g. 190 mmol) and 1,2-dichloroethane was cooled to l0-15*C and a solution of acetyl chloride (333.8 430 mnmol) dissolved in dichloroethane (50 ml) was dripped in slowly. Followinig this addition, an additional 100 in dichlo7oethane was added. The reaction was cooled to 0*C and aluminumn chloride (72.3 g, 540 mrnol) was added over the course of 45 minutes so that the temperature did not exceed l0'C. After complete addition, the reaction was heated to reflux and was stir-red for 18 hours under nitrogen. The reaction was cooled and was poured into ice. The resulting aqueous phase was extracted further with dichloromethane and the combinied extracts were washed wvith Ff20, dried with M~vgSO,. and concentratedL to yield 32.0 g of ]-(-%-ctlNmty-mio--yrx-hnleh none as a i Vn solid, 168-17]*C.

1-(-!?vdroxIq-3-rnethylamtin.ophenyl~ethanorne A mixture of I (3-N-acetyl-Nf-nmethyla rnino)-4-hyd roxyphenyllethanone g, 72.4 minol) and concentrated HCI (150 mld) was stirred at reflwc for 3 hours. The heat was terminated and the reaction stood overnight. T-he reaction mixture was transferred to a IL 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 contiued to be made basic by the addition of solid sodium bicarbonate. After pH 8 was achieved, the reaction mixture was extracted with ethyl acetate. The ethyl 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 e thyl acetate the phases were separated. The ethyl acetate extract was washed several more times with water, dried with M'vgSO, and concentrated to yield 10.5 a of a dark solid of *1-(4-hydroxy-3-methylaminopheny!)etha none.

I -f4-(3-chloropro-poxyJ-3-mnetihyimi'nophenytlehanone To a stirred suspension of sodium hydridle (0.87 g, 18.2 minol of a 50% oi~l dispersion) in dimethylfofmamide (25 ml) under nitrogen and cooled to Oo in an ice-salt bath was added. dropwise, a solution of 1-(4-hvdroxj-3-met hyla mi no-phenyil)-etha none (3.0 g, 18.2 minol) dissolved in 116 dLrnethvLccrmnamide (55 ml) so that the temperat-ure did not rise above 3'C. After the addition was complete, the reaction- Was stirred fo,- SO m-inutes at ambient temperature. The reaction-was-cooled to 5*C and a solution of I -bromo-3-ch lo ropro pane (3.1 g.0.0120 miol) in dirnethvliormnamide (20 ml) was added dropwise. After this addition was Complete, the ice bath was removed and the reaction was stirred at ambient te ,mperature for 2.5 hours. Water (75 ml) was carefully added and after stirring vigorously for 5 mintutes, the reaction was left to stand overnight. The aqueous mixhire was extracted with ethyl acetate and the ethyl acetate extract was washed with water, dried with M-50,, and concentrated to yield 3.9 g of a dlark 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 ofl 1-f 4-(3-chloropropoxy)-3-met hyl-aminophenvlIjetha none as a fluffy, beige Solid, rn.p. 115-117'C.

ANfALYSIS: Calculated for C 1 1 CINO,: 59.639oC 6.67%H 5-79%N Found: 59.49%C 6.64 %H 5.79%N\ >~04 C C f(D) -fl uoro 12-ben ziso t h izo 1-3 -yl- I-p ipe id inyllp ropoxy-5 met hylarninopheny!Iethantone Ifuna raie A stirred mixture of 6-fl uoro-3-(4-pipe rid iny D- 1,2-benziso thia zole (1.9 g 79 mmnol). 4-(3-chioropropoxy)-3-methyla minophenylletha none (1.9 g, 79 mmol), KCO, (1.1 KI (0.1 and acetonitrile (95 m) -was refluxed for 16 hours. The 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 fu maric acid (0.4 g, 0.003 mol) was added, and 1.9g of a white fumnarate salt was collected. The salt was recrystallized from dimethylformamide to yield 1.1 g(25%) of 0 I .2-ben~zis othiazol-3-yi)- I -pipe rid in yl lropoxv-3methylaminophenyl1)etha none fumw-ate as a white solid, m.P. 195-200'C.

ANALYSIS:

Calculated for C,H 3 ,FNOS: 60.31 %C 5.787oH Found: 60.02%/C 5.88%H 7.68%N EXAMPLE 74 N-r3-r3-f4-(6-Fuoro-12-bezisoth iazo-3-vl)-1-piperid in'l p 1RrOpROXYVl- 4-methoxv-12henyllacetimide N-134(3-ch lorop ropoxy)-4- nethoxyphenyllaceta mide To a stir-red suspension, under nitrogen, of sodium hydride (1.8 g,38 .2 rmol) in dimethylformamide (60 ml) was added dropWise, 1\-(3-hydroxy-4-methoxy)ace ta mid e (6.1 g, 34 rnmol) dissolved in dimethyifor-mamide (23 ml). After complete addition, the reaction was stirred at ambient temperature for 0.5 hour, and then 3-chloro-1 bromopropane (5.2 g, 33 minol) in dimethylformamide (10 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 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 chroma tographed on 200 g of silica.

gel, eluting the column with ethyl acetate, and subsequent concentrationt of the appropriate fractions afforded 2.4 g of a white solid. Recrvstafization of the compound from toluene yielded 2.2 g of N-[3-(3-chloropropoxy-4-methoxyphenyllacetarnid e, mn.p. =112-11 4C.

ANALYSIS:

Calculated for C-H,,CINO,: 55.93%C 6.26%H* 5.4.4 %N Fou nd: 56.2.5%C 6.29%H- 5.44%7N A stirred mixture of 6-fluoro-3-(4-Dioeridinvl)-1,2-benzisothiazole (4.0 g, 17 mmobl), N-(3-(3-chloroprotooxy)-4-methoxyphenvlacetamide (4.3 g, 17 =rno), KCO, (2-3 KI (0.2 g) and acetonitrile (200 m.1) was refluxed for 10 hours. The cooled reaction mnixtuire was filtered and the filtrate vwas concentrated to yield a dark oil. The oil was dissolved in acetone, and ether-eal HCO was added to yield 5.7 g of a yellow hy'drochloride salt. The salt was reversed to the free base and the resultant oil (5.2 g) was chroniatographed on a Waters Associates Prep LC utffizint:- ****sil-ica 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 yield 1.4 4g. (87) of N-(3-(3-[4-(6-fluoro-1,2-benzisothiazol-3-y)-1 -piperidinylipropoxy]- 4-met hoxyphenyl]-aceta mid e as a white'solid. 1.4 g, mn.p. =109-111 V.

ANALYSIS:

:Calculated for C,,H,,FNO 3 S: 63.00%C 6.1 717oH 9.18 10 N Found: 62.80%7C 6.-17 -aH 886% N EXAMPLE I -r4-f 3-446-Fl u gro-,-beflzisoth iazo 1-3-v D1-. pi 1eri diny[] propo~y1- 3-methoxv-phenyllethanone hydrochloride A stirred mixture of 6-fluoro-3-(4-pipe.idinvlI)-t,-2-benzisothiazole g, Mow 17 mmol), l-4-(3-chloropropox 0-3-methoxvphenyijetha none (4.1 g, 17 nimol), KCC, (2.3 K! (0.2 and acetonitrile (100 ml) was refluxed for 9 hours. The reaction was poured into water, and the aqueou-s mixture was extracted with ethyl acetate. The extract was wvashed (water), dried (MlgSO), and tile solvent was concentrated to a-ford S.0 g of a brown oil. The oil was chrornatog-raphed on a -aters Prep 5CO 'HPLC on sih-cj gel colu-=E- Con-en-I.ation of the appropriate rractions afforded a gumn-like residue, which uon trituration with isopropylei: afforded 1.9 g of a white solid. The solid was dissolved in absolute ethanol, and ethereal HCI was added to preci pitate 1.7 c- of a hydrochlorici- salt. Concentration of the isopropyl ether filrat, and similar treatment of the residue, afforded an addition~al 0.5 g of the salt. The samples were combined and reci-vstaILLzed from absolute ethanol to yiel 1.7 of l1-(413-(4-(6-fluoro- 1 ,-benzisothiazol-3-Yl)--pivericinyllpropoxy1-3-mietho-xy'henyllethanone hydrochloride as a white solid, rn.p. -221-223'C.

ANALYSIS:

Calculated for C, H,-FN,0 3 S.HCl: 60.18%,cC 5.89%H 56% *Found: 60.O17aC 5.9 7 /oH 5.79%NI V ***EXAMPLE 76 N, N-b im e thvl-4-3-[4-(6-f Iu oro-1,2-b enzis oxazol-3.vl)-pipe rd il Ipropo~xv-3-iethoxybenzamide N,N-dimethi.'l-4:-bromopropox-y-3-rnzetho.wvbentzamide *To i~,-iehl4hdoy3mtoyezmd (5.64 g, 20. mmo]) in A. acetonitrile (450 ml) was added potassium carbonate g) followed by hours and stirred at room temperature for 12 hours. The mixtur-e was filtered and conentate toan oil. Following purification by column chromatography, NN-d Amethyl-4-bromopropoxy-3-met hoxybenza mid e as a colorless oil (7.6 g) was N,N-dirnetiiyl-.4-[3-14- (6-fluoro-7 .2-b~nzis.ox-azol-3-yU,-l-piperidinyJ- A propoxvl-3 -rnethoxybenzaumide A stirred mixture of 6 -fluoro-3.-(4-piperidinyl)-1,2-benzisoxazole (3.9 g, 17.7 rnmo!), N.'N-dim..iehyl4 -bromopr-ocoxvp--methox-ybenzamide (5.54 g, 17.5 mmol) and KCO, (Q g) in acetonitrile (250 ml) was heated at reflux for one hour.

120 At the end of the reaction, the-insolubles were filteredl and washed with dichioromethane. The solvent- was removed on a rotary e vapo7ator. The residue was purified by flash chromatography over a silica gel colum-n. The product thus obtained as an oil weighed 7 g. Crystalization from hot ethanol (45 in]) afforded analytically pure N,N'-dimethyl-4-3-4-(6-fluoro-1 2 -benzisoxazol-3-yE)---piperidinyl Ipropoxy] -3-methoxybenza mid e, 3.95 g, 50%, as light yellow crystals, m.p.= 126-127'C- :e ANALYSIS: Calculated for CHFNO,: 65.92%C 6.64%H 9.22%N *Found: 65.76%C 6.64%/H 9.14%N EXAMPLE 77 I-r4-[34[4-(6-Fluoro-1 .2-benzisoxazo l-3-vl)-1-p iperid in vIlpropoxv 3-methoxv-phenyllethanone oxime A rruxture of 1 flu oro-1,2- benz isoxa zo 13-yI)- I l-pipeid inyll propoxyl-3-miethoxyphenyl let hanone (4.3 g, 10 mmol), prepared as in Example 3 above, hydr oxylamine hydrochloride (1.3 g, 15 inmol), ammonium acetate (1.7 g, 22 mmol) and ethanol-HO was stirred and refluxed for 16 hours.

4 The reaction was poured into water, and the mixture was cooled in an ice bath for 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. 16-218'C. The compound was dispersed in water and ammoniurm hydroxide was added until the suspension was decidedly basic. The basic suspension was then extracted with dichioromethane, and after washing with water, drying CNMgSO), and concentrating the extract, 3.0 g of white solid melting at 168-170'C were harvested. The compound was recrystallized from dirnethylforrnam ide to yield 2.3 g of 1-1 4 -[3-f4-(6-fluoro-I,2-benzisoxazol-3'-yl)-1 -piperidinylI propoxy]- 3-methoxy-phenylletha none oxime as a white solid, m~p. 16&-170'C.

ANALYSIS:

Calculated for C.,H,FN 3 63.29%-C 6.39%IH 9.52%N Found: 63.277%C 6. 4 9.46%N EXAMPLE 78 1-r4-r3-r4-(6-Fluoro-12-benzis6xazol-3-vl)-l-piperid inyl lorooxylmethoxvphenvilethanone oxime 0-methyl ether A solution of 1-[4-[-B-(6-fluoro-1,2-benzisoxazol-3-yl)-1 -piperidiyl]- 4..propoxylmethoxyphenyl]eth -none (4-3 g. 10 mmol), prepared as in Example 3 above, methoxylamine hydrochlori-de (0.93 g, 10 mmol) in pyridine (75 mI)/ethaniol ml) was refluxed for 16 hours. Most of the soIlet was evaporated under 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 70-72cC. The initial crop. oF-crystals was converted to its free base with aqueous NaOH. After extractive workurp with ethyl acetate, 1.2 gof the free base was :obtained- The two samples were combined and recrystallized from isopropyl ether toafor2- g of 1-(4-[3-[4-(6-fluoro-1,2-benziLsoxazol-3-yl)- :-piperid iryll propoxy]I-m ethoxyphenyl Ietha none oxime 0-methyl ether as colorless 0crystals, m 0. 7-99*C.

ANIALYSIS:

Calculated for CHj-FNO,: 65.92%C 6.64%H 9.22%76N Found: 65.89%C 6.86%H 9.15%N bo EXAMPLE 79 1-r4-3-f4-(6-Fluoro-12-benzisoxazol-3-vll-1-oinerid invilpropoxyl- 3-mnethon-p2henyllethancne hydrazone A stirred mixture of 1-[4-[34[4-(6-fluoro-1,2-benzisoxazol-3-ylpiperidinvllpropoxy]-3-methoxyphenyl] ethanone (4.3 g, 10 rnmol), prepared as in Example 3 above, hydrazine (0.8 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 resultanit solid was collected to afford 4.2 g o f 1-[4-[3-[4-(6-fluoro-1 ,2-beazisoxazol-3-yl)-I-iprdiy I ooy--eto~peyl ethanone hydrazone as a yellow solid. The compound w-as recrystallzed from isopropanol and then from toluene to afford 1L7 g (397c), m.p. 1 06-108'C.

AN'ALYSLS:

Calculated for C, 4

H,

9

FN

4 0 3 65.44%C 6. 6 4%H 12.72%N *Found: 65.38%C, 6.5%7H 12.557oN E EXAM PLE 8 b 6-Fluoro-3-111[3-[2-rnethoxv4-(1l-me thyleth en yl)2henoyl 2rorvl 1-4 piperidinyll-1,2-benzisoxazole hydrochloride A solution of butyllithium (4.7 ml of a 2.3 M solution in hexanes, 10.7 mmoi) iii tetrahydrofuran (65 ml) was stirred under nitrogen.and cooled to in an isoprdpyl alcohol-dry ice bath. M'vethyltriphenyipliosphoniurn bromide (3.8 g 10.6 mmol)-was added port ionwise over the course of 10 minutes. After. complete addition, the react ion was stirred at -65'C for one hour and was then allowed to gradually wvarmn up to ambieht temperature, where it was stirred for an additional hours. The reaction was cooled to 0 0 C, and -a solution of 1 443-f446- flu oral ,2-benzisoxazol-3-yl)-1 -p iperidinyll propoXy I -3-methoxyphenyllethanone prepared as in Example 3 above (4.7 g, 0.01l0 mol) dissolved in tetrahydrofuran (30 ml) was added, dropwise, over the coub of 30 minutes.

After the addition was complete, the reaction was stirred at ambient temperature 0 for 19 hours. The reaction was poure-d into water and the aqueous mixture was extracted with diethyl ether. The diethyl ether extract was washed several times withwater, dried with MgSO, and concentrated to yield 7.0 g of a light orange solid. Recrystallization from toluene-hexane provided 1.4 g of triphenylphosphine oxide and concentration of the filtrate afforded 5.5 gof a glass)', beige solid. This Was combined with an additional sample (6.5 g total) and purification by preparative HPLC (Water's Associates prep LC/System 300) gave 5.2 g of a beige solid, which remained contaminated by trirohe nvlphosphine oxide. The compound was taken up in anhydrous ethanol (300 ml) and methanol G5 drops) and ethereal HCI was added to precipitate 4.0 g ofl a pale, white solid, m.p. 192-1949C.

AlNALYSIS: Calculated for CIH C.PN,O,: 65.14c/C 6.56 5,H 6.08%N Found: 64.95%C 6.62%coH 6.04%N EXA MPLE.81- 3-methoxvphenyllethanone A mixture of 6-fluoro-3-(4-piperidinyl)-1 2-bcnzisoxazole (2.2 g, 10 mmol), KC0 3 (2 (E)-4k-[(4-bromo-2-butenyl)oxyl-3-iethoxyacetophelone K4. 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 2.67 g Recrystallization from ethanol:hexarie (20 rnl:5 ml) gave -[4-[[4-[4-(6-fRuoro-1 ,2-benzisoxazol-3-yl)- 1-piper-idinyli-2-bu tenyljoxyl-3-rnetho xv-phenyllethanone as off-white crystals: 2.46 g; imp. 791 -93 C.

ANALYSIS:

Calculated for C25H, FN,O 4 68.48%C 6.21 %H 6.39 96N Found: 68.28%C 6.12%H 6.2717aN EXAMPLE 82 (Z)-1-fTI4-Ch loro-2-bu ten vloxyvl-3-m ethoxyp henyl Iethan one A stirred mixture of 4-hyd.-oxy-3-methoxyacetophenone-i?6.6 g, 10 mmole), KCO, (14 g, 100 mmoi) 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 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 crys tals, 7.7 g, This was recrystallized from ether to give analytical pure MZ-l -(4-[C4-chloro-2-bu tenyl)oxyl-3-rnethoxyphenyiletha none (2.72 rn.p.

64-66'C.

AN~ALY51S: Calculated for C,,H 15 C1Q: 61.30%oC 5.94% H Found: 61.28%C 5.9 4% H EXAMPLE 83 (Z)-l-r4-[[4-14-(6-Fluoro-1L2-benzizsoxazol-3-vl)-l-Rpnridinyl]- 2-butenvlIloxvl-3-m ethoxvphenvflethanone A. stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.2 g, mmnol), KC0 3 (1.8 g, 13 mrnol) and (Z)-1-f4-[(4-chloro-2-butenyloxyl- .*3-methoxy-phenyllethanone (3.43 g, 9.7 mrnol).ini acetonitrile (100~ ml I) was heated *at reflu~x for 1-1 /2 hours. At the end of he reaction, the sblvent was re-moved and the inorganics were filtered after addition of dichloromethan-e (250 The dichioromethane 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 anialytically pure -[4-[[4-[4-(6-fluoro-1 .2-benzisoxazol-3-yl)-l -pi peri!'.in ylI- 2-butenylloxyl-3-methoxy-phenylethalone,,1.83 g~m. p. 57-59'C.

ANALYSIS Calculated for CH.,FtNI 07 C 6.21 %H 6.39%Nl Found: 68.2617C 6.1 IH 6.32%N EXAMIPLE 84.

(EM 3- [4-4 4-6-Flu oro-1.2- benzis OXaZol-3-D1)4-pip erid i nyl-2butenyvloxl-4-hydrox'vphenyllethanone hvdiochloiide The mixture of [4-[4-(6-'iioro-1;2-renzisox-azol-3-yl)-1-piperidiflyli- 2-butenyiloxyl -4-benz7yloxyphenyll ethanone (5.5 g, 10.7 mi-iol), acetic acid (50 ml 125 fl *0

S

and hydrochloric acid ml) w.-as heated at 75'C for 2 hours. At the end of 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 dichloromehare (3 x 250 ml). The dichloromethane solution was washed with brine and dried over Na.SO. A solid formed on concentration of the solvent. This was coljected by filtration (3.4 gi. Recrystallization from hot methanol (40 ml) gave 1.82 g of (E)1l-[3-ff4-[4-(6-fluoro-l,2-benzisoxazol-3-yl)- -Piperidinylj-2-butenylloxy- 4-hydroxy)phenyl-ethanone.hydrochloride as white crystals, 37.5%, m.p.

208-210'C.

ANALYSS:

Calculated for C, 4 H,FN,O, HCI: 62.54%C 5.69%H-f 6.08 %N Found: 62.40%C 5.609H 6.04 %N

S

it EXAMPLE (E)-1-f3-(f4-1-(-Fluoro-.2-benzisoxazol-3-vi)-l-piperidinyll-2butenvl]oxyl-4-benzvloxvphcnyliethanone '-brorno-2 -butenylorjI4-be zyloacetophenone To 4-benzyloxy-3-hydroxyacetophenone (17".6 g)-in acetonitrile (200 ml) was added potassium carbonate (10 followed by the addition of (E)-1,4-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 purified by flash chromatography to yield 20.5 g of mo2-butenyl)oxyi-4-benyloxy-acetophenone as white crystals.

-(3-[U4-14-(6-fluoro- ,2-benzisoxazol-3-I)-Z-piperidinyli-2-butenyiloxy H--benzyloxyphernyflethanone A mixture of 6-fluoro-3-(4-piperidinyl)-l .2-benzisoxazole (5.62 g. 25.5 mmol). KCO, g. 29 mmol). and (E)-3-((4'-b-ornc-2-butenyl)oxyj-4-bezyloxy- .0 0 0 *0d4 .0 S 400

S

acetophenone (00 g, 26.6 rnmol) in acetonitrile (125 MlD was heated at refILuX for hours. The mixture w.as cooled and concentrated to a crude solid. The residue was ext racted into dichloromethane (300 ml) and insolubles were filtered. The crude material from the dichioromethane solution was purified on a flash chromatography column. The prod uct thus pur-ified weighed 8 g as a pale white solid. Recrystalliation from hot ethanol gave 7.11 g of -(3-[4-[4-(6-fluoro-1,2-benzisoxazol-3-y)-1 -piperidinylj- 2-bu tenylloxy] -4-benzyloxyph enyl~etha none as off-white crystals, m.p. 124-125'C.

ANALYSIS:

Calculated for CjH,,FN,O 4 72.36%/'C 6.07%H 5.44%N Found: 72.2376C 6.04%H 5.014%N EXAMPLE 86 6-Fluoro-3-rl-[3-U(5-methoxv-1H-indol-6-vl)oxvlpronpvll-4-pioperidinvfl- 1,2-benzisaxazole 6f3 -Chlo To a stirred suspension of sodium hydride 0 .94 g, 19.6 mmol of a 50% oil dispersion) in dimethylformamide (20 ml) under nitrogen and cooled to -5C. was added, dropwise, 5-methoxy-6-hydroxyindole (3.2 g, 19.6 mmol) dissolved in dimethylfon-namide (60 ml) s0 that the temperature did not exceed After complete addition, the reaction was stirred for 45 minutes at O'C. While maintaining the reaction temperature between -5*C and 0"C, a solution of 17brorno-3-chloropropane (3.1 g, 19.6 mmol) dissolved in dimethylformamide mld) 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 extracted with ethyl acetate. The ethyl acetate extract was washed with water, dried with MgSO, and concentrated to yield 5.3 g of a dark, oily liquid. This was 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 L.1 g (30%i) of 6-(3-chloropropoxy)-5-methoxyin-dole -as beige crystals, m.p.

-Sh M 73-75 0

C.

ANALYSIS:

Calculated for Cj2H 14 ClNO,: Found: 60.13%,'C 60.26%C 3. 89% 1-1 5.86% H 5.S4 %N 5.777N a 0of.

6 U 0 -No 6-Fluoro-3 -T -T3 -1(5-methoxy-l H-indol-6-yil)oxylpropyil-A-piperndintyli- 1,2 -beuzisoxazrole A midxture 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 CO0(.6 g, 11.5 m-mol), KI (200 mg) and acetonitrile (100 mnl) was stir-red at reflux under nitrogen for 40 hours. The cool ed reaction was poured into water and extracted with ethyl acetate. The ethyl acetate extract was washed with water, washed with brine, dried with MgSO, 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---[1 -13-[(5-methoxy-i H-indol-6-yl)oxy]-propylj-4-piperidinvll-1,2benzi~soxazole as a beige solid, m.p. 156-158'C.

ANALYSIS:

Calculated for 65,07%C 6.19 %H 9.9276N Found: 67.89%C 6.07 %H 9.91 %N EXAMPLE 87 6-Flu oro-3-f I-r3-f 1H-indol-7-yl)oxyl prop yl 1-4-p iperid inll-1,2benzisoxazole hernifumarate 7-(3-Chloropropoxv)indole To a stirred suspension of sodium hydride (0.8 g, 17 mmol of a 50% oil dispersion) in d imethyl forma mide (20 ml), under nitrogen, was added dropwise 7-hvdroxvindole (2.1 g.15.7 mmol) in dimethylformamide (20 ml). After complete addition, the reaction w~as stirred at ambient temperature for 0.5 hour and thencooled to 15'C. To this cooled solution was added, droDowise, 1-br-omo-3-chloropropane (2.5 g, 15.7 mrnol) in dirnethvlfor-namide (5 nil). 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 CMgSO), and the solvent was concentrated to afford a dark brown oil. Following flash chromatography on silica gel, 7-(3-chloropropoxy)indole was obtained as a colorless oil, 1.0 g.

AINA oCalculated for C 11 H,,CINO: 63.01 %C 5.77%H 6.68% N 4gdFound: 63.25%C 5.6150H 6.65%N 6-Fluoro-3-f 1-[3-1(1 H-indoI-7-yfoxylpropy/--! -piperid inri-l 2benzisoxarzole hemifumnarate A stirred mixture of 7 -(3-chloropropoxy)-1H-indole 3 .5 g, 17 mmol), *6-Fluoro-3-(4-pipenidinyl)-1,2-benzisoxazole (3.5 g, 17 mmol), K.C0 1 (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 ethy] acetate was d washed with water, dried (MgSO), 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 mld) and fuma tic acid (0.97 g, 83 0F mmol) was added. The mixture was briefly heated to reflux, and then stirred at ambient temperature for 1.5 hours. The resultant insoluble white fumnarate salt was collected and afforded 4.2 g of product. Recrystallization of the salt from dimethylformamide yielded 3.1 g of 6-fluoro-3-[l H-indol-7-yl)oxyjpropyl]-4-piperid inyli- 1,2-benzisoxazole hemifumarate as a white solid, m.p- 213-215'C.

ANALYSIS:

Calculated for CH,,FNO,: 66.50%C 5.80%H 9.3 1 %N Found: 66.23%C 6.1-1% H 9.39%N EXAMPLE SB 6 -Fluoro-3-rl-(3-hvdroxvpronvl)-,oieridinv.l-1 .2-benzis-o.xazole A *w A stirred mixture of 6-fluoro-3-(4-pi per-idilyi)- I,2-benzisoxazole (10.0 g, rnm-ol), K,CO, (00.0 3-bromo-i-propanol (7.3 g, 46 rmL-nol) and acetonitrije (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 dichioromethane, 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 6-fluoro-3-(1 3 -hydroxypropyl)-4-piperidinyl.1 ,2-benzisoxazole as an off-white solid. A sample (4.0 a) was recrystallized from ethanol-water (wvith charcoal treatment) to yield 2.4 g of the alcohol as a white solid, m.p. 140-142C.

ANALYSIS:

Calculated for CTj[ 1,FN,O,: 64.735/C 6.88%H 10.06%N Found: 6491 r 07r C7 W-' t4.Jl SOIL I U. _0 tIq EXAMPLE 89 6-Fluoro-3-fl-(2-2vrimidn rpl--ieidni-,-ezsxzl fumnarate To a stirred suspension of 6 -fluoro-3-[l-(3-hydroxypropyi-4piperidinyl]-1,2-benzisoxazole (3.6 g, 13 mmcl) in tetra hyd rofuran (50 ml) was added dropwise, potassium bistri methyLsilyla mid e (2.6 g, 13 romol) dissolved in tetrahydrofuran (20 ml). After complete addition, the reaction was stir-red at ambient temperature -for 5 min, and then 2-chloropyrimidine (1.6 g, 14 mmol) was added. The reaction wvas stirred at ambient temperature for 4 hours, and TLC at this time indicated an incomplete reaction. An additional quantity of the base a) 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 mixture was extracted with dichloromethane. The extract was washed dried cKC 3 ,and the solvent wvas concentrated to afinrd a Solid. The solid was trituated with diethvl ether and the product th3t separated was collected to Yield g of the starting alcohol. The filtrate w.as then concentrated to afford 3.8 cg of a waxy, yellow solid. This m aterial was combined wih2.6 g fromn another run and the combined sample Rash chrome tographeci on silica gel, eluting first with ethyl acetate and then with 6% diethy'iamine-ethyl acetate. Concentration of the appropriate fractions afforded 3.0 g of the desired compound as a yellow solid.

The sol-id was converted to a funmrate salt wvith furnaric acid in acetone, and then 0 reversed to its free base. It was combined with another sample and the combined sample (3.8 g) chromatographed-on silica gel on H-PLC (4.5.7a methanol-dichlorornethane 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 (16%) of 6-fluoro-3-[l-C2-py rim idinoxy)-propyl]-4-piperid i nyl]-1, 2 benzisoxazole fumnarate, m.p. =184-186*C.

ANALYSIS:

*Calculated for C,,HrFNO,: 5S .47%C 5.33%H 11.86%N Found: 53.52%C 5.34%H I 1.80%N EXArVIPLE 6-Aceto-2-[4-(6-fl uoro-12-benz.isoxazol-3-vD)--pineridinvllmethvl- 1.4-be nzodiox ani '4 6-a ceto-2-nt:esylo.-yrnet hyl-l ,4-benz7odioxonz 6-Aceto-2-h yd rox ymethyl-1,4-benzodioxan (3.39 g, 16.3 mmol) was dissolved in trichloromethane (100 nil). Triethvlamine (2.5 0) was added to mesylchioride g, 1.35 eq) at 0 0 C. The mixture was stirred for 2 hours at room temperature.

The mixture was then diluted, wvashed with an ice/dilute hvdrochloric acid mixture (150 Ml), wVashed with sodium bicarbonate and brine, dried over magnesium sulfate, and concentrated to vield 5-6 g. Following chromratography on a SiQ, ~column, 3.64 g (7Sr%' Yield) of 6-ct%-ev vvmtv-,-bnoixf ere obtained.

6-acecto-2-14 6 -1quro-12bnfnao- I -pxblneth,1- A stirred mixture of 6 -flutoro-3-(4-piperidinyl)-1,2-benzisoxazole (3.0 g 13.6 mmol), KCO, (21g, 14.5 mmoi) and 6 -aceto-2- ines vloxyl-nethyl- 1,4-benzod ioxa n V. (3.5 12 mmol) in acetonitrile (100 ml) Was heated at reflUX for 3 hours. At the *end of the reaction the solvent was removed on a rotary~ evaporator. The residue was extracted into dichloromethane (350 ml) and the insolubles were filtered off.

The dichioromethane solution was concentrated and the crude oil was purified by flash chromatog-raphy. The product thus obtained weighed 3.3S g Recrystallization from ethanol gave 6-aceto-2-t4-(6-fl uo ro-l1,2-ben zisoxa zol-3-yl)- I -pi perid i ny I met hyl 1,4-benzodioxan as light yellow crystals (3.2 m.p. =122-123'C.

ANALYSIS:

*Calculated for CH,-FN,O,: 67.31 %C 5.65%H 6.835'oN Found: 67.24%C 5.0H 6.75%tN EXAMPLE 91 2-r4-(6-Fl uoro-1,2-benzisoxazol-3-yI)-I-p i perid in vi lmeth vI-]1,4 -be nzodi oxa n A stirred mixture of 6 -fluoro-3-(4-piperidinyb)-1,2-benzisoxazole (310g.

13.6 mmol), K 2 C0 (2.45 g, 17.7 mmol), 2-methanesulfonyloxymethyl- 1,4-benzcdioxan (3.35 g, 11.7mmole) in acetonitrile (100 ml) was heated at reflux for 12 hours. At the end of the reaction, the insolubles were filtered and rinsed with dihooehn.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-fluoro- I .2-benzisoxazol-3-vl)-1 -piperidinylimethyl-1,4-benzodioxan as off-white crystals, 2.22 g, m.p. 86-87*C.

ANALYSIS

Calculated for CHFNO: 68.47 35735H 7.60%N Found: 6S.33T 0 C 3.7H 7.l% 32 EXAMPLE 92 2-4 6-Fluoro-1,2-benzisoxazol-3-vl)-l-pip~eridinv11ethvll1-i.4-benzod ioxan 2-mesvlo-ryethyi-A,-berzodio-ran7 C C SC C 00 To the compound 2-hy-droxyethyl-b,4-ben-zodioxa n 011.96 g) in dichloromethane (450 ml) was added triethylamnine (0.12 mnol, 10 ml).

Mesylchioride (9.2 g) was then added dropwise and the reaction mi~xture 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-mesyloxyethyl-1,4benzodioxan, 17.08 g.

benz!Odioxan A mixture of 6-fluoro-3-(4-piperidinyl)-I,2-benzisoxazole (4.7 g, 21 mmcl), KCO, (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 reflux for 3.5 hours. At the end of the reaction, insolubles were filtered., The solid was washed with dichloromethane (200ml).-Th soltion wee combied and evaporated to an oil. This crude oil was purified by flash chromatografphy on a silica gel column. The material thus obtained -was crystallized from ethanol. The 2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)-I -piperidinvlJ]-ethyl J-1,4-benzodioxan crystals were collected and weighed 3.8 g, 481/, m.p. =112-113'C.

Calculated for 69.09 7C 6.0 6%'6H 7.32%N Found: 69.17%C 6.0276H 7.31 %N EXAMPLE 93 64f34446-171 uuro-1 .?-benz is oxazo 1-3-0~-1-p iperid in v I ropox.vl-7mnelhorv-l-tetra lone 6-(3 -chloropropoxry)-7-mtnhoxv-l -tel intone A mixture of 6-hydroxy-7-methoxy-1-tetralone Q. Org. Chem., 198,5, 4937) (1.5 g, 7.8 romol), K,CO, (1.7 g, 12.3 inmol), 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 midxture. After-total addition, the *reaction was heated to i-eflux and stirred under nitrogen fo r 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-(3-chloropropoxv)-7-methoxv-1 -tetralone as an a mber oil.

-i4-(6-flutoro-1,2-bL'n:isoxaz-ol-3 1-piperidinylipropoxry]-7niethoxy-N-etralone 'a A mixture of 6-.luoro-3-(4-piperidinyl)-1,2-benzisoxazole (0.78 g, 3.6 mmol), KCO, (0.60 g, 4.1 mmol), KY (100 mg), 6-(3-chloropropoxy)-7-rnethoxy- I-tetra lone (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 extra cted w ith ethyl acetate. The ethyl acetate extract was washed with brine, dried with NMgSO,'and concentrated to yield 1.7 g of a brown oil. The *oil was purified by preparative HPLC (Waters Associates Prep LClsystem 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-i2-benzsoxazol-3-y)-1 -piperidinyl Ipropoxyl-7-methoxy-1 -tetra lone as a beige powder, mp. 129-131'C.

ANALYSIS;

Calculated for 69.01lC 6.4 6 cH 6-19%N- Found: 6S.77%C> 6.4 H 6-16%N EXAMPLE 94 W-34-Fl or--1 2 benzisoxazo 1-3-v D-I -2iperid in l prop vl 1-6acetyl-2-benznoxazoi none N-(3-ch-iloro-propv'i -2-benzrrrazeclinore To a stirred suspension of sodium hydride 7 .8 g, 160 mmol, ether-washed) *in dimnethylfor-mamnide (75 nil) was added dropwise under nitrogen, 2?-benzoxazolinone (20.0 g, 150 mmol) dissolved in dimethylforniamide (150 m) 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-chloro-1 -bromopropane (46.6 g, *.300 mmiol) in dimethylforma-mide (50 nil) wvas added dropwise (temperature never exceeded OoC). The reaction wvas 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 wvater, dr-ied (N4gSO,), and the extract concentrated to afford 21.9 g of a brown solid. The solid was recrystallized from toluene-hexane to afford N-(3-chloropropvl)-2benzoxazolinone as large needles, 15.6 g, mnp. 264-266'C.

N-(3-cloropropyl)-6-acetyl-2-benizoxa--oizorne mixture of N-(3-chloropropyl)-2-benzoxazolin one (8.5 g.40 roinoiX polyp hospho ric acid -0 00 and acetic acid (2.4 g, 2.3 mil, '40 mmol), was stirred &loop and heated at 100*,Cfor 2 hours. The hot solution was poured into ice-water to deposit a yellow gum. The mixture was extracted with dichioromethane, and insolubles were filtered. The dichloromethane extract was washed with water, dried (K.C0 3 and concentrated to afford 6.4 g of a slightly green solid. This was recrvstailized from ethanol (9570 to yield N-(3-chloropropyl)-6-& v.2ezxazolinone as a brown solid. 3.5 g, mi.p 100-103'C.

6-ccet rozoinone

S..

S

.A mixcture of 6-fluoro-3-(4-pipe rid iny)-1,2-benz isoxa zo le (2.0 g, 9 mmol), N-(3-ch loro propyl)-6-acety 1-2-benzoxa zol ino ne (2.4 g, 9 mmol), K.CO, (3.6 a fewv 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 I yellow solid, and recrystallization from ethyl acetate yielded 1.2 g of N-[3-L4-(6-fluoro-1,2-benzisoxazol-3-y)-1 -piperidinylipropyli- -6-acetvl-2-benzoxazolinone. m.p. 152-154 0

C.

A.NALYSIS:

Calculated for C,,H,,FN 3 O,0: 65.899%C 5.53%H 9.61% N Found: 65.67%C 5.48%H 9352%N EXANIPLE N-13-[4-(6-f luoro-1,2-b enzisoxazo 1-3-0l-1 -pipe rid i nyl propyl ]phth a Iimid e A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (6.44 g, 29.1 mmole), K.CO, (6.4 g, 46 mmol), N-(3-bromopropvlphthalimide (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 chromat ography to give iN-(3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1piperidinyllpropyllphthalimide as a white solid. Recrystallization from ethanol yielded 9.8 g of off-white crystals, m.p. 129-130'C.

ANALYSIS:

Calculated for 67.89%C 5.44 7cH 10.31%N Found: 67,49' C 3. 35 c -H 10. 13 EXAMPLE 96 14(3-Arnin opropyl) 4-(6-f luoro-1,2-benzisoxazoI-3-vi) pipe rid in e dihvdrochioride A mixture of N(-4(-lool,-ezsxzl2y)1-iei y) propyflphthalimide (8.5 g, 21 rumol), 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 HO] to pH 1. The insolubles were filtered with the aid of a pad of Celite. The aqueous solution was basified with NaOH, (pH 13), then extracted with dichiororn ethane. The combined dichioromethane solution was washed with brine, then dried to a colorless oil The analytical sample (1.3 g) was prepared by treating the oil with HCI in etha nol at 0 0 C. The I-(3-a min opropyl)-4- (6-flu oro- 1,2- benzisoxazo 1-3-yl)pi perid ine dihydrochloride was obtained as white crystals, 2.03 g, rn.p. =231-234C.

ANALYSIS:

Calculated for Cj 5

H,

0 FNO.21-1: 51.44%C 6.3 3 76H 12.00%N Found: 51.35%C 6.49%coH H1.909%N EXAMPLE 97 cis-2-f 344- (6-F uoro-.2-b enzisoxazol-3-y D-T-p iperi din yl prop vilh exa hydro- IH-isoindole-1,3-d ion e hvdrochloride A mixture of 1 minopropyl)-4-(6-tluoro-1,2-benzisoxazol-3-yi)piperidine (3.01 g, 10.8 rnmol) and cis-1,2-cyclohexane-dicarboxylic anhydride 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 (675a). This was converted to the hyvdrochloride salt by treatment with HCI in ethanol (G0 ml). The cis-2-13- (44(6-flu oro- 1 2-benzis oxa zol- 3-vIl)- i-o~ioer-idinvlpropyl]-hexahv-dro-1 H-isoind,4ole -l,3-dmon-e hy-drochloride crvsta6so obtained weighed 3.0 g.p. =2412-245 0

C.

137

ANALYSIS:

Calculated for CH.,FNO 3 .HCl: 61-1 4cC 6_50 %R 9-34 %N Found: 6 1.32 %cC 6.32' H 9.277r N EXAMPFLE 98 N-r4-r41(6-Fluoro-1 .2-benzisoxazol-3-vlI)-i-pi c.tridinx'llbutyllphthalimide A mixt-ure of 6-fluoro-3-(4-piperidinvl)-1,2-benzisoxazole (5.5 g, 25 rrnol), 4-brornobutylphthalimide M8. g, 28.3 mmol, 1.13 Eql. KCO, (4.55 g, 32 mmol) in a~cetoniitrile (100 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 wvas concentrated gradually to allowv cvstallization. The crude crystals (5.9 g) were collected. The mother liquor was concentrated to a solid (5.5 Purification was by fla sh chromatography over a silica gel column.

