AU2001238623B2 - Substituted piperazine compounds - Google Patents

Description

IP AUSTRALIA 004218081 RECEIVED 14 MAR 2003 TITLE: SUBSTITUTED PIPERAZINE COMPO CNANBERRA

FEP

BACKGROUND OF THE INVENTION This application claims priority to U.S. Patent Application Nos. 60/184182 filed on February 22, 2000, 60/184457, filed on February 22, 2000, 60/206396, filed on May 23, 2000, 60/184306 filed on February 22, 2000, and to U.S. Patent Application 60/209262 filed on June 5, 2000, the specification of which is incorporated herein by reference.

1. Field of the Invention The present invention is concerned with substituted piperazine compounds, therapeutic dosage forms including one or more of the compounds, and methods for treating diseases in mammals, and in particular, in a human in a therapy selected from the group including protecting skeletal muscles against damage resulting from trauma, protecting skeletal muscles subsequent to muscle or systemic diseases such as intermittent claudication, to treat shock conditions, to preserve donor tissue and organs used in transplants, and to treat cardiovascular diseases including atrial and ventricular arrhythmias, Prinzmetal's (variant) angina, stable angina, and exercise induced angina, congestive heart disease, and myocardial infarction.

2. Description of the Art U.S Patent No. 4,567,264, the specification of which is incorporated herein by reference, discloses a class of substituted piperazine compounds that includes a compound known as ranolazine, (2,6-dimethylphenyl)-4-[2-hydroxy-3- (2-methoxyphenoxy)propyl]-l-piperazineacetamide, and its pharmaceutically acceptable salts, and their use in the treatment of cardiovascular diseases, including arrhythmias, variant and exercise-induced angina, and myocardial infarction.

U.S. Patent No. 5,506,229, which is incorporated herein by reference, discloses the use of ranolazine and its pharmaceutically acceptable salts and esters for the treatment of tissues experiencing a physical or chemical insult, including cardioplegia, hypoxic or reperfusion injury to cardiac or skeletal muscle or brain tissue, and for use in transplants. In particular, ranolazine is particularly useful for treating arrhythmias, variant and exercise-induced angina, and myocardial infarction by partially inhibiting cardiac fatty acid oxidation. Conventional oral and parenteral ranolazine formulations are disclosed, including controlled release formulations. In particular, Example 7D of U.S. Patent No. 5,506,229 describes a controlled 004218081 release formulation in capsule form comprising microspheres of ranolazine and microcrystalline cellulose coated with release controlling polymers Despite the important discovery that ranolazine is a very useful cardiac therapeutic agent, there remains a need for compounds that are partial fatty acid oxidation inhibitors that have a half-life greater than ranolazine and that have activities as least similar to ranolazine.

SUMMARY OF THE INVENTION This invention includes novel substituted piperazine compounds that are partial fatty acid oxidation inhibitors with good therapeutic half-lives.

This invention also includes novel substituted piperazine compounds that can be administered to a mammal to protect skeletal muscles against damage resulting from trauma, to protecting skeletal muscles subsequent to muscle or systemic diseases such as intermittent claudication, to treat shock conditions, to preserve donor tissue and organs used in transplants, and to treat cardiovascular diseases including atrial and ventricular arrhythmias, Prinzmetal's (variant) angina, stable angina, and exercise induced angina, congestive heart disease, and myocardial infarction.

This invention includes a class of substituted piperazine compounds having the following formula:

R

R3R R,

R

10

R

11

NN

R6R 7

R

8 R1

OH

R

16

R

15

R

14 wherein X is selected from the group consisting of whrem and 0 wherein m I or 2 or 3;

M

004218081 RI, R 2 R3, R4 and Rs are each independently selected from the group consisting of hydrogen, halo,

NO

2 CF3, CN, OR23, SR2 3

N(R

23 S(0)R22, SO2R22,

SO

2 N(R23)2,

NR

2 3 CO2R22, NR23CON(R23)2, COR23,

CO

2 R23, CON(R23)2,

NR

23 SO2R2,

C

1 5 alkyl, Cz 2 alkenyl, C2-15 alkynyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl and aryl substituent are optionally substituted with 1 substituent selected from the group consisting of halo, NO2,

CF

3 CN, OR23, SR23, N(R23)2, S(0)R22, and SO2R22, wherein R2 and R3 may join together to form a fused ring system having from three to four carbon atoms, and wherein R4 and R5 may join together to form -CH=C H CH CH R6, R7 and Rg are each independently selected from the group consisting of hydrogen and CI-15 alkyl; R9, Rlo R R1, R R13, R14, Ri5 and RI6 are each independently selected from the group consisting of hydrogen, CO2R23, CON(R23)2, CL-4 alkyl, and aryl wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo,

CF

3 CN, OR23, N(R23)2, CO2R23, CON(R23)2 and aryl, wherein R9 and R1o may together form a carbonyl, or R 1 and R12 may together form a carbonyl, or R13 and R14 may together form a carbonyl, or Rs5 and R6 may together form a carbonyl wherein R1 and RI3 or R9 and Rls or R9 and Ru or R,1 and Ris or R, and RI3 may join together to form a bridging ring system having from 1 to 4 carbon atoms and wherein R9 and Rio or R,1 and RI2 or R13 and R14 or Ris and R 1 6 may join to form a bridging ring system having from 1 to 5 carbon atoms.

R22 is selected from the group consisting of C-15 alkyl, aryl, and heteroaryl, wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, alkyl, monoalkylamino, dialkylamino, alkyl amide, aryl amide, heteroaryl amide, CN, O-C1-6 alkyl, CF3, and heteroaryl; R23 is selected from the group consisting of H, C1-15 alkyl, aryl, and heteroaryl, wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, alkyl, monoalkylamino, dialkylamino, alkyl, CN, -O-CI- 6 alkyl, and

CF

3 and dR24 is selected from the group consisting of alkyl, cycloalkyl, and fused phenylcycloalkyl wherein the point of attachment is on the cycloalkyl wherein the alkyl, cycloalkyl, and fused phenylcycloalkyl are optionally substituted with from 1 to three substituents selected from the group consisting of halo, CF3, CN, OR 23 SR23, S(O)R22, SOR22,

SO

2 N(R23)2,

NR

23 CO2R22, C-2 alkyl, and aryl, wherein the optional aryl substituent is 004464932v13.

optionally substituted with from 1 to 3 substituents selected from the group consisting of halo, phenyl, CF 3 CN, OR 2 3 and C1- 6 alkyl, and R18 wherein R 1 7

R

18

RI

9

R

20 and R 2 1 are each independently selected from the group consisting of hydrogen, halo, NO 2

CF

3 CN, OR 23

SR

2 3

N(R

23 2

S(O)R

22 S0 2

R

22

SO

2

N(R

23 2

NR

2 3

CO

2

R

2 2

NR

23

CON(R

2 3 2

COR

23 C0 2

R

2 3

CON(R

23 2

NR

23 S0 2

R

22 C1-1 5 alkyl, C 2 1 alkenyl, C2- 15 alkynyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, NO 2

CF

3 CN, OR 2 3

SR

23

N(R

23 2 S(0)R 22 and S0 2

R

22 In another embodiment the invention provides a substituted piperazine compound having the following formula: wherein m 1 or 2 or 3; RI, R 2

R

3

R

4 and R 5 are each independently selected from the group consisting of hydrogenCi-0o alkyl;

R

6

R

7 and R 8 are each independently selected from the group consisting of hydrogen and Cl-lo alkyl; 004464932v13

R

9 Rio, R 11

RI

2

R

1 3

R

14

R

15 and RI 6 are each independently hydrogen;

R

1 7

R

18 RI9, R 20 and R 2 1 are each independently selected from the group consisting of hydrogen, halo, OR 23 C1 15 alkyl, or R 17 and R 18 or R 18 and RI9 or RI9 and R 20 or R 20 and

R

2 1 may combine to form a saturated ring including from 5 to 6 carbon atoms wherein from 0 to 2 carbon atoms may be substituted with an oxygen atom, or R 17 and R 1 8 may together form -CH=CH-CH=CH-; and

R

2 3 is selected from the group consisting of C1- 3 alkyl, alkyl-CN.

In a further embodiment the invention provides a substituted piperazine compound having the following formula:

R

R3 R R 1

R

1 0 lO R 9

R

12 RK N N O R24

R

7

R

8 OH

R

5

R

16

R

15

R

14 wherein m 1;

R

1

R

2

R

3

R

4 and R 5 are each independently selected from the group consisting of hydrogen and Ci-lo alkyl,;

R

6

R

7 and R 8 are each independently hydrogen;

R

9 Rio, R 11

RI

2 Ri 3

RI

4

R

15 and RI 6 are each independently selected from the group consisting of hydrogen and C 1 4 alkyl;

R

24 is selected from the group consisting of Ci-lo alkyl, cycloalkyl, and fused phenylcycloalkyl wherein the point of attachment is on the cycloalkyl, wherein the alkylis optionally substituted with from 1 to three substituents selected from the group consisting of halo, CF 3 CN, OR 20 ,and C1- 2 alkyl; and

R

20 is selected from the group consisting of Cl- 3 alkyl.

In yet another embodiment, this invention is a method for administering one or more composition of this invention to a mammal in a treatment selected from the group consisting of protecting skeletal muscles against damage resulting from trauma, protecting skeletal 004464932v13 muscles subsequent to muscle or systemic diseases such as intermittent claudication, to treat shock conditions, to preserve donor tissue and organs used in transplants, and to treat cardiovascular diseases including atrial and ventricular arrhythmias, Prinzmetal's (variant) angina, stable angina, and exercise induced angina, congestive heart disease, and myocardial infarction.

It will be understood that the term "comprises" or its grammatical variants as used in this specification and claims is equivalent to the term "includes" and is not to be taken as excluding the presence of other elements or features.

Reference to any prior art in the specification is not, and should not be taken as, an acknowledgment or any form of suggestion that this prior art forms part of the common general knowledge in Australia or any other country.

004218081 DETAILED DESCRIPTION OF THE INVENTION This invention includes a class of substituted piperazine compounds having the following formula:

R

R R 8 3

OH

R

16

R

15

R

14

I

wherein X is selected from the group consisting of: and

O

wherein m 1 or 2 or 3;

R

1 R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, halo, NO 2 CF3, CN, OR 23 SR23,

N(R

23 S()R22, SO2R22,

SO

2 N(R23)2, NR23CO2R22,

NR

23 CON(R23)2,

COR

23

CO

2

R

23 CON(R23)2,

NR

23 SO2R22, C-1s alkyl, C2-15 alkenyl, C2- 1 5 alkynyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl and aryl substituent are optionally substituted with 1 substituent selected from the group consisting of halo, NO 2 CF3, CN, OR 23 SR23, N(R23)2, S(O)R22, and SO2R22 wherein R2 and R3 may join together to form a fused ring system having from three to four carbon atoms, and wherein R4 and Rs may join together to form -CH=CH-CH=CH-; R6, R7 and Rs are each independently selected from the group consisting of hydrogen and Ci- 15 alkyl; Rio, R 11 R12, R 13 R14, R1i and Ri6 are each independently selected from the group consisting of hydrogen, CO2R23, CON(R23)2,

C

1 -4 alkyl, and aryl wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo,

CF

3 CN, OR23,

N(R

23

CO

2

R

23 CON(R23)2 and aryl, wherein

R

9 and Rio may together form a carbonyl, or R 1 1 and R12 may together form a carbonyl, or R13 and RI4 may together form a carbonyl, or Ris and R6 may together form a carbonyl wherein Ri and R13 or R9 and 004218081

R

15 or R 9 and Ri or Rn and Ri5 or R, and RI3 may join together to form a bridging ring system having from 1 to 4 carbon atoms and wherein R, and Rio or Rin and R12 or R 13 and R 14 or Ris and RI6 may join to form a bridging ring system having from 1 to 5 carbon atoms; R22 is selected from the group consisting of CI-15 alkyl, aryl, and heteroaryl, wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, alkyl, monoalkylamino, dialkylamino, alkyl amide, aryl amide, heteroaryl amide, CN, O-CI-6 alkyl, CF3, and heteroaryl; R23 is selected from the group consisting of H, CI-ts alkyl, aryl, and heteroaryl, wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, alkyl, monoalkylamino, dialkylamino, alkyl-CN, -0-C1-6 alkyl, and

CF

3 and

R

24 is selected from the group consisting of alkyl, cycloalkyl, and fused phenylcycloalkyl wherein the point of attachment is on the cycloalkyl, wherein the alkyl, cycloalkyl, and fused phenylcycloalkyl are optionally substituted with from 1 to three substituents selected from the group consisting of halo, CF3, CN, OR 23

SR

23 S(O)R22, SO2R22,

SO

2 N(R23)2, NR23CO2R22,

C

1 2 alkyl, and aryl, wherein the optional aryl substituent is optionally substituted with from 1 to 3 substituents selected from the group consisting of halo, phenyl,

CF

3 CN, OR 2 3 and C 1 6 alkyl, and wherein R17, Ri, R9, R20, and R2i are each independently selected from the group consisting of hydrogen, halo, NO 2 CF3, CN, OR23,

SR

23

N(R

23 S(O)R22, S2R 2 2, SO 2 N(R23)2,

NR

23 COR22, NR23CON(R23)2, COR23, CO2R23, CON(R23), NR23SO2R22,

C

15 alkyl, C2-15 alkenyl, C2- 1 5 alkynyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of i 004464932v13 halo, NO 2

CF

3 CN, OR 23

SR

23

N(R

23 2

S(O)R

22 and S0 2

R

22 This invention also includes a subset of the class of substituted piperazine compounds identified in Formula I above having the following Formula (IA): R!1RR8

R

3 R R9 R12 R17 RI R4

R

5 16 Ri5 R14 13 R21

IA

wherein m 1, 2; RI, R 2

R

3

R

4 and Rs are each independently selected from the group consisting of hydrogen, halo, CF 3

OR

22 and Ci- 4 alkyl and wherein R 22 is a Ci-3 alkyl;

R

6

R

7 and Rs each independently selected from the group consisting of hydrogen and Ci- 3 alkyl;

R

9 Rio, R 1

RI

2 Ri 3

R

1 4

R

1 5 and R 16 are each independently selected from the group consisting of hydrogen and C 1 4 alkyl, or R 9 and Rio may together form a carbonyl, or R 11 and

R

1 2 may together form a carbonyl, or R 13 and R 1 4 may together form a carbonyl, or R 15 and

R

1 6 may together form a carbonyl wherein Rn 1 and RI 3 or R 9 and R 1 5 or R 9 and Rn 1 or R 11 and Ri 5 or R 9 and R 13 may join together to form a bridging ring system wherein the two R groups together comprise of from 1 to 4 carbon atoms with the proviso that Rg, Rio, R 11

RI

2

R

13

R

14

R

15 and R 1 6 are not all simultaneously hydrogen wherein R 17

R

1 8

R

1 9

R

20 and R 21 are all hydrogen.

R

1 7

R

1 8

R

19

R

20 and R 21 are each independently selected from the group consisting of hydrogen, halo, CF 3 CN, OR 22

S(O)R

22 S0 2

R

22

SON(R

22 2

CON(R

22 2

C

1 -4 alkyl wherein

R

22 is C1- 3 alkyl, or R 1 7 and R 18 may together form -CH=CH-CH=CH-, or R 1 8 and R 1 9 may together form -OCH 2 0-.

In more preferred compounds of Formula IA, RI, R 2

R

3

R

4 and R 5 are each selected from the group consisting of hydrogen, halo, CF 3

OR

23 and C 1 4 alkyl where R 23 is a C 1 -3 alkyl; R 6 is selected from hydrogen and methyl; R 7 Rs, R 9 Rio, R 11

R

12

R

13

R

14

R

1 5 and

R

1 6 are each independently selected from hydrogen and methyl or R 9 and Rio may together form a carbonyl, or Ri 3 and R 1 4 may together form a carbonyl with the proviso that R 9 Rio,

R

1 1

R

12 Ri 3

R

14

R

1 5 and R 16 are not all simultaneously hydrogen; R 1 7

R

18

R

1 9

R

20 and R 2 1 are each independently selected from the group consisting of hydrogen, halo, CF 3

OR

23 and, 7 r 004464932v13

C

1 3 alkyl, or R 1 7 and R 1 8 may together form -CH=CH-CH=CH-, or R 18 and RI9 may together form In still more preferred compounds of Formula IA, RI, R 2

R

3

R

4

R

5

R

6

R

7 and R 8 are each independently selected from the group consisting of methyl and hydrogen; R 9 Rio, R 11

RI

2

R

13

R

14

R

15 and R 16 are each independently selected from hydrogen and methyl or R 9 and Rio may together form a carbonyl, or RI3 and RI 4 may together form a carbonyl with the proviso that R 9 Rio, R 11 Rl 2

R

13

R

14

R

15 and R 16 are not all simultaneously hydrogen; R 1 7

R

18 RI9, R 20 and R21 are each independently selected from the group consisting of hydrogen, halo, CF 3

OR

23 wherein R 23 is methyl, or R 17 and Ris may together form -CH=CH-CH=CH-, or Rig and R 19 may together form -OCH 2 0-.

In an even more preferred compound of Formula IA, Ri and R 5 are each methyl; R 2

R

3

R

4 R6, R 7

R

8 are each hydrogen; R 9 Rio, Ri 1 Rl 2

R

1 3

R

14

R

1 5 and R 16 are each independently selected from hydrogen and methyl or R 9 and Rio may together form a carbonyl, or Ri3 and RI 4 may together form a carbonyl with the proviso that R 9 Rio, RII, RI 2

R

1 3 RI4, R 1 5 and R 16 are not all simultaneously hydrogen; R 1 7

R

18

R

19

R

20 and R 21 are each independently selected from the group consisting of hydrogen, halo, methyl, OR 23 wherein R 23 is methyl, or R17 and R 18 may together form -CH=CH-CH=CH-, or RiS and RI9 may together form -OCH 2 0-.

In still more preferred compounds of Formula IA, R, and R 5 are each methyl; R 2

R

3

R

4

R

6

R

7

R

8 are each hydrogen; R 9 Rio are selected from hydrogen, methyl, or may together form a carbonyl; R 1 and R 1 2 are selected from hydrogen and methyl; RI 3 and RI 4 are selected from hydrogen and methyl or may together form a carbonyl; R 15 and R 16 are hydrogen with the proviso that R 9 Rio, R 11

RI

2

R

13

R

14

R

15 and RI 6 are not all simultaneously hydrogen;

R

1 7 is selected from the group consisting of hydrogen, chloro, fluoro or methoxy; R 1 8 and RI9 are each selected from the group consisting of hydrogen or methoxy, or R 1 i and R 1 9 may together form -OCH 2 or R 17 and R 18 may together form -CH=CH-CH=CH-, R20 is hydrogen; and R21 is selected from hydrogen or chloro.

