NZ520782A

NZ520782A - Substituted piperazine compounds that are partial fatty acid oxidation inhibitors

Info

Publication number: NZ520782A
Application number: NZ520782A
Authority: NZ
Inventors: Jeff Zablocki; Elfatih Elzein; Grigory Nudelman; Tim Arquart; Vaibhav Varkhedkar; Prabha N Ibrahim; Venkata P Alle; Brent K Blackburn
Original assignee: Cv Therapeutics Inc
Priority date: 2000-02-22
Filing date: 2001-02-22
Publication date: 2004-03-26
Also published as: JP3980885B2; AU3862301A; KR100595942B1; WO2001062744A3; AU2001238623B2; NO20023954L; NO20023954D0; WO2001062744A2; BR0108592A; AR029229A1; CA2400176C; KR20020079893A; TWI236471B; JP2003531116A; MXPA02008213A; IL151178A0; CN1404471A; CA2657986A1; NO324837B1; CA2400176A1

Abstract

Substituted piperazine compounds of formula (I) and its pharmaceutically acceptable acid addition salts are disclosed, wherein: X is selected from the group consisting of formula (a) and formula (b): 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- 15alkyl, C2-15 alkenyl, C2-15 alkynyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl and aryl substituent are optionally substituted with 1 substituent selected from the group consisting of halo, NO2, CF3, CN, OR23, SR23, N (R23)2, S(O)R22, and SO2R22, wherein R2 and R3 may join together to form a fused ring system having from three to four carbon atoms, and wherein R4 and 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,-,, 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 when R24 is unsubstituted phenyl and when X is represented formula (b); 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; 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; 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, SO2R22, SO2N(R23)2, NR23CO2R22, C1-2 alkyl, and aryl wherein the optional aryl substituent is optionally substituted with from 1 to 3 substituents selected from the group consisting of halo, phenyl, CF3, CN, OR23, and C1-6 alkyl and a phenyl ring as described in the specification. Substituted piperazine compounds of formula (I) are useful in therapy to protect skeletal muscles against damage resulting from trauma or to protect 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, in the treatment of cardiovascular diseases including atrial and ventricular arrhythmias, Prinzmetal's (variant) angina, stable angina, and exercise induced angina, congestive heart disease, and myocardial infarction.

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number 520782 TITLE: SUBSTITUTED PIPERAZINE COMPOUNDS 5 BACKGROUND OF THE INVENTION This application claims priority to U.S. Patent Application Nos. 60/184182 filed on February 22, 2000, 60/184457, filed on February 22, 2000, 60/206396, filed on May 23, 2000, 60/184306 filed on February 22, 2000, and to U.S. Patent Application 60/209262 filed on June 5, 2000, the specification of which is incorporated herein by reference. 10 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 medicinal uses of such compounds for treating diseases in mammals, iand in particular, in a human in a therapy selected from the group including protecting skeletal muscles against damage resulting from trauma, protecting skeletal muscles 15 subsequent to muscle or systemic diseases such as intermittent claudication, to treat shock conditions, to preserve donor tissue and organs used in transplants, and to treat cardiovascular diseases including atrial and ventricular arrhythmias, Prinzmetal's (variant) angina, stable angina, and exercise induced angina, congestive heart disease, and myocardial infarction. 2. Description of the Art 20 U.S Patent No. 4,567,264, the specification of which is incorporated herein by reference, discloses a class of substituted piperazine compounds that includes a compound known as ranolazine, (±)-N- (2,6-dimethylphenyl)-4-[2-hydroxy-3- (2-methoxyphenoxy)-propyl]-l-piperazineacetamide, and its pharmaceutically acceptable salts, and their use in the treatment of cardiovascular diseases, including arrhythmias, variant and exercise-induced 25 angina, and myocardial infarction. U.S. Patent No. 5,506,229, which is incorporated herein by reference, discloses the use of ranolazine and its pharmaceutically acceptable salts and esters for the treatment of tissues experiencing a physical or chemical insult, including cardioplegia, hypoxic or reperfusion injury to cardiac or skeletal muscle or brain tissue, and for use in transplants. In particular, 30 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 intellectual property office of n.z. 2 9 JAN 200*1 received 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. 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 provides a class of substituted piperazine compounds having the following formula: SUMMARY OF THE INVENTION r. r-16 r15 r14 wherein X is selected from the group consisting of: 2 intellectual property office of n.7. 29 JAN 200*1 received and O wherein m = 1 or 2 or 3; Ri, R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, halo, N02, CF3, CN, OR23, SR23, N(R23)2, S(0)R22, S02R22, S02N(R23)2, NR23C02R22, NR23CON(R23)2, COR23, C02R23, CON(R23)2, NR23S02R22, Cm5 alkyl, C2-15 alkenyl, C2.i5 alkynyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl and aryl substituent are optionally substituted with 1 substituent selected from the group consisting of halo, N02, CF3, CN, OR23, SR23, N(R23)2, S(0)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 R5 may join together to form -CH=CH-CH=CH-; Rg, R7 and Rs are each independently selected from the group consisting of hydrogen and C X-15 alkyl; R9, Rio, Ru, Ri2, Ri3, R14, R15 and Ri6 are each independently selected from the group consisting of hydrogen, C02R23, CON(R23)2, Cm alkyl, and aiyl 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, C02R23, CON(R23)2 and aryl, wherein R9 and Rio may together form a carbonyl, or Ru and Ri2 may together form a carbonyl, or Ri3 and R14 may together form a carbonyl, or R15 and Ri6 may together form a carbonyl wherein Ru and Ri3 or R9 and R15 or R9 and R11 or Ru and R15 or R9 and Ri3 may join together to form a bridging ring system having from 1 to 4 carbon atoms and wherein R9 and Rio or Rj 1 and Rj2 or Ri3 and R14 or Ris and Rj6 may join to form a bridging ring system having from 1 to 5 carbon atoms with the proviso that R9, Rio, R11, R12, R13, R14, R15 and R]6 are not all hydrogen when R24 is unsubstituted phenyl and when X is 3 intellectual property office of n.z. 2 9 JAN 200*1 received R22 is selected from the group consisting of Cms alkyl, aiyl, and heteroaiyl, wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, alkyl, monoalkylamino, dialkylamino, alkyl amide, aryl amide, heteroaryl amide, CN, O-Ci-6 alkyl, CF3, and heteroaryl; R23 is selected from the group consisting of H, Cms alkyl, aryl, and heteroaryl, wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, alkyl, monoalkylamino, dialkylamino, alkyl, CN, -O-Ci_6 alkyl, and 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, 3 a intellectual property office of nx 29 JAN 2004 received t 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(0)R22, SO2R22, S02N(R23)2, NR23CO2R22, 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, 5 phenyl, CF3, CN, OR23, and C1-6 alkyl, and 10 wherein R17, R18, R19, R2o> and R2i are each independently selected from the group consisting of hydrogen, halo, NO2, CF3, CN, OR23, SR23, N(R23)25 S(0)R22, SO2R22, SC>2N(R23)2, NR23CO2R22, NR23CON(R.23)2, COR23, CO2R23, CON(R23)2, NR23SO2R22; Ci-15 alkyl, C2-15 alkenyl, C2-15 alkynyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl and aryl 15 substituents are optionally substituted with 1 substituent selected from the group consisting of halo, N02, CF3, CN, OR23, SR23, N(R23)2, S(0)R22, and S02R22. The invention also provides a substituted piperazine compound having the following formula: 20 R10 R11 intellectual property office of n.z. 23 JAN im received wherein m = 1 or 2 or 3; R1, R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, halo, N02, CF3, CN, OR23, SR23, N(R23)2, S(0)R22, S02R22, S02N(R23)2, NR23C02R22) NR23CON(R23)2, COR23, C02R23, CON(R23)2, NR23S02R22, Cm5 alkyl, C2-is alkenyl, C2-i5 alkynyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, N02, CF3, CN, OR23, SR23, N(R23)2, S(0)R22, and S02R22; R6, R7 and R8 are each independently selected from the group consisting of hydrogen and Ci-i5 alkyl; R9, R10, R11, R12, R13, R14, R15 and R16 are each independently selected from the group consisting of hydrogen, C02R23, CON(R23)2, Cm 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, C02R23, 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 Rn and R13 or R9 and R15 or R9 and R11 or Ru and R15 or R9 and R13 may join together to form a bridging ring system wherein the two R groups together comprise of from 1 to 4 carbon atoms and wherein R9 and R10 or R11 and R12 or R13 and R14 or R15 and R16 may join to form a spiro ring system wherein the two R groups together comprise of from 1 to 5 carbon atoms; R17, R18, R19, R20, and R21 are each independently selected from the group consisting of hydrogen, halo, N02, CF3, CN, OR23, SR23, N(R23)2, S(0)R22, S02R22, S02N(R23)2, NR23C02R22, NR23CON(R23)2, COR23, C02R23, CON(R23)2, NR23S02R22, Cms 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 j halo, N02, CF3, CN, OR23, SR23, N(R23)2, S(0)R22, and S02R22 and wherein R17 and R18 or R18 and R19 or R19 and R20 or R20 and R21 may combine to form a saturated ring including from 5 to 6 carbon atoms wherein from 0 to 2 carbon atoms may be substituted with an oxygen atom and wherein R17 and R18 may together form -CH=CH-CH=CH-; R22 is selected from the group consisting of C1-15 alkyl, aryl, or heteroaryl, wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, alkyl, monoalkylamino, dialkylamino, alkyl amide, aryl amide, heteroaryl amide, CN, O-C1-6 alkyl, CF3, and heteroaryl; and 4a intellectual property office of n.z. 2 9 JAN 2004 received - - • • - — R.23 is selected from the group consisting of H, Cms 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-C1-6 alkyl, or CF3. The invention also provides a substituted piperazine compound having the following formula: r2 wherein m = 1,2, or 3; R1, R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, halo, N02, CF3, CN, OR20, SR20, N(R20)2, S(0)R22, S02R22, SO2N(R20)2, NR20CO2R22, NR20CON(R20)2, COR20, C02R20, CON(R20)2, NR20SO2R22, Cms 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, N02, CF3, CN, OR20, SR20, N(R20)2, S(0)R22, and S02R22; R6, R7 and R8 are each independently selected from the group consisting of hydrogen and Ci-3 alkyl; R9, R10, R11, R12, R13, R14, R15 and R16 are each independently selected from the group consisting of hydrogen, C02R2°, CON(R20)2, Cm alkyl, and aryl wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, CF3, CN, OR20, N(R20)2, C02R20, CON(R20)2 or aryl, wherein R9 and R10 may together 1110 * -t form a carbonyl, or R and R may together form a carbonyl, or R and R may together form a carbonyl, or R15 and R16 may together form a carbonyl wherein Ru and R13 or R9 and R15 or R9 and R11 or R11 and R15 or R9 and R13 may join together to form a ring including from 1 to 3 carbon atoms; intellectual property office of n.z. ?? JAN 2Q0<1 received f R24 is selected from the group consisting of alkyl, cycloalkyl, and fused phenylcycloalkyl wherein the point of attachment is on the cycloalkyl, wherein the alkyl, cycloalkyl, and fused phenylcycloalkyl are optionally substituted with from 1 to three substituents selected from the group consisting of halo, CF3, CN, OR20, SR20, S(0)R22, SO2R22, SO2N(R20)2, NR20CO2R22, Ci-2 alkyl, and aryl, wherein the optional aiyl substituent is optionally substituted with from 1 to 3 substituents selected from the group consisting of halo, phenyl, CF3, CN, OR20, and C,_6 alkyl; R20is selected from the group consisting of H, Cm5 alkyl, aryl, and heteroaryl, wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, alkyl, mono- or dialkylamino, alkyl -CN, -O-Ci^ alkyl, and CF3; and R22 is selected from the group consisting of cms 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. The invention also provides a use of a therapeutically effective amount of a compound of the invention in the manufacture of a medicament for protecting skeletal muscles against damage resulting from trauma, protecting skeletal muscles subsequent to muscle or systemic diseases, treating shock conditions, preserving donor tissue and organs used in transplants, and treating cardiovascular diseases in a mammal in need thereof. v The invention also provides a pharmaceutical composition comprising the compound of the invention and one or more pharmaceutical excipients. In yet another embodiment, described herein is a method for administering one or more composition of this invention to a mammal in a treatment selected from the group consisting of protecting skeletal muscles against damage resulting from trauma, protecting skeletal muscles subsequent to muscle or systemic diseases such as intermittent claudication, to treat shock conditions, to preserve donor tissue and organs used in transplants, and to treat cardiovascular diseases including atrial and ventricular arrhythmias, Prinzmetal's (variant) angina, stable angina, and exercise induced angina, congestive heart disease, and myocardial infarction. 4c intellectual property office of n.z. 2 9 JAN 2004 received DETAILED DESCRIPTION OF THE INVENTION This invention includes a class of substituted piperazine compounds having the following formula: Rio Ru *24 5 wherein X is selected from the group consisting of: wherein m = 1 or 2 or 3; Ri, R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, halo, N02, CF3, CN, OR23, SR23, N(R23)2, S(0)R22, S02R22, S02N(R23)2, 10 NR23C02R22, NR23CON(R23)2, COR23, C02R23, CON(R23)2, NR23S02R22, Ci-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, N02, CF3, CN, OR23, SR23, N(R23)2, S(0)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 R5 may 15 join together to form -CH=CH-CH=CH-; R6, R7 and Rg are each independently selected from the group consisting of hydrogen and Ci-15 alkyl; R9, Rio, Ru, R12, R13, R14, R15 and Ri6 are each independently selected from the group consisting of hydrogen, C02R23, CON(R23)2, C1.4 alkyl, and aryl wherein the alkyl and aryl 20 substituents are optionally substituted with 1 substituent selected from the group consisting of halo, CF3, CN, OR23, N(R23)2, C02R23, CON(R23)2 and aryl, wherein R9 and Rio may together form a carbonyl, or Ru and Ri2 may together form a carbonyl, or R13 and R14 may together form a carbonyl, or Rt5 and Ri6 may together form a carbonyl wherein Ru and R13 or R9 and intellectual property office of n.z. 1 7 APR 2003 RECEIVED R15 or R9 and Ru or Ru 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 Rio or Ru and R12 or R13 and R14 or R15 and Ri6 may join to form a bridging ring system having from 1 to 5 carbon atoms; R22 is selected from the group consisting of Cms alkyl, aryl, and heteroaryl, wherein the 5 alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, alkyl, monoalkylamino, dialkylamino, alkyl amide, aryl amide, heteroaryl amide, CN, O-C1.6 alkyl, CF3, and heteroaryl; R23 is selected from the group consisting of H, C 1.15 alkyl, aryl, and heteroaryl, wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the 10 group consisting of halo, alkyl, monoalkylamino, dialkylamino, alkyl-CN, -O-C1-6 alkyl, and CF3; and R24 is selected from the group consisting of alkyl, cycloalkyl, and fused phenylcycloalkyl wherein the point of attachment is on the cycloalkyl, wherein the alkyl, cycloalkyl, and fused phenylcycloalkyl are optionally substituted with from 1 to three 15 substituents selected from the group consisting of halo, CF3, CN, OR23, SR23, S(0)R22, SO2R22, S02N(R23)2, NR23CO2R22, C1-2 alkyl, and aryl, wherein the optional aryl substituent is optionally substituted with from 1 to 3 substituents selected from the group consisting of halo, phenyl, CF3, CN, OR23, and C1-6 alkyl, and R21 wherein R17, Rig, R19, R20, and R21 are each independently selected from the group consisting of hydrogen, halo, N02, CF3, CN, OR23, SR23, N(R23)2, S(0)R22, S02R22, S02N(R23)2, 25 NR23CO2R22, NR23CON(R23)2, COR23, C02R23, CON(R23)2, NR23SO2R22, C145 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 intellectual property office of n.z. 6 1 7 APR 2003 received 15 20 25 ^ A 7 SR halo, N02,CF3,CN,0R23,SR23,N(R2j)2,S(0)R22, and SO2R22. • j , • / I U This invention also includes a subset of the class of substituted piperazine compounds identified in Formula I above having the following Formula (IA): / \ n ,_/ I H9 r7 _r8 ia wherein m = 1, 2; R1, R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, halo, CF3, OR22 and Cm alkyl and wherein R22 is a C1.3 alkyl; ft 7 o R , R and R 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 10 consisting of hydrogen and cm alkyl, or Ry and R10 may together form a carbonyl, or Ru and >11 R12 may together form a carbonyl, or R1J and R14 may together form a carbonyl, or R° and R16 may together form a carbonyl wherein Ru and R13 or R9 and R15 or R9 and Rn or Ru and R15 or R9 and R13 may join together to form a bridging ring system wherein the two R groups together comprise of from 1 to 4 carbon atoms with the proviso that R9, R10, Rn, R12, R13, R14, R15 and R16 are not all simultaneously hydrogen wherein Rn, Rig, R19, R20, and R21 are all hydrogen. 