CA2345108A1 - Substituted n-aliphatic-n-aromatic tertiary-heteroalkylamines useful for inhibiting cholesteryl ester transfer protein activity - Google Patents

Substituted n-aliphatic-n-aromatic tertiary-heteroalkylamines useful for inhibiting cholesteryl ester transfer protein activity Download PDF

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CA2345108A1
CA2345108A1 CA002345108A CA2345108A CA2345108A1 CA 2345108 A1 CA2345108 A1 CA 2345108A1 CA 002345108 A CA002345108 A CA 002345108A CA 2345108 A CA2345108 A CA 2345108A CA 2345108 A1 CA2345108 A1 CA 2345108A1
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group
methyl
fluoro
amino
trifluoro
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James A. Sikorski
Richard C. Durley
Margaret L. Grapperhaus
Deborah A. Mischke
Emily J. Reinhard
Barry L. Parnas
Melvin L. Rueppel
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Monsanto Co
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    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/08—Bridged systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
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    • C07C215/12—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic the nitrogen atom of the amino group being further bound to hydrocarbon groups substituted by hydroxy groups
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    • C07C217/14—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring
    • C07C217/18—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted
    • C07C217/20—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted by halogen atoms, by trihalomethyl, nitro or nitroso groups, or by singly-bound oxygen atoms
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    • C07C217/28—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines
    • C07C217/30—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines having the oxygen atom of at least one of the etherified hydroxy groups further bound to a carbon atom of a six-membered aromatic ring
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    • C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C217/56—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms
    • C07C217/58—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms with amino groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain
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    • C07C217/80—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings
    • C07C217/82—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings of the same non-condensed six-membered aromatic ring
    • C07C217/90—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings of the same non-condensed six-membered aromatic ring the oxygen atom of at least one of the etherified hydroxy groups being further bound to a carbon atom of a six-membered aromatic ring, e.g. amino-diphenylethers
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Abstract

The invention relates to substituted N-Aliphatic-N-Aromatic tertiary-Heteroalkylamine compounds useful as inhibitors of cholesteryl ester transfer protein (CETP; plasma lipid transfer protein-I) and compounds, compositions and methods for treating atherosclerosis, dyslipidemia, and other coronary artery disease.

Description

Substituted N-Aliphatic-N-Aromatictertiary-Heteroalkylamines Useful for Inhibiting Cholesteryl Ester Transfer Protein Activity This invention is in the field of treatin? cardiovascular disease, and specifically relates to compounds, compositions and methods for treating atherosclerosis and other coronary artery disease. More particularly. the 10 invention relates to substituted N-Aliphatic-N-Aromatictertian~-Heteroalkylamine compounds that inhibit cholesteryl ester transfer protein (CETP), also known as plasma lipid transfer protein-I.
BACKGROUND OF THE INVENTION

