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, ()-N- (2, 6-dimethylphenyl)-4- [2-hydroxy-3- (2-methoxyphenoxy)- propyl]-1-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

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 :

wherein X is selected from the group consisting of :

wherein m = 1 or 2 or 3 ; R"R2, R3, R4 and Rs are each independently selected from the group consisting of hydrogen, halo, NO2, CF3, CN, OR23, SR23, N (R23) 2, S(O)R22, SO2R22, SO2N(R23)2, NR23CO2R22, NR23CON(R23)2, COR23, CO2R23, CON(R23)2, NR23SO2R22, C1-5 alkyl, C2-15 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, CF3, CN, OR23, 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 R8 are each independently selected from the group consisting of hydrogen and C,-,, alkyl ; R, R, R10, R11, R12, R13, R14, R15 and R, are each independently selected from the group consisting of hydrogen, CO2R23, CON (R23) 2, C, 4 alkyl, and aryl wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, CF3, CN, OR23, N (R23) 2, CO2R23, CON (R23) 2 and aryl, wherein R, and R, o may together form a carbonyl, or R11 and R12 may together form a carbonyl, or R, 3 and R, 4 may together form a carbonyl, or R15 and R16 may together form a carbonyl wherein R11 and R13 or R9 and R, 5 or Rg and R, R11 and R15 or R9 and R, 3 may join together to form a bridging ring system having from 1 to 4 carbon atoms and wherein Rg and R, o or R11 and R12 or R13 and R14 or R15 and R, 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,-,, 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-Cl 6 alkyl, CF3, and heteroaryl ; R23 is selected from the group consisting of H, C1-5 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, CN,-°-CI 6 alkyl, and CF3 ; and R24 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, OR20, SR20, S (O) R22, SOzR22, SO2N (RZ°) 2, NRzoCO2R22, 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, CF3, CN, oR20, and C16 aLkyl, and wherein RI R18, R19, R20, and R2, are each independently selected from the group consisting of hydrogen, halo, NO2, CF3, CN, OR23, SR23, N (R23) 2, S (O) R22, SO2R22, SO2N (R23) 2, NR23CO2R22, NR23CON (R23) 2, COR23, CO2R23, CON (R23)2, NR23SO2R22, C1-5 alkyl, C2-15 alkenyl, C2-,, 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, CF3, CN, OR23, SR23, N (R23) 2, S (O) R22, and SO2R22.

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 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.

DETAILED DESCRIPTION OF THE INVENTION This invention includes a class of substituted piperazine compounds having the following formula : wherein X is selected from the group consisting of : wherein m = 1 or 2 or 3 ; RI, R2, R3, R4 and Rs are each independently selected from the group consisting of hydrogen, halo, NO2, CF3, CN, OR23, SR23, N (R23) 2 S (O) R22, SO2R22, S°2N (R23) 21 NR23CO2R22, NR23CON(R2302, COR23, CO2R23, CON (R23) 2, NR23SO2R22, C1-15 alkyl, C2-15 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, CF3, CN, OR23, 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 R8 are each independently selected from the group consisting of hydrogen and C,-, 5alkyl ; Ru R10, R11, R12, R13, R14, R15 and R16 are each independently selected from the group consisting of hydrogen, CO2R23, CON (R23) 2, C, -4 alkyl, and aryl wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, CF3, CN, OR23, N (R23) 2, CO2R23, CON(R23)2 anD aryl, wherein R, and R, o may together form a carbonyl, or R, l and Rl2 may together form a carbonyl, or R13 and R14 may together form a carbonyl, or R15 and R16 may together form a carbonyl wherein R11 and R13 or R9 and R15 or R9 and R11 or R11 and R15 or R9 and R, 3may join together to form a bridging ring system

having from 1 to 4 carbon atoms and wherein Rg and RIO or R11 and R12 or r13 and R14 or R15 and R, 6 may join to form a bridging ring system having from 1 to 5 carbon atoms ; R22 is selected from the group consisting of Cl-,, 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, 6 alkyl, CF3, and heteroaryl ; R23 is selected from the group consisting of H, Cl ls 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-C,-, alkyl, and CF3 ; and R24 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, oR20, SR20, S (O) R22, SO2R22, SO2N (R2°) 2, NR2°CO2R22, Cl 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, CF3, CN, OR20, and Cl 6 alkyl and wherein R17, R18, R19, R20, and R2, are each independently selected from the group consisting of hydrogen, halo, NO2, CF3, CN, OR23, SR23, N (R23) 2, S (O) R22, SO2R22, SO2N (R23) 2, NR23CO2R22, NR23CON(R23)2, COR23, CO2R23, CON(R23)2, NR23SO2R22, C1-5 alkyl, C2-15 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, CF3, CN, OR23, SR23, N (R23) 2, S (O) R22, and SO2R22.

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

wherein m = 1, 2 ; R', R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, halo, CF3, OR22 and C1-4 alkyl and wherein R22 is a C1-3 alkyl ; R6, R'and R8 each independently selected from the group consisting of hydrogen and Cl 3 alkyl ; R9, R10, R11, R12, R13, R14, R15 and Rl6 are each independently selected from the group consisting of hydrogen and Cl 4 alkyl, or R9 and R10 may together form a carbonyl, or R"and R 12 may together form a carbonyl, or Rt3 and R14 may together form a carbonyl, or R"and R'6 may together form a carbonyl wherein R11 and R13 or R9 and R15 or R9 and R or R,, and R, s or Rg and R, 3 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 R9, R'°, R", R'2, R'3, R R15 and R16 are not all simultaneously hydrogen.

R17, R18, R19, R20 and R21 are each independently selected from the group consisting of hydrogen, halo, CF3, CN, OR22, S (O) R22, SOZR22, SON (R22) 2, CON(R22)2, C1-4 alkyl wherein R22 is C1-3 alkyl, or R17 and R18 may together form-CH=CH-CH=CH-, or R18 and R19 may together form -OCH2O-.

In more preferred compounds of Formula IA, R1, R, R3, R4 and R5 are each selected from the group consisting of hydrogen, halo, CF3, OR22 and Cl alkyl where R22 is a Cl 3 alkyl ; R6 is selected from hydrogen and methyl ; R', R8, R9, R10, R", R12, R13, R14, R15 and R16 are each independently selected from hydrogen and methyl or R9 and R'° may together form a carbonyl, or R and R'4 may together form a carbonyl with the proviso that R9, R'°, R11, R, R13, R14, R15 and R16 are not all simultaneously hydrogen. ; R17, R18, R19, R20 and R21 are each independently selected from the group consisting of hydrogen, halo, CF3, OR22, C1-3 alkyl wherein R22 is C1-3 alkyl, or R17 and R18 may together form-CH=CH-CH=CH-, or R18 and R19 may together form-OCH2O-.

In still more preferred compounds of Formula IA, Rl, R2, R3, R4, R5, R6, R7 and R8 are each independently selected from the group consisting of methyl and hydrogen ; R9, R'°, R",

R'z, R'3, R'4, R's and R16 are each independently selected from hydrogen and methyl or RI and R'° may together form a carbonyl, or R13 and R14 may together form a carbonyl with the proviso that R9, R10, R", R12, R13, R14, R15 and R16 are not all simultaneously hydrogen ; R", R18, R19, R20 and R21 are each independently selected from the group consisting of hydrogen, halo, CF3, OR22 wherein R22 is methyl, methyl, or Rl7 and Rl8 may together form-CH=CH- CH=CH-, or R'8 and R'9 may together form -OCH2O- In an even more preferred compounds of Formula IA, R1 and R5 are each methyl ; R2, R3, R4, R6, R', R8 are each hydrogen ; R9, R'°, R", R12, R13, R14, R15 and R16 are each independently selected from hydrogen and methyl or R9 and R'° may together form a carbonyl, or R13 and R14 may together form a carbonyl with the proviso that R9, R'°, R", R, R13, R14, R15 and R16 are not all simultaneously hydrogen ; R", R18, R19, R20 and R21 are each independently selected from the group consisting of hydrogen, halo, methyl, OR22 wherein R22 is methyl, or R"and R'8 may together form-CH=CH-CH=CH-, or R'g and R'9 may together form-OCH2O-.