17 1 o 1 q 'jo 'y 1 R , R , R , R and R are each independently selected from the group consisting of hydrogen, halo, CF3, CN, OR22, S(0)R22, S02R22, SON(R22)2, CON(R22)2, Cm alkyl wherein R22 is C1.3 alkyl, or R17 and R18 may together form -CH=CH-CH=CH-, or R18 and R19 may together form -0CH20-. In more preferred compounds of Formula IA, R1, R2, R3, R4 and R5 are each selected from the group consisting of hydrogen, halo, CF3, OR23 and Cm alkyl where R23 is a C1.3 alkyl; R6 is selected from hydrogen and methyl; R7, R8, R9, R10, R11, R12, R13, R14, R15 and ,13 14 115 R16 are each independently selected from hydrogen and methyl or Ry and R1U may together form a carbonyl, or R13 and R14 may together form a carbonyl with the proviso that R9, R10, R11, R12, R13, R14, R15 and R16 are not all simultaneously hydrogen^; R17, R18, R19, R20 and R21 are each independently selected from the group consisting of hydrogen, halo, CF3, fOR33} 7 10 intellectual property office 6F n.z. 1 7 APR 2003 BereiotM OR23 and, C1.3 alkyl, or R17 and R18 may together form -CH=CH-CH=CH-, or R18 and R19 may together form -OCH2O-. In still more preferred compounds of Formula IA, R1, R2, R3, R4, R5, R6, R7 and R8 are each independently selected from the group consisting of methyl and hydrogen; R9, R10, R11, 5 R12, R13, R14, R15 and R16 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, R11, R12, R13, R14, R15 and R16 are not all simultaneously hydrogen; R17, 18 19 20 21 R , R , R and R are each independently selected from the group consisting of hydrogen, halo, CF3, OR23 wherein R23 is methyl, or R17 and R18 may together form -CH=CH-CH=CH-, 10 or R18 and R19 may together form -OCH2O- In an even more preferred compounds of Formula IA, R1 and R5 are each methyl; R2, R3, R4, R6, R7, R8 are each hydrogen; R9, R10, R11, R12, R13, R14, R15 and R16 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, R11, R12, 15 R13, R14, R15 and R16 are not all simultaneously hydrogen; R17, R18, R19, R20 and R21 are each independently selected from the group consisting of hydrogen, halo, methyl, OR23 wherein R23 is methyl, or R17 and R18 may together form -CH=CH-CH=CH-, or R18 and R19 may together form -OCH2O-. In still more preferred compounds of Formula IA, R1 and R5 are each methyl; R2, R3, 20 R4, R6, R7, R8 are each hydrogen; R9, R10 are selected from hydrogen, methyl, or may together 1112 1^14 form a carbonyl; R and R are selected from hydrogen and methyl; R and R are selected from hydrogen and methyl or may together form a carbonyl; R15 and R16 are hydrogen with the proviso that R9, R10, R11, R12, R13, R14, R15 and R16 are not all simultaneously hydrogen; R17 is selected from the group consisting of hydrogen, chloro, fluoro or methoxy; R18 and R19 25 are each selected from the group consisting of hydrogen or methoxy, or R18 and R19 may together form -OCH2O-, or R17 and R18 may together form -CH=CH-CH=CH-, R20 is hydrogen; and R21 is selected from hydrogen or chloro. Most preferably, the substituted piperazine compounds of Formula IA are selected from the group consisting of N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(2-30 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- intellectual property 8 office of n.z. 1 7 APR 2003 R CCEIEEii. 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]-3,3-dimethylpiperazinyl} acetamide, 2- {5-[(2S)-2-hydroxy-3-(2-5 methoxyphenoxy)propyl](lS,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- {4-10 [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]-3-15 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 - 20 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- 25 methylphenyl)acetamide, 2- {(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3- methylpiperazinyl}-N-[2-(l-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]-3-30 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]- 9 intellectual property office of n.z. 2 9 JAN 2004 deceived 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]-3-5 methylpiperazinyl}-N-(3-chlorophenyl) acetamide, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-(3,5-dichlorophenyl) acetamide, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-(4-methoxyphenyl) acetamide, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)'-2-hydroxypropyl]-3-methylpiperazinyl}-N-(4-methylphenyl) acetamide, 2- {(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3- 10 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- {(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-15 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-(2-20 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-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-(3,4-dimethoxyphenyl) 25 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. This invention includes a subset of substituted piperazine compounds of formula I having the following formula IB: 30 intellectual property office of n.z. 1 7 APR 2003 recei?ed 10 7 ib 20 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(0)R22, SO2R225 SC>2N(R23)2, NR23C02R22> NR23CON(R23)2j 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(0)R22, and SO2R22; R6, R7 and R8 are each independently selected from the group consisting of hydrogen and Ci-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, Cm 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 wherein the two R groups together comprise of 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 spiro ring system wherein the two R groups together comprise of from 1 to 5 carbon atoms; 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(0)R22, SO2R22, S02N(R23)2, NR23CO2R22J NR23CON(R23)2, COR23, C02R23> CON(R23)2, NR23SO2R22, Ci_i5 alkyl, C2-15 alkenyl, C2.15 alkynyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl and aryl intellectual property office of n.z. 11 1 7 APR 2003 RECEIVED 1297 substituents are optionally substituted with 1 substituent selected from the group consisting of halo, NO2, CF3, CN, OR23, SR23, N(R23)2, S(0)R22, and S02R22 or wherein R17 and R18 may join together may join together to form -CH=CH-CH=CH- or wherein R17 and R18 or R18 and R19 or R19 and R20 or R20 and R21 may combine to form a saturated ring including from 3 to 6 5 carbon atoms wherein from 0 to 2 carbon atoms may be substituted with an oxygen atom and wherein the ring may be optionally substituted with from 1 to 3 substituents selected from the group consisting of hydrogen, halo, NO2, CF3, CN, OR23, SR23, N(R23)2, S(0)R22, S02R22, S02N(R23)2, NR23C02R22, NR23CON(R23)2, COR23, C02R23, CON(R23)2, NR23S02R23, CM5 alkyl, C2.i5 alkenyl, C2.is alkynyl, heterocyclyl, aryl, or heteroaryl, wherein the alkyl and aryl 10 substituents are optionally substituted with 1 substituent selected from the group consisting of halo, N02, CF3, CN, OR23, SR23, N(R23)2, S(0)R22, or S02R22; R22 is selected from the group consisting of cms 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 15 amide, CN, O-C1-6 alkyl, CF3, and heteroaryl; and R23 is selected from the group consisting of H, Cms 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-C1-6 alkyl, or CF3. In preferred compositions of this invention, m = 1 or 2 or 3; R1, R2, R3, R4 and R5 are 20 each independently selected from the group consisting of hydrogen, halo, CF3, OR22 and Cm f\ 1 Q alkyl; R , R and R 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 and Cm 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 25 R15 and R16 may together form a carbonyl, or 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 ring including from 1 to 4 carbon atoms wherein R9, R10, R11, R12, R13, R14, R15 and R16 are not all hydrogen; and R17, R18, R19, R20 and R21 are each independently selected from the group consisting of hydrogen, halo, CF3, CN, OR23, S(0)R23, S02R23, SON(R23)2, CON(R23)2, Cm alkyl or R17 and R18 may together 30 form -CH=CH-CH=CH-, and phenyl. In other preferred compounds, R1, R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, halo, CF3, OR23 and Ci-2 alkyl wherein R23 is a C1.3 alkyl; R6, R7 and R8 are each independently selected from the group consisting of hydrogen 12 intellectual property office of n.z. 1 7 APR 2003 ■ c h g 1 g c A ^ :■:r\ 1 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, 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 5 R11 or R11 and R15 or R9 and R13 may join to form a ring including from 1 to 4 carbon atoms and R17, R18, R19, R20 and R21 are each independently selected from the group consisting of hydrogen, halo, CF3, CN, OR23, and Cm alkyl, and wherein R17 and R18 may together form a substituent selected from the group consisting of -CH=CH-CH=CH- and phenyl. In still other preferred compounds, m = 1 or 2; R1, R2, R3, R4 and R5 are each 10 independently selected from the group consisting of hydrogen, halo, CF3, OR23 and Cm alkyl where R23 is a C1-3 alkyl; R6, R7, R8, R9, R10, R11, R12, R13, R14, R15 and R16 are each independently selected from hydrogen and methyl; R17, R18, R19, R20 and R21 are each independently selected from the group consisting of hydrogen, halo, CF3, OR22, Ci_3 alkyl where R22 is methyl, or R17 and R18 may together form -CH=CH-CH=CH-, or R18 and R19 15 may together form -OCH2O-. In more preferred compounds, m = 1 or 2; R1, R2, R3, R4, R5, R6, R7 and R8 are each independently selected from methyl and hydrogen; R9, R10, R11, R12, R13, R14, R15 and R16 are 17 18 1Q 7fi 71 each hydrogen; and R , R , R , R and R are each independently selected from the group consisting of hydrogen, halo, CF3, and OR23 wherein R23 is methyl, or R17 and R18 may 20 together form -CH=CH-CH=CH-, or R18 and R19 may together form -0CH20-. In yet other preferred compounds, m = 1 or 2; R1 and R5 are methyl; R2, R3, R4 R6, R7, R8,R9, R10, R11, R12, R13, R14, R15 and R16 are hydrogen; R17, R18, R19, R20 and R21 are each independently selected from the group consisting of hydrogen, halo, and OR23 wherein R23 is methyl, or R17 and R18 may together form -CH=CH-CH=CH-, or R18 and R19 may together 25 form -OCH2O-. In still other preferred compounds, R1 and R5 are methyl; R2, R3, R4, R6, R7, R8,R9, R10, R11, R12, R13, R14, R15 and R16 are hydrogen; R17 is selected from the group consisting of hydrogen, chloro, fluoro and methoxy; R18 is selected from hydrogen and methoxy; R19 is 20 21 selected from hydrogen and methoxy; R is hydrogen; R is selected from hydrogen and 30 chloro, or R17 and R18 may together form -CH=CH-CH=CH-, or R18 and R19 may together form -OCH2O-. Most preferably, the substituted piperazine compounds of this invention are selected from N-(2,6-dimethylphenyl)-2-[4-(2-hydroxy-4-phenylbutyl)piperazinyl]acetamide; N-(2,6- 13 1ntellectualproperty office of n.z. 1 7 APR ?0O3 —. m* t "i* r~ A- dimethylphenyl)-2- {4-[2-hydroxy-3-(2-methoxyphenyl)propyl]piperazinyl} acetamide; 2-[4-(3-(2H-benzo[d]l,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-3-5 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-{4-10 [4-(2-fluorophenyl)-2-hydroxybutyl]piperazinyl} acetamide, N-(2,6-dimethylphenyl)-2-(4- {2-hydroxy-4-[4-(trifluoromethyl)phenyl]butyl}piperazinyl)acetamide, 2-[4-(3-(2H-benzo[d] 1,3-dioxolen-5-yl)-2-hydroxypropyl)piperazinyl]-N-(2,6-dimethylphenyl)-2-methylpropanamide, N-(2,6-dimethylphenyl)-2-[4-(2-hydroxy-3-phenylpropyl)piperazinyl]-2-methylpropanamide, N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(3,4,5-trimethoxyphenyl)propyl]piperazinyl}-2-15 methylpropanamide, N-(2,6-dimethylphenyl)-2-[4-(2-hydroxy-5-phenylpentyl)piperazinyl]acetamide, N-(2,6-dimethylphenyl)-2-{4-[5-(2-fluorophenyl)- 2-hydroxy-pentyl]piperazinyl}acetamide, and N-(2,6-dimethylphenyl)-2- {4-[5-(2-chlorophenyl)- 2-hydroxy-pentyl]piperazinyl} acetamide. This invention further includes a subset of compounds of Formula I above having the 20 following Formula IC: mCT R' ,24 r15 r14 IC wherein m = 1,2, or 3; 25 R1, R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, halo, N02, CF3, CN, OR20, SR20, N(R20)2, S(0)R22, S02R22, SO2N(R20)2, NR20CO2R22, NR20CON(R20)2, COR20, C02R2°, CON(R20)2, NR20SO2R22, Cms alkyl, C2.i5 intellectual property office of n.z. 1 1 APR 2003 RECEIVED 14 10 25 alkenyl, C2-15 alkynyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl and aryl substituent are optionally substituted with 1 substituent selected from the group consisting of halo, NO2, CF3, CN, OR20, SR20, N(R20)2, S(0)R22, and S02R22; 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, CO2R20, CON(R20)2, Cm alkyl, and aryl wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, CF3, CN, OR20, N(R20)2, C02R2°, CON(R20)2 or 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 with the proviso that R11 and R13 or R9 and R15 or R9 and Ru or Ru and R15 or R9 and R13 may join together to form a ring including from 1 to 3 carbon atoms; R24 is selected from the group consisting of alkyl, cycloalkyl, and fused phenylcycloalkyl wherein the point of attachment is on the cycloalkyl wherein the alkyl, cycloalkyl, and fused phenylcycloalkyl are optionally substituted with from 1 to three substituents selected from the group consisting of halo, CF3, CN, OR20, SR20, S(0)R22, SO2R22, SO2N(R20)2, NR20CO2R22, C1-2 alkyl, and aryl wherein the optional aryl substituent is optionally substituted with from 1 to 3 substituents selected from the group consisting of halo, phenyl, CF3, CN, OR20, and Cm alkyl; R20 is selected from the group consisting of H, Cms alkyl, aryl, and heteroaryl, wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, alkyl, mono- or dialkylamino, alkyl-CN, -O-C1-6 alkyl, and CF3; and R22 is selected from the group consisting of Ci-15 alkyl, aryl, and heteroaryl, wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, alkyl, monoalkylamino, dialkylamino, alkyl amide, aryl amide, heteroaryl amide, CN, O-C1-6 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, R1, R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, halo, CF3, OR22 and Cm alkyl and wherein R22 is Ci-3 alkyl. In other preferred compositions, R1, R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, CF3, OR20, and C1.2 alkyl. 