Numerous studies have demonstrated that, a low plasma concentration of high density lipoprotein (HDL) cholesterol is a powerful risk factor for the development of atherosclerosis (Barter and Rye, Atherosclerosis. 121, 1-12 ( 1996)). HDL is one of the major classes of lipoproteins that function in the 20 transport of lipids through the blood. The major lipids found associated with HDL include cholesterol, cholesteryl ester, triglycerides, phospholipids and fatty acids. The other classes of lipoproteins found in the blood are low density lipoprotein (LDL) and very low density lipoprotein (VLDL). Since low levels of HDL cholesterol increase the risk of atherosclerosis, methods for 25 elevatin' plasma HDL cholesterol would be therapeutically beneficial for the treatment of atherosclerosis and other diseases associated with accumulation of lipid in the blood vessels. These diseases include, but are not limited to, coronary heart disease, peripheral vascular disease, and stroke.
Atherosclerosis underlies most coronary artery disease (CAD), a major 30 cause of morbidity and mortality in modern society. High LDL cholesterol (above 180 md/dl) and low HDL cholesterol (below 35 mg/dl) have been shown to be important contributors to the development of atherosclerosis.
Other diseases, such as peripheral vascular disease, stroke, and hypercholesterolaemia are negatively affected by adverse HDL/L.DL ratios.
35 Inhibition of CETP by the subject compounds is shown to effectively modify plasma HDLILDL ratios, and to check the progress andior formation of these diseases.
CETP is a plasma protein that facilitates the movement of cholesteryl esters and trigiycerides between the various lipoproteins in the blood (Tall, J.
5 Lipid Res., 34, 12»-74 ( 1993)). The movement of cholesteryi ester from HDL to LDL by CETP has the effect of lowering HDL cholesterol. It therefore follows that inhibition of CETP should lead to elevation of plasma HDL
cholesterol and lowering of plasma LDL cholesterol, thereby providing a therapeutically beneficial plasma lipid profile (McCarthy. 6ledicinal Res.
10 Revs., 13, 139-59 ( 1993); Sitori, Pharmac. Ther., 67,443-47 ( 1995)). This exact phenomenon was first demonstrated by Swenson et al., (J. Biol. Chem., 264, 14318 ( i989)) with the use of a monoclonal antibody that specifically inhibited CETP. In rabbits, the antibody caused an elevation of the plasma HDL cholesterol and a decrease in LDL cholesterol. Son et al. (Biochim.
15 Biophys. Acta 79~. 743-480 ( 1984)), Morton et al. (J. Lipid Res. 35, 836-847 (1994)) and Tollefson et aI. (Am. J. Physiol., ZSS, (Endocrinol. Metab.
18, E894-E902 ( 1988))) describe proteins from human plasma that inhibit CETP. U.S. Patent x,519,001, issued to Kushwaha et al., describes a 36 amino acid peptide derived from baboon apo C-1 that inhibits CETP activity.
20 Cho et al. (Biochim. Biophys. Acta 1391, 133-144 (1998)) describe a peptide from hog plasma that inhibits human CETP. Bonin et al. (J. Peptide Res., 51, 216-225 { 1998)) disclose a decapeptide inhibitor of CETP. A depsipeptide fungal metabolite is disclosed as a CETP inhibitor by Hedge et al. in Bioarg.
Med. Chem. Lett., 8, 1277-80 ( 1998).
25 There have been several reports of non-peptidic compounds that act as CETP inhibitors. Barrett et al. {J. Am. Chem. Soc., 188, 7863-63 ( 1996)) and Kuo et al. (J. Am. Chem. Soc., 117, 10629-34 ( 1990) describe cyclopropane-containing CETP inhibitors. Pietzonka et al. (Bioorg. h~led.
Chem. Lett, 6, 1951-54 ( 1996)j describe phosphonate-containing analogs of 30 cholesteryl ester as CETP inhibitors. Coval et al. (Bioorg. ~yled. Chern.
Lett., 5, 605-610 ( 1995)) describe Wiedendiol-A and -B, and related sesquiterpene compounds as CETP inhibitors. Japanese Patent Application No. 10287662-A
describes polycyclic, non-amine containing, polyhydroxylic natural compounds possessing CETP inhibition properties. Lee et al. (J. Antibiotics, 35 49, 693-96 ( 1996)) describe CETP inhibitors derived from an insect fungus.
Buseh et al. (Lipids, 25, 216-220, ( 1990)) describe cholestervl acetyl bromide as a CETP inhibitor. Morton and Zilversmit (J. Lipid Res., 3~. 836-47 ( 1982)) describe that p-chloromercuriphenyl sulfonate, p-hydroxymercuribenzoate and ethyl mercurithiosalicylate inhibit CETP.
Connolly et al. (Biochem. Biophys. Res. Comm. 223, 42-47 ~ 1996)) describe 5 other cysteine modification reagents as C)rTP inhibitors. Xia et al.
describe _ 1,3,5-triazines as CETP inhibitors (Bioora. Med. Chem. Lett., 6, 919-22 ( 1996)). Bisgaier et al. (Lipids, 29, 81 I-8 ( 1994)) describe 4-phenyl-5-tridecyl-4H-1,2,4-triazole-thiol as a CETP inhibitor. Oomura ct al. disclose non-peptidic tetracyclic and hexacyclic phenols as CETP inhibitors in Japanese 10 Patent Application No. 10287662. In WO Patent Application No. 09914204, Sikorski describes 1,2,4-triazolylthiols useful as chIolesteryl ester transfer protein inhibitors.
Some substituted heteroalkylamine compounds are known. In European Patent Application No. 796846, Schmidt et al. describe 2-aryl-15 substituted pyridines as cholesteryl ester transfer protein inhibitors useful as cardiovascular agents. One substitutent at C3 of the pyridine ring can be an hydroxyalkyl group. In European Patent Application No. 801060, Dow and Wright describe heterocyclic derivatives substituted with an aldehyde addition product of an alkylamine to afford 1-hydroxy-1-amines. These are reported to 2 0 be ~3-adrenergic receptor agonists useful for treating diabetes and other disorders. In Great Britain Patent Application No. 230566, Fisher et al.
disclose 3-agonist secondary amino alcohol substituted pyridine derivatives useful for treating several disorders including cholesterol levels and artherosclerotic diseases. In European Patent Application No. 818448, 25 Schnudt et al. describe tetrahydroquinoline derivatives as chlolesteryl ester transfer protein inhibitors. European Patent Application No. 818197, Schmek et al. describe pyridines with fused heterocycles as cholesteryl ester transfer protein inhibitors. Brandes et al. in German Patent Application No. 19627430 describe bicyclic condensed pyridine derivatives as cholesteryl ester transfer 30 protein inhibitors. In WO Patent Application No. 09839299, Mulier-Gliemann et al. describe quinoline derivatives as cholesteryl ester transfer protein inhibitors. U.S. Patent 2,700,686, issued to Dickey and Towne, describes N-(2-haloaikyl-2-hydroxyethyl)amines in which the amine is further substituted with either 1 to 2 aliphatic groups or one aromatic group and one aliphatic 35 group. U.S. Patent 2,700.686 further describes a process to prepare the N-(2-haloalkyl-2-hydroxyethyl)amines by reacting halogenated-1.2-epoxyalkanes with the corresponding aliphatic amines and N-alkylanilines and their use as dye intermediates.
SUMiVIARY OF THE INVENTION
The present invention provides a class of compounds that can be used to inhibit cholesten~1 ester transfer protein (CETP) activity and that have the 10 general structure:
R~~\
'X Ry5\
IZ
( H ) n ~~Q
R3 g 14 In another aspect , the present invention includes pharmaceutical 15 compositions comprising a pharmaceutically effective amount of the compounds of this invention and a pharmaceutically acceptable carrier.
In another aspect, this invention relates to methods of using these inhibitors as therapeutic agents in humans to inhibit cholesteryl ester transfer protein (CETP) activity, thereby decreasing the concentrations of low density 20 lipoprotein (LDL) and raising the level of high density lipoprotein (HDL), resulting in a therapeutically beneficial plasma lipid profile. The compounds and methods of this invention can aiso be used to treat dyslipidemia (hypoalphalipoproteinemia), hyperlipoproteinaemia (chylomicronemia and hyperapobetalipoproteinemia), peripheral vascular disease, 25 hypercholesterolaemia, atherosclerosis, coronary artery disease and other CETP-mediated disorders. The compounds can also be used in prophylactic treatment of subjects who are at risk of developin' such disorders. The compounds can be used to lower the risk of atherosclerosis. The compounds of this invention would be also useful in prevention of cerebral vascular 30 accident (CVA) or stroke. Besides being useful for human treatment. these compounds are also useful for veterinary treatment of companion animals.
exotic animals and farm animals such as primates. rabbits, pigs, horses, and the Gke.
DESCRIPTION OF THE INVENTION

The present invention relates to a class of compounds comprising substituted N-Aliphatic-N-Aromatict~rtiary-Heteroalkylamines which are beneficial in the therapeutic and prophylactic treatment of coronary artery disease as given in Formula I-W.A (also referred to herein as "aIicyclic/cyclic 10 aryl/heteroaryl heteroalkylamines"):
Rl ~X Ki 5\ /~
.Z
R1 ~~( H )'~ N'~ Q
R2 n Yi R3 R14 (I-WA) or a pharmaceutically-acceptable salt thereof, wherein;
15 n is an integer selected from 1 through ~;
A and Q are independently selected from the group consisting of -CH2(CR37R38)v'(CR33R34O-T'(CR35R36Ov H, AQ-1 i 6 AQ-2 ~ll % 31 R5~J ~K1~2 R~ Riow / 3 K ~ ~R32 R4/D1 /D2\Re and R ~B ~ / 4r,.'R