In still more preferred compounds of Formula IA, R'and Rs are each methyl ; R2, R3, R4, R6, R7, R8 are each hydrogen ; R9, R'° are selected from hydrogen, methyl, or may together form a carbonyl ; R"and Rl2 are selected from hydrogen and methyl ; R"and R'4 are selected from hydrogen and methyl or may together form a carbonyl ; R 15 and R16 are hydrogen with the proviso that R9, R'°, R", R12, R13, R14, R15 and Rl6 are not all simultaneously hydrogen ; R17 is selected from the group consisting of hydrogen, chloro, fluoro or methoxy ; R'8 and R'9 are each selected from the group consisting of hydrogen or methoxy, or R18 and R19 may together form-OCH2O-, or R"and R"may together form-CH=CH-CH=CH-, R2'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-methoxyphenoxy) propyl]-3, 5-dimethylpiperazinyl}acetamide, 2-{(5S,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. 0] 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-[2-hydroxy-3-(2- methoxyphenoxy) propyl]-3, 3-dimethylpiperazinyl} acetamide, 2-{5-[(2S)-2-hydroxy-3-(2- methoxyphenoxy) propyl] (lys, 4S)-2, 5-diazabicyclo [2. 2. 1] hept-2-yl}-N-(2, 6-

dimethylphenyl) acetamide, N- (2, 6-dimethylphenyl)-2- {4- [2-hydroxy-4- (2- methoxyphenoxy) butyl]- piperazinyl} acetamide, N- (2, 6-dimethylphenyl)-2- {4- [4- (4- fluorophenoxy)-2-hydroxybutyl]-piperazinyl} acetamide, 2- (4- {4- [4- (tert-butyl) phenoxy]-2- hydroxybutyl} piperazinyl)-N- (2, 6-dimethylphenyl) acetamide, N- (2, 6-dimethylphenyl)-2- {4- [2-hydroxy-4- (4-phenylphenoxy) butyl] piperazinyl} acetamide, N-(2, 6-dimethylphenyl)-2-{4- [2-hydroxy-4- (4-methoxyphenoxy) butyl]- piperazinyl} acetamide, 2-{(3S)-4-[(2S)-3-(- fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-(2, 6-dimethylphenyl) acetamide, 2- { (3S)-4- [ (2S)-3- (2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N- (2, 6- dichlorophenyl) acetamide, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3- methylpiperazinyl}-N- (4-sulfamoylphenyl) acetamide, 2- { (3S)-4- [ (2S)-3- (2-fluorophenoxy)- 2-hydroxypropyl]-3-methylpiperazinyl}-N- (5-methoxy-3- (trifluoromethyl) phenyl] acetamide, 2- {(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylp iperazinyl}-N-indan-5- ylacetamide, 2- {(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylp iperazinyl}- N-naphthylacetamide, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3- <BR> <BR> <BR> <BR> methylpiperazinyl}-N- (4-chloronaphthyl) acetamide, 2- { (3S)-4- [ (2S)-3- (2-fluorophenoxy)-2- hydroxypropyl]-3-methylpiperazinyl}-N- (2-pyrrolylphenyl) acetamide, 2- { (3S)-4- [ (2S)-3- (2- <BR> <BR> <BR> <BR> fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-pheny lacetamide, 2- { (3S)-4- [ (2S)- 3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N- (2-chlorophenyl) acetamide, <BR> <BR> <BR> <BR> 2- {(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylp iperazinyl}-N-(2-chloro-4- methylphenyl) acetamide, 2- { (3S)-4- [ (2S)-3- (2-fluorophenoxy)-2-hydroxypropyl]-3- methylpiperazinyl}-N-[2-(1-methylvinyl) phenyl] acetamide, 2- { (3S)-4- [ (2S)-3- (2- fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-(2-me thylphenyl) acetamide, 2- <BR> <BR> <BR> <BR> {(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylp iperazinyl}-N-[6-methyl-2- (methylethyl) phenyl] acetamide, 2- { (3S)-4- [ (2S)-3- (2-fluorophenoxy)-2-hydroxypropyl]-3- methylpiperazinyl}-N- (3-methylthiophenyl) acetamide, 2- { (3S)-4- [ (2S)-3- (2-fluorophenoxy)- 2-hydroxypropyl]-3-methylpiperazinyl}-N- (4-chloro-2-methoxy-5-methylphenyl) acetamide, 2- { (3 S)-4- [ (2 S)-3- (2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N- [4- (dimethylamino) phenyl] acetamide, 2- { (3S)-4- [ (2S)-3- (2-fluorophenoxy)-2-hydroxypropyl]- 3-methylpiperazinyl}-N- (2, 4-dimethoxyphenyl) acetamide, 2- { (3S)-4- [ (2S)-3- (2- fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N- (3, 4-dichlorophenyl) acetamide, 2-f (3S)-4- [ (2S)-3- (2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N- (4- chlorophenyl) acetamide, 2- { (3S)-4- [ (2S)-3- (2-fluorophenoxy)-2-hydroxypropyl]-3- methylpiperazinyl}-N- (3-chlorophenyl) acetamide, 2- { (3S)-4- [ (2S)-3- (2-fluorophenoxy)-2- hydroxypropyl]-3-methylpiperazinyl}-N- (3, 5-dichlorophenyl) acetamide, 2- { (3S)-4- [ (2S)-3-

(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N- (4-methoxyphenyl) acetamide, 2- { (3S)-4- [ (2S)-3- (2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N- (4- methylphenyl) acetamide, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3- methylpiperazinyl}-N- (3-methylphenyl) acetamide, 2- {(3S)-4-[(2S)-3-(2-fluorophenoxy)-2- hydroxypropyl]-3-methylpiperazinyl}-N- (4-fluorophenyl) acetamide, 2- { (3S)-4- [ (2S)-3- (2- fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N- (4-cyanophenyl) acetamide, 2- {(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylp iperazinyl}-N-(4- acetylphenyl) acetamide, 2- { (3S)-4- [ (2S)-3- (2-fluorophenoxy)-2-hydroxypropyl]-3- methylpiperazinyl}-N- (2-methoxyphenyl) acetamide, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2- hydroxypropyl]-3-methylpiperazinyl}-N- [4- (trifluoromethyl) phenyl] acetamide, 2- { (3S)-4- [ (2S)-3- (2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N- [4-chloro-3- (trifluoromethyl) phenyl] acetamide, 2- { (3S)-4- [ (2S)-3- (2-fluorophenoxy)-2-hydroxypropyl]- <BR> <BR> <BR> 3-methylpiperazinyl}-N-(3, 5-dimethoxyphenyl) acetamide, 2-{(3S)-4-[(2S)-3-(2-<BR> <BR> <BR> <BR> <BR> <BR> fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-(4-mo rpholin-4-ylphenyl) acetamide, 2- {(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylp iperazinyl}-N- (3-fluoro-4-methoxyphenyl) acetamide, 2-f (3S)-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-methylpiperazin yl}-N-(3, 4-dimethoxyphenyl) acetamide, 2- { (3S)-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}-N-[2-(hydroxymethyl-6-me thylphenyl] acetamide.

This invention includes a subset of substituted piperazine compounds of formula I having the following formula IB : wherein m = 0, 1 or 2 or 3 ;

R', R2, R3, R4 and Rs are each independently selected from the group consisting of hydrogen, halo, NO2, CF3, CN, OR23, SR23, N (R23) 2, S (O) R22, SO2R22, SOIN (R23)2, NR23CO2R22, NR23CON(R23)2, COR23, CO2R23, CON(R23)2, NR23SO2R22, C1-15 alkyl, C2-15 alkenyl, C2 ls 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, CF3, CN, OR23, SR23, N (R23) 2, S (O) R22, and SO2R22 ; R6, R7 and R8 each independently selected from the group consisting of hydrogen or C1-15 alkyl ; R9, R'°, R", R'2, R'3, R'4, R15 and R16 are each independently selected from the group consisting of hydrogen, CO2R23, CON (R23) 2, C, -4 alkyl or aryl wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, CF3, CN, OR23, N (R23) 2, CO2R23, CON (R23) 2 or aryl, wherein R9 and R'° may together form a carbonyl, or R11 and R12 may together form a carbonyl, or R13 and R'4 may together form a carbonyl, or R15 and R16 may together form a carbonyl wherein R"and R'3 or R9 and R15 or R9 and R11 or R11 and R15 or R9 and R13 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 R9 and R'° or R"and R'2 or R13 and R14 or R15 and R16 may join to form a spiro ring system wherein the two R groups together comprise of from 1 to 5 carbon atoms ; R", R'8, R'9, Rzo, and R21 are each independently selected from the group consisting of hydrogen, halo, NO2, CF3, CN, OR23, SR23, N (R23) 2, S (O) R22, SO2R22, SON (R23) 21 NR23CO2R22, NR23CON (R23) 2, COR23, C02R23, CON(R23)2, NR23SO2R22, C1-15 alkyl, C2-15 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, CF3, CN, OR23, SR23, N (R23) 2, S (O) R22, and SO2R22 or wherein R"and R"may join together may join together to form-CH=CH-CH=CH-or wherein R17 and R18 or R18 and R19 or R19 and R20 or R20 and R21 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, NO2, CF3, CN, OR23, SR23, N (R23) 2, S (O) Ruz2, S02 W2, S02N (R23)2, NR23CO2R22, NR23CON(R23)2, COR23, CO2R23, CON (R) 2, NR23SO2R23, C1-15 alkyl, C2-15 alkenyl, C2-15 alkynyl, heterocyclyl, aryl, or heteroaryl, wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, NO2, CF3, CN, OR23, SR23, N (R23) 2, S (O) R22, or SO2R22 ;

R22 is selected from the group consisting of C,-,, 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-C16 alkyl, CF3, or heteroaryl ; and R23 is selected from the group consisting of H, C1-15 alkyl, aryl, or heteroaryl, wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, alkyl, mono-or dialkylamino, alkyl, CN,-0-C,-6 alkyl, or CF3.