15 1 7 APR 2003 received More preferably R1, R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, and methyl with R2, R3, and R4 as hydrogen and R1 and R5 as methyl being preferred. In other preferred compositions of Formula IC, R6, R7 and R8 each independently 5 selected from the group consisting of hydrogen and C1-3 alkyl with hydrogen or methyl being preferred and hydrogen being most preferred. In yet other preferred compositions of Formula IC, R9, R10, R11, R12, R13, R14, R15 and R16 are each independently selected from the group consisting of hydrogen, CON(R20)2, Cm alkyl, and aryl wherein the alkyl and aryl substituents are each optionally substituted with 1 10 substituent selected from the group consisting of halo, CF3, OR20, N(R20)2, CON(R20)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 with the proviso that 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 ring having from 1 to 3 carbon atoms. In alternative 15 preferred compositions, R9, R10, R11, R12, R13, R14, R15 and R16 are each independently selected from the group consisting of hydrogen and Cm alkyl, or R9 and R10 together form a carbonyl, or R11 and R12 together form a carbonyl, or R13 and R14 together form a carbonyl, or R15 and R16 together form a carbonyl. In another embodiment, R9, R10, R11, R12, R13, R14, R15 and R16 are each independently selected from the group consisting of hydrogen, and C1-2 alkyl, 20 wherein the alkyl substituent is optionally substituted with 1 substituent selected from the group consisting of N(R20)2> and aryl or wherein R9 and R10 may together form a carbonyl. More preferably, R9, R10, R11, R12, R13, R14, R15 and R16 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, R11 and R15 are each selected from the group consisting of 25 hydrogen or methyl, R9, R10, R12, R13, R14 and R16 are each hydrogen and R9 and R10 may together form a carbonyl, or, R9, R10, R11, R12, R13, R14, R15 and R16 may each be hydrogen. In compounds of Formula IC, R24 may be selected from the group consisting of alkyl, cycloalkyl, and fused phenylcycloalkyl wherein the point of attachment is on the cycloalkyl wherein the alkyl, cycloalkyl, and fused phenylcycloalkyl are optionally substituted with from 30 1 to three substituents selected from the group consisting of halo, CF3, CN, OR20, SR20, S(0)R22, S02R22, SO2N(R20)2, NR20CO2R22, Ci-2 alkyl, and aryl wherein the optional aryl substituent is optionally substituted with from 1 to 3 substituents selected from the group consisting of halo, phenyl, CF3, CN, OR20, and C1-6 alkyl. In certain preferred compounds of intellectual property 16 office of n.z. 1 7 APR 2003 f received Formula IC, R24 is selected from the group consisting of alkyl, cycloalkyl, and fused phenylcycloalkyl wherein the point of attachment is on the cycloalkyl wherein the alkyl, cycloalkyl, and fused phenylcycloalkyl are optionally substituted with from 1 to two substituents selected from the group consisting of halo, CF3, CN, OR20, SR20, S(0)R22, 5 SO2R22, C1-2 alkyl, and aryl wherein the optional aryl substituent is optionally substituted with 20 from 1 to 3 substituents selected from the group consisting of halo, phenyl, CF3, CN, OR , and C1-6 alkyl. In other preferred compounds of Formula IC, R24 is selected from the group consisting of alkyl, cycloalkyl, and fused phenylcycloalkyl wherein the point of attachment is on the cycloalkyl wherein the alkyl, cycloalkyl, and fused phenylcycloalkyl are optionally 10 substituted with from 1 to two substituents selected from the group consisting of halo, CF3, OR , and aryl wherein the optional aryl substituent is optionally substituted with from 1 to 3 substituents selected from the group consisting of halo, phenyl, CF3, CN, OR20, and Cm 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 15 phenylcycloalkylwith a phenyl that is optionally substituted with from 1 to 2 substituents selected from the group consisting of halo, CF3, OH, methyl, and aryl, and aryl that is optionally substituted with from 1 to 2 substituents selected from the group consisting of halo, CF3, OH, 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 20 optionally substituted with from 1 to 2 substituents selected from the group consisting of halo, CF3, OR20, C1-2 alkyl, and aryl or R24 is phenylmethyl that is optionally substituted with from 1 to 2 substituents selected from the group consisting of halo, CF3, OR20, Cm alkyl, and aryl. In the compounds of Formula IC, R20 is selected from the group consisting of H, Ci.3 alkyl, or aryl, wherein the alkyl and aryl substituents are optionally substituted with 1 25 substituent individually selected from the group consisting of halo, -OMe, and CF3. More preferably, R20 is selected from the group consisting of H or Ci_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- 30 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- intellectual prtfpeifry 17 office of n.z. 1 APR 2003 received {3 - [(2-fluorophenyl)methoxy] -2-hydroxypropyl} piperazinyl)acetamide, 10 25 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 (CI), 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 18 1 7 APR 2003 iPPCioeit 10 25 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 intellectual property office of n.z. 19 1 7 APR 2003 RECEIVED j 10 7 mono- or di-substituted with alkyl, aryl or heteroaryl groups, amidino, mta^optionaflly 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, 5 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 10 below. "Alkyl alkynyl" refers to a groups -ROCR' 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, 15 aryl, substituted aryl, aralkyl, substituted aralkyl, heteroalkyl, heteroarylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, or substituted cycloheteroalkyl as defined. "Alkylthio" denotes the group -SR, -S(0)n=i-2-R, where R is lower alkyl, substituted lower alkyl, aryl, substituted aryl, aralkyl or substituted aralkyl as defined herein. "Acyl" denotes groups -C(0)R, where R is hydrogen, lower alkyl substituted lower 20 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 25 defined herein or acyl. "Amido" denotes the group -C(0)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(0)0R, where R is hydrogen, lower alkyl, substituted 30 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, intellectual property 20 office of n.z. 1 7 APR 2003 RECEIVED 782 10 25 alkylsulfonyl, acyloxy, aryloxy, heteroaryloxy, amino optionally mono- or di-substituted with alkyl, aryl or heteroaryl groups, amidino, urea optionally substituted with alkyl, aryl, heteroaryl or heterocyclyl groups, aminosulfonyl optionally N-mono- or N,N-di-substituted with alkyl, aryl or heteroaryl groups, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, or the like. "Substituted aryl" refers to aryl optionally substituted with one or more functional groups, e.g., halogen, lower alkyl, lower alkoxy, alkylthio, acetylene, amino, amido, carboxyl, hydroxyl, aryl, aryloxy, heterocycle, hetaryl, substituted hetaryl, nitro, cyano, thiol, sulfamido and the like. "Heterocycle" refers to a saturated, unsaturated, or aromatic carbocyclic group having a single ring (e.g., morpholino, pyridyl or furyl) or multiple condensed rings (e.g., naphthpyridyl, quinoxalyl, quinolinyl, indolizinyl or benzo[b]thienyl) and having at least one hetero atom, such as N, O or S, within the ring, which can optionally be unsubstituted or substituted with, e.g., halogen, lower alkyl, lower alkoxy, alkylthio, acetylene, amino, amido, carboxyl, hydroxyl, aryl, aryloxy, heterocycle, hetaryl, substituted hetaryl, nitro, cyano, thiol, sulfamido and the like. "Heteroaryl" - alone or in combination means a monocyclic aromatic ring structure containing 5 or 6 ring atoms, or a bicyclic aromatic group having 8 to 10 atoms, containing one or more, preferably 1-4, more preferably 1-3, even more preferably 1-2, heteroatoms independently selected from the group O, S, and N, and optionally substituted with 1 to 3 groups or substituents of halo, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, acyloxy, aryloxy, heteroaryloxy, amino optionally mono- or di-substituted with alkyl, aryl or heteroaryl groups, amidino, urea optionally substituted with alkyl, aryl, heteroaryl or heterocyclyl groups, aminosulfonyl optionally N-mono- or N,N-di-substituted with alkyl, aryl or heteroaryl groups, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, or the like. Heteroaryl is also intended to include oxidized S or N, such as sulfinyl, sulfonyl and N-oxide of a tertiary ring nitrogen. A carbon or nitrogen atom is the point of attachment of the heteroaryl ring structure such that a stable aromatic ring is retained. Examples of heteroaryl groups are pyridinyl, pyridazinyl, pyrazinyl, quinazolinyl, purinyl, quinolinyl, isoquinolinyl, pyrimidinyl, pyrrolyl, oxazolyl, thiazolyl, thienyl, isoxazolyl, oxathiadiazolyl, isothiazolyl, tetrazolyl, imidazolyl, triazinyl, furanyl, benzofuryl, indolyl, benzothiazolyl, benzoxazolyl, and the like. intellectual property office of n.z. 21 1 7 APR 2003 RECEIVED 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 5 heteroatoms of O, S or N, and are optionally benzo fused or fused heteroaryl of 5-6 ring members and/or are optionally substituted as in the case of cycloalkyl. Heterocycyl is also intended to include oxidized S or N, such as sulfinyl, sulfonyl and N-oxide of a tertiary ring nitrogen. The point of attachment is at a carbon or nitrogen atom. Examples of heterocyclyl groups are tetrahydrofuranyl, dihydropyridinyl, piperidinyl, pyrrolidinyl, piperazinyl, 10 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 15 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, 20 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 25 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, 30 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 22 intellectual property office OF n.z. 1 7 APR 2003 RECEIVED 520? 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 5 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 10 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; 15 (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 20 intermittent claudication, to treat shock conditions, to preserve donor tissue and organs used in transplants, and to treat cardiovascular diseases including atrial and ventricular arrhythmias, Prinzmetal's (variant) angina, stable angina, and exercise induced angina, congestive heart disease, and myocardial infarction. The treatment is accomplished using a therapeutically effective amount of at least one compound of this invention and/or a pharmaceutically 25 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. 30 All of the aforementioned embodiments include the pharmaceutically acceptable acid addition salts thereof, particularly the mono- and dihydrochlorides, and mixtures thereof. The compounds having the general Formula I and IA can be prepared as outlined in Schemes 1A-7A. A general synthesis of the compounds of this invention is outlined in 23 intellectual property office of n.z. 1 7 APR 2003 R PHFItftfl Scheme IA. Compound IV can be prepared by N-acylation of substituted aniline II with 2-substituted chloroacetylchloride m. Compound II is available commercially or readily prepared through reduction of the corresponding nitrobenzene derivative (acid/SnCl2 or catalytic hydrogenation, see Advanced Organic Chemistry, Ed. J. March, (1992) A. Wiley-5 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, 4-10 fluoro-3-chloroaniline. intellectual property office of n.z. 1 7 APR 2003 RECEIVED ■ ■ u «. "" *' 23a WO 01/62744 PCT/US01/05606 SCHEME IA o ci-Jv0 ■A „ Rio 5n M L.rh H"W~P bATsr r«R«Rm 11 v ^ P- BOC,CBZorB«nzyl N N—P Dqmccct R«R,4R,j vn "«"i« 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 10 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- intellectuAl property office of n.z. 1 7 APR 2003 received 24 WO 01/62744 PCT/US01/05606 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 Vin through warming in an appropriate solvent (ethanol, DMF). SCHEME 2A R1« J*17 m X X = CI or Br Epoxide VHI (where m = 1 or 2) can be prepared as outlined in Scheme 2. Heating substituted phenol IX with epichlorohydrin, epibromohydrin, or 4-bromo-l,2-epoxybutane and potassium carbonate in acetone can afford epoxide Vm. Compound IX can be obtained from commercial resources. Example of commercially available compounds of compounds IX include 2-chlorophenol, 2-fluorophenol, 2-methoxyphenol, 2-methylphenol, sesamol, 2,6-dichlorophenol, 3,5-dichlorophenol, 2,6-difluorophenol, 2,4-difluorophenol5-indanol, 3-chloro-4-fluorophenol, 2,chloro-4-fluorophenol and 5,6,7,8-tetrahydro-2-naphthol. In some cases compound VHI can be obtained from commercial sources. Examples of commercially available compounds coiresponding to general stiucture VIII include benzyl glycidyl ether, glycidyl 2-methylphenyl ether, glycidyl 4-methoxyphenyl ether, glycidyl 4-chlorophenyl ether, glycidyl 2-chlorophenyl ether, glycidyl 2-methoxyphenyl ether, glycidyl 4-methylphenyl ether, glycidyl 3,4-dichlorophenyl ether and glycidyl 4-fluorophenyl ether. INTELLECTUAL PROPERTY office of N.Z. 1 7 APR 2003 RECEIVED 25 WO 01/62744 PCT/US01/05606 SCHEME 3A Bn— N A w —BOC XII t-BuLi.Rj.ioBr Bn—N u w —BOC TFA Oqnoiection XIII Bn—N K w XIV Diborane Bn—N W" 10 15 Compound V can be prepared as described in Scheme 3. Alkylation of compound XII with alkyl halides using t-BuLi as base can afford compound XIII as described by Pohlman et. al. (J. Org. Chem, (1997), 62, 1016-1022). Reduction of XIV using diborane can afford N-benzyl protected version of compound V after N-Boc deprotection with trifluoroacetic acid (TFA) [ for the diborane reduction see Jacobson et. al, J. Med. Chem, (1999), 42,1123-1144]. SCHEME 4A R* /V R» o -NH OH * v l.cotiplint Boc— nh OH XVI Bn" -NH OR xvn R-MMrEt ,to?* 2. TFA, ring do Hire "n£_^0 "-W.- xvm -Bn .is dibonne ^ IK H—N N—Bn \ Ar" xix R14 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 intellectual property office of n.z. 1 7 APR 2003 RECEIVED 26 WO 01/62744 PCT/USO1/05606 et al Bioorg. Med. Chem. Lett. (1998) p. 2369-2374]. Reduction of the diketopiperazine with diborane can afford compound XIX the N-benzyl protected version of compound V. Compound V also includes the bicyclic homologs of piperazine (lS,4S)-(+)-2,5-diazabicyclo[2.2.1]heptane 83, 3,8-diazabicyclo[3.2.1] octane 84, and 2,5-diazabicyclo[2.2.2] 5 octane 85. Commercially available bicyclic analogs include (lS,4S)-(+)-2,5-diazabicyclo[2.2.1]heptane 83. Compounds 84, 85, and the (1R,4R) isomer of 83 can be 10 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 15 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 20 acetone in the presence of K2C03 as described in Scheme 6. 27 WO 01/62744 PCT/US01/05606 scheme 5a <s~ NH, ^»CI hn nh ntNiHCO j/E»,0(l:l) \ &->KT JL~ v^. ElOH, CHPEA, reflux 24 hrs. h^o- scheme 6a acetone, K2C03 och3 6 A specific synthesis of compound 14 is described in Scheme 7. Compound 11 was prepared by opening of epoxide 6 with Boc-ethylenediamine through wanning in EtOH. 10 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 wanning in EtOH afforded compound 13. Reaction of compound 13 with 3 as described above afforded compound 14. 28 1 1 APR 2003 RECEIVED intiofpsal prop«ty office of n.z. WO 01/62744 SCHEME 7A r OCHj V-/H'+ PCT/US01/05606 -■O-X ti chloroaectyl chtoride HN DCM, DIPEA 12 OCH, l.TFA 2. EtOH, DIPEA OCH, EtOH, DIPEA The compounds having the general formula I and IB can be prepared as outlined in Schemes 1B-7B. A general synthesis of the compounds of this invention is outlined in Scheme IB. 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 coiresponding nitrobenzene derivative (acid/SnCl2 or catalytic hydrogenation, see Advanced Organic Chemistry, Ed. J. March, (1992) A. Wiley-Interscience). Some examples of commercially available substituted anilines of general structure II include 2,6-dimethylaniline, 2,3-dimethylaniline, 2-methylaniline, 4-methylaniline, 2,4-dichloroaniline, 3,4-dichloroaniline, 2,5-dichloroaniline, 2,4-dichloroaniline,. 2-chloroaniline, 3-chloroaniline, 2,6-difIuoroaniline, 2,5-difluoroaniline, 3,4-difluoroaniline, 2-fluoroaniline, 4-fluoroaniline, 3-fluoroaniline, 2-fluoro-6-chloroaniline, 4-fluoro-3-chloroaniline. 29 intellectual property office of n.z. 1 7 APR 2003 RECEIVED WO 01/62744 SCHEME IB PCT/USO1/05606 V-c" -Q-r J"R "• V, R II 010 att rM_lr'2 H—N P P* BOC CBZ or Benzyl »,•?" ?