The product (3.8 g) thus purified was recrystallized from ethanol (70 ml) to give 1 248 g of N-f4-[4-(6-fluoro-1. 2-benzisoxa3zol-3-vl)-1 -piperidiniyljbu tyl]phthalirniide as whitecerxstals, rn.p. 144-1-16'C.

ANALYS IS: Calculated for C,,H,,Ft\1O 3 6S.3917,C 5.7 4 %cH 9.97%N Fou nd: 68.34%C 5. 7 4 6H 9.84 EXAMPLE 99 1-(4-Am inobu tvD)A-(6-f I uoro-1,2-b enz isoxazol-3-N-I)p ipe ridin e dihydrochloride A mixture of N4(4-[4'-(6-fluoro-1 ,2-benziso,<azol-3--Y piperidinylbutvllphthalimide (6.9 g, 16.4 mmol) and hvdrazine monohydrate (1.64 g' 32.8 mmol) in methanol (70 ml) was healed at re,9u\ For 3 hours. At the end of the reaction. methanol was rero'ved to leave a cr-ude solid. This was dissolved in water and acidified wit;h HOiC to D),l I The ingsolubles were filtered. The aqueous solution was basified ih OcNaOH. and then extricted with dichioronmethane- The dichioromethane solution was washed w,.ith water- and brine, and then dried over N'1g50 4 The solvent was removed to a colorless oil: 4.48 This oil was treated with 2.5 equialents of HCI in etnanol. The solid wvas collected.

Recryvstallization from ethanol (65 mld) and meth~anol (20 ml) gave I -(4-aminobiityD)-4-(6-fluoro-] ,2-benzisdxazol-3-vl4[5ipe ridinie dihydrochldiide as white cry stals, rn.p. 234-237C.

AINALYRiS: Calculated for C 0 3 s.2,HCl: 52.75%C 6,64%H 11.53%N Found- 52.37%7C 6.59%H 11.07%cN

C.

C .4 4 C EXAMIPLE 100 ci--4[-6Fur-,-ezsczl3v)lpp~iivluvleaido 1H--isoindole-1,3-dione hvdrochloride* A mixture of 1 -(4-arninobutyl).4-C6-Hluoro-i-,2-benzisoxazol-3-yl)pipeiidine (4.7 g, 16.1 rnmol) and cis- 1,2-cyclohexa nedica rboxy lic anhydride (3.23 g, 21 mmol) An pyridine (45 ml) was heated at reflux for S 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 3.15 g as a clear oil. Th is oilI was dissolved in ethanol (15 ml), then was treated with HCI in ethanol (45 ml).

Crystallization took place upon cooling. The crystals were collected, 3.2 gm.p.= 229 -2 31C.

ANALYSIS:

Calculated for C,,HFN 3 'O,.KCI: 62.13%C 6.73% H_ 9. 06%N Found- 61.79%C 6.68%H 8.92%N EXAMIPLE 101 1-r4-3-4-6-Fuoro-,2-benzisoazol-3-vID)-I-p iperid inl,[ ro 12y] th iol-3me tho xvphen v I Ie th a none I -44(3 -ch toropr-opvI)thioI-3-methoxypenylleia rnone -4A Amixture of 1-(4-thio-3-methoxyphenyl)ethanonie (10.0 g, 54.9 mmol), potassiumr carbonate (9.0 g, 651 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-b.-omo-3-chloropropane (6.5 ml, 9.5 g, 60.4 mmol) dissolved in acetone (25 ml) was dripped into the reaction. After complete addition, the reaction was heated to reflux and stirred uinder nitrogen for 17 hours. After the reaction was carried to substantial completion, the reaction mixture was filtered *4 and the resulting filter cake was washed with acetone. The filtrate-was 4...concentrated to~providle an amber oil. A small sample was solidified by tbituration.

with hot cyclohexane to provide ]-[4-[C3-chloropropyl)thio]-- 3-methoxy-phenyljetlhanone as a yellow solid, 11.7 g, m.p. 53-55'C.

thiol-3-methoxypiEnvtfelkanone A mixture of.6-fluoro-3-(4-piped-dinyl)-1,2-benzisoxazole (3.0 13.6 mmol), 1-[4-[(3-chloropr6 pyl)-thioi -3-rnethoxyphenylletha none (3.5 g, 13.6 mrnol), KC0 3 g, 16.6 mnmol), KI (200 mng) and C HCN (100 ml) was stirred a t reflux under nitrogen for 7.5 hours and then w.as left at ambient temperature for-63 hours.. The reaction was Ipoured into water and the aqueous mixture was extracted with ethyl acetate. Th e ethyl acetate extract was washed twice.. with water, once with brine *and dried over MgSO 4 The solvent wvas removed- ir uacuo to afford 6.8 g of a: lighv-_ brown oil. The sample was purified by flash chromnatog'raphy. Concentration of appropriate fractions yielded 3.0 Recrystallization from ethanol provided 2.4 g (41%7) of 1-[4-(3-[4-(6-fluoro-1,2-benzisoxazol:3- l)-1 -pip~eridlinvllpropyllt-hio]- .,-methoxv-phen -il -ethanore as a beige solid, mp. 93-95C.

ANALYSIS:

Calculated for C,,H,.FN,O 3 S: 65.14%C 6.15H 6.3 3 N Found: 64.66%C 6.17%H 6.26%N EXAMPLE 102 4-(6-Fluoro-1,2-berizisoxazol-3-yl)-l-(2'7methoxy-phe nvl~b utylp iperdinle nialeate 2-(4-brornobuty~anisole 2-Bromoanisole (2.0 g, 1.07 rnxnol) in tetrahydrofuran (20 ml) was cooled to -78'C under nitrogen and secondary butyllithium (1.3 M, 10 ml, 1.3 eq) was 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.

he mixture was diluted with' ethyl acetate, washed with water and bine, and Ga* concentrated to an oil. Following o3orah n a SiC, column, 2.4 o 2-C4-bromobutyl)anisole were obtained.

-4 c6-fluioro-l 2-be'izisoxazoI-3 '-mett horphecnyl)bt y!piperidine mnaleate- A mixture of 6-fluorp-3-(4-piperidiniyl)-1,2-benzisoxazole (2.36 g, 107 dlN~bnimole), KCO, (2 g, 14.5 ri~mol) and. 2-(4-brornobutyl)anisole (2.4 g, 10'mmol) in acetonitrile (100 ml) vas heated at reflux for 2.5 hours. At the end of reaction, the solvent was removed. -The residue wvas; extracted into dichloromethane (200 ml) and filtered. The dichloromethane'so!lutionm was concentrated. The crude oil obtained wvas purified on a flash chromatography column. The material thus purified was a light yellowv oil (2.73 g, This oil was dissolved in ethanol and treated with maleic acid (607 mg, 1.0 eq) itt ethanol. The .4-(6-fluoro-1 ,2-benzi-soxazol-3-y)-1 -(2'-methoxyphenyl)-butylpiperidine niale'ate crystals formed on concentration and subsequent cooling to 0 0 C. These were collected and dried to yield 2.05 g, m.p. =132-133 0

C.

Calclated for CH QH 4 0 4 65.057cC -2 7 H 5.62%N Found' 65.235':C 6.30%H 5.70%N EXAMPLE 103 1-f4-(1.3-Dithian-2-vl)ethyllphenvl4-(6-fl uoro -1,2-benzisoxazol-3-vl)butyliperid ine- 4-bromo-l-(l,3-diihian-2-yl)efhylbenzene To the compound p-bromoacetophenone (36.85 g, 185 mmol) in tr-ichioromethane (300 ml) was added l,3-propanedithiol (23 g, 230 rnmol) and boron em..'trifluoride etherate (3 ml). The resulting mixture was stirred at room temperature for 48 hours. The mixture was diluted with dichloromethane (500 ml), washed twice- with 10%6 sodium hydroxide (200 ml), water, and br-ine, and then dried (NaSO,). The product was concentrated to an oil. A portion was stir-red 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 ,3-d ithian-2-yl)ethylbenzene.

4-(4-bronobuty0~- I .3-difhiiant-2-yI~etlhylbenzente A solution of 4-bromo-1-(1,3-dithian-2-yl)e thylbenzene (27.2 g, 94 mmol) in tetrahydro furan (200 ml) was charged with sec-butyllithium (99 ml, 1.3 M in cyclohexane, 0.13 mole) dropwise at -78'C under nitrogen. The mixture was 00 stirred at ambient temperature for 1.5 hours, and then quenched with 1,4-dibromobutane (42 g, 0.2 mole). After being stirred for 3 hours, the midxture was poured'into ethyl acetate, and then washed with water and brine. The organic solution was then dried (Na 2

SO

4 and concentrated ,to an oil. The crude product was purified by flash chromatography over a silica gel column. The 4-(4-bromobutyl)-1-(1,3-dithian-2-yl)-ethvlbenzene thus purified was a light oil, 22.3 g.

AN\ALYSIS:

Calculated for 52.17%C 6.13 i-i Found: 52.60%cC 6.2517cH 4-

*.I

goo 3 -yIbu ty piperfd* ine A mixture of 6-fluioro-3-(4-piperidinyl)-1,2-benzisoxazole (5 .4 g, 24.5 mmol), K,CO, (41.2 g, 30 rnol), 4-(4-bromobutyl)-1-(1,3-dithian-2-yl)ethylbDenzene (8.5 g,.

24.6 mmol) in acetonitrile (200 mld) 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 ethanol (50 ml) and hexane (100 ml) to afford 6.6 g of 1-[4-(l,--dithiani-2-yl)ethyllphenyl-4-(6-fluoro- 1,2-benzisoxazol-3-yl)butylpiperidine as light vellow crystals, m.p. =108-110'C.

ANALYSIS:

Calculated for: C,,H 33 PN,OS, 66.91 %C 6.86%H 5.78%N Found: 66.72%C -6.76%OH 5.71 %N EXAMPLE 104 1444-Ace top hen yl) butl -4-(641 uoro-1.2-be nzisoxazo 1-3-Y 1) pi eri dine A solution of 1-[4-(l,3-dithian-2-yl)ethylphenyl~butyl-4-(6-fluoro- 1,2-benziso-xazol-3-yl)piperidine (5.6 g, 11.6 mmol), w-.ater (5 nil), and methan -ol mil), in acetone (50 nil), was treated with mercury (11) perchlorate trihydrate g, 1.1 eq.) atroom temperature. After 30 minutes, the reaction was completed.

The solids were filtered, and the solvent was removed on a rotary evaporator. The crude product was dissolved in ethyl acetate (500 mil) and washed with water, brine, then dried over NaISO,. 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 witiv 1..1 g of oil prepared in the same fashion. Crystallization from ethanol (10 ml) an,,d hexane (20 mil) yielded 1-44'4acetophenyl)butylJ-4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidifle as off-white crystals, 2.32 g, m-p. 85-86 0

C.

AINALYSIS;

Calculated for 73 .07C 69% 71 Found: 7 2.6 S %cC 7.03'ioH 7.09%N

I*

-s 4 EXAMPLE 105 1-1r4-3-4-(6-Fluoro-1,2-bernzisoxazol-3-yI)-4-p iperidinyllpro'lamrinol-3metho.U-phenvilethanone To a stirred suspension Of sodium hydride (0.37 g, 7 mmol of a 50% oil dispersion) in dimethylformamide (20 ml) was added, dropwise, 1 -[4-[3-[4-(6-fluoro- 1,2-benzisoxazol-3-yl)-l -piperidinyl] propylamino]I-3-hyd roxyphenylletha none (2.9 g, 7 -rnmol) dissolved in dimethylformamide (25 ml). The reaction was stirred at ambient temperat ure for 15 minutes, and then it was cooled with an ice bath to about 5*C, whereupon methyl iodide (1.0 g, 7 mmol) in dimnethylformamide (I ml) was added dropwise. The reaction was stirred at ambient temperature for 30 min, and then wvater was added. The resulting aqueous mixture was extracted with ethyl acetate, the extract w.ashed with water, dried and the solvent was concentrated to afford 4.9 g of a brown oil, which solidified on standing. The solid was flash chrornatographed on silica gel. The appropriate fractions w~ere concentrated to yield 2.7 g of product as a yellow solid. Recrystallization from toluene-hexane yielded 2.0 g of analytically pure 1 oro- 1,2-benzisoxazol-3-yl)- I -pipe rid i nyl I propyla mino]J-3-methoxyphe nyllethanone as a yellow solid, m.p. =96-93'C.

ANALYSIS:

Calculated for 5

PN

3 6 7.75%7cC 6 .6 3 %lH 9.88%N Found: 67.93%C 6.72%rH 9.80%N EXAMPLE 106 (2,4-Difluorophenfl)-[1-(phenvlmethfl)-3-p~'rolidinyllmethanone oxalate- In a I liter round bottom flask, a solution of ethy-l-N-b enzvl-3-pyrrolidine carboxylate (213. g, 11.7 mrnol) in 140 ml of 6N HG w.as heated at reflux forhours. The solution was cooled and the solvent wvas removed to dryness with a vacuum pump. The residue was then treated with thionyl chloride (100 mld) for 16 hours at room temperature. After the reaction, the excess thionyl chloride was vacuum stripped to dryness (60*C, 4 hours). To the residue in the flask was added 1,3-difluorobenzene (30 g, 26 mmol) followed by aluminum chloride (25 g, 18.7 mrnol) in portions at room temperature. When the mixture turned homogeneous (in about 10 minutes) it was then heated at 550C for I hour. After the reaction was complete, excess 1,3-d ifl uoro benzene was removed under reduced pressure.

The residuie was partitioned between ice/water and dichloromethane (700 ml) and basified with 50% NaOH solution to pH 10. The dichioromethane solution was washed with water and brine, then dried over anhy,. us MgSO,. The solvent was **stripped and the crudle oil (31 g) was purified; by flash chromatography over a sil-ica gel column. The pure product thus obtained weighed 26 g as a yellow oil. An analytical sample w'.as prepared by dissolving 4.2 g of the oil in ethanol and treating with an ethanol solution of oxalic acid (0.33 g, 14.8 mmol). To the mixture was added ether dropwise to cause crystallization. Recrystallization from ethanol and ether gave 2.63 g of 9:.(2,4-7difluorophenyl)(1I (phenylmethyl)-3-pyrrolid ilyl Imetha nonle oxalate as white crysta Ls, m.p. I I4-116'C.

ANALYSIS:

Calculated for C, 0

H

1 9 ,FN0 5 61.38% C 4.89%H 3.58%N Found: 61.16%C 4.80%H 3.60 %N EXAMPLE 107 00 (2 ,4-dipfuorophenyl)f17(phenylrnefliyI)-3 .pyrrolidiny!)nietAn none oxime To the compound (2,4-difluorophenyl)E1-(pheflylmeth,"i.

3 pyrrolidinyljmethanone (22 g) in 93% ethanol (330 ml) and -wa ter (100 ml) was added NHOI- HCO (10.1 g) and ammoniumn acetate (12.7 g, 2.1- en). The resulting mixture refluxed for 3.5 hours. The mixture was then allowed to stir at room temperature for 24 hour-s. The reaction mixture was concentrated to remove ethanol, poured into water (500 ml), and extracted with dichloromethane (500 m~l.

145 This was followed by wvashing wit h v.ater, brine, and dryigavrmgnsu sulfate. The product xoas concen~trated to an oil and purified bN, colun chromatography to yield 12 g of 4 ifluorophenyl)( 1-(phenvlrnethyl)-3-pyrrolidinyllrnethanone oxime.

MB) 6-fluoro-3 4- -fphenylrct hyl)-3 -pyrrolidinyll- 1, -ben zisoxazole fuma rate A mixture of (2,4-difluorophenyl)f1-(phenylmethyl)- :3-pyrrolidinyllmethanone oxime (10.8 g, 34.2 mmol), potassium hydroxide (10 g), water (100 ml), and ethanol (100 ml) was heated at reflux for 2 hours. At the end of the reaction, the solution wvas cooled and ethanol was removed on a rotary *6Sevaporator. The aqueous mixture was diluted with water (100 ml) then extracted with dichloromethane (500 ml). The organic -solution was washed with brine and dried over anhydrous MgSO 4 The solution was concentrat ed to an oil (9.8 The crude product was purified by flash-dirumdtography over a silica gel column. The product thus obtained weighed 4.46 g as a light yellow oil. The oily product was dissolved in ethanol, and then treated with a solution of.'fumaric a-cid (1.

73 .g, 1.0 eq) in ethanol. Crystallization took place slowly with the addition ofl isopropy 4ether. Recrystallization from ethanol (15-ml) gave 4,6 g of 6-fl uo ro-3-[ D -(pheny Ine thyl)-3-py rrotid inyl I ,2-benziox:a zole fumalra te as white crysalsm~= 142-144'C Calculated for C_ H, 1 FN,0 5 64.07%C .13 %H 6.81 %N Found: 64.11 %C 5.05 %H 6.89%N EXAM PLE (EM -l4-r(4-hromn-2-buteny'l)o-Lvb3-m etho-rvphenyllethanone A mixture of 4'-hy-droxV;-3-mnethoxvacetophenone (10 g, 59 mmol), KCO, g, 1.2 q) and 1,4-dibromo-2-butene (>95%i trans, Aldrich, IS g, 1.2 eq) in acetone (500 ml) was heated at 55'C for 3-hours. At the end of the reacbon, the solvent wvas concentrated. The crude product wvas extracted into dichloronethane (750 ml) and the insolubles w.ere filtered;- then the Solution wvas concentrated again to an oil. Purification on a silica gel column (SiO. 100 g, elUted wvith dichioromethane) yielded 7.25 g of white solid. Recr-vstaLlization from ether gave analytically pure 14 [4(4-bromo-2-bu teny 1)oxy] -3-meth oxyphenyllI et ha none (3.91 m.p. =71-72'C.

ANALYSIS:

Calculated for C,,H~sBrO 3 52.19%C 5.50%H Found: 52i12%oC 4.9 4 L6H *aaa 4 4 a, a.

S* a* .e a *4 EXAMPLE 109 4-(3-Chloropropoxy)-3-metho-xvbenzaId eh vde a a ~a a 'a A mixture of vanillin (30.4 g, 200 mmol), K 2 CO, (27.6 g) and acetone (150 ml) was stirred and refluxed for 0.5 hours. Heating was removed and l.-bromo-3-chloropropane (40.8 g, 260 mmol) in acetone was added diro pwise. The reaction was -stirred and refluxed for 16 hours, and then it was poured into water.

The aqueous mixture was extracted ith diethyl ether, the extract was dried (MgSO,),:and the solution was concentrated K rdan oil, which upon evacuation solidified to a white solid (50.2 'An 8.0 _g sample was flash chromatographed on silica gel with 505/ ethyl acetatehexane as eluent.

Concentration of appropriate fractions gave 2.7 g of 4-3chloropropoxy)-3-methoxvbenza Idehyde as a %-whi te solid, m.p. 53-55'C.

ANALYSIS:

Calculated for C,,H,~l 3 77% 5.73 7aH -am 57.2176C 5.52%H Found: EXAMPLE 110 6-Fluoro -3-(-p-rolidinv)-12-benziso-<azole hydrochloride A m-ixture of 3-(6-filuoro-1 ,2 -benzisoxazol-3-yl)-1 -pyrrolidinvlcarboxylic acid ethenyl ester (5.1 18.4 mmol, hydrochloric acid (G ml), and isopropyl alcohol ml) was heated at reflux for 3.5 hours. At the end of the reaction, the solvent was reduced to about 30 ml on a rotary evaporator and the mixture was cooled to 0 0 C for 2 hours. -The crystals were collected by filtration and rinsed with cold 6 isopropyl alcohol. The 6-fuoro- -(3-pyrrolidinvl)-l ,2-benzisoxazole hydrochloride product weighed 3.09 g 225 -227*C.

ANALYSIS:.-

Calculated for C 1 Hj 1 NO.HCl: 54.,14%C 4.99%c.H 1 l.54%N Found: 54.35%C 4.99%l-IH 11.3.8% N EXAMPLE III *1-4-[3-446-Fd h -L,2-benzisoxazol-3-vI)4-1viperid invlnrov lam inol- 3-h yd roxymph en vllet han one A mixture of N-[3-[4-6-fluoro-1,2-benzisoxazol-3-yl)-1 -piperidinyllpropyl- 6-acetyl-2-benzoxazolinone (6.0 g, 14 mmol) and 10% aqueous sodium hydroxide ml) was stir-red and refluxed for 40minutes. Water was added and the 4reaction was made acid ic'.Aith 5% hydrochloric acid. Saturated Na 2 CO, was added until effervescence ceased. The aqueous mixture was extracted with dichloromethane.- The dichloromethane extract wvas .ashed dried (K.CO) and concentrated to afford 2.6 g of a tacky' solid. The crude solid was treated. with domo. saturated NaHCO, and extracted into dichlorormethane. The dichiloromethane was washed (brine and then -water), and dried (IMgSCd. The organic extract was then concentrated to yield 2.4 g of a brown solid, w.hich was combined with another sampleto. ield 5.0 g. This sample vwas lash chromatographed On silica. A small sample (0.25 g) wvas recrystallized from toluene to yield l-[4 -(4-(6-fluoro- 1,2-bea-zis-oa zol-3-'AYl-ipiperidinvllp,-opylamniol-3-h-vdo rovhn.lehnoea brownish solid, 0.15 g, imp. 150-152*C.

U.M

ANALY51S: Calculated for CHJFN 3

O

3 67.14%iC 6.3-%H 10.21%N Found: 67.-94%C 6.58%1H- 9.95%N EXAMPLE 112 A stir-red mixture of i1-[3-acetylarnino-4-hydroxyphienyll-ethainone 7 7 g 40 rnrol), K 2 C0 3 (5.7 3-chloro-1-bromopropane (8.9 g, 56 mmol), and acetone 4 0 (100 ml) wvas 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 recrystallzed from toluene and then from ethanol to afford g of an off-white solid. A 3.3 g simple 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 Sethanol-water to yield 2.2 g (51 of 1-(3-acetylamino- 1554-(3-chl oropropoxy)phenyl) etha none as a white solid, mn.p. 124-126*C.

ANALYSIS:

Calculated for CuH, 6

CINO

3 57.89%C 5,93%H- 5,19%iNi Found. 57.08%C 5.85%H 5.13% N lit__ EXAMPLE 113 N-f2-(3-hvdroXYPTOpoxv)p2henvl lacetamide A st irred mixture of 2-hydlroxypheny'laceta mid e (10.0 g, 66 mmol), KCO, (6.9 3-bromopropanol (12.8 g, 12 mmol), and acetone (250 mld) was refluxed for 16 hours. The reaction mixture was allowed to cool, and then it was filtered. The filtrate was concenrated 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 collectz'-.

The oil solidifie~d upon standing- An analytical samiple was obtained by recrNstallization from ethyl acetate to afford the alco'hol as an off-white solid, m~.78-SO'C.

A NA Calculated for C,,H 5 ,N0 3 63.14%C 7.23 51H 6.69%N Found: 63.10%C 7.32%U 6.64 N EXAMPLE 114 4-r4-(6-Fuor 12-benzisoxzo1-3-)ipiperidinvllbutvI bromide A mixture of 6-fiuoro-3-4-piperidiinyl)-l,2-benzisoxyazole (12 g, 55 mmcl), KCO, (13 g) and 1,4-dibrornobutane (20 g, 9.3 mmol, 1.7 eg) in acetonitTile (300 ml) was stirred at room temperature overnight. The inorganic material was V filtered. The solution was concentrated to -80 nil, when crystals crashed out. The :product was filtered to yield 14.16 g m.p. =243-245'C.

ANALYSIS:

Calculated For C,H-,BrFNO.C: 54.09%:-C 5.67%H 7.S9% IN **Found: 54.13%C -5.52%H 7.S3%oN EXAMIPLE 113 2-[4-(6-Fluoro-1,2-benzisoxazol-3-..)lpipecridinylethvI acetate funiarate A mixture of 6 -fluoro-3-(4-piperidiniyl)-1,2-benzisoxazole (310 g, 13.6 mmcl), KC,C0 (3.5 g, 25 mmol), 2-bromoethyl acetate (4 g, 26.5 mmcl) in acetonitrile mld) was heated at reflux for 4 hours. After cooling to room temperature, the inorganic salts were filtered and washed with DOM (dichloromethane 50 nil). The organic solvent was removed on a rotary evaporator to give an oil. The oily ~~product was purified on a flash chromatorah coun(0uo i 2 ltdwt MeCH 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.

l54-155*C.

ANALYSIS:

Calculated for CH,,FNOC,HO,: 56,S, C 3. -19 %H 6.63%>!N Found: 675C 5.4170H 6.54%N EXANMPLE 116 N-[2-I4-(6Fluoro-1,2-bc-nziso-xazol-3-vlI)-l-piperid inv I I ethv I niorph a in e A mixture of 6-fluoro-3-4-piperidlnyl)- 1-benzisoxazole (3.0 g, 13.6 mrnol), 2-chloropthy'l morpholine hydrochloride (4.46 g, 29.7 rnmol) and K 2 C0 3 (7.3 g, 2.2 eq) in acetonitrile (60 mil) wvas heated at reflU.X for 24 hours. The crude m-L'<ture was diluted with DCMY and filtered. The solvent was concentrated to an oil (-7.1 Purification on a silica gel column (55 g, SiO,, eluted with M%,eOH:DCNI) yielded a solid product weighing 4 g. Recrystallization from hot ethanol yielded 2.A g m.p. 131-132C.

ANALYSIS:

Calculated for C,,H,,Ft' 3 64.84%C 7.2 6 cH 12.60%7cN Found: 64.80%C 7.09%H 12.-/7%N EXAMPLE 117 N-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-vl)--piperidinvllethvllphthalimnide A mixture of 6-tluo.o-3-(4-piperidinyl)-1,2-benzisoxazole (5.15 g, 23.4 mmol), K,CO, (4.2 g, 30.4 minol) and 2-bromoethyl plithalimide (7.13 g, 28 mmol) i6~ acetonitrile (250 nil) was heated at reflux for 3.5 hours. The solids and solvent wyere removed. The residue was purified by flash chromatography (SiO 2 110 8, eluted with 2-4% CHOH:DCIM). The product thus obtained 'weighe-d 7.3 g (849o). Part of the material W, rersalie to give 2.3 5 g of off white crvstals, m.p. 148-149'C.

A NA LYSIS: Calculated for C-,,,FIN,0 3 67,177%C 5. 12%H 10.68%N Found: 67.01 %C 3.20 H 10.76%N N-I2-14-(6-F-luoro-I 2-bcrnzisoxc!o-3 1-&ri nlty1hhaird' Imivrod: bride To a solution of 8.0 g of oro ,-eiisoxazo1-3-vi)- 1-Piperidinv-lethv-Ilphthalimic,, in dcoreh vm- HCI in ether. The salt crystallized out rapidlv. ItL 6kas flltered off, washed wvith ethanol and dried to afford 8.15 gwith m.p. =257-259C, dec.

Recry-stallization provided 7.20 g of pure white salt, with M.P. Unchanged.

ANALYSIS:

Calculated for :C,.FH,.FNO,.HCl 61.47%oC 4.927%H 9.77%NI *Found: 61.12%C 5.21%5'oH 9.58S76N EXAMPLE 118 2

-F

4 -U3-.loro-.2-benziso-vcazol-3-vl-)-1..pipridinletii! Imethyl ether furnarate a .4 A mixture of -6-fluor-o-3-(4'-piper-idinvl])-1 ?-benizisoxazole (3175 g. 17 nmol), KC0 3 (3 a, 21.7 mmol), bromnoethyl methyl ether (2.84 g, 20.4 ramol) in acetonitrile (150 ml) was heated at reflux for 3.5 hours. The reaction was cooled. The inorganics were filtered and rinsed with DOM. The organic solution was concentrated down to an oil (7 Purification on a flash chromatography column (SiO,, 45 g; eluted with methanol/DCNOf gave a light yellow oil as product (4 g, This oil was dissolved into ethanol and treated with a solution of furnai-ic acid (1.67 g) in ethanol (20 ml). White crystals (5.15 g) were collected, rn.p.

66Calculated for 57.S6%,'C SS% r.H 7. 1 POFound: 57.53%C 5.944%H 6.94%N EXAMPLE 119 4-r4-(6Fluor)L?.2benzis~olo[>vi)-l-nperidinl yllbu tvl- acetate fumnarate A mixture of 6 tur--(4 -pipe rid invl) -i,2.benzizoxazolO (9.5 g. 41 mrnol).

K,C0 3 (7.2 g, 51 mrnol). and 4-bromobutyl acetate (10 g,51 mmoi) in acetonitrile

S.

0**e a

S

U.

'S

~t1 (200O ml) w, as heate-d at reflux icr .5 hourS. At the e,-d of the reaction, the solution cooled and filtered, The inorganic 5.sIt %Nas shed with DCI(50 Hit). The organic solvent was removed. The residue -was purified on a flash chromatography column (packed with Sorbsil C30 silica gel. 100 g, eluted with DOM, I liter, increasing methanol from 2 to 47o, 2.51). The material thus purified weighed 12.92 g A small sample (1.67 0) w'as dissolved in ethanol and treated with 1 equivalent of fumaric acid (580 rrug) in ethanol to yield white crystals: 1.3 g. n.p. 142-14-C.

ANALYSIS:

Calculated for C,,H, 1

N'O

3 .CHO,: 35.665%C 6.04 %cH 6.22% N Found: 5 8.5 6 c;C 6.02%HI 6.13%,N EXAMPLE 120 n-4(6-luoro-12-benzisoxazol-3-vl)-l-Piperidilvllbuta3noI fuma-ialf A mixture of 4-[4-(6-fluoro-1 .2-benzisoxazol-3-yl)-i -piperidi.nyllbutyl acetate (11.5 g, 34.4 rnrol), 15% NaOH (100 ml) and ethanol (M0 mnl) was heated at reflux for4 hours. Aft.er cooling to room temperature, the base was neutralized with H-lI to PH 7. The solution as concentrated down to a small volume (-50 then extracted w-.ith DCOM. The DCM solution w.as w-.ashed with brine and dried over MgSO 4 T he solvent was concentrated to give -10 g of crude oil. Purification by flash chromatography (Sorbsil C-30, 100 g, eluted with %.eOH:DCLV, 3 liters) yielded 9.8 g of white solid. The sample for testing was prepared by treatment of the'free base (2-0 cr) with Fumaric acid (780 mgr. 1.0 eq) in ethanol. The crystals were collected and dried: 1.5 g, m.p. 131-132'C.

ANALYSIS:

Calculated for FN,O,.CH404: 5S.S2%C 6-17% H 6.86%N Fou no: 58.811iCC 6.3 7% H 6.6 6 %cN EXAMPLE 121 4-4(--lcr)12b -iio-ao--i--ieifnvluv decanoate fumarale To a solution of 4-[4.(6-itnoro-12-be-zisoxazol--Yl)-1 -piperidinylbutanol, g& 6.64 mrnol, triethvlarnine (1,0 9, 10 mmol) in DCM~ (70 ml) decanoyl chloride (1.7 g, 8.9 rnrol) was added dropwise at room temuera Lure. The mixture was stirred for I hour., then was concentrated to a crude solid. The solid was extracted ito ethyl acetate, and the insoluble salts were filtered. The solvent-s were removed. Tme crude product was purified by flash chrornatog-raphy (Sorbsii.

30 g, eluted with a mixture of M~eOH in L)CMV). The oil thus obtained (2.5 g 81%) was converted to a fumnarate salt with ifumnaric acid (650 mg, 1.0 eq) in ethanol. Crystals were collected: 1.4-S g, m.D. 109-110'C.

*****ANALYSIS:

*.:Calculated for C, H Fi\,O.CHO,: 64.04%C 7.70%H 4.98%N *.Found: 6430%C 7.86%F 4.78,%,N EXAMPLE 122 3-4(-lno12bnioao--l--i rdnlpov decanoate fumarate To a solution 3- 47-(6-fluoro-1 ,2-benzisoxazol-3-yl)-1 -piper-idinylipropanol (1.81 g, 6.5 mmol) triethylamine (0.

9 g &9.0 mmol) in DOM (45 ml) was added decanoyl chloride(1.5 g, 7.8 mmol) dropwise at room temperature. The mixture as stirred for 20 minutes, then concentrated down to a cru de solid. The solid was removed- The crude oi1 was purified by flash choursomatography (Sorbsil 30 g; eluted with iMeODH:DCN4). The oil thus obtained (2.54 g, 90%) was converted to a fumarate salt with fumnaric acid (670 mg) in ethanol. The crystals collected weighed 1.61 g, m.p. IG0-102*C_

AINALYSIS:

dXPCalculated for CH, 7 FN.03CHO,: 63.52cIC 7.5 4 VH 5.11%N Found: -63.637GC 7.74%H 5.03%N EXAMPLE 123 NNDietb l4[-6fIuao12 ezsoa~ 3v- 2~ i n buh.'l carbamnate urnarnfe To a mixtare of 4[-6fur- ?bnicao-..--ieiivjuao (1.55 g, 5.3 rnol) potassiumn t-butoxide (730 Mg, 6.7 InmolIQ) in TH-F (100 mI), diethylcarbarryl chloride (900 mg., 5.63 rnrnol) wa aded dropwise at room temperature. The mixture ;was stirred for 2 hours, thien thle solvent was removed.

The residue was extracted into DCM. The DCM solution washed with brine and dried over M'gSO 4 The solution was concentrated. Thne product was purified on a flash chromatography column (SiO, 14 g~eluted %,ith 2% MeOH in DCM), to yield 1.84 g of oil. This oil dissolved into ethanol (-35 ml) and treated wvith a solution of furnaric acid (550 mg, 1.0 eq) in ethanoi. Crystallization was induced with a -small volume of isopropyl ether to produce 2.09 g, m.p. 152-153C.

t

ANALYSIS:

Calculated for 4 59.1 6zC 6.75 %H 8.28%N Found: 59.177Cc 6.84 %H S.16MN -EXAM'',PLE 1211 N-NMethvi-4-f4-(6-fluoro-1,2-benzisoxazol-3-vl1-1pRip eridirnvl bu-I carbamnate fumnarate To a mixture of' 44[4-(6-fiu-oro-l,2-benzisoxa-zol-3 -yl)-1-piperidinyllbutanoI g, 6.3 mrnoi) KCO, (830 mg) in chloroform, miethyl isocyanate (448 mg, 7.7 mnmol and 360 mg, 6.2 rnrol) was added dropwise in t-wo portions. The mixture was filtered and concentrated to a crude oil. Purification was done on a flash chromiatography column (SiO 2 11g lue ith 2% CHOH 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 1.0 eq). Crystallization was induced with drops of isopropyl ether. Weight: .1.36 g, m.p. 96-98*C.

ANALYSIS:

Calculated for C,,H, 4

FN,O

3 -CHO, 5 6 7 6C 6.06 %H 9.0 2%N Found: 56_2747C 6.037%H S86%11\ S S S a Sn.

6* d *5 *3 S* S EXANIPL.E 1.2 2-2f-6Fu r-.-ezsvz l3v)lpp rdnllli-,-ixn fumnarate A mixture of 6-fluo ro-3-(4-pipe rid in yl) 12-benzis oxa zole (2.0 g, 9.1 mmnol), K,C0 3 (1.5 g, 10.9 mrnol) and bromoethyl-1,3-dioxane (2.1 g, 10.7 mnmol) in acetonitrile (50 ml) was heated at reflux for 3 hours. At the end, the intsolubles were filtered and rinsed with DCM and the filtrate was evaporated down. The crude mixture was purified by flash chromatography over a silica gel colu-mn (Sorbsii C-30. 25 g; eluted with DCM and MeOH- in DCM). The fractions containing the pure product wvere combined and concentrated to give 3.13 g of oil.

The oil was treated with a ftrnzric acid (1.0 gr) ethanol solution. The crystals were collected: 3.95 g 161-162'C.

-ANALYSIS:

Calculated for C:.RjN,O,-Cj, 40: 53.66%C 6.04 %oH 6.22%N Found: 53-69%C 5.96%H 6.20% N p&A EXAMPLE 126 2-4(-loo12bnioao--ilppudnIehio hemnifumarate.

2-6-ua-7. bnioao-.vi-pipcrftiiny!Iethyi acelate 2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-i 7piper-idinyl JethylI acetate was prepared according to Example 115.

2-[4-(6-Fhwuro-l 2 -ben zfsoxa zol-3-vI-1 -pirjenidin ylletha nol hemifumnarate 2f4(6-Fluo ro- 1,2-benzisoxa zol-3-yll- I-pipe rid; nyl !ethyl acetate (10.58 g,.

34.6 mmol), 15% NaOH (100 ml) and ethanol (100 ml) was heated at reflux for 4 hours. The solution was cooled (-5cC) and neutralized with HCI to pH-7. The ethanol was removed under reduced pressure. The aqueous solution was basified with NaHCO, and extracted with DCNI (2 x 200 ml). The DC.M' solution was w.ashed w..ith brine and dried over IvgSO, and eva porated to give a w, hite solid: 6.SS qg A samole (2.03 u) was dissolVE'd in ethanol and treated with fumaric acid (660 mag, 1.0 eq Crystaliization was induced'it drops of isopropyl ether to yield off-white crystals: 1.43 g, rap. 150-161 VC.

ANALYSIS:

Calculated for CE-i.

7 F,O..0.5CH 4

O

4 5 9.6 27%oC 5.94%7ol 8.69%N Found: 5935%C 5.95%7H. 8.-;3%N 999 -EXAMYPLE 127 'lo 6 o12bezsxzl3v)l-ieiivltv decanoate fumnarate A mixture of 2-[4-(6.iuorb-1,2-befzlZ[oxazol-3yl)- -iperidilyl ]ethyl alcohol (1.6 g.5 mrmci) and triethylarnine (800 mag, 8 mmrnl) in chloroform (100 Ml) was treated with decanoyl chloride (1.3 g, 7.2 mmol) dropwise at room temnperatu .re.

The mixture w--as stirred for 4I hours. The solvent as removed to leave a crude solid. The solid was dissolved into a small amount of DOM (15 ml), then was filtered. The solution was concentrated.

The ourification was done by flash chromatography over a silica gel ex t column (Sorbsil C-30, 30 g; eluted with MeOH: DCM). The pur-ified oil (2.45 g, was treated wvith a fumaric acid (660 ma, 1.0 eq)/ethanol solution (15 ml).

Crystallization was, induced by adding drops of ether; yield: 1.97 g, m.p.= 109-1 1 0 0

C.

New

ANALYSIS:

Calculated for C.H.,FN 2 ,OCH,O,: 62.90%C 7-35%H 5.2',%N Found: 62.93cC '7-3 0 %H 5.14%NI EXAMPLE 12S N, itv--4(-lo o12b nzs -a o--i--~tei ivl ethyl carbamate fumarate to a mixtur-e of 2-4(-lool2bf~s~Oy) -iperidinyij ethanol (1.6 g.6 mmol) and potass5ium t-butoxide (SKI 7~ .6 rnimol) in THF (100 ml1) diethyl carbarnvi chloride (1.03 7.5 mmol) added drop.wsE! at room temperature. The mixture ;,as stirred for-4 hors.. The reaction mixture was concentrated to a cruode solid. The solid was dissolved in DCM and -purified on a flash chromatography column (Sorbsil C-30, 27 g; eluted with a IMeGH: DCM mixture). The product thus purified as a light oil (2.2 g, 91%) was dissolved into V. ethanol and treated with a fumaric acid (690 mg, 1.0 eq)/ethanol solution (15 mld).

Crystalization on cooling yielded 2.15 g of white crystals, mn.p. 133-135C.