Most preferably, the substituted piperazine compounds of Formula IA are selected from the group consisting of N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(2-methoxyphenoxy) propyl]-3-oxopiperazinyl} acetamide, N-(2,6-dimethylphenyl)-2- {4-[2-hydroxy-3-(2-methoxyacetamide, 2- {(5S,2R)-4-[2-hydroxy-3-(2-methoxy- -N-(2,6-dimethylphenyl)acetamide, 2- {2,5-diaza-5- [2-hydroxy-3-(2- 004218081 mehxpeoyprplb 6 -dimethyPheflY~actide, N-(2,6dimethylpheflW 2 t4[-yrx--2mthxpeoyPOYI3 oxopiperazil)l acetasnide, N-(2,6-dfimethY1PhenYlY 2 [2-hydroXY-3 mnethoxyphelOXY)PrOPYl 3 ,3 -dimethylpiPet82inYl} acetainide, 2-j{5 [R2S)-2-hYdrOXY- 3 methoxYphelOXY)PropyI](l S,4S)-2,5-diazabicYclo 2 2 l I]hept-2-yll ,6dimethylphenfl)acetride, N-(2,6-dimetlPbefl> 2 {4-[2-hy&0oXY 4 2 methoxypheflOXY)butYll piperazifll acetamide, N-(2,6-dflfethYIPhenYl) 2 {4-1I4-(4fluorophelOXY)-2h4doxybutYl] piperazil}acetamnide, {4-E4-(tert-bUtylPhenoxY- 2 hydroxybUtY1}PiPCIazinYI.N-( 2 ,6-dimethy1PheflYl) acetamide, N-(2,6-dimethY1PheflYl)- 2 {4- [2hdoy4(-hnlhnx~~tl piperazinyll acetamide, N-(2,6-dllfethY1PheflYl)- 2 {4- 2 -hydroxY-4-(4-nmethoxYPheno'xY)butYl]- piperazinyfllacetamide, 2- S-3 fluoropheflOXy)2hYdoxypropy1]-3methYlPiPerazinY} 2 9 6-dimfethY1PhenY)acetamnide, 2- 1(S--(S--2furpeoy--yrxpoyl3mtypprznl ,6dichioropheflyl) acetaniide, 2- (S--(S--2-loohnx)2-yrxpoy]3 methylpiperazilYl) -N-(4-sulfam0Y1PhenYl) acetainide, 2- S)-4-R(2S)-3 .{2-fluorOPhelOXY)- 2- (S4[2)3(-furpeoy--hdoYrpl -mtypprznl-N-incdan-S yiacetainide, 2- (S4[2)3-2furpenx)2hdoxpoy]3methylpiPerazil}-NnaphthylaCetamfide, 2- S)4 -(-loohnx)2hycroxypropy II -3 methylpiperazillN-(4-chdoronaPhthYl) acetanide, 2- (S--(S--2-loohnx)2 hydroxypropy]-3-methYPiPerazin~Yl} N-(2-pyrro1Y1PheflYl) acetamide, 2- S)-4-[(2S)-34 2 fluorophenOXY-2-hY&oxypropy1-3me±hy1PiPeraziyl} N-phenylaCetWTmide, 2- 3 2 -fluorophelOXY)2hYdoxyproPY1]-3methyPiPcrziy}-N-(2-chIorOPheflYl) acetamide, methylphelaCe1tnide, 2- (S--(S--2-loohnx)2-yrxpoy]3 methylpipetazifll -methY1Vifl)PhenYII acetarnide, 2- {(3S)-4-[(2SV-342fluorophenOXY)-2hYdroxyproPY1-3methyIPiperazinyl) N-(2-rmethylpheflYl) acetamnide, 2- S)-4-[(S--2-loohnoy--yroyrp -3 -methylpiperazilU N-I6-methY1- 2 (methylethy1)PhenYI] acetamide, 2- ((3S)4[2)3 -loohnoy--yrxpoyl3 methylpipetazilYl) -N-(3-rmetylthiophel acetamnide, 2- 2 -hydroxypropyI]-3-methY1PiPerazill acetamide, 2- 3

S)

4 2 S-324uorophnoxY)-2hY oxopI]3oPY]YlPieany)-[ (dimethylaiifo) phenyl] acetamide, 2- S)- 4 2 S)-3-(2fluoroPhenoxY>2hydoxyp1ropy]l 004218081 3 ~et 3 4iP3ZflU N(2,4dimeffioxYPhenYD) acetanaide, 2- S)-4-[(2SV 3 2 fluorohyleOX Y2hl xypropy ]3ethY 1Pipe iYl-N-(3 ,4 -dich1OrOPhef l aceta nide, 2chloropheflyl) acetanaide, 2- 3 2 -fluoropheflOXY)2h~XPO~ methylpiperaznYU N(-clr~hnl acetamide, 2-

S)-

4 -[(2S)-3-42-fhoroPhenoxY)- 2 hyrxpoyl--eh ~prznl-N-(3 ,5-dich1OrOPheflYl) acetamide, 2- 2 -fluorophefloxy)2-hYdrOXYPtOPYl]- 3 methylperaZifll (-nehxphn acetamide, methylpheflyl acetamide, 2-1(S--(S--2furpeoy--yrxpoyl3 methyh'iPetazin~Yl) -methylphe1Yl) acetainide, 2- (S--(S--2-loohnx)2 hydxoxyproPYfl3-methY1PiPerinyl N(4fluorOPhenYl) acetamide, 2- S)-4-[R2S)-3 fluorophelOXY)-2-hY&oxypropyl]- 3 methylpiPetazinYllNi can~en' acetamide, 2acetyipheflyl) acetarnide, 2- 3 S)-4[(2SY-32fluorOPhen-,oxy) 2 hydroy3)oPYll mnetbylpiPeraZinYl} -N-(2-methOXYPhenYl) acetainide, 2- 3 S)-4-[(2S-3-2fluoroPhenoxy)- 2 hydro~xyptpYlb 3 methylpiperazrnYU N[4(triflUOrOmnethY1)PhenYl) acetamide, 2- S)-4- S -2 f u r e O Y y r x O Y 1 3 m t y r z n l N -[4-ch1O rO 3 (trifluOrOmthY1)PhenYl] acetamide, 2-13)4[2)3(-lophexy2hdrYrOYI 3-methYlpipel1zinYI} ,54dmethOXYPhenYl) acetamide, 2- S)..4-t(2S)-34(2fluorophenOXY)-2-hY&OXYPrOPYI-3mcffiYlPiperaz y} -N-(4-nrrphOlifl4-YIPhenYI) i N acetamide, 2- 3 s)- 4 [(2s)3(2fluoroPhenoxY)- 2 YMJxpoyl--ntylieI (3f~oo-etoyhnl acetamide, 2- S)-4-R(2S)- 3 -(2-fluOrOPhefloxY)- 2 hydroxypropY1F-3-mnefiYPiPrni'nYll -N113,A,5-ttimethOXYPhenYl) acetamide, 2- S)-4- [(S)3(2fluorophefly-2hdOXYYphYox3mYPer yl] 3 metYP 3 dthxr hinyl) N acetarnide, 2- 2 -fluOrOPheflOxY)-2hYdOXWprPYl--thlieanl-N (4-ch1OrO-24flUOrOPhen~Yl) acetamide, and 2- 3 (2-fluoropheloxy)- 2 hydroxypropYI]-3-methY1PiPerazrnYl} 2 -(hydrOXYrnethY-6-methy1phenYlI acetamide.

004464932v13 This invention includes a subset of substituted piperazine compounds of formula I having the following formula IB: R R9 R10 R11R12 R17 R1 R3NN N R1 R6

R

7 Ra O H R4 R5 R16R 15

R

14 R13 R21 1B wherein m 1 or 2 or 3;

R

1

R

2

R

3

R

4 and R 5 are each independently selected from the group consisting of hydrogen, halo, NO 2 CF3, CN, OR 23

SR

23

N(R

23 2

S(O)R

22 S0 2

R

22

SO

2

N(R

23 2

NR

23 C0 2

R

22

NR

23

CON(R

23 2

COR

23 C0 2

R

2 3

CON(R

23 2

NR

23 S0 2

R

2 2 C1-1 5 alkyl, C 2 1 alkenyl, C2- 1 5 alkynyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl and aryl substituent are optionally substituted with 1 substituent selected from the group consisting of halo, NO 2

CF

3 CN, OR 2 3

SR

2 3

N(R

23 2

S(O)R

22 and S0 2

R

22

R

6

R

7 and R 8 are each independently selected from the group consisting of hydrogen and C 1 1 5 alkyl;

R

9 Rio, R 1 1

RI

2

RI

3

RI

4

R

1 5 and R 16 are each independently selected from the group consisting of hydrogen, C0 2

R

23

CON(R

23 2 C1-4 alkyl, and aryl wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, CF 3 CN, OR 23

N(R

23 2 C0 2

R

23

CON(R

23 2 and aryl, wherein R 9 and Rio may together form a carbonyl, or R 11 and R 1 2 may together form a carbonyl, or RI 3 and R 1 4 may together form a carbonyl, or R 15 and R 1 6 may together form a carbonyl wherein R 11 and R 13 or R 9 and

R

1 5 or R 9 and R 1 1 or R 11 and R 15 or R 9 and Ri3 may join together to form a bridging ring system wherein the two R groups together comprise of from 1 to 4 carbon atoms and wherein

R

9 and Rio or R 11 and R 12 or RI 3 and R 14 or R 1 5 and RI 6 may join to form a spiro ring system wherein the two R groups together comprise of from 1 to 5 carbon atoms;

R

17

R

1 8

R

1 9

R

20 and R 21 are each independently selected from the group consisting of hydrogen, halo, NO 2

CF

3 CN, OR 23

SR

23

N(R

2 3 2

S(O)R

22 S0 2

R

22

SO

2

N(R

23 2

NR

2 3 C0 2

R

2 2

NR

2 3

CON(R

2 3 2

COR

2 3 C0 2

R

2 3

CON(R

2 3 2

NR

2 3 S0 2

R

2 2 C1- 15 alkyl, C2- 1 004464932v13 alkenyl, C2-1 5 alkynyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, NO 2

CF

3 CN, OR 23

SR

23

N(R

2 3 2

S(O)R

22 and S0 2

R

22 or wherein R 17 and R 18 may join together may join together to form -CH=CH-CH=CH- or wherein R 17 and R 18 or R 18 and

R

1 9 or R 1 9 and R 2 0 or R 20 and R 21 may combine to form a saturated ring including from 3 to 6 carbon atoms wherein from 0 to 2 carbon atoms may be substituted with an oxygen atom and wherein the ring may be optionally substituted with from 1 to 3 substituents selected from the group consisting of hydrogen, halo, N02, CF 3 CN, OR 23

SR

23

N(R

23 2

S(O)R

2 2 S0 2

R

2 2

SO

2

N(R

2 3 2

NR

23 C0 2

R

22

NR

23

CON(R

23 2

COR

2 3 C0 2

R

23

CON(R

2 3 2

NR

23

SO

2

R

23 C1- 1 alkyl, C 2 -1 5 alkenyl, C2- 1 5 alkynyl, heterocyclyl, aryl, or heteroaryl, wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, N02, CF 3 CN, OR 23

SR

23

N(R

23 2

S(O)R

22 or S0 2

R

22

R

22 is selected from the group consisting of Ci- 15 alkyl, aryl, or heteroaryl, wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, alkyl, monoalkylamino, dialkylamino, alkyl amide, aryl amide, heteroaryl amide, CN, O-C 1 -6 alkyl, CF 3 and heteroaryl; and

R

23 is selected from the group consisting of H, Ci- 1 5 alkyl, aryl, or heteroaryl, wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, alkyl, mono- or dialkylamino, alkyl-CN, -O-C 1 6 alkyl, or CF 3 In preferred compositions of this invention, m 1 or 2 or 3; RI, R 2

R

3 R4 and R 5 are each independently selected from the group consisting of hydrogen, halo, CF 3

OR

22 and CI-4 alkyl; R 6

R

7 and R 8 each independently selected from the group consisting of hydrogen and

C

1 -3 alkyl; R 9 Rio, R 11

RI

2 Ri 3

R

14

R

15 and RI 6 are each independently selected from the group consisting of hydrogen and C-4 alkyl, or R 9 and Rio may together form a carbonyl, or

R

1 1 and R 12 may together form a carbonyl, or Ri 3 and R 1 4 may together form a carbonyl, or

R

15 and R 16 may together form a carbonyl, or wherein R 11 and Ri 3 or R 9 and R 15 or R 9 and R 1 1 or R 1 1 and R 1 5 or R 9 and Ri 3 may join together to form a ring including from 1 to 4 carbon atoms wherein R 9 Rio, RI 1

RI

2

RI

3

R

14

R

1 5 and R 1 6 are not all hydrogen; and R 17

R

1 8

RI

9

R

2 o and R 21 are each independently selected from the group consisting of hydrogen, halo, CF 3 CN, OR 23

S(O)R

23 S0 2

R

23

SON(R

23 2

CON(R

23 2 C1-4 alkyl or R 1 7 and R 1 8 may together form -CH=CH-CH=CH-, and phenyl.

In other preferred compounds, RI, R 2

R

3

R

4 and R 5 are each independently selected from the group consisting of hydrogen, halo, CF 3

OR

23 and C 1 2 alkyl wherein R 23 is a C 1 -3 004464932v13 alkyl; R 6

R

7 and Rs are each independently selected from the group consisting of hydrogen and methyl; R 9 Rio, R 11

R

12

R

13

R

14

R

1 5 and R 16 are each independently selected from the group consisting of hydrogen and C 1 2 alkyl, or R 9 and Rio may together form a carbonyl, or Ri 5 and R 16 may together form a carbonyl with the proviso that R 9 Rio, R 11

RI

2 Ri 3

R

1 4

R

1 and RI 6 are not all simultaneously hydrogen and wherein R 1 1 and RI3 or R 9 and Ri 5 or R 9 and

R

1 1 or R 1 and Ri 5 or R 9 and R 1 3 may join to form a ring including from 1 to 4 carbon atoms and R 1 7

R

18 RI9, R 20 and R 21 are each independently selected from the group consisting of hydrogen, halo, CF 3 CN, OR 23 and C 1 -4 alkyl and wherein R 17 and Ri 8 may together form a substituent selected from the group consisting of-CH=CH-CH=CH- and phenyl.

In still other preferred compounds, m 1 or 2; R 1

R

2

R

3

R

4 and R 5 are each independently selected from the group consisting of hydrogen, halo, CF 3

OR

23 and CI-4 alkyl where R 23 is a C1- 3 alkyl; R 6

R

7 Rs, R 9 RIO, R 1 1

R

12

RI

3

R

14

R

1 5 and RI 6 are each independently selected from hydrogen and methyl; R 17

R

18 RI9, R 20 and R 2 1 are each independently selected from the group consisting of hydrogen, halo, CF 3

OR

22 C1- 3 alkyl where R 22 is methyl, or R 17 and R 18 may together form -CH=CH-CH=CH-, or R 1 8 and R 19 may together form -OCH 2 0-.

In more preferred compounds, m 1 or 2; Ri, R 2

R

3

R

4

R

5

R

6

R

7 and R 8 are each independently selected from methyl and hydrogen; R9, Rio, R 1 1

R

12 R13, R 14 R15 and R16 are each hydrogen; and R17, R 18

R

1 9

R

20 and R 2 1 are each independently selected from the group consisting of hydrogen, halo, CF 3 and OR 23 wherein R23 is methyl, or R17 and Ris may together form -CH=CH-CH=CH-, or R 1 8 and RI9 may together form In yet other preferred compounds, m 1 or 2; R 1 and R5 are methyl; R 2

R

3

R

4

R

6 R7, Rs,R 9 Rio, R 11

RI

2

R

13

R

14 R5 and R 16 are hydrogen; R17, R 18

R

1 9

R

20 and R 21 are each independently selected from the group consisting of hydrogen, halo, and OR23 wherein R 2 3 is methyl, or R 1 7 and Rig may together form -CH=CH-CH=CH-, or R 1 8 and RI9 may together form -OCH 2 0-.

In still other preferred compounds, Ri and R 5 are methyl; R 2

R

3 R4, R6, R 7 Rs,R 9 RIO, R 11 RI2, RI 3

R

1 4

R

1 5 and RI 6 are hydrogen; R 17 is selected from the group consisting of hydrogen, chloro, fluoro and methoxy; R 18 is selected from hydrogen and methoxy; Ri 9 is selected from hydrogen and methoxy; R 20 is hydrogen; R21 is selected from hydrogen and chloro, or R17 and R 18 may together form -CH=CH-CH=CH-, or R 1 8 and Ri9 may together form -OCH 2 0-.

004464932013 Most preferably, the substituted piperazine compounds of this invention are selected from N-(2,6-dimethylphenyl)-2-[4-(2-hydroxy-4-phenylbutyl)piperazinyl] acetamnide; N-(2,6dimethylphenyl)-2- {4-[2-hydroxy-3-(2-methoxyphenyl)propyl]piperazinyl} acetamide; 2-[4- (3-(2H-benzo[d] 1 ,3-dioxolen-5-yl)-2-hydroxypropyl)piperazinyl] dimethylphenyl)acetamide; N-(2,6-dimethylphenyl)-2- {4-[2-hydroxy-3-(4methoxyphenyl)propyl]piperazinyl} acetamide; N-(2,6-dimethylphenyl)-2- {4-[2-hydroxy-3phenylpropyl]piperazinyl} acetamide, N-(2,6-dimethylphenyl)-2- {4-[4-(4-methoxyphenyl)-2hydroxybutyl]piperazinyl} acetamide, 2- {4-[4-(2,6-difluorophenyl)-2hydroxybutyl]piperazinyl} -N-(2,6-dimethylphenyl)acetamide, N-(2,6-dimethylphenyl)-2- {4- [4-(2-chlorophenyl)-2-hydroxybutyl]piperazinyl} acetamnide, {4-[4-(tert-butyl)phenyl] -2hydroxybutyl} piperazinyl)-N-(2,6-dimethylphenyl)acetamide, N-(2,6-dimethylphenyl)-2- {4- [4-(2-fluorophenyl)-2-hydroxybutyl]piperazinyl} acetamide, N-(2,6-dimethylphenyl)-2-(4- {2hydroxy-4-[4-(trifluoromethyl)phenyl]butyl} piperazinyl)acetamide, 2-[4-(3-(2H-benzo[d] 1,3dioxolen-5-yl)-2-hydroxypropyl)piperazinyl]-N-(2,6-dimethylphenyl)-2-methylpropanamide, N-(2,6-dimethylphenyl)-2-[4-(2-hydroxy-3-phenylpropyl)piperazinyl]-2-methylpropanamide, N-(2,6-dimethylphenyl)-2- {4-[2-hydroxy-3-(3,4,5-trimethoxyphenyl)propyl]piperazinyl} -2methyipropanamide, N-(2,6-dimethylphenyl)-2-[4-(2-hydroxy-5-phenylpentyl)piperazinyl] acetamide, N-(2,6dimethylphenyl)-2- -(2-fluorophenyl)- 2-hydroxy-pentyl]piperazinyl} acetamide, and N- (2,6-dimethylphenyl)-2- {4-[5-(2-chlorophenyl)- 2-hydroxy-pentyl]piperazinyl} acetamide.

This invention further includes a subset of compounds of Formula I above having the following Formula IC:

R

0 R 10 R12 NN N2

IR

7

R

8 R3 OH

R

16

R

15

R

14

IC

wherein m 1, 2, or 3; 004464932v13

R

1

R

2

R

3

R

4 and R 5 are each independently selected from the group consisting of hydrogen, halo, NO 2

CF

3 CN, OR 20

SR

20

N(R

20 2

S(O)R

22

SO

2

R

2 2

SO

2

N(R

20 2

NR

20 C0 2

R

22 NR20CON(R 20 2

COR

20 C0 2

R

20

CON(R

20 2

NR

20 S0 2

R

22 C1- 15 alkyl, C2- 1 alkenyl, C2- 15 alkynyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl and aryl substituent are optionally substituted with 1 substituent selected from the group consisting of halo, NO 2

CF

3 CN, OR 20

SR

2 0, N(R20) 2

S(O)R

22 and S0 2

R

22

R

6

R

7 and R 8 are each independently selected from the group consisting of hydrogen and C 1 -3 alkyl;

R

9 Rio, R 11

R

12

R

13

RI

4

R

1 5 and R 1 6 are each independently selected from the group consisting of hydrogen, C0 2

R

20

CON(R

20 2

C

1 -4 alkyl, and aryl wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, CF 3 CN, OR 20

N(R

20 2 C0 2

R

20 CON(R20) 2 or aryl, wherein R 9 and Rio may together form a carbonyl, or R 1 1 and R 12 may together form a carbonyl, or RI 3 and R 1 4 may together form a carbonyl, or R 15 and R 16 may together form a carbonyl with the proviso that RI and

R

1 3 or R 9 and R 15 or R 9 and R 11 or R 11 and Ri 5 or R 9 and Ri 3 may join together to form a ring including from 1 to 3 carbon atoms;

R

24 is selected from the group consisting of alkyl, cycloalkyl, and fused phenylcycloalkyl wherein the point of attachment is on the cycloalkyl wherein the alkyl, cycloalkyl, and fused phenylcycloalkyl are optionally substituted with from 1 to three substituents selected from the group consisting of halo, CF 3 CN, OR2o, SR 20

S(O)R

22

SO

2

R

22

SO

2

N(R

20 2

NR

20 C0 2

R

22 Ci- 2 alkyl, and aryl wherein the optional aryl substituent is optionally substituted with from 1 to 3 substituents selected from the group consisting of halo, phenyl, CF 3 CN, OR 2 0 and C1- 6 alkyl;

R

20 is selected from the group consisting of H, C1- 15 alkyl, aryl, and heteroaryl, wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, alkyl, mono- or dialkylamino, alkyl-CN, -O-C 16 alkyl, and CF 3 and

R

22 is selected from the group consisting of Cl- 1 5 alkyl, aryl, and heteroaryl, wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, alkyl, monoalkylamino, dialkylamino, alkyl amide, aryl amide, heteroaryl amide, CN, O-C 1 -6 alkyl, CF 3 and heteroaryl.