In preferred compositions of this invention, m = 0, 1 or 2 or 3 ; R', R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, halo, CF3, OR22 and Cl4 alkyl ; R6, R7 and R8 each independently selected from the group consisting of hydrogen and Cl 3 alkyl ; R9, R'°, R11, R'2, R'3, R'4, R15 and R16 are each independently selected from the group consisting of hydrogen and C, alkyl, or R9 and R'° may together form a carbonyl, or R"and R'2 may together form a carbonyl, or R13 and R14 may together form a carbonyl, or Rls and R16 may together form a carbonyl, or wherein R11 and R13 or R9 and R15 or R9 and R"or R"and R"or R9 and R'3 may join together to form a ring including from 1 to 4 carbon atoms wherein R9, R'°, R11, R12, R13, R14, R15 and R16 are not all hydrogen ; and R17, R18, R19, R20 and R21 are each independently selected from the group consisting of hydrogen, halo, CF3, CN, OR22, S (O) R22, SO2R22, SON (R22) 2, CON (R22) 2, C14 alkyl or R17 and R18 may together form- CH=CH-CH=CH-, and phenyl.

In other preferred compounds, R', R2, R3, R4 and Rs are each independently selected from the group consisting of hydrogen, halo, CF3, OR22 and C1-2 alkyl wherein R22 is a C,-3 alkyl ; R6, R7 and R8 are each independently selected from the group consisting of hydrogen and methyl ; R9, R'°, R", R12, R13, R14, R15 and Rl6 are each independently selected from the group consisting of hydrogen and C12 alkyl, or R9 and R'° may together form a carbonyl, or R15 and R16 may together form a carbonyl with the proviso that R9, R'°, R", R12, R13, R14, R15 and R16 are not all simultaneously hydrogen and wherein R"and R'3 or R9 and Rls or R9 and R"or R"and R"or R9 and R'3 may join to form a ring including from 1 to 4 carbon atoms and R", R'8, R'9, R20 and R21 are each independently selected from the group consisting of hydrogen, halo, CF3, CN, OR22, and C, alkyl wherein R22 is C1-3 alkyl, and wherein R17 and R18 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', R, R3, R4 and Rs are each independently selected from the group consisting of hydrogen, halo, CF3, OR22 and C1-4 alkyl where R22 is a Cl 3 alkyl ; R6, R7, R', R9, R'°, R", R12, R13, R14, R15 and R16 are each

independently selected from hydrogen and methyl ; R", R'8, R'9, Rzo and Wu are each independently selected from the group consisting of hydrogen, halo, CF3, OR22, C1-3 alkyl where R22 is methyl, or Rl7 and Rl8 may together form-CH=CH-CH=CH-, or R'8 and R'9 may together form -OCH2O-.

In more preferred compounds, m = 1 or 2 ; ; R', R, R3, R4, R5, R6, R7 and R8 are each independently selected from methyl and hydrogen ; R9, R'°, R", R12, R13, R14, R15 and R16 are each hydrogen ; and R, R, R19, R20 and R2'are each independently selected from the group consisting of hydrogen, halo, CF3, OR22 wherein R22 is methyl, or R17 and R18 may together form-CH=CH-CH=CH-, or R'g and R'9 may together form-OCH2O-.

In yet other preferred compounds, m = 1 or 2 ; ; R'and R'are methyl ; R2, R3, R4 R6, R7, R R9, R'°, R", R12, R13, R14, R15 and R16 are hydrogen ; R17, R18, R19, R20 and R21 are each independently selected from the group consisting of hydrogen, halo, OR22 wherein R22 is methyl, or R17 and R18 may together form-CH=CH-CH=CH-, or R 18 and R'9 may together form -OCH2O-.

In still other preferred compounds, R'and R 5are methyl ; R2, R3, R4, R6, R7,R8,R9,R10, R", R12, R13, R14, R15 and R16 are hydrogen ; R"is selected from the group consisting of hydrogen, chloro, fluoro and methoxy ; Rl8 is selected from hydrogen and methoxy ; R'9 is selected from hydrogen and methoxy ; R20 is hydrogen ; R2'is selected from hydrogen and chloro, or R"and R'8 may together form-CH=CH-CH=CH-, or R 18 and R9 may together form -OCH2O-.

Most preferably, the substituted piperazine compounds of this invention are selected from 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 ; N- (2, 6-dimethylphenyl)-2- {4- [2-hydroxy-3- (4- methoxyphenyl) propyl] piperazinyl} acetamide ; N-(2, 6-dimethylphenyl)-2- {4-[2-hydroxy-3- phenylpropyl] piperazinyl} acetamide, N-(2, 6-dimethylphenyl)-2- {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, 2- (4- {4- [4- (tert-butyl) phenyl]-2- hydroxybutyl} piperazinyl)-N- (2, 6-dimethylphenyl) acetamide, N- (2, 6-dimethylphenyl)-2- {4- <BR> <BR> <BR> <BR> [4- (2-fluorophenyl)-2-hydroxybutyl] piperazinyl} acetamide, N- (2, 6-dimethylphenyl)-2- (4- {2- hydroxy-4- [4- (trifluoromethyl) phenyl] butyl} piperazinyl) acetamide, 2- [4- (3- (2H-benzo [d] 1, 3- dioxolen-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}-2- methylpropanamide, 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.

This invention further includes a subset of compounds of Formula I above having the following Formula IC : wherein m = 1, 2, or 3 ; R', R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, halo, NO2, CF3, CN, OR20, SR20, N (R20)2, S (O) RI2, SO2Rz2, SO2N (Rz°) 2, NR20CO2R22, NR20CON(R2002, COR20, CO2R20, CON(R20)2, NR20SO2R22, C1-15 alkyl, C2-15 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, CF3, CN, OR20, SR20, N (R2°) 2, S (O) R22, and SO2R22; R6, R'and R8 each independently selected from the group consisting of hydrogen or Cl 3 alkyl ; R9, R'°, R", R12, R13, R14, R15 and R16 are each independently selected from the group consisting of hydrogen, CO2R20, CON (R2°) 2, Cl4 -4 alkyl, or aryl wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, CF3, CN, OR20, N (R2°) 2 CO2R20, CON(R2002 or aryl, wherein R'and R'° may together form a carbonyl, or R"and R'2 may together form a carbonyl, or R13 and R14 may together form a carbonyl, or R'S and R'6 may together form a carbonyl with the proviso that R"and R13 or R9 and Rls or R9 and R"or R"and R's or R9 and R'3 may join together to form a ring including from 1 to 3 carbon atoms ; R24 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, OR20, SR20, S(O)R22, SO2R22, SON (R20)2, NR20CO2R22, 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, CF3, CN, OR20, and C1-6 alkyl ; Wo is selected from the group consisting of H, Cl ls 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-C16 alkyl, or CF3 ; and R22 is selected from the group consisting of C1-15 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-Cl 6 alkyl, CF3, or 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', R2, R3, R4 and Rs are each independently selected from the group consisting of hydrogen, halo, CF3, OR22 and C1-4 alkyl and wherein R22 is a Cl3 alkyl. In other preferred compositions, R', R2, R3, R4 and Rs are each independently selected from the group consisting of hydrogen, CF3, OR20, or Cl 2 alkyl. More preferably R', R2, R3, R4 and Rs are each independently selected from the group consisting of hydrogen, or methyl with R2, R3, and R4 as hydrogen and R'and Rs as methyl being preferred.

In other preferred compositions of Formula IC, R6, R'and R8 each independently selected from the group consisting of hydrogen and C1-3 alkyl with hydrogen or methyl being preferred and hydrogen being most preferred.