ANALYSIS:

Calculated for C, 9 H,,Fi\' 3 O,.CHO,: 57.61 %C 6.31 %H 8.76%N Found: 57.49%C '6.25%H S.54%N EXAMPLE 129 r-12bn sxzl3y- Pi1eidnvl amne hemifumnarate N-f4-(6-fluoro-i ,2-beiiziso.Taz-J-yl)-l -piperidirnylethvI phthalimide N-[4-(6-fluoro-i ,2-benzisoxazol-3-yD)-1-piper-idin-yllethyl phtha limide was prepared according to Example 117.

a 2-!4-I(6-Fhora-2 ,2-benzisoxra Iol-3 -yI)-i -p.veridfniyliefh'Alarnine hemifurnarate A mixture of 2-[4-(6fluor-12-benzsoxazol-3yl)-1-piper-idiflIthyl phthalimide (4.6 g, 11.7 mmcl) and hyd razine monohydrate (1.17 g, 23.4 mmcil) in Onomethanol (50 mid) 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) a nd- acidified with HCO to pH 2. The insolubles were filtered. The aqueous solution was basified with 50% NaOH then extracted with DCM (2 x 250 ml). The DOM solution was washed with brine and dried over MgSO 4 The solvent was removed to produce a colorless oil: 2.12 g- This, oii wa treated with a solution of fumnarc acid (935 mg. 1.0 eq) in ethanol. The salt crystallized out: 0.99 g, m.p.= 203-205'C. A~ second crop o" 0.73 g =198-200'C) was collected later.

ANALYSIS:

Calculated for C 14 59.80%C 6.2 7%H, F 3.075%N Found: 59.51 %C 6.35%Hi 13.31%7N EXAMIE 130~ 2-f4-(6-Flor-,2-benzisoxazol-3-vl)-l-piiericdinvlethvlI decanamide fumnarat-e x..To a mixt-ure of 0 -[4-(6-.Fluoro-1,2-benzisoxazol-3-yl)--piperidin-yllethylarnine (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 day/nr to a crudle mixture. This crude mixture was purified by flash chromatography over a silica .gel colum n (SiO!, 20 g;eluted with a solution of tMeOH- in DOM). The fractions containing the pure product were pooled and concentrated to give 2.3 g of oil. This oil was I* converted to a fumarate salt, by treatment with fuma ric acid (655 m.g) in ethanol.

The ethanol wvas concentrated down to a small volume and 3 volumes of isopropyl ether was added. This mixture was stirred overnight to cause crystallization. The A solids were collected, weighed: 1.83 g n p. 10S-110'C.

ANALYS&S

Calculated'for C,,H,.FNO,.CHO,: 63-02%C 7.56%H 7.8 7 9,N Found: 62.42%C 7.58%H 7.66%N EXAMPLE 131 2-[4-(6-Fi uoro-l,.2-beniisoxazol-3-YII-1-piperidin vllethvI acetamide fumnarate Amixture of 2-(4-(6-fLuoro-1,2-benzisoxazol-3-vl)-1-piperidinvllethylamine (2.56 g, 9.7 mmol) and triethvlamine (1.45 v, 14.5 mmol) in DOM4 (50 mi) was treated wihdrooLwise addition of acetvl chloride (1.0 g.12-7 mmcl) at room temperat.Ure. The mixture wsstirred for 4 hour-s at roo-m temperature. The reaction mnixnure vaS di ,-ecwih DCNI and ,ahd'withn brin-. The org-anic solution dried over N-160, and concentrated to a cr-ue oil. The crude oil was purified by flash chromator-Pphy over a silica gel-colum n .(SiO. 20 g; eluted with (0-25/0) CHOH- in DCM)9. The pu.-e Product thus obtained vweig-hed 1.36 g It was converted to a fumnarate salt by treatment Lvt r -c557h)i ethanol. Recn',stallization from ethanol g~aVt2 w-hite crv'staL-; w.eight: 1.53 g, rn.p.

132-133'C- ANALYRiS: Calculated for C, 6 ,FN .C~ 4 57.00%,C 5.74%1H 9.97%N :..Found: 1;7.05%C 5.S5%7H 9.95%N EXAMIPLE 132 2-r r2-r4-(6-Fluoro-1 .2-benzisoxazol-3-vll-1-p iperid in vI Icth-, lam inolethvI acetate fumarate *A mixture of 2-[4-K[6-fluoro-1,2-benzisoxcazol-3-l)-1 -piperidinylleth 0 '!irine g, 7.6 mmol), K,C0 3 (1.38 g, 10 mmol) and bromoethyl acetate (1.40 g 8.3 rnmol) in acetonitrile (50 ml) was heated at reflux for 41 hours. At the end, the insolubies were filtered off and rinsed with DCM. The solvent w,.as evaporated down. The crude mixture was purified by flash chromnatog-raphy over a silica gel C 'column (Sorbsil C-30, 30 g; eluted with CHOi-i in DCiM,, 800 MO). The oil (1.15 g) thus obtained was treated with a solution of furnaric acid (3)58 mg) in,,ethanol.

Crystallization was induced by adding drops of ethyl ether, yield: 1.09 g' nM.= 116-I1S 0

C.

00 ANALYSIS: Calculated for 3 0 2 .CH,0 4 ;6.77%C 0% 9.03%cN Fou nd: 56-32%C 5-97%IH 9.94%N EXAMIPLE 133 Methyl 2-[4r(6 furo-.2-bezisoxaizol-3-vli)-1-mpieridinIethyl carbamnate ->-fum.rate A mixture of 24-[(6-fl uo ro-1,2-benziso.-xa zol-3-yl>-i -pipe rid inyllIethyllamnin e (2.0 g, 7.6 rnmol) and triethylanine (1.0 g, 10 mmol) in DOM (50 mld) was treated with methyl chloroforrnnte (S60 mg, 9.12 rrno!) drobv.'ise at room temperatue.

*The mixture was stirred for 1 hour. The reactio n mixtuire was diluted with DCMv and w.ashed with brine- The organic solution %.as drL 'oer MgSO, and concentrated to a crude oil. The purification was done by flash chromatography over a silica gel column (28 g of Sorbsil C-30, elUted withDCM and NeOH/DCM).

The pure oil thus obtained wveighed 2.34 gY. it was converted to a Fumnarate salt by treatment with fumnaric acid (840 mg, 1.0 eq) inethanol. Crystali~ization was *induced by adding drops of isopropyl ether, yield: 2.31 g. rn.p. =163-165'C.

4 ANALYSiS: Calculated for C 1 H, 54.92%C 5.53%H 9.61%cNl Found: 54.49%C 5.45%JH 9.24%coN EXAMIPLE 134 Z--2f-6Fur-,-ezsxzl3v)ipprdnlehleavio -IH-isoindole-1,3-dione fumarate A mixture of 1-(2-aminoethyl)-4-(6-fluoro- 1 ,2-benzisoxazol-3-yl)piEeridine (3.77 g.14.3 mmol) and cis-1 .2-cvclohexa ne-dica rbom lic anhydride (2.82 g, 18.2 m mol, 1.25 eq.) in dry pvr-ldine (50 ml) was heated at for 48 hours. The dark brown solution was concentrated to dryness on a rotar; evaporator. The crude residue was purified twice by flash chromiatography over a silica gel columrn (SiO, 45 g and 50 g, eluted .with DC!%M and 1 CH 3 OR in DCNI). The pure product thus obtained 2_35 g 4%.was converted to the fumnarate salt by treatment with Fumaric acid (660 ma) in ethanol. The crystals afiter two recrv~taliZ~tiC. .eigh-ci 1.37 g, T-7 C

ANALYSIS

Calculated for C-,FN 3 O'-.CdHO,: 60.57c-%C .S7%,H 8.i57.N Found: 60.40c7C 3.85 F EXAMPLE 135 -6-l o azs x -o D1 ip rd nlV2m t 'l -~..:propanol fumarate A mixture of 4-(6 fiuo,"o-1,2-benizisoxazol-3-Yl,~ipieridifle (7.2 g, 32.7 mmol), 32.6 mmol), K.CO,(7.19 g, 52 romol) in acetonitrile (230 ml1) wvas heated at reflux overnight. The insolubles were filtered off. The solvent was remioved at reduced pressure and the crude residue was *purified by silica gel 'chromatog-raphy (S iC), 84 ehuted with 21 ofl CHOH in D0.4) to give the target compound as an off-%w.hite solid (8.8 g, A11 sample of 1.7 g was converted to the fumarate salt by treatment with furnaric acid (710 mg) in ethanol, Recrystallization from ethanol yielded l.74"g of v.hite m.p. 119-121C.

ANALYSIS:

Calculated for C,,,HFN 2 0, 5S.S2%iC 6.177%H 6.86%1\ Found: 58.Sl %C 6.2 4 1,H1 6. 76 N EXAMPLE 136 4-6F r-.-en io ao-- 3- p rdiy)pop lpiei e difumnarate A mixture of It-(6-fl oro-1,2-benz iso xazo l-vl)pi Pe rid ine (3.0 g, !3.6 mmol), N-(3-chloropropYIpiperidifle hvdrochloride (4.05 g, 20.4 rno). KCO, (6 g, 43.4 mmol), tetrabutylainmoniurn hydrogen sulfate (phase transfer catalyst, 2.3 g) in acetonitrile (100 ml) and water (15 ml) was heated at reflux for 16 hours.

Th e mixn r wa wsed with brine and the lavers were separated. The organic solution was concentrated. The crude prodjuct 0 was Durified by flash over a silica g~el Column (55 g, scibsii C-3O; ehluid with 2%

CH

3 OH:0.5% D" 'A in DCNI, 1.41). The oil thus pur'.ied (45g) wstreated with frimaric acid (1.6 g) L- ethanol. The soli1 dS scollected.: weight 3.1 g, m.pJi7&-IS1'C. Re-r',stalliz-ation from ethanol yield[Ed '12S cog of white crystals, M.P. 19-192 0

C.

ANALYSIS:

Calculated for C ,9-,FN 3

C),.C

4 58.2%C 6.28%7cH 7.27%N Found: 5 8.3 9%c-C 6.36%cH 7.34%N :EXAM",PLE 137 I-(3-D ime th via min oprop vl)-4(6-f Iuoro-1,2-b enzisoxazo 1-3-vi) pi Rerid ine difumnarate A mixture of 6-fluoro-3-(4-piper-idinyl)-1,2-benzi-soxazole (3.05 g, 13.8 mmol), 3-dimethylarninopropyl chloride hydrochloride (3.4 g.21 mmol), K.C0 3 (6.2 45 mmol), tetrabutyla ,nrnoniumn hydrogen sulfate (phase transfer catalyst, 1.5 g) in acetonitrile (100 ml) and wvater (50 ml) was heated at 600C overnight. The aqueous phase was separated, and acetonitrile was removed at reduced pressure.

The residue was extracted into DCM. The organic solution was washed with HP and brine, then dried iMgSO 4 The solvent was removed and the crude product (4.3 g) wa s treated with fumaric acid (1.58 g, 1.0 ea) 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 0

C.

ANALYSIS:

Calculated for C 17 1-i, 4 F,O,.CH1 4 0: 55.86%C 6.00%H 7.82%N Found: 50. 11i7/C 5.94% H 7.86%5GN EXAMPLE 138 (R)-(-)-3-f4-(6-Fluor-1.2-bezisoxazo -3-vI)4-Rperid invi 1-2-m ethvl-l 2ropanol fumnaraitt :A muxt-ure oil 4-(6-fluoro-1,2-bertzisoxazol-3-y-I)piper-idine (14.5 65 mniol), KCO, (10 g, 72 mmol). (R)-(-)-3-b~orno-2-rnethyl-i-pr-opanol (10 a, 65.3 mmnl).

tetrabutvlammonium hydrogen sulfate (1.27 g. phase trainsfer catalyst) in acetonitrile (300 ml) and 1-1. (5 ml) was heated at reflux for 6 hours. The m-ixture 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, thle cr-ude product was purified by flash chromatography over a silica gel column (SiO 2 150 a; eluted wihDOM, 11; 2% CHOH in DCM, 1.61). The-material thus purified weighed 17 The *sample for testing was prepared by treatment of a sample (229S g) with Furmiric acid (953 m;7) in ethanol. The crystals formed slowly upon addition of isopropyl ether. These wvere collected and dried: weight 1.84 g, m.p. 11 Calculated for- C,,H.LFN,O,.CH 4 0 4 58.82%C 6-17%H 6.8 67rN! Found: 58.48%C 6.08%H 6.57%N EXAMPLE 139 00 3 -4 NIe tho x yet h yD-2- h ydro nmh e n o~ Ipr o p v 14- p ipei d iny1I 6 f Iuo ro-1,2-benz is o xaz o Ie A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (5.7 g, 26.0 mmol), 4-(3-chloropropoxy)-3-hyd roxy-a -met hyl benzenemetha no 1 (6.0 g, 26.0 mmol), NaHCO, (2-4 g, 28.6 mmol), I(200 mg) and CH 3 CN (150 ml) was stirred at reflux under N, for 17 hours. A TLC showed a trace of the alkylat ing side chain, therefore additional 6-fluoro-3-(4-piperid inyl)-1 .2-benzisoxazole (0.6 g, 2.7 mmol) and NaH-C0 3 (0.22 g. 2.6 mmcl) was added and the reaction was refluxed 3 hours longer- The cooled reaction was concentrated anct:.tn e o aspritoe between EtO.1c and H,0. The EOAc extract w2shed with -0 then brine and after drying with MIlSO, the extract asconcentrate-i to iild 11 .9 gof a beige oil. -The sample was purifiied preparative HPLC (W-Nater's As-sc-iates Prep LC/System 500 utilizing 2 silica gel columns andi eluting with 5% IvieOH-CH.Cl?).

Concentration of Later fractions afforded 4.2g of 4-[3-[4-(6-fluoro-l ,2-benzisoxazol-3-yl)-1 -piper-iiyl ropoxy]- 3-hydroxy-a-rnethylbenizeflemethalol. Concentration of earlier fractions gave 4.0 g of a mixture of 4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-I -nipe-ridi-nyllpropoxyl- 3-hydroxy-a-methylben--elmethanol and -met hoxyethyl)-?-hydroxyphenoxylpropyl-4-piperidilyll-6-fluoro-i2beizioxazole (the latter was apparently formed by the reaction of the former with MeOH on silica gel). The mixture was dissolved in anhydrous EtO (3-30 ml) and anhydrous MeCH (100 mld) and ethereal HCI was added. After stirring 1.5 hours, anhydrous rFtC was added and the resultant solid was collected and dried to yield 2. 9 g of a rmixture of the respective HCI salts. The solid wvas suspended in H,O and wvas basified with NHOH. The aqueous mixture was extracted with CH, 2

CI

2 and the extract was washed with H.0, dried w.ith MgSO, and concentrated to yield. 2.7 g of a Light beige oil. The oil was purified by preparative HPLC (Water's As sociates Prep LC/System 500 using 2 silica gel columns and 3% MeOH-CHC 2 as eluent).

Concentration of later fractions yielded 0.5 g of 4-[3-[4(6-fluor-1,2-benzisoxazol-3-yl)-l-piper-idiflyl]-prop',(y Kv-3-hydroxv-amethylbenz~enemethanol. Concentration of earlier- fractions gave an oil that solidified upon standing. The product was triturated with heptane and filte red to P yield 1.2 g- of a white powder. The compound was recryvstallized from EtOH to provide 1.1 g of -methoxyethyl )-2-hydroxyphenoxyipropyl -4-piperidinyl]- 6-fluoro-1,2-benzisoxazole as clean white crystals m.p.=.9-100'C.

ANALYSIS:

Calculated for 67.27%,'C 6.S25%H 6.54 N4 Found: 67.lS%7iC 8 FrH 6.5 4%cN EXAILE 140 6-Fluoro-3-f 1-f H-ind 01-3- v Doxvlpropvl I-4-p iperid in yl 1-1,2-benzisoxazo I e A mixt-ure of 6-.fluoroc-3-(4r-piper-idinvl)-1,2-benisCxazoe (2.6 g' 11.8 mcl) K,C0 3 (1.6 gjiH.6 rninoi), Ki (200 mg), 5-(3-chloropropoxv)indcoie (2.2 g& 10.5 rnrnol) and CHCN (100 ml) was stirred at reflux under N, for 1S hours. The Cooled reaction was poured into H,O %nd the aquieous mixture was extracted with too- EtOAc. The EtOAc extract was washed 2 tim-es with H-0, 2 timies with brie and after drying with Mg5O 4 the 5olvent was removed irn zvoct to yield 5.1 Z of a dark oil. The oil was purified by preparative H-PLC M~ater's Associates Frep .4'LC/System 500, using 2 silica gel columns and 4% MeOH-CHCI, as eluent) to afford 2.65 g of a beige solid. Recrystallization from ethanol gave 2.2 g of a beige powder, m.p. 118-12]'C.

ANALYSIS:

Calculated for CH~FN 3 72 6-15%H 10.68%NI.

*Found: 69.50%C 6.21 %H 10. 78 ccN EXAMPLE 141 6-Fl uo ro-34fl-3-[(isou iino 1-5-v1) oxvl [ropvll1-4 -pipe ridinyl -1,2ago" benzisoxazole sesquifumnarate A stirred mixture of 6-fluoro-3-(4-piperidinyl)-I,2-be-nzisoxazole (2.8 g, 13 rrno 5-(3-chloropropoxy)isoquinoline (2.8 g, -13 nmol), KCO, (1.7 g) and CHCN (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-0, and the aqueous suspension was extracted with CH,CL, The filtrate was also extracted with CH,CI,, and the extracts were combined, w.ashed dried (KCO~) and concentrated to yield 5.4 g of a brown oil. The oil was purified by HPLC on silica gel columns, eluting with CHCl 2 /MeOHl to afford 2.3 g of a yellow oil. The oil was dissolved in EtOAc and flimaric acid (0.66 g, I eq) was added. The mixture was refluxed brieiiv, and then stirred at ambient temperature for 16 hours.

The resulting wvhile solid was collected to afford 2 2 gc of the fumarate salt. The compound was recrystallized from IDMF to Yield 1.4 of the isoquinoline as a sesquifumarate, m.p. =213-215'C.

ANALYSIS:

Calculated for C 3 ,F NO,: 62.17%C 5.22 r.H 7.257oN Found: 62-01176C 5,11 %H 7.28%N EXAMPLE 142 6-Fluoro-3-f1-3-(I-H-indol-4-vl)o-xv popvvl-4-oiverid inyll-1,2-bernzisoxazole A mixture of 6 -fluoro- 3 -(4-piperidinyl)-1,2-benzisoxazole 3 .5 g, 16 rnmol).

KC0 3 (22.g, 16 mmol), KI (200 mg), 4-(3-chloropropoxy)indole (3.0 g, 14 mrnol) and CH,CN (100 ml) was stirred at reflux under N, for 7 hours and then at ambient temperature for 68 hours. Reflux was resumed for an additional 6 hours S .'whereupon a TLC revealed incomplete reaction. K,C0 3 (0.5 g, 4 mmol) was added o and the reaction was stirred at reflux for 17 hours. The cooled reaction was poured into H,0 and the aqueous mixture was extracted with EtOAc. The organic extract was washed with H,0 and saturated NaCI and after drying over IMgSO, the solvent was removed to a fford 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-c( H.C1 2 as elueni) to yield 3.4 g of a beige solid.

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

ANALYSTS:

Calculated for CH,,FN 3 70.21 '7C 6.15% H 10.68%N Found: 69.9076C 6.15%H 10.65%N EXAMPLE 143 6-Fl uoro-3-[1-l34f(6-methoxv-1H-indol-5-vl)oxvlpropvl14Apiperidinvl1,2benzisoxazole hmifumarate A mixture of 6 -flucro-3)-(4-piperidinyl)-1,2-benzsoxazole (3.0 g, 14 mmol), 5-C3-c'noropropoxy)-6-methoxyifldole (3.0 g, 13 mmol), KC0Q (2.1 g, 14 mmoi), KI (200 mg) and CH,CN (150 ml) Was stir-red at reflux under IN, for 48 hours. The cooled reaction was poured into HP and the aqueous miuxture was extracted with EtOAc. T[he EtOAc extract was washed with H,O and brine and was dried with MgSO 4 Rem-oval of the solvent in vacua gave 5.6 g of a dark oil- The oil was purified by preparative HPLC (Wa ter'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 mrnol) was added. The reaction was stirred at ca 400C 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'C.

A ANALYSIS: Calculated for C,,H,,FiNO 3 64.84%C 5.87%H 8.73% N Found: 64.22?%C 5.85%H, 8.55%N EXAMPLE 144 r446Fluoro-12-benzi sothiazol-3-yl)-l-P iperid in -4lpropoxyb3-a c(hyd roxvphenylle than one &Af -A mixture of 6-fluoro-3-(4-piperidiny)-,2-benzisothiazole (2.4 g, 10.1 mmol), 1-[4-(3-chloropropoxy)-3-hydroxyphenylI ethanone (2.5 g. ll..rnmol), NaHCO, (0.94 g, 11.1 mmol), K! (100 mg) and CH 3 CN (100 was stirred at reflux under N, for 65 hours. The cooled reaction was poured into HO and the aqueous mixture was extracted with EtOAc. The EtOAc extract was washed with HO Olx) and brine (3x) and after drying with MgSO, the solvent was evaporated to give 4-2 g of a dark solid. Three consecutive recrystallizatiois. from EtOH provided 2.1 g of glittery beige crystals m.p. =135-137*C.

A-ALYSIS:

Calculated for H25 FN,0 3 5; 64.47%7C 5.SS% H 6.5 4%,N Found: 64.44%/C 5.69 S.H 6-29%N EXAMPLE 145 4-r3-f4-(6-Fluoro4.12-benzisothiazol-3-vl)-1peridinvllP rolorvl-3rnethoxy-a-methylbenzenemethanol To a stirred solution of 1-[4-[3-[4-(6-fluoro-1, 2 -benzisothiiazol-3-yl)-1piperidinyllpropoxy]-3-methoxyphenyllethan-one (4.1 g, 9.3 mmol) in 60 nil MOH-THF under N, at ambient temperature, NaBH, (0.386 g, 10.2 Mmol) was added portionwise. After complete addition, the reaction was stirred for hours and was concentrated to yield a white g=m. This was triturated with HP 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 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 QVvaters'Associates prep LC/Systemn 500, using 2 silica gel columns and 2% EtNH-EtOAc) provided 2.7 g of a light beige solid. The product was recrystallized from EtOAc to afford 1.7 g of a pure white powder, m.p.

113-115'C.

ANALYS IS: Calculated for C,,H,,Ft\,O 3 S: 64.84%C 6.58%H 6.30%N Found: 64-85%C 6.44%H 6.19%N EXAMPLE 146 .2-benzisoxazol-3-vl)-l-piperid invll-2-meth 4-1-propyI acetate fumnarate To a mixture of flu oro-1,2-benzisoxazol -3-ylOpiperidinyll-2-rnethvl-1 -propanol (3.2 g, I I mmol), triethylamine (3- 2 g, 11 mmol) in DCM (100 ml), acetyl chloride (690 mg, 11.3 rnmol) 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 triethylam ine H-CI salt was filtered off using a small amount of DCM. The crude product was dissolved in DOM was purified by flash chromatography over a silica gel column GSO 2 30 g; eluted with DCM and 1% CH, 3 OH in DOW) The oil, thus purified, weighed 2.11 g This oil was treated with a solution of furnaric 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'C.

Calculated for C,1-1,FN,O,.C 4 HO,: 58.66%C 6.04%H 6.22%N :..Found: 58.53%C 5.76%H 8.91 %N V. EXAMPLE 147 1-(R)-(-)-f4-3-(6-Fluoro-1,2-benzisoxazol-3-vl)-1-p iplerid inyll-2-rnethvl-Ipropoxvl-3-methoxyphenyll ethanone fumarate .2-benzisoxazol-3-yfl-i-pivcridirnyl-2-methty1- 1-propy! methnnesulfonate To a mixture of oral ,2-benzisoxazl-3-yl)-1 pi peridinyll -2-met hyl-propa not (7.26 g, 24.8 rnmol), triethylamine (3 ml, mmoi) in methylene chloride (DCM, 120 ml), inethanesulfonyl chloride 1 3g, 27.3 mnmol) was added dropwise at O'C. The mixture was stirred at room temperature for I hour., then concentrated down to a crude mixture. Triethylamiune hydrochloride salt was removed by filtration wit h DCMI/ether as solvent. The crude oily mixture was purified with a flash chromatog-raphy 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, I ,2-benzisoxazol-3 -yf)-i -piperidinyll-2methylproproxyl-3-methoxyphenyl] ethanone furma rate A solution of the above mnethanesulfonate (5.48 g, 175 mmol) in DMF ml) was added in one portion to an aged hour) cold mixture of aceto va nil lone (4.13 g, 24.9 mmol) and sodium hydride (670 mg, 26.5 mmnol) in DMF (4 ml) at 00G. The resulting mixt-ure was warmed to -5OoC briefly and stirred at room temperature for 16 hours. The mixture was extr-acted into DCM' (500 ml) and washed twice with water, then brine. The organic solution was dried over MgSO, and concentrated to an oil. This crude mixture was purified twice by Hlash chromatography over a silica gel column. The material thus purified weighed 5.37 g.The fumarate salt was prepared by treat-ment of purified oil with fumaric acid eq.) in ethanol and ether. Slightly off-w-,hite crystals were collected: 3.76 g m.p. -141-142'C.

ANALYSIS:

Calculated for CH,FN, 4 O.CH,0 4 6.%C 5.98%H 5.03%N Found: 62.5251C 5.75%H 4.96%N EXAMPLE 148 3-4-(6-Fluoro-1,2-benzisoxazol-3-yl)-l-pi peridinyll-2,2-d imethyl-l-propanoI -fumnarale A mixture of 4-(6-fluoro-l,2-beflzisoxazol-3-yl)piperidifle (3-0 g, 13.6 mmol), K, CO, (12.5 g, 17-5 mmol), 3-bromo-2,2-dimethylA-propanol (3 g, 21 rnrnol, tetra-butylammonium hydrogen sulfate 01 g, phase transfer catalyst) in water 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) VW and washed with brine. The organic solution was dried and concentrated to a dark brown mixture. The crude mixture was purified carefully by Hlash chromatography (SiO~, 95 g to afford the dried pure product; 260 mg, as an oil. This oil was converted to the frnmarate salt by treatment with furnaric acid (98.5 mg, 1.0 eq.) in ethanol. Recrystallization from ethanol:ether yielded 210 mg of white crystals, m.p. 144-145*C.

Calculated for 59.70%C 6. 4 4 aH 6.63%N Found: 59.52%C 6.38%H 6.52%N EXAMPLE 149 1.(S)-(+l-[4-[3-[4-(6-Fuor-2-benzisoxazol-3-vll--piperidinvfl-2-methvl-1propoxyl-3-methoxvnPhenvll othanone fumnarate (4)3-14-W-fluoro-1 .2 -ben zzsoxazo1-3 -1 -p iperidiliy 1J-2 -mefhyll-propyl rnethanesulfonate To a mixture of (S)-(j-)-3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1 piperidinylj-2-methyl-1-propanol (8.8 g, 30 mrnol), triethylarnine (3.2 g, 32 rnmol) in dichioromethane (DCM. 150 ml), methanesulfonyl chloride (4 g, 35 mnmol) was added dropwise at OoC over 10 minutes. The mixture was stirred at room temperature for 1 hour, then concentrated. Triethylamine HCI salt %vas filtered off with a little DCM as solvent. The crude oil was purified with a flash chromatography column (SiO 2 90 g; eluted with DCMX_ The colorless oil thu-s purified weighed 5.28 g was used immediately in the following step.

7 ,2-benzisoxazol-3-yI)- 1-piperidinyll-2 met hyl-proproxyl-3-melhoxyphenyUl etharnone fumnarate A solution of (S)-(-)3-f4-(6-fluoro-l ,2-benzisoxa zol-3-yl)-1 piperidlinyll-2-rnethyl-l-propyl methanesulfonate (5.28 g, 14.27 mmol) in dimethylformarnide (DMF, 10 ml) was added in one portion to an aged (1 hour) CO cold mixture of acetovanillone (3.55 g, 33.1 mmol) and sodium hydride (530 mg, 22 mmol) in DMF (35 ml) at OOC under N, The reaction' was stirred overniight (16 hours.) at room temperature. The mixture was diluted with EtOAc and washed wit H,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.? The oil thus purified weighed 4.3 g, (687o) and was converted to the furnarate salt (fumaric acid, 1.13 g) in ethanol. Recrystallization from ethanol gave 1-36 g of white crystals, m.p. 163-165'C.

ANALYSTS:

Calculated for C,,H.,FN,O,.C 4 623SSC 5-9896H -03-%N Found: 62.40 5. S 4% H '4.92%,N a a *0*S EXAMIPLE 150 2-r4-(6-Fluoro-1,2-benzisoxazl-3-vl-l-p2ipericdinvlIlethvI thioacetate fumarate To a stirred solution of 0cC of triphenlyphosphine (13 .3 g, D0 mmol) in THF (150 ml), diisopropyiazodicarboxylate (10.2 ml, 50 rnmol was added dropwise. After stir-ring at 0 0 C for 0.5 hour, a solution of 6-fluoro-3-[1 -(2-hydr-oxyethyl)-4-piperidinyli- 1,2-benzisoxazole (8.5 g, 32 mTmcnl) and thioacetic acid (10.2 ml, 0.14 mol) in DMF (35 nml) was added dropwise. The reaction was then stirred at ambient temperature for 16 h, and then it was concentrated at 60 C, under vacuum, to yield a red oil. The oil was triturated with H 2 and then it was flash chromatographed on silica gel, eluting first with CHCI, and then with MeOH-CH,CI.,. The appropriate fractions were concentrated to yield 1 6.5 gof an oil. The oil was triturated with EtO 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 EtCH to fa'ford 1.0 g of the thioacetate as an off white solid, m-p- 118-120*C.

EXAMPLE 151 NJ2- 4-(6-Fl uoro-1,2-benzisoxazol-3-0l-1-p iperid invl ]ethyl]ichlorophthalimide A mixture of 24-f R[6- n uoro-1,2-benzisoxa zol-3-y0-1 -pi peridinyllethylJa mine (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 %M.

g, SiO, sorbsil C-30, elu ted with I MeOH. in DCM; 0.5% of N-HOH was added towards the end of elution). The material thus purified weighed 2.26 g as whit crystals. Recry-stallization twice from a large volume of hot ethanol (400 ml) 173 yielded 1.57 g of white shining crystals, M.P. 132-134"C.

ANIALYSIS:

Calculated for 1 C1,FN 3 0 3 57.1 67C 3.92-5cH Found: 57.13%C 3.63-,IH 9.09%7 N 8.93-7.N St *0

S..

*0 0 EXAMPLE 152 N-2f-6-loo12-ezstiazol-3-yl)-2-t'iperid invI ethvllphthalirr hydrochloride Amixture of 6-lo ;-4p ,rciv)12bezstizl 14 rnrol), 2-bromoethylphthalimfide (3.7g 14.7 rmcl), K,CO, (2.0g) and CH. ~5ml) was stirred and refluxed for 2.5 hours. Thle reaction was poured into -nd a white precipitate resulted, which was collected to aff6rd 2.0 g 0 .f prodU..2. aqueous filtrate. r~ 'extracted with CHCO, the extract washed (HkL 'ried (MgSOJ and was co 'IWated to afford 3.5 g of an off-white solid. Upon ration of this solid with acetone, an addition al 2.0 g of product was realized. The two samplef were combined and -suspended in NMeOH (50,ml), and ethereal HCI was added until the reaction mixture wvas acidic. After stirring for I hour at ambient temperatu.re, Et 2 Q (50 ml) was added to afford 3.7 g of the hydrochloride salt. The salt was recrystallized from MeOH-Et 2 O to yield 2.3 g of the compound as a white solid, m.p =271 273C.

ANALYSIS:

Calculated for C,.H,,FtNOSHCI: 59.25%C 4.75%76 9.42%N Found: 58.99%C 4:6 0 9.3 3%coN EXAMPLE 153 N-2[-6E-oo12b.-SX713y)l v etriivehyl- 3.6-dichlorophthalimidg_ A mixture of 2-l'[6t(luoro-1,2-benZ15Oxazol-3Svl-l -pin~eridiniyllet hyljamine 17 4 (2.44 cg, 9.24 mmcl) and 3,6-dichlorophthalic a-,hydride (2.01 g; 9.27 mnmol) in dich~orometh~ane (DOM, 50 ml]) was stirred- a, room temperature for 1 'hour. White precipitates formed and the TLC of the reaction mixture show.ed that there was no starting amine remaining. The solvent was strio:ed down and the white solids which were poorly soluble in DCM were loaded onto a flash chromatography column, (SiO,; 30 g) and the column was eluted with a solution of 1% CH-IH in DCM. The desired product thus obtained weighed 2.29 g *from hot ethanol yielded 2.15 gof white crystals, m.p. =163-164,c.

*.ANALYSIS:

**-Calculated for C,,H,,CI.FNO 3 57.16%C 3.92%H 9.09%N *Found: 57.16%C 3.64%H 9.13%N EXAMPLE 154 *N-F2-f4-(6-Fluoro-12-benzisoxazol-3-v)--piperid in yl ethyl lA-chl Droph thal im ide A mixture of 7-14-[(6-fluoro-1,2-benzisoxazol-3-yl)- 1-piperidinyllethyllarnine (2.13 a. 8.07 rmdl), 4-chlbrophthalic acid monosodiumn salt (2.2 g, 10, mmol) and lamb&dicyclohexylcarbodiimide (DCC, 4.25 g, 20.6 mmol) in acetonitrile (150 ml) was 4SUM stirred at room temperature for 24 hours. The cloudy mixture wvas filtered, then the solvent was stripped dlown. T he residue was partitioned between water and dichloromethane (DCMX_ The DCM solution was washed with brine and dried overMgSO 4 The solvent was removed. The crude product was purified on a flash chromatography column (SiO 2 35 g; eluted with DCM, and 1% CHPH in DOM). The desired product thus obtained weighed 1.3 g. Recrystallization from ethanol yielded 590 mg as-white crystals, rn.p. 170-171'C.

ANALYSIS:

*.Calculated for C,,H,,FN,0 3 61.76%C 4.4876H 9.82%N Found: 61.87%C 4. 39 'cH 9.8 9%IN EXAMPLE N-[2-f4-(6-Fl uoro1 ,2-benzisoxazo I-3-0l-1-p i prid in vI Ie th I -3-f Iuorophth a Iimide A mixtuftre of n uo ro-,2-benzisoxa zo -3-vl I-pi peridinyljethyl]a mine (2,37 g, 8.98 nol), 3-fluorophthalic acid (1.82 g, 9.9 mmol) and dicyclohexylcarbodjirnide (MCC, 5.5 g, 26.7 mmoi, 2.6 eq) in dichiorornethane (DCM, 250 ml) waS stirred at room temperature for 18 hours. The solids were filtered off. The organic solution was concentrated down. The residue was purified on a flash chromatography column (SiQ., 50 g; eluted with 1.4 liter; 2-6%.

CHOH:DCiM, I liter). The desired product thus obtained weighed 2.64 g 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,1 1

F,NT

3

O

3 64.22%C 4.6617c-{ 10. 21 **Fou nd: 64.11 %C 4.70 %H 10.14%N EXAMPLE 156 Ni[2-f4-(6-FluOrO-4,2-benzisoxazol-3-vl)-?r12iperidillet hyl l-4-fluorophthalimide 00 A-mixture of 2-[41[(6-fluoro.-1,2-benzisoxazol-3-y)-1 -piperidinyllethylian-mine dMMW g. 12 mmol), 4-fluoroohthalic a nhyd rde'. Freshly prepared according to th -e procedure of Marke ich, U.S. Patent,3,956221 19762.0 g, 12 mmol) and dicyclohexwlcarbodiimide (DCC, 2.48 g, 12'mmol) in chloroform (100 ml) was stirred a I room temperatui~efor 18 hours. The insolubles were Filtered off. The solution was loaded onto a flash chromatogra phy column (SiO,, 45 g) then was eluted with a solution of 2% methanol in methylene chloride. The f'ractions containing the desired product were pooled and concentrated to vield 2.9 gof white solid. The material was converted to a hydr-ochloride salt by treatment with a solution of hydrochloride in ethanol. Recrvscallization from ethanol gave the pure sample, 01 g. p. 253-255'C. AiNALYSIS: Calculated for 1

FN

3 'O,.HCl: 59.00%C 4.350ToH 9.38%N Found: 38.81%C 1.38% H 9.487%N EXAMPLE 157 N-[2-f4-(6-Flouro-12-benzisoxazol-3-yl)--piperidinvllelhvll-4-methylphthalim ide ft .A mixture of 2-[4-((-fluo ro-1,2-benzis xa zol1-3-yl)- 1 -pipe ridiny I Ie thyl Iarmine 2 4 4 g, 9.24 mmol), 4-rnethylphthalic anhydride (1.7 6 g, 10.8 mmc-nl) and dicyclohexylcarbodiimide (2.1 g, 1.0 mmol) in dichioromethane (DCM, 100 ml) was stirred at room temperature for 2 hours. The insolubles were filtered off. The DOM solution was concentrated to a crude solid. This Was purified on a flash chroma tography column (35 g, Sib 2 Sorbsil-C-30; eluted with I% CH 3 OH in 99% DCM). The material thus purified weighed 1.0 g as a white solid- Recrystallization from hot ethanol gave 665 mg of crystals, rn.p. 138-140'C.

ANALYSIS:

Calculated for CH,.FN 3

O

3 67.80%C 5.114%H 10.31]%1; Fon:67.67%C 5.43%H 10.30%N EXAMPLE 158 00 (6-171uoro-1,2-be nzisoxazo -3-yI)-l -p ipe rid in yl ethyl I- 4-methoryphthalimidq A stirred mixture of 2-14-f (6-fluoro-] ,2-benzisoxazol-3-yl)-1 piperidinyljethyllamine (2.63 g,10 mmol) and 4-methoxyphthalic anhydride (1.78 g, 10 mmcl) in dichloromethane (100 ml) is stir-red 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-benizisoxazol-3-vl)- I -Lpiperid inyl]I et hyll1-4 -met hoxy-ph tha li mid e.

EXAMPLE 159 4-(6-Fluoro-1,2-benzisoxazol-3-vl)-1-pive rid in NllIethyl 1-4nitrophthalirnide hydrochloride A mixure of 2-[-[(6-flucro-1,2-benzisoxazol-3-yl )-1-oi perid inyll ethyl Ia mine (2.9 g, 11 mmol), -nitrophthalic anhydride (2.33 g.12A mmol) and dicyclohexylcarbodiimide (2.25 g. 11 mmcl) in dichioromethane (DCM, 150 mi) was stirred at room temperature for 16 hours. The mixture was filtered. The brownish solution was leaded onto a [lash chromatography colum-n, (SiO 2 35 g; eluted with DCM, then 2% CHOH in DCLM). The desired product thus obtained weighed 2.35 g (4976) as a pale white solid, m.p. 191-193*C. This solid was converted to hydrochloride salt by treatment with an HCI solution in ethanol to yield 1-5-4 g, m-p- 250-753 0 C dec.

ANALYSIS:

*Calculated for CJi 1 9

FN

4 ,OCI 55.64%C 4.257%H 11.90%N Found: 55.8190C 4.0896H 11.67%N EXAMtYPLE 160 4-[4-(6-Fuoro-1,2-benzisoxazol-3-yl)-l-pipe rid in vl1-2-m ethvl-2hydroxybutane fumarate.

To a solution of ethyl 3-(4-(6-fluoro-1,2-benzisoxazol-3-yl)-1piperidinyllpropionate (3-21 g, 10 mmol) in tetrahydrofuran CTHF, 100 ml), was added methylrnagnesium bromide (10 ml, 30 mmol, 3M solution in ether) dropwise over 15 minutes at room temperature under The resulting mixture was stirred for 16 hours. The mixture was slowly hydrolyzed with aqueous NHCI solution. The THF solution was diluted with EtOAc (300 ml), then was washed with water and brine. The organic solution was separated and dried over M~gSO,.