In Formula IC, it is preferred that m 1 or 2 and most preferred when m 1.

In preferred compositions of Formula IC, R 1

R

2

R

3

R

4 and R 5 are each independently selected from the group consisting of hydrogen, halo, CF 3

OR

2 2 and C 1 -4 alkyl and wherein 004464932v13

R

22 is C1-3 alkyl. In other preferred compositions, R 1

R

2

R

3

R

4 and R 5 are each independently selected from the group consisting of hydrogen, CF 3

OR

20 and Ci-2 alkyl.

More preferably RI, R 2

R

3

R

4 and R 5 are each independently selected from the group consisting of hydrogen, and methyl with R 2

R

3 and R 4 as hydrogen and Ri and R 5 as methyl being preferred.

In other preferred compositions of Formula IC, R 6

R

7 and R 8 each independently selected from the group consisting of hydrogen and Ci- 3 alkyl with hydrogen or methyl being preferred and hydrogen being most preferred.

In yet other preferred compositions of Formula IC, R 9 Rio, R 1 1 RI2, RI 3

R

14

R

1 5 and

RI

6 are each independently selected from the group consisting of hydrogen, CON(R20) 2 CI-4 alkyl, and aryl wherein the alkyl and aryl substituents are each optionally substituted with 1 substituent selected from the group consisting of halo, CF 3

OR

20

N(R

20 2

CON(R

20 2 and aryl wherein R 9 and Rio may together form a carbonyl, or R 11 and R 12 may together form a carbonyl, or R 13 and R 1 4 may together form a carbonyl, or R 15 and R 1 6 may together form a carbonyl with the proviso that Rn 1 and Ri3 or R 9 and R 15 or R 9 and R 1 1 or R 1 1 and R 15 or R 9 and RI 3 may join together to form a ring having from 1 to 3 carbon atoms. In alternative preferred compositions, R 9 Rio, R 11

R

12

RI

3

R

1 4

R

1 5 and R 16 are each independently selected from the group consisting of hydrogen and Ci-4 alkyl, or R 9 and Rio together form a carbonyl, or R 11 and R 12 together form a carbonyl, or RI 3 and R 1 4 together form a carbonyl, or

R

15 and RI 6 together form a carbonyl. In another embodiment, R 9 Rio, Ri 1

RI

2

R

13

R

14

R

1 and RI6 are each independently selected from the group consisting of hydrogen, and Ci- 2 alkyl, wherein the alkyl substituent is optionally substituted with 1 substituent selected from the group consisting of N(R 20 2 and aryl or wherein R 9 and Rio may together form a carbonyl.

More preferably, R 9 Rio, R 11

RI

2

R

13

R

14

R

1 5 and R 1 6 are each independently selected from the group consisting of hydrogen and CI- 2 alkyl, or wherein R 9 and Rio may together form a carbonyl. In another embodiment, R 1 1 and R 15 are each selected from the group consisting of hydrogen or methyl, R 9 Rio, R 1 2 Ri 3

R

14 and R 16 are each hydrogen and R 9 and Rio may together form a carbonyl, or, R 9 Rio, R 1 1

R

1 2

R

13

R

14

R

1 5 and RI 6 may each be hydrogen.

In compounds of Formula IC, R 24 may be selected from the group consisting of alkyl, cycloalkyl, and fused phenylcycloalkyl wherein the point of attachment is on the cycloalkyl wherein the alkyl, cycloalkyl, and fused phenylcycloalkyl are optionally substituted with from 1 to three substituents selected from the group consisting of halo, CF 3 CN, OR 2 0

SR

20

S(O)R

22

SO

2

R

22

SO

2

N(R

20 2

NR

20 C0 2

R

22 C1- 2 alkyl, and aryl wherein the optional aryl 004464932v13 substituent is optionally substituted with from 1 to 3 substituents selected from the group consisting of halo, phenyl, CF 3 CN, OR 20 and C 1 6 alkyl. In certain preferred compounds of Formula IC, R 24 is selected from the group consisting of alkyl cycloalkyl, and fused phenylcycloalkyl wherein the point of attachment is on the cycloalkyl wherein the alkyl, cycloalkyl, and fused phenylcycloalkyl are optionally substituted with from 1 to two substituents selected from the group consisting of halo, CF 3 CN, OR 20

SR

20

S(O)R

22 S0 2

R

22 C1- 2 alkyl, and aryl wherein the optional aryl substituent is optionally substituted with from 1 to 3 substituents selected from the group consisting of halo, phenyl, CF 3 CN, OR 20 and C 1 -6 alkyl. In other preferred compounds of Formula IC, R 24 is selected from the group consisting of alkyl, cycloalkyl, and fused phenylcycloalkyl wherein the point of attachment is on the cycloalkyl wherein the alkyl, cycloalkyl, and fused phenylcycloalkyl are optionally substituted with from 1 to two substituents selected from the group consisting of halo, CF 3

OR

20 and aryl wherein the optional aryl substituent is optionally substituted with from 1 to 3 substituents selected from the group consisting of halo, phenyl, CF 3 CN, OR 2 0 and C1- 6 alkyl.

In still other preferred compounds of Formula IC, R 24 is selected from the group consisting of alkyl having from 1 to 6 carbon atoms, cycloalkyl having from 4 to 6 carbon atoms, fused phenylcycloalkylwith a phenyl that is optionally substituted with from 1 to 2 substituents selected from the group consisting of halo, CF 3 OH, methyl, and aryl, and aryl that is optionally substituted with from 1 to 2 substituents selected from the group consisting of halo,

CF

3 OH, C 1 2 alkyl, and aryl. In still other preferred compounds of Formula IC, R 24 is alkyl having from 1 to 6 carbon atoms and cycloalkyl or R 24 is a fused phenylcycloalkyl that is optionally substituted with from 1 to 2 substituents selected from the group consisting of halo, CF3, OR 20 C1- 2 alkyl, and aryl or R 24 is phenylmethyl that is optionally substituted with from 1 to 2 substituents selected from the group consisting of halo, CF 3

OR

2 0 C1-4 alkyl, and aryl.

In the compounds of Formula IC, R 20 is selected from the group consisting of H, Ci-3 alkyl, or aryl, wherein the alkyl and aryl substituents are optionally substituted with 1 substituent individually selected from the group consisting of halo, -OMe, and CF 3 More preferably, R 20 is selected from the group consisting of H or C 1 -3 alkyl and most preferably,

R

20 is methyl or H.

Most preferably, the substituted piperazine compounds of Formula IC are selected from the group consisting of 2-({2-[4-(3-isopropoxy-2-hydroxypropyl)piperazinyl]- 004218081 dimnethylpheflyl)acetrnde; N-(2 6 -dimnethy1phefylY-2442-hYdroxY-3indan- 2 yloxypropyl)piperninylacetmide; N-(2,6-dimfethYlPhenYlY- 2 {4-[2-hydrOXY-3- (phenylrnethOXY)PrOPYpiPe1rainYlI acetamide, 4 -(tert-bUtYl)PhenYllmethoxY} -2hydroxypropyl)PiPerazinyl-N-(2,6-dimefiYlPhenYI)aemie N-(2,6-dimethYlPhenYlV 2 4 3 2 -fluoropheflYl)ethoxY2hYoxypropyl}PPeaiYi)aemi f 3-11(2,4difluorophenYl)methOxY-2hdrox~roPYl} pipe nYl)N-26dmtlheYacari

N-

2 ,6-dimethYlPhenY1-24442-hYd0xy- 3 ff4- (trfiuoromethYl)PhenYtmethoxY}ProPY)PiPrzinYIctaie N-(2,6-dimnethYlPhenYD'- 2 2 -hydroxy-3-[(2-methoxYPhenY)methoxy]ProPY}lPperznlaeaie dimethoxyphefYl)methoxY-2hydroxropyl}PiPaiYl)N-26dmtypeyaeari N-(2,6-dimethYlPhenY1- 2 4 {2-hydTOXY-3[4- dN(+-iehlpey)2(-3[4 methoxyphenYl)methoxYProPylpiPerazinYl)acetm26dmehhhnlr 2 3[4 fluoropheflYl)methoxY-2-hyYroIrPY1}ppeinYl)aem N-(2,6-dimnethylPhenYD)- 2 2 -hydroxy-3-[R4-methylPhenY1)methoxY]ProPYl} piperaznyI)acetamide N-(2,6dimethylphenyl)- 2 4( 4 2 -hydroxy-3-[R4-PhenylPhenYl)methoxy]ProPYl) piperaziny)acetamfide' N-(2,6-dimethYlPhenYl)> 2 t3-(4-buty~pheny1)MfethoXY]- 2 -x3-2 hydroxypropyll piperazinyl)acetflmide, N-(2,6-dimethYlPhel- 2 {4-[2-hydOX-{2 naphthyhflethoxy)ProPYlPiPeainYl} acetamnide, N-(2,6-dimnethYlPhenYl)> 2 (cyclohexylmethOXY)2-hYdroxYProPYl)PiPerazinYl}acetamide, and N-(2,6-dimethYlPheflYlY>2 {3 4 -fluorophenYl)methoxYF-2hYdoxypYopyl}-3 3 -dimethylpiPeraziY)a-eta1ade- The following definitions apply to terms as used herein.

"Halo" or "Halogen" alone or in combination means all halogens, that is, chioro (Cl), fluoro bromo iodo (1.

-Hydroxyl" refers to the group -OH.

"Thiol" or "mercapto" refers to the group

-SN.

"Alkyl"' alone or in combination means an alicane-denved radical containing from I to 20, preferably 1 to 15, carbon atoms (unless specifically d efined). it is a straight chain alkyl, branched alkyl or cycloalkyl. Preferably, straight or branched alkyl groups containing from 1 -15, more preferably I to 8, even more preferably 1-6, yet more preferably 1-4 and most 3Q preferably 1-2, carbon atoms, such as methyl, ethyl, prop)'l, isopropyl, butyl, t-butyl and the like. The term "lower alkyl" is used herein to describe the straight chain alkyl group s described immediately above. Preferably, cycloalkyl groups are monocyclic, bicyclic or tricyclic ring systems of 3-8, more preferably 3-6, ring members per ring, such as cyclopropyl, 004218081 cyclobutyl, cyclopentyl, cyclohexyl, adamantyl and the like. Alkyl also includes a straight chain or branched alkyl group that contains or is interrupted by a cycloalkyl portion. The straight chain or branched alkyl group is attached at any available point to produce a stable compound. Examples of this include, but are not limited to, 4-(isopropyl)-cyclohexylethyl or 2-methyl-cyclopropylpentyl. A substituted alkyl is a straight chain alkyl, branched alkyl, or cycloalkyl group defined previously, independently substituted with 1 to 3 groups or substituents of halo, hydroxy, alkoxy, alkylthio, alkylsulfmyl, alkylsulfonyl, acyloxy, aryloxy, heteroaryloxy, amino optionally mono- or di-substituted with alkyl, aryl or heteroaryl groups, amidino, urea optionally substituted with alkyl, aryl, heteroaryl or heterocyclyl groups, aminosulfonyl optionally N-mono- or N,N-di-substituted with alkyl, aryl or heteroaryl groups, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, or the like.

"Alkenyl" alone or in combination means a straight, branched, or cyclic hydrocarbon containing 2-20, preferably 2-17, more preferably 2-10, even more preferably 2-8, most preferably 2 to 4 carbon atoms with at least one, preferably 1-3, more preferably 1-2, and most preferably one, carbon to carbon double bond. In the case of a cycloalkyl group, conjugation of more than one carbon to carbon double bond is not such as to confer aromaticity to the ring.

Carbon to carbon double bonds may be either contained within a cycloalkyl portion, with the exception of cyclopropyl, or within a straight chain or branched portion. Examples of alkenyl groups include ethenyl, propenyl, isopropenyl, butenyl, cyclohexenyl, cyclohexenylalkyl and the like. A substituted alkenyl is the straight chain alkenyl, branched alkenyl or cycloalkenyl group defined previously, independently substituted with 1 to 3 groups or substituents of halo, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, acyloxy, aryloxy, heteroaryloxy, amino optionally mono- or di-substituted with alkyl, aryl or heteroaryl groups, amidino, urea optionally substituted with alkyl, aryl, heteroaryl or heterocyclyl groups, aminosulfonyl optionally N-mono- or N,N-di-substituted with alkyl, aryl or heteroaryl groups, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, carboxy, alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, or the like attached at any available point to produce a stable compound.

"Alkynyl" alone or in combination means a straight or branched hydrocarbon containing 2-20, preferably 2-17, more preferably 2-10, even more preferably 2-8, most preferably 2-4, carbon atoms containing at least one, preferably one, carbon to carbon triple 19 004218081 bond. Examples of alkynyl groups include ethynyl, propynyl, butynyl and the like.

A

substituted alkynyl refers to the straight chain alkynyl or branched alkynyl defined previously, independently substituted with 1 to 3 groups or substituents of halo, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, acyloxy, aryloxy, heteroaryloxy, amino optionally mono- or di-substituted with alkyl, aryl or heteroaryl groups, amidino, urea optionally substituted with alkyl, aryl, heteroaryl or heterocyclyl groups, aminosulfonyl optionally

N-

mono- or N,N-di-substituted with alkyl, aryl or heteroaryl groups, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, or the like attached at any available point to produce a stable compound.

"Alkyl alkenyl" refers to a group -R-CR CR"' where R is lower alkyl, or substituted lower alkyl, may independently be hydrogen, halogen, lower alkyl, substituted lower alkyl, acyl, aryl, substituted aryl, hetaryl, or substituted hetaryl as defined below.

"Alkyl alkynyl" refers to a groups -RC-CR' where R is lower alkyl or substituted lower alkyl, R' is hydrogen, lower alkyl, substituted lower alkyl, acyl, aryl, substituted aryl, hetaryl, or substituted hetaryl as defined below.

"Alkoxy" denotes the group -OR, where R is lower alkyl, substituted lower alkyl, acyl, aryl, substituted aryl, aralkyl, substituted aralkyl, heteroalkyl, heteroarylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, or substituted cycloheteroalkyl as defined.

"Alkylthio" denotes the group -SR, where R is lower alkyl, substituted lower alkyl, aryl, substituted aryl, aralkyl or substituted aralkyl as defined herein.

"Acyl" denotes groups where R is hydrogen, lower alkyl substituted lower alkyl, aryl, substituted aryl and the like as defined herein.

"Aryloxy" denotes groups -OAr, where Ar is an aryl, substituted aryl, heteroaryl, or substituted heteroaryl group as defined herein.

"Amino" denotes the group NRR', where R and R' may independently by hydrogen, lower alkyl, substituted lower alkyl, aryl, substituted aryl, hetaryl, or substituted hetaryl as defined herein or acyl.

"Amido" denotes the group -C(O)NRR', where R and R' may independently by hydrogen, lower alkyl, substituted lower alkyl, aryl, substituted aryl, hetaryl, substituted hetaryl as defined herein.

"Carboxyl" denotes the group -C(O)OR, where R is hydrogen, lower alkyl, substituted 004218081 lower alkyl, aryl, substituted aryl, hetaryl, and substituted hetaryl as defined herein.

"Aryl" alone or in combination means phenyl or naphthyl optionally carbocyclic fused with a cycloalkyl of preferably 5-7, more preferably 5-6, ring members and/or optionally substituted with 1 to 3 groups or substituents of halo, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, acyloxy, aryloxy, heteroaryloxy, amino optionally mono- or di-substituted with alkyl, aryl or heteroaryl groups, amidino, urea optionally substituted with alkyl, aryl, heteroaryl or heterocyclyl groups, aminosulfonyl optionally N-mono- or N,N-di-substituted with alkyl, aryl or heteroaryl groups, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, or the like.

"Substituted aryl" refers to aryl optionally substituted with one or more functional groups, halogen, lower alkyl, lower alkoxy, alkylthio, acetylene, amino, amido, carboxyl, hydroxyl, aryl, aryloxy, heterocycle, hetaryl, substituted hetaryl, nitro, cyano, thiol, sulfamido and the like.

"Heterocycle" refers to a saturated, unsaturated, or aromatic carbocyclic group having a single ring morpholino, pyridyl or furyl) or multiple condensed rings naphthpyridyl, quinoxalyl, quinolinyl, indolizinyl or benzothienyl) and having at least one hetero atom, such as N, O or S, within the ring, which can optionally be unsubstituted or substituted with, halogen, lower alkyl, lower alkoxy, alkylthio, acetylene, amino, amido, carboxyl, hydroxyl, aryl, aryloxy, heterocycle, hetaryl, substituted hetaryl, nitro, cyano, thiol, sulfamido and the like.

"Heteroaryl" alone or in combination means a monocyclic aromatic ring structure containing 5 or 6 ring atoms, or a bicyclic aromatic group having 8 to 10 atoms, containing one or more, preferably 1-4, more preferably 1-3, even more preferably 1-2, heteroatoms independently selected from the group O, S, and N, and optionally substituted with 1 to 3 groups or substituents of halo, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, acyloxy, aryloxy, heteroaryloxy, amino optionally mono- or di-substituted with alkyl, aryl or heteroaryl groups, amidino, urea optionally substituted with alkyl, aryl, heteroaryl or heterocyclyl groups, aminosulfonyl optionally N-mono- or N,N-di-substituted with alkyl, aryl or heteroaryl groups, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, or the like. Heteroaryl is also intended to include oxidized S or N, such as sulfinyl, sulfonyl and N-oxide of a tertiary ring nitrogen. A carbon or nitrogen atom is the point of attachment of the heteroaryl ring 004218081 structure such that a stable aromatic ring is retained. Examples of heteroaryl groups are pyridinyl, pyridazinyl, pyrazinyl, quinazolinyl, purinyl, quinolinyl, isoquinolinyl, pyrimidinyl, pyrrolyl, oxazolyl, thiazolyl, thienyl, isoxazolyl, oxathiadiazolyl, isothiazolyl, tetrazolyl, imidazolyl, triazinyl, furanyl, benzofuryl, indolyl, benzothiazolyl, benzoxazolyl, and the like.

A substituted heteroaryl contains a substituent attached at an available carbon or nitrogen to produce a stable compound.

"Heterocyclyl" alone or in combination means a non-aromatic cycloalkyl group having from 5 to 10 atoms in which from 1 to 3 carbon atoms in the ring are replaced by heteroatoms of O, S or N, and are optionally benzo fused or fused heteroaryl of 5-6 ring members and/or are optionally substituted as in the case of cycloalkyl. Heterocycyl is also intended to include oxidized S or N, such as sulfinyl, sulfonyl and N-oxide of a tertiary ring nitrogen. The point of attachment is at a carbon or nitrogen atom. Examples ofheterocyclyl groups are tetrahydrofuranyl, dihydropyridinyl, piperidinyl, pyrrolidinyl, piperazinyl, dihydrobenzofuryl, dihydroindolyl, and the like. A substituted hetercyclyl contains a substituent nitrogen attached at an available carbon or nitrogen to produce a stable compound.

"Substituted heteroaryl" refers to a heterocycle optionally mono or poly substituted with one or more functional groups, halogen, lower alkyl, lower alkoxy, alkylthio, acetylene, amino, amido, carboxyl, hydroxyl, aryl, aryloxy, heterocycle, substituted heterocycle, hetaryl, substituted hetaryl, nitro, cyano, thiol, sulfamido and the like.

"Aralkyl" refers to the group -R-Ar where Ar is an aryl group and R is lower alkyl or substituted lower alkyl group. Aryl groups can optionally be unsubstituted or substituted with, halogen, lower alkyl, alkoxy, alkylthio, acetylene, amino, amido, carboxyl, hydroxyl, aryl, aryloxy, heterocycle, substituted heterocycle, hetaryl, substituted hetaryl, nitro, cyano, thiol, sulfamido and the like.

