CA2400176C - Substituted piperazine compounds - Google Patents

Substituted piperazine compounds Download PDF

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CA2400176C
CA2400176C CA002400176A CA2400176A CA2400176C CA 2400176 C CA2400176 C CA 2400176C CA 002400176 A CA002400176 A CA 002400176A CA 2400176 A CA2400176 A CA 2400176A CA 2400176 C CA2400176 C CA 2400176C
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alkyl
group
hydrogen
acetamide
compound
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CA2400176A1 (en
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Jeff Zablocki
Elfatih Elzein
Grigory Nudelman
Tim Marquart
Vaibhav Varkhedkar
Prabha N. Ibrahim
Venkata P. Palle
Brent K. Blackburn
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Gilead Palo Alto Inc
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CV Therapeutics Inc
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    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/145—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/15—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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Abstract

Novel compounds of the general formula:

Description

TITLE: SUBSTITUTED PIPERAZINE COMPOUNDS

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.
2o 2. Description of the Art U.S Patent No. 4,567,264, 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]-l-piperazineacetamide, and its pharmaceutically acceptable salts, and their use in the treatment of cardiovascular diseases, including arrhythmias, variant and exercise-induced angina, and myocardial infarction.
U.S. Patent No. 5,506,229, 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 1a release formulation in capsule form comprising microspheres of ranolazine and microcrystalline cellulose coated with release controlling polymers.
Despite the important discovery that ranolazine is a very useful cardiac therapeutic agent, there remains a need for compounds that are partial fatty acid oxidation inhibitors that have a half-life greater than ranolazine and that have activities as least similar to ranolazine.

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

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

R
Rs R, R~
O R9 R~ o R1z N N ---~ X
R4 i --I~ R24 Re R7 Rs R13 OH

wherein X is selected from the group consisting of:
and O
wherein m = I or 2 or 3;
Rõ R2, Rõ R4 and RS are each independently selected from the group consisting of hydrogen, halo, NO2, CF31 CN, ORZ,, SR23 N(R23)2, S(O)Ru1 SOZRZZ, SO2 N(R23)z, NR23C02R22, NR23CON(R23)2, COR23, C02R23, CON(R23)21 NR23SO2R22, C,.,s alkyl, Cz-is alkenyl, C2_,S alkynyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl and aryl substituent are optionally substituted with I substituent selected from the group consisting of halo, NO2, CF3, CN, OR2,, SR2,, N(R23)2, S(O)Ru, and SOZRu , wherein RZ and R, may join together to form a fused ring system having from three to four carbon atoms, and wherein R4 and R3 may join together to form -CH=CH-CH=CH-;
R6, R7 and Ra are each independently selected from the group consisting of hydrogen and C,-,s alkyl;
R9, R,o, R,,, R,Z, R13, R14, R15 and R16 are each independently selected from the group consisting of hydrogen, CO2R23, CON(R,)2, C,., alkyl, and aryl wherein the alkyl and aryl substituents are optionally substituted with I substituent selected from the group consisting of halo, CFõ CN, OR,,, N(Rõ)2, COZR,3, CON(R.3)2 and aryl, wherein R, and R,o may together form a carbonyl, or Rõ and R12 may together form a carbonyl, or Rõ and R14 may together form a carbonyl, or R,S and R16 may together form a carbonyl wherein Rõ and Rõ
or R, and R15 or R9 and Rõ or Rõ and R,S or R4 and R13 may join together to form a bridging ring system having from 1 to 4 carbon atoms and wherein R9 and R,o or Rõ and R12 or Rõ and R14 or R15 and R16 may join to form a bridging ring system having from 1 to 5 carbon atoms.
R,, is selected from the group consisting of C1-1S 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 arnide, heteroaryl amide, CN, O-C,-6allcyl, CF3, and heteroaryl;
R23is selected from the group consisting of H, C,_,S alkyl, aryl, and heteroaryl, wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, alkyl, monoalkylamino, dialkylamino, alkyl-CN, -O-C,-6alkyl, 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, OR23, SR23, S(O)R22, S02R22, SO2N(R23)2i NR23CO2R22, C1-2 alkyl, and aryljwherein the optional aryl substituent is optionally substituted with from 1 to 3 substituents selected from the group consisting of halo, phenyl, CF31CN, OR23, and C,_6 alkyl, and Rie R17 Ris wherein R,,, R,g, R19, RZO, and RZ, are each independently selected from the group consisting of hydrogen, halo, NOZ, CF3i CN, ORZõ SR23, N(R23)2, S(O)R22, SO3Ru, SO2N(R23)2, NR23CO2RZ2, NR23CON(Rz3)z, COR23, CO2R23, CON(R.3)2, NR,3SO2Rz2, C,-,s allcyl, C2a5 alkenyl, C2_15 alkynyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl and aryl substituent are optionally substituted with I substituent selected from the group consisting of halo, NOZ, CF,, CN, OR23, SR,3, 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, Prinzrnetal'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:

R
Rs R, Rlo N N X
R4 i R24 Re R7 Ra R13 OH

I
wherein X is selected from the group consisting of:

4-)-M--- and 0 wherein m = 1 or 2 or 3;
R,, R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, halo, NO2, CF31 CN, OR23, SR23, N(R23)2, S(O)RZZ, S02R22, SO2N(R23)2, NR23C02R22, NR23CON(R23)Z, COR23, C02*R23, CON(RZ3)2, NR23S02R22, C,_,s alkyl, 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, CF31 CN, OR23, SR23, N(R23)2, S(O)R22, and S02R22 , 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,_15 alkyl;
R9, R,o, R,,, R12, R13, R14, R,5 and R,6 are each independently selected from the group consisting of hydrogen, COZR23, CON(R23)2, C, alkyl, and aryl wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, CF31 CN, OR23, N(R23)2, CO,R23, CON(R23)2 and aryl, wherein R9 and R,o may together form a carbonyl, or Rõ and R12 may together form a carbonyl, or R13 and R14 may together form a carbonyl, or R15 and R16 may together form a carbonyl wherein Rõ and R13 or R9 and R15 or R9 and Rõ or Rõ and R15 or R9 and R13 may join together to form a bridging ring system .iaving from I to 4 carbon atoms and wherein R9 and R,o or Rõ and R12 or Rõ
and Rõ or R15 and R16 may join to form a bridging ring system having from 1 to 5 carbon atoms;
R22 is selected from the group consisting of C,_,S 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,.4 alkyl, CFõ and heteroaryl;
R23 is selected from the group consisting of H, C,-15 alkyl, aryl, and heteroaryl, wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, alkyl, monoalkylamino, dialkylamino, alkyl-CN, -O-C,.6 alkyl, and lo 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, OR23, SR23, S(O)R22, S02R22i S02N(R23)2, NRZ3COZR22, C1_2 alkyl, and aiyl wherein the optional aryl substituent is optionally substituted with from I to 3 substituents selected from the group consisting of halo, phenyl, CFõ CN, OR23, and C,.6 alkyl, and Rta Ri7, R,y Rqp R2, 20 wherein R,,, R1e, R,9, R20i and RZ, are each independently selected from the group consisting of hydrogen, halo, NOZ, CF3, CN, OR,,, SR23, N(R23)2, S(O)R22, SO2Ru, SOZN(R23)2, NR23CO2R22, NRZ,CON(R23)2, COR23, C0ZR23, CON(R23)2, NR23SO2R22, C,-,s alkyl, C2as alkenyl, C2-15 alkynyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of 25 halo, NOZ, CF3, CN, OR23 SR23, N(R23)2, S(O)R22, and S02R22.
This invention also includes a subset of the class of substituted piperazine compounds identified in Formula I above having the following Formula (IA):
FRIq R3 H '1-, O I OH
Rs R7 R8 W

IA
wherein m = 1, 2;
R', RZ, R3, R' and RS are each independently selected from the group consisting of hydrogen, halo, CF3, OR23 and CI-4 alkyl and wherein R23 is a C1_3 alkyl;