> N N—P R« \t R" R«R'«R1 \Y" f> Deprotect r4 V VII » R« r15R14 30 i jTEUECTUAL PROPERTY OFFICE OF N.Z. 1 7 APR 2003 RECEIVED WO 01/62744 PCT/US01/05606 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 5 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 wanning in an appropriate solvent 10 (ethanol, DMF). SCHEME 2B Ph3PCH2Br, NaH, THF •vuc| 1 r2° ^V^MgBr Diethylether mCPBA, DCM XI VIII 15 20 Epoxide VIII can be prepared as outlined in Scheme 2B. Epoxidation of substituted allylbenzene XI using mCPBA or hydrogen peroxide can afford epoxide VIII (G. Majetich, R. Hicks, G. Sun and P. McGill, (1998), 63, 2564-2573). Compound XI in turn can be prepared by reacting aldehyde IX with methylenetriphenylphosphorane under Wittig conditions or Horner Emmons conditions [Advanced Organic Chemistry, Eds. J. March, 31 WO 01/62744 PCT/US01/05606 (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 5 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 safirole and 1-10 allylnaphthalene. SCHEME 3B A K^o yg—BOC " " " ^ Bn—N^ Jk >n-H »-BOC Bn-/ \-BOC """"iSi XII XIII Bn—yJH ► Bn—N^ JiH MV 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 15 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). 32 WO 01/62744 PCT/US01/05606 SCHEME 4B R9 R1# O Boc— NH OH XVI diborane Ru ^ ,o Bn* -NH OR xvn R=MeorEt 9 l.coupling 2. TFA, ringdosure H—N I I. N Bn R1J H—N Diof C N K H: N—Bn ,13 XVIII XIX R 10 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 (lS,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. A Hlvf NH \ 83 84 85 Commercially available bicyclic analogs include (lS,4S)-(+)-2,5-15 diazabicyclo[2.2.1]heptane 83. Compounds 84, 85, and the (1R,4R) isomer of 83 can be prepared by published procedures (for 84 and 85- see Sturm, P. A et al, J. Med. Chem. 1974, 17,481-487; for 83 see- Barish, T. F. and Fox, D. E. J. Org. Chem., 1990, 55,1684-1687). A specific example of the preparation of a compound from this invention is disclosed in Scheme 5B to further illustrate how to prepare the compounds of this invention. In 33 WO 01/62744 PCT/USO1/05606 particular, 2,6-dichloroaniline was acylated with 2-chloroacetyl chloride 2 using saturated bicarbonate and ether (1:1) as base and co-solvent, respectively to afford the chloroacetamide derivative 3. Further reaction of compound 3 with piperazine afforded compound 5 through warming in ethanol. Reaction of compound 5 with epoxide 6 by warming both components in ethanol at reflux afforded piperazine derivative 7. SCHEME 5B nh2 —-*"CI satNaHCCy Et20(l:l) 0° —> RT JL- HN / \ N N nh EtOH, DIPEA, reflux 24 hrs. Compound 8 is commercially available and was epoxidized using 3-chloroperoxybenzioc acid in dichloromethane as illustrated in Scheme 6B. 10 Scheme 6B ?ch, ,oh ♦ c,wf || "* | r, f acetone, K2C03 8 ' °CH3 6b. m = 2 34 WO 01/62744 PCT/USO1/05606 Four carbon epoxide 15 can be prepared by coupling commercially available 4-methoxybenzyl chloride with allylmagnesium bromide followed by oxidation with mCPBA as illustrated in Scheme 7B. SCHEME 7B Ethylether OCH, 14 mCPBA, DCM OCH, 15 The compounds having the general Formula I and IC can be prepared as outlined in Schemes 1C-6C. A general synthesis of the compounds of this invention is outlined in Scheme IC. 10 35 WO 01/62744 PCT/USO 1/05606 SCHEME IC o 111 R R RT RJ H—N Rio ?n *XAl/R12 K R«RiSR14Rn —p P= BOC, CBZ or Ben Deprolect —P II B B n1S R15R14 VII *17 VIII OH R«Rl4Rl* '17 Compound IV can be prepared by N-acylation of substituted aniline II with 2-substituted chloroacetylchloride m. Compound II is available commercially or readily prepared through reduction of the corresponding nitrobenzene derivative (acid/SnCl2 or catalytic hydrogenation, see Advanced Organic Chemistry, Ed. J. March, (1992) A. Wiley-Interscience). Some examples of commercially available substituted aniline II include 2,6-dimethylaniline, 2,3-dimethylaniline, 2-methylaniline , 4-methylaniline, 2,4-dichloroaniline, 3,4- dichloroaniline, 2,5-dichloroaniline, 2,4-dichloroaniline, 2-chloroaniline, 3-chloroaniline, 2,6- 36 tuectual PROPERTY office of nx 1 7 APR 2003 RFCFI WO 01/62744 PCT/US01/05606 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 5 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 10 accomplished using the standard conditions (e.g. for Boc group use TFA, for CBZ and benzyl use hydrogenation). Compound I can be prepared by reacting compound VII with epoxide VIII through warming in an appropriate solvent (ethanol, DMF). SCHEME 2C R17—OH + N/ NaH, DMF x r17^-° IX X = Cl or Br VIH 15 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 VIH. In some cases compound VIII can be obtained from commercial resources. Examples of commercially available compounds of general structure Vin include glycidyl isopropyl 20 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 25 trifluoroacetic acid (TFA , for the diborane reduction see Jacobson et. al, J. Med. Chem, (1999), 42, 1123-1144). 37 WO 01/62744 PCT/US01/05606 SCHEME 3C Bn—N N—BOC 0-BuLi.R9.KPr \ / 1 XI B "l O Bn— H—BOC XII TFA Bn—N W Diborane XIII 10 Compound V can also be prepared through standard coupling (eg. EDC or PyBroP) of D or L amino acids as outlined in Scheme 4C [For preparations of diketopiperazines see - P. Cledera et al. Tetrahedron, (1998) p. 12349-12360 and R. A. Smith et al Bioorg. Med. Chem. Lett. (1998) p. 2369-2374]. Reduction of the diketopiperazine with diborane can afford the N-benzyl protected version of compound V. SCHEME 4C R* R1°,° Boo—NH OH XIV dlboraae Bnr* NH OR xv R-Me or Et l.coapllag 2. TFA, rii| dotarc N I H: H—N N—Bn R« H—N ■M -N fv N—Bn R" XVI V R14 A specific example of the preparation of a compound from this invention is disclosed in Schemes SC and 6C to further illustrate how to prepare the compounds of this invention. 38 INTELLECTUAL property OFFICE OF N.Z. 1 7 APR 2003 RECEIVE* WO 01/62744 PCT/US01/05606 / fl hOh ^ sat NaHCCV Et20 (1:1) \ / f ^ EtOH, DIPEA, reflux 24 hrs. 0° —> RT \=/ J, EtOH, reflux (p-o 7 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 5 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. 10 SCHEME 6C 00~oh bi NaH, DMF 39 WO 01/62744 PCT/US01/05606 The acid addition salts of the compounds of this invention may be converted to the corresponding free base by treating with a suitable base, such as potassium carbonate or sodium hydroxide, typically in the presence of aqueous solvent, and at a temperature of between about 0 degrees C and 100 degrees C. The free base form is isolated by conventional 5 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. 10 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 15 parentarally. Depending on the intended mode, the compositions may be in the form of solid, semisolid or liquid dosage forms, such as, for example, tablets, suppositories, pills, capsules, powders, liquids, suspensions, or the like, preferably in unit dosage forms suitable for single administration of precise dosages. The compositions may include one or more conventional 20 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 25 administration and the judgment of the prescribing physician. However, an effective dosage is in the range of 0.1-30 mg/kg/day, preferably 0.5-20 mg/kg/day. For an average 70 kg human, -this would amount to 7-2100 mg per day, or preferably 35-1400 mg/day. Since many of the effects of the compounds herein (protect skeletal muscles against damage resulting from trauma; protect skeletal muscles subsequent to muscle or systemic diseases 30 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 40 WO 01/62744 PCT/USO1/05606 fatty acid oxidation inhibition) dosages (and forms of administration) are all generally within the same general and preferred ranges for all these utilities. For solid compositions, conventional non-toxic solid include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, 5 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 10 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 15 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 20 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 25 formulations and the like. Such compositions may contain 10%-95% active ingredient, preferably 1-70%. Parenteral administration is generally characterized by injection, either subciitaneously, intramuscularly or intravenously. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspension 30 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. WO 01/62744 PCT/US01/05606 A more recently devised approach for parenteral administration employs the implantation of a slow-release or sustained-release system, such that a constant level of dosage is maintained. See, e.g., U.S. Pat. No. 3,710,795, which is incorporated herein by reference. In another recent approach, the compositions of this invention can be administered 5 orally in a sustained release dosage form using the compositions and/or methods disclosed in U.S. Patent Application Serial No. 09/321,522, filed on May 27, 1999, the specification of which is incorporated herein by reference. It is within the scope of this invention to administer one or more compounds of this invention to a mammal, and preferably to a human by other known routes of pharmaceutical 10 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. 42 WO 01/62744 Example 1 PCT/USO1/05606 N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(2-methoxy)propyI]-3,5-dimethylpiperazinyl} acetamide (7). H3CO. 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 NaHC03 (100 mL) and the reaction mixture was cooled in an ice/water bath. To the 10 cold solution was added chloroacetyl chloride 2 (9.17 g, 81.2 mmol) dropwise over a period of 2 h. The mixture was allowed to warm to RT over 14 h. The mixture was extracted with EtOAc (3 X 50). The combined organic layers were dried over MgS04, filtered and concentrated. The residue was triturated in ether and filtered to afford compound 3 as a white solid. 15 Part B. Synthesis of N-(2,6-dimethylphenyl)-2-(3,5-dimethy]piperazinyl)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 20 the residue was purified by column chromatography (10:1, DCM: MeOH) to afford compound 5. 25 43 WO 01/62744 PCT/US01/05606 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 MgS04 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. Synthesis of N-(2,6-dimethylphenyI)-2-{4-[2-hydroxy-3-(2-methoxy)propyI]-3,5-dimethylpiperazinyljacetamide (7). To a solution of compound 5 in 10 mL EtOH (0.4 g, 1.4 mmol) was added compound 6 (0.27 g, 1.5 mmol). The reaction mixture was refluxed for 24 h. The mixture was concentrated in vacuo and the residue was purified by using Prep. TLC (10:1, DCM:MeOH) to afford compound 7. 2-{(5S,2R)-4-[2-hydroxy-3-(2-methoxyphenoxy)propyl]-2,5-dimethylpiperazinyI}-N-(2,6-dimethylphenyl)acetamide (15) Part D. NH 'irA O O 44 WO 01/62744 PCT/US01/05606 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+l) = 456.4. N-(2,6-dimethylphenyI)-2-{4-[2-hydroxy-3-{2-methoxyphenoxy)propyI]-2-oxopiperazinyI}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+l) = 442.41. 2,5-diaza-5-[2-hydroxy-3-(2-methoxyphenoxy)propyI]bicyclo[4.4.0]dec-2-yl}-N-{2,6-dimethylphenyl)acetamide (17) Compound 17 was prepared in the manner of compound 7 substituting peihydroquinoxaline for 2,6-dimethylpiperazine 4 in part B to afford compound 17: Mass spectrum (M+l) = 482.4. 45 INTELLECTUAL propeitt OFFICE OF n.z. 1 7 APR 2003 ?cei?£fe WO 01/62744 PCT/USO1/05606 N-(2,6-dimethyIphenyl)-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+l) = 456.51 2-{5-[(2S)-2-hydroxy-3-(2-methoxyphenoxy)propyl](lS,4S)-2,5-diazabicyclo[2.2.1Jhept-2-yI}-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 h3c< <0-ir^-O N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-4~(2-methoxyplienoxy)butyl]-piperazinyl} acetamide (20) 46 WO 01/62744 PCT/US01/05606 Compound 20 was prepared in the manner of compound 7 substituting 4-bromo-l,2-epoxybutane 6b for epichlorohydrin 6a in part B to afford compound 20: Mass spectrum (M+l) = 442.37 N-(2,6-dimetbylphenyl)-2-{4-[4-(4-fliioropheDOxy)-2-hydroxybutyl]-piperazinyl} acetamide (21) Compound 21 was prepared in the manner of compound 7 substituting 4-bromo-l,2-epoxybutane 6b for epichlorohydrin 6a in part B to afford compound 21: Mass spectrum (M+l) = 430.35 2-(4-{4-[4-(tert-butyl)phenoxy]-2-hydroxybutyl}piperazinyl)-N-(2,6-dimethylphenyl) acetamide (22) Compound 22 was prepared in the manner of compound 7 substituting 4-bromo-l,2-epoxybutane 6b for epichlorohydrin 6a in part B to afford compound 22: Mass spectrum (M+l) = 468.32 /~V-« J—n: r~\ i i w \ / H 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-l,2-epoxybutane 6b for epichlorohydrin 6a in part B to afford compound 23: Mass spectrum (M+l) = 488.41 47 WO 01/62744 PCT/US01/05606 —\3yN och, N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-4-(4-methoxyphenoxy)butyI]-piperazinyl} acetamide (24) Compound 24 was prepared in the manner of compound 7 substituting 4-bromo-l,2-epoxybutane 6b for epichlorohydrin 6a in part B to afford compound 24: Mass spectrum (M+l) = 442.37 48 WO 01/62744 PCT/US01/05606 Example 2 g? en) N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(2-methoxyphenoxy)propyll-3-^ £=> oxopiperazinyl} acetamide (14) PartE. 5 Synthesis of (tert-butoxy)-N-(2-{[2-hydroxy-3-(2- methoxyphenoxy)propyl]amino} ethyI)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 10 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 in an ice water bath. To the cold 15 mixture was added dropwise chloroacetyl chloride in 5 mL DCM. The reaction mixture was allowed to stir at RT for 24 h. The mixture was diluted with 50 mL DCM and washed with 50 mL of water and 10% citric acid. The organic layer was dried over MgS04 and filtered. The solvent was evaporated under reduced pressure and the residue was crystallized from ethylether to afford compound 12. 20 Synthesis of l-[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 25 compound 13 which was used without further purification. Part F. Synthesis of N-(2,6-dimethyIphenyl)-2-{4-[2-hydroxy-3-(2- methoxyphenoxy)propyI]-3-oxopiperazinyl}acetamide (14) To a solution of compound 13 in 10 mL EtOH (0.1 g, 0.30 mmol) was added compound 3 30 (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, DCMrMeOH) to afford compound 14: Mass spectrum (M+l) = 442.34 49 intellectual property OFFICE OF N.Z. 1 7 APR 2003 receive0 WO 01/62744 Example 3 PCT/USO1/05606 The compounds listed in Table 1, below were made in the manner of compound 14 of Example 2. Table 1 R MIT 25 2,6-dimethylphenyl 430.3 26 2,6-dichlorophenyl 471 27 4-aminosulfonylphenyl 481.2 28 3-trifluoromethyl-5methoxyphenyl 500.2 29 5-indanyl 442.2 30 1-naphthyl 452.3 31 1 -(4-chloronaphthyl) 486.3 32 2-N-pyrrolyl-phenyl 467.3 33 Phenyl 402.2 34 2-chlorophenyl 436.2 35 2-chloro-4-methylphenyl 450.2 36 2-(l -methylethenyl)phenyl 442.3 37 2-methylphenyl 416.2 38 2-isopropyl-6-methylphenyl 458.4 39 3-methylthiophenyl 448.2 40 2-methoxy-4-chloro-5-methylphenyl 480.2 41 4-dimethylaminophenyl 445.3 42 2,4-dimethoxyphenyl 462.3 43 3,4-dichlorophenyl 471.1 44 4-chlorophenyl 436.3 45 3-chlorophenyl 436.2 46 3,5-dichlorophenyl 471.1 47 4-methoxyphenyl 432.3 48 4-methylphenyl 416.2 49 3-methylphenyl 416.2 50 4-fluorophenyl 420.2 51 4-cyanophenyl 427.3 52 4-acetylphenyl 444 53 2-methoxyphenyl 432.4 54 4-trifluoromethylphenyl 470.2 55 3-trifluoromethyl-4-chlorophenyl 504.1 56 3,5-dimethoxyphenyl 462.3 57 4-N-morpholinylphenyl 487.4 58 3 -fluoro-4-methoxyphenyl 450.2 50 WO 01/62744 PCT/US01/05606 59 3,4,5-trimethoxyphenyl 492.3 60 3,4-dimethoxyphenyl 490 61 2-fluoro-4-chlorophenyl 454.2 62 2-hydroxymethyl-6-methylphenyl 446 51 WO 01/62744 PCT/USO1/05606 Example 4 2-[4-(3-(2H-benzo[d]l,3-dioxoIen-5-yI)-2-hydroxypropyl)piperazinyl]-N-(2,6-dimethylphenyl)acetamide (7B). Part A. 5 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 NaHC03 (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 10 with EtOAc (3 X 50). The combined organic layers were dried over MgS04, filtered and concentrated. The residue was triturated in ether and filtered to afford compound 3B as a white solid. Part B. Synthesis of N-(2,6-dimethylphenyl)-2-piperazinylacetamide (5B). 