In yet other preferred compositions of Formula IC, R9, R'°, R", R12, R13, R14, R15 and R16 are each independently selected from the group consisting of hydrogen, CON (R2°) 2, C, -4 alkyl, or aryl wherein the alkyl and aryl substituents are each optionally substituted with 1 substituent selected from the group consisting of halo, CF3, OR20, N (R2°) 2 CON (R2°) 2 or aryl wherein R9 and R'° may together form a carbonyl, or R"and R 12 may together form a carbonyl, or R'3 and R'4 may together form a carbonyl, or R'S and R'6 may together form a carbonyl with the proviso that R"and R13 or R9 and R15 or R9 and R11 or R11 and R15 or R9 and R'3 may join together to form a ring. In alternative preferred compositions, R9, R'°, R", R'2, R'3, R'4, R's and R16 are each independently selected from the group consisting of hydrogen and C, alkyl, or R9 and R'° together form a carbonyl, or Rll and Rl2 together form a carbonyl, or R13 and R14 together form a carbonyl, or R'S and R'6 together form a carbonyl, R'° and R"together form-CH2CH2CH2CH2-. In another embodiment, R9, R'°, R", R12, R'3,

R R and R16 are each independently selected from the group consisting of hydrogen, or Cl 2 alkyl, wherein the alkyl substituent is optionally substituted with 1 substituent selected from the group consisting of N (R2°) 2 or aryl or wherein R9 and R'° may together form a carbonyl.

More preferably, R9, R'°, R", R'2, R'3, R'4, R'S and R'6 are each independently selected from the group consisting of hydrogen or Cl 2 alkyl, or wherein R9 and R'° may together form a carbonyl. In another embodiment, Rll and Rls are each selected from the group consisting of hydrogen or methyl, R9, R'°, R'2, Rl3, Rl4 and R16 are each hydrogen and R9 and R'° may together form a carbonyl, or, R9, R'°, R", R, R13, R14, R and R'6 may each be hydrogen.

In compounds of Formula IC, R24 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, CF3, CN, OR20, SR20, S (O) R22, SO2R22, SO2N (R2°) 2, NR2°CO2R22, Cl 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, CF3, CN, OR20, and Cl 6 alkyl. In certain preferred compounds of Formula IC, R24 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, CF3, CN, oR20, SR20, S (O) R22, SO2R22, Cl 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, CF3, CN, oR20, and Cl 6 alkyl. In other preferred compounds of Formula IC, R24 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, CF3, OR20, and aryl wherein the optional aryl substituent is optionally substituted with from 1 to 3 substituents selected from the group consisting of halo, phenyl, CF3, CN, oR20, and Cl 6 alkyl.

In still other preferred compounds of Formula IC, R24 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, CF3, OH, methyl, and aryl, and aryl that is optionally substituted with from 1 to 2 substituents selected from the group consisting of halo, CF3, OH, C12 alkyl, and aryl. In still other preferred compounds of Formula IC, R24 is alkyl having from 1 to 6 carbon atoms and cycloalkyl or R24 is a fused phenylcycloalkyl that is

optionally substituted with from 1 to 2 substituents selected from the group consisting of halo, CF3, oR20, C1-2 alkyl, and aryl or R24 is phenylmethyl that is optionally substituted with from 1 to 2 substituents selected from the group consisting of halo, CF3, OR20, C, alkyl, and aryl.

In the compounds of Formula IC, R20 is selected from the group consisting of H, Cl 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 CF3. More preferably, Wo is selected from the group consisting of H or Cl 3 alkyl and most preferably, R20 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]- N- ( {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-{[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, 2- (4- {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, 2- (4- {3- [ (2, 4- dimethoxyphenyl) methoxy]-2-hydroxypropyl} piperazinyl)-N- (2, 6-dimethylphenyl) acetamide, N- (2, 6-dimethylphenyl)-2- (4- {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, 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.

The following definitions apply to terms as used herein.

"Halo"or"Halogen"-alone or in combination means all halogens, that is, chloro (Cl), fluoro (F), bromo (Br), iodo (I).

"Hydroxyl"refers to the group-OH.

"Thiol"or"mercapto"refers to the group-SH.

"Alkyl"-alone or in combination means an alkane-derived radical containing from 1 to 20, preferably 1 to 15, carbon atoms (unless specifically defined). It is a straight chain alkyl, branched alkyl or cycloalkyl. Preferably, straight or branched alkyl groups containing from 1-15, more preferably 1 to 8, even more preferably 1-6, yet more preferably 1-4 and most preferably 1-2, carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl and the like. The term"lower alkyl"is used herein to describe the straight chain alkyl groups 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, 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, 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.

"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 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"'R"", where R is lower alkyl, or substituted lower alkyl, R', R"', R""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,-S (O) n=, 2-R, where R is lower alkyl, substituted lower alkyl, aryl, substituted aryl, aralkyl or substituted aralkyl as defined herein.

"Acyl"denotes groups-C (O) R, 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 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, e. g., 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 (e. g., morpholino, pyridyl or furyl) or multiple condensed rings (e. g., naphthpyridyl, quinoxalyl, quinolinyl, indolizinyl or benzo [b] thienyl) and having at least one hetero atom, such as N, O or S, within the ring, which can optionally be unsubstituted or substituted with, e. g., 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 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 of heterocyclyl 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, 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.

"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, e. g., 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, e. g., 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 15 carbon atoms.

"Substituted cycloalkyl"refers to a cycloalkyl group comprising one or more substituents with, e. g., halogen, lower alkyl, substituted lower alkyl, alkoxy, alkylthio, acetylene, aryl, aryloxy, heterocycle, substituted heterocycle, hetaryl, substituted hetaryl, nitro, cyano, thiol, sulfamido 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 : (i) 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, i. e., arresting its development ; or (iii) relieving the disease, i. e., 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.

Compounds 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.

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 2- substituted chloroacetylchloride III. Compound II is available commercially or readily prepared through reduction of the corresponding nitrobenzene derivative (acid/SnCl2 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, 4- methylaniline, 4-methylaniline, 2, 4-dichloroaniline, 3, 4-dichloroaniline, 2, 5-dichloroaniline, 2, 4-dichloroaniline, 2-chloroaniline, 3-chloroaniline, 2, 6-difluoroaniline, 2, 5-difluoroaniline, 3, 4-difluoroaniline, 2-fluoroaniline, 4-fluoroaniline, 3-fluoroaniline, 2-fluoro-6-chloroaniline, 4-fluoro-3-chloroaniline.

SCHEME 1 0 R Rs C Cl R2 Rs o O R NH R7XR8 10-R N ci R4 Rs R4 Rs 11 in 5 RIO Ril R10 R11 9RIO Rll H-N N-P R Rto R11 R12 O R 13 R N N N-P V RB R7 Re' P=BOC, CBZorBenzyl RA R13 Vl RsRioRnR R2 R / 101-1 R RB R Re RS R6 R15R14R13 R R13 R 16 RISK vn R18 R17 0 R18 R17 o R20 R21 ^ , 1 R20 R21 N N R6 R7 R8,' 1'OH/ R4 R5 R16 R13 R21 R20 I

Compound VI can be obtained by reacting compound IV with N-protected substituted piperazine V through warming in an appropriate solvent (e. 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 resources. Examples of commercially available compounds corresponding to general structure V include 2-methyl piperazine, 2, 5-

dimethyl piprazine and 2, 6-dimethyl piperazine. Deprotection of compound VI can be accomplished using the standard conditions (e. g. 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 2A Rie Rt p \ acetone, K zC03/ 0 pH + m Rts m X R20 21 R20 R21 X=ClorBr IX Epoxide VIII (where m = 1 or 2) can be prepared as outlined in Scheme 2. Heating substituted phenol IX with epichlorohydrin, epibromohydrin, or 4-bromo-1, 2-epoxybutane and potassium carbonate in acetone can afford epoxide VIII. Compound IX can be obtained from commercial resources. Example of commercially available compounds of compounds XI include 2-chlorophenol, 2-fluorophenol, 2-methoxyphenol, 2-methylphenol, sesamol, 2, 6- dichlorophenol, 3, 5-dichlorophenol, 2, 6-difluorophenol, 2, 4-difluorophenol5-indanol, 3- chloro-4-fluorophenol, 2, chloro-4-fluorophenol and 5, 6, 7, 8-tetrahydro-2-naphthol. In some cases compound VIII can be obtained from commercial sources. Examples of commercially available compounds corresponding to general structure VIII include benzyl glycidyl ether, glycidyl 2-methylphenyl ether, glycidyl 4-methoxyphenyl ether, glycidyl 4-chlorophenyl ether, glycidyl 2-chlorophenyl ether, glycidyl 2-methoxyphenyl ether, glycidyl 4- methylphenyl ether, glycidyl 3, 4-dichlorophenyl ether and glycidyl 4-fluorophenyl ether.