R6, R7 and R8 each independently selected from the group consisting:of hydrogen and C,_3 alkyl;
R9, R10, R", R'Z, R", R", R'S and R'6 are each independently selected from the group consisting of hydrogen and C, alkyl, or R9 and R10 may together form a carbonyl, or R" and R'Z may together form a carbonyl, or R" and R" may together form a carbonyl, or R15 and R16 may together fonn a carbonyl wherein R,, and Rõ or R9 and R15 or R, and R,, or Rõ and R15 or R9 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, R10, R", R'2, R'3, R'4, R15 and R16 are not all simultaneously hydrogen, when R , RI 8, Ri9, R20 and R21 are all hydrogen.
Rt7, R18, R19, R20 and Rz1 are each independently selected from the group consisting of hydrogen, halo, CF3, CN, OR23, S(O)R22, S02R22, SO2N(R23)2, CON(R23)2, C14 alkyl wherein R23 is C,_3 alkyl, or R" and R18 may together form -CH=CH-CH=CH-, or R18 and R19 may together form -OCH2O-.
In more preferred compounds of Formula IA, R', R2, R3, R4 and RS are each selected from the group consisting of hydrogen, halo, CF3, OR23 and C!-4 alkyl where R23 is a CI.3 alkyl; R6 is selected from hydrogen and methyl; R7, R8, R', R10, R", R'2, R'3, R'4, R'5 and R'6 are each independently selected from hydrogen and methyl or R9 and R10 may together form a carbonyl, or R13 and R14 may together form a carbonyl with the proviso that R9, R10, R", R'2, Rt3, R14, R15 and R16 are not all simultaneously hydrogen ; R", R18, R'9, R20 and RZ' are each independently selected from the group consisting of hydrogen, halo, CFõ OR23 and . C,_, alkyl, or R" and R'g may together form -CH=CH-CH=CH-, or R" and R'9 may together form -OCHZO-.
In still more preferred compounds of Formula IA, R', Rz, R3, R", R5, R6, R' and Rg are each independently selected from the group consisting of methyl and hydrogen;
R9, R10, R", R'Z, R13, R14, R'S and R'6 are each independently selected from hydrogen and methyl or R9 and R10 may together form a carbonyl, or R'3 and R" may together form a carbonyl with the proviso that R', R10, R", R'2, R", R'", R'S and R'6 are not all simultaneously hydrogen; R", R18, R19, R20 and RZ' are each independently selected from the group consisting of hydrogen, halo, CF3, OR23 wherein R23 is methyl, or R" and R'$ may together form -CH=CH-CH=CH-, or R'g and R" may together form -OCHZO-In an even more preferred compounds of Formula IA, R' and RS are each methyl;
R2, R3, R4, R6, R', Rg are each hydrogen; R9, R10, R", R'Z, R", R'4, R'5 and R'6 are each independently selected from hydrogen and methyl or R9 and R10 may together form a carbonyl, or R" and Rt4 may together form a carbonyl with the proviso that R9, R10, R", R'2, R13, R14, R'S and R'6 are not all simultaneously hydrogen; R", R'8, R'9, R20 and RZ' are each independently selected from the group consisting of hydrogen, halo, methyl, OR23 wherein R23 is methyl, or R" and R'g may together form -CH=CH-CH=CH-, or R18 and R" may together form -OCHzO-.
In still more preferred compounds of Formula IA, R' and RS are each methyl;
R2, R3, R", R6, R', Ra are each hydrogen; R9, R10 are selected from hydrogen, methyl, or may together form a carbonyl; R" and R'Z are selected from hydrogen and methyl; R" and R14 are selected from hydrogen and methyl or may together form a carbonyl; R15 and R16 are hydrogen with the proviso that R9, R10, R", R12, R", R'4, R'S and R'6 are not all simultaneously hydrogen; R"
is selected from the group consisting of hydrogen, chloro, fluoro or methoxy;
R1e and R19 are each selected from the group consisting of hydrogen or methoxy, or R'$ and R19 may together form -OCHzO-, or R" and R' S may together form -CH=CH-CH=CH-, R20 is hydrogen;
and RZ' is selected from hydrogen or chloro.
Most preferably, the substituted piperazine compounds of Fon=.nula 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-di aza-5-[2-hydroxy-3-(2-3o 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](1 S,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-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl } -N-(2,6-dimethylphenyl)acetamide, 2- {(3 S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl } -N-(2,6-dichlorophenyl) acetamide, 2- {(3 S)-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- {(3 S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl} -N-indan-5-ylacetamide, 2- {(3 S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl} -N-naphthylacetamide, 2- {(3 S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-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-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-phenylacetamide, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl} -N-(2-chlorophenyl) acetamide, 2- {(3 S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl} -N-(2-chloro-4-methylphenyl)acetamide, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl} -N-[2-(1-methylvinyl)phenyl] acetamide, 2- {(3 S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-(2-methylphenyl) acetamide, 2-{(3 S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl} -N-[6-methyl-2-(methylethyl)phenyl] acetamide, 2- {(3 S)-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-[(2S)-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- {(3 S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl} -N-(4-chlorophenyl) acetamide, 2- {(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-methylpiperazinyl} -N-(3-chlorophenyl) acetamide, 2- {(3 S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl} -N-(3,5-dichlorophenyl) acetamide, 2- {(3 S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-(4-methoxyphenyl) acetamide, 2- {(3 S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl} -N-(4-methylphenyl) acetamide, 2- {(3 S)-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-{(3 S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl } -N-(4-acetylphenyl) acetamide, 2- {(3 S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl} -N-(2-methoxyphenyl) acetamide, 2- {(3 S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-[4-(trifluoromethyl)phenyl] acetamide, 2-{(3S)-4-[(2 S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl} -N-[4-chloro-(trifluoromethyl)phenyl] acetamide, 2- {(3 S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-(3,5-dimethoxyphenyl) acetamide, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl} -N-(4-morpholin-4-ylphenyl) acetamide, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-(3-fluoro-4-methoxyphenyl) acetamide, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-(3,4,5-trimethoxyphenyl) acetamide, 2-{(3S)-4-[(2 S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl} -N-(3,4-dimethoxyphenyl) acetamide, 2- {(3 S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl} -N-(4-chloro-2-fluorophenyl) acetamide, and 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-[2-(hydroxymethyl-6-methylphenyl]
acetamide.
This invention includes a subset of substituted piperazine compounds of formula I
having the following formula IB:

2 R R1o R11 R12 17 R1s R

*.--)4 R 3- A-r R1s 6 R7 $ OH
R4 R5 R~6 R15R14R13 R21 R2o 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)Z, S(O)Ru, S02R22, SO2N(R2,)2i NR23CO2R22, NRZ,CON(RZ3)Z, CORZ3, C0ZRZõ CON(R23)2, NR23SO2R22, C1_15 alkyl, C2_,5 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, NOZ, CF,, CN, ORZõ SRZ,, N(R23)2, S(O)R22, and SOZRZZ;
R6, R7 and R8 are each independently selected from the group consisting of hydrogen and C,-,s alkyl;
R', R'o, R", R12, R13, R'a, R's and R16 are each independently selected from the group 1 o consisting of hydrogen, C02R23 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, CFõ CN, OR23, N(Rõ)2, CO2R", CON(R2,)2 and aryl, wherein R9 and R10 may together form a carbonyl, or R" and R'Z may together form a carbonyl, or R13 and R14 may together form a carbonyl, or R'S and R16 may together form a carbonyl wherein R" and R13 or R9 and R15 or R' and R" or R" and R15 or R9 and R" may join together to form a bridging ring system wherein the two R groups together comprise of from I to 4 carbon atoms and wherein R9 and R10 or R" and R'2 or R" and R" or R'S and R'6 may join to form a spiro ring system wherein the two R groups together comprise of from 1 to 5 carbon atoms;
R", R18, R19, R20, and RZ' are each independently selected from the group consisting of hydrogen, halo, NO2, CF31 CN, OR23, SR23, N(Rõ)Z, S(O)R22, SO2R22, SOZN(R23)Z, NR23CO2R22, NRZ3CON(R2,)2, CORZõ C02R23, CON(R23)2, NR23SO2R22, C,-is alkyl, C2.is alkenyl, CZ_15 alkynyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl and aryl substituent are optionally substituted with I substituent selected from the group consisting of halo, NO2, CF,, CN, ORZ,, SR23, N(RZ3)2i S(O)R22, and SO2R22or wherein R" and R18 may join together may join together to form -CH=CH-CH=CH- or wherein R17 and R`$ or R'a and R'9 or R19 and R20 or Rz0 and RZ' 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, CFõ CN, Oe, SR2', N(R~)2, S(O)R'2, S02RIZ, SOZN(R'3)2, NR'3C02R22, NR21CON(RZ')2, COR23, CO2R23, CON(RZ')Z, NRZ'S02R", C,-alkyl, C2-15 alkenyl, CZ-,5 alkynyl, heterocyclyl, aryl, or heteroaryl, wherein the alkyl and aryl substituents are optionally substituted with I substituent selected from the group consisting of halo, NOZ, CF31CN, OR23, SR23, N(R23 )2, S(O)RZZ, or S02R21;