After removal of solvent, the crude product was purified by flash chromatography g, SiC 2 eluted with I Cl-{OH:99 DOW,. The'material thus purified weighed 2.36 g (77-7) as white crystais. This was converted to the fumarate sal t by treatment with Eumaric acid (595 mg) in ethanol. Recrystallization From ethanol ilddwhite crvstals, 2.47 m.D.=15-55C

ANALYSIS:

Calculated for 4 4 -9.01-C 6. A45-oH 6.63%N Found: 59.40%C 6.27%'.H 6.28%N *..EXA fP LE 161 a. Ethyl 3-[4-(6-fluoro-,2-benzisoxazoI-3-vl)-1-ioeridinvfloropionate furmarate A mixture of 4-(6-fluoro)-1,2-ben~zisoxazol-3-yl)pioeriadine (5 g, 2.2.7 mmol), K,C0 3 (3S. 27.5 mmol) and ethyl bromnopropionate (G g, 27.6 mmrol, 1.2 eq) in acetonitrile (200 ml) was heated at refiux for 16 hours. The mi.xture was coaled and filtered. The solvent w.as removed, and the residue was purified on a flash chromatography column (60 a, SiC4 eluted with DCM). The material thus purified weighed 7.27 g(536). The fumarate salt w-.as prepared by treatment of the free b ase (2.17 g) with fumnaric acid (820 mg, 1.0 eq) in ethanol. Recrystallization from AiNALYSIS: Calculated for C,-HFit,O, 3 1 HO,: 579 64 Found: 7.86%kC 5.67%R 6.3 0 coN EXAXMPLE 162 2.3-d ihvdro-2-[2-[4-(6-Fluoro1,2-beiisoxazol-3-v)-ieridinvllethvll- 3-hvdroxv-1H-isoindol-1-one To a suspension of .N-[2-[4-(6-fluo,-o-112-be-izisoxiazol-3-yl)-ipi peridinyl )ethyl lphtha Iin ide (7.8 g, 19.8 mmo!) in methanol (250 ml) and DCM ml) was added NaBH, (1.7 45 mmol) at room temo~erature under nitrogen.

Afe sirigfo .5hur hehmgeneous reaction mixture was concentrated.

The remaining- solid Was 7pUified on a flash chro,-a:tography column (SiO, 1:1 EtOAc/[C. increased to 101%, MeGH1) to ci- 7.0 c, of the desired prodluct as a solid w-.hich wsre~zrvstilize.i f'rom, EtOAc, rn.o 17?-173CC.

ANALYSIS:

Calculated for C_,HFN 3 0 3 66.82'7C 5.6 IcH 10.63%N Found: 66.635/C 5.52%/*H 10.51%N ***~EXAMPLE 163 2,3-dihvdro-2-2-F4-(6-Fluoro-1,2-belzisoxazol-3-yl)-1-piperid invllethvll- IH-isoindol-1-one To 2-[2-[4-(6-fluoro-1,2--benzisoxazol-3-yl)-1 -piperidinyllethyll-2,3-dihydro-3hydroxy-I H-isoindol-I -one (2.2 S, 5.6 rhmol) 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 16 hours at which time it was poured into a NaHCO, (sat.).

The layers were separated and the aqueous phase was extracted-with DCM (3X) The combined organics were washed with brine and dried (lN'a 2 Filtration and concentration gave the crude product as a solid which was recrystallized from EtO~c to give 1.6 g of the desired product ais a white solid.

m.p. =166-168*C.

A N'ALYSES: Calculated for 69.64%C 5.84 %lH 11.07%iN Found: 69.37%C 5.70%H 11.00%N EXAMPLE 164 (S)-3-r4-(6-Fluoro-1,2-benZi5OXaZOI-3Y-v)-l-piperidinvfl-2-methlpropylmethyl carbarhate To a solution of 2-12-f4.(6-fRuoro-1 ,2-benzi-soxa zol-3.y1)-1-pi peridinyll ethyl] 23-dihvdr-3-hvdroxv-I H-soindol-1 -one (3.1 g, 10.6 mmol) in dry Ti-F (120 ml) was added methvl isocyanate (0.66 ml. 11.1 mrnol) follow.ed by milled K-CO 3 (2.2 15.9 mmol) at room temperature, under nitrogen. The reaction mrixture was stirredfor 3 days at which time it was filtered through a pad of Celite and the solidis washed with EtOAc. The combined filtrates were concentrated to give the crude product which was purified via flash column chromatography (silica gel, 2% EtN/EtOAc). The product containing fractions were concentrated to give 2.7 g of the desired product as an oil which solidified oin standing.

*Recrystallization from EtOAc/pet-ether gave the product as a solid, m.p. =72-74'C.

AN\ALYSIS:

Calculated for C,,H, 4 FN,0 3 61.88%C 6.92%H 12.03%N ***Found: 61.82%C 7.02%H 11.77%N EXAMPLE 165 (S)-3-r4-(6-FI uoro-1,2-benzisoxazol-3-vl)-1-piperid inyll-2- -methylpropyl decanoate fumarate To a solution of 2-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)- -piperidinyllethyll- 2,3-dlihydro-37hydroxy-IH-isoindol-l-one (3-2 g, 10.9 rnmol) in DCM (110 ml) was added decanoyl chloride (2.3 ml, 10.9 rnmol) at 0 0 C, under nitrogen. The reaction rrixture wa s stirred for 1.25 hours (W 0 C) at which time it was poured into NaHCO, The-layers were separated'ard the aqueous phase was extracted with DCM The combined organics were dried, filtered and concentrated to give the crude product-1which was purified via flash colirin chromatography (silica gel, EtOAc/DCM). The product containing fractions were concentrated to give 3.4 of the desired product asa yellow oil. The furniarate salt was prepared in ethanol with fumaric acid (1.03 The white -salt was filtered and washed with ikopropyl ether, m.p. 110-112'c.

AN~ALYSIS:

Calculated for C. 1 9 F'03'C 4

H

4 01: 4C .0l 4.9317N Found: 64.07%C -7.75%iH 4.90%N EXAMPLE 166 (S)-6-Fluoro-3-[-(3-methoxvphenvl-2-methvlproovl)-4-pioeridinvll-12benzi soxazolIe To a solution of 2-[4-(46-fluoro- 1,2-benzisoxazol-3-vl)-lI-piperid inylI Iethyl)- 23-dihydro-3Lhydroxy-]H-isoindol-l-on-e (3.3 g, 11.3 mmol) in dry TI-F (120 rrd) lwas added potassium tert-butoxide 01.9 g, 16.9 mmol) followed by dimethyl sulfate (0.2 ml,-11.9 mmol) at room temperature, under nitrogren. The reaction 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 givl the crude producf.: Purification via flash column chromatography (silica gel, 0-2L, acetone/DCM) afforded 1.6 g(46%) of the desired product' as a solid, m.p. 4 2 C.

ANALYSIS:

944- Calculated for C 17 H, 66.65%C 7.57%H 9A1 4%N *.*Found:- 66.49%C 1.48%H 9.12%N EXAMPLE 167, W±-6-Fl uore -3-f I-(3-hVd roxy bu ty1) -4-p ip eri d i n 11 -1,2 -b enziso xazo Ie Racemic 3-hydroxybutyl tosylate was prepared in a manner described by Ferreira et al., Tetrahedron, 4.6 pp. 6311-6318, (1990). To a solution of the racemic tosylate (9.2 g, 37.7 mmol) in acetonitrile (190 ml) was added 6-fluoro-3-(4piperidinyl)-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 througlh a pad of Celite and were washed with EtOAc. The combined filtrates were concentrated to give the crude product. Purification via preparative H-PLC (silica gel, 10% MeGH/EtOAc) afforded 6.3 g mn.p.- 100-102*C.

ANALYSIS:

Calculated for C, 6

H,

1 FN,0 2 Found: 65.735aC 65.595%C 7.2-1%H 7.30% H 9.58%N 9.52%N go at

A.

IEXAMPLE 168 6 Fluaro-3fl.(3hydrox-2-methvi propvl)4-piperidinvii- 1,2-benzisothiazole fumnarate A mixtuLre of 6 -Fluoro-3(4piperidiflyl)12-belzisothazole 20 mmol), (R----rm--ehllpoao (3.0 g, 20 mmol), K 2 C0 3 (2.7 g, 20 rnmol), tetrabutylammofliumn sulfate (0.058 CHCiN (95 ml) and HO (19 mld) was stirred and refluxed for 4.3 hours. After standing at ambient temperature for 16 hours, the reaction was poured into Hp, and subsequent extractive workup of 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

CI,

then 2% LMeOH-CH 2

CI

2 and finally 5% MeOH-CHClr Concentration of the appropriate fractions yielded 5.2 g of a waxy solid. The solid was dissolved in acetone and furnaric acid 01.9 g, 1.0 eq) was added and the reaction briefly heated at reflux. The resultant fumnarate salt precipitated from solution yielding 4.8 g of white solid. The compound was recrystallized from a6etonitrile to yield 3.1 g of the alcohol as a white solid, m.p. =151-153*C

ANALYS:

Calculated for C,,H,,FiN,OS.CHO 4 56-59%C 5.94%H 6.60%N Found: 5o.31 %C 5-96%H 6.48%N EXANTPLE 169 N-2f-6Fur)12bnz-oao-- -~ieiinvllethyll-3.6di flu oroo hlbali mid e A mixture of 2 6 -fluoro-1,2-befl~LSO"azol3.Y)l-pioeridinyllethylami- (1.53 g, 5.3 mmol), 3,6-difluorophthalic anhydride (1.0 7, 5.43 mmol) and dicyclohexvicarbodiimide (DCC, 1.84 g, 8.9 m, mol) in mnethylene chloride DCLM, 100 rl) was stirred for 6 hou-S, and then left standing overnight at room temperature. The solids were filtered off. The solution was loaded onto a silica gel column (35 g, Sorbsil C-30), then e-luted with a mixture of methanol and DCNI The fractions containling the desired product were pooled and concentrated to give L1.23 g of white solid. Recrystafization from DCM and hot ethanol yielded 1.03 g (44.5%70 of white crystals, m.p. 144-i45'C.

ANALYSIS:

Calculated for C,,H,,F 3

N

3 0 3 61.54%C 4.23 9.79%N Found: 61.63%C 3.83%H 9.77%N q t-.

*902 @9 4.

q*.

IO o e.g.

0 ~1

CI

EXAMPLE 170 N4[2-r4-(6-Fluoro-12-benzisoxazol-3-vB)--pip~eridinyllethll-2.3,4tetrahvdro-isociuinoline-1,3-dione A mixture of 2-[4-[(6-fluoro-1,2-benzisb xazol-3-yl)-1 -piperidinyllethyllam-ine (2.45 g, 9.28 mmol), hornophthalic anhydride (1.78 g, 10.9 mmol) and DCC (2.2 g, 10.7 mmol) in CHCI, (100 ml) was stirred at room temperature for hours. The insolubles Were filtered off. Thle solution was loaded onto a flash chromatography column (Sorbsil C-30, 40 eluted with DCM (1.5 2% CH 3

OH

in DCM 0(1 then~ washed, with 20% CHOIH 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, mp. 148-150*C.

ANALYSIS:

Calculated for CH,.FNO,: 67.80%C 5. 44 %H 10.31 %N Found: 67.5451cC 5.31%7aH 10.17%N EXAMIPLE 171 2-4[6Fur-,-ezstizl--,)lpprdnitvlmn sesquitumnarate To a stirred solution of N4-(2-[4-(6-fluoro-1,2-benizisolhiazo1-3-yl)-l piper-idinyllethyllphthalirnide (17.0 g, 42 mrnol) and MeCH (200 rml) under N, was added, dropwise, hydrazine monohydrate (4.2 g,83 rnol). After complete addition, the reaction was stirred at reflux for 17 hours. The reaction midxture was concentrated and the resultant residue was dissolved in H9O. The aqueous i: solution was acidified to pH -2 with concentrated HCI and the precipitate was filtered. The filtrate was basiFied with 50% NaOi- and the product was extracted :u.into CH,CI,. The CH,CI, extract was Washed with HO, dried with MgSO, and concentrated to yield 6.0 g (52%6) of a beige oil. A 5.8 g sample if the oil1 (21 mrnol) was warmed in EtOl-{ (100 ml) and ftimaric acid (27 g. 23 mmol) was added. The solution was refluxed gently for 15 minutes and was stirred at ambient temperature for 1.5 hours Anhydrous EtO (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 tMeOH-EtQ to provide 1.7 g of the sesquilurnarate salt as a white powder m.p. =169-171 C.

ANALYSIS:

Calculated for Cl-lFN 3 ,S-1I.5CH,0 4 52.97%C 5.35%H 9.27%N Found: 52.96%C 5.44 %H 9.39%N EXAMPLE 172 (S)6-Fluoro-3-[-(3-hydroxybutvi)-4-piperidilvll-1,2-belzisoxazo e (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, 23.0 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 GA. g, 42-0 mmcl) at room temperature under nitrogen. nhe 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 %-.ere wvashed wiJth EtOAc.

The combined filtrates were concentrated to give the crude product. Purification via flash column chromatography (silica gel, 0-10% MyeGH/EtOAc) afforded 5.5 g (67%7) of the desired product as an oil which solidified on standing, m.p. 84--86'C.

ANALYSIS:

Calculated for C 16 65.73%7C 7.24%H 9.58% N ssFound: 65.58%C 6.83'7o-H 9.50%N o s EXAMPLE 173 o* 55* (R)-6-FI uoro-3-[l-(3-hydroxvbutv)-4-iperidinyll12-benzisoxazole (R)-Hydroxybutyl tosylate was prepared in a manner described by Ferreira et Tetrahedron, A-6,pp. 63i]-6318, (1990). To a solution of the tosylate (8.4 v, 34.2 mmol) in acetonitriler(120 ml) was added 6-fluoro-3-(4-piperdinyl)-1,2benzisoxazole (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 cml via flash column chromatography (silica gel, 10% MeQHVEtOAc) afforded 6.0 g of the desired product as an oil which solidified on, standing, m.p. 8-2-84'C.

dft*

ANALYSIS:

Calc-ulated for CHj A 65-73%C 7.24%H- 9.59%N Found: 65.66%C 7.13%H 9.53%N EXAMPLE 174 N-[2-[4-(6-Fluoro-IH-indazol-3-yi)-l-piperazinvilethvilhthalimide A mixture of 5.fluoro-3-(4-piierazinvl).1H-indazole g, IS mmol), Y.,CO, (2.7 g, 20 mmoie), N-(2-bromoethyl)phthalimide (11.8 g, 19 mmole) and CHJ-N 1S6 (100 ml) was stirred at reflux under N, for -4 hours. Afe standing at ambient tempe Irature for 65 hours, the reaction was poured into H0O. The resultant sold was collected to yield 4.0 g of a yellow powder. The product Was recrystallized twice from ethanol to yield 3.5 g(50%) of a beige Powder m.p. 220-223*C.

ANALYSIS:

Calculated for C,,H,,FN,0 2 64.11]%C 5.12%H 17.8OlN *Found: 64.16%C 5.04% H 17.82%iN NI?42446-Fluoro-1 H-indazol-3-fiI-7 -pilterazin ulie-t h,rhtlw limide hud rochlorfde A 5.0 g sample of N-[2-[4-(6-fluoro-lH-indazol-3-yl)-l-piperazinylethyllphtha timid e was suspended in methanol (130 ml) and was made acidic with ethereal-HCI. After stirring for I hour, anhydrous ether (100 ml) was added and the suspension was stir-red for an additional 30 minutes. The solid was collected .*and dried to afford 4.5 g of an off-white powder. T-his was combined with an additional sample (7.3 g total) and recrystallization from MeOH gave 4.3 g of the salt as an off-wvhite powder, rnp =265-268C.

ANALYSIS:

C(Calculated for FNO,.HCl: 58.62%C 4.92%H 16.29%N Found: 58.60%C 4.83%H 16.19%N EXAMPLE 175 Ethyl 3-I4-(6-Fluoro-1,2-benzisothiazol-3-vH-l-piperidinllpropiorzz, hydrochloride A mixture of 6-fluoro-3-C4 -piperidinyl)-l,2-benzisothiazole (6.0 g, 25 mmol), ethyl 3-bromopropionate (4.5 g, 25 mmol), KC0 3 (3.5 g) and CH 3 CN (100 ml) was stir-red and refluxed for 16 hours. The reaction w-as pou-.ed into H,O, and afta-r extractive workup with EtOAc, 6.0 g of an orange oil was realized. The oi; a dissolved in Et.O and ethereal HCI was added to precipitate 6.3 g of a whihydrochloride saIlt The salt was recrystallized from CHCN to yield 6.0 g (6417) 1g7 of the dlesired comDOUnd. An ralytical sample obtained by recrystallization of a 1.0 gsample from EtOtH-Et 2 O to yieid 0.8 S of a ~*'iesolid, m.p. 197-199'C

ANALYSIS:

Calculated for C 17 H,,FN,OS.HCI: 5 J176 cZC 5.95%,H 7.51%N Found: 511.77 %C 5.99%HA 7.28%oN 7 XAMPLE 176 **44 -(6-F]uo ro-1,2 b e 6 sothiazo l-3-vDI)-ptipe rid invfl -2-m.-th Vl-2hx drox-vbutane hemni~umnaratc To a S irred solution unde N,,,of ethyl 3-[4-(6-fluoro-1,2-benzisothiazol-3-yl)- 1-piperidinylipropionate 9 mmol), in THF (100 ml) w_ s added, dropwise, methylmagnesiumn bromide (9.0 ml, 27 inmol of a 3M solution Iin ether). The *reaction was stirred at ambient temperature for 16 hours and then a saturated solyion NHCi -was added dropwise, with cooling. The reaction was further diluted with H,0. and after extractive workup of !he ajueousmftdxture with EtOAc, 2.8 g of a waxy solid resulted. The solid was dissolved in EtOAc and 3.0 g of contamninated with unreacted furnaric acid. The crude'salt was recrystallized from Me-Ol--EtAQ and then from DMYF to afford 1.6 g(45.7110 of the desired compound as a hemnifumnarate, m.p. 237-239'C.

ANALYSIS:

Calculated for C,,HFt\,OS.CHO,: 59.9SC 9 6 -6 4 c7. 7.36% 0

N

Found: 5 9.7 5 %cC 6.6 5 ci H 7.39%iN EXAMPLE 177 N-f 2-14-(6-Fluoro-1 .2-benzisoxazolI-3-vl)-1-ptiperid invil lthyl 1-3hydroxyhthalimide hydrochloride A mixture of 2-14-[(6-fuorc-1,2-benzisoxazol-3-yl -pipe rid inylI Iethylla mine 5** 0* at..

(2.48 9.3 mmol), 3-hydroxv.Ohthalic anhydride (0.8 10.9 rnocl) and dicyclohexylcarbodiimide (22g, 10.7 mnmol) in c'nlorofdrm (100 mil) was stirred at room temperature for 43 hours. The mixture was filteredz. The yellow solution was loaded onto a flash chromatography column (SiO, 40 gr; eluted with DCM, 1 1; and 2% CHOH in DCN'f, I The desired product thus obtained as a light yellow solid weighed 2-12 g m.p. =156-157 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, rn-p. 270-272'C dec.

ANALYSIS:

Calculated for C,,H,FNOHCI: 59,26%C 4-75%F1 9.42% N Found: 59.34%C 4.70%H 9.19%N EXAMPLE 178 N-r2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-i-piperidi nyle thv1-4-fl uoroph th alIimr ide Asolution of 2-[4-[(6-fluoro-1 ,2-benzisothiazol-3-yl)-l-piperidinyllethyllamine (2.7 g, 10 mmol), 4-fluorophthalic anhydride (1.6 g, 10 mmol) and DMF (50 ml) was stirred under at ambient temperature for 1 hour and then at 70' for 2 hours. Most Of the DMF was removed in vacua to afford 4.6 g of a damp, beige solid. The compound was dissolved in anhydrous EtO (100 nil) and ivlOH mil) and the insolubles were filtered off. The filtrate was made acidic with ethereal HCI to precipitate the HCI salt. Additional anhydrous EtO (500 ml) was added and the salt was collected to give 3.5 g of a beige solid. Recrystallization from EtOH provided 2.08g of an off-white powder, m.p. 269-271*C.

ANALYS S: Calculated for C..H 9 F,OS.HCI: 56.96%C 4.35%H 9.06%N Found: 57.33%7C 4.33%H 9.11 %N EXAMP'LE 179 6-Fluoro-3-f1-(3-hvdroxv-"-e Ih v I ent-vD)4-p iperid inx' v -1,2-benzisoxazolIe To a solution of ethyl 3-[4-(6-fluoro-l ,2-be-nzisoxazol-3-y)-1 pilperidinyllpropionate (3.9 g, 12.0 mmol) in THF (100 mD) was added ethylmagnesium bromide (12.0 mi, 36.0 rnrol, 3.0 IM 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 NHCl (sat., 20 mi). The precipitated :salts wvere dissolved into water (25 ml) and the layers were separated. The aqueous phase was extracted with EtOAc (MX) and the-.ombined organics were washed with brine and dried (iJaSO,). Filtration and concentration!gave the crude product which was purified via Hlash column chromatography (silica gel, 19% MeOH/DCLM) to give 2.4 g (61 of the desired product as an oil which solidified on standing, m.p. 50-53*C.

AN\ALYSIS:

Calculated for C, 9 Hj 7 68.24%C 8.14%H 8.38%N Found: 67.997oC S. I I %H .S~eN EXAMPLE 180 Decanoic acid 2-l2-k,1-(6-.Fluoro-1,2-benzis xazol-3-WI-1-piperidin lethYjL 3-oxo-2,3-dihydro-1H-isoindol-1-yI ester to a solution of 2-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1 -piperidinyiethyl-2,3)dihvdro-3-hvdroxy-1l-l-isoindol-1 -one (1.4 g, 3.5 mrnol) in DOM (30 mi) was added EtN (1.2 ml. 8.8 mmol) followed by decanovi chloride at 0OC under~ nitrogen. After stirring for Ilh in the cooling bath, the solvent was removed us5ing a stream of nitrogen. The remaining residue was diluted with EtOAc and the precipita ted. triethyla mine hydrochloride was filtered off. The filtrate was concentrated and the remaining oil was flushed through alumina wvith ether to give 1.6 g of the desired product as a vellow oil.

ANALYSIS:

Calculated for C 3 ,H,FNO,: 69.92% C 73 3,cH 7.64%N Found: 6 9.70 5cC 7.39'oH 7.56%N EXAMPLE 181 6 -Chloro-2-[2-r4-(6-fluoro-1,2benzisozol-3-vz)-piperidinvllethvl.

1H-benz[delisoouinoline-13(2H)-dione" A mixture of 2-[4-[(6-fluoro-1,2-benzisoxazol-3-y)-1 -piperidinyllethylia mine (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 wvas concentrated down to ml. The resulting mixture was loaded onto a flash chromatography column (SiO 2 50 g; elUted with dichloromethane, DOM, 1 1, and 2% CHOH in DC M, 1 1).

The prdc thus obtained as a light yellow solid weighed 2.61 g.

Recrysta llzatLion from CHC,/ethanol gave 2.5 g of pale white crystals, m.p.

207-209'C.

ANALYSIS:

MMCalculated for C,,H,,ClFiN'O,: 65.34%C 43%H 8.79%IN Found: 64.87%C 'H86% EXAMPLE 182 N4[2-r4-(6-Fluoro-,2-ber-isoxazol-3..')1p iperidinvllethvll-4-tertbutviphtha limide fumnarate A mixture of 2- uoro- 1,2benzisoxa zol-3-y 01 pi peridinyIleth VI)a mine g, 7.57 mmol) and 4-(t-butyl)phthalic anhydride (1.62 g, 7.94 mmol) in dimethylforrnamide (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 vacuum pump. The residue was Purified by flash chror-2tography over a silica gel column (5102. 35 g, eluteci with DCM,, and 1-21.7 crc methanol in DCM). 'Ihe product thus obtained as an oil was trituarated with isopropyl ether and dried to a waxy solid. This solid was converted to the fumnarate salt by treatment with a solution of fumnaric acid (71-S mg in ethanol. Th2 crystals were collected and weighed: 3.03 g, rn.p. =198-199'C.

ANALYSTS:

**Calculated for C,,H,,FN,0,.C 4 HO,: 63.71 %C 5.70%H 7.43%N *Found: 63.46%C 6.059.1- 7.27%N EXAMPLE 183 N-[2446-Fiu oro-1H-ind- zoi-3-yi)-Piperidiilethviluohthalimide hvdrochloride A mixture of 6-fluoro-3-(4-piperidlinyl)-1 H-indlazole (2.5 I1 m mol), 2-bromoethylphthaliirnidle (3.0 g, 10 mmoiX, NaHCO3 (1.0 g) and DMF (30 m,1) was stirred and heated at 60 C for 2.5 hours. The reaction was p~u red into H 0. and after extractive workup with EtOAc there remrained 4.0 g-of a golden oil. The oil was dissolved in EtOAc and etherealI HCI w-.as added to yield 193 g of' the hydrochloride salt as a white solid. The solid was recrystallized from \,eOH-EtO and then from DIF to afford 0.54 g of the compound as a white solid-, m.p.

270 272'C.6.5C 03HT8% Cacltdfor C..H,,FN 4 61.61 %C 5.17%7cH I13.067%N EXAMPLE 184t 2-f2-r4-(6-Fluoro-1.2-benzisothiazol-3-v)-l-o2iperidinyll-2,3--dihvdro-3- "hydroxv-IH-isoindol-1-one hvdrochloride To a stirred solution of the N-l2-[4'-(6-fluo,,ro-i,2-ber--zisothiazol-3-yl)-lpiperidlinyllethyllphthalimide (2.5 g, 6 mmol) in NteOH (50 m1)-CH-.Cl, (20 ml) was added NaBH, (0.8 21 mini). The reaction w"s siirred at ambient temoerature for 2 hours, and then the solvent was evaporated. The residue was diluted with H,O, and extractive workup of the aqueous with CHl-C, afforded 2-2 g of a bei--2 solid. The solid was combined with a ample from a prior runm and the combined sample (3.2 g) was chromatographed on a Waters Prep 500 LC, eluting with EtOAc-Et,NH Concentration oF the appropriate fractions afforded 2 2 g of a white solid. The solid wvas 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(31%) of a white solid, rn.p. 210-212'C.

ANIALYSIS:

Calculated for C,-H..FNO,S.HCi: 5S.99%C/ 5.1 S cH 9.38%N Found: '5S.89%;C 3.2 3 '76 9.16%N EXAMPLE 185 p N-f2-14-(6-Fluoro-1,2-benzisothiazol-3-v)--pieridinvllethyll-4methylphthalirnide hydrochloride Amixture of 2-[4-[(6-fluoro-1.2-benzisothia zol-3-yl)-1 -piperidinyllethy)ami,,ne (3.4 g, 12 mmol), 4-methylphthalic anhydride (2.0 12 mmol) andEDMF (75 ml) was stirred at 70'C under for 3.5 hours. tMost of the DMF was removed in vac uo, and the oily residue was diluted with HO. 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 fromn the Celite and was dissolved in CH,C,. The solution was filtered through the original Celite cake-, and the CHCl, filtrate was washed with H,0. dried with MgSO, and concentrated to yield 0.5 g of an off-white solid.

The phases of the EtOAc/H.0 filtrate were separated and the aqueous was further extracted with EtOAc. The EtOAc extract was washed with HAC) dried with MgSO, and concentrated to afford 3.5 8 of an off7yWhite solid.

The twvo samples were combined and recrytlie V5otO togv 22-o a white Dowder. The zoroduct was dissolved in anhvdrous ether (200 ml) Znd methanol (100 ml) and the soiuticn was made acidic: with etnereal HCI. After-ca.

minutes of stirring the sal: beg-an to precipitate.ditoa anhydrous ether (400 m1) was added over 2 hours and the resultant white solid was collected to yield 2.2 g. Recrx'stalization fronn MeOH-ether provided 1.7 of a white powder, 268-271*C.

ANALYSIS:

Calculated for C~fHi-FN 3 O-SHCl: 60-06%C 5.04%H 9.14 %N **Found: 60.01 %C 5.00%7H 9-12%N :.E-XANTPLE 186 6-Fiuoro-3-f1A3-hvdrorcv-3- rop~vlhex-vl)-4-piperidinv'l1-1,2-benzisoxazole livdrochloride Toa a solution of ethyl 3-[4-(6-fluoro-1,2-benzisox<azol-3-vl)-p-iperidinylpropionate (4.5ga, 14.0 mmcl) in THF (120 ml),vwas added propyl magnesium chloride (21.1 ml, 42.0 mmol, 2.0 M in ether) at room temperature under nitrogen (mild exothenn). The reaction mixture was stirred for 17 hours. at wvhich time it was carefully quenched w~itH ,NI-1C1 30 ml). The layers were separatted a nd the aqueous phase was extracted with EtOAc (2X).-The combined organics wvere washed wvith brine and dried (NaSO-). Filtration and concentration gave the crude product which was purified via flash- column chromatography (silica gel,2 EtN/e ther). After flushing the product through alumnina with ether, the hydrochloride salt was prepared in ether/EtOAc 40 ml, I drop IPA) with ethereal HO to give 2.5 g of the desired product as a white solid, 163-1 64'C.

ANALYSS

Calculated for 6 3-2)5C S.0S%H- 7.0 2 7 N Foud:62.97%C 7.9% 7.01 %N EXAMPLE 187 N-2-f4-(6-Fluoro-1.2-benzisoxazo-3I)fl-12iljeidinvflethll-3nitrophthalirnide fumarate A mixture of. -[4-[(6-fluoro- 1,2-benzisoxazol-3-yl)- I -piperidlinylj ethyllarmine (2.09 g, 7.9 mmoi) and 3-nitrophthalic anhydride (1.6 g, 8.3 mrnol, 1.05 eq) in dime thyl-formarnide (DiMF, 20 ml) was heated at 135'C for 3 hours. The solvent a was removed on a rotaryv evaporator under vacuum and further dried on a vacuum pump. The residue was purified by flash chromratography over a silica gel column (SiC 2 35 g; eluted with dichloromethane, 300 ml, and 37. CH-jH in DCM, 300 ml). The product thus obtained, 2.01 g, was dissolved into DCM ml) and ethanol (5 ml) and was treated with a solution of fumnaric acid (530 mg, eq) in ethanol (15 ml). The crystals were collected and weighed: 2.03 Z, rn.p.

237-239'C.

A ANA'LYSIS: Calculated for C..H,,FNO 5 .CHO,: 56-32%C 4.18%H Found: 55.9476C 4.23%H 9.87%N EXArvLE 188 2-iA-(6-Fluoro-1,2-benzisoxazol-3--v)--p ipe rid in yle thl.4hydrox-vphthalimjde hydrochloride zA mixture of 2-[4(6 -fl uoro-1 ,2-benzisoxazol[-3-vl)-bpipericlinyll]ethyllJamine g, 18.9 mn'rol), 4-hydroxyphthalic acid (4.14 g, 1.2 eq), and dicyclohexvlcarbodiimide (DCC, 8.61 g, 4.18 mmol) in dirnethylforrnamide (50 ml, was -stirred and heated at 75"C for IS hours. The m ixture was cooled, and the solids (DCU) were filtered and rinsed with dichloromnethane (DOM). The solution was concentrated down to dryness. The residue was dissolved into dichlorornethaie (100 ml) and the insoluble5, which contained the product also, were filtered and collected. The solution was concentrated down to 50 ml arnd loaded onto a flash chromatography column (SiC 2 50 g; eluted with DCM, and rnethanol:DCMN mixt-ure). The desired product was collected as a pinkish solid, 195 1 .71 g.This solid was converte d to the hydrochloride salt in ethanol w-,ith an HCI in ether solution (IM, 5 ml). The crystals were collected and dried: weight: 1.2 rn.p. 272-275'C dec.

ANALYSIS:

Calculated for C_.H, 0

FLNO

4 .HCl: 59.26%C 4.7D-%H 9.42%N Found: 59.0O90C 4.60%H 9.34%N 00 EXAMPLE 189 hydrochloride A mixtuire of 6-loo3(-ieiiyl-,-ezstizl (3.9 g, 17 mrnol), K,COJ (2.3 g, 17 mmol. (±)-3-hydroxvbutyl tosylate (4.0 g, 16 mmol) and CHJCN (100 Ml) was stirred at reflux under N, for 5 hours. The cooled reaction was *filtered through Celite and the cake wvas rinsed with EtOAc. The filtrate was concentrated to afford 6.7 g of a red oil. Purification via preparative

HPLC

(Water's Associates Prep LC/System 500, using 2 silica gel columns and MeOH-CH 2 provided 2.5 g of a beige solid. The product was dissolved in anhvdrous Et.O and a minimal amount- of MPOH and the solution was acidified with ethereal HCI. Kdditional Et 2 O was added to precipitate 1.9 g of the HCI salt.

Recrystallization from NMeOH-EtO gave 1.7 g and a second recrystallization from 'M CH 3 CN yielded 1.0 g(18%) of a light beige powder, m.p. 182-184'C.

ANALYSIS:

Calculated for C 1 2 F,OS.HCl: 55.72%7C 6.4317H 8.12%iN Found: 55.S3%7C 6.54 H 8.19%N EXAMPLE 190.

Decanoic acid I I-diethvl34(6lur2benzioxazol3vl)lpiperidinyllpropvl ester hydrochalide To a solutionof6fur3l(3dOX eYle v)4ppiinY1 2 benzisoxazole (2.5 g, 7.48 mnmol) in DOM (100 mnl) was added Jecanoyl chloride ml, 7.48 mmol) at 0 C, under nitrogen. The reaction mixture was stir-red for 4 days at which time it was poured into NaHCO, (sat., 50 ml). The layers were separated and the aqueous phase was extracted with DOM The combined organics were dried, filtered and concentrated to give the crude product_ which was purified via flash column chromatography (silica gel, 20-40% EtOAc/DCM\).

The product containing fractions were concentrated to give 3.0 g of the desired Product as a yellow oil. The hydrochloride salt was prepared in anhydrous *ether (60 ml) And isopropanol (1 ml) with ethereal HCI. The white salt was filtered and washed with anhydrous ether, m.p. 159-161'C.

ANALYSIS-

Calculated for C,,H, 3 Fi\,O,.HCI: 66.33%oC 8.83%H- 5.33%N Found: .66.45%C 9.01 %H 5.31 %N EXAMPLE 191 2-4(6-Fluoro-1,2- benz isoxazol-J-vl-I -p ipe rid inyl lethyl 1-2,3-n aph th alim ide A mixture of 2-[4--(6-fluo ro-1,2-benzisoxa zol-3-y)-1 -piperid inyll ethyla mine g, 7.58 mmol), and 2.3-naphthalenedicarboxylic anhydride (1.58 g, 7.95 mmol) in dlimethvlforrnamidle (20 ml, DNMF) was heated -at 150'C for 2 hours. At the end, ci the mixture was cooled and the solvent was removed to dryness. The residue was purified by flash chromatography over silica gel column (60 g of SiC,, eluted with dichioromethane CDCM), and 1.5% CHOH in DCO). The product crystallized out 4MM" on concentration; weight:, 1:6 g Recrystallization from chloroformethanol gave 1.38 g, of off-white crystals, m.p. 192-193C.

ANALYSIS:

Calculated for C,,HI.FN,O,: 70.4217C 5. 00%1.H 9.48%N Found: 69.85%C 4359%H 9.27%7N f8* 0**t a.

S

0 0.50 0* U 0

N

EXAMPLE 192 2,3-D ih yd ro-2-(2444-6.Iu oro-12- benzisoxazol-3-l)-l-p ip eridiny IlethvLL' 3-hvdroxv-3-methvl-1 H-isoindol-1-one furnara te To the solution of -(6-fluoro-1,2-benzisoxazol-3-yl)-I -piper idinyllethyl]jph thalimide (6.2 15.87 rnmol) in tetrahydrofuran (THF, 80 ml) was added dropwise a solution of rnethyLrnagnesium bromide (3M. 6.5 ml, 1.2 eq) in ether at room temperature under N, The mixture was stirred at 55'C for 16 hours. The reaction mixture was treated with NH 4 Cl solution (10 ml) and partitioned between brine and ethyl acetate. The EtOAc solution was washed with brine and dried.

Filtration and concentration gave a crudle product (3.9 This crude product was purified on a flash chromatography column (40 g, Si0 2 eluted with 0.576 CH 3

OH

in DOW) 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*C.

AIN ALYS IS: Calculated for C, l-lFNO,.CHO 4 61 .71 %C 5.37%H- 8.00%N Found: 61.47%C 5.67%H 7.82%oN EXAMPLE 193 2,3-Dihvdro-2-r24[4-(6-fluoro-1,2-benzisoxazol-3-vl)-l-p iperidinflethvll- 3-rnethylene-IH-iscindol-I-one hydrochlor-ide To the solution of 2.3-d ihydro-2-(-[4-(6-fluoro-1 ,2-benzisoxazol-3-yl)-1 piperid inyl Iethyl]-3-hvd roxy-3-meth l- I H -isoindol-1I-one (4.88 g, 11.9 rnmol) in chloroform (50 ml) was added HCl-ether (IM, 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 chromatography over silica gel column (SiO,. 60 g; elu ted with DCNI). The pur'&' product thus obtained weighed 3.28 g (70%Xc) Treatmnent w,,ith HCI-ethe-. solution in ethanol gave 1.52 S of w.hite crystals, m.p. 261-263C AiKALYSIS: Calculated for CH,,F~jO.HCI: Found: 64.56 %C 64.47%C 5.42%i H 5.1 H 9.82 %IN 9.72%N

S**

S SC

S

50.9 5

S

5* d EXAM\4PLE 194 1424611uoo12b zsxz D1- peidi ll hy yl ean hydrochloride To pentamethylene bis(magnesiumn bromide) (35.0 ml, 17.5 mrnol, 0.5 M in THF) was added a solution of ethyl 3-f 4-(6-fluoro-1 ,2-benzisoxazol-3-yll-'.piperidinyllpropionate (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 for 17 hours at which time it was carefully quenched with NHCI (sat., 50 ml). The precipitated salts were dissolved into water (25 ml) and the layers we re separated.

The aqueous phase was extracted with EtOAc and the combined organics were then dried (NaSO,)- Filtration and concentration gave the crude product which was purified via flash column chromatography (silica gel, 50% EtOAc/DCNI 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, rn.p. =210'C (dec.).

ANALYSIS:

Calculated for C, 2

.H,

7

FN

2 62 .74% C 7.37%H 7.32%N Founid: 62.85%7C 7.53%H 7.14%N EXAMPLE 195 f44-7 oo12b zs hiao--i--ip i in vI-3-ethvl -3-h vdroxyp en lane hydrochloride To a stirred solution, under N 2 of ethyl 31(4-(6-fluoro-1,2-benzisothiazol-3-vl)- 1 -piperidinvylpropionate (5.3 g, 16 rnmol) in THFP (2M0 ml). was added dropwise, ethyl magnesium bromide (15.7 nml of a 3.0 Mi solution in Et~fl). *Yhe reaction was stirred at ambient temperature for 16 hour-s and then following cooling in an ice bath, a saturated solution of NHCI was added dropwise. The aqueous mixture was extracted with EtOAc, and the extract was -washed (H40), dried (MgSO 4 and the solvent was concentrated to afford 5.8 a of a yellow oil. The oil was chromatographed on a preparative HPLC, upon a silica gel column, eluting with 6% MeOH/CHC 2 Concentration of the appropriate fractions yielded 3.7 g of a yellow oil. The oil was dissolved in E-tO and ethereal HCI was added to precipitate 4.0 g of a white salt. The salt was recrystallized twice from EtCH-Et,O to afford 1.4 g (22L) of the alcohol as a w.hite solid, m.p. 207-209vC.

s...ANALYSIS: *:Calculated for C 1 9 HjN,Os.HCI: 58.98%7cC 7.29%H 72% Found: 58.95%C 7.63 %aH T1 1%N EXAMP'LE 196 Ethyl 37 4-(6-fluoro-lH-indazol-3-vl14l-ierainlPropionate hydrochloride To a stirred suspension of 6-fluoro-3-(4-piperazinyl)-IH,--indazole (9.9 g, mmol), KCO, (6.8 g. 49 mrnol0) and CH 3 CN (210 nil) under N, was added, dropwise, ethyl 3-bromopropionate (3.1 g, 45 mmol) in CHCN (20 ml). After complete addition, the reaction was stirred at refiux for 16.5 hours. A TLC -da% revealed remaining starting indlazole: therefore. triethylamine (1.5 g, 14 romol) was I nn added dropwise to the cool reaction mixture. The reaction was stir-red at reflux for I hour longer with no additional change bLy TLC. The reaction was cooled, filtered, and the filtrate concentrated to yield 1 4.6 g of an off-white solid. The material was purified by preparative 1-IPLC (Water's Associates Prep LC/System 500A using 2 silica gel columns and 6.57r MeOH-CHClkas eluent). Concentrati on of appropriate fractions gave 8.1 g (5151) of a grev-v.hite solid. A 1.5 g sample was dissolved in MeOH (45 ml) and was acidified wsith ethereal HCI. The solution was stirred for 5 minutes and anhydrous ether ml) wsadded. Within one minute the HQI salt precipitated. More anhydrous ether (100 ml) was added and the salt was collected and dried to vield 1.5 g a %-hite solid. Recrystallization from ethanol provided 1.2 g of" fluffy wiecrystals, mn.p. =2-)4-226C.