15 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. 20 Synthesis of 5-(oxiran-2-ylmethyl)-2H-benzo[rf]l,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 25 diethyl ether (200ml), and it was washed with saturated sodium bicarbonate (3x100ml). The organic layer was dried over MgS04 , and concentrated in vacuo . The residue was purified using Prep. TLC (2:1 hexane: ethyl acetate) to yield 6B. Part D. 52 WO 01/62744 PCT/US01/05606 2-[4-(3-(2H-benzo[d]l,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 (MH+1) = 426.34. N-{2,6-dimethylphenyl)-2-[4-(2-hydroxv-4-phenyIbutyI)piperazinyl]acetamide (9B). Compound 9B was prepared in the manner of compound 7B substituting 4-phenyl-butene for 3-(3,4-methylendioxyphenyl)-l-propene in part C to afford compound 9B: Mass spectrum (MH+1) = 396.32. N-(2,6-dimethylphenyI)-2-{4-[2-hydroxy-3-(2-methoxyphenyl)-propyljpiperazinyl} acetamide (10B) Compound 10B was prepared in the manner of compound 7B substituting 3-(2-methoxyphenyl)-l-propene for 3-(3,4-methylendioxyphenyl)-l-propene in part C to afford compound 10B: Mass spectrum (MH+1) = 412.35. 53 WO 01/62744 PCT/US01/05606 OCH 3 N-(2,6-dimethyIphenyl)-2-{4-[2-hydroxy-3-(4-methoxyphenyI)propyl]piperazlnyI} acetamide (11B). Compound 11B was prepared in the manner of compound 7B substituting 3-(4-methoxyphenyl)-l-propene for 3-(3,4-methylendioxyphenyl)-1-propene in part C to afford compound 11B: Mass spectrum (MH+1) = 412.35. N-(2,6-dimethylphenyI)-2-{4-[2-hydroxy-3-phenylpropyl]piperazinyl}acetamide (12B) Compound 12B was prepared in the manner of compound 7B substituting 3-phenyl-1-propene for 3-(3,4-methylendioxyphenyl)-l-propene in part C to afford compound 12B: Mass spectrum (MH+1) = 382. N-(2,6-dimethyIphenyl)-2-[4-(2-hydroxy-3-naphthylpropyl)piperazinyI]acetamide (13B). Compound 13B was prepared in the manner of compound 7B substituting 3-(l-naphthyl)-l-propene for 3-(3,4-methylendioxyphenyl)-1-propene in part C to afford compound 13:Mass spectrum (MH+1) = 432.55. 54 WO 01/62744 PCT7US01/05606 EXAMPLE 5 Part A Intermediate (14B): To a solution of 4-methoxybenzyl chloride (2-mmol) in anhydrous ether (10 mL), was added allylmagnesium bromide ( 4 mL, 1M solution in THF) and the reaction 5 mixture was allowed to stir for 16h at room temperature. Sat. ammonium chloride solution 91mL) was added and the ether layer was separated, washed with water and dried. Evaporation of ether under reduced pressure afforded olefin 14B as an oil. It was used in the next reaction without purification. Part B 10 Intermediate (15B): To an ice cold solution of 15B (2 mmol) in dichloromethane was added dropwise a solution of 3-chloroperoxybenzoic acid (4 mmol) in 20 mL dichloromethane over a period of 1 h. The reaction mixture was allowed to stir at RT for 12 h. The reaction mixture was filtered to remove any solids and concentrated in vacuo. To the residue was added diethyl ether (200ml), and it was washed with saturated sodium bicarbonate (3x100ml). 15 The organic layer was dried over MgS04, and concentrated in vacuo. The residue was purified using Prep. TLC (2:1 hexane: ethyl acetate) to yield 15B. PartC Synthesis of N-(2,6-dimethylphenyl)-2-{4-[4-(4-methoxyphenyI)-2- hydroxybutyl]piperazinyl} acetamide(l 6B) 20 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+l) = 426.3 25 55 wo 01/62744 pct/uso1/05606 2-{4-[4-(2,6-difluorophenyl)-2-hydroxybutyl]piperazinyl}-N-(2,6-dimethylpbenyl)acetamide(l 7B) 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 rVvpi 18 N-(2,6-dimethylphenyl)-2- {4- [4-(2-chlorophenyI)-2-hydroxybutyl] piperazinyl} acetamide(l 8B) Compound 18B was prepared in a manner similar to that of compound 16B substituting 2-chlorobenzyl chloride for 4-methoxybenzyl chloride. (M+l) = 430.2 2-(4-{4-[4-(tert-butyl)phenyl]-2-hydroxybutyl}piperazinyI)-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 rVvp 20 F 56 WO 01/62744 PCT/USO1/05606 N-(2,6-dimethyIphenyI)-2-{4-[4-(2-fluorophenyl)-2-hydroxybutyl]piperazinyl}acetamide(20B) Compound 20B was prepared in a manner similar to that of compound 16B substituting 2-fluorobenzyl chloride for 4-methoxybenzyl chloride. (M + 1) = 414.2 N-(2,6-dimethylphenyl)-2-(4-{2-hydroxy-4-[4-(trifluoromethyl)phenyl]butyl}piperazinyl)acetamide(21B) Compound 21B was prepared in a manner similar to that of compound 16B substituting 4-trifluoromethylbenzyl chloride for 4-methoxybenzyl chloride. (M + 1) = 464.2 2-[4-(3-(2H-benzo[d]l,3-dioxolen-5-yI)-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 23 57 wo 01/62744 pct/uso1/05606 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+l) 5 =410.34. QCH3 c ^ 24 N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(3,4,5-trimethoxyphenyl)propy]]piperaz[nyl}-2-methyIpropanamide (24B) This compound was prepared in a manner similar to that of 7B, substituting 2-chloro-2-10 methylpropionyl chloride for chloroacetyl chloride in part A and 3,4,5-trimethoxy alkybenzene for 8B. (M+l) = 472.54 25 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+l) = 410.4. N-(2,6-dimethylphenyI)-2-{4-[5-(2-fluorophenyI)- 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+l) = 428.1. 58 WO 01/62744 PCT/US01/05606 CI 27 N-(2,6-dimethylpbenyI)-2-{4-[5-(2-chlorophenyI)- 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+l) = 444.3 59 WO 01/62744 PCT/US01/05606 Example 6 N-(2,6-dimethyIphenyI)-2-[4-(2-hydroxy-3-indan-2-yIoxypropyl)piperazinyl]acetamide (7C) Part A. 5 Synthesis of N-(2,6-dimethylpheny])-2-chIoroacetamide (3C). 2,6-dimethylaniline (9.8g, 81.2 mmol) was dissolved in ether (100 mL) and saturated aqueous NaHCOj (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 10 mL ether and the organic layer was dried over MgS04) 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 15 (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) 20 To a solution of 60% NaH (0.18g, 4.5mmol) in DMF (10ml) cooled to 0 degrees was added 2-propanol (0.5g, 3,73mmol) in DMF (2ml) dropwise. After stirring for 30minutes epibromohydrin (1.1 lg, 8.18mmol) in DMF (1ml) was added dropwise. The reaction was allowed to warm to room temperature and stirred for 48 h. The solvent was removed in vacuo and the residue was purified using Prep TLC (30:1, DCM:MeOH) to afford compound 6C. 25 Part D Synthesis of N-(2,6-dimethyIphenyi)-2-[4-(2-hydroxy-3-indan-2-yIoxypropyl)piperazinyl] acetamide (7C) To a solution of 6C (0.43g, 2.3mmol) in ethanol(4ml) was added 5C (0.405g, 1.64mmol). The solution was heated to reflux and stirred for 24 h. Upon completion the solution was 30 concentrated in vacuo and purified using Prep TLC (10:1, DCM:MeOH) to yield 7C. Mass Spectrum (M+l) = 438.36. 60 WO 01/62744 PC T/U SO1/05606 2-({2-[4-(3-isopropoxy-2-hydroxypropyl)piperazinyl]- N-({2,6-dimethylphenyl)acetamide (IOC) Compound 10C was prepared in a similar manner to compound 7C, substituting the commercially available glycidyl isopropyl ether for 2-(oxiran-2-ylmethoxy)indane in part D to afford 10C : Mass spectrum MS (MH+) = 364.37. N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3 (phenylmethoxy)propyl]piperazinyl}acetamide (1 IC) Compound 11C was prepared in a similar manner to compound 7C, substituting the commercially available benzyl glycidyl ether for 2-(oxiran-2-ylmethoxy)indane in part D to afford 11C. Mass Spectrum (M+l) = 412.36. 2-({2- [4-(3-cyclopentyloxy-2-hydroxypropyI)piperazinyl] -dimethylphenyl)acetamide (12C) N-({2,6- 61 wo 01/62744 pct/us01/05606 Compound 12C was prepared in a similar manner to compound 7C, substituting the commercially available cyclopentanol for 2-indanol in part C to afford 12C: MS (MH+) = 390. 2-({2-[4-(3-cycIohexyloxy-2-hydroxypropyI)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. dc^oo 2-[4-(3-{[4-(tert-butyI)phenyI]methoxy}-2-hydroxypropyl)piperazinyl]-N-(2,6-dimethylphenyl)acetamide (14C): Compoimd 14C was prepared in a similar manner to compound IC, substituting the commercially available 4-t-bu-benzylalcohol for 2-propanol in part C. MS (M+l) = 468.44 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 IC, substituting the commercially available 2-fluorobenzylalcohol for 2-propanol in part C. MS (M+l) = 430.39 dcTOjCoOCr' 16 62 WO 01/62744 PCT/US01/05606 2-(4-{3-[(2,4-difluorophenyI)methoxy]-2-hydroxypropyl}piperazinyI)-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+l) = 448.38 ckYx^JtojCr1' 17 N-(2,6-dimethyIphenyI)-2-[4-(2-hydroxy-3-{[4- (trifluoromethyl)phenyl]methoxy}propyl)piperazinyl]acetamide (17C): Compound 17C was prepared in a similar manner to compound 7C, substituting the commercially available 4-trifluoromethyl-benzylalcohol for 2-propanol in part C. MS (M+l) = 480.37 18 N-(2,6-dimethylphenyI)-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+l) = 442.41 19 2-(4-{3-[(2,4-dimethoxyphenyI)methoxy]-2-hydroxypropyI}piperazinyl)-N-(2,6-dimethylphenyl)acetamide (19C): Compound 19C was prepared in a similar manner to 63 WO 01/62744 PCT/US01/05606 compound IC, substituting the commercially available 2,4-dimethoxy-benzylalcohol for 2-propanol in part C. MS (M+l) = 472.42 N-(2,6-dimethyIphenyI)-2-(4-{2-hydroxy-3-[(4- methoxyphenyl)methoxy]propyl}piperazinyI)acetamide(20C): Compound 20C was prepared in a similar manner to compound IC, substituting the commercially available 4-methoxy-benzylalcohol for 2-propanol in part C. MS (M+l) = 442.42 21 N-(2,6-dimethylphenyl)-2-(4-{3-[(4-fluorophenyl)methoxyJ-2- hydroxypropyl}piperazlnyl)acetamide (21C) Compound 21C was prepared in a similar manner to compound IC, substituting the commercially available 4-fluoro-benzylalcohol for 2-propanol in part C. MS (M+l) = 430.40 N-(2,6-dimethyIphenyl)-2-(4-{2-hydroxy-3-[(4- methylphenyl)methoxy]propyl}piperazinyl)acetamide (22C): Compound 22C was prepared in a similar manner to compound IC, substituting the commercially available 4-methyl-benzylalcohol for 2-propanol in part C. MS (M+l) = 426.41 64 WO 01/62744 PCT/US01/05606 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+l) = 488.42 N-(2,6-dimethyIphenyI)-2-(4-{3-[(4-butyIphenyI)methoxy]-2- hydroxypropyl}piperazinyI)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 N-(2,6-dimethylphenyI)-2-{4-[2-hydroxy-3-(2- naphthyhnethoxy)propyl]piperazinyl}acetamide (25Q 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+l) = 462.41 26 65 WO 01/62744 PCT/US01/05606 I\-(2,6-dimethyIphenyl)-2-{4-[3-(cyclohexyImethoxy)-2- hydroxypropyllpiperazinyl}acetaraide (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+l) = 418.55 N-(2,6-dlmethyIphenyI)-2-(4-{3-[(4-fluorophenyI)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+l) = 458.5 66 WO 01/62744 PCT/USO1/05606 Example 7 Mitochondrial Assays Rat heart mitochondria were isolated by the method of Nedergard and Cannon (Methods in Enzymol. 55, 3,1979). 5 Palmitoyl CoA oxidation - The Palmityl CoA oxidation was carried out in a total volume of 100 micro liters containing the following agents: 110 mM KC1, 33 mM Tris buffer at pH 8, 2 mM KPi, 2 mM MgCl2,0.1 mM EDTA, 14.7 microM defatted BSA, 0.5 mM malic acid, 13 mM carnitine, 1 mM ADP, 52 micrograms of mitochondrial protein, and 16 microM 1-C14 palmitoyl CoA (Sp. Activity 60 mCi/mmole; 20 microCi/ml, using 5 microliters per 10 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, 15 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 uM 30 uM 3 uM Ranolazine 75% 90% 14 — — — 7 85% 98% 107% 15 78% 97% 103% 17 89% 98% 100% 16 100% 96% — 18 17% 19 - 22 25% 23 - 9B 84% 84% — 10B — -- — 7B -- -- « 11B 83% 92% — 12B 42% 95% 13B — — — 16B 37% 17B 78% 18B 78% 19B 35% 67 WO 01/62744 PCT/USO1/05606 20B 56% 21B 56% 23B 70% 24B 72% 10C 100% 97% -- 7C 68% — — 11C 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 5 containing the following agents: 110 mM KC1, 33 mM Tris buffer at pH 8, 2 mM KPi, 2 mM MgCl2, 0.1 mM EDTA, 0.1 mg/ml of defatted BSA, 0.5 mM malic acid, 3 mM ADP, 52 micrograms of mitochondrial protein, and 43 microM 1-C14 palmitoyl carnitine (Sp. Activity 60 mCi/mmole; 20 microCi/ml, using 5 microliters per assay). The compounds of this invention were added in a DMSO solution at the following concentrations: 100 microM, 30 10 microM, and 3 microM. In each assay, a DMSO control was used. After 15 min at 30 °C, the enzymatic reaction was centrifuged (20,000 g for 1 min), and 70 microliters of the supernatant was added to an activated reverse phase silicic acid column (approximately 0.5 ml of silicic acid). The column was eluted with 2 ml of water, and 0.5 ml of the eluent was used for scintillation counting to determine the amount of C14 trapped as C14 bicarbonate ion. The data 15 are presented as % activity of control. 68 WO 01/62744 PCT/US01/05606 Table 2 Inhibition of mitochondrial fatty acid oxidation using palmitoyl carnitine as substrate % of Control At 3 concentrations. Compound # 100 uM 30 ixM 3\iM Ranolazine 63% 98% — 14 — — — 7 95% 102% 109% 15 82% 98% 106% 17 80% 88% 103% 16 64% (8) — — 9B — — — 10B — — — 7B — — 1 ib — — ~ 12B 56% — — 13B — — — 10C 80% — — 7C — — ~ 11C — — — 12C ~ — — 13C — — — 69 WO 01/62744 PCT/US01/05606 Example 9 Metabolic Stability: As a measure of metabolic stability the compounds of this invention were incubated with human liver S-9 microsomal fractions. After, 30 minutes at 37 C, the 5 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 10 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. 15 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 20 buffer), kept at room temperature; 0.05M MgCl2 kept at 4°C; P-Nicotinamide adenine dinucleotide phosphate, tetrasodium salt, reduced form (NADPH), 0.02M solution in water (~16.6mg/mL) from Sigma Lot # 79H7044 prepared on day of use. ImM of ranolazine or Compounds 43, 45, 47, 52, 70, 74, 76, 78, and 80 in ACN further diluted to obtain 100(j.M in 10% ACN; Human S9 stock: 20mg/mL from Gentest. 25 Procedure: Incubation mixtures were prepared as follows: 70 WO 01/62744 PCT/US01/05606 Table 3 Component Volume per 0.25mL of Incubation Mixture Final concentration 10}iM CVT compounds 25 (iL 10 \iM MgCl2 25|iL 0.005 M NADPH 25 uL 0.002 M S9 25 uL 2 mg/mL Incubation Buffer 25 uL 0.05 M Water 125uL — * 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 jiL/incubate, add 25 jiL of compound being tested, mix, and initiate reaction by addition of S-9. Combine all components with incubation buffer and re-pipette 200 (iL/tube + 25|iL of the compound being tested along with 25|iL of S-9. 10 After 5 min of pre-incubation at 37°C, at 0 and 30min after starting the reaction, a 50 jil aliquot of the incubation mixture was removed and added to 100 |iL of 9:1 acetonitrile: methanol containing the internal standard. The mixture was centrifuged and a 100 |_iL aliquot of the supernatant was diluted in lmL of solvent C (0.1% Formic Acid in water). Then samples were analyzed for change 15 between the ratio of compound to internal standard at time zero and 30 minutes by LC/MS (injected 10 p.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. 20 Following the above procedure resulted in the following relative stability factors as compared to ranolazine for the compounds of this invention as illustrated in Table 4. If a compound is more stable than ranolazine in the liver S9 assay, than the stability factor will be greater than 1.0. If a compound is less stable than ranolazine, than the stability factor will be less than 1.0. 71 </div>

Claims

<div class="application article clearfix printTableText" id="claims"> WO