RZZ is selected from the group consisting of C,_,S alkyl, aryl, or heteroaryl, wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, alkyl, monoalkylamino, dialkylamino, alkyl amide, aryl amide, heteroaryl amide, CN, O-C,_6 alkyl, CF3, and heteroaryl; and b R23 is selected from the group consisting of H, C,.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, -O-C,_6 alkyl, or CF,.
In preferred compositions of this invention, m= -p, 1 or 2 or 3; R', R2, R3, R` and RS
are each independently selected from the group consisting of hydrogen, halo, CF31 OR23 and 1 o C,-4 alkyl; R6, R7 and Rg each independently selected from the group consisting of hydrogen and C,., alkyl; R9, R10, R", R'z, R'3, R", R'S and R 16 are each independently selected from the group consisting of hydrogen and C,., alkyl, or R' and R10 may together form a carbonyl, or R" and R12 may together form a carbonyl, or R" and R" may together form a carbonyl, or R'S
and R16 may together form a carbonyl, or wherein R" and Rt3 or R9 and R15 or R9 and R" or 15 R" and R15 or R9 and R" may join together to form a ring including from 1 to 4 carbon atoms wherein R9, R'o, R", R12, R13, R", R`s and R16 are not all hydrogen; and R", R1e, R", R20 and RZ' are each independently selected from the group consisting of hydrogen, halo, CFõ CN, OR23, S(O)RZZi S02R22, SO2N(R23)2i CON(R23)2,C,.4 alkyl or R" and R1e may together form -CH=CH-CH=CH=, and phenyl.
20 In other preferred compounds, R', RZ, R', R and RS are each independently selected from the group consisting of hydrogen, halo, CFõ OR23 and CI_Z alkyl wherein R23 is a CI_3 alkyl; R', R7 and Rg are each independently selected from the group consisting of hydrogen and methyl; R', R10, R", R'Z, R", R'4, R'S and R16 are each independently selected from the group consisting of hydrogen and C,_Z alkyl, or R9 and R10 may together fonn a carbonyl, or 25 R15 and R" may together form a carbonyl with the proviso that R9, R10, R", R'Z, R'3, R'4, R'S
and R16 are not all simultaneously hydrogen and wherein R" and R" or R9 and Rt5 or R9 and R" or R" and R'S or R9 and R13 may join to form a ring including from 1 to 4 carbon atoms and R", R18, R19, R20 and RZ' are each independently selected from the group consisting of hydrogen, halo, CF3, CN, OR23, and C,., alkyl and wherein R" and 30 R" may together form a substituent selected from the group consisting of -CH=CH-CH=CH-and phenyl.
In still other preferred compounds, m= I or 2; R', R2, R', R4 and RS are each independently selected from the group consisting of hydrogen, halo, CF3, OR23 and CI.a alkyl where R23 is a C,_, alkyl; R6, R', R', R9, R10, R", R'Z, R", R'4, R'S and R'6 are each independently selected from hydrogen and methyl; R", R1e, R19, R20 and RZ' are each independently selected from the group consisting of hydrogen, halo, CF3, OR22, C1_3 alkyl where R22 is methyl, or R" and R18 may together form -CH=CH-CH=CH-, or R1e and R19 may together form -OCHZO-.
In more preferred compounds, m = 1 or 2; R', R2, R', R6, R' and Re are each independently selected from methyl and hydrogen; R9, R10, R", R'2, R", R'4, R'S and R'6 are each hydrogen; and R17, R'g, R19, R20 and R 2' are each independently selected from the group consisting of hydrogen, halo, CFõ and OR23 wherein R2-3 is methyl, or Rt7 and R18 may together form -CH=CH-CH=CH-, or R'g and R19 may together form -OCHZO-.
In yet other preferred compounds, m = 1 or 2; R' and RS are methyl; R2, R3, R
R6, R7, R$,R9, R10, R", R'2, R'3, R'4, R'5 and R'6 are hydrogen; R", R'e, R", R20 and RZ' are each independently selected from the group consisting of hydrogen, halo, and OR23 wherein R23 is methyl, or R" and R'$ may together form -CH=CH-CH=CH-, or Rt8 and R" may together form -OCHZO-.
In still other preferred compounds, R' and RS are methyl; R2, R6, R7, R8,R9, R10, R", R12, R13, R'a, R's and R16 are hydrogen; R" is selected from the group consisting of hydrogen, chloro, fluoro and methoxy; R18 is selected from hydrogen and methoxy; R19 is selected from hydrogen and methoxy; R20 is hydrogen; RZ' is selected from hydrogen and chloro, or R" and R1e may together form -CH=CH-CH=CH-, or R18 and R19 may together form -OCHZO-.
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-[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, ,,4-(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-fluo:opl:enyl)- 2-hydroxy-pentyl]piperazinyl}acetamide, and N-(2,6-dimethylphenyl)-2- {4-[5-(2-chlorophenyt)- 2-hydroxy-pentyl]piperazinyl}
acetamide.
This invention further includes a subset of compounds of Formula I above having the following Fonnula IC:

O Rlo Rtt R'Z
N N m O~ R24 ~ R R$ R13 ON
Rs R R16 WIs Ru IC
wherein m 1, 2, or 3;
R', Rz, R', R4 and RS are each independently selected from the group consisting of hydrogen, halo, NO2, CF3, CN, OR20, SRZO, N(RZ)2, S(O)e, SOZRZZ, SO2N(RZ)2, NR20CO2R22, NR20CON(RZ)2, CORZO, CO2RZ0, CON(RZ0)2, NR20S02R22, C,_,s alkyl, C24s 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, CFõ CN, OR20, SR20, N(e)Z, S(O)R22, and SOZRn ;
R6, R' and R8 are each independently selected from the group consisting of hydrogen and Ci_3 alkyl;
R9, R,o, R", R12, R", R14, R15 and R16 are each independently selected from the group consisting of hydrogen, CO2R20, CON(R2)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, CFõ CN, OR20, N(R2)2. CO2RZ0, CON(R2)Z or aryl, wherein R' and R10 may together form a carbonyl, or R" and R'Z may together form a carbonyl, or R" and R" may together form a carbonyl, or R15 and R16 may together form a carbonyl, wherein R" and R" or R9 and R'S or R9 and R" or R" and R15 or R9 and R" may join together to form a ring including from I 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, :ycloalkyl, and fused phenylcycloalkyl are optionally substituted with from I
to three substituents selected from the group consisting of halo, CFõ CN, OR20, SR20, S(O)RZZ, SO2RZ', SO2N(R20)2, NR2DC02R22, C,.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, CF31CN, OR20, and C,., alkyl;
R20 is selected from the group consisting of H, C1_15 alkyl, aryl,and heteroaryl,wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, allcyl, mono- or dialltylamino, alkyl-CN, -O-C,-6alkyl, and CF3; and RZZ is selected from the group consisting of L,_,5 alkyl, aryl, and heteroaryl, wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, alkyl, monoalkylamino, dialkylamino, alkyl amide, aryl amide, heteroaryl amide, CN, O-C,-, alkyl, CF3, and heteroaryl.
In Formula IC, it is preferred that m=1 or 2 and most preferred when m = 1.
In preferred compositions of Formula IC, R', R2, R', W and RS are each independently selected from the group consisting of hydrogen, halo, CFõ OR'' and C,, alkyl and wherein R22 is C,_, alkyl. In other preferred compositions, R', RZ, R', R" and RS are each independently selected from the group consisting of hydrogen, CFõ OR20, and C1_2 alkyl. More preferably R', RZ, R3, R4 and RS are each independently selected from the group consisting of -.'hydrogen, and methyl with RZ, R3, and R' 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 C,_, alkyl with hydrogen or methyl being preferred and hydrogen being most preferred.
In yet other preferred compositions of Formula IC, R9, R10, R", R'2, R", R'4, R15 and R16 are each independently selected from the group consisting of hydrogen, CON(R2)2, C,l alkyl, and aryl wherein the alkyl and aryl substituents are each optionally substituted with I
substituent selected from the group consisting of halo, CF31 OR20, N(R20)2, CON(R2)2 andaryl wherein R9 and R10 may together fomi a carbonyl, or R" and R'2 may together form a carbonyl, or R" and R10 may together form a carbonyl, or R'S and R'6 may together form a carbonyl, wherein R' 1 and R13 or R9 and R15 or R9 and R" or R" and R'5 or R9 and R13 may join together to form a ring having from 1 to 3 carbon atoms. In alternative preferred compositions, R9, R10, R", R'2, R'3, R'r, R'S and R'6 are each independently selected from the group consisting of hydrogen and Cl _a alkyl, or R9 and R10 together form a carbonyl, or R' 1 and R1Z together form a carbonyl, or R13 and Ri4 together form a carbonyl, or R15 and R16 together form a carbonyl, R10 and R' 1 together fomi -CH2CHZCH2CH2-. In another embodiment, R9, R'O, R", R12, R13, R'4 , R15 and R16 are each independently selected from the group consisting of hydrogen, and C1_2 alkyl, wherein the alkyl substituent is optionally substituted with I
substituent selected from the group consisting of N(R2)2,and arylor wherein R9 and R10 may together form a carbonyl.
More preferably, R9, R10, R", R'Z, R'3, R'4, R'S and R'6 are each independently selected from the group consisting of hydrogen and C1_2 alkyl, or wherein R9 and R10 may together form a carbonyl. In another embodiment, R" and R15 are each selected from the group consisting of hydrogen or methyl, R', R10, RIZ, R'3, R'a and R`6 are each hydrogen and R9 and Rl0 may together form a carbonyl, or, R', R10, R", R'Z, R13, R'4, R'S and R'6 may each be hydrogen.
In compounds of Formula IC, R24 may be selected from the group consisting of alkyl, l0 cycloalkyl, and fused phenylcycloallcyl wherein the point of attachment is on the cycloalkyl wherein the alkyl, cycloalkyl, and fused phenylcycloalkyl are optionally substituted with from I to three substituents selected from the group consisting of halo, CF3, CN, OR20, SR 20, S(O)R22, SO2R'2, SO2N(R20)2, NR20COZR2, C,_Z 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, CF31CN, OR20, and C,, 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, CFõ CN, OR20, SR20, S(O)RZZ, S02RZZ, 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, CF31 CN, OR20, and C, 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 I to two substituents selected from the group consisting of halo, CF31 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, CF31CN, OR20, and C,_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 I to 2 substituents selected from the group consisting of halo, CFõ OH, C1_2 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, CF31 OR20, C,_Z 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, C,_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, R20 is selected from the group consisting of H or C1_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, arnidino, 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)t,_,_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, 0 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 0, 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 0, 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 :ffective 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 lA-7A. A general synthesis of the compounds of this invention is outlined in Scheme IA. Compound N 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/SnC12 or catalytic hydrogenation, see Advanced Organic Chemistry, Ed. J. March, (1992) A. Wiley-Interscience). Some examples of commercially available substituted anilines corresponding to general structure II include 2,6-dimethylaniline, 2,3-dimethylaniline, 2-methylaniline, , 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 lA

RZ Ri CICI R2 Ri O
R NH m R7 Ra R N CI
Ra Ra R7 Re R, RS R4 RS
II IV
Ria Rtt R
~ LR12 H-N'J"~\N-P Rg io RiiRi2 RR2 Ri 0 1aR15Rii 13 R N N N-P
V _ I e~
Ra R7 Re PaBOC,WZaBmzyi R4 RS R 16 R15R14 R13 VI
RyRia RitRu R Ri DViot- R NN ~H
Ra R/7Re R4 RS Rie R15R14Rn VII
Rie R77 0 0`~~
Ri m R10 Ri1 R Ri 0 Rt` I~R12 R17 Ria VIII R ! N N YS 0 Ri9 Ra R7 Re OIH
R4 R R/e Ri5R74R13 s R21 R2o 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).

Rte Rn Rie R17 O
acetone, K 2CO3 ~ m ~ O
R1 OH + R~y -X=CIorBr IX VIII
Epoxide VIII (where m = 1 or 2) can be prepared as outlined in Scheme 2.
Heating substituted phenol IX with epichiorohydrin, epibromohydrin, or 4-bromo-l,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-chiorophenol, 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 methylphenyl ether, glycidy13,4-dichlorophenyl ether and glycidyl 4-fluorophenyl ether.

Ri/ Rs O
~ /i %~[/ TFA
14 _ t-BuLi,R9,loBr Deprotection Bn-N\ ~ BOC Bn-N BOC
Talk-oil XII XIII

Ri oRs O R Rio BH3 ~
Bn- N \-~1H Bn-N_ JVH

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].

R10Rs 0 R9 Rlo O R13 p ~
Rta` l.coupling H-N N-Bn + \~~ Rta Bou NH OH
Bn'NH OR 2. TFA, ring dosure 0 ta XVIII R
XVI XVII
R-7MeorEt s R~oR
dibo~ane H-N N-Bn t Rts 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.

HN NH HN NH H NH

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 5A, 6A and 7A to further illustrate how to prepare the compounds of this invention.
In particular, 2,6-dichloroaniline was acylated with 2-chloroacetyl chloride 2 using saturated bicarbonate and ether (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 K2C03 as described in Scheme 6.

0 CI cl HN \- NH

NHZ , C I
satNaHCO3/Et20(1:1) H EtOH,DIPEA,tetlux24hts.
0 -> RT

O r-~ 6 N NH
N
H EtOH,Reflux ~---(`

H,CO
~
c H J-' N N~O ` /
~ OH

OH
acetone, KZC03 O
+ CI _ 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.

e_c CH3 I7" c H OCH, r HNf4HZ O
\ HN r H
= Ol- O

I I \

O OCHs 1. TFA
chbroacetyl chloride ~oc O H

DCM, DIPEA 2. EtOH, DIPEA

\ I \
H
OCH3 3 H OCHy ^ Q N
HN O I\ ~N~ O
EtOH, DIPEA / 0 The compounds having the general formula I and IB can be prepared as outlined in 5 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/SnC12 or catalytic hydrogenation, see Advanced Organic Chemistry, Ed. J.
10 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.

z Rll C J-2~- CI z R~
O
III R~
Rs iH Ra R N CI
Ra Re R' Re a II IV
Rio R"
Ra` \ ' R1z H-N/ ~N_P Rz RaRlo R>>R1z ~ ~

R~s, 14R~3 R R R3 N~ N N-P
~
V Re R~ Re P=BOC,CBZorBenzy R4 R e R'e R15R74R~3 VI
RaR1o R>>
Rz R~
R R iz Deprotect R / \ N itr N N-H
- Re R7 Ra R4 R5 R1 a RuRtaR13 VII
Rla R 17 Ria n O R' RaRto R>>R1z R 17 Rte Rzo R 21 O J --~ ~
VIII Rs NJ'~N/ N Rta /`
AW~ Ra R7 Re OH
R 4 R5 R1e R1eRtaR1a R21 Rzo 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).

R \ CHO R18 I I \ CI
R1 ~ R21 R1 ~ R21 2p IX X R

/MgBr PhgPCH2Br, NaH, THF
Diethylether mCPBA,DCM
>

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 Homer 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.

RioRa O

~ Deprotection 14 _ n-BuLi, R9,IpBr Bn-N~-2 BOC Bn-N\ 2 BOC
V
XII XIII

Ri oR9 0 R'Rs~
BH3 ~
Bn-N_ ~~ JJH Bn-N_ JJH
\~~v // \~//
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).

R9 Rlo O R13 p `
R1aN1.coupling H-N N-Bn + ~/~ )~R13 Boc--NH OH
Bn-'- NH OR 2, TYA, ringdosure 0 ta XVIII R
XVI XVII
It=MeorEt RlaRs diborane ~

H-N N-Bn Rts xix R14 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.

1 fl\

HN

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 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.

O
HN NH
CI C I ~~

2 N~CI 4 sat NaHCO3/ Et20 (1:1) H EtOH, DIPEA, reflux 24 hrs.
0 ---> RT

N NH
EtOH, Reflux H

O

N
/ =
H
OH

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

OH
~ + Ci acetone, K2C= O m m 9 6a.m=1 8 OCH3 6b. m= 2 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.