ANALYSIS::

Calculated for C,,H,,FNO,.HCl: _53.86%C 6.21 %cH 15.707cN Found: 53-81 %C 5.88%1- 15.37%7N EXAMIPLE 197 4-4(-loo12bnioao--v)ipprdnl--ehiuy decanoate fumnare te S' .To a mixture of 4 i[ 4 6 -fluoro-1,2benzs-oxazo3y)lpiperidinylh-2methyl butanol (4.63 g, 15.3 rmcl) and triethylamine (2.23 g, 22.3 mrnol) in chloroform ml) was added decanoyl chloride (3.5 g, 1S.4 mmnol, 1.2 eq) dropwise at 00C The reaction wvas stirred at ambient temperature for 4 hours. The-solvent was 9 removed. The residue was purified by flash chromatography over a silica gel columin (Si0 2 65 cg, eluted with DCN. V 1, 1l% CH 3 OH11 Ln DON!, 1 The product thus purified weighed 5.7 g as an oil. This oily product was converted to the fumnarate salt in ethanol with Fumaric acid (1.51 g, 1.0 eq) to yield 3.34 g,mr.p.

=133-134'C.

ANALYSTS:

Calculated for C,,H, 4 FN,0 3 .CH,0 4 64.56%C 7.S77%H 4386%N Found: 64.42%C 7.74%aH 4.787%N EXAMIPLE 193 2-2f4(-luoo12bnioao--i- pip i in v Iet hy 11-2 3-d ihvdro- 3-methvl-1H-isnifl-1-ofle hdrochloride A mixture of 2-2[-6fur-,- e-z~xzl3y)ippriiyitvl23 dihvdro-3hdroxv-3methvl1IH-idol-I one (3.96 g, 9.7 mmol) and lithiumn aluminum hvdride (1.1 g, 50% in oil, 1.5 eq).in tetrahYdrofuran (50 ml) was stirred at room temcerat..re for 16 hours. The mi,\ture was quenched carefully with a small amount of ice, then asdiluted wvith ethyl acetate (200 ml). The mixture was stirred for 20 mninutes. The insolubles were filtered. The org,--ic solution wyas dried over tMgSO, and concentrated down to a yellow; oil (45g). This oil was purified by flash chromatogiaphy over silica gei column (SiO, 53 g; eluted with D)CMv, 1 1, and 1% CHOH in DCM). Only 1.91 g of diesiredl product was obtained.

This material was treated with HCO (OM HCI in ether, 6 ml) in ethanol followed by i-sopropyl ether to yield 1.48 g m.p. 213-215'C.

Calculated for CH,,FNO, 2 .HCl 64.25%7C 5.86%7H 9.77-7aN Found- 63.88SC 5.74%H- 9.44%N *.at '0 .4E EXAMPLE 199 1-2f-6Fur-12bnioao-3y)lpprcinvllethy Icyclopentanal hydrochloride In a flame-dried 500 ml round-bottom flask, equipped with addition6r funnel and condenser, was placed magnesium metal (3.4 g, 140 mmol). and anhydrous ether (20 nil). A solution of 1.4-dibromobutane (4.4 ml,36_5 mm)b) in anhydrous ether (10 mnl) was then syringed into the addition Funnel and added dropwvise to the magnesium metal. Initially no reaction took place, but with th~e addition of a few crystals o" iodine and gentle heating the Grignard reagent began-to forim- The rate of addition was such that a gentle refiux ,vas. maintained. Up o ncomplete addition, the Grignard .vas stirred for 0.5 hours. A solution of 3-[,4-(6-fluoro-1,2benziso xazol-3-l)iercinylIpropiornte (9.0 a_ 2 8.1 mnmol) in THF (75 mld) was then added (dropwise, exothermic) at room temperature and stirred for 21.5 hours.

The reaction~ mixture was carefully quenched with NHCl-sat.' 100 mld) and the precipitated magnesium salts were dissolved into water (50 ml). The layers were separated6 and the aqueous Dhase was extracted with EtOAc Tne' combined org'anics were dried (NaSO,). filtered and concentrated to give the crude product.

Purificanon via flash column chromatography (silica, gel, 50% EtOAc/ClO) gave 6.2 g(67 of the desired Product as a white solid, The hvdrochloide salt was FTpre in EtOAc- (53 nfl). eth e (40 ml).,aria metn.3no! (5 T:11wit ethereal HCI.

-ANALYSIS:

Calculated for C,,H 2 iFN,O,.FCl: 61.87%C 7. 1O51H 7.59 N Found. 61.79%,C 7.09 4cH 7.53%N EXAMPLE 200 h vd rochiori de a. To a stred solution of ethyl 3-[4-(6-Fluoro-1H-ifldazol3-Y)piperazinyllpropioflate (5.0 g, 16 mmol) in THF (120 ml) under IN. was added, dropwise, methvimagniesium bromide (15.6 nil of a 3.0 M' solution in EtO; 0.047 *moD. The temperature was maintained belok-. 30'C during the addition by usingl 3 water bath. After complete addition, the reaction was stirred at ambient temperature for 5 hours The reaction was cooled in an ice bath and saturated NHC[ (25 ml) was added. The mixture was extracted with EtOAc, and the EtOAc extract wa ah ihHPO, dried with Na-SO, and concentrated to yil .0g of a white solid. The product was recrystallized from EtOAc to yield 3.8 g of white crystalline flakes. The compound was dissolved in anhydrous EtPO (200 ml) and MeOH (20 ml) and the insolubles were filtered away. The filtrate was acidified with ethereal HCI to precipitate the salt. Additional anhydrous Etp (200 ml) was added and the suspension was stirred 15 minutes. The solid was won" collected to yield.4-5 g of a white powder. Two recrystallizatiofls from IMeGH gave 2.2 g. The concentrated mother liquor from the LMeGH recrys talliza tions g) was recrystallized from D.MP to afford 1.2 g. The two -samples were combined and a final recrystallization from MeQH provided 3.0 g (577%) of a white powder mn.p. 254-256'C.

ANALYSIS::

Calculated for C,,,HnF-N 4 O.HCI: 51 6. 0 5 C 7.0 6%H 16.3 4 N Found- 55-99%C 6.9 9%'cH 62%' EXAMPLE 201 N'[-4(-Ioo12be zsxz etyl-4 -iminophthalimide fumarate A solution containing 2-[4-[(6-fluor-o-1,2-benzisoxazol-3-yl)-lpiper-idinyllethyllamine (6.8 g& 25.7 mmol), dlicyclohexyl carbodlimide (DCC, 8.2 g, 39 muiol) and 4-am-inophthatic acid (4.57 g, 25.2 mmol) in dirnethylformrnmide (DMiF, 100 ml) was heated at 110*C for 5 hours and kept at 65*C fo r 1S hours. At Sthe end of tlhe reaction, the solids (DCU) were filtered and the solvent was removed on a rotary evaporator using a vacuum pump. The resulting crude product was purified by fl -ash chromatography (SiC 2 130 g) and provided 7.5 g of the desired product. It was converted to the furnarate salt which wvas recrystalized from ethanol and isopropyl ether: 7.1 g, m p. 229-230,C.

ANALYSIS:

**Calculated for C.,H, 1 FN,0 3 .CH,0 4 59.54 %C 4.80%,H 10.68%N 69Found: 58.99%C 4.79%H 1.37%/N EXAMPLE 202 N-r2-[4-(6-Fl uoro-1 ,2-b enz isoxazol1-3-y D-1-V i pe ri d inyl le th MI -6-pyrrol o- 3,4.61pvridine-5,7-dione fLumarate A solut ion of 24(6-fluoro-12-benziso xa zol.3-vt)- -pi Pefld iny1] ethylafmine (4.14 g, 15.7 romole) and 3,4-pyridinedicarboxylic anhyd ride (2.64 g, 17.7 mrnol) in dimethylformamide (DMF, 100 ml) was heated at 130*C for 18 hours. The solvent asremoved 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 en), then the solution was concentrated to 120 mt. Isopropyl ether (120 ml) was added 'and the mixture was stirred overnight. The white crystals (3.1 g. m.p. 203-206'C, were collected and recrystallized again from ethanol to give 2.3-1 g of pure product.

m.p. 20S-200'C.

ANALYSIS.

Calculated for C,,H,,N 4 ,0 3 .CLHIC4* Found: 5S.82'%C 58.59C 4.675-cH 10.987oN 10.71 %N *0 .w EXAMPLE 203 N-23Eoyrpl4(-loQ12bniaao--l1i~rdn fumnarate A mixture of 4-(6-fluoro-1,2-benzisoxazol-3- yIpiperidifle (11 g, 50 mmol), KCO, (7.5 g, 54.mmol) and epibr omohydrin (9 g, 54 inmol) in acetonitfie (150 i] was heated at reflux for 16 hours- The mixture was filtered and concentrated to dryness. The crude product was purified by flash chromatography (SiO,, 180 g eluted with methylene chloride (DOM), and 1-2%o CHOH in DOM). The material thus purified as off-white solids weighed 8.7 g This material (3 g) was converted to fumarate salt in ethanol and isopropyl ether to give 3.27 g of white crystals, m.p. =145-147C.-

ANALYSIS:

Calculated for 58.16%C 5.39%H 7.147oN Found: 57.93%C 5.35%76H _7.02%/N EXAMPLE 2D4 4-f3-r4-(6-Fluoro-1,2-benzisoxazoI-3-yf)l-1 -iperid invll-2-hydroxy- 1-nrnoxvlnhenvl mnethvi ether A mixture of 4-(6-Fiuoro-1,2-benzisoxazol3-l)piperidine g, 20 rnrol) and 2,3-epoxypropyl-4-methoxy-phelyl ether (3.7 g, 20.5 mrnol) in isopropyl alcohol ml) was heated to reflux for 2 hours. The mixture was cooled and the crystals were collected to yield 6.51 g m.p. 134-135*C.

ANALYSIS:

Calculated for C.HLFN,O,: 65.99 %cC 6.29%7cH 7.0V0%N Found: 6 6.11ic-CC 6.31 %H 6.84%N EXAMPLE 205 3-F4-(6-Fluoro-1,2-benzisoxaz7o I-3-V)-1-piperid i ni-I 1-2-hNdroxv-1propvlph th Iimide A mixture of 4-(6 luoro-1,2-benzisoxazol-3-vlI)piperi-din-e (5.5 g, 25 rnmrol) and N-(2,3-epoxypropyl)phthalimide (5-1 g, 25.5 MMrOD) in LSOpropanol (100 mld) 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% CHOH in DOM, 1.5 The pure product thus obtained weighed 7.91 g, 75%. Recrystallization from DCM and isopropyl ether yielded 4.0 Z, m.p.

162-1 63'C.

ANALYSIS:

Calculated for CH,,FN 3

O

4 C: 63.24%C 3-24 LH 9.92%cN Found- 65.00%C 5.03%H 9.77 %N *EXAMPLE 206 14-(6-Fl uoro-i,2-b en7 isoxazol-3-0l-1 -pi pe rid in yl -3-ph tha Iimni d o- 2-12rOpyl decanoate fumarate To a solution of 3-44-(6-fluoro-1 .2-benzisoxazol-3- 1)-i -p iperidinyll-2-hydroxy- I-propylphthalimide (6.26 g, 14.5 mmol), t-iethylamine (2.0 g, 20 mi-nol) in chloroform (200 ml) was charged with decanoyl1 chlold e (3.6 g, 18.9 rnol, 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, 597-). This oil was converted to fumaraie salt in a dilute ethanol solution to yield 2.0 g, m.p.

138-1 A N A LYS IS: Calculated for CH,,FNO 5 .Cd-IO 4 64. C6 7cC 6.397cH 6.06%N Found: 63.90i-C 639 c-H 5.SS EXAMPLE ?07 N-f ?f-'-(6-Fluoro-1 H-inda.-zol-3-vfl)-l-p iperazin vilecth vi 14-nethyiph thaiiirnide di hvd rochlIoride A solution of 2- fl uoro- IH-indlazol-3-NylD- I-pipe razinyl1lethyllamine (1.9 g 7.2 mmol), -mtlhhali ahydride (1.2 g, 7.4 rnioi) and DMF (50 Ml) was stirred at 75*C for 5 hours. M'vost of the DMF was removed it- vacuo and the resultant red oil was triturated with HO to produce a brown solid. The product was dissolved ini CH-,CI, and the organic extract was washed with H 2 0, dried with MgSO, and concentrated to afford 2.8 g of a foam. The compound was sus~pended in MeOl- (50 ml) and made acidic with ethereal HC~and the resultant solution was stirred for Ihour. Anhydrous Et,O w.as added to precipitate 2.5 g of an offwhite powder. This wvas combined with an additional sample (4.3 g total), and two recrystallizations1 from M'veOH-Et:O provided 3.0 g of an off-white powder, imp. =235-241 C.

ANrALYSIS: Calculatedi for C..H.,CIFNO, .2H-CI: 55.01 %C 5.04%H 14.55%iN Found: 55.35%C 5.09%H 14.56%cN EXAMPLE 208 N-[2-14-(6-Fluoro-I H-indazol-3-vl-1-piperazin yllethyll-4fluorophthilimide hydrochloride A solution of 2-f 4-f (6-fluoro-1 H-indazol-3-yl)-l-piperazinyllethyllarnine (4.0 g, mmoil), 4-fluorophthalic anhydride (2.5 g, 15 mmol) and DMEt (75 ml) was stirred -at 75'C under N, for 4 hours. The reaction was concentrated to yield 6.7 g of a brown solid. The product Was suspended in MN-eOH (150 ml) and was acidified with ethereal HCI. After stirring for 30 minutes, anhydrous EtOwas added and the resultant beige solid was collected to yield g. The compound was recrystallized From N~eOH-ether to give_3.8 g (567r) of an off-white pow.der, 2S2-2S3*C.

AiNALYSIS: Calculated For C,,H,F-i:FNiO:,HCI: 56.32%c- 4.%5 56 4%50N Pond 6.07PicC 4-3517H 15.63%.N EXAM,-PLE 209 N-12.[4-(6-Fluoro-1,2--benzisoxaizoI--vl'- -piperidiny I ethv 11--(1 d ecano vi a m in oph h a I i m id e To a solution of 2-4-(6~fluoro-1,2-benisoxazol3-vl--piperidiflyllethyl]4am-inophthalimide (0.5 g.3.67 mmol), triethylamine (0.46 rng, 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 (01 mg, 0-52 mrnol) was added to complete the reaction. The mixture was concentrated down, and the Crude product was purified on a flash chromatography column (30 g of silica gel; eluted w Iith dichioromethane (DOM) and N% C.H1in -DCM). The oily product was -dissolved in ethanol and treated with ether to yield white crystals L04 np 139-]60*C.

ANALYSIS:

Calculated for 68.31 %C 6.99%H 9.96%N Found: 68.47%C 7.27%H 9.55%N EXNMPLE 210 N-12-4(6-Fl uoro-1 .2-berizisoxazo 1-3-vl)D -pip~erid invI]ethyl l- 41 decanovl~nxyphthalimnide fumarate

C

room te4-erature. The mixture was stirred at room temperaure overnight (16 hours). The solu~tion was diluted with methylene chloride (DCM, 150,ml) and washd wih brne.jhe organic solutio6n was dried and concentrated t a crud mixture. I~rficaction on a fRash chromatographyv column (SiC,. 100 g, eluted with DCM and 1%7iCHOH in DCLV) 'yielded a colorless oil (50 g, 717o). This, product was t-eatedl %v h fuma ic aud (1-0 g) in tao l and isopropyl ether (13 to giv e 3.1 g of white crystals. mn OS I Os

ANALYSIS:

*Calculated for C,,HFNQ 5

-C

4

H

4 63.61 %C 6.2 3% H 6.18%N Fouiind: 63-71 cC 6.30%H 6.25%N EXAMPLE 211 2-f 4- (6-Fl uo ro-1H- in d azo -3 -y-1 -p i perazin y Ile th l-23- d ihyd ro- 3-hydroxv-lH-isoindol-l-one hemifumarate .To a stirred suspension of N2-12-(4-(6)-fluoro-I H-indazol-3-yl)-lpiperazinyllethyli-phthalimide (4.0 g, 10 mmol) in IMeGH (125 ml) and CH~l, ml) under was added NaBH, (0.89 g, 23 rnrnol) in one portion. The reaction was stirred at ambient temperature for 45 minutes and was concentrated to yield a damp Iwhite solid. Flash chromatography using silica gel and 57% MeOH-CJ-f, increasing to 10%1 MeOH-CH,Cl"as eluent, provided 4.5 g of a' beige liquid. 'The lquid was dissolved in MeOH (-50 ml), and the solution-was acidified with.

ethereal HCi. Anhydrous EtO wvas added to p~ecipita te.2.9 g of a white solid.

This vas combined with an additional sample (4.6 g total) and was sus pended r H,0 (100 ml). NaHCO, was added to attain pH--7 and the gummy mixture was extracted with CH.CI 2 The CH 2

CI

2 extract was d-ried with MgSO, and concentrated-to yield 4.1 g of a white foam. The compound was purified by preparative HPLC (Waters5 Associates Prep LC/System 500, using 2 silica gel columns and 5% EtNH-EtOAc as eluent). Concentration o f appropriate fractions gave 2.1 g (5.3 mmol) of a beige foam. The compound was dissolved in EtOAc (Arml) arnd the insolubles were filtered away. The filtrate was gently warmed and fumaric acid (0.70 g, 6.0 mmol) was added.. After stirring armildl reflux for minutes and at ambient temperature for.] hour, the mixture was diluted with anhydrous Et0 (50 ml).

The resultantsolid was collected and dried to yield 2.2_g. Recrystallizationfrom ethanol-ether provided 1.1 g of the hemi-fumarate salt as a slightly offwhite solid m.p. 165-16S*C.

209

ANALYSIS:

Calcula ted for C.HNO'.CH 60,91% C .5.3 Z)%,cH 15.45%N Found: 60.417cC 5.15 %H 15-22%oN EXAMPLE 212 4-r3-r4-(6-FI uoro-1,2-benzisoxazol-3-yl)-l-piperid in yll-2-hydroxpropoxyl-3-methoxyhenyl methanone A stirred mixture of 4-( 2 ,3-epoxypropoxy)-3-methoxyphenyl niethanone 4 .5 g, *22.5 mmol) and 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (5.36 g, 24-3 mrnol) in iopropyl alcohol (150 mi) was heated at 55C for 16 hours. The rnhture was cooled and the solvent was removed on a rotary evaporator. The residue was purified by flash chromatography over a silica gel column (SiO, 80 g; eluted with dichioromethane, DOM, and 1%c CH 3 0H in DCM). 71-e oil thus obtained solidified I.....quickly, weight: 9.47 g. Recrystallization from ethanol 'and isopropyl ether, then *toluene provided 8.6 g of white crystalIs, m.p. =107-1 03'C.

ANALYSIS:

Calculated for C, 4 H, 65.15%C 6.15%H 6.33%iN Found: 65.35%C 6.04%H 6.05%N EXAMPLE 213 1-f4-(6-Fluoro-L,2-benzisoxazol-3-yl)-1-Piperid inyl 1-2-2ropanone hydrochloride A mixture of 4-(6-fluor-o-l 7 -benziLsoxazol-3-yl)piperidine (7.45 g, 33.4, mmol), KCO, (5.5 g) and bromo-2,2-dimethoxypropane (6.84 g, 37.6 mmol) in acetonitrile (200 mld) was heated and stirred at reflux for 4 hours. An additional charge of bromo-2,2-dimethoxypropane (5.1 g, 28 nimol) was added and the mixture wvas refluxed overnight. After being cooled to room temperature, the mixture was filtered, and the solvent w~as removed on a rotary evaporator. The residue was purified by flash chromnatography over a silica gel column (SiC 2 100 g, eluted with dichlorornethane, and I j' CHOH in DCM). The oil product thus obtained weighned 2.2 g (21"7c) The o'I urodiuct wvas dissolved into ethanol (10 MI) then was treated with HOI in ether solution (VA, 9 mld) at room temperature. The crystals were collected, 2.08 gc, m p. 220-2'C dec.

ANALYSIS:

Calculated for C, 5 H,,FN,O,.HCI: 5 7.6 0 5cC 5.80%H 8.96%N Found: 57.49%C 5.97%H 8.67%N EXAMPLE 214 Ir(4-Aceto-2-methoxy)phenoxyl-3-[4-(6-fluoro-1,2-benzisoxazol-3-vl)- 1-piperidinyll-2-propv I d ecanoate furiara te To a stir-red mnixtuJre of 4-(3-[4-(6-fluoro)-1,2-benizisoxazool-3-vlD-1-piperidinyl]-2hydroxy-1 -propoxyl-' -methcxyphenyl metha none (3.64 g, 8.23 mmol), triethylamnine (1.6 g, 16 mrnol) in chloroform (050 ml) was added decanoyl chloridle A (2.35 g, 12.4 mrrole, 1.5 eq) dropwise at. room temperature. The mixture was then heated at reflux for- 1 hour The mixture was cooled and diluted with methylene chloride (DCMI) and washed with water and brine. The organic solution was dried and concentrated to a crude mixture. Purification on a flash chromautog-raphy column NSO,. 65 g; eluted with DCM, 0.4 1 and 1% CHOH in DCM, 0.6 1) yielded a colorless oil: 3.29 g This product was treated with fumnaric acid (623 mg) in ethanol (10 ml) and i-sopropyl ether (50 ml) to give 2.64 g of a white soLid, m.p.

=109-110,C.

ANALYSIS:

Calculated for C,,H,5FiNJ 2 O.CHO,: .64.03%C 6.93%H- 3.93%N ag"Found: -63.86%oC 6.88%H 3.74%IN EXAMPLE 215 N-[2-[4-(6-Flu oro-12-benzisoxazol-3-YD-I-pi peri d i nyllethyl Ith i aphth alliie A mixture of N-(2-(4t-(6-fluoro-i.2-benzisoxazo-3-vl)-l -pipe ridinyll ethyl]Iphthalimide (3.93 g, 10 mmol) and 2.4t-bis(4-methoxv-phenvl!)-1,32,'Adithiadephosphetane-2,4-disutfide (2.02 g, 5 mrnol, I eqti. Lzwesson's Reagent) is stirred and heated in anhvdrous tetrahydrofuran for 3 hours at 60'C. The reaction mixture is evaporatEd on silica gel and purified by chromatograpny on a silica gel column. The product is further purified by recrystalization to afford fluoro-.1,2-be-nzisoxazol-3-yl)-l -piperidinyllethylithiaphthaliiflide.

*..*EXAMPLE 216 By using substantially the same procedure as descr-ibed in Example 215 except that 10 mmol (2 equiv.Y of Uawesson's Reagent is used and the reaction time at is extended to 5 hours there is obtained N-[2-[4-(6-fluoro-1,2-benzisoxazol-3is :EXAMPLE 217 P4 N-r2-r4-r6-FI uoro-4-decanoyl-1 H-in dazol-3-vl)-l-p iperazinyllethyllphthalimide maleate To a stirred suspension of NaH (0.50 g of a 50% oil dispersion, 12_5 mrnol) in DMF (10 ml) under N, and cooled to -15*C, was added dropwise, fluoro-1 H-indazol-3-yl)-1 -piperazinyl)ethyllphthal1imide (4.0 g, 10.2 mmnol) dissolved in JM.F (45 ml) over 45 minutes so that the temperature did not exceed 00 8VC. The reaction was stirred for I hour allowing the temperature to warm to 0 0

C.

The reaction was cooled to -12'C and a solution of decanoyl chloride (2.9 g, 15.3 mnmole) in DMF (13 ml) was added dropwise so that the temperature remained below -5* 0 C. After complete addition, the reaction was stirred at ambient temperature for 18 hours. The reaction was poured into ice-cold HO (125 ml) and the aqueous mixture was extracted with EtOAc. The EtOAc extract was washed with HO/Brine dried with MlgSO 1 and concentrated to yield 5.7 g of a beige oil that readily crystallized. This was combined with another sample (6.4 g total) and purification via flash chromatography, over silica gel using 3% LNeOH/CHCI, as eluent, afforded 4.9 g of a white solid. Another previously pu-rified sample was combined with this (6.3 g.11.5 mimol total) and the product was dissolved in hot absolute ethanol (100 ml). Maleic acid (1.4 g, 12.1 inm-ole) was added and the solution as stir-red at a mild reflux for 30 mninutes. The reaction was concentrated to a white slush that was diluted ,Nith petroleum ether (100 ml) and stirred for ca 2 hours. The resultant solid was collected to yield 5.5 g of shiny white crystals. T1he 5alt was recrystallized twice from absolute ethanol to afford g and a third recrystalliza" m from CHCN gave 3.8 g of the analytically pure rnaleate sialt as a white solid, rn.p. =154-156C.

ANALYSIS:

Calculated for C,,HPN 5

O

3 .CHO,: 63.34%C 6.38%H 110.55%N Found: 63.46%C 6.33%H- 10.60%N EXAMPLE 218 -24[4-f 6-Fluoro-1,2-benzisoxazol-3-vfl-l-pip~ericiinvI propvl amnine 4 *dihvdrochioride hemihvdrate A 2 -146-Fluo ro- 1,2 -ben zisoxazTol-3 -yO-1 -p iperidity!Ip ropion it rite A mixture of 4-(6-fluoro-1,2-benzisoxazol-3-yl)-i-piperidine (10 g, 45.4 mmol); 2-chloroprovionitril (10 g, 112 mmol)X KC0 3 (9.4 g, 1.5 eq) in acetonitrile (100 n-l) wvas stirred and heated at 80'C for 16 hours. The mixture was filtered and concentrated to dryness. The crude solids were purified by flash chromatography CSiO 2 160 g; eluted with methylene chloride, (DOMv) 1.5 1; and 1% CHJOH in DCM, 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. 133-134*C.

ANALYSIS:

Calculated for C,,IH 16 FN,O: 65.92%C 5.90%cH 15.3776N Found: 65.927.C 5.85%H 15. 52% N 2-(--Fur-,2-a::sxoI3-)-l-ip iryra'!ric' dihndrochloride heuznhmvdrae To a solution of 2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)-l-piper-idinyllpropionitrile (6.7 g, 24.5 rrnol) in THE (200 ml) was added lithium aluminum hydride (3.6 g V. 50% in cii, 2 eq) in portions under N, at room temperature for 3.5 hours. At the end of the reaction, the excess of LAH was carefully hydrolyzed with ice-ch-ips (7 mld) under N, A solution oF 15%o NaOH (2 ml) was added, then the mixture wvas ce stirred for 30 minutes. The in5olubles 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 Hcl (6 ml, IM in ether). The white solid wvhich precipitated wvas collected and recrystallized from ethanol to give 703 mg, m.p. 215-217'C of the dlihydrochloride hemihydrate.

ANALYSIS:

Calculated for C,5H,oFNO.2HCI-0.5H,O: .50.140/C 6.45 %H 11.69%N 2.50%H,O Found: 49.94%c 6.17%l7l H 11.11 %N 21 2?%H,O EXAMPLE 219 N-r2-r4-(6-Fluoro-1,2-benzisoxazol-3-vl)-l-piperidin vllproovl lohthal imide hydrochloride To a stir-red mixture of 2-(4-[(6-fluoro-l,2-benzisoxaizol-3-yl)-1-piperidinylj]propyllarnine 2.56 g, 9,2 rnmol) and triethylamine (1.35 g,13.5 mmol) in 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 crudle residue was dried in vacuo. The purification was done by flaszh chromatography over a silica gel column (40 g, SiO, eluted wvith methylene chloride, then increase the MveOH n I,, concentration to 276). The pure product thus obtained: (2.18 g) wscombined with another batch of same ouality material (1.53 g) and Uhan coniverted to t"he hydrochloride salt with HCI in ether solution. The wvhite solid was recrystaLlized from methanol to give 3.12 2-2 Calculated for CH..,FN 3 C0,HCl: 62.23%C 5.22%5v 9.47%N Found: 61.935'C 5.3 2 5aH 9.46%N 0@* .s8.

4 .4 04 cc U.

4. 4 04*4 EXAMPLE 220) N-f 2-14-(l -De can oxycarbonvl-6-f luoro-1 FNin dazo I-3-vl)-l-pi P eraz in v Ile th vI phthalimide hy'drochloride A mixture of decanvi chloroformnate,(2.4 g.11 rmnl), and N -1.2-46-fluoro- I H-indazol-3-yl)-1 -piperazinyll]ethyl lphtha limide (3.9 g, 10 mmol) was warmed on the steam bath for 15 minut es. The reaction was allowed to cool to ambient temperature, and then ether was added to the residue. The resulting solid was filtered to afford N-[2-[4-(l-decno xy-6-fluoro-1 H-indazol-3-yl)-Ipiperazinyllethylliphthalimide hydrochloride.

EXAMPLE 221 N-r2-r4-(6Fluoro-,2-benzisoxazol-3-vl)l-pipcrid invllethyll-3methoxvphthalimide hvdrochloride A mixture of 2-[4-(6-tluoro-l,2--benisoxZOl- -piperidiinyllethyl]-3hvdroxvphthalimide hydrochlorid e (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 buto xide (1.1 g, 10 mmol) and the mi~xture was stirred at room temperature for 4 hours. The reaction mixture was concentrated and the residue was extracted with DCM (400 ml). The organic lavewas Filtered and concentrated and the resulting reSiduIE Was Chrornatographed on silical gel (47 g SiO,), eluting with DCN4 and N'eOH-i:DCM mixture. The resulting produc: iAg wazs !Q rc o the ,Itioid si t hcinl with 1 N-HCI in ether. 7he -esultilng v.,hte was re-7. vstalized "Tom methanol to give 1.12 g, mp 247-2:0'C.

A NALYSLS.

Calculated for 60.07%~C 5.04%14 9.14%N Found: 59.79%C 5.05%H 8.98%N

MEMO.

mop- EXAIP LE 222- 6-171u oro-3-Fl-[3-(2.5-d imet hoxNphenoxy)p ropy] 1-4-p i peridj nXII-i 2benzisoxazole hydrochloride 2-0'-ChforoprooxyM-? 4-dim tethoxvbenizene A mixtu re of 2,3-dimethoxyphenol (29 g, 0.19 mol), 'K,C0 3 (35 g], 3-chloro'brornopropane (38.5,g, 0.25 mol) and acetone (250 ml) was stirred and refluxed, for 6 hours, and then stir-red at ambient temperature for 16 hours-- The reaction w.as filtered, andthe filtrate was concentrated to an orange liquid. The liquid was taken up into EtO, and- the organic layer washed with IN NaOH, H-s, dried (,MvgSO,) and was concentrated- to yield 37.8 g of anl orange solid. An 11.7 g sample of this solid was flash chromatographed on silica gel (1S0 g) with EtOAc/CHCl, as eluent. -Co-Licentr"Iton 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.

A N A L Y56: Calculated for C,,H,,ClO,:i 5.7.27%C 6.557cRH Found: 57.197,C 6.52% 0

H

1,.2 -benzfSoxazIo!l'doclok A m-ixture of 6-fluoro-3)-(4'-piperidinyl)-1,2-ben-zis5oxazole (3.0 g, 14.0 minol), 2- (3-chloropropoxy)-1,4-dimetlhoxybenzene, KC0 3 (2.1 g) and acetonitrile (50 mL) was stirred and refluxed for 24 hours. The reaction was filtered and the filtrate 0 40 was concentrated to 5.0 g of an oil. The oil was chromnatographed on a preparative HPLC on a silica gel column with MeOH-CH,CI, as eluent. Concentration of the appropriate fractions afforded 4.6 g of an oil, which, w~ith ethereal HCI; .*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, nvp. 186-188C,

ANALYSIS:

Calculated for CF{.

7 Fi\JO,.HCI: 61.265/aC 6.26%H 6.2176N Found: 61.14%C 6.38%H 6.15%N a EXAMIPLE 223 4-[3-[4-(6-Fluoro-7 ,2-benzisoxazol-3-yl)-1-piperid in viipropoxvl-2-hvdroxy-

LO

14 -4 Chlo rop ropoxy) 2-hyd raxy meth oxyph enyllet han one A mixture of 2,4-dihvdroxv-5-rnethoxvacetophenone (1.4 g.7.7 mmol), KC,C0 (1.4 g, 10.0 mmol), 3-chlorobrornopropane (1.6 g, 10.0 mrnol) and acetone (25 mL) was stirred and refluxed under N, for 16 hours. The reaction was poured into H,O, 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 an offwhite solid. Recrystallization twice from ethanol afforded 0.4 g-of the alkylated phenol as a solid, rn.p. 99-101 'C.

ANALYSIS:

Calculated for C,,H 15 Cl0 1 -;3.7111 %C 5.5 4 ii Found: 55.615%C 5.92cH go ago* .A mixture of 6-fluoro-3-C4-piperidinyl)-1,2-benzisoxazole (4.2 g.19 mrnmol), 1-[4- (I-chloropropoxy)-2-hydroxy'-5-methoxyphenyllethanone (5.0 g, 19 mmol), NaHCQ) (1.8 g, 20 mmol) and acetonitrile (120 rnL) was sti-red 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 precipitate 8.7 g of an off-white hydrochloride sailt. A 2.0 gsam rple of the silt was Converted to its free base and chromatographed by preparative HPLC (silica gel with *MeOH/CH,CI, 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 65.15%C 6.15%H 6.33%N C lFound: 6-193%/C 6-23,7H 6.20%N 4-13414 -t6-Fluoro- 1,2 -ben-zisoxazol-3-yI)- -,Piper.idinyipropo.xyJ-2-hydroxy- To a stirred solution of 4-t3-1-(6-uro-l,2-benzisoxazol-3-vl)-l-piperidinyl-2g, 6.8 tnmol) in tetrahvdrofu ran/ ethanol 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 tritura ted with HO and the aqueous suspension was extracted -with CH.CL, The extraclt was washed w -ith HO' dried (Mgso 4 and concentrated to afford 3.4 g of a wvhite solid. The solii was~ re:rYstalIlzed from &MeOH and then fronn EtOIH to yield U.30 of solid, 156-1 56'C.

ANALYSIS:

Calculated for C,,&HNFLN:O: 64.S5%'C 6.5Sc%H 6.30JN Found: 64.73C7oC 6. 5317cH 6.13%-N EXAMPLE 224 N-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-vl)-l1ieridinvllethvl1Phthalimide 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)-I -piperid inyllIethyl Jphtha Liride (1.52 g, 3.86 mmol) ini 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 *fu ma rate salIt, mo. 231-2 'C.

ANALYSIS:

Calculated for C.,H.OFNIO0 C HO,: 61.29%C 4.75%H 8 -25 51,N O Found: 61-03%C 4.68.%H 8 .3 5% N EXAMPLE 225 66 N-[2-E4-(6-Fluoro-1L2-benzisoxazol-3-yl)-l1Piperid inyflbutvllphthalirnide 1 '(6-Fluoro-l 2-benzisoxczzol-3-yl)-l -pipe-ridinyUl-2-hvidroxybuttane A stirred mixture of 4-(6-fluoro-1,2-benzisoxazol-3-yl)pipefidirie (5.5 g, mmol) and 1,2-expoxybutane (1.89 g, 26.3 mmol) in isopropyl alcohol (100 mld) was heated at 65 C for 2 days. This mixture was cooled and the solvent was removed to leave a brown oil which was purified by flash chromatog-raphy over a silica gel column (SiQ, 70 g; eluted with DCM, I11 and MI-eOH:DCIMI 98%) to give an off-white solid weighing 6.3 Recrvstallization from hot ethanol yieldied 1.96 g of fine crystals. m.p. S7-SS*C.

ANAL!YSIS:

Calculated for CH.FrN,O.: 65.73%OC 72-1 Found: 65'.s3C 7.121%;-i 9.54% N *A solution of diethyl %zodicarboxylate (DEAD, 4.9 g. 28.3 mmol) in THF n-l) was added dropwvise to a solution of 2-[4'-(6-fluoro-i,2-benzisoxazol-3-yl)-1piperidinyllbutanol (6.9 g, 23.6 mmol), phthalimide (4.16 g, 1.2 eq), and triphenylphosphine (7.4 g, 2S.3 mmol) in THIF (200 nil) 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 mld) and the *insolubles were remnoved by filtration. The oily residue from concentration of thle ether solution was purified by two flash chromatography (5i0,, 75 g, eluted with dichioromethane. DOM, ar-.1 1-25/6 CH 3 OH- in DOM) and (100 g of SiO eluted with DCNI, 11, and I1% CH 3 OH in DOM, 1.2 Two close compounds were separated .*64 and the top compound on TLC (1.6 g) wvas recrystallized From isopropyl ether to yield 0.76 S of white crystals, m.p. 56-85'C.

AN~'ALYSIS:

4 Calculated for C,,H,,FN 3 0 3 8S.3 9 c-cC 9.97%N Found: 6S.47%C 5. 67 %H 9.97%N EXAMPLE 226 -Fluoro-1,2-benzisoxazol-3-l-l-piperid inll butvl-lphthalim ide hydrocfiloride A solution of diethyl azodica rbo-xylate (DEAD, 4.9 g, 2.5.3 mmol) in THF ml) added dropwise to a solution of 2[-6fur-.-ezsxzl3y)1 piperidinvll-butanol (6.9 g.23.6 mmol). phthalimide (4.16 gm. 1.2 eq), and trip henvl phosphine (7.4 g, 28.3 mmol) in TH-F (200 nnl) at room temperature. T he solution 5a tirred room temoerature for 24 hours. After the reaction, the :1.

a000 0* 6 weS 0.

solvent wsstrippei an",c ht_ rcsidue was stirrc-a in 2,hncr (200 ml). _The insolubles wvere removed by filtration. The oily residue fromi concentration of the ether solution was uur-ified bv' two flash chromatography (SiO,, 75 r~eluted w ith dichioromethane, DCM, and 1-2i- CHOH in DCLM) an'd SIO~, 100 eluted with DCM, 1 1; and 1% CHOH in DCM, 1.2 Twvo close compounds wvere separated.

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

ANALYSIS:

Calculated for C,,H,,FNO,.HCI: .62'.95oC- 5.50',oH 9.18% N Found: 6 2. 7 0% 'C 5.5S%H 9.13%N

ILS

,t a 600St EXAMIPLE 227 4-Fluoro-N-12-r4-(6-filoro-1 H-inda7.ol-3-vl)-l--piperic invllethvllph-thnlimide maleate I -Ben 1y- 6-flucro -phc oxycorbow.' -irc nyl)-z H-naOle To a solution of 1 -bcnizovl1-6,-fuoro-3-(l -methyl-4'-pi peridinyl)-1 H-indazole g, 5.93 mmol) in dichloromethane (100 ml) was added phenyl chloroforrnate (3.9 ml, 29.65 mmol) at room temperature. The reaction mnixture w~as stirred at room temperature for 24 hours, refluxed for anadditional 0.5 hours-and subsequently concentrated. The remaining residue wvas dissolved into dichloromethane and washed with 10% HCI The organic phase was died (NMgSO), filtered, and concentrated to give an oil which wvas purified via flash column, chromatography (silica gel, 20% DCM Y/EI.OAc). Concentration of the product -conta ini ng fractionts gave an oil which solidified on standing. The ;hite solid wa-s wvashed with EtOAc, leaving 0.417 a of the desired product. mE 137-139'C.

ANALYSIS:

Calculated for C,,-bFN,Q, 70.4'2 c 3. 0 0 TcH 9.431:N Found: 70.38:7c 4..S I -H 9.4 27cN wO0 9-;;1116 0 1 U 9 41120 4 To a suspension of "i-benzovl-6-fluoro-3'-( I-phenoxycarbonyl-4.'piper-idinyl)-i Hindazole (31.6 g.71.3 rnol) in ethanol (500 m0 was added 507c KOH(aq.) (100 8 of KOH in 100 g HO) at room temperature. The reaction mixture was warmed to reflu.- for 4 hours and cooled to room temperature. After adjustin~g the pH,- to about one (to litmus) usinz HCI (con., 110 ml)W, the volatiles were removed under reduced pressure. The remaining wet solid was dilhited with,,water and collected via filtration. The-solid material was dssolved into hot water to wyhich NaOH(aq.) was added (pH wvas about 10. to litmus5). The precipitated 47(6-fluor-, 1 H-indazol-3-yl~oiperidine ('10.