01/62744 PCT/USO1/05606 Table 4 Compound # Liver S9 Stability Factor Ranolazine 1.0 5 0.45 7 1.51 15 1.20 16 0.15 17 0.45 9b 1.18 10b 1.03 7b 1.46 11b 1.33 12b 1.38 13b 0.10 16B 0.99 17B • 0.71 18B 0.68 19B - 20B - 21B - 22B 1.49 23B 0.5 24B 1.05 25B - 26B - 27B - 21C « 22C 0.61 23C 0.05 24C 0.02 25C 0.01 26C — 27C — 72 We claim: ^ 1. A substituted piperazine compounds having the following formula: Rio Ri r16 R« R *24 15 r*14 5 wherein X is selected from the group consisting of: m and m O wherein m = 1 or 2 or 3; Ri, R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, halo, N02, CF3, CN, OR23, SR23, N(R23)2, S(0)R22, S02R22, S02N(R23)2, 10 NR23C02R22, NR23CON(R23)2, COR23, C02R23, CON(R23)2, NR23S02R22, Cms alkyl, C2.i5 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, N02, CF3, CN, OR23, SR23, N(R23)2, S(0)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 R5 may 15 join together to form -CH=CH-CH=CH-; Re, R7 and Rg are each independently selected from the group consisting of hydrogen and Cm5 alkyl; R9, Rio, R11, Ri2, Ri3, Rh, R15 and Ri6 are each independently selected from the group consisting of hydrogen, C02R23, CON(R23)2, Cm alkyl, and aryl wherein the alkyl and aryl 20 substituents are optionally substituted with 1 substituent selected from the group consisting of halo, CF3, CN, OR23, N(R23)2, C02R23, CON(R23)2 and aryl, wherein R9 and Rio may together form a carbonyl, or RI 1 and Ri2 may together form a carbonyl, or Ri3 and R14 may together form a carbonyl, or R15 and Ri6 may together form a carbonyl wherein Rn and Ri3 or R9 and 73 INTELLECTUAL PROPERTY OFFICE OF N.Z. 1 7 APR 2003 received Ris or R9 and Rn or Rn and R]5 or R9 and R13 may join together to form a bridging ring system having from 1 to 4 carbon atoms and wherein R9 and Rio or Rn and R12 or R13 and R14 or R15 and Ri6 may join to form a bridging ring system having from 1 to 5 carbon atoms with the proviso that R9, Rio, Rn, R12, R13, R14, R15 and Rj6 are not all hydrogen when R24 is unsubstituted phenyl and when X is R22 is selected from the group consisting of Cm5 alkyl, aryl, and heteroaryl, wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, alkyl, monoalkylamino, dialkylamino, alkyl amide, aryl amide, heteroaryl amide, CN, O-Ci-6 alkyl, CF3, and heteroaryl; R23 is selected from the group consisting of H, Ci-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[j] -CN, -0-Ci.6 alkyl, and CF3; and R24 is selected from the group consisting of alkyl, cycloalkyl, and fused phenylcycloalkyl wherein the point of attachment is on the cycloalkyl, wherein the alkyl, cycloalkyl, and fused phenylcycloalkyl are optionally substituted with from 1 to three substituents selected from the group consisting of halo, CF3, CN, OR23, SR23, S(0)R22, SO2R22, SC>2N(R23)2, NR23CO2R22, C1-2 alkyl, and aryl, wherein the optional aryl substituent is optionally substituted with from 1 to 3 substituents selected from the group consisting of halo, phenyl, CF3, CN, OR23, and Ci-6 alkyl, and INTELLECTUAL PROPERTY office of n.z. 74 2 9 JAN 2m received wherein Rn, Rig, R19, R20, and R21 are each independently selected from the group consisting of hydrogen, halo, N02, CF3, CN, OR23, SR23, N(R23)2, S(0)R22, S02R22, S02N(R23)2, NR23C02R22, NR23CON(R23)2, COR23, C02R23, CON(R23)2, NR23S02R22, Ci-15 alkyl, C2.I5 alkenyl, C2-i5 alkynyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, N02, CF3, CN, OR23, SR23, N(R23)2, S(0)R22, and S02R22. The substituted piperazine compound of claim 1 having the following formula: y"18 R15R14 1 10 wherein m = 1 or 2 or 3; Ri, R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, halo, N02, CF3, CN, OR23, SR23, N(R23)2, S(0)R22, S02R22, S02N(R23)2, NR23C02R22, NR23CON(R23)2, COR23, CO2R23, CON(R23)2, NR23S02R22, C1.15 alkyl, C2-15 alkenyl, C2_i5 alkynyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl and aryl 15 substituents are optionally substituted with 1 substituent selected from the group consisting of halo, N02, CF3, CN, OR23, SR23, N(R23)2, S(0)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 R5 may join together to form -CH=CH-CH=CH-; R6, R7 and Rg are each independently selected from the group consisting of hydrogen 20 and Cm5 alkyl; R9, Rio, R11, Ri2, Ri3, R14, R15 and Ri6 are each independently selected from the group consisting of hydrogen, C02R23, CON(R23)2, Cm alkyl, and aryl wherein the alkyl and aryl 75 INTELLECTUAL PROPERTY OFFICE OF N.Z. 29 JAN 200't r r c IU ^ n 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 Rio may together form a carbonyl, or Rn and R12 may together form a carbonyl, or R13 and R14 may together form a carbonyl, or Ri5 and Rie may together form a carbonyl wherein Rn and R13 or R9 and 5 R15 or R9 and Rn or Rn 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 Rio or Ri 1 and Ri2 or R13 and Rn or R15 and Ri6 may join to form a bridging ring system having from 1 to 5 carbon atoms with the proviso that R9, Ri0, Rn, R12, R13, R14, R15 and Ri6 are not all hydrogen when Rn, Ris, R19, R20, and R2i are all hydrogen; 10 R17, Rig, Ri9, R20, and R2i are each independently selected from the group consisting of hydrogen, halo, NO2, CF3, CN, OR23, SR23, N(R23)2, S(0)R22, S02R22, S02N(R23)2, NR23CO2R22, NR23CON(R23)2, COR23, CO2R23, CON(R.23)2, NR23SO2R22S Cms alkyl, C2-15 alkenyl, C2-15 alkynyl, heterocyclyl, aiyl, and heteroaryl, wherein the alkyl and aryl substituent are optionally substituted with 1 substituent selected from the group consisting of halo, NO2, 15 CF3, CN, OR23, SR23, N(R23)2, S(0)R22, and SO2R22; R22 is selected from the group consisting of Ci-15 alkyl, aryl, and heteroaryl, wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, alkyl, monoalkylamino, dialkylamino, alkyl amide, aryl amide, heteroaryl amide, CN, O-C1-6 alkyl, CF3, and heteroaryl; and 20 R23 is selected from the group consisting of H, Cms alkyl, aryl, and heteroaryl, wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, alkyl, monoalkylamino, dialkylamino, alkyl, CN, -O-Ci-6 alkyl, and CF3. 3. The compound of claim 2 wherein Ri, R2, R3, R4 and R5 are each 25 independently selected from the group consisting of hydrogen, halo, CF3, CN, OR23, SR23, N(R23)2> S(0)R22, SO2R22J S02N(R23)2, NR23CO2R22, NR23CON(R23)2> COR23, CO2R23, CON(R23)2, NR23SO2R22, C1-8 alkyl, C2-g 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 30 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-; R<s, R7 and Rg are each independently selected from the group consisting of hydrogen and C1-8 alkyl; 76 INTELLECTUAL PROPERTY OFFICE OF N.Z. 1 7 APR 2003 received Rt>, Rio, Rn, R12, R13, Rm, R15 and Ri6 are each independently selected from the group consisting of hydrogen, Cm 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 Rio may together form a 5 carbonyl, or Ri 1 and R12 may together form a carbonyl, or R13 and R14 may together form a carbonyl, or R15 and Ri6 may together form a carbonyl wherein Rn and R13 or R9 and R15 or R9 and Ri 1 or Ri 1 and R15 or R9 and R13 may join together to form a bridging ring including from 1 to 4 carbon atoms ; and R17, Rig, R19, R20, and R2i are each independently selected from the group consisting 10 of hydrogen, halo, NO2, CF3, CN, OR23, SR23, N(R23)2, S(0)R22, SO2R22, S02N(R23)2, NR23CO2R22, NR23CON(R23)2, COR23, CO2R23, CON(R23)2, NR23SO2R22, Ci.,5 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, N02, CF3, CN, OR23, SR23, N(R23)2, S(0)R22, and S02R22 15 4. The compound of claim 2 wherein Ri, R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, halo, CF3, CN, OR23, SR23, N(R23)2, S02N(R23)2, COR23, C02R23, 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 20 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-; Re, R7 and Rg are each independently selected from the group consisting of hydrogen or C1.3 alkyl; R9, Rio, R11, R12, R13, R14, R15 and Ri6 are each independently selected from the group 25 consisting of hydrogen, Cm alkyl, or aryl wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, CF3, CN, OR23, N(R23)2, CO2R23, CON(R23)2 and aryl, wherein R9 and Rio may together form a carbonyl, or Ri 1 and Ri2 may together form a carbonyl, or Ri3 and R14 may together form a carbonyl, or Ri5 and Ri6 may together form a carbonyl wherein Ri 1 and Ri3 or R9 and R15 or 30 R9 and Rn or Rn and R15 or R9 and Ri3 may join together to form a ring including from 1 to 4 carbon atoms; Rn, Rig, R19, R2o, and R21 are each independently selected from the group consisting of hydrogen, halo, CF3, CN, OR23, COR23, C02R23, CON(R23)2, CM5 alkyl, C2-15 alkenyl, C2. 77 INTELLECTUAL PROPERTY OFFICE OF N.Z. 1 7 APR 2003 received 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(0)R22, and S02R22; R22 is selected from the group consisting of Ci-15 alkyl, aryl, and heteroaryl, wherein 5 the alkyl and aiyl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, alkyl, monoalkylamino, dialkylamino, alkyl amide, aiyl amide, heteroaryl amide, CN, O-C1-6 alkyl, CF3, and heteroaryl; and R23 is selected from the group consisting of hydrogen, Q.g alkyl, aryl, and heteroaryl, wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected 10 from the group consisting of halo, -O-C1-3 alkyl, and CF3. 5. The compound of claim 2 wherein Ri, R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, halo, CF3, CN, OR23, SR23, N(R23)2, S02N(R23>2, COR23, CO2R23, CON(R23)2, Ci-6 alkyl, C2-6 alkenyl, heterocyclyl, and heteroaryl, wherein the alkyl substituent is optionally substituted with OR23, wherein R2 15 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-; Re, R7 and Rg are each independently selected from the group consisting of hydrogen and methyl; R9, Rio, R11, Ri2» R13, R14, R15 and Ri6 are each independently selected from the group 20 consisting of hydrogen and C1.2 alkyl, wherein R9 and Rio may together form a carbonyl, or Rn and R12 may together form a carbonyl, or R13 and R14 may together form a carbonyl, or R15 and Ri6 may together form a carbonyl; R17, Ri8, R19, R2o, and R2i are each independently selected from the group consisting of hydrogen, halo, CF3, CN, OR23, COR23, CO2R23, CON(R23)2, Ci„8 alkyl, C2.g alkenyl, C2-8 25 alkynyl, heterocyclyl, atyl, 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 Cm alkyl, aryl, and heteroaryl, wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group 30 consisting of halo, alkyl, O-C1-3 alkyl, and CF3; and R23 is selected from the group consisting of H, C1.5 alkyl, aryl, or heteroaryl, wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, -OMe, and CF3. 78 INTELLECTUAL PROPERTY OFFICE OF N.Z. 1 7 APR 2003 received 6. The compound of claim 5 wherein m = 1 or 2. 7. The compound of claim 5 wherein Ri, R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, halo, CF3, CN, OR23, SR23, N(R23)2, S02N(R23)2, COR23, CO2R23, CON(R23)2, C1.3 alkyl, C2-e 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 Rg are each independently selected from the group consisting of hydrogen and methyl; R9, Rio, Ru, R12, R13, Rm, R15 and Ri6 are each independently selected from the group consisting of hydrogen and Ci.2 alkyl, wherein R9 and R10 may together form a carbonyl, or Rn and R12 may together form a carbonyl, or R13 and R14 may together form a carbonyl, or R15 and Ri6 may together form a carbonyl; R17, Ri8, R19, R2o, and R21 are each independently selected from the group consisting of hydrogen, halo, CF3, CN, OR23, COR23, CO2R23, CON(R23)2, and Ci-g alkyl; R22 is Cm alkyl; and R23 is selected from the group consisting of hydrogen and C1.5 alkyl. 8. The compound of claim 5 wherein Ri, R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, halo, CF3, CN, OR23, SR23, N(R23)2, S02N(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-; Re, R7 and Rg are each hydrogen; R9, R10, Rn, R12, R13, R14, R15 and Ri6 are each independently selected from the group consisting of hydrogen and C1-2 alkyl, wherein R9 and Ri0 may together form a carbonyl, or Rn and R12 may together form a carbonyl, or R13 and R14 may together form a carbonyl, or R15 and Ri6 may together form a carbonyl; R17, Rig, R19, R2o, and R21 are each independently selected from the group consisting of hydrogen, halo, CF3, CN, OR23, COR23, CO2R23, CON(R23)2, and Ci-g alkyl; R22 is Ci-2 alkyl; and R23 is selected from the group consisting of hydrogen and Ci-2 alkyl. ,t£lt£ctual PROPERTY 79 office of N.Z. ; 1 7 APR 2003 RECEIVES 9. The compound of claim 5 wherein Ri, R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, halo, CF3, CN, OR23, SR23, N(R23>2, S02N(R23)2, COR23, C02R23, CON(R23)2, C]-3 alkyl, C2.3 alkenyl, heterocyclyl, and heteroaryl, wherein the alkyl substituent is optionally substituted with OR23, wherein R2 5 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-; Rg, R7 and Rg are each hydrogen; R9, Rio, R11, Ri2, R13, R14, R15 and Ri6 are each independently selected from the group consisting of hydrogen and methyl, wherein R9 and Rio may together form a carbonyl, or R13 10 and R14 may together form a carbonyl; R17, Rig, R19, R2o, and R2i are each independently selected from the group consisting of hydrogen, halo, CF3, CN, OR23, and Ci-2 alkyl; R22 is methyl; and R23 is selected from the group consisting of hydrogen and methyl. 15 10. The compound of claim 5 wherein Rig, R19, R2o, and R2i are each hydrogen, and R17 is selected from the group consisting of halo and OR23. 11. The compound of claim 10 wherein Ri2 is (S)-methyl and R9, Rio, R11, R13, R14, R15 and Ri6 are each hydrogen. 12. The compound of claim 10 wherein R9 and Rio together form a carbonyl Ru, 20 Ri2, R13, R14, R15 and Ri6 are each hydrogen. 13. The compound of claim 10 wherein R9, Rio, R11, Ri2, R15 and Ri6 are each hydrogen and R13 and R14 together form a carbonyl. 14. The compound of any one of claims 3 to 13 wherein m = 1. 15. The compound of claim 10 wherein Ri, R2, R3, R4 and R5 are each 25 independently selected from the group consisting of hydrogen, halo, CF3, CN, OR23, SR23, N(R23)2, S02N(R23)2, COR23, C02R23, 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-. 30 16. The compound of claim 2 wherein m = 1 or 2; Ri, R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, halo, CF3, OR23 and Ci.2 alkyl wherein R23 is a Ci-2 alkyl; 80 raiECTUAL PROPHTK OFFICE OF N.Z. ' 7 APR 2003 deceived, H2 0 Re, R7 and Rg each independently selected from the group consisting of hydrogen and methyl; R9, Rio, R11, R12, R13, R14, R15 and Ri6 are each independently selected from the group consisting of hydrogen and Cm alkyl, or R9 and Rio may together form a carbonyl, or Rn and 5 Rj2 may together form a carbonyl, or R13 and R14 may together form a carbonyl, or R15 and Ri6 may together form a carbonyl with the proviso that R9, Rio, Ru, R12, R13, Rh, R15 and Ri6 are not all simultaneously hydrogen and wherein Rn and R13 or R9 and R15 or R9 and Ru or Rn and R15 or R9 and R13 may join to form a ring including from 1 to 4 carbon atoms; R17, Rig, R19, R20, and R21 are each independently selected from the group consisting of 10 hydrogen, halo, OR23, Cm 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. 17. The compound of claim 16 wherein Ri, R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, and methyl. 15 18. The compound of claim 16 wherein Re, R7 and Rg are each hydrogen. 19. The compound of claim 16 wherein R9, Rio, Ru, R12, R13, Ri4, R15 and Ri6 are each independently selected from the group consisting of hydrogen and C1-2 alkyl, or R9 and Rio may together form a carbonyl, or R15 and Ri6 may together form a carbonyl with the proviso that R9, Rio, Rn, R12, R13, Ri4, R15 and Ri6 are not all simultaneously hydrogen and 20 wherein Rn and R13 or R9 and R15 or R9 and Rn or Rn and R15 or R9 and R13 may join to form a ring having from 1 to 2 carbon atoms. 20. The compound of claim 16 wherein R9, Rio, Ru, R12, R13, Ri4, R15 and Ri6 are each independently selected from the group consisting of hydrogen and Ci-2 alkyl, or R9 and Rio may together form a carbonyl, or Ru and R12 may together form a carbonyl, or R13 and 25 R14 may together form a carbonyl, or R15 and Ri6 may together form a carbonyl. 21. The compound of claim 16 wherein R9 and Rio together form a carbonyl, R15 and Ri6 together form a carbonyl or both R9 and Rio together form a carbonyl and R15 and Ri6 together form a carbonyl. 22. The compound of claim 16 wherein Rn, Rig, Ri9, R2o and R2i are each 30 independently selected from the group consisting of hydrogen, halo, Cm alkyl and OR23 wherein R23 is C1-2 alkyl. 