CI MgBr fo H3CO Ethylether OCH3 mCPBA, DCM

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, CI CI R R, O
R3 7H III R7 R8 R / ~ N CI
-00- 7 JI-r _ R6 _ Ro R7 RB

TI IV
RIo Rtt R9~ R12 H-N N~P RyRIo RItR~z R R, ~
R~s Rts R14R~3 R N JY V -P

V I _ r= soC, csz or senzy RB R7 I~1s R13 R
R4 Rs RIsR1a VI
RyR~o R1t R R, )L4(.R12 Deprotect R3 N N ~ H
Rs R7 R4 Rs R~~a R~sR~aR~3 VII

~ 0 Rto Rtl R~z 0 Ro V III
00- R N O~R~~
R OH
R4 Rs R6 R7 R16 RtsRtaR13 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/SnC12 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).

NaH, DMF
R~' ~OH =
X R
IX
X=C1orBr VIII
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).

O RtoRa O

~ n-BuLi, R910Br ~~ TFA
Bn-N N-BOC Bn-N N-BOC

RtoRs O Rt R9 Bn-N NH OW gn-N NH
XIII
V

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.

9 R10 O R14 R13 O `~4 1.coupling H-N N-Bn +
Boc-NH OH ~4 Rta pl >
Bn-~ N H OR Z, TFA, ring dosure 0 R14 XIV XV XVI
R=Me or F1 RR1oR9 diborane H-NN-Bn Rt ~
Rt4 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.

HNN H

CI~CI `~ 4 ()-NH2 sat NaHCOy/ Et20 (1:1) H EtOH, DIPEA, reflux 24 hrs.
0 ---> RT

O
~O

'N `N H
N \v/ EtOH, retlux H

S

~
N~N N~O
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.

B -~A ():::~_OH O

NaH, DMF

$ 6 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. The effective amount ranges from about 0.01 to about 100 mg/kg weight of the mammal. 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.
In another recent approach, the compositions of this invention can be administered orally in a sustained release dosage form.

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).

O
/-<,*
c NN N 0 ~
OH

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 MgSO4, 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 colunm chromatography (10:1, DCM: MeOH) to afford compound 5.

NH
Ir N~ OH OCH3 O I N O

/
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). K2C03 (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.

&O00e H~
O N O N%00000~
2-{(5S,2R)-4-[2-hydroxy-3-(2-methoxyphenoxy)propyl]-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.

NH
re N%% N 00009 OH OCH 3 O N O
I

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.

NH
i 1000~ OH OCH3 O N O
O

2,5-diaza-5- [2-hydroxy-3-(2-methoxyphenoxy)propyl] bicyclo [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.

O ~

0000,~ N N O ~ ~
H
OH
N-(2,6-dimethylphenyl)-2-{4- [2-hydroxy-3-(2-methoxyphenoxy)propyl]-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 .QH_ ~
N
O
HN r N

2-{5- [(2 S)-2-hydroxy-3-(2-methoxyphenoxy)propyl] (1 S,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 (lS,4S)-(+)-2,5-Diazabicyclo[2.2.1]heptane for 2,6-dimethylpiperazine 4 in part B to afford compound 19:
Mass spectrum (M+l) = 481.5 O

J~~`N
N
OH
N-(2,6-dimethylphenyl)-2-{4- [2-hydroxy-4-(2-methoxyphenoxy)butyl]-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 F
O

c JL--,~ N N
H
OH
N-(2,6-dimethylphenyl)-2- {4- [4-(4-fluorophenoxy)-2-hydroxybutyl] -piperazinyl}acetamide (21) Compound 21 was prepared in the manner of compound substituting 4-bromo-1,2-epoxybutane 6b for epichlorohydrin 6a in part B to afford compound 21: Mass spectrum (M+1) = 430.35 O
O
N JL..~ N N
- ` 7 OH
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 O
/~ p N N "T"*--, OH
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 jQoj OH

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)propyl]-3-oxopiperazinyl}acetamide (14) Part E.

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

Epoxide 6 (1.0 g, 5.5 mmol) and Boc-ethylenediamine (0.88 g, 5.5 mmol) were dissolved in 20 mL EtOH and the mixture was heated at reflux for 24 h. The solvent was evaporated and the residue was purified using column chromatography (1:1, Hex:EtOAc) to afford compound 11.

Synthesis of N-{2-[(tert-butoxy)carbonylamino]ethyl}-2-chloro-N[2-hydroxy-3-(2-methoxyphenoxy)propyl]acetamide (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 niL DCM and washed with 50 mL of water and 10% citric acid. The organic layer was dried over MgSO4 and filtered. The solvent was evaporated under reduced pressure and the residue was crystallized from ethylether to afford compound 12.
Synthesis of 1-[2-hydroxy-3-(2-methoxyphenoxy)propyl]piperazin-2-one (13).
Compound 12 (0.5 g, 1.5 mmol) was dissolved in 10 mL TFA. The mixture was allowed to stir at RT for 2 h. TFA was removed under reduced pressure. The residue was dissolved in 20 mL EtOH and treated with diisopropylethyl amine (0.76 g, 4.5 mmol). The mixture was heated at reflux for 24 h. The solvent was removed under reduced pressure to afford compound 13 which was used without further purification.
Part F.

Synthesis of N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(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 s ,,.
R~N
i,#/~s\O
N N
~~ ~
O ~ OH

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-dimeth 1 hen l 430.3 26 2,6-dichloro hen 1 471 27 4-aminosulfon 1 hen 1 481.2 28 3-trifluorometh 1-5methox hen 1 500.2 29 5-indanyl 442.2 30 1-na hth 1 452.3 31 1 - 4-chlorona hth 1 486.3 32 2-N-p ol 1- hen 1 467.3 33 Phenyl 402.2 34 2-chloro hen l 436.2 35 2-chloro-4-meth 1 hen 1 450.2 36 2- 1-meth lethen 1 hen 1 442.3 37 2-meth 1 hen 1 416.2 38 2-iso ro 1-6-meth 1 hen 1 458.4 39 3-meth lthio hen 1 448.2 40 2-methox -4-chloro-5-meth 1 hen 1 480.2 41 4-dimeth lamino hen 1 445.3 42 2,4-dimethox hen 1 462.3 43 3,4-dichloro hen 1 471.1 44 4-chloro hen 1 436.3 45 3-chioro hen 1 436.2 46 3,5-dichloro hen 1 471.1 47 4-methox hen 1 432.3 48 4-meth 1 hen 1 416.2 49 3-meth 1 hen 1 416.2 50 4-fluoro hen 1 420.2 51 4-c ano hen 1 427.3 52 4-ace 1 hen 1 444 53 2-methox hen 1 432.4 54 4-trifluorometh 1 hen 1 470.2 55 3-trifluorometh 1-4-chloro hen 1 504.1 56 3,5-dimethox hen 1 462.3 57 4-N-mo holin 1 hen 1 487.4 58 3-fluoro-4-methox hen 1 450.2 59 3,4,5-trimethox hen 1 492.3 60 3,4-dimethox hen 1 490 61 2-fluoro-4-chloro hen 1 454.2 62 2-h drox eth 1-6-meth 1 hen 1 446 Example 4 2- [4-(3-(2H-b enzo [d] 1,3-dioxolen-5-yl)-2-hydroxypropyl)piperazinyl] -N-(2,6-dimethylphenyl)acetamide (7B).

NH O
I ~ N 000 j = o N =
\/
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 MgSO41 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[d]1,3-dioxane (6B).
To an ice cold solution of 8 (1.0 g, 6.17 mmol) in dichloromethane was added dropwise a solution of 3-chloroperoxybenzoic acid (1.8 g, 10.43 mmol) in 20 mL
dichloromethane over a period of 1 h. The reaction mixture was allowed to stir at RT for 12 h. The reaction mixture was filtered to remove any solids and concentrated in vacuo. To the residue was added diethyl ether (200m1), 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 6B.
Part D.

2-[4-(3-(2H-benzo [d] 1,3-dioxolen-5-yl)-2-hydroxypropyl)piperazinyl]-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 (NIII+1) =
426.34.

NH
000 I ~ N OH
O N
/
N-(2,6-dimethylphenyl)-2-[4-(2-hydroxy-4-phenylbutyl)piperazinyl]acetamide (9B).

Compound 9B was prepared in the manner of compound 7B substituting 4-phenyl-butene for 3-(3,4-methylendioxyphenyl)-1-propene in part C to afford compound 9B: Mass spectrum (MH+1) = 396.32.