SCHEME 3A Rs O Rio R9 0 TUFA t-BuLi, Rg loBr Deprotection Bn-N-BOC Bn-N-BOC Talk__ L% J XII XIII 0 R Ro /\ BH3 Xlv V XIV 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. (J. 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].

SCHEME 4A 1OR9 0 Rs Rtu O Rt3 p R9O l. coupling H-N N-bon + BoNH OH BocNH OH Bn_NH OR L TFA, ringdosure °R14 Bn g Rta XVI xvll XVIII 1R MeorEt 9 R100 dibomne \J diborane L > rn H-N N-Bn v R13 w XIX Ra

Compound V can also be prepared through standard coupling (eg. EDC or PyBroP) of D or L amino acids and standard deprotection 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 compound XIX the N-benzyl protected version of compound V.

Compound V also includes the bicyclic homologs of piperazine (1S, 4S)- (+)-2, 5- diazabicyclo [2. 2. 1] heptane 83, 3, 8-diazabicyclo [3. 2. 1] octane 84, and 2, 5-diazabicyclo [2. 2. 2] octane 85.

Commercially available bicyclic analogs include (1S, 4S)- (+)-2, 5- 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 SA, 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 (1 : 1) 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 K2CO3 as described in Scheme 6.

SCHEME 5A 0 HN NH NH2 Ni,-Cl /\ \, rCI ' N HZ N' sat NaHCO ;/Et y0 (1 : 1) H EtOH, DIPEA, tetlux 24 hts. 0°-> RT 3 H, CO 6 N N N H H ETOK Reflux 5 EtOH, Reflux 5 HsCO N N ou

SCHEME 6A CH3 0 Oh acetone, K2C03 cl 8 oc3 6 8 6

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

Acylation of compound 11 was accomplished using chloroacetyl chloride in dichloromethane using diisopropylethyl 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 6 as described above afforded compound 14.

CH, c cH, H CH- 10 it azol 10 6 11 I H/OCH s 1. TFA chbroacetyl chloride ¢oc HN-JJ% \% 2. EtOH, DIPEA 12 I H Oc, 3 H ^ 3 N HN \ N O N EtOH, DIPEA/ O 0 13 14 The compounds having the general formula I and IB can be prepared as outlined in Schemes 1B-7B. A general synthesis of the compounds of this invention is outlined in Scheme 1B. Compound IV can be prepared by N-acylation of substituted anilines of general structure II with 2-substituted chloroacetylchloride III. Compound II is available commercially or readily prepared through reduction of the corresponding nitrobenzene derivative (acid/SnCl2 or catalytic hydrogenation, see Advanced Organic Chemistry, Ed. J.

March, (1992) A. Wiley-Interscience). Some examples of commercially available substituted anilines of general structure II include 2, 6-dimethylaniline, 2, 3-dimethylaniline, 2- methylaniline, 4-methylaniline, 2, 4-dichloroaniline, 3, 4-dichloroaniline, 2, 5-dichloroaniline, 2, 4-dichloroaniline, 2-chloroaniline, 3-chloroaniline, 2, 6-difluoroaniline, 2, 5-difluoroaniline, 3, 4-difluoroaniline, 2-fluoroaniline, 4-fluoroaniline, 3-fluoroaniline, 2-fluoro-6-chloroaniline, 4-fluoro-3-chloroaniline. R' O III R Rs I I H _ R N CI In 4 R4 Rs II IV Rio 4 'Rz v-I-I-r Re R7 Re V Re R Re 4 R R5 R R Vu Vu Deprotect R N N N-H On. 1 7 Rye VIT Viol Roar 17 Riz I O R R RsRo RmRz R Re R20 R21 0 Vl Vill 3 N N N Rlg Vll R18 p17 OH Ré R5 RR 15R 1\4 R13 21 20 I I

Compound VI can be obtained by reacting compound IV with a N-protected substituted piperazine V through warming in an appropriate solvent (e. 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 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 (e. g. 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 R 17 R 17 R1aCHO R1s\H CHO TCI R1 R21 R R21 in 21 Rp In RD20 \/v\/M x Br Ph3PCH2Br, NaH, THF \/ Diethylether R17 R17 Rte R18 O I \ JV \ mCPBA, DCM I \ N V R21 R R2t R20 R20 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 (G. 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 Horner Emmons conditions [Advanced Organic Chemistry, Eds. J. March,

(1992), Wiley-Interscience publication and S. Pine, G. Shen and H. Hoang, Synthesis, (1991), 1]. 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, 4- fluorostyrene, 2-chlorostyrene, 3-chlorostyrene, 4-chlorostyrene, 2, 6-dichlorostyrene, 3, 4- dichlorostyreneand 3, 4-dimethoxystyrene. Other examples of commercially available compounds with the general structure XI include (where m = 1) 4-methoxyallylbenzene, 2- hydroxyallylbenzene, 4, 5-dimethoxyallylbenzene, 2-methylallylbenzene safrole and 1- allylnaphthalene.

SCHEME 3B J R1Ro Deprotection n-BuLi, R9. IOBr Bn-N-JJ-BOC Bn-N_ fl-BOC all ! XII XIII O R Rs ors Bn-N NH----Bn-N NH

FIV 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. (J. 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).

SCHEME 4B RP JO \lu R'4N4 l. coupling H-N N-Bn + ruz Boc---NH OH NH OR 2. TFA, ringdosure R14 XVI ! XVIU XVI XVII XVIII It=MeorEt R9 diborane H-N N-Bn 'I R13 XIX R14 X ! X P

Compound V can also be prepared through standard coupling (eg. EDC or PyBroP) of D or L amino acids and standard deprotection (e. g., 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 (1S, 4S)- (+)-2, 5- diazabicyclo [2. 2. 1] heptane 83, 3, 8-diazabicyclo [3. 2. 1] octane 84, and 2, 5-diazabicyclo [2. 2. 2] octane 85.

Commercially available bicyclic analogs include (1S, 4S)- (+)-2, 5- 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, SS, 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

particular, 2, 6-dichloroaniline was acylated with 2-chloroacetyl chloride 2 using saturated bicarbonate and ether (1 : 1) 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 5 with epoxide 6 by warming both components in ethanol at reflux afforded piperazine derivative 7.

SCHEME 5B 0/-- HN NH CI-Y CI NH z sat NaHC03/Et20 (1 : 1) H ETOH, DIPEA, reflux 24 hrs. \ o°-> RT \ 3 1 6 N NH EtOH, Reflmx H 5 0 s OU 7

Compound 8 is commercially available and was epoxidized using 3- chloroperoxybenzioc acid in dichloromethane as illustrated in Scheme 6B.

Scheme 6B CH3 OH/ acetone, K2C=' m /". m 6a. m=1 OCH3 6b. m = 2 6 6

Four carbon epoxide 15 can be prepared by coupling commercially available 4- methoxybenzyl chloride with allylmagnesium bromide followed by oxidation with mCPBA as illustrated in Scheme 7B.

SCHEME 7B mu Br MgB/\ H3C Ethylether OCH3 14 mCPBA, DCM tXOCH3 bu-OCH3 15

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.

u R R C C R R O III R R8 R3 III R7 R XRs R7 R8 IV v Rg9< R12 1I IV Ro Rtt R9 Rz H-N ff R3< INX R R3 N N-P v I Raz V P= BOC, CBZ or Benz R4 Rs 16 RssRr4 13 Ra RS RsRa VI R. RioRiio \/ o \L-k O Deprotect R N N H 3 B-B B RRB VII 0 Rto RtR2 R R R O Rs/ i I I I R17 OU Ra RS Rg R7 Rg RtsRtaRa I Compound IV can be prepared by N-acylation of substituted aniline II with 2-substituted chloroacetylchloride III. Compound II is available commercially or readily prepared through reduction of the corresponding nitrobenzene derivative (acid/SnCl2 or catalytic hydrogenation, see Advanced Organic Chemistry, Ed. J. March, (1992) A. Wiley-Interscience). Some examples of commercially available substituted aniline II include 2, 6-dimethylaniline, 2, 3- dimethylaniline, 2-methylaniline 4-methylaniline, 4-methylaniline, 2, 4-dichloroaniline, 3, 4- dichloroaniline, 2, 5-dichloroaniline, 2, 4-dichloroaniline, 2-chloroaniline, 3-chloroaniline, 2, 6-

difluoroaniline, 2, 5-difluoroaniline, 3, 4-difluoroaniline, 2-fluoroaniline, 4-fluoroaniline, 3- fluoroaniline, 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 (e. 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 (e. g. 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 2C 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 VIII 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 XIII as described by Pohlman et. al. (J. 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).

SCHEME 3C

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 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.