"Heteroarylalkyl" refers to the group -R-HetAr where HetAr is an heteroaryl group and R lower alkyl or substituted lower alkyl. Heteroarylalkyl groups can optionally be unsubstituted or substituted with, halogen, lower alkyl, substituted lower alkyl, alkoxy, alkylthio, acetylene, aryl, aryloxy, heterocycle, substituted heterocycle, hetaryl, substituted hetaryl, nitro, cyano, thiol, sulfamido and the like.

"Cycloalkyl" refers to a divalent cyclic or polycyclic alkyl group containing 3 to carbon atoms.

"Substituted cycloalkyl" refers to a cycloalkyl group comprising one or more substituents with, halogen, lower alkyl, substituted lower alkyl, alkoxy, alkylthio, 0 04218081 acetylene, aryl, aryloxy, heterocycle, substituted heterocycle, hetaryl, substituted hetaryl, nitro, cyano, thiol, sulfarnido and the like.

"Alkyl cycloalkyl" denotes the group -R-cycloalkyl where cycloalkyl is a cycloalkyl group and R is a lower alkyl or substituted lower alkyl. Cycloalkyl groups can optionally be unsubstituted or substituted with e.g. halogen, lower alkyl, lower alkoxy, alkylthio, acetylene, amino, amido, carboxyl, hydroxyl, aryl, aryloxy, heterocycle, substituted heterocycle, hetaryl, substituted hetaryl, nitro, cyano, thiol, sulfamido and the like.

"Optional" and "optionally" mean that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, "optional pharmaceutical excipients" indicates that a formulation so described may or may not include pharmaceutical excipients other than those specifically stated to be present, and that the formulation so described includes instances in which the optional excipients are present and instances in which they are not.

"Treating" and "treatment" refer to any treatment of a disease in a mammal, particularly a human, and include: preventing the disease from occurring in a subject which may be predisposed to the disease but has not yet been diagnosed as having it; (ii) inhibiting the disease, arresting its development; or (iii) relieving the disease, causing regression of the disease.

The compositions of this invention are useful for treating mammals in a therapy selected from the group consisting of protecting skeletal muscles against damage resulting from trauma, protecting skeletal muscles subsequent to muscle or systemic diseases such as intermittent claudication, to treat shock conditions, to preserve donor tissue and organs used in transplants, and to treat cardiovascular diseases including atrial and ventricular arrhythmias, prinzmetal's (variant) angina, stable angina, and exercise induced angina, congestive heart disease, and myocardial infarction. The treatment is accomplished using a therapeutically effective amount of at least one compound of this invention and/or a pharmaceutically acceptable acid addition salt thereof in admixture with a pharmaceutically acceptable excipient.ompounds falling within the scope of this invention include the optical isomers and and R- and S- isomers of the above-identified compounds and mixtures thereof. This invention includes the individual isomers and all possible mixtures thereof.

004218081 All of the aforementioned embodiments include the pharmaceutically acceptable acid addition salts thereof, particularly the mono- and dihydrochlorides, and mixtures thereof.

The compounds having the general Formula I and IA can be prepared as outlined in Schemes 1A-7A. A general synthesis of the compounds of this invention is outlined in Scheme 1A. Compound IV can be prepared by N-acylation of substituted aniline II with 2substituted chloroacetylchloride m. Compound 1 is available commercially or readily prepared through reduction of the corresponding nitrobenzene derivative (acid/SnC12 or catalytic hydrogenation, see Advanced Organic Chemistry, Ed. J. March, (1992) A. Wiley- Interscience). Some examples of commercially available substituted anilines corresponding to general structure II include 2,6-dimethylaniline, 2,3-dimethylaniline, 2-methylaniline, 4methylaniline, 2,4-dichloroaniline, 3,4-dichloroaniline, 2,5-dichloroaniline, 2,4dichloroaniline, 2-chloroaniline, 3-chloroaniline, 2,6-difluoroaniline, 2,5-difluoroaniline 3,4difluoroaniline, 2-fluoroaniline, 4-fluoroaniline, 3-fluoroaniline, 2-fluoro-6-chloroaniline, 4fluoro-3-chloroaniline.

SCHEME 1A R R 1 C 2 R t R r N m)R 7 1 ft C1

R

6 RI

R

R4 Rs 4

R

I

[V

R R RR11 H-N N-P R 1 SBOC N N N-P

V-

B-C. ,BZ aB R.

VI

R 9t10 R"111 xN( H pi R17 0 Compound VI can be obtained by reacting compound IV with N-protected substituted piperazine V through wanning in an appropriate solvent DMF, EtOH). Protection of the nitrogen of compound V is only required when it is useful to control the regiochemistry of the addition of Compound V with compound IV. In some cases, compound V can be obtained from commercial resources. Examples of commercially available compounds corresponding to general structure V include 2-methyl piperazine, dimethyl piprazine and 2,6-dimethyl piperazine. Deprotection of compound VI can be accomplished using the standard conditions for Boc group use TFA, for CBZ and benzyl use hydrogenation). Compound I can be prepared by reacting compound VII with epoxide Vf through warming in an appropriate solvent (ethano, DMF).

SCHEME 2A RIB R1 7 RIa R 17 0 R. OHK on Xm a KcetoneC, K COz R

X

R, 2 p X=Cl orBr Va Lx Epoxide VIII (where mn 1 or 2) can be prepared as outlined in Scheme 2. Heating suostituted phenol IX with epichlorohydri, epibromohydrin, or 4-bromo-1,2-epoxybtant and potassium carbonate in acetone can afford epoxide VI. Compound IX can be obtained from commercial resources. Example of commercially available compounds of compounds ix include 2-chloropheLnol, 2-fluorophenol, 2-methoxyphenol, 2-methypheno, sesamol, 2,6is dichlorophenol, 3,5-dichlorophenol, 2,6-difluorophenol, 2,4-difluorophenol5-indanol, 3chloro-4-fluorophenol, 2,chloro-4-iluorophenol and 5,6,7,S-tetrahydro-2-naphthol. In some cases compound VIII can be obtained from commercial sources. Exampies of commercially available compounds corresponding to general structure VIII include benzyl glycidyl ether, glycidyl 2-methylphenyl ether, glycidyl 4-methoxyphenyl ether, glycidyl 4-chloropheny ether, glycidyl 2-chlorophenyl ether, glycidyl 2-mnethoxyphenyl ether, glycidyl 4methylphenyl ether, glycidyl 3,4-dichlorophenyl ether and glycidyl 4-fluorophenyl ether.

004464932v13 SCHEME 3A 0 R R9 0 0i R° BTFA St-BuLi, R 9 ,o Br Deprotection Bn-N N-BOC Bn-N N-BOC XII XIII R O Diborane R Bn--N NH Bn-N NH XIV V Compound V can be prepared as described in Scheme 3. Alkylation of compound XII with alkyl halides using t-BuLi as base can afford compound XIII as described by Pohlman et.

al. Org. Chem, (1997), 62, 1016-1022). Reduction of XIV using diborane can afford Nbenzyl protected version of compound V after N-Boc deprotection with trifluoroacetic acid (TFA) [for the diborane reduction see Jacobson et. al, J. Med. Chem, (1999), 42, 1123-1144].

SCHEME 4A Boc- NH OH

XVI

R14 13 Bn NH OR Bn^ 1. coupling 2. TFA, ring closure

XVII

R=Meor Et

XVIII

diborane

XIX

Compound V can also be prepared through standard coupling (eg. EDC or PyBroP) of D or L amino acids and standard deprotection as outline in Scheme 4 [For preparations of diketopiperazines see P. Cledera et al. Tetrahedron, (1998) p. 12349-12360 and R.A. Smith WO 01/62744 PCT/US01/05606 et al Bioorg. Med. Chem. Lett. (1998) p. 2369-2374]. Reduction of the diketopiperazine with diborane can afford compound XIX the N-benzyl protected version of compound V.

Compound V also includes the bicyclic homologs of piperazine diazabicyclo[2.2.1]heptane 83, 3,8-diazabicyclo[3.2.1] octane 84, and 2,5-diazabicyclo[2.2.2] octane HN H HN NH HN 83 84 Commercially available bicyclic analogs include diazabicyclo[2.2.1]heptane 83. Compounds 84, 85, and the (1R,4R) isomer of 83 can be prepared by published procedures (for 84 and 85- see Sturm, P. A. et al, J. Med. Chem. 1974, 17, 481-487; for 83 see- Barish, T. F. and Fox, D. E. J. Org. Chem., 1990, 55, 1684-1687).

A specific example of the preparation of a compound of Formula IA is disclosed in Schemes 5A, 6A and 7A to further illustrate how to prepare the compounds of this invention.

In particular, 2,6-dichloroaniline was acylated with 2-chloroacetyl chloride 2 using saturated bicarbonate and ether as base and co-solvent, respectively to afford the chloroacetamide derivative 3. Further reaction of compound 3 with 2,6-dimethyl piperazine afforded compound 5 through warming in ethanol. Reaction of compound 5 with epoxide 6 by warming both components in ethanol at reflux afforded 2,6-dimethyl piperazine derivative 7.

Compound 6 in turn was prepared by warming epichlorohydrin with 2-methoxyphenol in acetone in the presence of KCO 3 as described in Scheme 6.

SCHEME SA 0 Sa CO -EL20(1) 0 RT

H

A 4 EtO DIP&r ux24 o.

N6

S

SCHEME 6A 9 0 acetone,

KZCO,

A specific synthesis of compound 14 is described in Scheme 7 Compound 11 was prepared by opening of epoxide 6 with Boc-ethylenediaine through warming in EtH.

SAcylaion of compound I was accomplshed sing co accmp~shP usng hloroacetyl choride in dichloromethane using diisopropyethy amine as a base. Removal of the Boc group using TFA followed by ring closure through warming in EtOH afforded compound 13. Reaction of compound 13 with 3 as described above afforded compound 14.

28 SCHEME 7A II H 0 ON ~H NI 6i ehkroacttyl chloride 0 0~LF 1)CM, Dl PEA 2 t~ IE

HNN

,,(EtOR, DIPEA 0 140 0 1 Trhe compounds having the greneral formula I and lB can be- prepared as outlined in Schemes IB-7B. A general synthesis of the compounds of this invention is outlined in Scheme 13B. Compound IV can be prepared by N-acylation of substituted anilines of general structure nI with' 2-substituted chloroacetylchloflde in. Compound 11 is available commercially or readily prepared through reduction of the corresponding nitrobenlzene derivative (acidISnCI2 or catalytic hydrogenation, see Advanced Organic Chemnisty, Ed. j.

March, (1992) A. Wiiey-Interscience). Some examples of commercialiy available- substituted anilines of generl structure I1 include 2,5-dimethylanfline, 2,3-dimethYlanilirnt, 2rnethylanilifle, 4-metbylanilitle, 2,4-dichloroamhfle, 3 ,4-dichloroafinC, 2,5-dichlor02frlifle 2 ,4-dichloroalifl,. 2-chloroanile, 3--chloroaniline, 2,6-difluoro anilinle, 2,5 -difluoroalinc, 3 ,4-difiuoroaniiine, 2-fluoroanilinC, 4-fluoroanilifle, 3-fluoroaniline, 2-fluoro-6-chIOrOafilifle, 4-fluoro-'3-cblOroalil..

004464932013 SCHEMEMl

R

3

NHN

R4 R Rg R 1 RIR1 H-N N-P R 6RI5 R 14

R

13

V

P BOC, CBZ or Beozyl Deprotect

R

7

R

8

R

9 Rio R11R 1 2 R2R, R

N-P

I

8

R

7 R6 1 1 1 Re R 1

RIIR

Re R 7

R

1

R

1

R

4

R

3

R

5 VII RB R 17 0

R

20 R2 Vill 004464932v13 Compound VI can be obtained by reacting compound IV with a N-protected substituted piperazine V through warming in an appropriate solvent DMF, EtOH). Protection of the nitrogen of compound V is only required when it is useful to control the regiochemistry of the addition of Compound V with compound IV. In some cases, compound V can be obtained from commercial sources. Examples of commercially available compounds of general structure V include 2-methyl piperazine, 2,5-dimethyl piperazine and 2,6-dimethyl piperazine.

Deprotection of compound VI can be accomplished using the standard conditions for Boc group use TFA, for CBZ and benzyl use hydrogenation). Compound I can be prepared by reacting compound VII with epoxide VIII through warming in an appropriate solvent (ethanol,

DMF).

SCHEME 2B R17 R17 RIB I CHO R Cl SR21 R

R

2

R

20 R 20 IX x MgBr Ph 3

PCH

2 Br, NaH, THF Diethylether R17 mCPBADCM 1 9 R 2 mCPBA,

DCM

R9 RR21 XI

VIII

Epoxide VIII can be prepared as outlined in Scheme 2B. Epoxidation of substituted allylbenzene XI using mCPBA or hydrogen peroxide can afford epoxide VIII Majetich, R.

Hicks, G. Sun and P. McGill, (1998), 63, 2564-2573). Compound XI in turn can be prepared by reacting aldehyde IX with methylenetriphenylphosphorane under Wittig conditions or Homer Emmons conditions [Advanced Organic Chemistry, Eds. J. March, WO 01/62744 PCT/US01/05606 (1992), Wilcy-Interscience publication and S. Pine, G. Shen and H. Hoang, Synthesis, (1991), The compound XI can also be conveniently prepared by coupling a halide with the general formula X with allyl magnesium bromide. In some cases compound XI can be obtained from commercial sources. Examples of commercially available compounds corresponding to the general structure XI include (where m 0) 3-fluorostyrene, 4fluorostyrene, 2-chlorostyrene, 3-chlorostyrene, 4-chlorostyrene, 2,6-dichlorostyrene, 3,4dichlorostyreneand 3,4-dimethoxystyrene. Other examples of commercially available compounds with the general structure XI include (where m 1) 4-methoxyallylbenzene, 2hydroxyallylbenzene, 4,5-dimethoxyallylbenzene, 2-methylallylbenzene safrole and 1allylnaphthalene.

SCHEME 3B RIoR9 o 1i-BuLi, R9,j1r Deprotection Bn- N -Boc B n-N -Boc XII XIII R, R9 0 R R9 R e O BH, Bn-N H B Bn-N H

XIV

XV

Compound V can be prepared as described in Scheme 3B. Alkylation of compound XII with alkyl halides using t-BuLi as base can afford compound XIII as described by Pohlman et. al. Org. Chem, (1997), 62, 1016-1022). Reduction of XIII using diborane can afford N-benzyl protected version of compound V after N-Boc deprotection with trifluoroacetic acid (TFA for the diborane reduction see Jacobson et. al, J. Med. Chem, (1999), 42, 1123-1144).

004464932v13 SCHEME 4B

R

9 Ro O Boc-NH OH

XVI

R

1 4

R

13 O0 Bn NH OR

BXV

XVII

1.coupling 2. TFA, ring closure H-N N-Bn

R

3 XVII R1

XVIII

R=Meor Et diborane

IN

R

1 o H-N N-Bn SR13 R14

XIX

Compound V can also be prepared through standard coupling (eg. EDC or PyBroP) of D or L amino acids and standard deprotection Boc removal by TFA treatment) as outlined in Scheme 4 [For preparations of diketopiperazines see P. Cledera et al.

Tetrahedron, (1998) p. 12349-12360 and R. A. Smith et al Bioorg. Med. Chem. Lett. (1998) p.

2369-2374]. Reduction of the diketopiperazine with diborane can afford the N-benzyl protected version of compound V.

Compound V also includes the bicyclic homologs of piperazine diazabicyclo[2.2.1]heptane 83, 3,8-diazabicyclo[3.2.1] octane 84, and 2,5-diazabicyclo[2.2.2] octane J 84 Commercially available bicyclic analogs include diazabicyclo[2.2.1]heptane 83. Compounds 84, 85, and the (1R,4R) isomer of 83 can be prepared by published procedures (for 84 and 85 see Sturm, P. A. et al, J. Med. Chem. 1974, 17, 481-487; for 83 see Barish, T. F. and Fox, D. E. J. Org. Chem., 1990, 55, 1684-1687).

A specific example of the preparation of a compound from this invention is disclosed in Scheme 5B to further illustrate how to prepare the compounds of this invention. In 33 004464932v13 particular, 2,6-dichloroaniline was acylated with 2-chloroacetyl chloride 2 using saturated bicarbonate and ether as base and co-solvent, respectively to afford the chloroacetamide derivative 3. Further reaction of compound 3 with piperazine afforded compound 5B through warming in ethanol. Reaction of compound 5B with epoxide 6B by warming both components in ethanol at reflux afforded piperazine derivative 7B.

SCHEME SCI HN

NH

sat NaHCO 3 Et 2 0 EtOH, DIPEA, reflux 24 hrs 00 RT-

H

3 0 0 0 OHOCH3 CI acetone, K2CO3 0 O-m 8

OCH

9 6 m=l OCH3 64m=2 WO 01/62744 PCT/USO 1/05606 Four carbon epoxide 15 can be prepared by coupling commercially available 4methoxybenzyl chloride with allylmagnesium bromide followed by oxidation with mCPBA as illustrated in Scheme 7B.

SCHEME 7B H3CO C

H

3

CO

MgBr Ethylether

OCH

3 mCPBA, DCM *-110 I0 OCH 3 The compounds having the general Formula I and IC can be prepared as outlined in Schemes 1C-6C. A general synthesis of the compounds of this invention is outlined in Scheme 1C.

SCHEME 1C R, C1 4 a0, R

R,

.IVs' SRiRc P-t R o HR$BPr, 5 fTR R R rJL s frN R$6 R,5 6 fU 7 R Rv

VI

Dcprrnc! W 130c, CBZ r am Ks K ft 1, 1$t 7

RR

VII

F t R, Y4 "J2 V fll R r ~j r 16 R R4 V, KI ft 11 Compound rV can be prepared by N-acylation of substituted aniline I with 2 -substituted chloroacetylcjloride IT. Compound H1 is available coltmercially or readily Prepared through reduction of the corresponding nitrobenzene derivative (acid/SnCl 2 or catalytic hydrogenation, S see Advanced Organic Chemistry, Ed. J. March, (1992) A. Wiley-Interscience). Some examples of commercially available substituted aniline H include 2 6 -dinethylanjline, 2,3dimethyl aniline, 2 -mehylaniline 4 -methylaniline, 4 -rethylaniline 2 1 4 -dichloroaniline. 3,4dichloroaniiine, 2 5 -dichl oroaniine, 2 4 -dichloroaniline, 2 -chloroaniine, 3 -chloroaniline, 2,6- 004464932v13 difluoroaniline, 2,5-difluoroaniline, 3,4-difluoroaniline, 2-fluoroaniline, 4-fluoroaniline, 3fluoroaniline, 2-fluoro-6-chloroaniline, 4-fluoro-3-chloroaniline.

Compound VI can be obtained by reacting compound IV with N-protected substituted piperazine V through warming in an appropriate solvent g. DMF, EtOH). Protection of the nitrogen of compound V is only required when it is useful to control the regiochemistry of the addition of compound V with compound IV. In some cases, compound V can be obtained from commercial sources. Examples of commercially available compound corresponding to the general structure V include 2-methyl piperazine, 2,5-dimethyl piperazine, 2,6-dimethyl piperazine and 4-benzyloxycarbonylpiperazin-2-one. Deprotection of compound VI can be accomplished using the standard conditions g. for Boc group use TFA, for CBZ and benzyl use hydrogenation). Compound I can be prepared by reacting compound VII with epoxide VII through warming in an appropriate solvent (ethanol, DMF).

SCHEME 2C 0

R

1 7 -OH X NaH,DMF IX R17 x

VIII

vill X Cl or Br Epoxide VIII can be prepared as outlined in Scheme 2C. Heating alkyl alcohol IX with epichlorohydrin or epibromohydrin and sodium hydride in DMF can afford epoxide VIII. In some cases compound VI can be obtained from commercial resources. Examples of commercially available compounds of general structure VIII include glycidyl isopropyl ether, N butyl glycidyl ether, T butyl glycidyl ether and iso-butyl glycidyl ether.

Compound V can be prepared as described in Scheme 3C. Alkylation of compound XII with alkyl halides using t-BuLi as base can afford compound XII as described by Pohlman et. al. Org. Chem, (1997), 62, 1016-1022). Reduction of XIV using diborane can afford N-benzyl protected version of compound V after N-Boc deprotection with trifluoroacetic acid (TFA, for the diborane reduction see Jacobson et. al, J. Med. Chem, (1999), 42, 1123-1144).