7 a) w.as filtered and used without further purification.

To a Stirred suspenlsion of 4-(6-fluoro-1 H-indazoi-a-vl~piperidine (4.95 g., 22.6 mmol) and NaHCO,'(2.1 g, 2 4 S9 mmol) in dry acetonitrile (110 ml) was added chloroacetonitrile (1.6 ml, 24.9 mmoi) at room temperature, under nitrogen. The -suspension -was warmed to reflux for 22.5 hours, cooled to room temperature, and subsequently filtered. The remaining solids wyere washol with DCM and the combined filtrates wyere concentrated. The resulting brown oil wvas dissolved into a" EtAc and washed with wvater. The organic phasez-.as dried (MgSQ 4 fiitered 4WD and concentrated to giv'e a brown solid which was re-dissolved into DCMv/EtOAc 2h- 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:

Calculatedj for C~jHj-~N, 6. 5. 10% 'C 5.SSoH 21.69%iN Found: 6 4.S4%C 5.90% H 21.74%N To a solution of [.6uoiH-indazol-3v)-1 -ip)eidiny-l-acetunitrilte (61 4 2.3.6 mmicl) in drv THF (235 ml) was added (droDwi-se) lithium alumninumhYdride (LAHI4) (23.4 mmcl, 1.0 NI in THF) at room ternpe.-:!ii'e, under nitrogen- Upon complete addition, the reaction mixture w~as warme-d to retILIX For 3 hours. After cooling to 0 C in an ice bath, the reaction was carefully cuenched with %-ater (4.6 mld). The solids were removed via filtration and washed with THF. The combined filtrates were concentrated to give 5.6 g of the dlesired product. This material was suspended in DOM4 and Fitered to give the product as an off-white solid, rn.p. 125- *0 128C

AN'ALYS[S:

Calculated for 64.10%C 7.30%H 21.36%N Found: -63.60%C 7.10%oH 21.03%N 4-Fhtzoro-N-12-14 -(6-luoro-1I--it dazol-3 7yU- i-piperidiniylle~hyliphialiride mateale *To a solution of 2-[4-(6-fluoro-I H-3-indazolyl)-I -piperidi nyli ethyla mine (6.1 g, 23.3 mmol) in DMtF (230 ml) was added 4-fluorophthalic anhydride (4.2 g, 25.5 m..rmol) at room temperature under nitrogen. The reaction mi.xture ;vas war-med to C for 2.5 hours at which time it was allowed to cool to room temperature. The V DMF was removed under reduced pr essure to give a brow'~n oil which was dissolved into DCM/M eOH. Purification -via flash column chromatography (silica c4gel, 2% MeOH/DCM) afforded 3.6 g of the des ired product as a white solid. The maleate salt was prepared in methanol (75 ml) using rnaleic acidi (2.1 The precipitated salt was collected via filtration and recrystallized from acetonitrile to giv.e a white solid, m.p.,193-195'C.

ANJALYSIS:

Calculated for 4 59.3 1%C 4.59%oH 10.64%N Found: 3 9.15%C 4.B80%H l0.8OlN EXAMPLE 228 N-[2-4-(6-Fluoro-1 H~-indazol-3-0l-1-2incrazinv I lethvil-3methviphthalimid? hvdrochloride off A solution of 2-[4-[(6-fluoro-1 H-indazol-3-vl)-1 -piperazinyl] ethylam-ine (5.9 g, 22.4 mmol), 3-methyphthalic anhydride (3.7 g, 22.5 mmol) and DN4F (120 ml) was stirred at 85 C for 22) hours under N, Most of the DIA4F was distilled off to afford 12.5 g of a dark oil. The oil was purified by preparative HPLC (Waters Associates Prep 500 using 2 silica gel columns and 4% MeOH-CH.tCl, as eluent) to yield 6.4 g of a yellow foam. A 1.0 g sample was suspended in MeGH (25 ml) and the mnixture was mnade acidic with ethereal ICI. After about 20 minutes the resultant solution was filtered and the filtrate was diluted with anhydrous EtpO t o precipitate the salt. The light yellowv solid w.as collected to give 0.90 gr which was triturated with boiling CHCN (40 ml) and after cooling the product was'collected to provide 0.7-c g of a white solid, m.p. 266-269*C.-

ANALYSIS:

Calculated for CH,,FNI 5 O,.HCl: 59.53%C 5.22%0cH 15.78%N Found: 5 9..3 1 %oC 4.98 7cH 15.77%H S S

S

,EXAMPLE 229 N-F2-r4-(6-F~uoroH-indazol-3-l)--piperainvllrOpvllphthalimide hydrochloride A mixture of 6-fluoro-3-(,-piperazinyD)-IH-indazole (7.0 g, 31.8 mmol), NaHCO 3 (2-9 g, 34.5 mmol), N-(3-bromopriopyl)phthialimide (8.5 g, 31.8 mmol) and acetonitrile (200 ml) was stirred at reflux under N, for 21 hours. 'Most of the acefonitrile was removed ir, vacuo and the resultant yellow residue was triturated with H,0 to afford a solid. The product was isolated by filtration and dried to yield 12.7 g. Recrystallization from EtCH gave 7.S g off a yellow solid. A 2.0 g sample ,%as su~spended in N-eOH (25 ml) and the pH- was adjusted to pH.-1 with ethereal-HCI. After 30 minutes of stirring at ambient temperature, the thick suspension was diluted with isopropyl ether (10 ml) and EtD (50 ml) and the salt collected to yield 1.9 g. Recrystallization fromn FAQ H provided 1.4 g of a light yellow solid, m~p. 261-264*C.

ANALYSIS:

Calculated for C,,HFNO,.HCl: 59.5376C 5,22%cH 15.7817N Found: 59.48%C 5.257oH 15.56%N 2-EXAMPLE 230 .4-Fluoro-N- 2-4-(JH-indazcl-3- 1 -1-piperazinvilethyl phthalimide maleate A) 1-B~e ufoy-3 -0 -phenoxtycarbonyIAi--p~uerazinyI 1H-inidi.zole To a solution of 1 -benzenesulfonyl-3-( I-methyl-4-piperazinyl)-1 H-indazole (2.1 5.89 rnmol) in dlichloromethane (100 ml) was. added phenyl chloroformate (3.8 mld, 29.45 mmol) at room temperatu re. The realction mLxture was warmed to reflux for 2 hours, cooled to room temperature, arid concentrated. The residue was diluted with ethyl acetate, filtered and purified via flash column chromatography (silica gel, ethyl acetate). Concentration of the product containing fractions gave an oil which solidified on standing. The product wvas washed well with heptane to CA give 1.5 g of a white'solid, m.p. 112-114-C..- A NA LYS IS: dMVCalculated for C,H,.NOS: 62.32%C 4.797cH 12.1 %N Found: 62.28%C 4.73%H 12-115%N i4-ClH-[ndazoI-3-yI)-I -piperazfi~llacdton itnrik To a suspension of 1-benzenesulfonyl-3-(1 -phenoxvcarbonyl-4-piperazinyl)-1

H-

indlazole (31.3 g, 67.7 mmol) in ethanol (500 ml) was added 50% KOH (100 g of KOH in 100 g HO) at room temperature. The reaction mixture was warmed to reflux for 6.5 hours and cooled to room temperature. After adjusting the pH to about tw-o using HI-Ci (c on., 120 ml), the volatiles were removed under reduced pressure. The remaining residue was diluted with water and removed via filtration. The aqueous filtrate was washed with EtOAc and basified to pH=8 using 50% NaOH The product was extracted into 10:1 dichlororethane/isopropylalcohol. The combined organics were dried (MgSO), filtered, and concentrated to give 13.0 g of desired 3-piperazin-l-yl-lH-indazole as a brown solid which was used without further purification.

To a stirred suspension of 3-piperazin-l-yl-1H-indazole (6.0 g, 29.7 mmol) and NaHCO 3 (27 g, 32.7 mmol) in dry acetonitrile (125 ml) was added chloroacetonitrile (2.1 ml, 31.2 mmol) at room temperature, under nitrogen. The suspension was warmed to reflux for 17.5 hours, cooled to room temperature, and subsequently filtered. The remaining solids were washed with dichloromethane and the combined filtrates were concentrated. The resulting brown oil was purified via flash column chromatography (silica gel, 0-50% EtOAc/DCM) to give 4.0 g of product as an off-white solid, m.p. 121-123'C.

ANALYSIS:

Calculated for CHsNs: 64.71%C 6.27%H 29.02%N S Found: 64.47%C 6.23%H 28.82%N S(C) 4-Fluoro-N-12-[4-(lH-indazol-3-yl)-l-piperazinyllethyll- S phthalimide maleate dMef To a solution consisting of [4-(lH-indazol-3-yl)-l-piperazinyl]acetonitrle (8.7 g, 36.1 mmol) in tetrahydrofuran (360 ml) was added lithium aluminum hydride (dropwise, 43.3 ml of a 1.0 M solution in tetrahydrofuran, 43.3 mmol) at room temperature, under nitrogen. The reaction mixture was warmed to reflux for 3 hours at which time it was allowed to cool to room temperature. The reaction was carefully quenched with water (3.5 ml) and the precipitated salts were removed via filtration and washed with EtOAc. The combined filtrates were concentrated to give a solid. This material was suspended in ether (4 days) and collected via filtration to give 4.7 g of 2-[4-(l-indazol-3-yl)-l-piperazinyl]ethylamine which was used without further purification.

A so1lution of intermediate I -ind izoi-3-Dl- I -oi era zi nvllet hvlain ine g4.1 nmol) and I-fluoroplithalic anhydride (0.75 dimethyl-formrnmide (40 ml) was warmed to SO C for 4 hours. After cool-ing to room temperature, the dimethvlforamid was removoi in vacuo mmHg, C) to give a brown oil which solidified on standing. rohe solid material was suspended in EtOAc and warmed to reflux for 3 hours. The desired product remained as a yellow solid (0.86 g) and was collected via filtration and dried under higrh vacuum. The maleate salt was prepared in refluxing methanol using rnaleic acid (0.53 g, 4.6 mmiol). The off-white solid wvas collected via filtration and V. washed with methanol, m.p. 211-215*C.

ANALYSIS:

Calculated for C,,H,,FN5O,.C 1

H

4

O

4 0: 5S.94%iC 4.75%H 13.7375%[ Found: 58.69%C 4.91 %H 13.-/7%N EXAMPLE 231 N-[2-4-(-Decanovl-6-fluoro-IH-ind-azol-3-yl)-1-piperazinvllethvl 2hthalimide mnaleate To a stirred suspension of NaH (0.50 g of a 6017 oil dispersion, 12.5 mmcl) in dimethylformamide(DMF) (10 ml) under N, and cooled to -15 C, was added CA cldropwise, 2-[2-[4-(6-fluoro-I H-indazol-3-yl)-l -piperazinyl ]ethyl]1 -1 H-isoindol-1,3- (2.H)-dione (4.0 g, 10.2 inrool) dissolved in DMF (45 n-l) over 45 minutes so that bo the temperature did not exceed -8 C. The reaction was stirred for I hour allowinz doompthe temperature to warm to 0 C. The reaction was cooled to -12 C and a solution of decanovl chloride 2 .9 g, 15.3 mmol) in DiMvF (13 nil) was added drQpwise so that the temperature remained below -5 C. 'After complete addition, the reaction was stir-red at ambient temiperature for 18 hours. The reaction was poured into ice-cold H.,O (125 ml) and the aqueous mixture wvas extracted with EtOAc. The EtOAc extract was washed with H,O/brine, dried with MN-gso, and concenilrated-to yield 5.7 g of a beige oil that readily crystallized. This was combined with anothesample (6.4 g total) and purification via flashn chromatography, over silica gel usingic 3% NMeOH-CHCl, as eluent. afforded 4.9 g of a white solid. Another previously purified samrple was comnbinedl with this (6.3g 11.5 nmol total) and the product was dissolved in hot absolute ethanol (100 nil). iMa-leic acid (1.4 g, 12.1 -nmol) was added and the solution was stirred at a mild -eFux for 30 minutes. The reaction was concentrated to a white slush that was diluted with petrolEum ether (100 ml) and stirred for 2 hours. The resultant solid was collected to yield 5.5 gof shiny white crystals. The salt was recrystallized twice from absolute ethanol to afford 4.3 g and a thi rd recrystallization from CHGN gave 3.8 g of the maleate salt as a wyhite solid, m.o. 154-156*C.

-ANALYSIS:

Calculated for C,, 1 -1F 5 2

C

4 4 4 334C 63 10,55%N Found: 63.467,C 1..6.33%H 10.60%N :EXAMPLEt 232 N-[2-f 4-0 -B enzovl-6-f I uoro-1 H-in dazol-3-vl)-1 -Ri eraz i nIlet hl Iphthalimide hydrochloride A mixture of 2-[2-4-(6-fluoro-1I-indlazol-3-vl0-1 -pi perazinyIlethyl]1-1 Hisoindol-1,3-(2H-)-dione (6.C g;15 mmol) and benzoyl chloride (25 ml) was stirred dIWD at 175 C under N, for 2.0 hours. The reaction was cooled and diluted with -anhydrous EtO and the resultant hydrochloride salt was collected to yiel d 7.2 g.

OWN The compound was stirred in boiling absolute ethanol (300 ml) for 1 hour and then at ambient temperature overnight. The solid was collected and dried to afford 6.9 g. Recrystallization from MveOH gave 3.9 g of a light grey solid, m.p. 237-260*C.

ANALYSIS:

Calculated for C.,H,,Fi\ 5 0,.HCI: 62.98,%,C 4.72%H- 13.129/oN *Found: 62.92%-,C 4.7017H I1.22% N EXAMPLE 233 NI-f2-f4-(l-Ethoxvcarbonvl-6-flutorn-1H-indlazol-3-vl,)-l-p2ioerazinvllethyllphthalimide maleate mnixtu~re of N-[2-4-(6-fluoro-l H-indazol-3-ylI)- 1 -pi perazinyllI ethyl] phthatimnid e (1.8 g4.6 mnmol) and ethyl chloroformate (5.7 g, 52.3 mmol) was heated on a stream bath for 10 minutes. The reaction was cooled and an additional 2.3 g (20.9 rornol) ethyl chioroforroate was added. The reaction -was returned to the steam bath for 10 minutes longer and then cooled. The resultant solid was triturated *with anhydrous EtO and collected to yield 2.0 g. The solid was suspended in H,O (100 ml) and NaHCO 3 was added to make the pH=S. The aqueous mixtuare was extracted with CHCI, and the CH,CI. extract was washed with HO, dried with NaSO, and concentrated to afford 2-0 g of a yellow,. oil that crystallized readily. The product was flashed over 80 g silica gel using 2V6 EtNH-EtOAc as eluent to afford 1.10 g (2.36 mmol) of an off-white solid. The compound was dissolved in hot absolute ethano, (55 ml) and maleic acid (0.28 g,2.3 6 mmol) was added. The solution was refluxed gently for 10 minutes and then cooled. Most of the ethanol was removed In vacuo and the resultant white suspension was diluted with anhydrous Et,O (50 mnl). The solid that was produced was collected to yield 1.35 g. Recrystalli-zation from CHCN gave 1.15 g of the maleate salt as a white soft powder,m.p. 214-216*C.

ANALYSIS:

00Calculated for C, 1 H,,FNS0 4 .C H 4 0 4 57.83%C 4.S5%Hl- 12.04%Nf Found: 57.87%C 4.9 6%1oH 11.98%N EXANJPLE 234 3-[2-[4-(6Fluoro-1.2-benzisoxazol-3-v)-l-piperidiny 1 lethyll- 2-mnethyl-3-ou inazolin-4 -one A stirred mix(ture of 3-(4-piperidinyl)-6-fluor-oben-zi~oxazole (4 g, 18.2 n-mol), KCO, (3.76 g, 27.2 mmol) and 3.(2-chloroethyl).-cthl-3H-4-luinazolinofle g27 rnmol) in acetonitrilc (30 Qml) ~.sheated at reilUX for 1.6 hourIs. noreaction was complete as judged by TLC. The solids were filred arid thne solvent waIs evaporated. The residue was purified over a Plash ch rom~a tog raphy column (SiO..

gm,. eluted with dichioromethane and L~eOH in dichlorornethiane). The pure product thus obtained weighed 6.5 gin. Recrystallization from ethan~ol yielded white crystals, 3.94 gm rnp. 164-165*C. This material appeared pure by TLC over silica. gel plates.

ANALYSIS:

Calculated for CHFNO,: 67.97%C 5.0H13.78%N -Found: 67.6676C 5.6 6%coH 13.60%N EXAMPLE 233 4-(6-Fluoro-1,2-benzisoxazol-3-Yl)-1-f3-(2,3-dihvdro4 H-isoindol- 2-yl)propyllyipcricline difumarate A stirired mixture of 3-[4-(6-fluoro-1 ,2-benzisoxazol-3-yl)-1 -piperidinyl IpropyI amine (3.46 g, 12.5 rnmol), K,CO, (4 g, 29 mmol) arid a.&'-dibromo-o-xylene (3.3 g, 12.5 mmol) in acetonitrile (30 0 ml) was heated at refluEX for 3.5 hours. The mixture was cooled and the insoluhies were filtered. The dlark red solution was K concentrated dlown to a dark oil. This oil Was. PUrified by flash chromatography over a silica gel column (SiC 2 45 g; eluted KI Uhloromethane and MeOH in The product thus obtained weighed 1.95 g as an oil. This oil goo was dissolved in ethaniol and w as 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 gin, m.p. 206-209'C.

ANALYSIS:

Calculated for C,,H 2 ,FNO.2C,H, 60.8890C 5.60L7H 6.87%Nl Found: 60..17%7C 5.5lcH &:84%N EXAMIPLE 236 4-(6-Fluoro-1,2-benzisoxazol-3-vi)-l-l2-l2,3-dihlvdrO1 -l-isindol10-2-vllethv!Lpiperidiine dihydrochloride A mixture of 2-V-,(6-tl ucro-1I,2-benzisoxa zol-3-yi)- 1-piperidinylliethylamine (2.67 g, 10.1 mmol), a,ct-ciibromo-o-xylene (2.76 g, 10.4 mmol) and KCO, (3.2 g, 23 ga mniol) in acetonitrile (300 MD) Was heated at reflux for 1 hour. The mixture tur-ned pinkish and reaction was complete. The mixture %vas cooled, then filtered. The solution was concentrated down to a foam. Extraction with ether yielded 1.1.3 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, INO!. The crystZ115 which forrned weig hed 2.35 g, Nvith nip. =259-262'C.

ANALYSIS:

Calculated for C..H-,,FN 3 'O,.2H{CI: 60.28%iC 5.9896H 9.59%N ***Found: 59.9370C 5.83%oH 9.4S%N EXAMPLE 237 4-(6-Fluoro-1,2-benzisoxazol-3-vfl)--12-(5-fl uoro)-2,3-dihvdro-Iisoindol-2-yi )ethyllpineriding difumarate To a solution of fluo ro-1 ,2-benzisoxa zol1-3-yl0- 1 -p iperid inyl le thy-4fluorophthalimide (4.5 g, 10.9 nrnol) in tetrahydrof uran (120 ml) was charged with doom a solution of lithium aluminum hydride (35 nil, 35 mmol, IM in ether) dropwise under NI, 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 mil of 2050 NaOH. The mixture was stirred for I. hour, diluted with EtOA (200 mil) then filtered. The organic solution was concentrated to dryness. The residue wvas purified by flash chromatography over a silica gel column (SiC 2 70 gmn; elu ted with 1%c CHO 3 H: 99%k dichloroniethane). The product thus obtained (weighed g) was di~ssolved into ethanol and treated w-ith a solution of Furnaric acid (91S mg) in ethanol. T he crystalIs formed w'ere coillected to vield 2.25 g of white crystals, m~p. 223-229'C.

ANALYSIS:

Calculated for C-H FNO2CHO,: 5S&5376C 5. 0SK 6.8376N Found: 5 S. 485%C 4.9SoH 6.78%N EXAMPLE 238 *4-(6-Flu oro-1,2-benzi soxazol1-3-vlI-14[2-(22-d i hyd ro-1 H- iso ind ol 2-vl~propyllpiperidine ftimarate A stirred mixture of 2-[4-(6-fluoro-1,'-benzisoxaizol-3-yl)-1piperidinyllpropylarnine (2.92 g, 10.5 mmol), cta-dibromo-o-xylene (3.0 g, 1.03 mmol) and K.CO, (3.5 g, 25.3 rnmol) in aceotnitrile (150 ml) was heated at reflux for 6 hours. The insolubles were filtered off. The solven~t was removed on a 6. rotary evaporator. The residue was purified twice by flash chromatogaphy over 1 silica gel column (410 g and 45 g of silica gel). The product after purification weighed 1.15 g- This oil was treated with a solution of furnaric acid (490 rng) in etao.The off white crystals wvere collected to yield 6S0 mg,rn.p. 164-165'C.

ANALYSIS:

Calculated for CH,,.FN 3 'OCH&O,: 65.447oC 6. 10% oH 8.48%N Found: 64.83%C 6.01 %H 8.08%N EXAMPLE 239 N-[3-[4-(6-Fluoro-1,2-benzisoxazol-,3-vl)-l-pipecridinvll-2-hydroxv-lprop ll-2,a-dihydro4IH-isoindole dihvdrochloride To a stir-red mixture of i-(3-amino-2-hydroxx'propl-4-(6-fluoro-1,2benzisoxazol-3-yl~piperidine (2.24 g, 7.6 rnrol), K,C0 3 (1.61 g, 11.7 mrnol) in acetonitrile (100 ml) was added e..&-dibrorno-o-xvlene (1.54 g, 6.1 mrnol). The mixture was heated at reflux for 4 hours then cocled. The in5olubles were filtered.

The dark red solution was concentrated down. The residue was purified by flash chromatography over S Silica el Column (SiC.. 30 cluted! wI CHOH in dichloromnethane). The produICt SO Obtainal weighed 940 nig as an oil. This oil was dissolved in ethanol and w,,as treated wvith a solution of HCI in ethanol (iSS mg of AcCI in ethanol). Thle dark solidis wvere collected and recrystallized again in ethanol to yield off-white crystals (1.01 mn.p. 240-243'C.

ANALYSIS:

Calculated for C23H, 6

N

3 O,.2,HCi: 58,98%C 6.03% 0 H 8.97%N Found: S.%C 6.16%,H 8.94%N EXAMPLE 240 N-f2-f4-(6-Flu oro-1,2-benz.soxziol-3-vfl)lpipe rdi l hv roplsilylloXV--lH-isoindole difumarate A mixture of 2-[4I-(6-fluoro-l,2-betzisoxazol-3Y -piperidinyllethyIami ne- S.(1.52 g, 5.73 rnmol), 1,2-dibroino-A-(triisopropyliyl)oxy-xylene (2.4 g, 5.7 mmol) and KCO, (1.8 g, 13 rnmol) in acetonitrile (300 ml) was stirred overnight (18 hours) at room temperature. The mixture was filtered and the solvent was stripped. The residue was purified by flash chromatography over a silica gel column (7 gmr of(SiQ; eluted with 1-3% CHOHi in dichlorometharie. The product CI~bthus purified (weight: 900 mg) was converted to the fun-uarate salt by treatmient .i with fumaric acid (194 mg) in hot ethanol. The crystals were collected and weighed 590 mg, rn.p. 20S-2lT*C.

ANALYSIS:

MWCalculated for C,,H, 4 FN,O.Si.2C 4 HO,: 60,84%C 6.SIoH 5.4 6 S.N Found: 60.41 ,C 6.S7%cH 5.35 N EXANTPLE 241 .2-f 4-(6-Flu oro-,2- benzisox azol-30-1 pPrid iny ,L ethyl1-2,3-dihvdro-5-hdroxy-H-isoindole fumarate hydrate To a stirred Solution o piper-idinvlethyl]1-2.3-dihvdrizo-5-(triioproLsi6il)o-xv.- H-iLsoindole 1.5 g. 21.5 n-ml) in tetrahydrofuran (50 ml) was added a solution of tetrabutyl ammonuiar fluoride (IMIY in tetrahydrofuran. 24 ml, 24 nimol) in portions at room temperature.

The midxture was stirredz for 2 hours, then diluted with methylene chloride (200 mUJ. T-he organics was washed with H-0 and brine, dried with anhydrous MgSO, The solvents were removed arid the residue was purified by flash chromatography ,~,over a sil-ica gel column (90 gof SiO,; eluted Nvith 1-4% of CHOH in methylene chloride). The desired fract-ions were combined and concentrated to give 1.5 g of 9: free base. This solid was recrystallized From ethanol to yield 570 mg of off white V. crystals. The crystals were converted to furnarate salt in hot ethanol and water to see!%*give pinkish crystals, 560 mng, m.p. 191-193 C.

ANALYSIS:

Calculated for FNO,.-CHO, 4 .H1O: 60.57%oC 5,87%H S. 15 %N Found: 6 0.20 16C 5.737oH 8.04%N EXAPYPLE 242 44C6-Fluoaro-I H-indaxol-3-y D -2-(2,3-di ihvd ro- H -is o indo I -2-Yl)e Ih vl *agopiperidine dirnaleate To a solution of N-[2-4-(6-fluoro-IH-inda zo piperidinyllethyllphthatirnide hydroc hloride (Example 183) (3.1 g, 7.91 mmcli) in THF (100 ml) was added lithium aluminum hydride (16.6 ml of a 1.0 M solution in THF. 16.6 mmol) 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. The solids were wasr., d with DOM' anid 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 rnaleic acid. The light green precipitate was collected via filtration and wyashed with methanol.

Recrystallization From methanol gave g of the desired product as an off-white solid, m.v. 196-199'C.

A N ALYS[S- Calculated for C-r,3F,2,H,, 60.40%.c R Found: 6 0.3 3%5cC 5. 42 1~ 9.4 2 EXAMPLE 243 2-[4-(6-Fluoro-,2-benzisoxazol-3vi)-l-ieridnvll.l-(23- ihvdro-1 H-isoindol-2ethanone OO* 2-14-(5-flutoo-J .2-bmio~o13-l- prdzy~ct: The miidtue of 4 -&lur-,-ezsxzl3y~ieiie(6.77g 30.7 mmol), KCO, (3 g, 36".2 nmiol) and 2-brornoacetamnide (4.46 32.3 nimol) in acetoniffile (250 mil) was heated to reflux for 4 hours. The irsolubles wyere filtered and rinsed with dichioromethane (DCOM). The solvents were remov:ed- The residual Solid was dissolved in DOM and upon concentration of this solution, 2.3 g of product crystallized out and was collected when the Volume was reduced to about 50 mil.

The rest of the product in DOM was purified by flash chromatography over a silica gel column (80 gin, Si%: eluted with DCOM and IG Ci[,QH inl DCM). Thle total product (4.2 g) thus purified was recrystallized from ethanol to yield 2.82 g of white crystaLs, 170-172*C dec.

AiNALYSIS: deoCalculated for Cl, 4 HiFNO,: 60.6-l%C 5-52%H 15. 15 N Found: 6 0.6 6 5.57%H 15. 2 -I46-Fluoro-l 2-benisoxazol-3 -y0)-1 -Pipt.'ridin ylI-lI 4-(2-dihydro- 1 H d1- 2-1) e r, o o: To a i\xure of -4(-lo-l2bnioao.-l. iviivjcerie (2.56 s, 9. imoll in DNIF (40 nil) was chipped inl soliumn hydride (770 mg, 60c%' in oil, 20.1 mmol) at rooimn term-)eature under The mixture wa ;s heated to 65 C foe 3 hours. a~a -dibromoxvlane (2.43! a" 9.2 rnrno!) asadded and the resulting midxture was heated at 70 C for 4hours, then left sta nding overnight for 16 hours.

The DM.F mixture was poured into H4O (400 ml) and the organics were extracted into ethyl acetate (250 ml). The ethyl acetate solutio~n was washed with brine and dried over, MgSO 1 The solvent was removed. and the residue was purified by flash chromnatography over a silica_ gel colurmn (SA0, 45 gin; elu Led with 1% CH-fOH: 997o DCMA). The product thus purified as a white solid weighed 1.73 g Recrystalliza lion from a small amnount of ethanol yielded white czystaLs: 1.65 F, 184-185*C

ANALYSIS:

CalIculatLed for C,,H,,Ft 3 O, 69.64%C, 5.8476H 11.07%N 'Found: 69.48%7C 5.67%H 11,05%N 4.* 4.4.

r EXAMPLE 244 2-[4-(6-Fluoro-1,2-benzisoxazoI-3-yl)-l-p iperid inyll-l-(2.3-d ihvrdro-TH-isoin-d ol- 2-yl~ethanone fuhinarate Free base (1 g, -Example 243B) of 2-[4-(6-fluoro-1.?-berizisoxazol-3-yl)-1piperidinyl]-1 -(2,3-dihydro-l H-isoindol-2-yl)etha none dissolved in, hot ethanol H-1 n-d was treated with a solution of f umnaric acid (306 ing) in hot ethanol. The miuxture was cooled and the prodluct collected,. 1.2 gmn m.p:223-275*C.

ANALYSIS:

Calculated foY C,.H..FNi\O,C'H,0 4 63.02%C 5.29%H 8.48%N Found: **6.6C 5.03%H 8.39%N EXANMPLE 243 44(6-Fl uoro-1I-indazoi-a-vl)-1-r2-(5-fti uoro-2,5-dih-vd ro-1Hisoindol-2-vl)ethyllpiperidine dimaleate To a soluti consistigo 2-[4-(6-fluoro-1H-nd a piperidlinyllethylarnine (6.1 g.23-2 rnrol) in DMF: (230 ml) was added Afluo~ophthalic anhydr-idL (4.2 g.25.5 rnol) at room temperatu~re, under nitrogen- The reaction midxture was warmed to 80'C for 215 hours which time it was allowed to cool to room temperature. The DM%,F wvas removed under reduced *pressure mng, n5 to give a brown. oil which was dissolved into DCIM/MeOH. 'Purification via flash columnt chromatography (silica gel, 2% :.MeOH/DCMI) affoided 3.6 gof 4-fluoro-N-[ 2 -[4-C6-Iuoro-lH-indazo]-3-yl)-l piperidinyllethyllphthalimide. 'To a solution of the latter compound 3 -6-g 5:8 mmbl) in anhydrou, THF (100 m])--was addled LAH (18.4 ml of a 1.0 MI olution in THF, 18.4 mmfol) at room temperature, under nitro'gen- The reaction mixtuire was warm ed to reflfzx for 4 hours. Upon cooling toroorn tempera tu-e, the rea ction was quenched with water (1.5 dropwirse)._ The piecipitated salts were remrovedvia filtration and v.ashe d with DOM. The combined filtrates were concentrated to give a solid. which was purified via flashvColumn chrornabo-graphy (silica gel, 0-8%i MveOH/DCM). The product conrtaininlg fractions-vwere concentrated to give 2-4 g pr-oduct as an off-white solid. The dimaleate salt ;~sprepared in methanol us'ing 2.4 ~q fmaleic acid'. The white -precipitate was collected via filtration and washed with mhethanol, m.p. f96-im8C.'

ANALYSIS:

Calculated for C,,H,FRN,.2C1-1 4 0: -58.635kC 5,25%H- 9.12% N Found: 8.4 5 16C I9H .0 ?9 H 907%I EXAMPLE 246 4-(1H-Indazol-3-y)-I-f2-(2,3-d ihvdro-5-fluoro-I H-isoindol-2-y D ethvllpiijerazine dirialeate

S

S.

C'

To a suspension consisting of 4-fluoro-2-[2-[4-(IH-indazol-3-yI)-1piperazinyllethyllphthalimide (4.8 g, 12.1 mmcl) in THF (120 m.1) was added LAH (dropwise, 25.5 ml of a 1.0 M solution in TI-IF, 25.5 mmdl) at room temperature.

under nitrogen. The reaction mi xture was -warmed to reflux for 4 hours during which time it became homogeneous., Upon cooling to rooin temperature, the, reaction was carefully quenched with water (11.5 ml) and the precipit~ated salts were removed via filtration and washed with DOM. The combined filtrates were concentrated to give the crudle product. This material was dissolved into DCM'/MeOH (minimal),and purified via preparative I-C (single column of silica gel, 5% MeOH/DCM, 4L, then increased to 10% iMeOH/DCM, 3 LU to, give 2.9 g of the desired product. The dimnaleate salt was-prepared in methanol (200 ml) using' maleic acid (2.2 eq., 2.0. g, 17.5 inmol). The resulting salt was collected via filtration and washed with methanol to give an off-White solid, m-p. 182-184'C.-

ANALYSIS:

Calculated for C,HFN.2CH,0 4 58.2917C 5.40%H 11.727oN Found: 57196%C, 5.-39%H 11.65%IN EXA MP LE 247 .4-(6-Fluoro-lH-indazl-3-y)-1-[2-(2.,3-d ihvd ro4-methvl-IHisoindol-2-vl)ethvlloinerazine difumarate To a stirred sblution of 2-[2-[4-(6-fluoro-1 H-indazol-3-y)-1 -piperazinyllethyll-3methy4phthalimide (5.4 g,13.3 inmol) in TI-fF (200 ml) under was added, dropwise, LAH (30.0 ml of a 1.0 NI LAI-l/THF solution). After complete addition, the reaction was stirred at reflux for 4.5 hours. The reaction ascooled in an ice bath and H,O (2 ml) was carefuly ndded followed by 1.0 N1 NaOi G3 The mixture wa filtered and the filtrate wvas concentrated tb Yield 5.0 gof a 1braw,%n oil. Trituration of the oil, with E,O produced a white solid that wvas isolated by filtration to give 2.1 g of a white solid. The compou nc w.as ouriflied via ff-eparative HLPLC (Water's Associates Prep LC/5C0 using 2 silica gel columns and eluting: in~itial-ly with LMcOH,-CH,Cl. changing, to 15',o MeOH-CH.CI,). Concentration of appropriate fractions yielded 1.5 g (4.0 mmol) of a beige solid. The compound wa~sdissolved in EtOAc (125 mld) and MeOH (4 H) and the solution was w.armed and filtered.

The filtrate Was stirred near reflux and a solution of furnaric acid (0.92 g, mrnol) in hot MeOH.-EtOAc ml) was added. The mixture was allowed to cool and the resultant product was collected to give 2.1 g of an off-white soLd,m.p. 212-2IT*C.

ANALYSIS:

Calculated for C.,H,-9CHO,: 58.9196C 5.60%H 111A5% N Found: 5S8 8 17cC 5.66%H 'I1.62%t', EXAMP LE 248 4-(6-FI uoro-1 H-indazol-3-vl[)14r2-(2,3idihvdro-5m ethvl- -1H-isoindo l-2-yl)ethyllpiperazine difunarat~e To a stir-red'solution~of 2-[ 2 -t 4 6 -fluorQ-1H-indazoi-3-yl)-1-piperaziyljethy]..4 methylphthalirnide (5.46, 13.3 mm:D) in THE (200 ml) under N, was added, dropwise, LAH (30.0,m 1l of a 1.0 NI LAH/THF solution). After-comolete addition, the reaction was stirred at reflux for 4.5 hours.-- The reaction mixture was cooled in an ice bath and H,0 (2 ml) was carefully added followed by 1.0 MNaOH (3 ml).

The mixture was filtered and the filtrate wvas concentrated to yield 4.L7 g of a brown solid. The compou-nd was triturated with-.Et,O and filtered to give 2.4 g of a white solid. The compound waS.Pudified by' preparative HPLC CyWater's- Associates Prep 500 using 2 silica gel columns and',eluting 'initi ally with LdeOH-CH.-,l switching to 15% X-eQH-CH.Cl). <Concentration of appropriate f -actions gavel1.7 g (4.5 mol) ofla beige solid. The solid was dissolved in EtOAc (130 ml) and N-eOH cmd filtered. The filtrate wa-Zs 5tirre-d near reflux and was treated withi a solution of fumnaric acid (1.04 g, 9.0 r-nmol) 'dissolved i hot MeC'I- (6 mld) and EtOAc (6 mlA). The mixture was cooleci to-ambient tem, perature and the salt was isolate-cl by filtration to provide 2.4 g of an off-whiLe solid, mn.p.

212-215'C.

A NA L-YSIS Calculated for 2 %,FN&CH0O,- 5-91 %C 5. 6 0%cH 112A576N Found: 58.63%C 5.33%H '7 2N EXAMPLE 249 4-(6-Fluoro-1H-indazol-3-vl)-l-r2-(5-fluorD-2,-dihvdro-1H-iS oindol-2-vl) ethyllperazine dimaleate 9* a. To a stirred solution'of 2-(24(4-(6-fluoro-1 H7!indzol-3:tYl)-] I pip&,razinyl-ethyll-4-fluorophthalimide (2.9 g, 7.1 rnmol) in THF (100 ril) udiN wa si.a dded, dropwise. LAR (16.0 ml of a 1.0 Mi LAR/THE solution) over *;.miniutes. The reaction was stirred at ambient temperature for I1 hour, reflux fo F hours and then at ambient for 18 hours. The reaction vwas cooled in an ice bath and H70 (2 ml) was carefully added Followed by 1.0MN NaOH (2 MlD. The mixti::? was filtered and -the filter cake was rinsed with 10% NleOH-EztOAc. The filtrate was-concentrated to yield 2.5 g of a beige solid. The compound ivas purified by pepraive HPL C (Waters -Associates Pre' 500 using ?siiica gel columns and ii luin idtal ly with H6 MeO H-CHCl~ increasin' thepolarity to 12%NeH CHCI;) toel 1.7 g (4.3 mmol), of a, grey solid! The comnpound was dissolved Ln wi~arm EtOAc (75 mO) and i'AeOH (7 ml) and filtered. The filtrate was warmed and stirred and maleic acid (1.0 g, 8.6 rniol) w.as added. The reaction was stirre at gentie reflux for 15 minutes and then.at aimbient temnperature for 45 minutes.

Anhydrouis Et,O (100 ml) was added and the solid,%,.as collected to give 2.5 g.

Recrystallization from, CHCN provided 1.7 g of the-dirnaleate salt as a light grey solid, M.P. 1905-19Y*C.

ANALYSIS:

Calculated for F N.2'C 4 H&0 4 56.58ic 0 8 FS% 11.38' N Found 5 56 .3SC 87 5. 0l1%Hc 11,38TcN Q 7EXAMPLE 230 Z 4-(1H-lndazol-3-vfl)-l--(2 3-dihvdro-1H-isoindol-2-vl)ethvilpiperazine dirnaleate A suspension of 4-(,.iH-Lndazol-3-yl)pipera-zine (1.6 g, 7.9 rnrnol1), N-(2bromoethyl)phtha~d g.,7.9 rnrnol), and- sodlium bicarbonate (0.7 g, 8.3 mrnol) in acetonitrile (160 ml) was.warrned to reflux-for 24 hours. Upon cooling to room temperature, the reaction mixtuire was filtered through a pad of celite and the solids were washed with DCM. The combie fitrates were concentated to ._give the N-[2-[4-IH-indazol-3-y)-l-piperazinyllethyllphthialimide which was used :without further purification.

To a su-spenision consisting of N4[2-14-0 H-indlazol-3-yl)-i-p iperazinyl Iethyl]phthalimide 2.9 g, 7.9 mmol) in THF (100 ml) vwas added-LAH- (dropwise, 19.0 ml of a LO IM solution in TH-F, 19.0 mmol) at roomn temperature, under- nitrogen. The reaction mixture was warmed to reflux for 4 hours during, which time it became homogeneous. Upon cooling to room temperatu~re, the reaction was carefully *qece wt ae 15 ml) and the, lre ipitated salts were removed via Filtration .:.and washed with DOMI. The combined filtrates were conicentrated to give the crude product as an, oil. Purification via 'flash column-i chromao hyslc gel, %MeOH/DCM) afforded,,0.7 7g of th~e desire-d pi~oduct. The dirnaleate salt wasprepared inmethanol uiamlecacid (2.1 eq., 0.54 The resulting salt was collected via filtration arnd ws9hed wvith methanol to gv-a greenish solid, m.p.

178-iS3C.