with the provisos that one of A and Q must be AQ-I and that one of A and Q
20 must be selected from the group consisting of AQ-2 and 'CH2(CR37R38w'(CR33R3~u-T-(CR35R36)w H;
T is selected from the group consisting of a single covalent bond, O. S.
S(O), S(O)2, C(R33)=C(R35), and C$C;
v is an integer selected from 0 through 1 with the proviso that v is 1 when any one of R~3, R34, RCS, and R36 is aryl or heteroaryl;
a and w are integers independently selected from 0 through 6;
A1 is C(R30);
Dl, D', J 1. J2 and K 1 are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more than one of Dl, D', Jl, J2 and Kl is a covalent bond, no more than one of D1, D2, J1, J2 and K1 is O, no more than one of Dl, D2, Jl, JZ and K1 is S, one of D1, D2, Jl, JZ and Kl must be a covalent bond when two of D1, D2, J1, J2 and K1 are O and S, and no more than four of D1, D2, Jl, J2 and K1 are N;
B l, B2, D3, D4, J3, J4 and K2 are independently selected from the Group consisting of C, C(R3~), N, O, S and a covalent bond with the provisos that no more than ~ of B l, B2, D3, D~, J3, J4 and K2 are a covalent bond, no more than t<vo of B 1, B2, D3, D;~, J3, J~ and K2 are O, no more than two of B 1, B2, D3, D4, 33, J,~ and K2 are S, no more than two of B l, B2, D3, D4, J3, J4 and K2 are simultaneously O and S, and no more than two of B1, B2, 2 0 D3, D4, J3, J4 and K2 are N;
B 1 and D3, D3 and 13, J3 and K2, K2 and J~, J,~ and D~, and D~
and B2 are independently selected to form an in-ring spacer pair wherein said spacer pair is selected from the jroup consisting of C(R33)=C(R35) and N=N
with the provisos that AQ-2 must be a ring of at least five contiguous members, that no more than two of the group of said spacer pairs are simultaneously C(R33)=C(R35), and that no more than one of the group of said spacer pairs can N=N unless the other spacer pairs is other than C(R~3 j=C{R3~), O, N, and S;
5 R16 is selected from the group consisting of hydrido, alkyl, acyl, aroyl, heteroaroyl, and trialkylsilyl;
X is selected from the group consisting of O, H, F, S, S(O), NH, N(OH), N(alkyl), and N(alkoxy) with the proviso that there is no R16 wherein X is H or F;
10 R1 is selected from the group consisting of haloalkyl, haloalkenyi, haloalkoxyalkyl, and haloalkenyloxyalkyl;
R2 is selected from the group consisting of hydrido, aryl, aralkyl, alkyl, alkenyl, alkenyloxyalkyl, haloalkyl, haloalkenyl, halocycloalkyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy, 15 halocycloalkoxyall'yl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalhyl, heteroaryl, dicyanoalkyl, and carboalkoxycyanoalkyl;
R3 is selected from the group consisting of hydrido, hydroxy, cyano, aryl, aralkyl, acyi, alkoxy, alkyl, alkenyl, alkoxyalkyl, heteroaryl, alkenyloxyalkyl, haloalkyl, haloalkenyl, haloalkoxy, haloaikoxyalkyl, 20 haloalkenyloxyalkyl, monocyanoalkyl, dicyanoalkyl, carboxamide, and carboxamidoalkyl;
Y is selected from a group consisting of a covalent single bond, (C(R14)2)q wherein q is an integer selected from 1 through 4 and (CH(R1~)b O-(CH(R1~)p wherein g and p are integers independently 25 selected from 0 through 2;
R14 is selected from the group consisting of hydrido, hydroxy, cyano, hydroxyalkyl, acyl, alkoxy, alkyl, alkenyl, alkynyl, alkoxyalkyl, haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, monocarboaikoxyalkyl, monocyanoalkyl, dicyanoalkyl.
carboalkoxycyanoalkyl, carboalkoxy, carboxamide. carboxamidoalkyl:
Z is selected from the group consisting of covalent single bond, (C(R 15)2)q wherein q is an integer selected from 1 through 2, and 5 (CH(R15))j-O-(CH(R15))k wherein j and k are integers independently selected from 0 through 2:
R15 is selected from the group consisting of hydrido, cyano, hydroxyalkyl, acyl, alkoxy, alkyl, alkenyl, alkynyl, alkoxyalkyl. haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyaikyl.
10 monocarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl. carboalkoxy, carboxamide. and carboxamidoalkyl:
R30 is selected from the group consisting of hydrido, alkoxy, alkoxyalkyl, halo, haloalkyl, alkylamino, alkylthio, alkylthioalkyl, alkyl, alkenyl, haloalkoxy, and haloalkoxyalkyl with the proviso that R30 is selected 15 to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen;
R30, when bonded to A 1, is taken together to form an intra-ring linear spacer connecting the A 1-carbon at the point of attachment of R30 to the point of bonding of a group selected from the group consisting of R 10, R 11 ~ R 12' 20 R31, and R32 wherein said intra-ring linear spacer is selected from the group consisting of a covalent single bond and a spacer moiety having from 1 through 6 contiguous atoms to form a ring selected from the group consisting of a cycloalkyi having from 3 through 10 contiguous members, a cycloalkenyl having from 5 through 10 contiguous members, and a heterocyclyI having 25 from 5 through 10 contiguous members;
R30, when bonded to A 1, is taken together to form an intra-ring branched spacer connecting the A 1-carbon at the point of attachment of R30 t°
the points of bonding of each member of any one of substituent pairs selected from the group consisting of subsitituent pairs R10 and RI 1, R10 and R31, R 10 and R3~, R 10 and R 1 ~, R 11 and R31. R 11 and R3~, R 11 and R 1 ~. R31 and R32, R31 and R12, and R3~ and R12 and wherein said intra-rind branched spacer is selected to form two rings selected from the group 5 consisting of cycloallyl having from 3 through 10 contiguous members, cycloalkenyl having from 5 through 10 continuous members, and heterocyclyl having from 5 through 10 contiguous members;
R4, R5, R6, R~. R8, R9. R 10, R 11. R 1 ~. R 13, R31, R3 ~ , R33.
R3,~, R3~, and R36 are independently selected from the group consisting of 10 hydrido, carboxy, heteroaralkylthio, heteroaralkoxy, cycloalkylamino, acylalkyl, acylalkoxy, aroylalkoxy, heterocyclyloxy, aralkylaryl, aralkyl, aralkenyl, aralkynyl, heterocyclyl, perhaloaralkyl, aralkylsulfonyl, aralkylsulfonylalkyl, aralkylsulfinyl, aralkylsulfinylalkyl, halocycloaikyl, halocycloalkenyl, cycloalkylsulfinyl, cycloalkylsulfinylallyl, 15 cycloalkylsulfonyl, cycloalkylsulfonylalkyl, heteroarylamino, N-heteroarylamino-N-alkylamino, heteroarylaminoalkyl,haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl, haloalkoxylaikyl, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy, cycloalkoxyalkyl, cycloalkylalkoxy, cyeloalkenyloxyalkyl, cyeloalkylenedioxy, halocycloalkoxy, 20 halocycloalkoxyalkyl, halocycloalkenyloxy, halocycloalkenyloxyalkyl, hydroxy, amino, thin, vitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, arylthioalkyl, heteroaralkoxyalkyl, alkylsulfinyl, alkylsulfinylalkyl, arylsulfinylalkyl, arylsulfonylalkyl, heteroarylsulfinylalkyl, heteroarylsulfonylalkyl, alkylsulfonyl, 25 alkylsulfonyialkyl, haloalkylsulfinylalkyl, haloalkylsulfonylalkyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyi amidosulfonyi, monoarylamidosulfonyl, arylsuifonamido, diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl, 30 heteroarylsulfonyl, heterocyclylsulfonyl, heterocyclylthio, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroara(kanoyl, haloalkanoyl, alkyl, aikenyl, alkynyl, alkenyloxy, aikenyloxyalky, alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkylalkanoyl, cycloalkenyl, lower cycloalkylalkyl, lower cycloalkenylalkyl, halo, haloalkyl, haloalkenyl, haloalkoxy, hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyt, hydoxyheteroaralkyl, haloalkoxyalkyl, aryl, heteroaralkynyl, aryloxy, aralkoxy, aryloxyalkyl, saturated heterocyclyl, 5 partially saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyi, arylalkenyl, heteroarylalkenyl, carboxyalkyl, carboalkoxy, alkoxycarboxamido. alkylamidocarbonylamido, arylamidocarbonylamido.
carboalkoxyalkyl, carboalkoxyalkenyl, carboaralkoxy, carboxamido, carboxamidoalkyl, cyano, carbohaloalkoxy, phosphono, phosphonoalkyl.
10 diaralkoxyphosphono, and diaralkoxyphosphonoalkyl with the provisos that R4~ R5~ R6, R7~ R8, R9, R 10, R 11, R 12, R 13, R31, R32 , R33, R34~ R3~, and R36 are each independently selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen, that no more than three of the R33 and R34 15 substituents are simultaneously selected from other than the group consisting of of hydrido and halo. and that no more than three of the R35 and R36 substituents are simultaneously selected from other than the group consistubg of hydrido and halo;
R9' R 10' R 11 ~ R 12' R 13 ~ R31 ~ and R32 are independently selected to 20 be oxo with the provisos that B 1, B2, D3, D4, J3, J4 and K2 are independently selected from the group consisting of C and S, no more than two of Rg, R10, R11, R12~ R13~ R31~ and R32 are simultaneously oxo, and that R9' R 10' R 11 ~ R 12' R 13 ~ R31 ~ and R32 are each independently selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the 25 divalent nature of sulfur, and the divalent nature of oxygen;
R4 and R5, Rj and R6, R6 and R~, R~ and R8, R9 and R10, R 10 and R 11 ~ R 11 ~d R31 ~ R31 and R3 ~. R32 and R 12, and R 12 and R 13 are independently selected to form spacer pairs wherein a spacer pair is taken together to form a linear moiety having from 3 through 6 contiguous atoms connecting the points of bonding of said spacer pair members to form a rind selected from the group consisting of a cycloalkenyl ring having ~ through 8 contiguous members, a partially saturated heterocyclyl ring having ~ through 8 contiguous members, a heteroaryl ring having ~ through 6 contiguous 5 members, and an aryl with the provisos that no more than one of the Croup consisting of spacer pairs R4 and R5, R~ and R6, R6 and R ~, and R~ and R8, are used at the same time and that no more than one of the group consisting of spacer pairs R9 and R 10, R 10 and R 11, R 11 and R31. R31 and R~2, R32 and R12, and R12 and R13 are used at the same time;
10 R9 and R 11, R9 and R 12, R9 and R 1 ~ , R9 and R31, R9 and R32~
R10 and R12, R10 and R13, R10 and R31, R10 and R32, R11 and R12. R11 and R13, R11 and R32, R12 and R31, R13 and R31, and R13 and R32 are independently selected to form a spacer pair wherein said spacer pair is taken together to farm a linear spacer moiety selected from the group consisting of a 15 covalent single bond and a moiety having from 1 through 3 contiguous atoms to form a ring selected from the group consisting of a cycloalkyl having from through 8 contiguous members, a cycloalkenyl having from ~ through 8 contiguous members, a saturated heterocyclyl having from 5 through 8 contiguous members and a partially saturated heterocyclyl having from 5 20 through 8 contiguous members with the provisos that no more than one of said group of spacer pairs is used at the same time:
R3~ and R38 are independently selected from the group consisting of hydrido, alkoxy, alkoxyalkyl, hydroxy, amino, thio, halo, haloalkyl, alkylamino, alkylthio, alkylthioalkyl, cyano, alkyl, alkenyl, haloalkoxy, and 25 haloalkoxyalkyl.