004464932v13 SCHEME 3C R9 ~0 R

SO

Bn-MN -BOC a-O~uLI R0.jd

TFA

R, 1 Si- Bn-lhl rH

JUH

Diborane Rio R9 an- ZD Compound V can also be prepared through standard coupling (eg. EDC or PyBroP) of D or L amino acids as outlined in Scheme 4C [For preparations ofdiketopiperazines see-P. Cledera et al. Tetrahedron, (1998) p. 12349-12360 and R. A. Smith et al Bioorg. Med. Chem. Lett.

(1998) p. 2369-2374]. Reduction of the diketopiperazine with diborane can afford the Nbenzyl protected version of compound V.

SCHEME 4C R, Rl O Boc-NH OH

R

1 4

R

1 3

O

O

NH OR Bn 1. coupling 2. TFA, ring closure Rio H-N N-Bn

O

R 13 SR14

XIV

R Me or Et diborane R9 H-N N-Bn R13 R14 A specific example of the preparation of a compound from this invention is disclosed in Schemes 5C and 6C to further illustrate how to prepare the compounds of this invention.

WO 01/62744 PCT/USO 1/05606 NH2 HN NH C CI

N

sat NaHCO/ Et20 EtOH, DIPEA, refux 24 hrls 0 0

RT

0 NH6C EtOH re N NH H EtOH, renux 7C In particular, 2,6-dichloroaniline was acylated with 2-chloroacetyl chloride 2 using saturated bicarbonate and ether as base and co-solvent, respectively to afford the chloroacetamide derivative 3. Further reaction of compound 3 with piperazine afforded compound 5 through warming in ethanol. Reaction of compound 5B with epoxide 6C by warming both components in ethanol at reflux afforded piperazine derivative 7C. Compound 6C in turn was prepared by warming epibromohydrin with 2-indanol in DMF in presence of NaH as described in Scheme 6C.

SCHEME 6C Br-A

>-OH

6C 6C NaH, DMF WO 01/62744 PCT/US01/05606 The acid addition salts of the compounds of this invention may be converted to the corresponding free base by treating with a suitable base, such as potassium carbonate or sodium hydroxide, typically in the presence of aqueous solvent, and at a temperature of between about 0 degrees C and 100 degrees C. The free base form is isolated by conventional means, such as extraction with an organic solvent.

Salts of the compounds of this invention may be interchanged by taking advantage of differential solubilities and volatilities, or by treating with the appropriately loaded ion exchange resin. This conversion is carried out at a temperature between about 0°C and the boiling point of the solvent being used as the medium for the procedure.

Administration of the active compounds and salts described herein can be via any of the accepted modes of administration for therapeutic agents. These methods include oral, parenteral, transdermal, subcutaneous and other systemic modes. The preferred method of administration is oral, except in those cases where the subject is unable to ingest, by himself, any medication. In those instances it may be necessary to administer the composition parentarally.

Depending on the intended mode, the compositions may be in the form of solid, semisolid or liquid dosage forms, such as, for example, tablets, suppositories, pills, capsules, powders, liquids, suspensions, or the like, preferably in unit dosage forms suitable for single administration of precise dosages. The compositions may include one or more conventional pharmaceutical excipients and at least one active compound of this invention or the pharmaceutically acceptable salts thereof and, in addition, may include other medicinal agents, pharmaceutical agents, carriers, adjuvants, diluents, etc.

The amount of active compound administered will, of course, be dependent on the subject being treated, the subject's weight, the severity of the affliction, the manner of administration and the judgment of the prescribing physician. However, an effective dosage is in the range of 0.1-30 mg/kg/day, preferably 0.5-20 mg/kg/day. For an average 70 kg human, this would amount to 7-2100 mg per day, or preferably 35-1400 mg/day.

Since many of the effects of the compounds herein (protect skeletal muscles against damage resulting from trauma; protect skeletal muscles subsequent to muscle or systemic diseases such as intermittent claudication; treat shock conditions; preserve donor tissue and organs used in transplants; and treat cardiovascular diseases including atrial and ventricular arrhythmias, Prinzmetal's (variant) angina, stable angina, exercise induced angina, congestive heart disease, and myocardial infarction) are achieved through a similar mechanism (partial WO 01/62744 PCT/US01/05606 fatty acid oxidation inhibition) dosages (and forms of administration) are all generally within the same general and preferred ranges for all these utilities.

For solid compositions, conventional non-toxic solid include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like may be used. The active compound as defined above may be formulated as suppositories using, for example, polyalkylene glycols, for example, propylene glycol, as the carrier. Liquid pharmaceutically administrable compositions can, for example, be prepared by dissolving, dispersing, etc. an active compound as defined above and optional pharmaceutical adjuvants in a excipient, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like, to thereby form a solution or suspension. If desired, the pharmaceutical composition to be administered may also contain minor amounts of nontoxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like, for example, sodium acetate, sorbitan monolaurate, triethanolamine sodium acetate, triethanolamine oleate, etc. Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania, 15th Edition, 1975. The composition or formulation to be administered will, in any event, contain a quantity of the active compound(s), a therapeutically effective amount, i.e. in an amount effective to alleviate the symptoms of the subject being treated. For oral administration, a pharmaceutically acceptable non-toxic composition is formed by the incorporation of any of the normally employed excipients, such as, for example pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium, carbonate, and the like. Such compositions take the form of solutions, suspensions, tablets, pills, capsules, powders, sustained release formulations and the like. Such compositions may contain 10%-95% active ingredient, preferably 1-70%.

Parenteral administration is generally characterized by injection, either subcutaneously, intramuscularly or intravenously. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions. Suitable excipients are, for example, water, saline, dextrose, glycerol, ethanol or the like. In addition, if desired, the pharmaceutical compositions to be administered may also contain minor amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like, such as for example, sodium acetate, sorbitan monolaurate, triethanolamine oleate, etc.

41 WO 01/62744 PCT/US01/05606 A more recently devised approach for parenteral administration employs the implantation of a slow-release or sustained-release system, such that a constant level of dosage is maintained. See, U.S. Pat. No. 3,710,795, which is incorporated herein by reference. In another recent approach, the compositions of this invention can be administered orally in a sustained release dosage form using the compositions and/or methods disclosed in U.S. Patent Application Serial No. 09/321,522, filed on May 27, 1999, the specification of which is incorporated herein by reference.

It is within the scope of this invention to administer one or more compounds of this invention to a mammal, and preferably to a human by other known routes of pharmaceutical dosage form administration including, but not limited to by bolus, intravenously, transdermally, through inhalation, sub-cutaneously, or any other therapeutic agent administration method or route know to one skilled in the art.

The following Examples are representative of the invention, but are not to be construed as limiting the scope of the claims.

WO 01/62744 PCT/US01/05606 Example 1 N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(2-methoxy)propyl]-3,5dimethylpiperazinyl} acetamide

H

3

CO

0

OH

7 Part A.

Synthesis of N-(2,6-dimethylphenyl)-2-chloroacetamide 2,6-dimethylaniline (9.8 g, 81.2 mmol) was dissolved in ether (100 mL) and saturated aqueous NaHCO, (100 mL) and the reaction mixture was cooled in an ice/water bath. To the cold solution was added chloroacetyl chloride 2 (9.17 g, 81.2 mmol) dropwise over a period of 2 h. The mixture was allowed to warm to RT over 14 h. The mixture was extracted with EtOAc (3 X 50). The combined organic layers were dried over MgSO 4 filtered and concentrated. The residue was triturated in ether and filtered to afford compound 3 as a white solid.

Part B.

Synthesis of N-(2,6-dimethylphenyl)-2-(3,5-dimethylpiperazinyl)acetamide To a solution of compound 3 (5 g, 25.2 mmol) in ethanol (100 mL) was added 2,6dimethylpiperazine 4 (2.1 g, 25.0 mmol) and N,N-diisopropylamine (3.2 g, 25.2 mmol). The reaction mixture was refluxed for 24 h. The mixture was concentrated in vacuo and the residue was purified by column chromatography (10:1, DCM: MeOH) to afford compound WO 01/62744 PCT/US01/05606 Part C.

Synthesis of glycidyl 4-methoxyphenyl ether 2-methoxyphenol (1.0 g, 8.0 mmol) and epichlorohydrin (3.7 g, 40.0 mmol) were dissolved in acetone (20 mL). K 2

CO

3 (2.2 g, 16.0 mmol) was added and the mixture was heated at 70 °C for 24 h. The reaction mixture was concentrated in vacuo. The residue was dissolved 100 mL of EtOAc washed with 100 mL water, dried over MgSO 4 and filtered. The mixture was evaporated to dryness and the residue was purified using column chromatography (2:1, hexane: ethyl acetate) to afford compound 6.

Part D.

Synthesis of N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(2-methoxy)propyl]-3,5dimethylpiperazinyl} acetamide To a solution of compound 5 in 10 mL EtOH (0.4 g, 1.4 mmol) was added compound 6 (0.27 g, 1.5 mmol). The reaction mixture was refluxed for 24 h. The mixture was concentrated in vacuo and the residue was purified by using Prep. TLC (10:1, DCM:MeOH) to afford compound 7.

'N NH NOH OCH 3 N O 2-{(5S,2R)-4-[2-hydroxy-3-(2-methoxyphenoxy)propyl]-2,5-dimethylpiperazinyl}-N-(2,6dimethylphenyl)acetamide Compound 15 was prepared in the manner of compound 7 substituting (2R, dimethylpiperazine for 2,6-dimethylpiperazine 4 in part B to afford compound 15: Mass spectrum 456.4.

H N OH OCH 3 001 0 N 'Y N-(2,6-dimethylpbenyl)-2-(4-[2-hydroxy-3-(2-methoxyphenoxy)propyl]-2oxopiperazinyl}acetamide (16) Compound 16 was prepared substituting 4-benzyloxycarbonyl-2-oxo-piperazine for 2,6direthylpiperazine 4 in part B of compound 7 that was carried on to the final target in the manner of compound 7 after removal of the CBZ protecting group (hydrogenation 20 psi, 10% palladium on carbon) to afford compound 16: Mass spectrum 442,41.

NH N OH OCH 3 0 N 0 2,5-diaza-5- [2-bydroxy-3-(2-methoxyphe oxy)propyl bicyco [4.4.0]dec-2-yl}-N-(2,6dimethylphenyl)acetamide (17) Compound 17 was prepared in the manner of compound 7 substituting perhydroquinoxaline for 2,6-dimethylpiperazine 4 in part B to afford compound 1.7: Mass spectrum 482.4.

WO 01/62744 WO 0162744PCT/US01/05606

HN

C

OH

N-(2,6-dimethylplienyl)-2-{4- 12-hydroxy-3-(2-methoxyphenoxy)propyl]-3,3dimethylpiperazinyl~acetamide (18) Compouind 18 was prepared in the manner of compound 7 substituting 2,2-dimethylpiperazine for 2,6-dimethylpiperazine 4 in part B to afford compound 18: Mass spectrum (M+1) 456.51

H

3

CO

HN N,0o b 0 2-15- [(2S)-2-hydroxy-3-(2-methoxyphenoxy)propyll(1 S,4S)-2,5-diazabicyclol2.2.1 Ihept- 2-yl}-N-(2,6-dimethylphenyl)acetamide (19) Compound 19 was prepared in the manner of compound 7 substituting Diazabicyclo[2.2. 1]heptane for 2,6-dimethylpiperazine 4 in part B to afford compound 19: Mass spectrum 481.5

H

3

C

N NJL, f\N

OH

N-(2,6-dimethylphenyl)-2-{4-[2-hydroxv-4-(2-methoxyphenoxy)butylpiperazinyijacetamide WO 01/62744 PCTfUSOI/05606 Compound 20 was prepared in the manner of compound 7 substituting 4-bromo- 1,2epoxybutane for epichiorohydrin in part B to afford compound 20: Mass spectrum 442.37 0 N \Om" N' -0

H

C \OH N-(2,6-dimethylphenyl)-2-{4-[4-(4-fluorophenoxy)-2-hydroxybutylpiperazinyl acetamide (21) Compound 21 was prepared in the manner of compound 7 substituting 4-bromo-1 ,2-epoxybutane for epichiorohydrin in part B to afford compound 21: Mass spectrum 430.35

N

OH

[4-(tert-butyl)phenoxyj-2-hydroxybutyl}piperazinyl)-N-(2,6-dimethylphenyl) acetamide (22) Compound 22 was prepared in the manner of compound 7 substituting 4-bromo-1,2epoxybutane for epichiorohydrin in part B to afford compound 22: Mass spectrum 468.32 H 0 OH -r' N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-4-(4-phenylphenoxy)butylj piperazinyllacetamide (23) Compound 23 was prepared in the manner of compound 7 substituting 4-bromo-1,2epoxybutane for epichiorohydrin in part B to afford compound 23: Mass spectrum 488.41 WO 01/62 744 PCT/US01 05 606 0

OCH

3

HO

N-(,6-ime'y'heyl)2-f-r2hydOX--x-methoxyph enoxy)butylj..

PiperazinyIqacetalide (24) Compound 24 was prepared in the mlanner Of comnpound 7 substituting 4-bromo- 1,2epoxybuae for epichorohydi in part B3 to afford compound 24: Mass spectrum 1) 4 2 3 7 004218081 Example 2 N-(2,6-dimethylphenyl)-2- 4-[2-hydroxy-3-(2-methoxyphenoxy)propyl]-3oxopiperazinyl}acetamide (14) Part E.

Synthesis of (tert-butoxy)-N-(2-{[2-hydroxy-3-(2methoxyphenoxy)propyl amino}ethyl)carboxamide (11).

Epoxide 6 (1.0 g, 5.5 mmol) and Boc-ethylenediamine (0.88 g, 5.5 mmol) were dissolved in 20 mL EtOH and the mixture was heated at reflux for 24 h. The solvent was evaporated and the residue was purified using column chromatography Hex:EtOAc) to afford compound 11.

Synthesis of N-{2-[(tert-butoxy)carbonylamino] ethyl}-2-chloro-N[2-hydroxy-3-(2methoxyphenoxy)propyl] acetamide (12) Compound 11 (1.0g, 3.0 mmol) was dissolved in 20 mL DCM and treated with diisopropylethyl amine (0.76 g, 4.5 mmol). The mixture was cooled in an ice water bath. To the cold mixture was added dropwise chloroacetyl chloride in 5 mL DCM. The reaction mixture was allowed to stir at RT for 24 h. The mixture was diluted with 50 mL DCM and washed with 50 mL of water and 10% citric acid. The organic layer was dried over MgSO4 and filtered. The solvent was evaporated under reduced pressure and the residue was crystallized from ethylether to afford compound 12.

Synthesis of 1-[2-hydroxy-3-(2-methoxyphenoxy)propyl]piperazin-2-one(13).

Compound 12 (0.5 g, 1.5 mmol) was dissolved in 10 mL TFA. The mixture was allowed to stir at RT for 2 h. TFA was removed under reduced pressure. The residue was dissolved in 20 mL EtOH and treated with diisopropylethyl amine (0.76 g, 4.5 mmol). The mixture was heated at reflux for 24 h. The solvent was removed under reduced pressure to afford compound 13 which was used without further purification.

Part F.

Synthesis of N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(2methoxyphenoxy)propyl]-3-oxopiperazinyl} acetamide(14) To a solution of compound 13 in 10 mL EtOH (0.1 g, 0.30 mmol) was added compound 3 (0.7 g, 0.36 mmol) and diisopropylethyl amine (0.76 g, 0.36 mmol). The reaction mixture was heated at reflux for 24 h. The mixture was concentrated in vacuo and the residue was purified by using Prep. TLC (10:1, DCM:MeOH) to afford compound 14: Mass spectrum 442.34 WO 01/62744 WO 0162744PCT/US01/05606 Example 3 The compounds listed in Table 1, below were made in the manner of compound 14 of Example 2.

Table 1 R MHW 2,6-dimethylphenyl 430.3 26 2,6-dichiorophenyl 471 27 4-amimosulfonylphenyl 481.2 28 3-trifluoromethyl-5methoxyphenyl 500.2 29 5-indanyl 442.2 1 -naphthyl 452.3 31 1 -(4-chloronaphthyl) 486.3 32 2-N-pyrro yl-phenyl 467.3 33 Phenyl 402.2 34 2-chiorophenyl 436.2 2-chloro-4-methylphenyl 450.2 36 2-(1 -methylethenyl)phenyl 442.3 37 2-methyiph enyl 416.2 38 2-isopropyl-6-methylphenyl 458.4 39 3-methyithiophenyl 448.2 2-methoxy-4-chloro-5-methylphenyl 480.2 41 4-dimethylamninophenyl 445.3 42 2,4-dimethoxyphenyl 462.3 43 3,4-dichiorophenyl 471.1 44 4-chlorop enyl 436.3 3-chlorophenyl 436.2 46 3,5-dichiorophenyl 471.1 47 4-methoxyphenyl 432.3 48 4-methyiphenyl 416.2 49 3-methylphenyl 416.2 4-fluorophenyl 420.2 51 4-cyanophenyl 427.3 52 4-acetylphenyl 44 53 2-methoxyphenyl 432.4 54 4-trifluoromethylphenyl 470.2 3-trifluoromethyl-4-chlorophenyl 504.1 56 3,5-dimethoxyphenyl 462.3 57 4-N-morpholinylphenyl 487.4 58 3-fluoro-4-methoxyphenyl 1450.2 WO 01/62744 PCT/US01/05606 59 3,4,5-trimethoxypheny1 492.3 3,4-dimethoxypheny1 490 61 2-fluoro-4-chlorophenyl 454.2 62 2-hydroxymethyl-6-methylphenvl 446 WO 01/62744 PCT/US01/05606 Example 4 2-[4-(3-(2H-benzo[d]1,3-dioxolen-5-yl)-2-hydroxypropyl)piperazinyl]-N-(2,6dimethylphenyl)acetamide (7B).

S NH OH O O

NO

Part A.

Synthesis of N-(2,6-dimethylphenyl)-2-chloroacetamide (3B).

2,6-dimethylaniline (9.8 g, 81.2 mmol) was dissolved in ether (100 mL) and saturated aqueous NaHCO, (100 mL) and the reaction mixture was cooled in an ice/water bath. To the cold solution was added chloroacetyl chloride 2B (9.17 g, 81.2 mmol) dropwise over a period of 2 h. The mixture was allowed to warm to RT over 14 h. The mixture was extracted with EtOAc (3 X 50). The combined organic layers were dried over MgSO 4 filtered and concentrated. The residue was triturated in ether and filtered to afford compound 3B as a white solid.

Part B.

Synthesis of N-(2,6-dimethylphenyl)-2-piperazinylacetamide To a solution of compound 3 (5 g, 25.2 mmol) in ethanol (100 mL) was added compound 4B (2.1 g, 25.0 mmol) and N,N-diisopropylamine (3.2 g, 25.2 mmol). The reaction mixture was refluxed for 24 h. The mixture was concentrated in vacuo and the residue was purified by column chromatography (10:1 dichloromethane: methanol) to afford compound Part C.

Synthesis of 5-(oxiran-2-ylmethyl)-2H-benzo[d]1,3-dioxane (6B).

To an ice cold solution of 8 (1.0 g, 6.17 mmol) in dichloromethane was added dropwise a solution of 3-chloroperoxybenzoic acid (1.8 g, 10.43 mmol) in 20 mL dichloromethane over a period of 1 h. The reaction mixture was allowed to stir at RT for 12 h. The reaction mixture was filtered to remove any solids and concentrated in vacuo. To the residue was added diethyl ether (200ml), and it was washed with saturated sodium bicarbonate (3x100ml). The organic layer was dried over MgSO 4 and concentrated in vacuo The residue was purified using Prep. TLC (2:1 hexane: ethyl acetate) to yield 6B.

Part D.

WO 01/62744 PCT/US01/05606 2-14-(3-(2H-benzoldjl ,3-dioxolen-5-yI)-2-hydroxypropyl)piperazinylj-N-(2,6dimethylphenyl)acetamide (7B) To a solution of compound 5B (0.4 g, 1.64 mmol) in ethanol (100 mL) was added compound 6B (0.38 g, 2.14 mmol) in 10 mL EtOH. The reaction mixture was refluxed for 24 h. The mixture was concentrated in vacuo, and the residue was purified by using Prep. TLC (10:1 dichioromethane: methanol) to afford compound 7B: Mass spectrum (MIH+1) 426.34.