Ct ANALYSIS: Calculated for C ,HN .2CH,0 4 60.10%C 5.7 4 %H -12.08%N i-Fo und: 59.82%C 5.65%H 12.10%1, N EXAMPLE 231 4-(6-Fluoro-l-H-indazol-3-vll-I-f2-(2,3-dihvdro4IH--isoindol-2-v)etvlpioerazine dimnaleate To a stirred solution of 11-6foo-Hiaol3l)ipprznvetyphthalirnide (5.5 go, 14.0 rurn-ol) in THF (123 rrl) unde, N, a, ambielit tennperaturre was added, dropwise, LAd-i (33.0 ml of a 1.0 MLAFI-/TIHF solution) over minutes. After complete addition the reaction~ was siedat ambient temperature for 45 minutes, andl then at refilux for 4.5 hou'rs. After stirring at ambient temperature for 64 hours, the reaction was cooled in an ice bath and HO-. (5.0 ml) was carefully added follow~ed by 1 M4 lN 9 aOH (2 The reaction was fil tered and the oily filter cake wvas r-insed with THF arnd 10% MeGH-EtOAc. The comnbined ,*.organic filtrate was concentrated to afford 5.5 go of a sticky white substance. This was combined wvith an additional sam'ple (7.5 a total) and purification via .:preparative HPLC (Water's A-sociates Prep LC/500 using 2 silica gel columns and as eluent) provided 6.0 g NO~. mmol) of a beige solid. The product i'as dissolved in warm FtOAr (150 ml) and treated with Darco-G60 for minutes. The decolorizing carbon wvas removed by filtratio n through a bed of celite and the warm filtrate vas treated with a solution of mnaleic acid (3.6 g' 32.8 mmol) in hot EtOH (17 ml). A white solid precipitated -and the mixture w,,as stirred 1.5 hours at ambient temperatures The compound was isolated by filtration to afford 8,9 g of a light grey solid. Recrystallization from IMeGH gave 5.2 g'of the dimaleate salt, nt-p. 205-2OT'C.-

ANJALYSI'S:

Calculated for C, 1 Ft\!,2C 4 F1 4 0 4 58.29%c7, 5.40%H 1,.72%N Found: -'5S.27%coC 5.31 %H 11.69%N N-p2henyl IH-indazole-1 arboxarnide dimnaleate Toestire supenio ofNaH(040 a of 60' ail-dispersion; 10.0 mmnol) in ml) -under NI. and cooled to was added. dropwise, a solution Uof 4-(6fluoro-IH-;indazol-3-yl)-l-( ?.3-dihy-dro-1H-k~oi ndol-?-vl)eth'I] piperak-ine 3 g' mmol) in DIM (5 ml) over 60 minutes, maintaining the temperature below 0 C.

-;The mixttire was stirred for 60 minues at 0 C a-zd the-n a solution of pheny'l isocyarnate (1.2 g, 10.0 mnol), in D.MF (5 rl) wa ade ropvvise at--2C. After com-oiete additon th reaction was stirred a, ambient tem-coerature for 20 hours.

The reaction~ ,was pured into H,O, and the aque-ous mnixture was extracted v.ith ethyl acetate. The ethyl acetate extract was washed with washed with brine, dried with NMgSO 4 and concentratedi to afford. -6 P_ ofa dark oil The oilI w.as purified by preparative HPLC (Waters Associates Prep 500 using 2 silica gel columns and MeOH-CH 2 Cl, as eluent) to yield 2.9 g of a dark oil. A 2.7 g (5.6 mrnol) sam ple was dissolved in warm EtOAc (100 ml) and MeOIH (5 ml) and the particulate matter was filtered away. The filtrate was wva-ned and stirred and a solution of maleic acid (1.3 .11.2 mmiol) in hot MeOHi- (5 ml) was added. The *:reaction was refluxed lldly'for 15 minutes and then w',as stirred at ambient temperature for 2 hours. The resultant suspension was diluted with petroleum etner (150 Ml) and -the dark solid collected to yield 3.

2 g. The compound was, recrvstallized from CHJCN (utilizing Darco G-60odecolorizina carbon) to afford 1_6 q Of a c-rny solid, rn~p. 189-19F C.

ANALYSIS:

*Calculated for C,,H,,F 1 60'33%C 5.20%cH Y1.73% N Found: 0'0.36%C 4.86%Ff 11.85%1 EXAMPLE 253 4-(1-Decanovl-6-fluoro-1H-indazol-3-yi)-l-[ 24(2,-d illYdro-1 H-isoindol- 2-vl~ethvilpirjerazine dimaleate To a stirred suspension of NaH (0.40 g of'60% oil dispersion, 10.0 mmol) in VW DLMFC10 ml) under N, and cooled to -3 C was added, dropwise, a solution of 4-(6fluorol H- indazol-3-yl ihydro-1 H-isoindol -2 vl)ethyllpiperazine (3.3-g, mmol) in DiMF (45 ml) over 65 minutes so that the temperature was maintained below 0 C. The reaction was stirred fo 0 I hour anid was cooled to A solution of decanovl chloride (1.9 10.0 nmm'l in DMF (5 ml) was added droowisLe over 10 minutes. After complete additi reaction was stir-red at ambient temperature for 20 hours. The reaction poured into HO0 (75 ml) and the aaueous mix'ture wvas extracted with DCO? -r e EtOAc extriact was washed wit i-,0,wased ithbrie, rie wih MI a nd concentrated to afford 5.1g of a dark oil. The oil .%as curified by prepaativc HPLC CvVate Pre piOGO utilizing i silica gel column and 4% eOH-CHC 2 as eluent) 3. vel 1 g(66%) of a dark oil. The-~oil (2.75 g< 313 mmol) insdiscl'>rcl i wa _mtOAc (100 mid) was treated with maleic acid (1.26 g, 10.9 mmol). After'warming the grey suspension was stirred at ambient tempraur for 60 minutes. The reaction was diluted with anhydrous Et,O1;30 ml) and petroleum ether M20 mld)' and the resultant dark grey solid .was collecte-d to yield 3.777 g. Trne salt was fromn CHCIN (using Darco G-60) to yield 2.6 g ot a light grey solid, 191-194t.

Calculated for CnH, ,F~I\O2CH,0 4 62.309oC 6.Y7%H 9.31 %N Found: 62-3"'%C 6.74%H 9-23 %N EXAMPLE 254 4-(6-Fluoro-1 H-indazol-3-x'l)-l-[3-(2,3-di*hvdro-1 H-isoindol-2-vl)tpropyllpilperazine dimnaleate To a stirred solution of- 2-[4-(6-fluoro-1 H-indlazol-3piperazinyllpropyliphthalimide (5.3 g, 13.0 m'mol) in THF (200 ml) under N, was added, dropwise, LAH- (27.0 ml of a 1.0 M LAH/THF solution). After complete .addition,-the reaction was stirred at reflux for 4.5 hours. The reaction was cooled in-an ice bath and H.,O (2 mnl) w-as carefully added, followed by1.0 M NaOH (3, mIX) The mixture wvas filtered and the filtrate was concentrated to a fford 4.8 gof a -white solid. The compoundvwas purified by preparative HPLC (Water's Associates Prep 500, utilizing 2 silica gel columns and 5% EtNEIH-EtOAc as eluent) to give g of a beige solid. Recrystallization from EtOAc provided 1.1 g (2.9 mmol) of an off~white solid. The compound was dissolved in hot EtOAc,*(200 ml) and vleGH ml) and maleic acid (0.6S g, 5.8 mmocl) wvas added. The reaction was warmed for 15'r-ninutes and after strigat ambient tempera ~ure for 30 m inutes and standing at about 4 C for L.5 hours, the dimaleate salt was collected to yield 1.7 of an off-white solid. mo. iS3-lS6'C.

ANALYSIS:

Calculate-d for C.,HFN;.2C,HIO,: 5 3. 9 1 jCC 5.6 0T H Found: SS.92qC 5'.47 H 11. 53% EXAMPLE 2-f4-(6-Fluor-o-1,2-benzisoxazol-3-vl)--iperidinvll- 1-(2,3dihvdroindol-1-yl)ethanone fumarate A stirred mixture of 4-(6-fl uo ro-i,2-be nz isoxazol1-3-yl)pi pe rid ine 1 0 g 45.4 rol), KC,C0 cg 52-- mmcl) and N-(2-b rom oa cetyl) indo line (12 g, 5 0 rnrol) in S 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: weichL 12.68 g- The mother liquor wis concentrated to dryness.

a The residues were purified further by flash chromatography to vield an additional 1- 35 g. TotalI yield -was 14-03 g- A72 g sample was dissolved in ethanol/methylene chloride and was treated with a solution of Furmaric-acid (62 g) in ethanol to 'I yield 2.58 g, imp. 226-227'C

ANALYSIS:

Calculated for 4 H,0 4 63.02%C -;29%H S. 4S qN Found: r62.79%C 5.30%Hf 8.40%N EXAMPLE 256 l-(l.2,3,4-Tetrahvdro-1 H-isoau inolin-2 yl)-2-14-(6-fluoro-1.2-benzisoxazol- 3-y D-1-pipe rid invil-ethiiane hy.drochloride e&hanolate A Mixture of -i-(6-fIuoro-1.2-bea-zisoxazol-3-vl) pipecridine (4.33 g, 19.7 m ol), KCO, (3.45g. 2, 5 rnmol,.25 e-q) a nd 2-bromnoa ce" v I-l,2.3,4 -tetra hyd roisoqu inoli ne g, 20 mi-nol) in Pcetonitrile (.200 rl) was heated at -eflux for 2. hours. The reCtion 6a00e a-nd thie insolubles weefil~ered. Thec soivert was removed and the crude oil was puriiied by flash chrom-iatography over a silica gel column g of SiO,;- eluted with DCM and 1% CHOH in DOM-. The oil thus purified ~veighed 6.41 g. A 3 g sample was dissolved ino ehnol- (20 ml) and was treated with ItM-HOl-ether solutio n (10 ml). The cr-vsta Is wvere collected and recrystallized twice L1orn ethanol to yield 2.43 g of white crystals as the hydrochloride ethaniolate, m.p. 266-20SCr

ANALYSIS:

-*Calculated, fo r CflH,, 4 FNO?.HCl.C,HO: 63.087,C 6.56%HF 8.83%N .Found: 63.24%-,C 6-62% H 8.89%N 0 0 E X A P L 2 D7 -4 (6F u r n io az l3 v)l- i Erdn.,l t v h dr ioain li diua-al see To solutin 4--Fi uo ro- 2-benzisox azl 3 y -1 -p peridin ,-ll l-I2 te~ra hyd ro-I H-isocluinobin-2' letha none g, 6 mmol) in THF (40 M11) Was charged lithium aluminumi hydride:05 ml iMn ether) drom-tjseunder N, at room-temperature.' The mixture -was stfrred fo~ r-3 hours at room temperat"Ure.r At the end, the excess of hydride was quenched with ice chips and-2 ml of 207a NaO0H. The mixture was diluted with EtOAc and filtered. The soIlns were removed to dryness. The residue Was5 pu rifi ed, by Ptash chrormatographv over a silia gel column (SiO 2 18 g;eluted-with 1% CHO-H in DOM), The pro-duct thus obtained weighed 1.62 g. This material was dissolved into hot ethanol and was treated with a solution of fumnaric acid (490 mg) in ethanol. The mixture was cooled and the crystals w.ere col-lected -to yieldj.11 g, m.p. 2lS-22(C.-

IS:

Calculated for CH,i~FNO2CHO,: 60.885%C 5. 60%H 6.8.7 Found: 61 .00%C 3507,H -6.64% N EXAIMPLt 2-

A~A

MOM*.

4119Mbenzisoxazol'-vl)-1-1-piperidinvlleth'ano-ne furnaraite A solution of (6-fluoro-1,2-benzisoxazoli-3-v l)operp2 IdL.-e (4.4 g.2 mmiX1 triethylamine (2.1 g, 21 mmel) in chloroform (50 ml) was added to a solution of -chloroacetyl chloride (2.5 g& 22 mmol) in chloroform (100 dropwise at room tempera ture. The mixture was stirred for 2 hours, The solution was dfluted with dichiorometh ne (DOA, 100 ml) and then washed wvith-HOan rne h solvent was removed and the oily product was purified by flash charornatogra~h (SiO,, 50 g; eluted w,.-ith DC4- and i% CHOH in DCM)-. The pur-e product obtained as an ojil, 4.2 g.Crystallization from ethanol yielded 2 2 g oF white crytalls, m.D. 101'102'C.

AN\ALYS[S:-.

Calculated for C,,H;,CIFir,O,: 56.6-7%C '-76%H 9.44 N Found: -570C -1.75%Ff 9.4 676N 22 ATc~rkydolH-sotio~in2-y -!4-(6-fluoro--- A mixture of -(&-Pfluoro-1,2-benzisoxazol-3-yi)--i-pipe,-idinyl-2-chloroacetamide (3Og 10- mmol), KCQ, (1.5 gm, 10.8 mmol) and I -tetra-hvdroisoquinoline OA.4g, 1035 mmiol) in acetonitrile (90 ml) Was heated at reflux for 41 hours. The reaction was cooled and filtered. The solvent was removed, and the residue was purified by flash chroma tography over a silica, gel column (50 g of SiO 2 eluted with DCM and I CHOH in DCM). The light yellow oil (3.25. a)thus obtained was dissolved in ethanol and treated with a solution of funrirc acid (968 mg) in ethanol. The solid crystals were collected and rcvslizdag-ain to0 give 3.15 g 0' off-white crystals. rn.D. ISS-1S9'C 247 Calculated for C,K-q:FNKO.'CH 4 Found.- 63 65 %-oC 6 3A 2'%C x4 ST,- S.25 N S. 16 %N EXAMPLE 259 N4[3-446-71uror-l--benzisoxazol-3vlpiperid in VI1-2 hydroxv--roovll-l2.,3,-tet-rahvdroisociuinoline difumarate A- mixture of N-(3-(2,3-epoxy)prcopyl]-4-(6-fluoro-1,2-benzisoxaz-3-ylI)Diperidine (3.56 c, 12.9 mnmol) and 1,2.3,4-'-tetrahyldrois-coquinoline (2.06 15.4 mrmol) in isopropyl alcohol (150 ml) was heated at reflux for 4 hours. At the end of the reaction, the solvent was removed. The resi dual oil was purified by flashchromatography over a silica gel column (SiG,, 45 g, eluted with "I%7 CH;OH-: 9 9 methylene chloride). The product thus Purified as a* light oil, wveighed 4 .15 g. T1he oil was treated with a solution of furnaric acid (1-98 gin. 17 mmol) in ethanol. T4h e white cryVstals so obtained were recrystalL-ed in a large volume of hot ethanol (m-150 ml). The recrystalliZedl crystals weigrhed 2.75 p. 179 -181 Y AMNALYSiS: Calculated for C 2 H, FNu.2CH,0 4 59.907,C 5.66 i;H 6.557,Ni Found: 60-06%C 37c H o.69

U

EXAM'NPLE 260 .6,-Dimethoxv-2-[3-[4-(6-fluoro-1,2-bEnzisorazol---'fl-1piperid.invL- 2-hvdroxv-1-propvll-1.2,3,4-tetrahvdroisooujinoline A stir-red mixture of 1 -(2,3'-epoxyoro:)vl)-4-(6-f Luoro-1 ,2-benzisoxazol-3yl)piperidine (3.2g 1c'1.6 mmol), K:CO, (2 grn- 1.25 eq) anid 6,7-dimethoxv-1,2,3,4tetra hclrois;oquinoline hvldrchlnride (3-3 S, 1-75 eq.) in isopropvi alcohol (200ml was heated at reflux for 6 hours. T he mixture wscooled' and filtered. The solvent was removed to about 350 ml and the solut ion allowed to stand overznight. Crystals (C0.6 g)formed and were Collecte-d. The Mother I:quor wvas concentrate- to a white solid. Recrystallization tw .ice frm ethanol yieldedJ tile product (0.95 g, rn.p- 153-154'C_ ANALYRiS: Calculated for C 2 HNO:66.31%C 6.S77H 6V .5N Found: -66.51 %C 7.0 5 H SS3%N .409 *E XAMTPLE 261' N-[244-(6-Fluoro-IH-indazol-3-vD)-l-piperidinvllethvll-1,2,3,4tet-rahvdroisoqiiinoline dimaleate To a solution of 4 -(6-fluoro-lH-inciazol 3-Yl)piperidine6'(4.S g, 18.9 rnrnol) in

C

3 CN (200 ml) was added 2-brorno- 1-02,3,4- tetra hydro isoqu ino Iin-2- riDetha non-e (4.8gz 18.9 mmol) and sodlim bicarbonate (1.9.g 222.7 rnmoi).at room temperathure.

The reaction mixture was %viarrned to reflux (4 hours), cooled to room temperatue a nd filtered through a pad of celite. The solids w.ere wvashed with DCM and thlecombined filtrates were concentrated. The rej-haining residue was purified via preparative'HPLC (silica gel, 5-10% IMeOH/DCMA) to give 4.1 g of 1-01,2,3,4- -~tetrahydroisoqu inoin--yl)-2--[4-(6-fluoro-1I H-inda zo 1-3-Lyl)- I -piperidinyl let ha none whichi was used withoutr-further purification. To a suspension -of thle latter (3.7g 9.4 mmnol) in THE (100 ml) wvas add~ed _(dropwise) ,1lithiuml aluminum hydride 13 Co ~~ml of 1.0 MI solution in THF; 11.3 mobl) at room temrn trudr irgn The reaction miixture was warmed to reflux (5 hours), cooled to room -temperature and carefully ouenched -with -water (10 ml). The precipitated salts were removed via filtration and washed with 1:1 EtOAc/DCA., The combined filtrates were concentrated and the rem1ainling oil-was purified ,ia flash -column chromatography (silica gel, 110% MeOH/DCM) to give;2.2 g of the product. The dirmleate salt was prepared in methanol (30 ml) with maleic acid (3.0 m.p. 1SS-187*C.

ANALYSIS:-

Calculated fo- CH_-N 4 .2CHO,: 60.9SocC 78%7 H 9.18%N Found: 60.S5c%.C 5.75%l7- 9.09%1\ EXAMfPLE 262 2446-FI u oro-l H-ind azo 1-3-v Dml-p ipe rayin v 11- iI(1,2,3,4-tra hvdro- 1H-isoquinolin-2-Yl)ethanone difumarate A -mixt-ure of 6-fluoro-3-(4"-piperazinyl)-1H-indlazole 53.1 g, 14 mmol), 2aey. 2,,-etaydosotinln 14 mmol), Na HCO 3 (1.4 17 mnol) and CHCIN (130-mi) was stirred at reflux under N, for 6 hours. The cooled reactioni was filtered and the filtrate was concentrated to yield 6.1 g of an off-white foam. The compound was purified by-preparative HPLC (Water's As sociates prep *500 using-2 silica gel co lumnirs and 5% MeOH-CH,,C 2 as eluent). Concentration of appropriate fractions gave 4.1 g of an off-white solid. A 0.8 og (2.0 mmol) samnple was dissolved in warm EiOAc (30, ml.1 and NleCH (4 ml)2_ ~nd filtered. The filtrate was heated to reflux anid was treated with a sblution of fumaric acid (0.47 mmnol) inMeOH/EtOAc 8 ml):iThe mixture was cooled and the resultant wh* wite solid was collected to yield 0.88 g 'nis was combined with anothe .r smnallI samrple (1.0 g total) and recrystallizati6n frorti ethanol provided 0.75 g of a 'vhite solid, m.p. 235-238 'C.

ANALYSIS:-

Calculated for C ,,FN,0.2CHO,: 57.60%C 5.16%H l.1% Found: __''57.687 0 C -5.26%H- 11 .31 %N EXAMPLE 263 N- 2-4-(6-Flubro-l H-i rd azo 1-3-07 -pip erazin ylle th yll- 12JA3.-tetrahydroisoguinoline difumara te To a stirred solution of 2-[4-(6-fluoro-lH-inaazole-3-yl)-1-piper-azinyl]-l-- (1,2,3,4-tetrahyd ro-I H-isoquinolin-2-yl)etha none (3.2 g.8.1 mmol) ini THF (73 rid) under N, was added dropwise, LAH (20.0 ml of a 1.0 M LAH/THF solution) After complete addition, the reaction was stirred at -ambient tem~perature for hous.Therectin-as cooled in an ice bath and cold H-.0 was added followed by I ml of,1 .0 NI Nabri. The rnixtuire was filtered ar~d the filter cake was washed with EtOAc. The filtrate was concentrated to yield 2.5 gof a.--1hte solid. The compound was pu.rified by preparatige HPLC (Waters5 1socia t es p, 500, using I silica gel colum n and 10%/ MeOH--CH 2 CI, as elUent) to yield 2.0 g.,or a white solid. A* 1.8 g (4.7 mcl) sarnple was stired as a solution in, w arm EtOAc (100, ml) and was trea ted vwith isolution of furharic acid 1 g,.5 mmcl) in boiling MeGH (Q2 mld). The reaction was warmed for 15 m-inutes and after stirring at ambient temperature for 1.5 hours the resultant white solid wa-s collected to yield 2.7 g of the difumnarate salt, m.p. 210-213C

-ANALYSIS:

Ca IulIa te for CHN -CH 58.91 %C 5.6076H 11'.45%N Found: 58,7-/%C 5.4 2%C l1. 2-756>N EXAM4PLE 264 1(1 9.3 4-Telrahvdro-TH-ou-inolin-l-v)-2-[4-(6-fluoro -1,2-benzis xazol- C* -3-0l-1-p iperidinylle than one furmarate A stirred mixture of 4-(6-fluoro-1 ,2-benzisoxazol-3-yl)piperildine g, tetra hydroquinoline (6 g, 23.6mmol) in acetonitrile (200 ml) wa~s heated at reflux for 1.5 hours. The mixture was co-oled and the solids w.ere filtered off. =The .0 solvent was stripped to dryness. The residlue-was purified by flash chromatography (SiC 2 100 gin; eluted with methylene chloride (DCM) and 1%7

CH

3 0H in DOW) The product thus purified weighed 7.75 g. A sample of 1.88g in ethanol was treated with a solution of fumnaric acid, (550 mg, 1.0 eq) in ethanol to yield the fumaric salt, 2-15 g, m.p. 162-1 63 C., ANALY515: Calculated for CH,FrOCH0 4 63.65%C 3.54%H 2N Found: 63.52%C 5.46%H S. 17 *EXANPLE 265 N-f2-446-FI uor..o-1.2-benzis oxazol-3-vl)-l-piveridinvllethvll-12,3,1trtahvdronuinoline fumnarate To a sti rred solution of fluoro-1.2-benzisoxazol1-3-yl)-1-piperidfivll.I-1tetra hyd roqui no] in-1, -yl) etha no ne (5.51 g,-14 mmol) in THF (50 ml) was :..charged with lithium aluminum ihydride (17 ml,_ 17 mnmol, 1 M 'i etherYdropwise unfder N 2 at roomn ternperature.. The mixture wvas sbrred for 8 hours at room *temperature. At the end of this period the excess of hydride was quenched with .ice chips and 3Imi of 20% r."aOH. The mixture was diluted with EtOAc (150 mld) *and sti-red for-1 hour.TeEOcwsdidwt gO and filtered. The solve nt was removed to dry-ness. The residue was- 'urified bv flash chromatography over a silica gel columnn (SiO 553 gxeiu ted wvith 1-3%a CHOH:l DCM). The product thjus obtained weighed3 1.83 g.This materidl w-.as dissolved *into hot ethanol and was treated with a solution of lumaric acid (700 mg) in ethanol. The crystals were collected and weighed 1.85 g, m I 92-193'C.

ANALYSIS:

*Calculated for CH,FirO.-CHO,: 6 1%C 6.10H 7,.P48%N Found: -65.20 %7 C 6.19 %H 8.32 %N A stirred mixture of N-(2, 3 -epoxvprcipyIl)-4-(6-fluoro-1,2 benzisoxazol-3vl~piperid in 1e (141 g, 8-73 mnmo!), l,,4-tet--ah ydroquinoline (1.33 g, 10 mmol, in purified by flash chromatography over a silica gel column (SiG, 40 g, eluted with recrystal-lied: again from ethanol (50 ml) to yield 1.0g of e.hite crystals, as a hemdfumarate, rn.p. 170- 171 C

ANALYSIS:

Calculated for CHtI!OG5-,,, 66.79%C 6.47%H 8.99,7N Founid: 66.27%C 6.54%H 8.86%N VA.0- EXAMPLE 267 N-r2-446-FI uor6- 1.2- benzisoxazol-3-vl )-l-pi peridinvllacetvll- 10,11-dihVdro-5H-dibenzfb,flazepine fumarate A -stirred 'mixture of -chl6froacetvl-10, 11 -dihvdro-5H-dibeniz(b~flazepine (6.6 g, -24 3 mm1). '-(6-fluor6-1,2-benzisox azol-3-ylDpiperidline (5 g, 2-27 mmol) and K.CO, -gj-*40 mrnol)in acetonitrile (300 ml) was heated at reflux for 4 hours. The Lnsolu bles Wxere filtered,ard -the solvent-was removed on a rotary evaporator. The crude.p product vwas -purified'by flash chromatography over a silica gel colun~n (100 g of SiOI; eluted with dichloromethane (0CM) and 1-2% CH 3 OH in DCM). The product- thus o bta-ined:, w eighed 87 g as a yellowV. oil- A sample (1.5 g) of this 'material- was dissolved :inethanrol and was treated with a solution of fumnaric acid in etfiano! (360 mg/-3 The solidsc6lected wvere recrystallized from acetonitrile to yield 890mg of, white cry,.tals, m-.p..182-183C.

ANALYSIS

Calculated for C, 5 HF 67.24%C .9H73 N Fou nd. 66.66%C 5.1 7%JH 7.33%rN EXAMPLE 268 :ethoxvnhthalimide hemnihvdrate A mixture of 3-(G--oioeridrnyl) 6 fluo-obenzisoxazo- (3.42 g 15 mmoi), bromoethoxx')-phthahirnicle (4.3 16 m mo 6 a nd K-CO, (Z6 &A 18 mmol) in acetonitrile (150 ml) was heated. at reflux [or-2 hours- The solids were removed and the solvent was evaporated. The residue was puriied over a flash chromatography column (packed with 5i0 2 60 eluted with dichioromethane (DCN4) and CHOH in CM). The pure product thus obtained, weighing 6-S g was crystallized from DCM:ethanol. Recrystai liza (ion- from ethanol and i-propyl ether yielded white crystals (2.4 g, rn.p. 125-127'C) as the hemihydrate.

0~*.ANALYSIS: Calculated for CH FN,,0H,O: 5.05%H 10.04%N 2-15%H,O Found: 63.20%C 5.16%H 9.80%N 2.32%H,O EXAMPLE 269 3-r4-f&-.Fluor-L.2-benzisoxazol-3-vl)-l-piperid invll-2-hydroxv- 1-propylamine hyvdrochloride hydrate A stirred mi'xture of 3-(4-(6-fluoro-1 ,-benzisoxazol1-3-yl)-1-piper-idinyl]-2hydroxy-l-propylphthalimide (6.2 g, 14.6 mmol) and hydrazine hydrate (1.4 g, 28 mmol) in methanol (300 ml) w~as heated at reflux for 4 hours, then at 65 C for 16 :hours. The mixture was cooled and the solvent was stripped to dryness. The white residue was stirred with HO (40 mI) and acidified with HCI to pH=3. The mnilky white solids, were filtered with the aid of Celite. The light yellow solution wvas basified. with 50% NaOH to pH=9, then extracted with mrtethylene chloride (DCM, 3x180 ml). The DCM solutionwas washed with brine, dried and stripped to give an oil (2.93 g) which solidified slowly. A- I gmi sample of this solid was treated with a HCI/MeOH solution to precipitate out a hydrochloride salt. This salt was recrystallized from ethanol =H,0 to yield 0.52 g of white crystals, 150-152'C.

ANALYSIS:

Calculated for C,5H.cPFNjO,-HCl.H,O: 51.80'.C 6.67%H 12.08%7N Found: -51.745%C 6.3 2%7;H 12.057oN EXAMPLE 270 N,\-[2-r4-r6-Fuoro-1,2-bei-zisoxazol-3-vl)-l-piperidinv ethil -3- 2vridiniecarboxarnide dihvdrochloride hydrate To a mi]xt-ure of 2-(4-(6-Eluoro-lh2-benzisoxa zol-3-yI)- 1- piper-idinylilethylarmine 0 (.11 g, 4.34 mmol) and triethylarnine (1.08 g, 10-8 mmol) in chlorof-or-m (30 mld) was added nicotinoyl chloride hydrochloride (0.96 g, 5.4 rniiol) in one portion.

The mixture Was stirred for I hour at room. temperature. The solution was diluted with methylene chloride (0CM) and washed with brine and dried over anhydrous MgSO 4 The solution was concentrated and the crude product was purified by flash chromatography over a silica gel column (510:, 25 g: eluted with- DCM and r- 3%MeGOH in DOW) The free base thus purified weighed 1.7 g. This product was treated w-,ith I1AM. HCI in ethanol and recr-ystallized tw.ice from methanoi:isiproply **ether to yield w.hite crystals, 1.19 g, m.p. 243-245C as'a dihydrochloride hydrate.

ANALYSIS:

Calculated for Cj-2IH, 1 N0-2HCl.l 2

O):

5.2.30%C 5.49% H 12.20%N 3>.927oH,O Found: 52.-34%C 5.39%H 12.11%IN 3.68%H,O EXAMPLE 271 N42-r4-(6-Fl uoro-I Fl-in dazol-3-yfl-1-pip eraz invilethy] 1-3-phen vi-2quinoxalinamine dihvdrochloride A mixture of 2-r4-[(6-fluoro-1H-indazol-3-yl)-1-piperazinyllethylamihe (4.3 g, 16.3 mmol) and 2-chloro-3-phenylquinoxa line (4.7 g, 19.5 mmol) was heated at, 160"C for 5 hours in an autoclave. After standing- at ambient temperature for 2 days, the residue wvas partitioned between ClHI:Cl and H,O. The CH.C1 2 extract was washed ith dried with NgO and concentrtdt brown solid. The solid was purified by preparative HPLC (Water's Associates Prep LC System 500, using 2 silica gel columns and 4.5%;c NMe'0H-CHC, as eluent).

Concentration of late.r fractions afforded 2.3 of the desired product as a yellow *5* foamn. A 1.4 g sample %vas suspended in N-ihcOH (30 ml) and ED-O-HECI (6.0 ml of a m EtAOC solution) was added. Initially a yellow; solution 5o'rrned end about midnutes later a precipitate began to form. The suspension was stirred for mriniutes longer and anhydrous EtO (100 nil) wvas added. The resultant light yellow solid, was collected to give 1.5 g. The product was stirred in boibng CHCN: (10Q nild) for 1.0 hour and after cooling the solid was isolated by filtration to afford 1.2 g of a light yellow solid, nip. 244-246*C.

AINALYSIS:

Calculated for C.,,H,,FN 7 .2HCI: 60.00%tc-' -84H Found: 59.79%C 52?7%H 18.34%N EXAMPLE 272 1.2-bis-[4-(6-Fluoro-,2-benzisoxazol-3-vl)-l-piperid inv) ]ethane difurnarate S S 41 To a stir-red mixture of 4-(6-fluoro-I,2-benzisoxazol-3-Yl)piperidine (2.2 g, mmol) and K 2 C0 3 (1.47 g, 11 mnmol) in acetonitrile (50 ml) w~as added 1,2dioromoethane (1g, 5.4-mmol) dropwise at room ~temper~attire. The mixture was stir-red at room temperature for 16 hours. The, reaction' mixture was filtered and the solvent was removed on a rotary evaporator. The 'crud e solid was purified by flash chromatography (SiC,, 30 g; eluted with methylene chloride, DOM, and MeOH- in DCNI). The product thus purified' weighed 513 mg. This solid was treated with fumnaric acid (270 mig, 2 eq) in ethanol. The crystals collected were rerystalILzed from~ ethano:H-tO to yield 630 mig of white crystats, m.p. =246- 24 7*C.

ANALYSIS:

Calculated for C,H,,F,N 4 CO,: 58.45%C 5-19%H 8.02%N Found: 5S.36%C 5.22'1H 7.927%N EXAMPLE 273 1.3-Bis-14 -(6-fl uoro-1.2-bhenziso~cazol-3-vI)-1-pi peridinyll-27 hvdrox-vpropane dihvdrochloridte A s irred miXure o' -23eovrpi--5fiOOi,-ezsxzl3 yl~piperidine (1.19 cg, 4.3 mmoi) and ziscxazol-3-Vl) pi~er-idine (0.95 g, 4.3 minol) in isopropyl alcohol GO0 ml) wvas heated at reflux for I hour, then stirred at 65*C for 16 hours. The solvent was removed on a rotary evaporator. The solid residues were purified by Flash chlromnatogaphy over a silica gel column (SiO,, 35 g~eluted with rmethylene chloride, D)CM, and CHOH ixn DCM). The product thus obtained, weighed 55 ga This material was dissolved in ethanol and was treated w.ith a solution of HC (I IM in ether). The salt *.:collected weighed 2_35 g, m.p. >270*C dec.

AN~ALYSIS:

*Calculated for C,,HF2, 4

O

3 .2HCl: 56.95%C 5.66%H 9.81 Found: 5 6.5S5 cC 5.3% II of~ EXAMPLE 274 -A-L'~luoro-I 2-benzisoxazol-3-vl)-1-piperidinvllethvI ~enyl-1,3indiand ine A midxture of 44(6- fluoaro-1,2-benzisoxazol -3-ylIpi peridine (2.2 g, 10 mmol), '4KCQ (1.6 g, 11.6 mmol) and 2-toluenesulIfonyl-2-ph enyl-l,3-indafldi one (4.2 g, mmol) in acetonithlle (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 wvas purified twice using a flash chromatography column CSiO 2 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, rn.p. 149-150'C.

ANALYSIS:

Calculated foF 7 4.3 4-7C 5.38% H 3.98%1\ Found: 7. 4ciC 5.50;%H 5.S 7a N EXAMPLE 2-f 4-(6-Fluoro-..2-benzisoxa--ol-3-x'l)-l-piperi-dinvI lacetonitri Ie A mixture of 4'-(6-fluoro-12-benzisoxazol-3-yl~piperidinie (11 g, 50 rmol), K,C0 3 (8.5 g, 61.6 mmol) and 2-chloroacetonitrile (5.5 73 rnmol) L-n acetonitrile (250 ml) was heated at reflux for 24 hours. The insolubIes were filtered off and rinsed with rnethylene chloride (DCM). During concentration of the solvents oil the rotary evaporator, crystals appeared. The crystals were collected and weighe d 5.79 g- The product in the mother liquor was further purified by Hlash chrom~atography over a silica gel column (5102, 70 g; eluted with DCM, and 1% CHOH in DOW. The second crop of product thus obtained weighed 5.2 g. The total yield was 10.9 g. The sample was recrystallized once more form ethanol, m.o. 130-132*C.

A NALYSIS: Calculated for Cu Hn ,FN 3 IO. 64.85%C -5.44%H 16.21%N ~*Found. 64.687%C 5.32 %H 16.26%cN EXAMPLE 276 3-f 4-(6-Fluoro-,2-benzisoxazol-3-yl)-l-2iPeridinvllpropionitrile A mixture of '4-(&fluoro-1,2-benziso~cazol1-3-yl)piperidine (11 KC0 3 (8.5 g, 74 mnmol) and 3-brornopropionitrile (6.2 g, 1.2 eg) in acetonitrile (300 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 (5102, 120.

The product thus purified weighed 8.94 g. Recrystallization from ethanol Yielded the nitrile as white crystals 41.3 g, m.p. i00-101'C.

ANALYSIS:

Calculated for C, 5

H,,FN

3 0O: 65.927rC 5-90%H 15.37%-% Found: 65.87%C 5.87%~H 13.375LkN EXAMPLE 277 l-Phenoxvcarbonvl-3-UI-phenoxvcarbonvl-4-o iperidinvl)4IH-indazole To a suspension of 3-0l-:-,ethyl-4-pi perid inyi0-iHidzl (5.0 g, 232 nrol) in DOM (100 ml) was added p-otasium carbonate (8.0 g, 58.0 rnrol) followed by the dropwise addition of phenyl chioroform, ate (6.9 ml, 51.0 mmol)- at room ~..temperature. After stirring for fivedays, the reaction was filtered through a pad of cebte and the solids were washed with DOM. The combined filtrates'were, concentrated and the-remaining- solid was purified via flash colunn chromatographyz (silica g .el, 10% rnetha~nol/DCM)'to give 6.7 ag.ft1phenoxvcarbonyl-3-(1-methyl-4-piperidinyl)-1H-indazole as the hydrochloride salt..

The free amine of the latter compound was prepared in NaCO, (sat.) and extracted into EtOAc. Concentration. of the organic layer afforded 4.7 g of the free amine which was used without futirher purification.

To a solution of I -phenoxycarbonv-3-1 -methyi-4-piperidinyl)-1 H-i ndazole) g, 14.0 mmol) in DOM (100 ml) was added potassium carbonate (0.35 g.6.2 rrunol) followed by plhen I chlorofomnate (2.1 ml, 15.4 mmol) at room tem'perature.

under nitrogen. After stirring for 2 days, the reaction mixture was filtered throughi a pad of celite and the solids- were washed with DOM. The remaining oil was purified via flash column chromatography (silica gel, DOW) to give another oil which solidified fromn EtOAc/pet. ether. The w hite solid (4.2 g) was collected via filtration and washed with pet(ether, m p. 113 116*C.

A NA LYS IS: Calculated for CiH23NO,: 70.74%C;I: 5.25%H 9.52%N Found: 7 0.4 5.17%oH 9.33%,N EXAMPLE 278 [4-(6-Fluoro-lH-indazol-3-y)-1 piperazinvlacetonit-ile A mixture of 6-Fiuoro-3-(4'-piperazinyl) IH 'noac-ole (6.0 g, 2.7 mmoi), NaHCO, g, 3.0 mmcl) chloroacetonit rile (2.5 g, 11. mmoil and CH 3 CN (150 mol) was l.a.

sti--ed at ref-Ix unde N. IS. houis._ The coolei c!ic -v.as pcue-1 inito H-0O and the aqueous solution was extracted wvith EtOAc. The ELOAc extract was washed with H,0 vwashed w.ith brine, dried-w;i th MgSO, and concentrated to yield g of a tan solid, A 1.3 g-sample wvas recrystallized from EtOAc to yield 0.65 g of a beige solid, rop. 154-1

ANALYSIS:--

Calculated for C 13

H-

14

FN

5 60_22%7C 5.44%H 27.01 %N Found: 59.97cC. 5.35 71H 26.9 170N EXAMPLE 279 1443-Chloropropox-V-3-me thoxyphen vl I-2-h vd roxvetha none 4b A- solution of 1 -(4-(3-chiloropropoxy)-3-rnethoxyphenyilethi none (4.3 g, 17.7 mmol), jbis(f 171fluo roacetoxy)iodo ]benzene 6.2 mmol); H,0 (18 rnld),-

-CF

3 C0,H-(2.8.mI and CH CN (90 nil) was refluxed for 3 hours. The-CI-TCN wa-s rmedunder reduced pressure and the resulting yellow li. quid w.as partitioned between-H-O0and CH,Ck. The biphasic mixture w as" fhite~ed the organic phasecollected, washed with saturated NaHCO, solution and concentrated to afford g off an arn~rphouirsbrovwn solid. The solid was flashchromatographeol ori silica el eutngth clumn with i~ Et cC C% Cnetto -of similar f ractions afforded.0.7 g of the comp ;ou-n d as a-Dale yello sol d -m P. 99 101 C.

EXAM. PLE 280 1-[4-[3-[4-(6-Fluoro-1,2-benziso'xazol-3 fl-l-piperidinvllpropoxvl methoxv-phenvfl-2-hvdro-,vethainone A mixture of 3-(+-)iperidinyl)-6-fluoro-l1 -zis-- azole (1.3 ,8 MMcl) Ij [4-(3--chlo-,opro Poxv)-_3-methoxv-phen~l-2-hvdrok,,,et-a:-io-e 01.5 g, 53 >26C' INaHCO 3 (.g)and 1-methyl-2-py-nrolici~none (50 r-n) wsstir-red under N, at 100'C for 6 hours. The reaction was poured into H,O, and the aqueous su-spen-sion was ext-acted with EtOAc. The extract wa s was~hed dried (Mg-SO 4 and concenitrated to afford the product.