SCHEME 4C RioR'o Rotors O s R° O Ra 0 9 l. coupling H-N N-Bn Ra NH OR Bn~ 2. TFA, ring dorure 0 R XIV XV xi R=Me or Et R9 1OR9 diborane \J diborane H-N N-Bn \/R13 v R v 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.

HN N H CI-v CI HN NH z s t NaHCOj/Et2O (1 : 1) H BtOH, DIPEA, reflux 24 hrs. 0°---> RT 3 O m-°~ç0 0 ZON NH EtOH, retlux H > L A v X 5 N O N OH In particular, 2, 6-dichloroaniline was acylated with 2-chloroacetyl chloride 2 using saturated bicarbonate and ether (1 : 1) 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 5 with epoxide 6 by warming both components in ethanol at reflux afforded piperazine derivative 7. Compound 6 in turn was prepared by warming epibromohydrin with 2-indanol in DMF in presence of NaH as described in Scheme 6C.

SCHEME 6C

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, semi- solid 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

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.

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, e. g., 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.

Example 1 N-(2, 6-dimethylphenyl)-2-{4-[2-hydroxy-3-(2-methoxy) propyl]-3, 5- dimethylpiperazinyl} acetamide (7).

Part A.

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

2, 6-dimethylaniline (9. 8 g, 81. 2 mmol) was dissolved in ether (100 mL) and saturated aqueous NaHCO3 (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 MgS04, 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 (5).

To a solution of compound 3 (5 g, 25. 2 mmol) in ethanol (100 mL) was added 2, 6- dimethylpiperazine 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 5.

Part C.

Synthesis of glycidyl 4-methoxyphenyl ether (6).

2-methoxyphenol (1. 0 g, 8. 0 mmol) and epichlorohydrin (3. 7 g, 40. 0 mmol) were dissolved in acetone (20 mL). K2CO3 (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 MgSO4 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, 5- dimethylpiperazinyl} acetamide (7).

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. 2-{(5S, 2R)-4-[2-hydroxy-3-(2-methoxyphenoxy) propyll-2, 5-dimethylpiperazinyl}-N-(2, 6- dimethylphenyl) acetamide (15) Compound 15 was prepared in the manner of compound 7 substituting (2R, 5S)- dimethylpiperazine for 2, 6-dimethylpiperazine 4 in part B to afford compound 15 : Mass spectrum (M+1) = 456. 4.

N- (2, 6-dimethylphenyl)-2- {4- [2-hydroxy-3- (2-methoxyphenoxy) propyl]-2- oxopiperazinyl} acetamide (16) Compound 16 was prepared substituting 4-benzyloxycarbonyl-2-oxo-piperazine for 2, 6- dimethylpiperazine 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 (M+1) = 442. 41.

2, 5-diaza-5-[2-hydroxy-3-(2-methoxyphenoxy) propyllbicyclo [4. 4. 0] dec-2-yl}-N- (2, 6- dimethylphenyl) 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 15 : Mass spectrum (M+1) = 482. 4.

N- (2, 6-dimethylphenyl)-2- {4- [2-hydroxy-3- (2-methoxyphenoxy) propyll-3, 3- dimethylpiperazinyl} acetamide (18) Compound 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

2-{5-[(2S)-2-hydroxy-3-(2-methoxyphenoxy) propyll (lS, 4S)-2, 5-diazabicyclo [2. 2. 1] hept- 2-yl}-N-(2, 6-dimethylphenyl) acetamide (19) Compound 19 was prepared in the manner of compound 7 substituting (1S, 4S)- (+)-2, 5- Diazabicyclo [2. 2. 1] heptane for 2, 6-dimethylpiperazine 4 in part B to afford compound 19 : Mass spectrum (M+1) = 481. 5 N-(2, 6-dimethylphenyl)-2-{4-[2-hydroxy-4-(2-methoxyphenoxy) butyll- piperazinyl} acetamide (20) Compound 20 was prepared in the manner of compound 7 substituting 4-bromo-1, 2- epoxybutane 6b for epichlorohydrin 6a in part B to afford compound 20 : Mass spectrum (M+1) = 442. 37

N- (2, 6-dimethylphenyl)-2- {4- [4- (4-fluorophenoxy)-2-hydroxybutyl]- piperazinyl} acetamide (21) Compound 21 was prepared in the manner of compound 7 substituting 4-bromo-1, 2-epoxybutane 6b for epichlorohydrin 6a in part B to afford compound 21 : Mass spectrum (M+1) = 430. 35

2- (4- {4- [4- (tert-butyl) phenoxy]-2-hydroxybutyl} piperazinyl)-N- (2, 6-dimethylphenyl) acetamide (22) Compound 22 was prepared in the manner of compound 7 substituting 4-bromo-1, 2- epoxybutane 6b for epichlorohydrin 6a in part B to afford compound 22 : Mass spectrum (M+1) = 468. 32

N- (2, 6-dimethylphenyl)-2- {4- [2-hydroxy-4- (4-phenylphenoxy) butyl] piperazinyl} acetamide (23) Compound 23 was prepared in the manner of compound 7 substituting 4-bromo-1, 2- epoxybutane 6b for epichlorohydrin 6a in part B to afford compound 23 : Mass spectrum (M+1) = 488. 41

N- (2, 6-dimethylphenyl)-2- {4- [2-hydroxy-4- (4-methoxyphenoxy) butyl]- piperazinyl} acetamide (24) Compound 24 was prepared in the manner of compound 7 substituting 4-bromo-1, 2- epoxybutane 6b for epichlorohydrin 6a in part B to afford compound 24 : Mass spectrum (M+1) = 442. 37

Example 2 N- (2, 6-dimethylphenyl)-2- {4- [2-hydroxy-3- (2-methoxyphenoxy) propyll-3- oxopiperazinyl} acetamide (14) Part E.

Synthesis of (tert-butoxy)-N-(2-{[2-hydroxy-3-(2-methoxyphenoxy) propyllamino} 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 (1 : 1, Hex : EtOAc) to afford compound 11.

Synthesis of N-{2-[(tert-butoxy) carbonylamino] ethyl}-2-chloro-N [2-hydroxy-3-(2- methoxyphenoxy) propyllacetamide (12) Compound 11 (1. 0 g, 3. 0 mmol) was dissolved in 20 mL DCM and treated with diisopropylethyl amine (0. 76 g, 4. 5 mmol). The mixture was cooled to °C. 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) propyllpiperazin-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- (2- methoxyphenoxy) 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 (M+1) = 442. 34 Example 3

The compounds listed in Table 1, below were made in the manner of compound 14 of Example 2.

Table 1 R MH+ 25 2, 6-dimethylphenyl 430. 3 26 2, 6-dichlorophenyl 471 27 4-aminosulfonylphenyl 481. 2 28 3-trifluoromethyl-5-methoxyphenyl 500. 2 29 5-indanyl 442. 2 30 1-naphthyl 452.3 31 1-(4-chloronaphthyl) 486. 3 32 2-N-pyrrolyl-phenyl 467. 3 33 Phenyl 402. 2 34 2-chlorophenyl 436. 2 35 2-chloro-4-methylphenyl 450. 2 36 2-(1-methylethenyl)phenyl 442. 3 37 2-methylphenyl 416. 2 38 2-isopropyl-6-methylphenyl 458. 4 39 3-methylthiophenyl 448. 2 40 2-methoxy-4-chloro-5-methylphenyl 480. 2 41 4-dimethylaminophenyl 445. 3 42 2,4-dimethoxyphenyl 462. 3 43 3,4-dichlorophenyl 471. 1 44 4-chlorophenyl 436. 3 45 3-chlorophenyl 436. 2 46 3, 5-dichlorophenyl 471. 1 47 4-methoxyphenyl 432. 3 48 4-methylphenyl 416. 2 49 3-methylphenyl 416. 2 50 4-fluorophenyl 420. 2 51 4-cyanophenyl 427. 3 52 4-acetylphenyl 444 53 2-methoxyphenyl 432. 4 54 4-trifluoromethylphenyl 470. 2 55 3-trifluoromethyl-4-chlorophenyl 504. 1 56 3, 5-dimethoxyphenyl 462. 3 57 4-N-morpholinylphenyl 487. 4 83-fluoro-4-methoxyphenyl450. 2 59 3, 4, 5-trimethoxyphenyl 492. 3 60 3, 4-dimethoxyphenyl 490 61 2-fluoro-4-chlorphenyl 454. 2 62 2-hydroxymethyl-6-methylphenyl 446 Example 4 2- [4- (3- (2H-benzo [d] 1, 3-dioxolen-5-yl)-2-hydroxypropyl) piperazinyll-N- (2, 6- dimethylphenyl) acetamide (7B).

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 NaHCO3 (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 MgSO4, 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 (5B).

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 5B.

Part C.