O N
N-(2,6-dimethylphenyl)-2-{4- [2-hydroxy-3-(2-methoxyphenyl)-propyl]piperazinyl}acetamide (10B) Compound lOB 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 lOB: Mass spectrum (MH+1) = 412.35.

&rOtO0cH3 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)-1-propene in part C
to afford compound 11B: Mass spectrum (MH+1) = 412.35.

NH
I \ N -.O~ OH
/ O N

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-l-propene for 3-(3,4-methylendioxyphenyl)-1-propene in part C to afford compound 12B:
Mass spectrum (MH+I) = 382.

I NH N .000 OH I

/ o ~ I N /
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 (1VII1+1) = 432.55.

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 9lmL) 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 (200m1), 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-hydroxybu tyl] piperazinyl} 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 H F
N N~"") H
O N

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+l) 432.2 H
N~ OH
O N

C
N-(2,6-dimethylphenyl)-2-{4- [4-(2-chlorophenyl)-2-hydroxybutyl] 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 H
N N H
O N

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 H
N *"'' N H
O N
F

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 H
N )f'~ N

N-(2,6-dimethylp henyl)-2-(4-{2-hydroxy-4- [4-(trifluoromethyl)phenyl] butyl}piperazinyl)acetamide(21 B) 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 O--\
"
HO

2-[4-(3-(2H-benzo [d] 1,3-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+l) = 454.54 H

N-(2,6-dimethylphenyl)-2- [4-(2-hydroxy-3-phenylpropyl)piperazinyl]-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.

/
H I
q N~ ~ O CH3 N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(3,4,5-trimethoxyphenyl)propyl]piperazinyl}-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 H

N-(2,6-dimethylphenyl)-2-[4-(2-hydroxy-5-phenylpentyl)piperazinyl]acetamide (25B) This compound was prepared in a manner similar to that of 16B, substituting phenethyl 15 chloride for 4-methoxybenzyl chloride in part A. (M+1) = 410.4.

H
H
I I N~ ON
O =

N-(2,6-dimethylphenyl)-2-{4-[5-(2-fluorophenyl)- 2-hydroxy-pentyl] 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.

H
N%,rN~
O N

CI

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 MgSO41 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 (l Oml) cooled to 0 degrees was added 2-propanol (0.5g, 3,73mmol) in DMF (2ml) dropwise. After stirring for 30minutes epibromohydrin (1.11g, 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, 1.64mmo1).
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.

O fMOON, N N N O
H
OH
2-({2-[4-(3-isopropoxy-2-hydroxypropyl)piperazinyl]- N-({2,6-dimethylphenyl)acetamide (lOC) 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.

NH
N OH
O N O
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.

O
L.,~ /-\
N N
H ~ O
OH
2-({2-[4-(3-cyclopentyloxy-2-hydroxypropyl)piperazinyl]- N-({2,6-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.

2-({2-[4-(3-cyclohexyloxy-2-hydroxypropyl)piperazinyl]- N-({2,6-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.

H
N,,r.,~ N") 2-[4-(3-{ [4-(tert-butyl)phenyl] methoxy}-2-hydroxypropyl)piperazinyl]-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 H
N~N~ H
~ ~

N-(2,6-dimethylphenyl)-2-(4-{3-[(2-fluorophenyl)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 H
\ F
N H F/ I
/ O ~l \

2-(4-{3- [(2,4-difluorophenyl)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 H F
\ NH F
O NO

N-(2,6-dimethylphenyl)-2-[4-(2-hydroxy-3-{ [4-(trifluoromethyl)phenyl]methoxy}propyl)piperazinyl]acetamide (17C): Compound 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 H

OK,, O O 18 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 H O/ O
NN~I qH
O ~N\/\~

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 H I
N~

N-(2,6-dimethylphenyl)-2-(4-{2-hydroxy-3- [(4-5 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 H
~ ~N^ H / I F
O ~N~0 N-(2,6-dimethylphenyl)-2-(4-{3- [(4-fluorophenyl)methoxy]-2-hydroxypropyl}piperazinyl)acetamide (21C) Compound 21C was prepared in a similar 10 manner to compound 7C, substituting the commercially available 4-fluoro-benzylalcohol for 2-propanol in part C. MS (M+1) = 430.40 O rN~N,,",) OH

N-(2,6-dimethylphenyl)-2-(4-{2-hydroxy-3-[(4-15 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 O r"~N"^~O
\ N~NJ OH

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'~)'O
JNj OH
H

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+l) = 468.45 f-*' N")-"O I \ \
N NJ OH

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 H
N'~Y' N~
/ O ~N O

1V-(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 H
NN H F
O N

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: I 10 mM KC1, 33 mM
Tris buffer at pH 8, 2 mM KPi, 2 mM MgC1Z1 0.1 mM EDTA, 14.7 microM defatted BSA, 0.5 mM
malic acid, 13 mM camitine, 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 C14 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% --7 85% 98% 107%
15 78% 97% 103%
17 89% 98% 100%
16 100% 96% --18 17%

22 25%

9B 84% 84% --11 B 83% 92% --12B 42% 95%

16B 37%
17B 78%
18B 78%
19B 35%

20B 56%
21B 56%
23B 70%
24B 72%
10C 100% 97% --7C 68% -- --11 C 79% -- --12C 41%
-- --13C 30% -- --14C 21% - -15C 100% - -16C 97% - -17C 35% - -18C 96% - -19C 97% - -20C 100% - -21C 87% - -22C 45% - -23C 12% - -24C 15% - -25C 38% - -26C 70% - -27C 73% - -Example 8 Palmitoyl Carnitine Oxidation The Palmitoyl carnitine oxidation was carried out in a total volume of 100 microliters containing the following agents: 110 mM KCI, 33 mM Tris buffer at pH 8, 2 mM
KPi, 2 mM
MgCIZ1 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 colunm (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 M 30 M 3 M
Ranolazine 63% 98% --7 95% 102% 109%
15 82% 98% 106%
17 80% 88% 103%
16 64% 8 -- --l OB -- -- --12B 56% -- --10C 80% -- --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 MgC12 kept at 4 C; (3-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 100 M 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 compounds MgC12 25pL 0.005 M
NADPH 25 L 0.002 M
S9 25 L 2 mg/mL
Incubation Buffer 25 L 0.05 M
Water 125 L ----* 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 5 mL of NADPH, 3.75 mL of water. Then pipette 200 L/incubate, add 25 L of compound being tested, mix, and initiate reaction by addition of S-9.

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

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

The mixture was centrifuged and a 100 L aliquot of the supematant was diluted in lmL 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 L).
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 1Ø If a compound is less stable than ranolazine, than the stability factor will be less than 1Ø

Table 4 Compound # Liver S9 Stabili Factor Ranolazine 1.0 0.45 7 1.51 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 22B 1.49 23B 0.5 24B 1.05 --22C 0.61 23C 0.05 24C 0.02 25C 0.01

Claims (45)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVELEDGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A substituted piperazine compound having the following formula:
wherein m = 1 or 2 or 3;
R1, R2, R3, R4 and R5 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, C1-15 alkyl, C2-15 alkenyl, C2-15 alkynyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, 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 R5 may join together to form -CH=CH-CH=CH-;
R6, R7 and R8 are each independently selected from the group consisting of hydrogen and C1-15 alkyl;

R9, R10, R11, R12, R13, R14, R15 and R16 are each independently selected from the group consisting of hydrogen, CO2R23, CON(R23)2, C1-4 alkyl, and aryl wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, CF3, CN, OR23, N(R23)2, CO2R23, CON(R23)2 and aryl, wherein R9 and R10 may together form a carbonyl, or R11 and R12 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 R13 may join together to form a bridging ring system having from 1 to 4 carbon atoms and wherein R9 and R10 or R11 and R12 or R13 and R14 or R15 and R16 may join to form a bridging ring system having from 1 to 5 carbon atoms with the proviso that R9, R10, R11, R12, R13, R14, R15 and R16 are not all hydrogen;