N-(2,6-dimethylphenyl)-2- [4-(2-hydroxy-4-phenylbutyl)piperazinyllacetamide (9B).

Compound 9B was prepared in the manner of compound 7B substituting 4-phenyl-butene for 3-(3,4-methylendioxyphenyl)-l1-propene in part C to afford compound 9B: Mass spectrum (MHl-Ii) 396.32.

N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(2-methoxyphenyl)propyljpiperazinyllacetamide (1OB) Compound 10B was prepared in the manner of compound 7B substituting 3-(2methoxyphenyl)-1 -propene for 3-(3,4-methylendioxyphenyl)-l1-propene in part C to afford compound lOB: Mass spectrum (MH+1) 412.35.

WO 01/62744 WO 0162744PCT/US01/05606 N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(4inethoxyphenyl)propyl] piperazinyl~acetamide (11iB).

Compound 11B was prepared in the manner of compound 7B substituting 3-(4methoxyphenyl)-1 -propene for 3-(3,4-methylendioxyphenyl)-1-propene in part C to afford compound 1 1B: Mass spectrum (MH+ 1) 412.3 N-(2,6-dintethylphenyl)-2-{4-12-hydroxy-3-phenylpropyllpiperazinyl acetamide (12B) Compound 1 2B was prepared in the manner of compound 7B substituting 3-phenyl-l1-propene for 3-(3,4-methylendioxyphenyl)-1-propene in part C to afford compound 12B: Mass spectrum (MlrI) 382.

N OH N-(2,6-dimethylphenyl)-2-14-(2-hydroxy-3-naphthylpropyl)piperazinyljacetamide (13B).

Compound 13B was prepared in the manner of compound 7B substituting 3-(1-naphthyl)-1propene for 3-(3,4-methylendioxyphenyl)-1-propene in part C to afford compound 13:Mass spectrum (MHII+) 432.55.

WO 01/62744 PCT/US01/05606 EXAMPLE Part A Intermediate (14B): To a solution of 4-methoxybenzyl chloride (2-mmol) in anhydrous ether mL), was added allylmagnesium bromide 4 mL, 1M solution in THF) and the reaction mixture was allowed to stir for 16h at room temperature. Sat. ammonium chloride solution 91mL) was added and the ether layer was separated, washed with water and dried.

Evaporation of ether under reduced pressure afforded olefin 14B as an oil. It was used in the next reaction without purification.

Part B Intermediate (15B): To an ice cold solution of 15B (2 mmol) in dichloromethane was added dropwise a solution of 3-chloroperoxybenzoic acid (4 mmol) in 20 mL dichloromethane over a period of 1 h. The reaction mixture was allowed to stir at RT for 12 h. The reaction mixture was filtered to remove any solids and concentrated in vacuo. To the residue was added diethyl ether (200ml), and it was washed with saturated sodium bicarbonate (3xl00ml).

The organic layer was dried over MgSO 4 and concentrated in vacuo. The residue was purified using Prep. TLC (2:1 hexane: ethyl acetate) to yield Part C Synthesis of N-(2,6-dimethylphenyl)-2-{4-[4-(4-methoxyphenyl)-2hydroxybutyl]piperazinyl}acetamide(16B) To a solution of compound 5B (0.4 g, 1.64 mmol) in ethanol (100 mL) was added compound (2.14 mmol) in 10 mL EtOH. The reaction mixture was refluxed for 24 h. The mixture was concentrated in vacuo, and the residue was purified by using Prep. TLC (10:1 dichloromethane: methanol) to afford compound 16. 426.3

H

N N

H

O NT 17

F

WO 01/62744 PCT/US01/05606 2-{4-[4-(2,6-difluorophenyl)-2-hydroxybutyllpiperazinyl-N-(2,6dimethylphenyl)acetamide(17B) Compound 17B was prepared in a manner similar to that of compound 16B substituting 2,6difluorobenzyl chloride for 4-methoxybenzyl chloride. 432.2 N-(2,6-dimethylphenyl)-2-{4- 14-(2-chlorophenyl)-2hydroxybutyljpiperazinyl} acetamide(1 8B) Compound 18B was prepared in a manner similar to that of compound 16B substituting 2chiorobeuzyl chloride for 4-methoxybenzyl chloride. 430.2 14-(tert-butyl)phenyll-2-hydroxybutyl~piperazinyl)-N-(2,6dimethylphenyl)acetamide(19B) Compound 19B was prepared in a manner similar to that of compound 16B substituting 4-tbutylbenzyl chloride for 4-methoxybenzyl chloride. (M 1) 452.3 WO 01/62744 PCT/US01/05606 N-(2,6-dinethylphenyl)-2-{4- [4-(2-fluorophenyl)-2hydroxybutyllpiperazinyl Compound 20B was prepared in a manner similar to that of compound 16B substituting 2fluorobenzyl chloride for 4-methoxybenzyl chloride. (M 1) 414.2

H

0 NN 21 N-(2,6-dimethylphenyl)-2-(4-2-hydroxy-4-[4- (trifluoromethyl)phenylJ butyl piperazinyl)acetamide(21B) Compound 21B was prepared in a manner similar to that of compound 16B substituting 4trifluoromethylbenzyl chloride for 4-methoxybenzyl chloride. (M 1) 464.2

H

22 2-14-(3-(2H-benzol[d] ,3-dioxolen-5-yI)-2-hydroxypropyl)piperazinyll-N-(2,6dimethylpheuyl)-2-methylpropanamide (22B) This compound was prepared in a manner similar to that of 7B, substituting 2-chloro-2methylpropionyl chloride for clloroacetyl chloride in part A. 454.54

N

23 WO 01/62744 PCT/US01/05606 N-(2,6-dimethylphenyl)-2- [4-(2-hydroxy-3-phenylpropyl)piperazinylJ-2methyipropanamide (23B) This compound was prepared in a manner similar to that of 7B, substituting 2-chloro-2methyipropionyl chloride for chioroacetyl chloride in part A and allylbenzene for 8B. 1) =410.34.

CH

3 H CH3

HH

24 N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(3,4,5trimethoxyphenyl)propyljpiperazinyl}-2-methylpropanamide (24B) This compound was prepared in a manner similar to that of 7B, substituting 2-chloro-2methyipropionyl chloride for chioroacetyl chloride in part A and 3,4,5-trimethoxy alkybenzene, for 8B. 472.54

H

N-(2,6-dimethylphenyl)-2-[4-(2-hydroxy-5-phenylpentyl)piperazinyl] acetamide This compound was prepared in a manner similar to that of 16B, substituting phenethyl chloride for 4-methoxybenzyl chloride in part A. 410.4.

26

F

N-(2,6-dimethylphenyl)-2-14-[5-(2-fluorophenyl)- 2-hydroxypentyl] pip erazinyllacetamide(26B) This compound was prepared in a manner similar to that of 16B, substituting 2fluorophenethyl chloride for 4-methoxybenzyl chloride in part A. (NM±1) 428. 1.

WO 01/62744 PCT/US01/05606 27 N-(2,6-dimethylphenyl)-2-{4-[5-(2-chlorophenyl)- 2-hydroxypentyl] piperazinyl~acetamide(27B) This compound was prepared in a manner similar to that of 1613, substituting 2chiorophenethyl chloride for 4-methoxybenzyl chloride in part A. (M41) 444.3 WO 01/62744 PCT/US01/05606 Example 6 N-(2,6-dimethylphenyl)-2-[4-(2-hydroxy-3-indan-2-yloxypropyl)piperazinyl]acetamide (7C) Part A.

Synthesis of N-(2,6-dimethylphenyl)-2-chloroacetamide (3C).

2,6-dimethylaniline (9.8g, 81.2 mmol) was dissolved in ether (100 mL) and saturated aqueous NaHCO, (100 mL) and the reaction mixture was cooled in an ice/water bath. To the cold solution was added chloroacetyl chloride 2C (9.17 g, 81.2 mmol) dropwise over a period of 2h. The mixture was allowed to warm to RT over 14 h. The mixture was diluted with 100 mL ether and the organic layer was dried over MgSO 4 filtered and concentrated to afford compound 3C as a white solid.

Part B.

Synthesis of N-(2,6-dimethylphenyl)-2-piperazinylacetamide To a solution of compound 3C in 100 mL EtOH (5 g, 25.2 mmol) was added compound 4C (2.1 g, 25.0 mmol) and N,N-diisopropylethylamine (3.2 g, 25.2 mmol). The reaction mixture was refluxed for 24 h. The mixture was concentrated in vacuo and the residue was purified by column chromatography 10:1, DCM:MeOH) to afford compound Part C.

Synthesis of 2-(oxiran-2-ylmethoxy) propane (6C) To a solution of 60% NaH (0.18g, 4.5mmol) in DMF (10ml) cooled to 0 degrees was added 2-propanol (0.5g, 3,73mmol) in DMF (2ml) dropwise. After stirring for epibromohydrin (1.11g, 8.18mmol) in DMF (1ml) was added dropwise. The reaction was allowed to warm to room temperature and stirred for 48 h. The solvent was removed in vacuo and the residue was purified using Prep TLC (30:1, DCM:MeOH) to afford compound 6C.

Part D Synthesis of N-(2,6-dimethylphenyl)-2-[4-(2-hydroxy-3-indan-2yloxypropyl)piperazinyl]acetamide (7C) To a solution of 6C (0.43g, 2.3mmol) in ethanol(4ml) was added 5C (0.

4 05g, 1.64mmol).

The solution was heated to reflux and stirred for 24 h. Upon completion the solution was concentrated in vacuo and purified using Prep TLC (10:1, DCM:MeOH) to yield 7C. Mass Spectrum 438.36.

WO 01/62744 PCT/US01/05606 2-(Q2-[4-(3-isopropoxy-2-hydroxypropyl)piperazinyll- N-({2,6-dimethylphenyl)acetamide Compound IOC was prepared in a similar manner to compound 7C, substituting the commercially available glycidyl isopropyl ether for 2-(oxiran-2-ylmethoxy)indane in part D to afford 10C :Mass spectrum MS 364.37.

00 NOH N-(2,6-dimethylphenyl)-2-4-12-hydroxy-3 (phenylmethoxy)propyl] piperazinyll acetamide (1 IC) Compound 11C was prepared in a similar manner to compound 7C, substituting the commercially available benzyl glycidyl ether for 2-(oxiran-2-ylmethoxy)indane in part D to afford 11G. Mass Spectrum 412.36.

0 N N -O

O

H

C OH 2-({2-[4-(3-cyclopentyloxy-2-hydroxypropyl)piperazinyll- N-(12,6dimethylphenyl)acetamide (1 2C) WO 01/62744 PCT/US01/05606 Compound 12C was prepared in a similar manner to compound 7C, substituting the commercially available cyclopentanol for 2-indanol in part C to afford 12C: MIS (MH+) 390.

2-({2-[4-(3-cyclohexyloxy-2-hydroxypropyl)piperazinyl]- N(26 diniethylphenyl)acetamide (1 3C) Compound 13C was prepared in a similar manner to compound 7C, substituting the commercially available cyclohexanol for 2-indanol in part C to afford 13C MS (NM+) 404.

14 [4-(tert-butyl)phenyllmethoxy}-2-hydroxypropyl)piperazinyl]-N-(2,6dimethylphenyl)acetamide (14C): Compound 14C was prepared in a similar manner to compound 7C, substituting the commercially available 4-t-bu-benzylalcohol for 2-propanol in part C. MS 468.44 15

NO,

N-(2,6-dimethylphenyl)-2-(4-13-[(2-fluorophenyl)methoxy]-2- Compound 15C was prepared in a similar manner to compound 7C, substituting the commercially available 2-fluorobenzylalcohol for 2-propanol in part C. MS 430.39 WO 01/62744 PCT/US01/05606 [(2,4-difluorophenyl)methoxy]-2-hydroxypropyl~piperazinyl)-N-(2,6dimethylphenyl)acetamide(16C): Compound 16C was prepared in a similar manner to compound 7, substituting the commercially available 2,4-difluorobenzylalcohol for 2propanol in part C. MIS 48.38 N-(2,6-dimethylphenyl)-2-14-(2-hydroxy-3-{ [4- (trifluoromethyl)phenyll methoxy~propyl)piperazinyllacetamide (1 7C): Compound 17C was prepared in a similar manner to compound 7C, substituting the commercially available 4trifluoromethyl-benzylalcohol for 2-propanol in part C. MS 480.37 18 N-(2,6-dimethylphenyl)-2-(4-{2-hydroxy-3-[(2methoxyphenyl)methoxyjpropyllpiperazinyl)acetamide (1 8C): Compound 1 8C was prepared in a similar manner to compound 7C, substituting the commercially available 2methoxy-benzylalcohol for 2-propanol in part C. MS =442.41 2-(4-13-[(2,4-dimethoxyphenyl)methoxyJ-2-hydroxypropyllpiperazinyl)-N-(2,6dimethylphenyl)acetamide (19C): Compound 19C was prepared in a similar manner to WO 01/62744 PCT/US01/05606 compound 7C, substituting the commercially available 2,4-diiinethoxy-benzylalcohol for 2propanol in part C. MS 472.42 H

H'

N-(2,6-dimethylphenyl)-2-(4-{2-hydroxy-3- methoxyphenyl)methoxylpropyllpiperazinyl)acetamide(20C): Compound 20C was prepared in a similar manner to compound 7C, substituting the commercially available 4methoxy-benzylalcohol for 2-propanol in part C. MS 442.42

H

0 N N f C Ha 21 N-(2,6-diniethylphenyl)-2-(4-{3-[(4-fluorophenyl)methoxy]-2hydroxypropyllpiperazinyl)acetamide (21C) Compound 21C was prepared in a similar manner to compound 7C, substituting the commercially available 4-fluoro-benzylalcohol for 2-propanol. in part C. MS =430.40 H 22 N-(2,6-dimethylphenyl)-2-(4-{2-hydroxy-3-[(4methylphenyl)methoxyjpropyllpiperazinyl)acetamide (22C): Compound 22C was prepared in a similar manner to compound 7C, substituting the commercially available 4methyl-benzylalcohol for 2-propanol in part C. MS 426.41 WO 01/62744 PCT/US01/05606 N-(2,6-dimethylphenyl)-2-(4-{2-hydroxy-3-[(4phenylphenyl)methoxyjpropyl~piperazinyl)acetamide (23C) Compound 23C was prepared in a similar manner to compound 7C, substituting the commercially available 4-phenylbenzylalcohol for 2-propanol in part C. MS 488.42 N O

H

24 N-(2,6-dimethylphenyl)-2-(4-13-[(4-butylphenyl)methoxy]-2hydroxypropyllpiperazinyl)acetamide (24C): Compound 24C was prepared in a similar manner to compound 7C, substituting the commercially available 4-n-bu-benzylalcohol for 2propanol in part C. MS 468.45 H N-(2,6-dimethylphenyl)-2-4- 12-hydroxy-3-(2naphthylmethoxy)propylpiperazinyl acetamide (25C) Compound 25C was prepared in a similar manner to compound 7C, substituting the commercially available 2-naphthylmethanol for 2-propanol in part C. MS 462.41

H

0 KN 0O 26 WO 01/62744 WO 0162744PCT/US01/05606 N-(2,6-climethylphenyl)-2-14- 13-(cyclohexylmethoxy)-2hydroxypropyljpiperazinyl)acetamide (26C) Compound 26C was prepared in a similar manner to compound 7C, substituting the commercially available cyclohexylinethanol for 2propanol in part C. MS 418.55

H

0 N N 27 N-(2,6-dimethylphenyl)-2-(4-13- [(4-fluorophenyl)methoxyJ-2-hydroxypropyl}-3,3dimethylpiperazinyl)acetamide (27C) Compound 27C was prepared in a similar manner to compound 7C, substituting the commercially available 4-fluorobenzylalcohol for 2-propanol in part C and 2,2-dimethylpiperazine for compound 4 part B. MS 458.5 WO 01/62744 PCTUSO 1/05606 Example 7 Mitochondrial Assays Rat heart mitochondria were isolated by the method of Nedergard and Cannon (Methods in Enzymol. 55, 3, 1979).

Palmitoyl CoA oxidation The Palinityl CoA oxidation was carried out in a total volume of 100 micro liters containing the following agents: 110 mM KCI, 33 mM Tris buffer at pH 8, 2mM KPi, 2mM MgCl 2 0.1mM EDTA, 14.7 microM defatted BSA, 0.5 m2M malic acid, 13 mM carnitine, 1 mM ADP, 52 micrograms of mitochondrial protein,* and 16 microM 1-C14 palmitoyl CoA (Sp. Activity 60 mCi/mmole; 20 microCi/mi, using 5 microliters per assay). The compounds of this invention were added in a DMSO solution at the following concentrations: 100 microM, 30 microM, and 3 microM. In each assay, a DMSO control was used. After 15 min at 30 oC, the enzymatic reaction was centrifuged (20,000 g for 1 min), and 70 microliters of the supernatant was added to an activated reverse phase silicic acid column (approximately 0.5 ml of silicic acid). The column was eluted with 2 ml of water, 1 5 and 0.5 ml of the eluent was used for scintillation counting to determine the amount Of C 14 trapped as C 14 bicarbonate ion.

Table 1 Inhibition of mitochondrial fatty acid oxidation using palmitoyl CoA as substrate of Control at 3 Compound 100 4±M 30 .M 3 4~M Ranolazine 75% 90% 14 7 85% 98% 107% 78% 97% 103% 17 89% 98% 100% 16 100% 96% 18 17% 19 22 25% 23 9B 84% 84% lOB 7B 11B 83% 92% 128 42% 13B 16B 37% 17B 78% 18B 78% 19B 35% WO 01/62744 PCT[USOI/05606 2B56% 56% 23B 24B 72% 1C100% 97% 7C68% hGc 79% 12C 41%- 13C 3% 14C 2 16C 97% 17C 35% 18C 96% 19C 97% 100% 21C87% 45% 2C12% 15% 2C38% 27C 173% Example 8 Palmitoyl Carnitine Oxidation The Palmitoyl carnitine oxidation was carried out in a total volume of 100 microliters containing the following agents: 110 mM KCl, 33 mM Tris buffer at pH 8, 2 mM K.Pi, 2 mM MgCl 2 0.1 mM EDTA, 0.1 mg/mi of defatted BSA, 0.5 mM malic acid, 3 mM ADP, 52 micrograms of rnitochondrial protein, and 43 microM I1-C 14 palmitoyl carnitine (Sp. Activity mCi/mmole; 20 mricroCi/mi, using 5 microliters per assay). The compounds of this invention were added in a DMSO solution at the following concentrations: 100 microM, microM, and 3 microM. In each assay, a DMSO control was used. After 15 min at 30 TC, the enzymatic reaction was centrifuged (20,000 g for I min), and 70 microliters of the supernatant was added to an activated reverse phase silicic acid column (approximately 0.5 ml of silicic acid). The column was eluted with 2 ml of water, and 0.5 ml of the eluent was used for scintillation counting to determine the amount of C 14 trapped as C] 4 bicarbonate ion. The data are presented as activity of control.

WO 01/62744 WO 0162744PCT/US01/05606 Table 2 Inhibition of mitochondrial fatty acid oxidation using palniitoyl carnitine as substrate of Control At 3 concentrations. Compound 100 PM 30 gM 3 gM Ranolazine 63% 98% 14 7 95% 102% 109% 82% 98% 106% 17 80% 98% 103% 16 64%(8) 9B 7B 11B 12B 56% 13B lOG 80% 7C 11C---- 12C 13GC---- WO 01/62744 PCT/US01/05606 Example 9 Metabolic Stability: As a measure of metabolic stability the compounds of this invention were incubated with human liver S-9 microsomal fractions. After, 30 minutes at 37 C, the amount of parent drug remaining was determined using LC-mass spec. The response factors for each compound was determined by establishing a standard curve and using an internal standard during the analysis of the samples. An average of five experiments for percentage of ranolazine remaining at the 30 minute time point is 57%. The compounds of this invention were assayed as described in the protocol below and the percentage of parent remaining was divided by the average of ranolazine remaining affording a metabolic stability factor.