Synthesis of 5-(oxiran-2-ylmethyl)-2H-benzo [dQ1, 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 (3xlOOml). The organic layer was dried over MgS04, and concentrated in vacuo. The residue was purified using Prep. TLC (2 : 1 hexane : ethyl acetate) to yield 6B.

Part D.

2- [4- (3- (2H-benzo [d] 1, 3-dioxolen-5-yl)-2-hydroxypropyl) piperazinyll-N- (2, 6- dimethylphenyl) 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 dichloromethane : methanol) to afford compound 7B : Mass spectrum (MH+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)-l-propene in part C to afford compound 9B : Mass spectrum (MH+1) = 396. 32.

N- (2, 6-dimethylphenyl)-2- {4- [2-hydroxy-3- (2-methoxyphenyl)-<BR> propyllpiperazinyl} acetamide (1OB) Compound 10B was prepared in the manner of compound 7B substituting 3- (2- methoxyphenyl)-1-propene for 3- (3, 4-methylendioxyphenyl)-1-propene in part C to afford compound 10B : Mass spectrum (MH+1) = 412. 35.

N- (2, 6-dimethylphenyl)-2- {4- [2-hydroxy-3- (4- methoxyphenyl) propyl]piperazinyl}acetamide (11B).

Compound 11B was prepared in the manner of compound 7B substituting 3- (4- methoxyphenyl)-1-propene for 3- (3, 4-methylendioxyphenyl)-l-propene in part C to afford compound 11B : Mass spectrum (MH+1) = 412. 35.

N- (2, 6-dimethylphenyl)-2- {4- [2-hydroxy-3-phenylpropyl] piperazinyl} acetamide (12B) Compound 12B was prepared in the manner of compound 7B substituting 3-phenyl-1-propene for 3- (3, 4-methylendioxyphenyl)-1-propene in part C to afford compound 12B : Mass spectrum (MH+1) = 382.

N- (2, 6-dimethylphenyl)-2- [4- (2-hydroxy-3-naphthylpropyl) piperazinyl] acetamide (13B).

Compound 13B was prepared in the manner of compound 7B substituting 3- (1-naphthyl)-1- propene for 3- (3, 4-methylendioxyphenyl)-1-propene in part C to afford compound 13 : Mass spectrum (MH+1) = 432. 55.

EXAMPLE 5 Part A Intermediate (14B) : To a solution of 4-methoxybenzyl chloride (2-mmol) in anhydrous ether (10 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 (3xlOOml).

The organic layer was dried over MgSO4, and concentrated in vacuo. The residue was purified using Prep. TLC (2 : 1 hexane : ethyl acetate) to yield 15B.

Part C Synthesis of N- (2, 6-dimethylphenyl)-2- {4- [4- (4-methoxyphenyl)-2- hydroxybutyllpiperazinyl} acetamide (16B) To a solution of compound 5B (0. 4 g, 1. 64 mmol) in ethanol (100 mL) was added compound 15B (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. (M+1) = 426. 3

2- {4- [4- (2, 6-difluorophenyl)-2-hydroxybutyl] piperazinyl}-N- (2, 6- dimethylphenyl) acetamide (17B) Compound 17B was prepared in a manner similar to that of compound 16B substituting 2, 6- difluorobenzyl chloride for 4-methoxybenzyl chloride. (M+1) 432. 2 N- (2, 6-dimethylphenyl)-2- {4- [4- (2-chlorophenyl)-2-<BR> <BR> hydroxybutyll piperazinyl} acetamide (18B) Compound 18B was prepared in a manner similar to that of compound 16B substituting 2- chlorobenzyl chloride for 4-methoxybenzyl chloride. (M+1) = 430. 2

2- (4- {4- [4- (tert-butyl) phenyl]-2-hydroxybutyl} piperazinyl)-N- (2, 6- dimethylphenyl) acetamide (19B) Compound 19B was prepared in a manner similar to that of compound 16B substituting 4-t- butylbenzyl chloride for 4-methoxybenzyl chloride. (M + 1) = 452. 3 N- (2, 6-dimethylphenyl)-2- {4- [4- (2-fluorophenyl)-2- hydroxybutyl] piperazinyl} acetamide (20B) Compound 20B was prepared in a manner similar to that of compound 16B substituting 2- fluorobenzyl chloride for 4-methoxybenzyl chloride. (M + 1) = 414. 2

N- (2, 6-dimethylphenyl)-2- (4- {2-hydroxy-4- [4- (trifluoromethyl) phenyl] butyl} piperazinyl) acetamide (21B) Compound 21B was prepared in a manner similar to that of compound 16B substituting 4- trifluoromethylbenzyl chloride for 4-methoxybenzyl chloride. (M + 1) = 464. 2

2- [4- (3- (2H-benzo [dll, 3-dioxolen-5-yl)-2-hydroxypropyl) piperazinyl]-N- (2, 6- dimethylphenyl)-2-methylpropanamide (22B) This compound was prepared in a manner similar to that of 7B, substituting 2-chloro-2- methylpropionyl chloride for chloroacetyl chloride in part A. (M+1) = 454. 54

N- (2, 6-dimethylphenyl)-2- [4- (2-hydroxy-3-phenylpropyl) piperazinyll-2- methylpropanamide (23B) This compound was prepared in a manner similar to that of 7B, substituting 2-chloro-2- methylpropionyl chloride for chloroacetyl chloride in part A and allylbenzene for 8B. (M+1) = 410. 34.

N- (2, 6-dimethylphenyl)-2- {4- [2-hydroxy-3- (3, 4, 5- trimethoxyphenyl) propyllpiperazinyl}-2-methylpropanamide (24B) This compound was prepared in a manner similar to that of 7B, substituting 2-chloro-2- methylpropionyl chloride for chloroacetyl chloride in part A and 3, 4, 5-trimethoxy alkybenzene for 8B. (M+1) = 472. 54 N- (2, 6-dimethylphenyl)-2- [4- (2-hydroxy-5-phenylpentyl) piperazinyllacetamide (25B) This compound was prepared in a manner similar to that of 16B, substituting phenethyl chloride for 4-methoxybenzyl chloride in part A. (M+1) = 410. 4.

N- (2, 6-dimethylphenyl)-2- {4- [5- (2-fluorophenyl)- 2-hydroxy- pentyll piperazinyl} acetamide (26B) This compound was prepared in a manner similar to that of 16B, substituting 2- fluorophenethyl chloride for 4-methoxybenzyl chloride in part A. (M+1) = 428. 1.

N- (2, 6-dimethylphenyl)-2- {4- [5- (2-chlorophenyl)- 2-hydroxy- pentyl] piperazinyl} acetamide (27B) This compound was prepared in a manner similar to that of 16B, substituting 2- chlorophenethyl chloride for 4-methoxybenzyl chloride in part A. (M+1) = 444. 3

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 NaHCO3 (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 MgSO4, filtered and concentrated to afford compound 3C as a white solid.

Part B.

Synthesis of N- (2, 6-dimethylphenyl)-2-piperazinylacetamide (5C).

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 5C.

Part C.

Synthesis of 2- (oxiran-2-ylmethoxy) propane (6C) To a solution of 60% NaH (0. 18g, 4. 5mmol) in DMF (I Oml) cooled to 0 degrees was added 2-propanol (0. 5g, 3, 73mmol) in DMF (2ml) dropwise. After stirring for 30minutes epibromohydrin (1. 1 lg, 8. 18mmol) in DMF (lml) 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-2- yloxypropyl) piperazinyl] acetamide (7C) To a solution of 6C (0. 43g, 2. 3mmol) in ethanol (4ml) was added 5C (0. 405g, 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 (M+1) = 438. 36.

2- ( {2- [4- (3-isopropoxy-2-hydroxypropyl) piperazinyl]- N- (f{2, 6-dimethylphenyl) acetamide (10C) Compound 10C 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 (MH+) = 364. 37.

N- (2, 6-dimethylphenyl)-2- {4- [2-hydroxy-3 (phenylmethoxy) propyl] piperazinyl} acetamide (11 C) 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 11C. Mass Spectrum (M+1) = 412.36.

2- (12- [4- (3-cyclopentyloxy-2-hydroxypropyl) piperazinyll- N- (f2, 6- dimethylphenyl) acetamide (12C)

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 : MS (MH+) = 390. <BR> <BR> <P>2- (12- [4- (3-cyclohexyloxy-2-hydroxypropyl) piperazinyl]- N- (12, 6- dimethylphenyl) acetamide (13C) 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 (MH+) = 404.