23. The compound of claim 2 wherein m = 1; 81 INTELLECTUAL PROPERTY OFFICE OF N.Z. 1 7 APR 2003 received Ri, R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, and methyl; Re, R7 and Rg are each hydrogen; R9, Rio, Rn, R12, R13, Rm, R15 and Ri6 are each independently selected from the group 5 consisting of hydrogen and Cm alkyl, or R9 and Rio may together form a carbonyl, or Ri 1 and R12 may together form a carbonyl, or R]3 and Ri4 may together form a carbonyl, or R15 and Ri6 may together form a carbonyl with the proviso that R9, Rio, Rn, R12, R13, R14, R15 and Ri6 are not all simultaneously hydrogen and wherein Rn and R13 or R9 and R15 or R9 and Rn or Rn and R15 or R9 and Ru may join to form a ring including from 1 to 4 carbon atoms; 10 Rn, Rig, R,9, R20 and R21 are each independently selected from the group consisting of hydrogen, halo, Cm alkyl and OR23; and R23 is C1-2 alkyl. 24. The compound of claim 23 wherein Ri and R5 are each methyl and R2, R3, and R4 are each hydrogen. 15 25. The compound of claim 23 wherein Rn, R12, R13, R14, R15 and Ri6 are each hydrogen and R9 and Rio together form carbonyl. 26. The compound of claim 23 wherein R9, Rio, Rn, R12, R15 and Ri6 are each hydrogen and R13 and R14 together form carbonyl. 27. The compound of claim 23 wherein R9, Ri0, Rn, R12, Ri3, Ri4, R15 and Ri6 are 20 each independently selected from the group consisting of hydrogen and methyl. 28. The compound of claim 23 wherein R9, R12, R13, R14, R15 and Ri6 are each hydrogen and Rio and Rn together form a ring having from 1 to 4 carbon atoms. 29. The compound of claim 23 wherein R9, Rio, R12, R13, R14 and Rt6 are each hydrogen and Ri 1 and R15 together form a ring having from 1 to 3 carbon atoms. 25 30. The compound of claim 23 wherein Rig, R19 and R21 are each hydrogen and R17 and Rig are each methyl. 31. The compound of claim 23 wherein Rn, is -OCH3, and Rig, R19, R2o and R21 are each hydrogen. 32. The compound of claim 16 wherein, Rn, Rig, R20 and R21 are each hydrogen 30 and R19 is selected from the group consisting of -OCH3, -F, Cm alkyl and aiyl. 33. The compound of claim 2 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- Ro 3 ^'cllectual PROPERTY ^ | office OF N.Z. j , - | 1 1 APR 2003 RECEIVED f 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, 5 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](lS,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- 10 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-(2-15 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, 20 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-(2-25 fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl} -N-phenylacetamide, 2- {(3 S)-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- {(3 S)-4-[(2S)-3-(2-30 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- {(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-(3-methylthiophenyl) acetamide, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)- 83 INTELLECTUAL PROPERTY OFFICE OF N.Z. 2 3 JAN 2004
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-(2-5 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]-3-methylpiperazinyl}-N-(3,5-dichlorophenyl) acetamide, 2- {(3S)-4-[(2S)-3-10 (2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl} -N-(4-methoxyphenyl) acetamide, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-(4-methylphenyl) acetamide, 2- {(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-(3-methylphenyl) acetamide, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl} -N-(4-fluorophenyl) acetamide, 2- {(3S)-4-[(2S)-3-(2-15 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)-4-20 [(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-4-ylphenyl) acetamide, 2- {(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl} -N-25 (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)-2-30 hydroxypropyl]-3-methylpiperazinyl} -N-[2-(hydroxymethyl-6-methylphenyl] acetamide. 34. A substituted piperazine compound having the following formula: 84 SNTcLLECTUAL property office OF N.Z. 1 7 APR 2003 ftECEIVE0~ R10 R11 10 15 20 25 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(0)R22, S02R22> S02N(R23)2, NR23C02R22> 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(0)R22, and SO2R22; R6, R7 and R8 are each independently selected from the group consisting of hydrogen and Ci-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, Cm 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 Rn 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 wherein the two R groups together comprise of from 1 to 4 carbon atoms and wherein R9 and R10 or Rn and R12 or R13 and R14 or R15 and R16 may join to form a spiro ring system wherein the two R groups together comprise of from 1 to 5 carbon atoms; R17, R18, R19, R20, and R21 are each independently selected from the group consisting of hydrogen, halo, NO2, CF3, CN, OR23, SR23, N(R.23)2, S(0)R22, SO2R22, S02N(R23)2, NR23CO2R225 NR23CON(R23)2, COR23, CO2R23, CON(R23)2, NR23SO2R22, Ci-15 alkyl, C2-is alkenyl, C2.is alkynyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of .16 >11 .13 85 INTELLECTUAL PROPERTY OFFICE OF N.Z. 1 7 APR 2003 receiv&p halo, N02, CF3, CN, OR23, SR23, N(R23)2, S(0)R22, and S02R22 and wKerem R^ afid , Q 1 A 1 A <«n A < R and R or R and R or R and R may combine to form a saturated ring including from 5 to 6 carbon atoms wherein from 0 to 2 carbon atoms may be substituted with an oxygen atom and wherein R17 and R18 may together form -CH=CH-CH=CH-; 5 R22 is selected from the group consisting of Cm5 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-Cj.6 alkyl, CF3, and heteroaryl; and R23 is selected from the group consisting of H, Cms alkyl, aryl, or heteroaryl, wherein 10 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-C1-6 alkyl, or CF3. 35. The compound of claim 34 wherein R1, R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, halo, N02, CF3, CN, OR23, SR23, N(R23)2, S(0)R22, S02R22, S02N(R23)2, NR23C02R22, NR23CON(R23)2, COR23, CO2R23, 15 CON(R23)2, NR23S02R22, Ci-15 alkyl, heterocyclyl, aryl, and heteroaryl; R6, R7 and R8 each independently selected from the group consisting of hydrogen or Ci_g alkyl; R9, R10, R11, R12, R13, R14, R15 and R16 are each independently selected from the group consisting of hydrogen, C02R23, CON(R23)2, Cm alkyl, and aryl, wherein R9 and R10 may 1110 1*31.4 20 together form a carbonyl, or R and R may together form a carbonyl, or R and R 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 Ru and R15 or R9 and R13 may join together to form a bridging ring system wherein the two R groups together comprise of from 1 to 4 carbon atoms ; 17 1R 1Q 9ft J1 R , R , R , R , and R are each independently selected from the group consisting of 25 hydrogen, halo, CF3, CN, OR23, SR23, N(R23)2, COR23, C02R23, CON(R23)2, Ci-15 alkyl, C2_6 alkenyl, C2-6 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, and OR23, and wherein R17 and R18 or R18 and R19 or R19 and R20 or R20 and R21 may combine to form a saturated ring including from 5 to 6 carbon atoms wherein from 0 30 to 2 carbon atoms may be substituted with an oxygen atom and wherein R17 and R18 may together form -CH=CH-CH=CH-; INTELLECTUAL PROPERTY. OFFICE OF N.Z. 1 7 APR 2003 RECEIVED R.22 is selected from the group consisting of Ci-g alkyl, aryl, or heteroaryl, wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, alkyl, CN, and CF3; and R23 is selected from the group consisting of H, C1-8 alkyl, aryl, or heteroaryl, wherein the 5 alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, alkyl, alkyl -CN, and CF3. 36. The compound of claim 34 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, Ci-g alkyl, aryl, and heteroaryl; f 7 o 10 R,R and R each independently selected from the group consisting of hydrogen and C1-5 alkyl; R9, R10, R11, R12, R13, R14, R15 and R16 are each independently selected from the group consisting of hydrogen, Cm alkyl, and aryl, wherein R9 and R10 may together form a carbonyl, IIIO 1*31/1 or R and R may together form a carbonyl, or R and R may together form a carbonyl, or 15 R15 and R16 may together form a carbonyl wherein Ru 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 wherein the two R groups together comprise of from 1 to 2 carbon atoms ; 17 18 19 20 21 R , R , R , R , and R are each independently selected from the group consisting of hydrogen, halo, CF3, CN, OR23, Ci-s alkyl, aryl, and heteroaryl, and R19 and R20 may combine 20 to form a saturated ring including from 5 to 6 carbon atoms wherein 2 carbon atoms may be substituted with an oxygen atom and wherein R17 and R18 may together form -CH=CH-CH=CH-; R22 is selected from the group consisting of Cm alkyl, and aryl; and R23 is selected from the group consisting of H, Cm alkyl, and aryl; 25 37. The composition of claim 34 wherein R1, R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, halo, CF3, CN, OR23, and Cm alkyl; 6 7 8 • R , R and R each independently selected from the group consisting of hydrogen and C1-3 alkyl; 30 R9, R10, R11, R12, R13, R14, R15 and R16 are each independently selected from the group consisting of hydrogen, and C1-3 alkyl, wherein R9 and R10 may together form a carbonyl, or 1110 1*31/1 R and R may together form a carbonyl, or R and R 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 87 INTELLECTUAL PROPHmg. OFFICE OF N.Z. 1 7 APR 2003 ] WECElyEpA R11 and R15 or R9 and R13 may join together to form a bridging ring system wherein the two R groups together comprise of from 1 to 2 carbon atoms ; 17 18 10 "7ft "?1 R , R , R , R , and R are each independently selected from the group consisting of hydrogen, halo, CF3, CN, OR23, and Ci_6 alkyl, and R19 and R20 may combine to form a 5 saturated ring including from 5 to 6 carbon atoms wherein 2 carbon atoms may be substituted with an oxygen atom and wherein R17 and R18 may together form -CH=CH-CH=CH-; R22is C1.3 alkyl; and R23 is selected from the group consisting of H and C1.3 alkyl. 10 38. The compound of claim 37 wherein m = 1 or 2 or 3. 39. The compound of claim 37 wherein 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, R13 and R14 may together form a carbonyl, wherein R11 and R13 or R9 and R15 or Rn and R15 or R9 and R13 may join together to form a bridging ring 15 system wherein the two R groups together comprise of from 1 to 2 carbon atoms. 40. The compound of claim 37 wherein R9, R10, R11, R12, R13, R14, R15 and R16 are each independently selected from the group consisting of hydrogen, and methyl. 41. The compound of claim 39 or 40 wherein R6, R7 and R8 are each independently selected from the group consisting of hydrogen and methyl. . 20 42. The compound of claim 37 wherein R9, R10, Rn, R12, R13, R14, R15 and R16 are hydrogen. 43. The compound of claim 37 wherein R1, R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, halo, and C1.2 alkyl; R6 is hydrogen; and 7 8 25 R and R are each independently selected from the group consisting of hydrogen and methyl; and R9, R10, R11, R12, R13, R14, R15 and R16 are each independently selected from the group consisting of hydrogen, and C1-3 alkyl, wherein R9 and R10 may together form a carbonyl, or R13 and R14 may together form a carbonyl; 17 18 19 20 21 30 R , R , R , R , and R are each independently selected from the group consisting of hydrogen, halo, CF3, CN, OR23, C1-6 alkyl, and R19 and R20 may combine to form a saturated ring including from 5 to 6 carbon atoms wherein 2 carbon atoms may be substituted with an oxygen atom and wherein R17 and R18 may together form -CH=CH-CH=CH-; 88 INTELLECTUAL PROPERTY office OF N.Z. 1 7 APR 2003 received R-22 is methyl; and «=, ^ R23 is selected from the group consisting of H, and methyl. *3) tO, {J) j^jjr ' 44. The compound of claim 43 wherein R9, R10, Rn, R12, R13, R14, R15 and R16 are each independently selected from the group consisting of hydrogen, and methyl. 5 45. The compound of claim 43 wherein R9, R10, R11, R12, R13, R14, R15 and R16 are hydrogen. 46. The compound of claim 43 wherein R17, R18, R19, R20, and R21 are each independently selected from the group consisting of hydrogen, halo, CF3, OR23, and Cm alkyl, and R19 and R20 may combine to form a saturated ring including from 5 to 6 carbon atoms 17 10 10 wherein 2 carbon atoms may be substituted with an oxygen atom and wherein R and R may together form -CH=CH-CH=CH-. 47. The compound of claim 43 wherein R17, R18, R19, R20, and R21 are each independently selected from the group consisting of hydrogen, halo, CF3, OR23, and Cm alkyl, and R19 and R20 may combine to form -O-CH2-O- or -OCH2CH2O- and wherein R17 and R18 15 may together form -CH=CH-CH=CH-. 48. The compound of claim 34 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 Ci_2 alkyl; R6, R7 and R8 each independently selected from the group consisting of hydrogen and 20 methyl; 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 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 including from 1 to 4 carbon atoms; and 17 18 1Q 71 25 R , R , R , R , and R are each independently selected from the group consisting of hydrogen, halo, OR23, C1.3 alkyl, C2-4 alkenyl, C2-4 alkynyl, heterocyclyl, aryl, and heteroaryl, 17 18 18 1Q wherein R23 is C1-2 alkyl and wherein R and R or R and R may together form a ring selected from the group consisting of -CH=CH-CH=CH-, -O-CH2-O, and -O-CH2-CH2-O-. 49. The compound of claim 48 wherein R1, R2, R3, R4 and R5 are each 30 independently selected from the group consisting of hydrogen, and methyl. f\ 7 8 50. The compound of claim 48 wherein R , R and R are each hydrogen. 51. The compound of claim 48 wherein R9, R10, R11, R12, R13, R14, R15 and R16 are each independently selected from the group consisting of hydrogen and C1-2 alkyl. 89 intellectual PROPERTY office OF N.Z. 1 7 APR 2003 RECEIVED 52. The compound of claim 48 wherein R9, R10, R11, R12, R13, R14, R15 and R16 are each independently selected from the group consisting of hydrogen and methyl. 53. The compound of claim 48 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 5 together form a carbonyl. 54. The compound of claim 48 wherein R17, R18, R19, R20 and R21 are each independently selected from the group consisting of hydrogen, halo, C1-3 alkyl and OR23 wherein R23 is C1-2 alkyl. 55. The compound of claim 48 wherein R17 and R18 or R18 and R19 together form a 10 ring selected from the group consisting of -CH=CH-CH=CH-, and -O-CH2-O. 56. The compound of claim 34 wherein m = 1 or 2; R1, R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, and methyl; 15 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 Cm 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 and wherein Ru and R13 or R9 and R15 or R9 and R11 or R11 20 and R15 or R9 and R13 may join to form a ring including from 1 to 4 carbon atoms; it 1 o 1 q ori "i 1 R , R , R , R and R are each independently selected from the group consisting of hydrogen, halo, Cm alkyl, CF3 and OR23; and R23 is C1.2 alkyl. 57. The compound of claim 56 wherein R1 and R5 are each methyl and R2, R3, and 25 R4 are each hydrogen. 58. The compound of claim 56 wherein R9, R10, R11, R12, R13, R14, R15 and R16 are each independently selected from the group consisting of hydrogen and methyl. 59. The compound of claim 56 wherein R9, R10, R11, R12, R13, R14, R15 and R16 are each hydrogen. 30 60. The compound of claim 56 wherein, R17, R18, R19, R20, and R21 are each selected from the group consisting of hydrogen, CI, F, -OCH3, -CF3 and Cm alkyl. 61. The compound of claim 60 wherein R18, and R20 are each hydrogen. 62. The compound of claim 60 wherein R19 is -OCH3. —— : U ECTUAL PROPERTY 90 off'ce OF N.Z. 1 7 APR 2003 #ecEi?£B 63. The compound of claim 56 wherein R17 is -OCH3, and R18, R19, R20 and R21 are each hydrogen. 64. The compound of claim 56 wherein, R17, R18, R20 and R21 are each hydrogen and R19is selected from the group consisting of-OCH3, -F, CF3, and Cm alkyl. 