A compound with a stability number greater than 1.2 has a better stability than ranolazine in the liver S-9 assay. A compound with a stability number between 1.2 and 0.8 has an equivalent stability in the liver S-9 assay. A compound with a stability number less than 0.8 is less stable than ranolazine in the liver S-9 assay.

The purpose of this experiment is to compare the percentages remaining for compounds of this invention with the percentage remaining for ranolazine after 30 minutes of incubation with human liver S9 fractions.

Reagents: The following reagents were used; Potassium phosphate, 0.5M pH 7.4 (incubation buffer), kept at room temperature; 0.05M MgC 2 kept at 4°C; P-Nicotinamide adenine dinucleotide phosphate, tetrasodium salt, reduced form (NADPH), 0.02M solution in water (-16.6mg/mL) from Sigma Lot 79H7044 prepared on day of use. 1mM of ranolazine or Compounds 43, 45, 47, 52, 70, 74, 76, 78, and 80 in ACN further diluted to obtain 100pM in ACN; Human S9 stock: 20mg/mL from Gentest.

Procedure: Incubation mixtures were prepared as follows: WO 01/62744 PCT/US01/05606 Table 3 Component Volume per 0.25mL of Incubation Final Mixture concentration CVT 25pL 10 LM compounds MgC1 2 25tL 0.005 M NADPH 25pL 0.002 M S9 25gL 2 mg/mL Incubation Buffer 25pL 0.05 M Water 125pL 1% organic solvent (acetonitrile) was used in incubation mixture. Generally, 30 incubates were prepared at a time by pre-mixing 0.75 mL of MgCl 2 0.75 mL of incubation buffer, 0.75 mL of NADPH, 3.75 mL of water. Then pipette 200 tL/incubate, add 25 ItL of compound being tested, mix, and initiate reaction by addition of S-9.

Combine all components with incubation buffer and re-pipette 200 pL/tube of the compound being tested along with 25pL of S-9.

After 5 min ofpre-incubation at 37 0 C, at 0 and 30min after starting the reaction, a ptl aliquot of the incubation mixture was removed and added to 100 gL of 9:1 acetonitrile: methanol containing the internal standard.

The mixture was centrifuged and a 100 gL aliquot of the supernatant was diluted in lmL of solvent C Formic Acid in water). Then samples were analyzed for change between the ratio of compound to internal standard at time zero and 30 minutes by LC/MS (injected 10 pL).

Analytical and Data Calculations: Samples were analyzed for the starting compounds and potential metabolite/s by LC/MS using an internal standard and an ODS-C18 column with a flow rate of 0.25 ml/min.

Following the above procedure resulted in the following relative stability factors as compared to ranolazine for the compounds of this invention as illustrated in Table 4. If a compound is more stable than ranolazine in the liver S9 assay, than the stability factor will be greater than If a compound is less stable than ranolazine, than the stability factor will be less than WO 01/62744 WO 0162744PCT/US01/05606 Table 4 Compound Liver S9 Stability Factor Ranolazine 0.45 7 1.51 1.20 16 0.15 17 0.45 9B 1.18 108 1.03 7B 1.46 11B 1.33 12B 1.38 13B 0.10 1 6B 0.99 1 7B 0.71 1 8B 0.68 1 9B 21B 22B 1.49 23B 24B 1.05 26B 27B__ 21C 22C 0.61 23C 0.05 24C 0.02 0.01 26C__ 27C__

Claims (77)

1. A substituted piperazine compound having the following formula: R R 3 RO R 11 0 R -R12 4N N X R24 R R 7 R 8 ^Ri3 OH 6R R1 3 OH R 5 R 16 R 15 R 14 wherein X is selected from the group consisting of: and wherein m 1 or 2 or 3; R 1 R 2 R 3 R 4 and R 5 are each independently selected from the group consisting of hydrogen, halo, CF 3 CN, OR 23 SR 23 N(R 2 3 2 SO 2 N(R 23 2 COR 23 C1- 15 alkyl, C2-1 5 alkenyl, heterocyclyl and aryl; or R 2 and R 3 may join together to form a fused ring system having from three to four carbon atoms; or R 4 and R 5 may join together with the phenyl group to which they are attached to form an optionally substituted naphthyl moiety; R 6 R 7 and R 8 are each independently selected from the group consisting of hydrogen and Ci- 15 alkyl; R 9 Rio, R 1 1 Ri 2 Ri 3 RI 4 R 5 and RI 6 are each independently selected from the group consisting of hydrogen, C-4 alkyl, and aryl; or R 9 and Rio, R 1 1 and RI2, RI 3 and R 14 or R 1 5 and R 16 may together form a carbonyl; or R 1 1 and R 1 s, or R 9 and R 13 may together form a bridging ring system having from 1 to 4 carbon atoms; or R 9 and Rio or R 11 and R 12 or R 1 3 and R 1 4 or R 15 and R 1 6 may join to form a bridging ring system having from 1 to 5 carbon atoms with the proviso that R 9 Rio, R 1 l, RI 2 R 13 R 1 4 R 1 5 and R 1 6 are not all hydrogen when R 24 is phenyl and when X is: 004464932v14 m0 o R 23 is selected from the group consisting of H, and CI- 3 alkyl; and R 24 is selected from the group consisting of alkyl, cycloalkyl, fused phenylcycloalkyl wherein the point of attachment is on the cycloalkyl, and R 1 8 R 17 Ri9 X R21 wherein R 17 R 18 Ri 9 R 2 0 and R 21 are each independently selected from the group consisting of hydrogen, halo, OR 23 CI- 15 alkyl, C2-1 5 alkenyl, and phenyl, and further wherein the alkyl substituent is optionally substituted with from 1 to 3 substituents selected from the group consisting of halo, phenyl, CF 3 OR 20 and Ci- 6 alkyl.

2. A substituted piperazine compound of claim 1 having the following formula: R R, 0 R9 R12 R 17 R1 R3 R 15 R 14 1 R19 4 R 5 R14 RR21 IA wherein m 1 or 2; RI, R 2 R 3 R 4 and R 5 are each independently selected from the group consisting of hydrogen, halo, CF 3 CN, OR 2 3 SR 23 N(R 2 3 2 SO 2 N(R 23 2 COR 23 C1- 15 alkyl, C 2 -1 5 alkenyl, heterocyclyl, and aryl; or R 2 and R 3 may join together to form a fused ring system having from three to four carbon atoms; R4 and R 5 may join together with the phenyl group to which they are attached to form an optionally substituted naphthyl moiety; I 004464932v14 R 6 R 7 and R8 are each independently hydrogen; R9, Rio, R 11 RI2, RI3, R 14 R 15 and R 16 are each independently selected from the group consisting of hydrogen, CI-4 alkyl, or R9 and Rio, R 1 1 and R12, Ri 3 and R14, or Ri5 and R16 may together form a carbonyl, or RII and R 1 5 or R9 and Ri 3 may join together to form a bridging ring system having from 1 to 4 carbon atoms, or R9 and Rio, R 1 1 and R12, R13 and R14, or R 1 5 and R 1 6 may join to form a ring system having from 1 to 5 carbon atoms with the proviso that R 9 Rio, R 1 1 R12, R 13 RI4, R 1 5 and RI6 are not all hydrogen when m equals 1; R 1 7 Ri1, R19, R20, and R21 are each independently selected from the group consisting of hydrogen, halo, OR23, C 1 -1 5 alkyl, and phenyl; and R 2 3 is selected from the group consisting of H and C 1 -3 alkyl.

3. A compound of claim 2 wherein RI, R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, halo, CF 3 CN, OR23, SR 23 N(R 2 3 2 SO 2 N(R 23 2 COR 23 C 1 -8 alkyl, C2- 8 alkenyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl substituent is optionally substituted with 1 substituent selected from the group consisting of OR23, or R 2 and R3 may join together to form a fused ring system wherein having from three to four carbon atoms, or R4 and R5 may join together with the phenyl group to which they are attached to form an optionally substituted naphthyl moiety; and R9, Rio, Ri, RI2, RI3, R14, Ri5 and RI6 are each independently selected from the group consisting of hydrogen and C1- 4 alkyl, or R9 and Rio, Rl1 and R12, R13 and RI4, or R15 and R16 may together form a carbonyl, or R1, and R13, R9 and Ri5, R9 and R1, R11 and R15, or R9 and RI3 may join together to form a bridging ring including from 1 to 4 carbon atoms.

4. A compound of claim 3 wherein RI, R2, R3, R 4 and R5 are each independently selected from the group consisting of hydrogen, halo, CF 3 CN, OR23, SR 23 N(R 23 2 SO 2 N(R 23 2 COR 23 C1- 6 alkyl, C2- 6 alkenyl, heterocyclyl, and heteroaryl, wherein the alkyl substituent is optionally substituted with OR23, or R2 and R3 may join together to form a fused ring system having from three to four carbon atoms, or 004464932v13 R 4 and R 5 may join together with the phenyl group to which they are attached to optionally substituted naphthyl moiety; R 9 Rio, R 1 1 R 12 RI 3 R 14 R 15 and R 1 6 are each independently selected from the group consisting of hydrogen and C1- 2 alkyl, or R 9 and Rio, R 11 and RI 2 R 1 3 and R 14 or R 1 5 and RI 6 may together form a carbonyl; and R 17 R 1 8 RI9, R 20 and R 2 1 are each independently selected from the group consisting of hydrogen, halo, OR 23 C 1 -8 alkyl and phenyl.

A compound of claim 4 wherein RI, R 2 R 3 R 4 and R 5 are each independently selected from the group consisting of hydrogen, halo, CF 3 CN, OR 23 SR 23 N(R 23 2 S02N(R 23 2 COR 23 C 1 3 alkyl, C2- 6 alkenyl, and heterocyclyl, wherein the alkyl substituent is optionally substituted with OR 23 or R 2 and R 3 may join together to form a fused ring system having from three to four carbon atoms, or R 4 and R 5 may join together with the phenyl group to which they are attached to form an optionally substituted a naphthyl moiety; and R 9 Rio, R 1 1 R 12 R 1 3 R 14 R 15 and R 16 are each independently selected from the group consisting of hydrogen and C 1 -2 alkyl, or R 9 and Rio, R 11 and R 12 R 13 and RI 4 or R 15 and R 16 may together form a carbonyl.

6. A compound of claim 5 wherein R 9 Rio, R 11 R 1 2 R 1 3 R 14 R 1 5 and RI6 are each independently selected from the group consisting of hydrogen and methyl, or R 9 and Rio, or R 1 3 and R 14 may together form a carbonyl; R 17 R 1 8 R 19 R2o, and R 21 are each independently selected from the group consisting of hydrogen, halo and C 1 2 alkyl; and R 23 is selected from the group consisting of hydrogen and methyl.

7. A compound of claim 4 wherein R 18 R 1 9 R 20 and R 2 1 are each hydrogen, and R 1 7 is selected from the group consisting of halo and OR 23

8. A compound of claim 7 wherein R 1 2 is (S)-methyl; and R 9 Rio, R 11 R 13 R 14 R 15 and R 1 6 are hydrogen.

9. A compound of claim 7 wherein R 9 and Rio together form a carbonyl; and I 004464932v13 R 11 R 1 2 RI 3 RI 4 R 1 5 and RI 6 are hydrogen.

A compound of claim 7 wherein R 9 Rio, R 11 RI 2 R 1 5 and RI 6 are each hydrogen; and R 13 and R 1 4 together form a carbonyl.

11. A compound of any one of claims 3 to 10 wherein m 1.

12. A compound of claim 7 wherein RI, R 2 R 3 R 4 and R 5 are each independently selected from the group consisting of hydrogen, halo, CF 3 CN, OR 23 SR 23 N(R 23 2 SO 2 N(R 23 2 COR 23 C1- 3 alkyl, C2- 3 alkenyl, N-morpholino, and pyrrolyl, wherein the alkyl substituent is optionally substituted with OH, or R 2 and R 3 may join together to form a fused ring system having three carbon atoms, or R 4 and R 5 may join together with the phenyl group to which they are attached to form an optionally substituted naphthyl moiety.

13. The compound of claim 2 wherein R 1 R 2 R 3 R 4 and R 5 are each independently selected from the group consisting of hydrogen, halo, CF 3 OR 23 and C1- 2 alkyl; R 9 Rio, RII, R 12 R 13 RI 4 R 1 5 and R 1 6 are each independently selected from the group consisting of hydrogen and C1-4 alkyl, or R 9 and Rio, R 1 1 and RI 2 RI 3 and R 14 or R 15 and R 1 6 may together form a carbonyl, with the proviso that R 9 Rio, R 1 1 RI2, RI 3 RI 4 R 15 and R 16 are not all simultaneously hydrogen when m 1, or R 11 and RI 3 R 9 and R 5 l, R 9 and R 11 Rn 1 and R 5 l, R 9 and Ri 3 may join to form a ring including from 1 to 4 carbon atoms; R 1 7 R 18 R 19 R 20 and R 21 are each independently selected from the group consisting of hydrogen, halo, OR 23 C1-4 alkyl, and aryl; and wherein R 23 is C1- 2 alkyl.

14. A compound of claim 13 wherein RI, R 2 R 3 R 4 and Rs are each independently selected from the group consisting of hydrogen, and methyl. A compound of claim 13 wherein R 9 Rio, R 11 R 12 R 1 3 RI 4 R 1 5 and R 1 6 are each independently selected from the group consisting of hydrogen and C1- 2 alkyl, or R 9 and Rio, or R 1 5 and R 16 may together form a carbonyl with the proviso that R 9 Rio, R 1 1 R 1 2 RI 3 RI 4 R 15 and RI 6 are not all simultaneously hydrogen when m 1, or 004464932v13 Rl 1 and RI 3 R 9 and R

1 5 R 9 and R 11 R 11 and R 15 or R 9 and RI 3 may join to form a ring having from 1 to 2 carbon atoms.

16. A compound of claim 13 wherein R 9 Rio, R 11 R 12 Ri 3 R 14 R 1 5 and R 1 6 are each independently selected from the group consisting of hydrogen and C 1 -2 alkyl, or R 9 and Rio, or R 11 and R 1 2 or R 13 and R 14 or R 1 5 and RI 6 may together form a carbonyl.

17. A compound of claim 13 wherein R 9 and Rio together form a carbonyl, R 1 5 and R 16 together form a carbonyl or both R 9 and Rio and R 15 and R 1 6 together form a carbonyl.

18. A compound of claim 13 wherein R 17 R 1 8 Ri 9 R 20 and R 2 1 are each independently selected from the group consisting of hydrogen, halo, Ci-4 alkyl and OR 23 wherein R 23 is C1- 2 alkyl.

19. A compound of claim 2 wherein m 1; RI, R 2 R 3 R 4 and R 5 are each independently selected from the group consisting of hydrogen, and methyl; R 9 Rio, R 11 R 12 RI 3 Ri 4 R 15 and R 16 are each independently selected from the group consisting of hydrogen and CI-4 alkyl, or R 9 and Rio, R 11 and R 12 Ri 3 and Ri 4 or R 1 5 and Ri 6 may together form a carbonyl with the proviso that R 9 Rio, R 11 RI 2 Ri 3 RI 4 R 15 and R 16 are not all simultaneously hydrogen or Rli and R 1 3 or R 9 and R 15 or R 9 and R 11 or R 11 and R 1 5 or R 9 and R 11 may join to form a ring including from 1 to 4 carbon atoms; R 1 7 R 1 8 RI9, R 20 and R 21 are each independently selected from the group consisting of hydrogen, halo, Ci-4 alkyl and OR 23 and R 23 is C 1 2 alkyl.

A compound of claim 19 wherein R 1 and R 5 are each methyl and R 2 R 3 and R4 are each hydrogen.

21. A compound of claim 19 wherein R 11 R 12 RI 3 Ri 4 R 1 5 and Ri 6 are each hydrogen and R 9 and Rio together form carbonyl.

22. A compound of claim 19 wherein R 9 Rio, R 1 1 Ri2, R 1 5 and R 1 6 are each hydrogen and Ri 3 and RI 4 together form carbonyl. 004464932013

23. A compound of claim 19 wherein R 9 R, 0 R, 1 RI 2 RI 3 RI 4 RI 5 and RI 6 are each independently selected from the group consisting of hydrogen and methyl.

24. A compound of claim 19 wherein R 12 R 13 R 14 R 15 and R 16 are each hydrogen and RIO and R, 1 together form a ring having from 1 to 4 carbon atoms.

A compound of claim 19 wherein R 9 Rio, R 12 R 13 R 14 and R 16 are each hydrogen and R, I and R 15 together form a ring having from 1 to 3 carbon atoms.

26. A compound of claim 19 wherein RI 8 RI 9 and R 21 are each hydrogen and RI 7 and RI 8 are each methyl.

27. A compound of claim 19 wherein RI 7 is -OCH 3 and RI 8 9 R 1 R 2 o and R 2 1 are each hydrogen.

28. A compound of claim 19 wherein R 1 R 18 R 20 and R 21 are each hydrogen and Rig is selected from the group consisting of -OCH 3 and C14 alkyl.

29. A compound of claim 2 selected from the group consisting of: N-(2,6-dimethylphenyl)-2- {4-[2-hydroxy-3-(2-methoxyphenoxy)propyl]-3- oxopiperazinyl}I acetamide, N-(2,6-dimethylphenyl)-2- {4-[2-hydroxy-3-(2-methoxyphenoxy)propyl] dimethylpiperazinyl} acetamide, S,2R)-4-[2-hydroxy-3-(2-methoxyphenoxy)propyl]-2,5-dimethylpiperazinyl} -N- (2,6-dimethylphenyl)acetamide, 2- {2,5-diaza-5-[2-hydroxy-3-(2-methoxyphenoxy)propyl]bicyclo[4.4.O]dec-2-yl} -N- (2,6-dimethylphenyl)acetamide, N-(2,6-dimethylphenyl)-2- {4-[2-hydroxy-3-(2-methoxyphenoxy)propyl]-3- oxopiperazinyl} acetamide, N-(2,6-dimethylphenyl)-2- {4-12-hydroxy-3-(2-methoxyphenoxy)propyl]-3 ,3- dimethylpiperazinyl} acetamide, 2- {5-[(2S)-2-hydroxy-3-(2-methoxyphenoxy)propyl]( 1 S,4S)-2,5- diazabicyclo[2.2.1I ]hept-2-yl} -N-(2,6-dimethylphenyl)acetamide, N-(2,6-dimethylphenyl)-2- {4-[2-hydroxy-4-(2-methoxyphenoxy)butyl]- piperazinyl} acetamide, 004464932v1 3 N-(2,6-dimethylphenyl)-2-{f4-[4-(4-fluorophenoxy)-2-hydroxybutyl]- piperazinyl}I acetamnide, f{4-[4-(tert-butyl)phenoxy] -2-hydroxybutyl) piperazinyl)-N-(2,6-dimethylphenyl) acetamnide, N-(2,6-dimethylphenyl)-2- f{4-[2-hydroxy-4-(4-phenylphenoxy)butyl] piperazinyl} acetamnide, N-(2,6-dimethylphenyl)-2- {4-[2-hydroxy-4-(4-methoxyphenoxy)butyl]- piperazinyl} acetamide, 2-1{(3 S)-4-I(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl] -3-methylpiperazinyl} dimethylphenyl)acetaimide, 2- f{(3 -(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl} dichiorophenyl) acetamnide, S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl} sulfamoylphenyl) acetamide, 2- S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl] -3-methylpiperazinyl} methoxy-3-(trifluoromethyl)phenyl] acetamide, 2- f{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl} -N- 2- S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl] -3-methylpiperazinyl} -N- naphthylacetamide, 2- {(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl} chloronaphthyl) acetamnide, S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl} pyrrolyiphenyl) acetamide, 2- S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl] -3-methylpiperazinyl} -N- phenylacetamide, S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl} chiorophenyl) acetamide, S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl] -3-methylpiperazinyl} chloro-4-methylphenyl)acetamide, S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl} 1- methylvinyl)phenyl] acetamide, 004464932013 2- f{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl] -3-methylpiperazinyl} methyiphenyl) acetamide, 2- {(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl] -3-methylpiperazinyl} methyl-2-(methylethyl)phenyl] acetamide, 2- S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl} methyithiophenyl) acetamnide, 2- {(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3 -methylpiperazinyl} acetamide, S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl} (dimethylamino) phenyl] acetamide, 2- S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl} dimethoxyphenyl) acetamide, S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl] -3-methylpiperazinyl} ,4- dichiorophenyl) acetamide, 2- S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl} chiorophenyl) acetamide, 2- S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl} chiorophenyl) acetamide, 2- {(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl} dichiorophenyl) acetamide, 2- S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl] -3-methylpiperazinyl} methoxyphenyl) acetamide, 2- f{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl} methyiphenyl) acetamide, 2- S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl] -3-methylpiperazinyl} methyiphenyl) acetamide, 2- S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl} fluorophenyl) acetamide, S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl] -3-methylpiperazinyl} cyanophenyl) acetamide, 2- S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl} acetylphenyl) acetamide, 004464932013 S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl} methoxyphenyl) acetamide, [(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl} (trifluoromethyl)phenyl] acetamide, S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl} chloro-3-(trifluoromethyl)phenyl] acetamide, 2- S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl} dimethoxyphenyl) acetamide, S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl] -3-methylpiperazinyl} morpholin-4-ylphenyl) acetamide, S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl} fluoro-4-methoxyphenyl) acetamide, 2- S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl} -N- (3 ,4,5-trimethoxyphenyl) acetamide, 2- {(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl} ,4- dimethoxyphenyl) acetamide, S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl)}-N-(4- chloro-2-fluorophenyl) acetamide, and 2- {(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl} (hydroxymethyl-6-methylphenyl] acetamide.