*This invention thus provide's a-group of chemr-ical compounds 'that are capable of producing antlpsycnouic effects and may be capable of affecting negative *4 symptoms of schizophrenia in a beneficial manner. In addition, many of the compounds may also have reduced tendencies to produce extraovramidial side effects Ln mammals.'-

Claims

4. 4* S S* -4 S *5 1. .55 A with the proviso that in formula '14) Z L, noL'j CHwhben X is Q? is -CU- Y is hydrogen, lower alkyl, lowyer alkoxy, hydroxy or halogen, and pis Ior2; with the proViso that in formula (14) Z is not I- wheni X is -SQ 2 is -H- Y is hydrogen, halogen, lower alkyl, lower alkoxy or hydroxy, p is I or 2, R is hydrogen, and m i3 1; with the proviso that in formula (14) Z is not-N- when X is Q2 is R is chlorine, fluorine, brom ine, iodine, lower alk-yl, lower aikoxy, lower alkyl thio, lower mono- or dialkylarrifno, amrino, cyano, hydroxy, trifluoromethyl; F, is, aryl; *Y is hydrogen, halogen, lower alky,_,.'lower alk6xy or hydroxy, p is.1 or?2; with the proviso that in formula (14) Z is not when X is -NH- or wvhere R, is 1by. er alkyl, aryl lower alkyl, or phenylsulfonyl, Y is hydrogen, halogen, lowet aIkl, lower-alkoxy or hydroxy, p is I or 2 and Q2 is -CH2-; with the prox iso..that Y, is not the moiety of formula(8) wehen -Z is X is O. p is 1. and Y is hydrogen, lower alkyl, lower alkoxy, chlorine, fluorine, bromine, iodine ora hydroxyl group;.I 9ththe proviso that in formula Z is not -Nwhen X is 0 or S, Y is hydrogen, R is hydrogen, )alkyl, chlorine, fluorine, bromine,-i6dine, cyano, (CC-C, )alkoxy, aryl, -COOR.s where R 25 is (C,-C,)alkyl; with the proviso that in formula Z is not wvhen 1 is 5 ,R is H, and rn 1; r with the proviso that in formula R, is not hydrogen when Y is 6-F, X is Z isCHb and nis 2,3or 4; wi th tha t the proviso tha t in formula 0iS) is not H when Z is X is -NH- or where R, is lower alkyl;' aryl lower alkyl, or phenyisuffonyl, Y is hydrogen, lower alkyl, lower a[ko.xy, chlorine, fluorine, bromine, iodine or a hydroxyl group and D is Ior 2; with the proviso that in formula R, is not H when X is where R, is phenyl, Z and Y is hydrogen, lower alkyl, lower alkoxy, chlorine, fluorine, bromine, iodine ora hydroxyl group; with the proviso that in formula R, 5 and R 1 are not lower alkyl when Z is ,X is -N(R 2 and R: is aryl and Y is hydrogen, lowver alkyl, lower alkoxy, chlorine, fluonrne, bromine, iodine or a hvd roxyl group; 271 Uit the proviso that in formula when- X is s 1 hydrogen, lower alkyl, lower alkoxy, chlorine, fluorine, brormine, iodine or a hydroxyl, group, and RI, are not lowver alkyl; wvith the -proviso that in formula RI, and are not hydrogen when R, is Z is X is and Y is 6-F;1 all geometric, optical and stereoisomers thereof, or a pharmaceutically 4 acceptable acid addition salt thereof. The compound of claim 1 having the formula: *0 ()IN Y, 3. The compound of claim 2 wherein X is -N(R 2 4. The compound-of claim 3 wherein R, is (C 1 C,)alkan6yl or (C,-C 1 )alkoxycarbonyl. The compound of cla im 4 which is -decanoyl-&-fluoro-I H-ildazol-3- yD-l -pipe razinylI ethyl] ph tha limicle anid its pharrruceutically acceptable acidaddition salts.
6. The compound of claim.i 2 wherein Y, is
7. The compound of claim 6 wherein R, is -CH,CH(OH)CH..-, or -CH .Ci-[OCC=O)(C,-C )al'kv I CH S. Te compound of claim 7wherein R is indepencdently selected from, hydrogen, (C.-Calkoxy or (QCC,)alknnoyl and mn is I or 2.
9. The compound of claim S w-.herein X is and Z is *H The compoun d of claim 9 which is 4-[3-14--(6-fluoro-1 ,2-benziscxazol-3-yl)- piperidinyl]-2-hydroxy-l-propoxylphenyl methyl ether and its pharmaceutically acceptable acid addition salts. I. The c ompound of claim 9 which is 4-[3-[4-(-fluoro-1,2-benzisoxazol-3-yl)- apipe rid in yil-2-hyd roxy-I -propoxy]-3--me thoxyph enylme th anon e and its pharmaceutically acceptable acid addition salts.
12. The compound of claim 9.;%hich. is 1-[(4-aceto-?-methoxy)phenoxy-3-(4-(6- .fluoro-l,2-benzisoxazol-3-yl)-1-piperid-inyll-,2-propyl decanoate and.its :pharmaceutically acceptable acid addition sdlts.
13. The compound of Cl'aim 9 which is luoro-3 (I (a3-(2,-1 dimethoxyphenoxy)p'rbpyl]--piperidinyl] I 2-benzi-soxazole and its Loharrnaceutically acceptable acid addition salts.
14. The compound of Claim 9 which -is 1 4Lt ofuoo1)benzisoxazol-3-yl)- I-piperidinyll propox- hyh- o-'>-methoxyphenyllethanone and its pharmaceutically acceptableacid addition salts.
16. The compound of claim 2 wherein Y, is A B~ y
17. The compoudo claim 1l wherein R, is -CH 2 CH-, -CH-(OH)CI-L-, -CH,CH,CH,-, -CHCH-(CH 3 -CH(CIH)CH,- or )aLkyIJCH,-. The compound of claim 17 wherein A i-s 0=0, B~and B.are C, and U isO. -19. The compound of clairn 18 wherein X is -C)-and Z is -CH-. O The compound of claim 1~9 which is N\-[3-[4-(6-fluoro-1,2-ben-zisoxazol-3-i-- pipe ridinyl]1-2-hyd roxv- I -propyl lphthaliniide and its pharmaceutically acceptable-acid addition salts. Sao:%21. The compound of claim 19 which is 1-[4-(6-rluoro-1.,2-benzisoxazol-3-yl)-1- piperidinyl]-3-phthalimido-?-propyl decanoa te and its pllarniaceutically acceptable acid addition salts.
22. The compound of claim 19 which is N-[2-[4-(6-fIluor-1 ,2-benzisoxazol1-3-vl)-l pipe rid inyl Ipropyljphtia li mide and its pha rmaceutica lly acceptable acid addition salts. 2-3. The compound of claim 19 which is N -[2-[4'-(6-fluloro-1,2-ben-zisoxazol-3-y)-1- piperidin.Yllethyl]-3,6-d ifluorophtha li mid e and its pha rrnaceutically acceptable acid addition salts.
24. The comouound of claim 19 which isNL\-[2-f4-(6-tluorc.1,2-benzisoxazol-3-yl)-l piperidinyl] ethylIl-3-hydroxyphthalimide and its pharmaceutically acceptable acid addition salts. -Che compound oi claim 19 which is NP(-5fu~.12bnioao---)1 pipe ridinvlMe th Y-1]-4-tert-butyI lpha limid e and its pha~maceuticaliv acceptable acid additio nsalts. The cornpouxid 6f claim 19 whinis 1-benzisoxa zo 1-3-yl)-1 piperidinyl]e!hYl-3nirh~hahiciie-and its pnarmaceutically acceptable acid adition isalts a 2~~7 The comipound0 odcaim 9wihi ioo,-ezs~zl3y)1 ppendml~ethll-4 Vdroxy6hthahimide an i hrriaceutically acceptable acid to addition salts 7 The cormound of c %im9wich isN 7[44 (6furx 7bnioazol-3yl)-]- _.piperidiny lletl-yl-aminophthahmxd anid -It- PhIa rmacufically~acceptable acid -add ition saltil j- 29 Th ompoutnd of'&claim.19v hihi fluoro-t'i' benzisoxzol-107-y,'t ieid",yllethylHA4(1d decano-y'larqnphthihmde and its bharmbaceutxcll 11 apabl a-kcdaddlition- alts A .21 piprimyletyl-4Cldecnol~~ypth~i-ue rd its .hii-iiaceuqncqly acceptq le 0- ~31. Theco6mound of~cairm 19 w-hitb is N k Co fuo6 4 o-1 7bntoao~~y)1 pxpend inylethyl] 3-m_ o'yypthiitide-and'its oharrnaceutialy-acceptable acid addition salits
32. ;The compounfd of Claim 19 %Vhich'is N (7 2 fluoro-12 V benzxsox azol-3-y):- 'Ierdny utdphtharrud e iand its pharmxaceuiticalSi accepta ble a cid add'ition The compound of Claim 19 wh, ich is ,N-[3-[4-(6-fluor -1,2-benzisoxazol- 1 p-iperidinyllbutvllphth~limid~ and itS pharmaceutically acceptable acid addition salts. A Th cmpun ol Claim '9 which is -(6-fiuor-o--L2-benzisoxazol '1v)-l1 prenu-i~th l~~i rontahru~and its onra tcivacceutable acid addition sazLs. The comnpound of cla i-8 ISWherein X is and Z~~-CH- 6. reorbudo la- 3wihi -2I (6-floro -l,2-benzisothiazol-3-yl)- and its haaceuica Hy acceptable acid addition salts. 17. The compound o~clainn35,which is N-[2-[4-(6luoro-1,2-benzisothiazol-3-yl)- 1l-pip~eridi~nyllethyl]-4-methylphthaln de and its pharmaceutically acceptable acid addition -salts- .33. The cowapound of claim 35 which is ioc12-ezshao- y) 1-piperidinyllethvlj'phtha limide and-its phar naceutically acceptable acid addition salts.
39. Tne compound of claim 1S wherein X is NiJH- and Z L's -H Tie compound of claim 39 which is N-(24[4 flu oo 1H11-in dazo1-,3-yl)-1I- piperidinyllethyliphthalimide and its pharrnace~utica lx acc epta-hle acid addition salts.
41.: The compound of Claim 39 whichls4-lunra N (2 k (6-fluoro-IH-indazol-3- yl)-l-piperidinyl~ethyllphthalimide and its pharrnaceutic ally-acceptable acid addition salts.
42. T-e compound of claim IS wherein Xi;s -NH- and Zis
43. the com[ound of claim 42 which is N-[27[4-(6-luoo-l H-iidazol-3-yl)-1- pin~erazinyllethyilphthalimide and its pharmnaceutically acceptable acid addition salts. 4. Thre compnound 0of claim 42 which isN[1-6fur- iindlazol-3-lvl)-I pipraznyiethll-mehylhthlimdeand its pha-,m:ceuiicallv acceptable acid 27' addition salts. The compound of Claim 42:which ii; 4-flUoro-N-(2-[4-(I H-indazol-3-vfl-1- piperazinyllethyflphthalimide and its parcuici cetbeacid addition salts.,
46. Thne compound of claim 4'2 Which is N-f2-1k-(6-fiuoro-I H-indazol-3-Yl)-1- piperazinyllethyl]-3-methylphthalimide and its pharmaceutically acceptable acid addition salts..
47.' The compound of Claim.42 which is N-f 2-[4-(6-loro-IH-indazol-3-yl)-I- piperazjiyl1propyllphthalimide and its pharmaceutically acceptable aicid addition Salts.- 43_ The2 c pudOF Claim*i Is erein X' is c.R.and 7 S49. The-compou-nd of Claim 43S whic-h is- N i2-[4!-Q-deca noyl-6'-fluoro-l--indazol1- J-yl)-i piperazinylleth'i6phthalIirnide and its pharmaceutically acceptable acid addition salts. The comnoound of Claim'-48 which is iN-[2-f4-(1-ben-,iovl-6-fluoro-I H-indlazol-3- yl)-I -pipe razinyll ethyl) phtha limide and its pha Irmraceutically acceptable acid addition salts.
51. The compound of Claim 43 which is Ni?'(-[4-(1-ethoxvcarbonyl-6-fluoro-IH- *indazol-3-yl)>piperazinvi ]ethyl] phtha limid e and its pharmaceutically acceptable acid addition salts.
52. Tne compound of claim 13 wherein A is By and B, are C, and U isO0.
53. The compound of claim 52 wherein X is 4. -n1o~c~ of claim 53 w.hich s 4 -o-l 1,-ben zi soxzo--l4 pipridny~etyl]2~-divdr-3hy'rox1H -i-soindol-1 -on ,e and its pharmaceuticzally acceptabiE.aCid addition salts. a **a a a t oar a ~S 2 *O aS.. U. u~. LI The compound of claim 53 which is decancic acid 2-[2-4-(6-fluoro-1,2- benzisoxazol-3-yl)-l-piperidinyllethyl-3-ox--2,3-dihydro- H-i-soindol-1 -yl ester and its pharmaceutically acceptable acid aiddition salts.
56. The compound of claim 52,wherein X is---
57. The compound of claim 56 which is 2-[2-[4-(6-fluord-1,2-benzisothiazol-3-y])-l- pip eridinyl~ethyl]-2,3-dihydro-3-hydroxy-1 H-L-soindol-l-one and its pharmaceutically acceptable-acid addition salts.-
58. The compound of claim 52 wherein X is -NH-.
59. The compound of claimv 58 which is 2-[244-(&-fluoro-1 H--indazol-3-yl)-l -piperazinyllethyl]-2,3-dihydro-3-hydroxy-1 l--soindol-I-one and its pharmaceutically acceptable acid addition salts. The compound of claim 16 w herein A~is B, and B, are C, and U is 0. 6 Tne compound of claim 60 wherein X is
62. The compound of claim 61 which is N-(2-(4-(6-fluoro-1,2-benzisoxazol-3-y)-1- piperidinyl]ethyll thiaphthalimid e and its pharmaceutically acceptable acid addition, salts.
63. The compound of claim 16 wherein A is B, and B. are C, and U is S. 6-4. -The comzpound of claim-63 wherein X is The com:pound of claim 6-4 which is -(6-fiuoro-1 ,2-berizisoxazol-3-yl)-1 piperid inyl Iethyl]-,1,3-bis-,h-iaPh thalimid e and its phanm-aceutically acceptable acid addition salts.
66. The compound of claim 16 wherein A is C(CH,)OH, By and B, are C, and U is 0.
67. The compound of claim 66 wherein X Ls -68. The compound of claim 67 which is 2,3-dihydro-2-12-[4-(6-fluoro-1,2?- benzisoxazoi-3-yI)-1 -piperid inylle thyl] -3-hyd roxy-3-methy 1-1 H-isoindol-I -one and its pharmaceutically acceptable acid addition salts.
69. The compound of claim 16 wherein A is CH(CHI), By and B. are C, and U isO0 The compound of cla im 69 wherein X is
971. The compound of claim 70 which is 2-[2-[4-(6-fluoro-1,2-benzis-oxazol-3-yl)-1- piperidinyllethyl1-2,3-dihydro-3-methyl-I H-Lsoindol-i-one and its pharmaceutically acceptable acid addition salts. 72. The compound of claim 16 wherein A is C=CH., By-and BareCand U Ls0. 73 The compound of claim 72 wherein X is 74. The compound of claim 73 which is 2,3-dihydro-2-(2-[4-(6-fluoro -1,2- benzisoxazol-3-yl -pi perid inyll ethyl] -3-me th ylene- I H-isoindlol- I -one and its pharmaceutically acceptable acid addition salts. The compound of claim 16 wherein A is CH,~ BY and B. are C,and UisO0. 76. The compound of claim 73 wherein X is 77. The compound of cla im 76 which is 2-[2-(-(-Luoro-i,2-benzisoxazol-3-yi)-I piperid inyllethyl]-2,3-dihydro-l H-isoindol-b-one and its pharmaceuticaily acceptable 279 r'V t~J YJ~ I I UC.U acid addition salts. 78. The compound of claim16 wherein Ais B~ andB, a re C, and Uis 0. *79. The compound of claim 78 wherein X. is So. The compound of claim 79 which is N-(2-44-(6-.fluoro-l1,2-benzisoxazol-3-yl)-l- .pipe ridinylI ethyl] -12,3,4-tetra hydroisoquin ol i- 1,3-d ione and its pharmaceutically acceptable acid addition salts. 81. The compound of claim 16 wherein A is C=0, B, is C, B: is N, and U is 0.- The compound of claim 81 wherein X is *83. The compound of claim 62 which is N-[2-[4.-(6-fluorro--4,2benzisoxazol-3-yl)-,I- piperidinyllethyl-6-pyrrolo[3,4-blpyridine-5,7-dione and its pharmaceutically:- 84. The compound of Claim 16 wherein A is B, ,and B.are C and Uis 0. The compound of Claim -4wherein X 86. The compound of Claim 85 which is 3-1[2-(4-(-fluoro-1,2-benzisoxazol-3-yl)-I piperidinyllethyl2-methyl3-quIiazolil-4-ofle. 87. The compound of Claim 2 wherein is R- 2 S\ -88. The compound of Claim 87 wherein X isO0 and Z is -CAi The compound of Claim 88 which is 4-(6fluoro-1-ezsxzl3y)1D _-3-dihydro-lH-i-soindol-2-yl)propyllpiperidinle and its pharmaceutically acceptable acid addition salts. The compound of Claim 88 which is 4-(6-fluoro -1,2-benzisoxazol-3-yD)-l-(2,3- dihydro-I H-isoind ol-2-yl) ethyl] pipe rid in e and its phaimaceutically acceptable acid addition salts. 91. The compound of Claim 88,,which is 4-(6-fluoro-1,2-benzisoxazol-3-Yl)71-(2-(5- z fluoro-2,3-dihydro-] H-isoindol-2-yl)ethyllpiperidine and its pharmaceutically acceptable acid addition salts. 92. The compound of Claim 88 which is 4-(6-fluoro-1 ,2-benzisoxazol-3-yl)-l (2,3-dihydro-l H-isoindol-2-yl)propyllpipe-id in e and its pharmaceutically'acceptable acid addition salts. £493. The compo und of Cla i nm 88 which is -Iluo ro-l ,2-benzisoxazol1-3-yl)- 1 W pipe-idinyli-2-hydroxy-l-propyll-2,--d ihydro-l H-isoinidole and its pharmaceutically acceptable acid addition salts. 94 The compound of Claim 83 which is N-(2-[4-(6-fluoro-1 ,2-benizisoxazol-3-yl)-1 piper-id inyl ethyl]-2,3-d ihyd ro-5-(tri isopropytsilyl~oy- I H-isoindole and its pharmaceutically acceptable acid addition salts. The compound of Claim ES6 which is N-[2-[4-(.Ilu;oro- ,2-beazisoxazol-3-Wi)-I pipe-nd in vllet hvl .2,3-d ihyd ro-5-hydroxy-l H-isoindole and its pharmaceutically acceptable acid addition salts- 96. The compound of Claim 87 wherein X is and Z is INN~ 4 *9 'I 'a *4 97. Tne compound of Claim 96 which is 4-(6-fluoro-il--ndaz-ol-3-yvl)-1[-23 dihydro-1 H-isindol-i-yl -)ethgIl Ipperidine and its pha maceutica liv acceptable acid addition salts. 98. The comp~ound of Claim 96 which is 2-[4-f6-fluoro-1,2-benZisoxaZOl-3-vl)-l- pi peridlinyl-1 ihyd ro-I so ind ol-2-yl) ethan one and its pharmnaceutically-, acceptable acid addition salts. 99. The compound of Claim 96 which is 4-(6-fluoro-I H-indazol--y1)-1-[2-5- fluoro>-2,3-ihydro-l H--isoindol-2-yl)cfihyllpiperidine and its pharmaceutically acceptable acid addition salts. 100. The compound of Cla im S7 wherein X is -NH- and Z i N-- 101. The compound of Cla im 100 which is 4-0 H-indazol-3-yl)-] -[2-(2,3-dihydro-5- Hluoro-1 H-isoindol-2-yl)ethyllpipera zine and its pha rrnaceutical ly acceptable acid addition salts. 102. The compound of Claim 100 which is 4-(6-fluoro-1 i-indazol-3-yl)-1-(2(2,2- dlihydro-4- methyl-1 H-isoindol-2-Yl)ethylipiperazine and its pharmaceutically acceptable acid addition salts. 103. The compound of Claim 100 which is 4-(6-fluoro-l H-indazol-3-y)---(2-(2,3- dihydro-5-methyl-1 H-isoindol-2-yl)ethyllpiperazine and its pharmceutical ly acceptable acid addition salts. 104. The compound of Claim 100 which isA-(6-fluoro-1 H--indlazol-3-yl)-1-(24-( fluoro-2,3-d ihydro- I H 4soind ol-2ty)et hyl Ipipe ra zine and its pharmaceutically acceotable acid addition salts. 105. The compound of Claim 101 which is 4-01 H-indazol-3-vl)-1-(2-(2,3-dihvdro)- 1H-isoindol-2-yl)ethv l1piperazine and its pha =a.ceuticalv, acceptable acid addition salIts. n W. I *e* *5 S S e S 106. The compound ol'Claimn 101 which is 4-(6-fiuoro-! -nao--i--2C,3 zd~ydro- H-isoindol-2yl)ethl~Upiperazine and its pharma~ceutically acceptable acid addition salts. 107. The compound of Claim 101 which is 4-(6-fluoro-IH-indazoi-3-y)--[3-(2,3- dihydro-l H-iLsoindol-2-yl)prop~yllpiperazine and its pha rraceu ticaLly acceptable acid addition salts. 108. The compound of Claim 87 wherein X is and Z 109. The compound of Claim 108 which is 6-fluoro-3-(4-(2-(2,3-d ihydro-1 H7- isoindol-2-yl)ethyl]-1-piperazinyl]-iN-phenyl-IH-inidazole-1-carboxamide and its pharmaceutically acceptable acid addition salts. 110. T-he compound of Claim 105 which is 4-(1-delcanoyl-6-fliuoro-1 H-indazol-3-yi)- 1-(2-(2,3--dihydro-1 H-isoindol-2-Yl)ethyllpiperazine and its pharmaceutically acceptable acid addition salts. 111. The compound of Claim 108 which isN-(2-(4-C-decanoxycarbonyl-6-fluoro- 1 H-indazoI-y)--piperazinyllethyllphthalimide and its pharrmaceutically acceptable acid addition salts. 112. The compound of Claim?2 wherein Y, is 113. The compound of C1airn 112 wh ere in X is Oand Z Ls 11 "I I.- 114. The compound of Cla irn 13 w.hich, is 2-f 4-(6-fluoro-,2-benzisoxazol-3-ylI)-1 pipcridinyllI--(2,3-d ihyd roindol-1 eth anone and its phirmaceutically acceptable acid addition salts. 115. The compound of Claim 2 wherein Y. is 31 R 3 2 R, 9 (R4)q R-YS 116. The compound of 'Claim 115 wherein X i5O and Z is L5 117. The compound of Claim 116 which is l-(1,2,3,4-tetrahydro-1H-isoquinolin-2- yl)-2-(4-&fluo ro-1,2-benzisoxazoI-3-yl)-l -pipe rid iny'lle tha none and its pharmaceutically acceptable acid addition salts. ]Is. The compound of Claim 116 which is iN-[.2-[l-(6-Fiuoro-1,2-benzisoxazol-3-yl)- I -piperidinyll ethylI-1,2,3,4-tet rahyd rosbqu inloline and its ph=rmaceutically- acceptable acid addition salts. 119. The compound of Claim 116 which is 2-(1,2,3,4-teti'ahNdro-iH-icocuLinolin-2-- yl)-I fluoro-1,2-benzisoxa zol-3-yl)-l -pipe rid i rvlf etha 11onle and its pharmaceutically acceptable acid addition salts. 120. The compound of Claim 116 which -is N-f 3-f 4-(6-fluoro-1,2-benzisoxazol-3-vl "I-piperid inyl)-2-hyd roxy-1 -:ro pyl- 123,4 -etra h d roisomuinoline and its pharmfaceutically acceptable acid addition salts. 121. Tne compound of- Claim 116 which is 6,7-dimctnoxv-2-f -1,2- 6* a.. a C. CS C C s-C a eq* CC.. ben zisoxazol-3-ylD-] -pi Perid in y1-2-hydrowy I -propy II- 1,2,.3,-ttetrah' 'd ro isoq io[in~ and its pharmtaceutically acceptable acid addition silts. 122. The compound of Claim 115 wherein X is NH and Z is -CH- 123. The compound of Claim 122 which is jN-[2-[4-(6-fluoro-I H-indazol-3-yl)-i- pipe ridinyllIe thyl-1 tetra hyd roisoqu inolin e and its pha i-maceu ticaiiy acceptable acid addition salts. 124. The compound of Claim 115 wherein X is NH and Z iL-N 125. The compound of Claim 124 is N-(2-f4-(6-fluoro-1H-indazol-3-yi)-l- piperazinvleth-vl]-1,23,4-tetrahydroisoquinoI ine and its dharw-aceutically acceptable acid addition'salts. 126. The comi~poun~d of Claim 124 which is 2-k-(6-fluoro-I H--indazol-3-yl)-1- piperazinyll-(1,2,3,4-tetrahy'diro-I H--isoquinolin-2-yl)etha none and its pha rrnaceutically-acceptable acid addition salts. 127. The compound of Claim 2 wherein Y2 is 0 *C p ~C CCC. C C a d a- 128. The compound of Claim 127 wherein X isO0 and Z is CH 129. The compound of Claim 1 28 which is I -(1,2,3,4-tetrahydro-1 H-quinolin-l-yl)- 2 [4-(6-fluoro-l 2 -be nzisoxa zol-3yl) pipe rid iny112 thanone and its pharmaceutically acceptable acid addition salts. 130. The compound of Claim 128 which is N-[P-[4-(6-fluoro-1,2-beilzisoxazol-3yl)- 1.piperidinyllethyl]-1,2'3,4-tetra hydroquifloline and its pharaceutically acceptable acid addition salts. 131. The comipound of Claim- 128 which is N-(3-[4-(6fluoro-1,2-belziSoxazol-3-yl)- I -pi peridinyI) hydrox y-I-pro pyl- 1,2,3,4- t etra hyd roqu i nolirte and its pharmaceutically acceptable acid addition -alts. 132. The compound of Claim 2 wherein, Yj is R4)m I)-N 133. The compound of Claim 132 which is N-(2-[4-(6-fluoro-1,2-benzLZ5Oxazul3yl)- I-piperidinyllacetyl 4 OA, I -dihydro-5H-dibenz(bflazepifle and its pharmaceutically acceptable acid addition salts. 134. The compound of claim 2 wherein Y; is 0~ \I 135. The compound of claim 134 wherein R, is -CH,-CH,1-. pos 136. The compound of claim 135 which is 6-chloro-2-[2-[4-(6-fluoro-1,2- phrmcetialyacceptable acid addition salts.anis 137. The compound of claim 2 wherein Y 2 is 0 0 138. =The compound of claim 137 wherein R, i s 139. The compound of claim 138 which is N-2-[2-[4-(6-fluoro-1,2-benzisoxazol-3- yl)-1-piperidinyllethyll-2,3-naphthalimide and its pharmaceutically. acceptable acid addition salts. 140. Tecompound o~claim 2 wherein Y, is -,OR, 141. The compound of claim 140 wherein*R,, is hydrogen. 142. The compound of claim 141 wherein X is 143. The compound of claim 14? which is L-)-6-fluoro-3-[1-(3-hydroxybuty!)-4- piperidinyl]-1 ,2-benzisoxazole and its pharmaceutically acceptable acid addition 144. -The compound of claim 142 which is (S)-6-fluoro-3-[1-3-hydroxybutyl)- piperidinyl]-1,2-benzisoxazole and its pharmaceutically acceptable acid addition -salts. 145. The compound of claim 142 which is (R)-&fiuoro-3-UI-(3-hydroxybutyl)-4- piperidinyl-1,2-benzisoxazole and its pharmaceutically acceptable acid addition salts. 146. The compound of claim 142 which is 6-fluoro-3-[1-(3-hyd roxy-3-ethyl pen tyl)- .**.*4-piperidinyl-12-benzisoxazole and its pharmaceutically acceptable acid addition salts. 147. The compound of claim 142 which is 6-fuor-o-3-[1-(3-hydroxy--propy hem~}7~-i .4-piperidinyl]-12-benzisoxazole a nd its pharmaceutically acceptable acid additioL salts. 148. The compound of claim 142 which is 1(-4(-loo12bni~a~ l 9piperidinyllethyllcyclohexanol and its pharmaceutically acceptable acid addition salts. V. 149. The compound of claim 142 which is 1-[2-i'4-(6-fluoro-1,2-benzisoxazol-3-yl)-1- piperidinyllethyllcyclopentanol and its pharmaceutically acceptable acid addition salts. 0 C '150. The compound of Claim. 141 wherein R, 2 is N 0 -151. The compound of Clairn 150 which is N-[2-[4-(6-fluoro-1 ,2-benzisoxazol-3-yl)- I-piperidinyIlethoxyphthalimide and its pharmaceutically acceptable acid addition salts. 152- The compound of claim 141 wherein X is 153. The compound of claim 152 which is (S)-6-fluoro-3-Ll-(3-hvdroxy-2- methyl propyl)-4-piperidinyl]- 1,2-benzisothiazole and its pharmaceutically acceptable acid addition salts. 154 The compound of claim 152 which is 4-(4"-(6-fluoro-1,2-benz-isothiazol-3-yl)-1- piperidinyl]-2-rnethyl-2-hyd roxybura ne and its pharmaceutically acceptable acid addition salts. I 155. The compound of claim 152 which is 5 (4-(6-fluoro-1,2-benzisothiazol-3yl)-1-- pipe ridlinyll -3-ethyl i-hydrox) pen tan e and its pharmaceutically acceptable acid additiiIs. pirdiy. a ar C'nie a Cp P 2bnid dis0Ik beai~diinsf _156. The compound of claim l57 which is pipeazi~yi-2-ydrxy-2-ii6-hylutd r n-t raeicaiiadtil4epbacidiidn adito salnstlt peiin- ompundof ciaml 14 hr R,-i -QO-C.CZik 160. The compound of claim 159 wherein x is -H 151. The compound of ca im 60whch is' (S)3-6 fuooI 2-t-naa xzoL- yl 1-piperizinyl-2-mhyy-"meylbutcanae and its pharmaceutically acceptable acid -~addition salts. 159. The compound of claim 160 wherein Rj-aoic aCC-O) (C 1 -C 1 i )ayl.-3-4(rloo 1,2bnioao--l--piperidinyl]--etypropy estoet and its pharmaceutically acceptable i acid addition salts. 163. The compound of claim 160 which is 4-(4-(&fluoro-1,2-b--:nzisoxazo 2 -3-yi)-l- pipe rid i nvl-2-met hylbu ty I decanoate and its pharmaceutically acceptable acid addition saILs. 16-4. The compound of claim? 2wherein Y, is 165. The compound of claim 164 wherein R, and are h yd rogenr. U A S 166. Thecco-mpound of clairn165 wnfih is 9 [(6-4luoro-1,2-benZisothiazol-3-yl)-1- Ip iper-dLny~I;ethvljarniflC and its pharrmaceuticaib' acceptable acid addition salts. 167.: Th Ec o ripou ndc o f ca imn 16 5 v.hich u* o ruoro-1L2-benzisoxazol-3-y])-l- 16S. I ThLoaon r li 6 I~h 3 f'~-loo12-benzisoxazol-3-yl-1- PI pe ric inA'li -drFox',-1 -proox lam ine andJ- Ztharm:-Ziceuticilly acceptable acid '6VI The copon df C'm64;hrnR 3 irogen and, is -(C=O)py-ridyl. U& Tic .com dnVClai 6wihi L4( fquoro-1 ,cenzisoxazol-3-yI)- piperidiovlhhvl] .W and'its ,pharm1ceuticallh acceptable acid 171. o! e opudP-drt4~~ rein R: is hydrogen and Rois N (RNn IN 17?. The compound of Claim 171 which is N-[2-f4-(S-fluoro-1 H-indazol-3-yl)-1- piperazinvllethy-1l--3ptnYL-2-cuinoxalinamine a-01- is pna-rraceutically acceptable 290 a c d addition 173. The compound of Claim 164 wherein NR,,Rlg tur a piperidinyl ring. 174. The COopund of Claim 173 which is 1 2-bi ['4(6-flu~r-.bfZs~ZI yl)-I -pip ridinyl]ethan t and its phamaiceutiCal1y-<a~ccptable acid addition salts. 175. The compound of Claim 173 which is I 2-bis-[4,-(&4-luoro-1,2-benzisoxa zol-3- y1)-4pipeidiyV-2 hydroxYyiopaI e and i .ts pharmaceutically acceptable acid addition salts. 176. The compound of Caim_2 where Y, is (R 4 )q 0 177. Tecmpound of Claim 176' wich is 2-2(-6fur-,-bnio~zl3y)i piperidin yl Iethyl l-2-ph enyH 1,3-inda nd ione and its pha rmaceu tically acceptable acid Addition salts. 178 -[4-(6-Fluoro-1 ,2-ben zisoxazoi-,3 yl)-l -piperid inyl]-2-methylpropyl methyl carbarnate and its pharmaceutically acceptable acid addition-salts. 179. Ethyl 3-4(-loo12bniohao-'yl pprdnlpoint n t pharmaceutically acceptable acid addition salts. Ethyxl 3-[4-(6-fluoro-I H-indazol:3-yl)-1 -pip~razinylpropionate and its pharmnaceutically acceptable acid1 addition, salts. 181. (S)-6i-Fluoro-3-[ (-ptoypey--ehypoy)4pieii l12- benzisoxazole and its phariimaceuticallY acceptable acid addition sls 1S2, N 3 .EL~o-.pr-opyl)4C6Ruoro-12-benzi.5oxazol3' Dpiperidine and its pharrnaceiitically acceptable acid addition salts. :291 K- 183. *1 tluoro-1 ,2-benzisoxa zol-3-yl)- I -pipe rid iny I 1-2-pro pa none and its pharmaceutically acceptable acid addition salts, 184. 2-t4-(6-Fluoro-1,2-benzisoxazol-3-y0-] -piperid inyllace ton it rile and its pharmaceutically acceptable acid addition salts. :*185. 344-(6-Fluorro- 12-benzisoxa zo-3-y D-I -piperid inyllIprop ion it rile and its see. pharmaceutically acceptable acid addition salts. 186. 1 -Phenox yca rbonyl-3-(l -phe noxyca rbo nyl -4 -pipe rid inyl H-inda zolE! and its pharmaceutically acceptable acid addition salts.. 187. [4-(6-Fluoro-I H-i ndazol-3-yI)-1-pipera zinyilace ton i tri lea and -it pharmaceutically acceptable acid addition salts. 188. 1 -4-(3-Chloro pro poxy) -3-met hoxyphe nyl]-2-hyd ro~yet ha none. 189. 1-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yDi -pi perid inyllpropoxy]-3- meto, yphnyl-2- ydoxythaoneand its pharmaceutically acceptable acid addition salts. 190. An antipsychotic cormposition which comprises the compound of Claim 1 in an amount sufficient to produce an antipsychotic effect and a pharmaceutically acceptable carrier. 191. A method of treating psychoses which c prssadministering to a mammal a psychoses- trea ting amount of a compound of Claim 1. 192. An analgesic cam position which comprises a compound of Claim I in an amount sufficent to produce a pain.-relieving effect and a pharm-nceutically acceptable carrier. a *e* C a s e o* frf 193. A method of alleviating pain which comprises administering to a mammal a pain-relieving effective amount of the compound of Claim 1. 194. A depot pharmaceutical composition which comprises a pharmaceutically acceptable carrier and a therapeutically effective amount of the compound of claim I wherein the compound contains a hydroxy group, an amino group or a nitrogen at the 1-position of a indazole ring which has been acylated. 195. The depot pharmaceutical composition of claim Iq4 wherein the hydroxy group or amino group is acylated with an (C,-C,)alkanoyl group or an (C 4 -Cia)alkoxycarbonyl group. 196. The composition of claim iq t which contains a pharmaceutically acceptable oil. 197. The composition of claim l 0 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. 198. The composition of claim \qi which contains a pharmaceutically acceptable oil. 199. The composition of claim (L whereinithe 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. 200. A depot pharmaceutical composition-which comprises a pharmaceutically acceptable carrier and a therapeutically effective amount of the compound of claim 201. A depot pharmaceutical composition which comprises a pharmaceutically acceptable carrier and a therapeutically effective amount of the compound of claim 21. 202. A depot pharmaceutical composition which comprises a pharmaceutically *4 S* 4 S S. 54.. acceptable carrier and a therapeutically-effective amount of the compound of claim 29. 203. A depot pharmaceutical composition which comprises a pharmaceutically acceptable carrier and a therapeutically effective amount of the compound of claim 204. A depot pharmaceutical composition which comprises a pharmaceutically acceptable carrier and a therapeutically effective amount of the compound of claim 34. 205. A depot pharmaceutical composition which comprises a pharmaceutically acceptable carrier and a therapeutically effective amount of the compound of claim 49. 206. A depot pharmaceutical composition which comprises a pharmaceutically acceptable carrier and a therapeutically effective amount of the compound of claim 207. A depot pharmaceutical composition which comprises a pharmaceutically acceptable carrier and a therapeutically effective amount of the compound of claim 162. 208. A depot pharmaceutical composition which comprises a pharmaceutically acceptable carrier and a therapeutically effective amount of the compound of claim 163. 209. A method for providing a long acting antipsychotic effect which comprises injecting into a mammal an amount of the composition of claim 194 sufficient to produce a long acting antipsychotic effect. 210. A method for providing a long acting antipsychotic effect which comprises injecting into a mammal an amount of the composition of claim 195 sufficient to produce a long acting antipsychotic effect. 211. A method for providing a long acting antipsychotic effect which comprises injecting into a mammal an amount of the composition of claim 199 sufficient to produce a long acting antipsychotic effect. )ri2 A method for providing a long acting antipsychotic effiect which ccmI-rises iniecting irito a mammal an atir-umt of the composition of cULam 2' -it~ct produce a long acting antipsychotic effect ,Z 13. A method for providing a long actigantipsychotic effct which compni-ses injecting into a mammral an amunt of the composition of claim 201 sufELpnt to produce a long ac ing antipsychotic effect V+4. A method for providing a long acting antipsychotic effect which c~mpises injecting into a n-2narul an amount of the composition of claim 202 sufficient to produce a long acting antipsychotic effect. A method for providing a long acting antisychotic effect which com~rises injecting into a mammal ant amount of the composition of cim 2n03 sufcinto prdue. long acting antipsychotic effect. XA.A method for providing a long acting antipsychotic effect which comprises injecting into'a marninal an amount of the composition of claimn 204 sufficient to produce a long acting antipsychotic effect. a* 2I1-.~A method for providing a long acting antipsychotic effect which comprises injecting initoa mammal an amount of the Composition of claimn 206 sufficient to produce a long acting antipsychotic effect. A method for providing a long acting antipsychotic effect which comprises injecting into a mammnal an amount of the composition of claim 206 sufficient to produce a long acting antipsychotic effect .A.The pharmaceutically acceptable acid addition salts of N-(2-[4-(&-fluoro-l .2. benzsoxazol-3-ylH--piperdiyl ethyl lph ha lide. 22. The compound of claim 220 which is Nf2[-(-loo42bnzsxzl3y) I-piperidinyl Iethyl] ph Lhaliiid e hydrochloride. 2~.An antipsychotic composition which comprises5 the comnpound of Chlim 220 in an amount sufficient to produce an antipsychotic effect and a pbz- n'aceutically acceptable carrier. A methodi of treating psychoes which comprises administering to a manural a psychoses-treating amount of a cornpou-nd of Claim 220. ~.An antipsychotic composition which compri .ses the compound of Claim 221 in an amount sufficient to produce an anitipsychotic effect and a pharrnaceuticalfly acceptable carrer. Z2. A method of treating psychoses which comprises admixristering to a mamnmal a psychoses-treating amount of a compound of Clm 21 ZQ6. A method bf treating psychoses which comprises administecring to a "nirnmal a psychosis-Lreating amount of the compound of Claim 189. 2,2-r. An antipsychotic composition which comprises the compound of Cairn 189 in an amount sufficient to produce an antipsychotic effectand a pharmraceutica]ly acccetable carrier. DATED this 18th day of December 1998,. HOECH.ST MARION ROUSSEL, ICC.