WO 00/18723 PC'T/US99/22123 In another embodiment of compounds of Formula I-WA, compounds are alcohols and have the Formula I-WO ( also referred to herein as "alicyclic/cyclic aryl/heteroaryl aminoalkanols"):
R 16\
\0 ,Z
R1~
~''~ , ~, / rr t ti j n R3 ( I -WO ) or a pharmaceutically acceptable salt thereof, wherein;
R16 is hydrido;
Rl, R2, R3, n, A, Y, Q, and Z arc dcfincd as given above for Formula I-WA.
In a more specific embodiment of compounds of Formula I-WO, compounds have the Formula 1-WOPA:
H\
Z
N/
~~(CH)~
R2 n R8 R~ ( I-WOPA) or a pharmaceutically acceptable salt thereof, wherein;
n is an integer selected from 1 through 2;
A is selected from the group consisting of C3-C8 alkyl, C3-C8 alkenyl> C3-C8 alkynyl, C3-C8 haloalkyl, C3-C8 haloalkenyl, C3-C6 alkoxy C 1-C2 alkyl, and C3-C8 hydroxyhaloalkyl, wherein each member of group A
may be optionally substituted at any carbon up to and including 6 atoms from the point of attachment of A to Z with one or more of the group consisting of R33, R34, R3~, and R3b with the provisos that R33, R34, R3~, and R36 must not be attached to the carbon directly linking A to Z and that R33, R34 R35, and R36 must be selected from other than aryl and heteroaryl when substituting the carbon 2 atoms from Z wherein Z is a single covalent bond;
5 R1 is selected from the Group consisting of haloalkyl and haloalkoxymethyl;
R2 is selected from the Group consisting of hydrido, aryl, alkyl, alkenyl, haloalkyl, haloalkoxy, haloalkoxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, and heteroaryl;
10 R3 is selected from the group consisting of hydrido, aryl, alkyl, atkenyi, haloalkyl, and haloalkoxyalkyl;
Y and Z are independently selected from the Group consisting of a covalent single bond, oxy and alkylene;
R4 and R8 are independently selected from the group consisting of 15 hydrido and halo;
R5, R6, and R~ are independently selected from the group consisting of hydrido, alkyl, halo, haloalkyl, haloalkoxy, aryl, alkylthio, arylamino, arylthio, aroyl, arylsulfonyl, aryloxy, aralkoxy, heteroaryloxy, alkoxy, aralkyl, cycloalkoxy, cycioalkylalkoxy, cycloalkylalkanoyl, heteroaryl, 2 0 cycloalkyl, haloalkylthio, hydroxyhaloalkyl, heteroaralkoxy, heterocyclyloxy, aralkylaryl, heteroaryloxyalkyl, heteroarylthio, and heteroarylsulfony(;
R4 and R5, R~ and R6, R6 and R~, and R~ and R8 are independently selected to form spacer pairs wherein a spacer pair is taken together to form a linear moiety having from 3 through 6 contiguous atoms connecting the points 2 5 of bonding of said spacer pair members to form a rind selected from the group consisting of a cycloalkenyl ring having 5 through 8 contiguous members, a partially saturated heterocyclyl ring having S through 8 contiguous members, a heteroaryl ring having 5 through 6 contiguous members, and an aryl with the proviso that no more than one of the group consisting of spacer pairs R4 and R5, R~ and R6, R6 and R~, and R~ and R$, is used at the same time;
R33~ R34~ R35- and R36 are independently selected from the ;roup group consisting of alkyl, halo, hydroxy, cyano, haloalkyl, haloalkoxy, aryl, 5 alkylthio, arylamino, arylthio, aroyl, arylsulfonyl, aryloxy, aralkoxy, heteroaryloxy, alkoxy, aralkyl, cycloalkoxy, cycloaiky(alkoxy, cycloalkylalkanoyl. heteroaryl, cycloalkyl, haloalkylthio, hydroxyhaloalkyl, heteroaralkoxy, heterocyclyloxy, aralkylaryl, heteroaryloxyalkyl, heteroarylthio, and heteroarylsulfonyl.