R17, R18, R19, R20, 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, SO2N(R23)2, NR23CO2R22, NR23CON(R23)2, 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;
R22 is selected from the group consisting of C1-15 alkyl, aryl, and heteroaryl, wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, alkyl, monoalkylamino, dialkylamino, alkyl amide, aryl amide, heteroaryl amide, CN, O-C1-6 alkyl, CF3, and heteroaryl;
and R23 is selected from the group consisting of H, C1-15 alkyl, aryl, and heteroaryl, wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, alkyl, monoalkylamino, dialkylamino, alkyl, CN, -O-C1-6 alkyl, and CF3.
2. The compound of claim 1 wherein R1, R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, halo, CF3, CN, OR23, SR23, N(R23)2, S(O)R22, SO2R22, SO2N(R23)2, NR23CO2R22, NR23CON(R23)2, COR23, CO2R23, CON(R23)2, NR23SO2R22, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, CF3, CN, OR23, SR23, and N(R23)2, wherein R2 and R3 may join together to form a fused ring system wherein having from three to four carbon atoms, and wherein R4 and R5 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-8 alkyl;

R9, R10, R11, R12, R13, R14, R15 and R16 are each independently selected from the group consisting of hydrogen, C1-4 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 R9 and R10 may together form a carbonyl, or R11 and R12 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 R13 may join together to form a bridging ring system having from 1 to 4 carbon atoms ; and R17, R18, R19, R20, 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, SO2N(R23)2, NR23CO2R22, NR23CON(R23)2, COR23, CO2R23, CON(R23)2, NR23SO2R22, C1-15 alkyl, C2-15 alkenyl, C2-15 alkynyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, NO2, CF3, CN, OR23, SR23, N(R23)2, S(O)R22, and SO2R22.
3. The compound of claim 1 wherein R1, R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, halo, CF3, CN, OR23, SR23, N(R23)2, SO2N(R23)2, COR23, CO2R23, CON(R23)2, C1-6 alkyl, C2-6 alkenyl, heterocyclyl, and heteroaryl, wherein the alkyl substituent is optionally substituted with 1 substituent selected from the group consisting of CF3, and OR23, wherein R2 and R3 may join together to form a fused ring system having from three to four carbon atoms, and wherein R4 and R5 may join together to form -CH=CH-CH=CH-;

R6, R7 and R8 are each independently selected from the group consisting of hydrogen and C1-3 alkyl;

R9, R10, R11, R12, R13, R14, R15 and R16 are each independently selected from the group consisting of hydrogen, C1-4 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 R9 and R10 may together form a carbonyl, or R11 and R12 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 R13 may join together to form a bridging ring system having from 1 to 4 carbon atoms;
R17, R18, R19, R20, and R21 are each independently selected from the group consisting of hydrogen, halo, CF3, CN, OR23, COR23, C02R23, CON(R23)2, C1-15 alkyl, C2-15 alkenyl, C2-15 alkynyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, NO2, CF3, CN, OR23, SR23, N(R23)2, S(O)R22, and SO2R22;
R22 is selected from the group consisting of C1-15 alkyl, aryl, and heteroaryl, wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, alkyl, monoalkylamino, dialkylamino, alkyl amide, aryl amide, heteroaryl amide, CN, O-C1-6 alkyl, CF3, and heteroaryl;
and R23 is selected from the group consisting of hydrogen, C1-8 alkyl, aryl, and heteroaryl, wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, -O-C1-3 alkyl, and CF3.
4. The compound of claim 1 wherein R1, R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, halo, CF3, CN, OR23, SR23, N(R23)2, SO2N(R23)2, COR23, CO2R23, CON(R23)2, C1-6 alkyl, C2-6 alkenyl, heterocyclyl, and heteroaryl, wherein the alkyl substituent is optionally substituted with OR23, wherein R2 and R3 may join together to form a fused ring system having from three to four carbon atoms, and wherein R4 and R5 may join together to form -CH=CH-CH=CH-;

R6, R7 and R8 are each independently selected from the group consisting of hydrogen and methyl;

R9, R10, R11, R12, R13, R14, R15 and R16 are each independently selected from the group consisting of hydrogen and C1-2 alkyl, wherein R9 and R10 may together form a carbonyl, or R11 and R12 may together form a carbonyl, or R13 and R14 may together form a carbonyl, or R15 and R16 may together form a carbonyl;

R17, R18, R19, R20, and R21 are each independently selected from the group consisting of hydrogen, halo, CF3, CN, OR23, COR23, CO2R23, CON(R23)2, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, CF3, and OR23;
R22 is selected from the group consisting of C1-4 alkyl, aryl, and heteroaryl, wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, alkyl, O-C1-3 alkyl, and CF3; and 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, -OMe, and CF3.
5. The compound of claim 4 wherein m = 1 or 2.
6. The compound of claim 4 wherein R1, R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, halo, CF3, CN, OR23, SR23, N(R23)2, SO2N(R23)2, COR23, CO2R23, CON(R23)2, C1-3 alkyl, C2-6 alkenyl, heterocyclyl, and heteroaryl, wherein the alkyl substituent are optionally substituted with OR23, wherein R2 and R3 may join together to form a fused ring system having from three to four carbon atoms, and wherein R4 and R5 may join together to form -CH=CH-CH=CH-;
R6, R7 and R8 are each independently selected from the group consisting of hydrogen and methyl;

R9, R10, R11, R12, R13, R14, R15 and R16 are each independently selected from the group consisting of hydrogen and C1-2 alkyl, wherein R9 and R10 may together form a carbonyl, or R11 and R12 may together form a carbonyl, or R13 and R14 may together form a carbonyl, or R15 and R16 may together form a carbonyl;

R17, R18, R19, R20, and R21 are each independently selected from the group consisting of hydrogen, halo, CF3, CN, OR23, COR23, CO2R23, CON(R23)2, and C1-8 alkyl;
R22 is C1-4 alkyl; and R23 is selected from the group consisting of hydrogen and C1-5 alkyl.
7. The compound of claim 4 wherein R1, R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, halo, CF3, CN, OR23, SR23, N(R23)2, SO2N(R23)2, COR23, CO2R23, CON(R23)2, C1-3 alkyl, C2-6 alkenyl, heterocyclyl, and heteroaryl, wherein the alkyl substituent is optionally substituted with OR23, wherein R2 and R3 may join together to form a fused ring system having from three to four carbon atoms, and wherein R4 and R5 may join together to form -CH=CH-CH=CH-;
R6, R7 and R8 are each hydrogen;

R9, R10, R11, R12, R13, R14, R15 and R16 are each independently selected from the group consisting of hydrogen and C1-2 alkyl, wherein R9 and R10 may together form a carbonyl, or R11 and R12 may together form a carbonyl, or R13 and R14 may together form a carbonyl, or R15 and R16 may together form a carbonyl;

R17, R18, R19, R20, and R21 are each independently selected from the group consisting of hydrogen, halo, CF3, CN, OR23, COR23, CO2R23, CON(R23)2, and C1-8 alkyl;
R22 is C1-2 alkyl; and R23 is selected from the group consisting of hydrogen and C1-2 alkyl.
8. The compound of claim 4 wherein R1, R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, halo, CF3, CN, OR23, SR23, N(R23)2, SO2N(R23)2, COR23, CO2R23, CON(R23)2, C1-3 alkyl, C2-3 alkenyl, heterocyclyl, and heteroaryl, wherein the alkyl substituent is optionally substituted with OR23, wherein R2 and R3 may join together to form a fused ring system having from three to four carbon atoms, and wherein R4 and R5 may join together to form -CH=CH-CH=CH-;
R6, R7 and R8 are each hydrogen;

R9, R10, R11, R12, R13, R14, R15 and R16 are each independently selected from the group consisting of hydrogen and methyl, wherein R9 and R10 may together form a carbonyl, or R13 and R14 may together form a carbonyl;

R17, R18, R19, R20, and R21 are each independently selected from the group consisting of hydrogen, halo, CF3, CN, OR23, and C1-2 alkyl;

R22 is methyl; and R23 is selected from the group consisting of hydrogen and methyl.
9. The compound of claim 4 wherein R18, R19, R20, and R21 are each hydrogen, and R17 is selected from the group consisting of halo and OR23.
10. The compound of claim 9 wherein R12 is (S)-methyl and R9, R10, R11, R13, R14, R15 and R16 are each hydrogen.
11. The compound of claim 9 wherein R9 and R10 together form a carbonyl R11, R12, R13, R14, R15 and R16 are each hydrogen.
12. The compound of claim 9 wherein R9, R10, R11, R12, R15 and R16 are each hydrogen and R13 and R14 together form a carbonyl.
13. The compound of any one of claims 2 to 12 wherein m = 1.
14. The compound of claim 9 wherein R1, R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, halo, CF3, CN, OR23, SR23, N(R23)2, SO2N(R23)2, COR23, CO2R23, CON(R23)2, C1-3 alkyl, C2-3 alkenyl, N-morpholino, and pyrrolyl, wherein the alkyl substituent is optionally substituted with OH, wherein R2 and R3 may join together to form a fused ring system having three carbon atoms, and wherein R4 and R5 may join together to form -CH=CH-CH=CH-.
15. The compound of claim 1 wherein m = 1 or 2;