A substituted piperazine compound having the following formula: R2 R, R9 Rio R11R 12 R1R8 0 R3 NNN Ri ~~R16R 15 R 14 ,R13R1R2 wherein m= lor 2or 3; 004464932v13 R 1 R 2 R 3 R 4 and R 5 are each independently selected from the group consisting of hydrogen and Ci-lo alkyl; R 6 R 7 and R 8 are each independently selected from the group consisting of hydrogen and Ci-lo alkyl; R 9 Rio, R 1 R 1 2 Ri 3 RI 4 R 1 5 and R 16 are each independently hydrogen; R 17 R 18 RI9, R 20 and R 2 1 are each independently selected from the group consisting of hydrogen, halo, OR 23 C1- 1 5 alkyl, or R 1 7 and R 1 8 R 8 i and R 1 9 R 1 9 and R 20 or R 20 and R 21 may combine to form a saturated ring including from 5 to 6 carbon atoms wherein from 0 to 2 carbon atoms may be substituted with an oxygen atom, or R 17 and R 18 may together form -CH=CH-CH=CH-; and R 23 is selected from the group consisting of C1-3 alkyl.

31. A compound of claim 30 wherein RI, R 2 R 3 R4 and R 5 are each independently selected from the group consisting of hydrogenand C 1 -8 alkyl; R 6 R 7 and R 8 each independently selected from the group consisting of hydrogen and alkyl; and R 17 R 18 RI9, R 20 and R 21 are each independently selected from the group consisting of hydrogen, halo, OR 23 C 1 -8 alkyl, or RI9 and R 20 may combine to form a saturated ring including from 5 to 6 carbon atoms wherein from 0 to 2 carbon atoms may be substituted with an oxygen atom or R 1 7 and R 18 may together form -CH=CH-CH=CH-.

32. A composition of claim 34 wherein R 1 R 2 R 3 R 4 and R 5 are each independently selected from the group consisting of hydrogen and C 1 6 alkyl; R 6 R 7 and R 8 each independently selected from the group consisting of hydrogen and C 1 3 alkyl; and R 17 R 18 R 1 9 R 20 and R 2 1 are each independently selected from the group consisting of hydrogen, halo, OR 23 and C1- 6 alkyl, or R 19 and R 2 0 may combine to form a saturated ring including from 5 to 6 carbon atoms wherein 0 to 2 carbon atoms may be substituted with an oxygen atom, or wherein R17 and R 18 may together form -CH=CH-CH=CH-.

33. The compound of claim 32 wherein 004464932v13 R 6 R 7 and R 8 are each independently selected from the group consisting of hydrogen and methyl.

34. A compound of claim 32 wherein RI, R 2 R 3 R 4 and R 5 are each independently selected from the group consisting of hydrogen and C 1 -2 alkyl; R 6 is hydrogen; and R 7 and R 8 are each independently selected from the group consisting of hydrogen and methyl; and R 23 is selected from the group consisting of H and methyl.

35. A compound of claim 34 wherein R 17 R 1 8 RI9, R 20 and R 21 are each independently selected from the group consisting of hydrogen, halo, OR 23 and C-4 alkyl, or R 1 9 and R 20 may combine to form a saturated ring including 5 carbon atoms wherein 2 carbon atoms may be substituted with an oxygen atom or wherein R17 and R 18 may together form -CH=CH-CH=CH-.

36. A compound of claim 34 wherein R 1 7 Ri 8 RI 9 R 20 and R 2 1 are each independently selected from the group consisting of hydrogen, halo, OR 23 and CI-4 alkyl, or Ri 9 and R 20 may combine to form -O-CH 2 or -OCH 2 CH 2 0- or R 1 7 and R 1 8 may together form -CH=CH-CH=CH-.

37. A compound of claim 30 wherein m 1 or 2; RI, R 2 R 3 R 4 and R 5 are each independently selected from the group consisting of hydrogen, halo and C 1 -2 alkyl; R 6 R 7 and Rs each independently selected from the group consisting of hydrogen and methyl; and R 1 7 R 18 R 19 R 20 and R 2 1 are each independently selected from the group consisting of hydrogen, halo, OR 23 and C 1 -3 alkyl, or R 17 and R 18 or R 1 8 and R 19 may together form a ring selected from the group consisting of-CH=CH-CH=CH-, -O-CH 2 and -O-CH 2 -CH 2 and R 23 is C1- 2 alkyl.

38. A compound of claim 37 wherein R I R 2 R 3 R 4 and R 5 are each independently selected from the group consisting of hydrogen, and methyl. 004464932v13

39. A compound of claim 48 wherein R 6 R 7 and R 8 are each hydrogen.

A compound of claim 37 wherein R 17 R 1 8 R 1 9 R 20 and R 21 are each independently selected from the group consisting of hydrogen, halo, C1- 24 alkyl and OR 23 and R 23 is C1- 2 alkyl.

41. A compound of claim 37 wherein R 1 7 and R 18 or R 18 and RI9 together form a ring selected from the group consisting of- CH=CH-CH=CH-, and -O-CH 2 -O.

42. A compound of claim 30 wherein m 1 or 2; RI, R 2 R 3 R4 and R 5 are each independently selected from the group consisting of hydrogen, and methyl; R 6 R 7 and R 8 are each hydrogen; R 1 7 R 18 R 19 R 20 and R 21 are each independently selected from the group consisting of hydrogen, halo, C 1 -4 alkyl, and OR 23 and R 23 is C1- 2 alkyl.

43. A compound of claim 42 wherein R 1 and R 5 are each methyl and R 2 R 3 and R 4 are each hydrogen.

44. A compound of claim 42 wherein R 17 R 18 R 1 9 R 20 and R 2 1 are each selected from the group consisting of hydrogen, Cl, F, -OCH 3 -CF 3 and C1- 4 alkyl.

45. A compound of claim 44 wherein R 1 8 and R 20 are each hydrogen.

46. A compound of claim 44 wherein R 19 is -OCH 3

47. A compound of claim 42 wherein R 17 is -OCH 3 and R 1 8 RI9, R 20 and R 21 are each hydrogen.

48. A compound of claim 42 wherein R17, R 18 R 20 and R 2 1 are each hydrogen and R 19 is selected from the group consisting of-OCH 3 and Cl-4 alkyl.

49. A substituted piperazine compound of claim 30 selected from the group consisting of: N-(2,6-dimethylphenyl)-2-[4-(2-hydroxy-4-phenylbutyl)piperazinyl] acetamide; N-(2,6-dimethylphenyl)-2- {4-[2-hydroxy-3-(2- methoxyphenyl)propyl]piperazinyl} acetamide; 2-[4-(3-(2H-benzo[d]1,3-dioxolen-5-yl)-2-hydroxypropyl)piperazinyl]-N-(2,6- dimethylphenyl) acetamide; 004464932013 N-(2,6-dimethylphenyl)-2- f{4-[2-hydroxy-3-(4- methoxyphenyl)propyl]piperaziny}I acetamide; N-(2,6-dimethylphenyl)-2- {4-[2-hydroxy-3-phenylpropyl]piperazinyl} acetamide; N-(2,6-dimethylphenyl)-2- f{4-[4-(4-methoxyphenyl)-2-hydroxybutyl]piperazinyl} acetamide, 2- {4-[4-(2,6-difluorophenyl)-2-hydroxybutyl]piperazinyl} -N-(2,6-dimethylphenyl) acetamide, N-(2,6-dimethylphenyl)-2- {4-[4-(2-chlorophenyl)-2-hydroxybutyl]piperazinyl} acetamide, {4-[4-(tert-butyl)phenyl]-2-hydroxybutyl} piperazinyl)-N-(2,6-dimethylphenyl) acetamide, N-(2,6-dimethylphenyl)-2- f{4-[4-(2-fluorophenyl)-2-hydroxybutyl]piperazinyl} acetamide, N-(2,6-dimethylphenyl)-2-(4- {2-hydroxy-4-[4-(trifluoromethyl)phenyl]butyl} piperazinyl)acetamide, -(2H-benzo[d] 1 ,3-dioxolen-5-yl)-2-hydroxypropyl)piperazinyl] dimethylphenyl)-2-methylpropanamnide, N-(2,6-dimethylphenyl)-2-[4-(2-hydroxy-3-phenylpropyl)piperazinyl]-2- methyipropanamide, N-(2,6-dimethylphenyl)-2- {4-[2-hydroxy-3-(3,4,5-trimethoxyphenyl)propyl] pip erazinyl} -2-methyipropanamnide, N-(2,6-dimethylphenyl)-2-[4-(2-hydroxy-5-phenylpentyl)piperazinyl] acetamide, N-(2,6-dimethylphenyl)-2- {4-[5-(2-fluorophenyl)- 2-hydroxy-pentyl]piperazinyl} acetamide, and N-(2,6-dimethylphenyl)-2- {4-[5-(2-chlorophenyl)- 2-hydroxy-pentyl]piperazinyl} acetamide.

A substituted piperazine compound having the following formula: I 004464932v13 R 0 -R24 R R6 R 7 R8 R13 OH R 5 R 16 R 15 R 14 wherein m 1; R 1 R 2 R 3 R 4 and R 5 are each independently selected from the group consisting of hydrogen and C 1 o alkyl; R 6 R 7 and R 8 are each independently hydrogen; R 9 Rio, R 11 R 1 2 Ri 3 R 14 R 1 5 and RI 6 are each independently selected from the group consisting of hydrogen and CI-4 alkyl; R 2 4 is selected from the group consisting of C-lo 0 alkyl, cycloalkyl, and fused phenylcycloalkyl wherein the point of attachment is on the cycloalkyl, wherein the alkylis optionally substituted with from 1 to three substituents selected from the group consisting of halo, CF 3 OR 20 ,and CI- 2 alkyl; and R 20 is selected from the group consisting of C 1 -3 alkyl.

51. The compound of claim 50 wherein Ri, R 2 R 3 R 4 and R 5 are each independently selected from the group consisting of hydrogen and C 1 -8 alkyl.

52. A compound of claim 50 wherein RI, R 2 R 3 R 4 and R 5 are each independently selected from the group consisting of hydrogen and C.-5 alkyl; R 24 is selected from the group consisting of Ci-lo alkyl, cycloalkyl, and fused phenylcycloalkyl wherein the point of attachment is on the cycloalkyl, wherein the alkyl is optionally substituted with from 1 to two substituents selected from the group consisting of aryl, wherein the optional aryl substituent is optionally substituted with from 1 to 3 substituents selected from the group consisting of halo, phenyl, CF 3 OR 20 and C 1 -6 alkyl.

53. The compound of claim 50 wherein R 1 R 2 R 3 R4 and R 5 are each independently selected from the group consisting ofhydrogenand C 1 -3 alkyl; R 9 Rio, R 1 R 12 RI 3 RI 4 R 1 5 and R 16 are each independently selected from the group consisting of hydrogen and C 1 2 alkyl; and I 004464932v13 R 24 is selected from the group consisting of Cl-lo alkyl, cycloalkyl, and fused phenylcycloalkyl, wherein the point of attachment is on the cycloalkyl, wherein the alkylis optionally substituted with from 1 to two substituents selected from the group consisting of aryl, wherein the optional aryl substituent is optionally substituted with from 1 to 3 substituents selected from the group consisting of halo, phenyl, CF 3 CN, OR 20 and C 1 6 alkyl.

54. A compound of claim 50 wherein RI, R 2 R 3 R 4 and R 5 are each independently selected from the group consisting of hydrogen and C 1 -3 alkyl.

A compound of claim 50 wherein R 1 R 2 R 3 R 4 and R 5 are each independently selected from the group consisting of hydrogen and C1- 2 alkyl; R 9 Rio, R 1 1 RI 2 RI 3 RI 4 R 1 5 and RI 6 are each independently selected from the group consisting of hydrogen and C1- 2 alkyl; R 24 is selected from the group consisting of C- 1 lo alkyl, cycloalkyl, and fused phenylcycloalkyl wherein the point of attachment is on the cycloalkyl, wherein the alkylis optionally substituted with from 1 to two substituents selected from the group consisting of aryl, wherein the optional aryl substituent is optionally substituted with from 1 to 2 substituents selected from the group consisting of halo, phenyl, CF 3 OR 20 and C-4 alkyl..

56. A compound of claim 50 wherein R 24 is selected from the group consisting of Ci-o alkyl, cycloalkyl, and fused phenylcycloalkyl wherein the point of attachment is on the cycloalkyl, wherein the alkylis optionally substituted with 1 substituent selected from the group consisting of aryl wherein the optional aryl substituent is optionally substituted with from 1 to 2 substituents selected from the group consisting of halo, phenyl, CF 3 OR 2 0 and Ci-4 alkyl.

57. The compound of claim 55 wherein R 1 R 2 R 3 R 4 and R 5 are each independently selected from the group consisting of hydrogen and methyl.

58. A compound of claim 55 wherein R 24 is C1- 6 alkyl or C2- 6 cycloalkyl.

59. A compound of claim 55 wherein R 24 is a fused phenylcycloalkyl.

A compound of claim 55 wherein R 24 is phenylmethyl.

61. A compound of claim 55 wherein R 2 R 3 and R 4 are each hydrogen and R 1 and R 5 are each methyl.

62. A compound of claim 50 wherein R 1 R 2 R 3 R 4 and R 5 are each independently selected from the group consisting of hydrogen or methyl; 004464932013 R 9 9 R 10 R 1 R 12 R 13 R 14 R 15 and R 16 are each hydrogen; and R 24 is selected from the group consisting Of C 1 6 alkyl, C 2 6 cycloalkyl and fused phenylcycloalkyl.

63. A compound of claim 50 selected from the group consisting of: {2-[4-(3-isopropoxy-2-hydroxypropyl)piperazinyl]- {2,6-dimethylphenyl) acetamide; N-(2,6-dimethylphenyl)-2-[4-(2-hydroxy-3-indan-2-yloxypropyl)piperazinyl] acetamide; N-(2,6-dimethylphenyl)-2- {4-[2-hydroxy-3-(phenylmethoxy)propyl]piperazinyl} acetamide, {2-[4-(3-cyclopentyloxy-2-hydroxypropyl)piperazinyl]- 2,6-dimethylphenyl) acetamide, {2-[4-(3-cyclohexyoxy-2-hydroxypropyl)piperazinyl] {2,6-dimethylphenyl) acetamide, [4-(tert-butyl)phenyl]methoxy} -2-hydroxypropyl)piperazinyl]-N-(2,6- dimethylphenyl)acetamide, N-(2,6-dimethylphenyl)-2-(4- {3-[(2-fluorophenyl)methoxy]-2-hydroxypropyl} piperazinyl) acetamide, {3-[(2,4-difluorophenyl)methoxy]-2-hydroxypropyl}piperazinyl)-N-(2,6- dimethylphenyl)acetamide, N-(2,6-dimethylphenyl)-2-[4-(2-hydroxy-3- [4-(trifluoromethyl)phenyl]methoxy} propyl)piperazinyl]acetamide, N-(2,6-dimethylphenyl)-2-(4- {2-hydroxy-3-[(2-methoxyphenyl)methoxy]propyl} piperazinyl)acetamide, {3-[(2,4-dimethoxyphenyl)methoxy]-2-hydroxypropyllpiperazinyl)-N-(2,6- dimethylphenyl)acetamide, N-(2,6-dimethylphenyl)-2-(4- f{2-hydroxy-3-[(4-methoxyphenyl)methoxy]propyl} piperazinyl)acetamide, N-(2,6-dimethylphenyl)-2-(4- {3-[(4-fluorophenyl)methoxy]-2-hydroxypropyl} piperazinyl)acetamide, N-(2,6-dimethylphenyl)-2-(4- {2-hydroxy-3-[(4-methylphenyl)methoxy]propyl} piperazinyl)acetamide, 004464932v13 N-(2,6-dimethylphenyl)-2-(4-{2-hydroxy-3-[(4-phenylphenyl)methoxy]propyl} piperazinyl)acetamide, N-(2,6-dimethylphenyl)-2-(4-{3-[(4-butylphenyl)methoxy]-2-hydroxypropyl} piperazinyl)acetamide, N-(2,6-dimethylphenyl)-2- {4-[2-hydoxy-3-(2-naphthylmethoxy)propyl]piperazinyl} acetamide, N-(2,6-dimethylphenyl)-2- {4-[3-(cyclohexylmethoxy)-2-hydroxypropyl]piperazinyl} acetamide, and N-(2,6-dimethylphenyl)-2-(4-{3-[(4-fluorophenyl)methoxy]-2-hydroxypropyl} -3,3- dimethylpiperazinyl)acetamide.

64. A method of treatment comprising administering a therapeutically effective amount of a compound according to any one of claims 1 to 63 to a mammal in need of a treatment selected from the group consisting of protecting skeletal muscles against damage resulting from trauma, protecting skeletal muscles subsequent to muscle or systemic diseases, treating shock conditions, preserving donor tissue and organs used in transplants, and treating cardiovascular diseases.

A method according to claim 64 wherein the cardiovascular disease is selected from the group consisting of atrial and ventricular arrhythmias, Prinzmetal's (variant) angina, stable angina, exercise induced angina, congestive heart disease, and myocardial infarction.

66. A method according to either claim 64 or 65 wherein the therapeutically effective amount ranges from about 0.01 to about 100 mg/kg weight of the mammal.

67. A method according to any one of claims 64 to 66 wherein the mammal is a human.

68. A pharmaceutical composition comprising the compound according to any one of claims 1 to 63 and one or more pharmaceutical excipients.

69. A pharmaceutical composition according to claim 68 wherein the pharmaceutical composition is in the form of a solution.

A pharmaceutical composition according to claim 68 wherein the pharmaceutical composition is in a form selected from the group consisting of a tablet and a capsule.

71. Use of an effective amount of a compound according to any one of claims 1 to 63, for the preparation of a pharmaceutical composition for the administration to a mammal in need of a treatment selected from the group consisting of protecting skeletal muscles against I 004464932v16 damage resulting from trauma, protecting skeletal muscles subsequent to muscle or systemic diseases, treating shock conditions, preserving donor tissue and organs used in transplants, and treating cardiovascular diseases.

72. Use of claim 71, wherein the cardiovascular disease is selected from the group consisting of atrial and ventricular arrhythmias, Prinzmetal's (variant) angina, stable angina, exercise induced angina, congestive heart disease, and myocardial infarction.

73. Use according to either claim 71 or 72, wherein the therapeutically effective amount ranges from about 0.01 to about 100 mg/kg weight of the mammal.

74. Use according to claim 73, wherein the mammal is a human.

75. A substituted piperazine compound according to claim 1 or 30 or substantially as described herein with reference to the examples.

76. A method of claim 64, substantially as described herein with reference to the examples.

77. A use according to claim 71, substantially as described herein with reference to the examples. CV Therapeutics, Inc By its Registered Patent Attorneys Freehills Carter Smith Beadle 3 August 2004