In another more specific embodiment of compounds of Formula I-WO, compounds have the Formula I-WOPC:
H\
Z

~~(CH)' R2 n '~ b (I-WOPC) 15 or a pharmaceutically acceptable salt thereof, wherein;
n is an integer selected from 1 through 2;
A is selected from the group consisting of C3-C 10 cycloalky l, C~-C 10 cycloalkenyl, C4-C9 saturated heterocyclyl, and C4-C9 partially saturated heterocyclyl, wherein each ring carbon may be optionally substituted with R30, 2 0 a ring carbon other than the ring carbon at ahe point of attachment of A
to Z
may be optionally substituted with oxo provided that no more than one ring carbon is substituted by oxo at the same time, ring carbon and nitrogen atoms adjacent to the carbon atom at the point of attachment may be optionally substituted with R9 or R13, a ring carbon or nitrogen atom adjacent to the R9 position and two atoms from the point of attachment may be substituted with Rl~, a ring carbon or nitrogen atom adjacent to the R13 positiorx and two atoms from the point of attachment may be substituted with R12, a ring carbon or nitrogen atom three atoms from the point of attachment and adjacent to the -5 Rl~ position may be substituted with R1 l, a ring carbon or nitrogen atom three atoms from the point of attachment and adjacent to the R12 position may be substituted with R32, and a ring carbon or nitrogen atom four atoms from the point of attachment and adjacent to the Rl 1 and R32 positions may be substituted with R31;
10 Rl is selected from the group consisting of haloalkyl and haloalkoxymethyl;
RZ is selected from the group consisting of hydrido, aryl, alkyl, alkenyl, haioalkyl, haloa(koxy, haloalkoxyalkyI, perhaIoaryl, perhaloaraikyl, perhaloaryloxyalkyl, and heteroaryl;
15 R3 is selected from the group consisting of hydrido, aryl, alkyl.
alkenyl, haloalkyl, and haloatkoxyalkyl;
Y and Z are independently selected from the group consisting of a covalent single bond, oxy and alkylene;
R4 and Rg are independently selected from the group consisting of 2 0 hydrido and halo;
R9 and R 13 is halo;
RS, R6, and R ~ are independently, selected from the group consisting of hydrido, alkyl, halo, haloalkyl, haloalkoxy, aryl, alkyIthio, arylamino, arylthio, aroyl, arylsulfonyl, aryloxy, aralkoxy, heteroaryloxy, alkoxy, 25 aralkyl, cycloaIkoxy, cycloalkylalkoxy, cycloalkylalkanoyl, heteroaryl, cycloalkyl, haioalkylthio, hydroxyhaloalkyl, heteroaralkoxy, heterocyclyloxy, aralkylaryl, heteroaryloxyalkyl, heteroarylthio, and heteroarylsulfonyl;
R4 and R5, RS and R~, R~ and R~, and R~ and R8 are independently selected to form spacer pairs wherein a spacer pair is taken together to form a linear moiety having from 3 through 6 contiguous atoms connecting the points of bonding of said spacer pair members to form a rind selected from the group 5 consisting of a cycloaIkenyl rind having 5 through 8 contiguous members. a partially saturated heterocyclyi ring having 5 through 8 contiguous members, a heteroaryl ring having ~ through 6 continuous members. and an aryl with the proviso that no more than one of the group consisting of spacer pairs Rø and R~, RS and R6, R6 and R~, and R~ and R8, is used at the same time;
10 R 10, R 11 ~ R 12. R31 ~ and R32 are independently selected from the group group consisting of alkyl, halo, haloalkyl, haloalkoxy. aryl, alkylthio, arylamino, arylthio, aroyl, arylsulfonyl, aryloxy, aralkoxy, heteroaryloxy, alkoxy, aralkyl, cycloalkoxy, cycloalkylalkoxy, cycloalkylalkanoyl, heteroaryl, cycloalkyl, haloalkylthio, hydroxyhaloalkyl, heteroaralkoxy, heterocyclyloxy, 15 aralkylaryl, heteroaryloxyalkyl, heteroarylthio, and heteroarylsulfonyl;
R30 is selected from the group consisting of alkoxy, alkoxyalkyl, halo, haloalkyl, alkylamino, alkylthio, alkylthioalkyl, alkyl, alkenyl> haloalkoxy, and haloalkoxyalkyl.
In another more specific embodiment of compounds of Formula I-WO, 20 compounds have the Formula I-WOHA:

R1 /~ ~N D l-~ 1 R? ,) Y ~ n:l K6 R
i D2-J
Rs R~ (I-WOHA) or a pharmaceutically acceptable salt thereof, wherein;
n is an integer selected from I through 2:
A is selected from the group consisting of C3-C8 alkyl, C3-C8 alkenyl, C3-C8 alky-nyl, C3-C8 haloalkyl, C3-C8 haloalkenyl, C3-C6 alkoxy C1-C2 alkyl, and C3-C8 hydroxyhaloalkyl, wherein each member of group A
may be optionally substituted at any carbon up to and including 6 atoms from the point of attachment of A to Z with one or more of the group consisting of a R33, R3~, R35, and R~6 with the provisos that R~~, R3;~, R~~, and R36 must not be attached to the carbon directly linking A to Z and that R33, R34, R35, and R36 must be selected from other than aryl and heteroaryl when substituting the carbon 2 atoms from Z wherein Z is a single covalent bond;
D1, D2, J 1, J2 and K 1 are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more than one of DI, D2. Jl, J2 and K1 is a covalent bond, no more than one of Dl, D2, J~, J2 and K1 is O, no more than one of D1, D'. J1. J' and K1 is S, one of D1, D2, J I, J2 and K1 must be a covalent bond when two of D1, D2, J1, J2 and K1 are O and S, and no more than four of D1, D2, J1, J2 and Kl are N;
R1 is selected from the group consisting of haloalkyl and haloalkoxymethyl;
R2 is selected from the group consisting of hydrido, aryl, alkyl, alkenyl, haloalkyl, haloalkoxy, haloalkoxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, and heteroaryl;
R3 is selected from the group consisting of hydrido, aryl, alkyl, alkenyl, haIoalkyl, and haloalkoxyalkyl;
Y and Z are independently selected from the group consisting of a covalent single bond, oxy and alkylene:
R4 and R8 are independently selected from the group consisting of hvdrido and halo:

WO 00/18723 PC'T/US99/22123 R5, R6, and R~ are independently selected from the croup consisting of hydrido, alkyl, halo, haloalkyl, haloalkoxy, aryl. alkylthio. arylamino, arylthio, aroyl, arylsulfonyl, aryloxy, aralkoxy, heteroaryloxy, alkoxy, aralkyl, cycloalkoxy, cycloalkylalkoxy, cycloalkylalkanoyl, heteroaryl.
5 cycloalkyl, haloalkylthio. hydroxyhaloalkyl, heteroaralkoxy, heterocyclyloxy.
aralkylaryl, heteroaryloxyalkyl, heteroarylthio, and heteroarylsulfonyl;
R4 and R~, R~ and R6, R6 and R~, and R~ and R8 are independently selected to form spacer pairs wherein a spacer pair is taken together to form a linear moiety having from 3 through 6 contiguous atoms connecting the points 10 of bonding of said spacer pair members to form a ring selected from the o oup consisting of a cycloalkenyl ring having 5 through 8 contiguous members, a partially saturated heterocyclyl ring having ~ through 8 contiguous members, a heteroaryl ring having 5 through 6 contiguous members, and an aryl with the proviso that no more than one of the group consisting of spacer pairs R~, and 15 R~, RS and R6, R6 and R~, and R~ and R8, is used at the same time;
F'33~ R34~ R35~ ~d R36 ~'e independently selected from the group group consisting of alkyl, halo, hydroxy, cyano, haloalkyl, ha(oalkoxy, aryl, alkylthio, arylamino, arylthio, aroyl, arylsulfonyl, aryloxy, aralkoxy, heteroaryloxy, alkoxy, aralkyl, cycloalkoxy, cycloalkylalkoxy, 20 cycloalkylalkanoyl, heteroaryl, cycloalkyl, haloalkylthio, hydroxyhaloalkyl, heteroaralkoxy, heterocyclyloxy, aralkylaryl, heteroaryloxyalkyl, heteroarylthio, and heteroarylsulfonyl.
In still another more specific embodiment of compounds of Formula I-WO, compounds have the Formula I-WOHC:
H
Z R4 RS _ Rl ~~ ~N n L~ 1 R2 tCHy n ~Y K

Rg R'7 ( I _ylOHC ) or a pharmaceutically acceptable salt thereof, wherein;
5 n is an integer selected from 1 through 2;
A is selected from the Group consisting of C3-C10 cycloalkyl, CS-C10 cycloalkenyl, C4-C9 saturated heterocyclyl, and C4--C9 partially saturated heterocyelyl, wherein each ring carbon may be optionally substituted with R30, a rind carbon other than the rind carbon at the point of attachment of A to Z
10 may be optionally substituted with oxo provided that no more than one rind carbon is substituted by oxo at the same time, rind carbon and nitrogen atoms adjacent to the carbon atom at the point of attachment may be optionally substituted with Rg or R13, a rind carbon or nitrogen atom adjacent to the Rg position and two atoms from the point of attachment may be substituted with 15 R1~, a ring carbon or nitrogen atom adjacent to the RI3 position and two atoms from the point of attachment may be substituted with RI2, a ring carbon or nitrogen atom three atoms from the point of attachment and adjacent to the R1~ position may be substituted with RI I, a ring carbon or nitrogen atom three atoms from the point of attachment and adjacent to the R12 position may 20 be substituted with R32, and a ring carbon or nitrogen atom four atoms from the point of attachment and adjacent to the RI 1 and R~2 positions may be substituted with R31;
Dl, D2, J1, J2 and Kl are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more 5 than one of D1. D~, Jl, J2 and Kl is a covalent bond, no more than one of Dl, D2, J1, J2 and K1 is O, no more than one of D1, D2, J1, J2 and K1 is S, one of Dl, D2, J 1, J2 and K1 must be a covalent bond when two of Dl, D2, J 1, J2 and KI are O and S, and no more than four of D1, D2, J 1, J2 and K1 are N;
10 R1 is selected from the group consisting of haloalkyl and haloalkoxymethyl;
R2 is selected from the group consisting of hydrido, aryl. alkyl, alkenyl, haloalkyl, haloalkoxy, haloalkoxyalkyl, perhaloaryl, perhaloarallyl, perhaloaryloxyalkyl, and heteroaryl;
15 R3 is selected from the group consisting of hydrido, aryl, alkyl, alkenyl, haloalkyl, and haloalkoxyalkyl;
Y and Z are independently selected from the group consisting of a covalent single bond, oxy and alkylene;
R4 and R8 are independently selected from the group consisting of 20 hydrido and halo;
R9 and R 13 is halo;
R5, R6, and R~ are independently selected from the group consisting of hydrido, alkyl, halo, haloalkyl, haloalkoxy, aryl, alkylthio, arylamino, arylthio, aroyl, arylsulfonyl, aryioxy, aralkoxy, heteroaryloxy, alkoxy, aralkyl, cycloalkoxy, cycloalkylalkoxy, cycloalkylalkanoyl, heteroaryl, cycloalkyl, haloalkylthio, hydroxyhaloalkyl, heteroaralkoxy, heterocyclyloxy, aralkylaryl, heteroaryloxyalkyl, heteroarylthio, and heteroarylsulfonyl;
R4 and R~, R~ and R6, R6 and R~, and R~ and R8 are independently selected to form spacer pairs wherein a spacer pair is taken together to form a linear moiety having from 3 through 6 contiguous atoms connecting the points of bonding of said spacer pair members to form a ring selected from the Group 5 consisting of a cycloalkenyl rind having 5 through 8 contiguous members. a partially saturated heterocyclyl ring having 5 through 8 contiguous members, a heteroaryl ring having 5 through 6 contiguous members, and an aryl with the proviso that no more than one of the group consisting of spacer pairs R,~ and R5, R~ and R6, R6 and R~, and R~ and R8, is used at the same time;
10 R 1 p, R 11 ~ R 12~ R31 ~ and R32 are independently selected from the group group consisting of alkyl, halo, haloalkyl, haloalkoxy, aryl, alkylthio, arytamino, arylthio, aroyl, arylsulfonyl, aryloxy, aralkoxy, heteroaryloxy, alkoxy, aralkyl, cycloalkoxy, cycloalkylalkoxy, cycloalkylalkanoyl, heteroaryl, cycloalkyl, haloalkylthio, hydroxyhaloalkyl, heteroaralkoxy, heterocyclyloxy, 15 aralkylaryl, heteroaryloxyalkyl, heteroarylthio, and heteroarylsulfonyl;
R3~ is selected from the group consisting of alkoxy, alkoxyalkyl, halo, haloalkyl, alkylamino, alkylthio, alkylthioalkyl, alkyl, alkenyl, haloalkoxy.
and haloalkoxyalkyl.
20 In a preferred specific embodiment of compounds of Formulas I-WOPA, I-WOHA, I-WOPC, and I-WOHC, n is the integer 1;
R1 is selected from the group consisting of trifluoromethyl, 1,1,2,2-tetrafluoroethoxymethyl, trifluoromethoxymethyl, difluoromethyl, 25 chlorodifluoromethyl, and pentafluoroethyl;
R2 is selected from the group consisting of hydrido, methyl, ethyl, propyl, butyl, vinyl, phenyl, 4-trifluoromethylphenyl, 1,1,2,2-tetrafluoroethoxymethyl, trifluoromethoxymethyl, difluoromethyl, pentafluoroethyl, trifluoromethyl, and 2,2,3,3,3-pentafluoropropyl;