2- [4- (3-1 [4- (tert-butyl) phenyl] methoxyl-2-hydroxypropyl) piperazinyll-N- (2, 6- dimethylphenyl) 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 (M+1) = 468. 44 N-(2, 6-dimethylphenyl)-2-(4-{3-[(2-nuorophenyl) methoxy]-2- hydroxypropyl} piperazinyl) acetamide (15C) : Compound 15C was prepared in a similar manner to compound 7C, substituting the commercially available 2-fluorobenzylalcohol for 2-propanol in part C. MS (M+1) = 430. 39

2-(4-{3-[(2, 4-dinuorophenyl) methoxy]-2-hydroxypropyl} piperazinyl)-N-(2, 6- dimethylphenyl) acetamide (16C) : Compound 16C was prepared in a similar manner to compound 7, substituting the commercially available 2, 4-difluorobenzylalcohol for 2- propanol in part C. MS (M+1) = 448. 38 N-(2, 6-dimethylphenyl)-2- [4-(2-hydroxy-3- { [4- (trifluoromethyl) phenyl] methoxy} propyl) piperazinyl] acetamide (17C) : Compound 17C was prepared in a similar manner to compound 7C, substituting the commercially available 4- trifluoromethyl-benzylalcohol for 2-propanol in part C. MS (M+1) = 480. 37 N-(2, 6-dimethylphenyl)-2-(4-{2-hydroxy-3- [(2- methoxyphenyl) methoxy] propyl} piperazinyl) acetamide (18C) : Compound 18C was prepared in a similar manner to compound 7C, substituting the commercially available 2- methoxy-benzylalcohol for 2-propanol in part C. MS (M+1) = 442. 41 2-(4-{3-[(2, 4-dimethoxyphenyl) methoxy]-2-hydroxypropyl} piperazinyl)-N-(2, 6- dimethylphenyl) acetamide (19C) : Compound 19C was prepared in a similar manner to

compound 7C, substituting the commercially available 2, 4-dimethoxy-benzylalcohol for 2- propanol in part C. MS (M+1) = 472. 42 N- (2, 6-dimethylphenyl)-2- (4- {2-hydroxy-3- [ (4- methoxyphenyl) methoxy] propyl} piperazinyl) acetamide (20C) : Compound 20C was prepared in a similar manner to compound 7C, substituting the commercially available 4- methoxy-benzylalcohol for 2-propanol in part C. MS (M+1) = 442. 42 N- (2, 6-dimethylphenyl)-2- (4- {3- [ (4-fluorophenyl) methoxy]-2- hydroxypropyl} piperazinyl) 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 (M+1) = 430. 40 N- (2, 6-dimethylphenyl)-2- (4- {2-hydroxy-3- [ (4- methylphenyl) methoxy] propyl} piperazinyl) acetamide (22C) : Compound 22C was prepared in a similar manner to compound 7C, substituting the commercially available 4- methyl-benzylalcohol for 2-propanol in part C. MS (M+1) = 426. 41

N- (2, 6-dimethylphenyl)-2- (4- {2-hydroxy-3- [ (4- phenylphenyl) methoxy] propyl} piperazinyl) acetamide (23C) Compound 23C was prepared in a similar manner to compound 7C, substituting the commercially available 4-phenyl- benzylalcohol for 2-propanol in part C. MS (M+1) = 488. 42 N-(2, 6-dimethylphenyl)-2-(4-{3-[(4-butylphenyl) methoxy]-2- hydroxypropyl} piperazinyl) acetamide (24C) : Compound 24C was prepared in a similar manner to compound 7C, substituting the commercially available 4-n-bu-benzylalcohol for 2- propanol in part C. MS (M+1) = 468. 45 N- (2, 6-dimethylphenyl)-2- {4- [2-hydroxy-3- (2- naphthylmethoxy) propyl] piperazinyl} 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 (M+1) = 462. 41

N- (2, 6-dimethylphenyl)-2- {4- [3- (cyclohexylmethoxy)-2- hydroxypropyl] piperazinyl} acetamide (26C) Compound 26C was prepared in a similar manner to compound 7C, substituting the commercially available cyclohexylmethanol for 2- propanol in part C. MS (M+1) = 418. 55 N- (2, 6-dimethylphenyl)-2- (4- {3- [ (4-fluorophenyl) methoxy]-2-hydroxypropyl}-3, 3- dimethylpiperazinyl) 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 (M+1) = 458. 5

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 Palmityl CoA oxidation was carried out in a total volume of 100 micro liters containing the following agents : 110 mM KCl, 33 mM Tris buffer at pH 8, 2 mM KPi, 2 mM MgCl2, 0. 1 mM EDTA, 14. 7 microM defatted BSA, 0. 5 mM 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/ml, 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, and 0. 5 ml of the eluent was used for scintillation counting to determine the amount of C14 trapped as C'4 bicarbonate ion.

Table 1 Inhibition of mitochondrial fatty acid oxidation using palmitoyl CoA as substrate-% of Control at 3 concentrations. Compound # 100 M 30 M 3 M Ranolazine 75% 90%-- 14 -- -- -- 7 85% 98% 107% 15 78% 97% 103% 17 89% 98% 100% 16 100% 96%-- 18 17% 19- 22 25% 23- 9B 84% 84% 10B---- 7B---- 11B 83% 92% 12B 42% 95% 13B --- 16B 37% 17B 78% 18B 78% 19B 35% 20B 56% 21B 56% 23B 70% 24B 72% 10C 100% 97% -- 7C 68% -- -- iic 79% 12C 141% 13C 30% 14C 21%- 15C100% 16C 97% 17C 35% 18C 96% 19C 97%- 20C100% 21C 87% 22C 45% 23C 12% 24C 15% 25C 38% 26C70% 27C 73%

Example 8 Palmitoyl Carnitine Oxidation The Palmitoyl camitine 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 KPi, 2 mM MgCl2, 0. 1 mM EDTA, 0. 1 mg/ml of defatted BSA, 0. 5 mM malic acid, 3 mM ADP, 52 micrograms of mitochondrial protein, and 43 microM 1-C14 palmitoyl carnitine (Sp. Activity 60 mCi/mmole ; 20 microCi/ml, 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 °C, 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, and 0. 5 ml of the eluent was used for scintillation counting to determine the amount of C14 trapped as C14 bicarbonate ion. The data are presented as % activity of control.

Table 2 Inhibition of mitochondrial fatty acid oxidation using palmitoyl carnitine as substrate- % of Control At 3 concentrations.

Compound # 100 µM 30 µM 3 µM Ranolazine 63% 98%-- 14 -- -- -- 7 95% 102% 109% 15 82% 98% 106% 17 80% 88% 103% 16 64% (8) -- -- 9B -- -- -- 10B -- -- -- 7B -- -- -- 11B -- -- -- 12B 56% 13B-- 11B -- -- -- 12B 56% -- -- 13B -- -- -- 10C 80% -- -- 7C -- -- -- 11C -- -- -- 12C -- -- -- tic

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 (57%) 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 MgCl2 kept at 4°C ; ß-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 100iM in 10% ACN ; Human S9 stock : 20mg/mL from Gentest.

Procedure : Incubation mixtures were prepared as follows :

Table 3 Component Volume per 0. 25mL of Incubation Final Mixture concentration 10pM CVT 25pL 10 µM compounds MgC'2 25pL 0. 005 M NADPH 25pL 0. 002 M S9 25pL 2 mg/mL Incubation Buffer 25 L 0. 05 M Water 1251lL * 1% organic solvent (acetonitrile) was used in incubation mixture. Generally, 30 incubates were prepared at a time by pre-mixing 0. 75 mL of MgCl2, 0. 75 mL of incubation buffer, 0. 75 mL of NADPH, 3. 75 mL of water. Then pipette 200 FL/incubate, add 25 gel 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 + 25µ L of the compound being tested along with 25pL of S-9.

After 5 min of pre-incubation at 37°C, at 0 and 30min after starting the reaction, a 50 gl aliquot of the incubation mixture was removed and added to 100 pL of 9 : 1 acetonitrile : methanol containing the internal standard.

The mixture was centrifuged and a 100 uL aliquot of the supernatant was diluted in 1mL of solvent C (0. 1% 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 µL).

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 1. 0. If a compound is less stable than ranolazine, than the stability factor will be less than 1. 0.

Table 4 Compound # Liver S9 Stability Factor Ranolazine 1. 0 5 0. 45 7 1. 51 15 1. 20 16 0. 15 17 0. 45 9B 1. 18 10B 1. 03 7B 1. 46 11B 1. 33 12B 1. 38 13B 0. 10 16B 0. 99 17B 0. 71 18B 0. 68 19B 20B - 21B- 22B 1. 49 23B 0. 5 24B 1.05 25B - 26B - 27B - 21C -- 22C 0. 61 23C 0. 05 24C 0. 02 25C 0. 01 26C -- 27C --