R1, R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, halo, CF3, OR23 and C1-2 alkyl wherein R23 is a C1-2 alkyl;
R6, R7 and R8 each independently selected from the group consisting of hydrogen and methyl;

R9, R10, R11, R12, R13, R14, R15 and R16 are each independently selected from the group consisting of hydrogen and C1-4 alkyl, or R9 and R10 may together form a carbonyl, or R11 and R12 may together form a carbonyl, or R13 and R14 may together form a carbonyl, or R15 and R16 may together form a carbonyl with the proviso that R9, R10, R11, R12, R13, R14, R15 and R16 are not all simultaneously hydrogen and wherein R11 and R13 or R9 and R15 or R9 and R11 or R11 and R15 or R9 and R13 may join to form a bridging ring system having from 1 to 4 carbon atoms;

R17, R18, R19, R20, and R21 are each independently selected from the group consisting of hydrogen, halo, OR23, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, CF3, and OR23 wherein R23 is C1-2 alkyl.
16. The compound of claim 15 wherein R1, R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, and methyl.
17. The compound of claim 15 wherein R6, R7 and R8 are each hydrogen.
18. The compound of claim 15 wherein R9, R10, R11, R12, R13, R14, R15 and R16 are each independently selected from the group consisting of hydrogen and C1-2 alkyl, or R9 and R10 may together form a carbonyl, or R15 and R16 may together form a carbonyl with the proviso that R9, R10, R11, R12, R13, R14, R15 and R16 are not all simultaneously hydrogen and wherein R11 and R13 or R9 and R15 or R9 and R11 or R11 and R15 or R9 and R13 may join to form a ring having from 1 to 2 carbon atoms.
19. The compound of claim 15 wherein R9, R10, R11, R12, R13, R14, R15 and R16 are each independently selected from the group consisting of hydrogen and C1-2 alkyl, or R9 and R10 may together form a carbonyl, or R11 and R12 may together form a carbonyl, or R13 and R14 may together form a carbonyl, or R15 and R16 may together form a carbonyl.
20. The compound of claim 15 wherein R9 and R10 together form a carbonyl, R15 and R16 together form a carbonyl or both R9 and R10 together form a carbonyl and R15 and R16 together form a carbonyl.
21. The compound of claim 15 wherein R17, R18, R19, R20 and R21 are each independently selected from the group consisting of hydrogen, halo, C1-4 alkyl and OR23 wherein R23 is C1-2 alkyl.
22. The compound of claim 1 wherein m = 1;

R1, R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, and methyl;

R6, R7 and R8 are each hydrogen;

R9, R10, R11, R12, R13, R14, R15 and R16 are each independently selected from the group consisting of hydrogen and C1-4 alkyl, or R9 and R10 may together form a carbonyl, or R11 and R12 may together form a carbonyl, or R13 and R14 may together form a carbonyl, or R15 and R16 may together form a carbonyl with the proviso that R9, R10, R11, R12, R13, R14, R15 and R16 are not all simultaneously hydrogen and wherein R11 and R13 or R9 and R15 or R9 and R11 or R11 and R15 or R9 and R13 may join to form a bridging ring system having from 1 to 4 carbon atoms;

R17, R18, R19, R20 and R21 are each independently selected from the group consisting of hydrogen, halo, C1-4 alkyl and OR23; and R23 is C1-2 alkyl.
23. The compound of claim 22 wherein R1 and R5 are each methyl and R2, R3, and R4 are each hydrogen.
24. The compound of claim 22 wherein R11, R12, R13, R14, R15 and R16 are each hydrogen and R9 and R10 together form carbonyl.
25. The compound of claim 22 wherein R9, R10, R11, R12, R15 and R16 are each hydrogen and R13 and R14 together form carbonyl.
26. The compound of claim 22 wherein R9, R10, R11, R12, R13, R14, R15 and R16 are each independently selected from the group consisting of hydrogen and methyl.
27. The compound of claim 22 wherein R10, R12, R13, R14, R15 and R16 are each hydrogen and R9 and R11 together form a bridging ring system having from 1 to 4 carbon atoms.
28. The compound of claim 22 wherein R9, R10, R12, R13, R14 and R16 are each hydrogen and R11 and R15 together form a ring having from 1 to 3 carbon atoms.
29. The compound of claim 22 wherein R18, R19 and R21 are each hydrogen and R17 and R20 are each methyl.
30. The compound of claim 22 wherein R17, is -OCH3, and R18, R19, R20 and R21 are each hydrogen.
31. The compound of claim 15 wherein, R17, R18, R20 and R21 are each hydrogen and R19 is selected from the group consisting of -OCH3, -F, C1-4 alkyl and aryl.
32. The compound of claim 1 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-(2-methoxyphenoxy)propyl](1S,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-(2-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-methylpiperazinyl}-N-indan-5-ylacetamide, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-naphthylacetamide, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-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-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-phenylacetamide, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-(2-chlorophenyl) acetamide, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-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-methylphenyl) acetamide, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-[6-methyl-2-(methylethyl)phenyl] acetamide, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-(3-methylthiophenyl) acetamide, 2-{(3S)-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-(4-chloro-2-methoxy-5-methylphenyl) acetamide, 2-{(3S)-4-[(2S)-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-{(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]-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]-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-methylpiperazinyl}-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]-3-methylpiperazinyl}-N-(3,5-dimethoxyphenyl) acetamide, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-(4-morpholin-ylphenyl) acetamide, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-(3-fluoro-4-methoxyphenyl) acetamide, 2-{(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-methylpiperazinyl}-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-methylphenyl] acetamide.
33. A pharmaceutical composition comprising the compound of any one of claims 1 to 32 and one or more pharmaceutical excipients.
34. A pharmaceutical composition comprising the compound of claim 1 or 2 and one or more pharmaceutical excipients.
35. The pharmaceutical composition of claim 33 or 34 wherein the pharmaceutical composition is in the form of a solution.
36. The pharmaceutical composition of claim 33 or 34 wherein the pharmaceutical composition is in a form selected from the group consisting of a tablet and a capsule.
37. Use of a prophylactically effective amount of the compound according to any one of claims 1 to 32 or the pharmaceutical composition according to any one of claims 33 to 36 for protecting skeletal muscles against damage resulting from trauma or protecting skeletal muscles subsequent to muscle or systemic diseases in a mammal in need of such therapy.
38. Use of an effective amount of the compound according to any one of claims 1 to 32 or the pharmaceutical composition according to any one of claims 33 to 36 for preserving donor tissue and organs used in transplants.
39. Use of a therapeutically effective amount of the compound according to any one of claims 1 to 32 or the pharmaceutical composition according to any one of claims 33 to 36 for treating a shock condition or a cardiovascular disease in a mammal in need of such therapy.
40. The use according to claim 39 wherein the cardiovascular disease is selected from the group consisting of atrial and ventricular arrhythmias, Prinzmetal's angina, stable angina, exercise induced angina, congestive heart disease, and myocardial infarction.
41. The use according to any one of claims 37, 39 or 40 wherein the effective amount ranges from about 0.01 to about 100 mg/kg weight of the mammal.
42. The use according to any one of claims 37, 39, 40 or 41 wherein the mammal is a human.
43. Use of the compound according to any one of claims 1 to 32 in the preparation of a medicament for protecting skeletal muscles against damage resulting from trauma or protecting skeletal muscles subsequent to muscle or systemic diseases.
44. Use of the compound according to any one of claims 1 to 32 in the preparation of a medicament for treating shock conditions or cardiovascular diseases or for preserving donor tissue and organs used in transplant.
45. The use according to claim 44 wherein said cardiovascular disease is selected from the group consisting of atrial and ventricular arrhythmias, Prinzmetal's angina, stable angina, exercise induced angina, congestive heart disease, and myocardial infarction.
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