WO 00/18723 PCTlUS99/22123-R3 is selected from the o oup consisting of hydrido, phenyl, 4-trifluoromethylphenyi, methyl, ethyl, vinyl, trifluoromethyl, trifluoromethoxymethyl, difluoromethyl, chlorodifluoromethyl, and pentafluoroethyl;
5 Y and Z are independently selected from the group consisting of a covalent single bond, oxy, and methylene with the proviso that only one of Y
and Z are simultaneously oxy;
R4 and R8 are independently selected from the group consisting of hydrido and fluoro;
10 RS is selected from the group consisting of 4-aminophenoxy, benzoyl, benzyl. benzyloxy. ~-bromo-2-fluorophenoxy, 4-bromo-3-fluorophenoxy.
4-bromo-2-nitrophenoxy, 3-bromobenzyloxy, 4-bromobenzyloxy, 4-bromophenoxy, ~-bromopyrid-2-yloxy> =L-butoxyphenoxy, chloro, 3-chlorobenzyl, 2-chlorophenoxy, 4-chlorophenoxy, 15 4-chloro-3-ethylphenoxy, 3-chloro-4.-fluorobenzyl, 3-chloro-4-fluorophenyl, 3-chloro-2-fluorobenzyloxy, 3-chlorobenzyloxy, 4-chlorobenzyloxy, 4-chloro-3-methylphenoxy, 2-chloro-4-fluorophenoxy, 4-chloro-2-fluorophenoxy, 4-chlorophenoxy, 3-chloro-4-ethylphenoxy, 3-chloro-4-methylphenoxy, 3-chloro-4-fluorophenoxy, 20 4-chloro-3-fluorophenoxy, 4-chlorophenylamino, 5-chloropyrid-3-yloxy, 2-cyanopyrid-3-yloxy, 4-cyanophenoxy, cyclobutoxy, cyclobutyl, cyclohexoxy, cyclohexylmethoxy, cyclopentoxy, cyclopentyl, cyclopentylcarbonyl, cyclopropyl, cyclopropylmethoxy, cyclopropoxy, 2,3-dichlorophenoxy, 2,4-dichlorophenoxy, 2,4-dichlorophenyl, 25 3,5-dichlorophenyl, 3,5-dichlorobenzyi, 3,4-dichlorophenoxy, 3,4-difluorophenoxy, 2,3-difluorobenzyloxy, 2.4--difluorobenzyloxy, 3,4-difluorobenzyloxy, 2,5-difluorobenzyloxy, 3,5-difluorophenoxy, 3,4-difluorophenyl, 3,5-difluorobenzyloxy, 4-difluoromethoxybenzyloxy, 2,3-difluorophenoxy, 2,4-difluorophenox'y, 2,~-difluorophenoxy, 30 3,5-dimethoxyphenoxy, 3-dimethylaminophenoxy, 3,~-dimethylphenoxy, 3,4-dimethylphenoxy, 3,4-dimethylbenzyl, 3,4-dimethylbenzyloxy, 3,5-dimethylbenzyloxy, 2,2-dimethylpropoxy, 1,3-dioxan-2-yl, 1,4-dioxan-2-yl, 1,3-dioxolan-2-yl, ethoxy, 4-ethoxyphenoxy, 4-ethylbenzyloxy, 3-ethylphenoxy, a--ethylaminophenoxy.
3-ethyl-~-methylphenoxy, fiuoro, 4-fiuoro-3-methylbenzyl.
4-fiuoro-3-methylphenyl, 4-fiuoro-3-methylbenzoyl, ~i-fiuorobenzyloxy, 2-fiuoro-3-methylphenoxy, 3-fiuoro-=1-methylphenoxy, 3-fluorophenoxy.
5 3-fiuoro-2-nitrophenoxy, 2-fiuoro-3-trifiuoromethylbenzyloxy, 3-fiuoro-5-trifiuoromethylbenzyloxy, 4-fiuoro-2-trifiuoromethylbenzyloxy, 4-fiuoro-3-trifiuoromethylbenzyioxy, 2-fluorophenoxy. =1-fiuorophenoxy, 2-fiuoro-3-trifiuoromethylphenoxy, 2-fiuorobenzyloxy, 4-fiuorophenylamino, 2-fluoro-4-trifiuoromethylphenoxy.
10 4-fiuoropyrid-2-yloxy, 2-furyl, 3-furyl, heptafiuoropropyl, 1,1,1,3,3,3-hexafluoropropyl, 2-hydroxy-3,3,3-trifluoropropoxy, 3-iodobenzyloxy, isobutyl, isobutylamino, isobutoxy, 3-isoxazolyl.
4-isoxazolyl, 5-isoxazolyl, isopropoxy, isopropyl. 4-isopropylbenzyioxy.
3-isopropylphenoxy, 4-isopropylphenoxy, isopropylthio, 15 ~I~-isopropyl-3-methylphenoxy, 3-isothiazolyl, 4-isothiazolyl, S-isothiazolyl, 3-methoxybenzyl, 4-methoxycarbonylbutoxy, 3-methoxycarbonylprop-2-enyloxy, 4-methoxyphenyl, 3-methoxyphenylamino, a--methoxyphenylamino, 3-methylbenzyloxy, ~-methylbenzyloxy, 3-methylphenoxy, 3-methyl-.~-methylthiophenoxy, 20 4-methylphenoxy, 1-methylpropoxy, 2-methylpyrid-5-yloxy, 4-methyIthiophenoxy, 2-naphthyloxy, 2-nitrophenoxy, 4-nitrophenoxy, 3-nitrophenyl, 4.-nitrophenylthio, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, pentafiuoroethyl, pentafiuoroethylthio, 2,2,3,3,3-pentafluoropropyl, 1,1,3,3,3-pentafluoropropyl, 1,1,2.2,3-pentafluoropropyl, phenoxy, 25 phenylamino, 1-phenylethoxy, phenylsulfonyl, 4-propanoylphenoxy, propoxy, 4-propylphenoxy, ~-propoxyphenoxy, thiophen-3-yl, sec-butyl, 4-sec-butylphenoxy,tert -butoxy, 3-tert -butylphenoxy, 4-tent -butylphenoxy, 1,1,2,2-tetrafluoroethoxy, tetrahydrofuran-2-yl, 2-(5,6,7,8-tetrahydronaphthyloxy), thiazol-2-yl, thiazol-.~-yl, thiazol-5-yl, 30 thiophen-2-yl, 2,3,x-trifluorobenzyloxy, 2,2,2-trifluoroethoxy, 2,2,2-trifluoroethyl, 3,3,3-trifluoro-2-hydroxypropyl, trifluoromethoxy, 3-trifiuoromethoxybenzyloxy, 4-trifluoromethoxybenzyloxy, 3-trifiuoromethoxyphenoxy, 4-trifiuoromethoxyphenoxy, trifluoromethyl, 3-trifluoromethylbenzyloxy, 4-trifluoromethylbenzyloxy, 35 2,4-bis-trifluoromethylbenzyloxy, 1,I-bis-trifluoromethyl-1-hydroxymethyl, WO 00118723 PC'T/US99/22123 3-trifluoromethylbenzyl. 3,5-bis-trifluoromethylbenzyloxy.
E-trifluoromethylphenoxy. 3-trifluoromethylphenoxy, 3-tritluoromethylphenyl, 3-trifluoromethylthiobenzyloxy, =L-trifluoromethylthiobenzyloxy, 2,3,4-trifluorophenoxy, 5 2,3,=1-trifluorophenU, 2,3,x-trifluorophenoxy, 3,4.x-trimethylphenoxy.
3-difluoromethoxyphenoxy, 3-pentafluoroethylphenoxy, 3-(1.1,2,2-tetrafluoroethoxy)phenoxy, 3-trifluoromethylthiophenoxy~. and trifluoromethylthio;
R6 is selected from the soup consisting of chloro, fluoro, hydrido, 10 pentafluoroethyl, 1,1,2,2-tetrafluoroethoxy. trifluoromethyl, and trifluoromethoxy;
R~ is selected from the croup consisting of hydrido, fluoro. and trifluoromethyl.
15 In a more preferred specific embodiment of compounds of Formulas I-WOPA, I-WOHA, I-WOPC, and I-WOHC, n is the integer 1;
R1 is selected from the group consisting of trifluoromethyl, 1.I,2,2-tetrafluoroethoxymethyl, trifluoromethoxymethyl, difluoromethyl, 20 chlorodifluoromethyl, and pentafluoroethyl;
R2 is selected from the ;coup consisting of hydrido, methyl, ethyl, phenyl, 4-trifluoromethylphenyl, trifluoromethoxymethyi, 1,1,2,2-tetrafluoroethoxymethyl, difluoromethyl, pentafluoroethyl, trifluoromethyl, and 2.2,3,3,3-pentafluoropropyl;
25 R3 is selected from the group consisting of hydrido, phenyl, 4-trifluoromethylphenyl, methyl, trifluoromethyl, difluoromethyl, and chlorodifluoromethyl;
Y and Z are independently selected from a covalent single bond and methylene;
30 R4 and R$ are independently selected from the Group consisting of hydrido and fluoro;