65. A substituted piperazine compound of claim 34 selected from the group consisting of: N-(2,6-dimethylphenyl)-2-[4-(2-hydroxy-4-phenylbutyl)piperazinyl]acetamide; N-(2,6-dimethylphenyl)-2- {4-[2-hydroxy-3-(2-methoxyphenyl)propyl]piperazinyl}acetamide; 2-[4-(3-(2H-benzo[d] 1,3 -dioxolen-5-yl)-2-hydroxypropyl)piperazinyl]-N-(2,6-dimethylphenyl)acetamide; N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(4-methoxyphenyl)propyl]piperazinyl} acetamide; N-(2,6-dimethylphenyl)-2- {4-[2-hydroxy-3-phenylpropyljpiperazinyl} 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, N-(2,6-dimethylphenyl)-2-[4-(2-hydroxy-3-phenylpropyl)piperazinyl]-2-methylpropanamide, N-(2,6-dimethylphenyl)-2- {4-[2-hydroxy-3-(3,4,5-trimethoxyphenyl)propyl]piperazinyl}-2-methylpropanamide, N-(2,6-dimethylphenyl)-2-[4-(2-hydroxy-5-phenylpentyl)piperazinyl]acetamide, N-(2,6-dimethylphenyl)-2- {4-[5-(2-fluorophenyl)- 2-hydroxy-pentyljpiperazinyl} acetamide, and N-(2,6-dimethylphenyl)-2- {4-[5-(2-chlorophenyl)- 2-hydroxy-pentyl]piperazinyl} acetamide. 66. A substituted piperazine compound having the following formula: INTELLECTUAL PROPERTY OFFICE OF N.Z. 1 7 APR 2003 received wherein m = 1, 2, or 3; 5 R1, R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, halo, N02, CF3, CN, OR20, SR20, N(R20)2, S(0)R22, S02R22, SO2N(R20)2, NR20CO2R22, NR20CON(R20)2, COR20, C02R2°, CON(R20)2, NR20SO2R22, Cms alkyl, C2.i5 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, N02, 10 CF3, CN, OR20, SR20, N(R20)2, S(0)R22, and S02R22; f\ 7 R R , R' and R° 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, CO2R20, CON(R20)2, Cm alkyl, and aryl wherein the alkyl and aryl 15 substituents are optionally substituted with 1 substituent selected from the group consisting of halo, CF3, CN, OR20, N(R20)2, CO2R20, CON(R20)2 or 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 ring including 20 from 1 to 3 carbon atoms; R24 is selected from the group consisting of alkyl, cycloalkyl, and fused phenylcycloalkyl wherein the point of attachment is on the cycloalkyl, wherein the alkyl, cycloalkyl, and fused phenylcycloalkyl are optionally substituted with from 1 to three substituents selected from the group consisting of halo, CF3, CN, OR20, SR20, S(0)R22, 25 S02R22, SO2N(R20)2, NR20CO2R22, Ci.2 alkyl, and aryl, wherein the optional aryl substituent is optionally substituted with from 1 to 3 substituents selected from the group consisting of halo, phenyl, CF3, CN, OR20, and Ci.6 alkyl; 92 INTELLECTUAL PROPERTY I OFFICE OF N.Z. 1 7 APR 2003 received R20 is selected from the group consisting of H, Cms alkyl, aryl, and heteroaryl, whei^ir 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-Ci-6 alkyl, and CF3; and R22 is selected from the group consisting of Cms alkyl, aryl, and heteroaryl, wherein 5 the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, alkyl, monoalkylamino, dialkylamino, alkyl amide, aryl amide, heteroaryl amide, CN, O-Ci-6 alkyl, CF3, and heteroaryl. 67. The compound of claim 66 wherein R1, R2, R3, R4 and R5 are each 20 20 independently selected from the group consisting of hydrogen, halo, CF3, CN, OR , SR , 10 N(R20)2, SO2N(R20)2, C02R2°, CON(R20)2, Ci-g 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, N02, CF3, CN, OR20, SR20, N(R20)2, S(0)R22, and S02R22; R6, R7 and R8 each independently selected from the group consisting of hydrogen and 15 C 1.3 alkyl; R9, R10, R11, R12, R13, R14, R15 and R16 are each independently selected from the group consisting of hydrogen, CON(R20)2, and Cm alkyl, or 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; and 20 R20 is selected from the group consisting of H, C 1.15 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, alkylcyano, -O-Ci-6 alkyl, and CF3. 68. The compound of claim 66 wherein R1, R2, R3, R4 and R5 are each 25 independently selected from the group consisting of hydrogen, halo, CF3, OR , C 1.5 alkyl, C2. 3 alkenyl, and C2-3 alkynyl, wherein the alkyl substituent is optionally substituted with CF3; R6, R7 and R8 are each independently selected from the group consisting of hydrogen and Ci-3 alkyl; R9, R10, R11, R12, R13, R14, R15 and R16 are each independently selected from the group 30 consisting of hydrogen, CON(R20)2, and Cm 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; R24 is selected from the group consisting of alkyl, cycloalkyl, and fused 93 INTELLECTUAL PROPERTY OFFICE OF N.Z. 1 7 APR 2003 B SPeiBtH 0 10 25 phenylcycloalkyl wherein the point of attachment is on the cycloalkyl, wherein the alkyl, cycloalkyl, and fused phenylcycloalkyl are optionally substituted with from 1 to two substituents selected from the group consisting of halo, CF3, CN, OR20, SR20, S(0)R22, SO2R22, C1-2 alkyl, and aryl, wherein the optional aryl substituent is optionally substituted with from 1 to 3 substituents selected from the group consisting of halo, phenyl, CF3, CN, OR20, and Q.6 alkyl; and R20 is selected from the group consisting of H, Ci-g 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. 69. The compound of claim 66 wherein R1, R2, R3, R4 and R5 are each 9ft independently selected from the group consisting of hydrogen, halo, CF3, OR , C1.3 alkyl, C2-3 alkenyl, and C2-3 alkynyl, wherein the alkyl is optionally substituted with CF3; 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 C1-2 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; R24 is selected from the group consisting of alkyl , cycloalkyl, and fused phenylcycloalkyl, wherein the point of attachment is on the cycloalkyl wherein the alkyl, cycloalkyl, and fused phenylcycloalkyl are optionally substituted with from 1 to two substituents selected from the group consisting of halo, CF3, OR20, S(0)R22, C1-2 alkyl, and aryl, wherein the optional aryl substituent is optionally substituted with from 1 to 3 substituents selected from the group consisting of halo, phenyl, CF3, CN, OR20, and C1-6 alkyl; and 9ft R 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. 70. The compound of claim 66 wherein m = 1 or 2; R1, R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, halo, CF3, OR20 and Cm alkyl and wherein R20 is a C1-3 alkyl; R6, R7 and R8 each independently selected from the group consisting of hydrogen and C1-3 alkyl; 94 INTELLECTUAL PROPERTY office of n.z. 1 7 APR 2003 received R9, R10, R11, R12, R13, R14, R15 and R16 are each independently selected from the group consisting of hydrogen, CON(R20)2, C1-4 alkyl, and aryl wherein the alkyl and aryl substituents are each optionally substituted with 1 substituent selected from the group consisting of halo, CF3, OR20, N(R20)2i CON(R20)2 and aryl wherein R9 and R10 may together form a carbonyl, or 5 Ru 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 Rn and R15 or R9 and R13 may join together to form a ring including from 1 to 3 carbon atoms; R24 is selected from the group consisting of alkyl, cycloalkyl, and fused 10 phenylcycloalkyl wherein the point of attachment is on the cycloalkyl, wherein the alkyl, cycloalkyl, and fused phenylcycloalkyl are optionally substituted with from 1 to two substituents selected from the group consisting of halo, CF3, OR20, and aryl, wherein the optional aryl substituent is optionally substituted with from 1 to 3 substituents selected from the group consisting of halo, phenyl, CF3, CN, OR20, and C1-6 alkyl; and 15 R20 is selected from the group consisting of H, C1.3 alkyl, and aryl, wherein the alkyl and aryl substituents are optionally substituted with 1 substituent individually selected from the group consisting of halo, -OMe, and CF3. 71. The compound of claim 70 wherein R9, R10, R11, R12, R13, R14, R15 and R16 are each independently selected from the group consisting of hydrogen and Cm alkyl, or R9 and 20 R10 together form a carbonyl, or R11 and R12 together form a carbonyl, or R13 and R14 together form a carbonyl, or R15 and R16 together form a carbonyl. 72. The compound of claim 70 wherein R9, R10, R11, R12, R13, R14, R15 and R16 are each independently selected from the group consisting of hydrogen, CON(R20)2, C1-3 alkyl, and aryl, wherein the alkyl and aryl substituents are optionally substituted with 1 substituent 25 selected from the group consisting of halo, N(R20)2, and aryl or wherein R9 and R10 may 1119 1 1 1 ^ together form a carbonyl, or R and R may together form a carbonyl wherein R and R or R9 and R15 or R9 and R11 or R11 and R15 or R9 and R13 may join together to form a ring including from 1 to 3 carbon atoms. 73. The compound of claim 70 wherein R9, R10, R11, R12, R13, R14, R15 and R16 are 30 each independently selected from the group consisting of hydrogen, and C1-2 alkyl, wherein the alkyl substituent is optionally substituted with 1 substituent selected from the group consisting of N(R20)2, and aryl or wherein R9 and R10 may together form a carbonyl. 95 INTELLECTUAL PROPERTY OFFICE OF N.Z. 1 7 APR 2003 received 3^1 . 74. The compound of claim 66 wherein R1, R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, halo, CF3, OR20, and C1.3 alkyl wherein the alkyl substituent is optionally substituted with CF3. 75. The compound of claim 66 wherein R6, R7 and R8 each independently selected 5 from the group consisting of hydrogen and methyl. 76. The compound of claim 66 wherein m=l. R1, R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, CF3, OR20, and C1.2 alkyl; f 7 8 R , R and R are each hydrogen; 10 R9, R10, R1', R12, R13, R14, R15 and R16 are each independently selected from the group consisting of hydrogen and C1.2 alkyl, or wherein R9 and R10 may together form a carbonyl; 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 15 substituents selected from the group consisting of halo, CF3, OR20, and aryl, wherein the optional aryl substituent is optionally substituted with from 1 to 2 substituents selected from the group consisting of halo, phenyl, CF3, OR20, and Cm alkyl; and 70 R is selected from the group consisting of H and C1-3 alkyl. 77. The compound of claim 76 wherein R24 is selected from the group consisting 20 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 1 substituent selected from the group consisting of halo, CF3, OR20, and aryl, wherein the optional aryl substituent is optionally substituted with from 1 to 2 70 substituents selected from the group consisting of halo, phenyl, CF3, OR , and Cm alkyl. 25 78. The compound of claim 66 wherein 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 1 substituent selected from the group consisting of halo, CF3, OR20, and aryl wherein the optional aryl substituent is optionally substituted with from 1 to 2 30 substituents selected from the group consisting of halo, phenyl, CF3, OR20, and Cm alkyl. 79. The compound of claim 76 wherein R1, R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, halo, CF3, OCH3, and methyl. 96 intellectual PROPERTY office of n.z. 1 7 APR 2003 received 80. The compound of claim 76 wherein R1, R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, and methyl. 81. The compound of claim 76 wherein R11 and R15 are each selected from the group consisting of hydrogen and methyl, R9, R10, R12, R13, R14 and R16 are each hydrogen, or 5 R9 and R10 may together form a carbonyl. 82. A compound of claim 66 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; 10 R11 and R15 are each selected from the group consisting of hydrogen and methyl, R9, R10, R12, R13, R14 and R16 are each hydrogen, and R9 and R10 may together form a carbonyl; 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 1 substituent selected 15 from the group consisting of halo, CF3, OR20, and aryl, wherein the optional aryl substituent is optionally substituted with from 1 to 2 substituents selected from the group consisting of halo, phenyl, CF3, OR20, and Cm alkyl; and R20 is methyl or H. 83. The compound of claim 82 wherein R24 is alkyl having from 1 to 6 carbon 20 atoms or cycloalkyl. 84. The compound of claim 82 wherein R24 is a fused phenylcycloalkyl that is optionally substituted with 1 substituent selected from the group consisting of halo, CF3, OR20, and aryl. 85. The compound of claim 82 wherein R24 is phenylmethyl when the phenyl 25 substituent is optionally substituted with from 1 to 2 substituents selected from the group consisting of halo, CF3, OR20, Cm alkyl, and phenyl. 86. The compound of claim 82 wherein R2, R3, and R4 are each hydrogen and R1 and R5 are each methyl. 87. The compound of claim 66 wherein m=l; 30 R1, R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen or methyl; R6, R7 and R8 each hydrogen; R9, R10, R11, R12, R13, R14, R15 and R16 are each hydrogen; and 97 INTELLECTUAL PROPF' OFFICE OF N.Z. 1 7 APR 2003 receive! R24 is selected from the group consisting of alkyl having from 1 to 6 carbon atoms, cycloalkyl having from 4 to 6 carbon atoms, and fused phenylcycloalkyl wherein the phenyl of the fused phenylcycloalkyl is optionally substituted with from 1 to 2 substituents selected from the group consisting of halo, CF3, OH, methyl, and aryl, wherein the optional aryl 5 substituent is optionally substituted with from 1 to 2 substituents selected from the group consisting of halo, CF3, OH, C1-2 alkyl, and phenyl. 88. The compound of claim 66 selected from the group consisting of substituted piperazine compound selected from the group consisting of 2-({2-[4-(3-isopropoxy-2-hydroxypropyl)piperazinyl]- N-( {2,6-dimethylphenyl)acetamide; N-(2,6-dimethylphenyl)-2-10 [4-(2-hydroxy-3-indan-2-yloxypropyl)piperazinyl]acetamide; N-(2,6-dimethylphenyl)-2- {4-[2-hydroxy-3-(phenylmethoxy)propyl]piperazinyl} acetamide, 2-( {2-[4-(3-cyclopentyloxy-2-hydroxypropyl)piperazinyl]- N-( {2,6-dimethylphenyl)acetamide, 2-( {2-[4-(3-cyclohexyloxy-2-hydroxypropyl)piperazinyl]- N-( {2,6-dimethylphenyl)acetamide, 2-[4-(3- {[4-(tert-butyl)phenyl]methoxy}-2-hydroxypropyl)piperazinyl]-N-(2,6-dimethylphenyl)acetamide, N-15 (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-[(2-20 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)-2-25 (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- 30 (cyclohexylmethoxy)-2-hydroxypropyl]piperazinyl} acetamide, and N-(2,6-dimethylphenyl)-2-(4-{3-[(4-fluorophenyl)methoxy]-2-hydroxypropyl}-3,3-dimethylpiperazinyl)acetamide. 98 INTELLECTUAL PROPERTY OFFICE OF N.Z. 29 JAN 2004 RECEIVED 89. A use of a therapeutically effective amount of a compound of claim 1 or 2 or 34 or 66 in the manufacture of a medicament for protecting skeletal muscles against damage resulting from trauma, protecting skeletal muscles subsequent to muscle or systemic diseases, treating shock conditions, preserving donor tissue and organs use in transplants, and treating cardiovascular diseases in a mammal in need thereof. 5 90. A use of claim 89 wherein the cardiovascular disease is selected from the group consisting of atrial and ventricular arrhythmias, Prinzmetal's (variant) angina, stable angina, exercise induced angina, congestive heart disease, and myocardial infarction. 91. A use of claim 89 wherein the therapeutically effective amount ranges from about 0.01 to about 100 mg/kg weight of the mammal. 10 92. A use of claim 89 wherein the mammal is a human. 93. A pharmaceutical composition comprising the compound of claim 1 or 2 or 3 or 34 or 66 and one or more pharmaceutical excipients. 94. The pharmaceutical composition of matter of claim 93 wherein the pharmaceutical composition is in the form of a solution. 15 95. The pharmaceutical composition of matter of claim 93 wherein the pharmaceutical composition is in a form selected from the group consisting of a tablet and a capsule. 96. A substituted piperazine compound as claimed in claim 1 substantially as herein described with reference to any example thereof. 97. A substituted piperazine compound as claimed in claim 34 substantially as herein described with reference to any examples thereof. 98. A substituted piperazine compound as claimed in claim 66 substantially as herein described with reference to any example thereof. 99. A use as claimed in claim 89 substantially as herein described with reference to any example thereof. 100. A pharmaceutical composition as claimed in claim 93 substantially as herein described with reference to any example thereof. II® ©IF CHAM 99 INTELLECTUAL PROPERTY OFFICE OF N.Z. 29 JAN 2004 received </div>