R~ is selected from the group consisting of benzyloxy. 5-bromo-2-fluorophenoxy, =i-bromo-3-fluorophenoxy, 3-bromobenzyloxy.
4-bromophenoxy, 4.-butoxyphenoxy, 3-chlorobenzyloxy, 2-chlorophenoxy, 4-chloro-3-ethylphenoxy, 4-chloro-3-methylphenoxy, 5 2-chloro-4-fluorophenoxy.4-chloro-2-fluorophenoxy.4-chlorophenoxy, 3-chioro-4-ethylphenoxy, 3-chloro-4--methylphenoxy, 3-chloro-4-fluorophenoxy, ~l-chloro-3-fluorophenoxy. =4-chlorophenylamino, ~-chloropyrid-3-yloxy, cyclobutoxy, cyclobutyl, cyclohexylmethoxy, cyclopentoxy, cyclopentyl, cyclopentylcarbonyl, cyclopropylmethoxy, 10 2,3-dichlorophenoxy, 2,=t-dichlorophenoxy, 2,4-dichlorophenyl, 3,5-dichlorophenyl, 3,5-dichlorobenzyl, 3,4-dichlorophenoxy, 3,4-difluorophenoxy,?,3-difluorobenzyloxy, 3,5-difluorobenzyloxy.
difluoromethoxy, 3,~-difluorophenoxy, 3,4-difluorophenyl, 2,3-difluorophenoxy> 2,4-difluorophenoxy, 2,~-difluorophenoxy, 15 3,5-dimethoxyphenoxy,3-dimethylaminophenoxy, 3,4-dimethylbenzyloxy, 3,5-dimethylbenzyloxy, 3,5-dimethylphenoxy, 3,4-dimethylphenoxy, 1,3-dioxolan-2-yl, 3-ethylbenzyloxy. 3-ethylphenoxy. 4-ethylaminophenoxy, 3-ethyl-5-methy(phenoxy, 4-fluoro-3-methylbenzyl, 4-fluorobenzyloxy, 2-fluoro-3-methylphenoxy, 3-fluoro-4-methylphenoxy, 3-fluorophenoxy, 20 3-fluoro-2-nitrophenoxy, 2-fluoro-3-trifluoromethylbenzyloxy, 3-fluoro-5-trifluoromethylbenzyloxy, 2-fluorophenoxy, 4-fluorophenoxy, 2-fluoro-3-trifluoromethylphenoxy, 2-fluorobenzyloxy, 4.-fluorophenylamino, 2-fluoro-=1-trifluoromethylphenoxy, 2-furyl, 3-furyl, heptafluoropropyl, 1,1,1,3,3,3-hexafluoropropyl, 25 2-hydroxy-3,3,3-trifluoropropoxy, isobutoxy, isobutyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, isopropoxy, 3-isopropylbenzyloxy, 3-isopropylphenoxy, isopropylthio, 4-isopropyl-3-methylphenoxy, 3-isothiazolyl, 4.-isothiazolyl, 5-isothiazolyl, 3-methoxybenzyl, 4-methoxyphenylamino, 3-methylbenzyloxy, 4-methylbenxyloxy, 3-methylphenoxy, 3-methyl-~-methylthiopllenoxy, 4-methylphenoxy, 1-methylpropoxy, 2-methytpyrid-~-yloxy, 4.-methylthiophenoxy, 2-naphthyloxy, 2-nitrophenoxy. 4-nitrophenoxy, 3-nitrophenyl, 2-oxazolyl, 4-oxazolyl, 5'oxazolyl, pentafluoroethyl, pentafluoroethylthio, 2,2,3,3,3-pentafluoropropyl, 1,1,3,3,3-pentafluoropropyl, 1,1,2,2,3-pentafluoropropyl, phenoxy, phenylamino, 1-phenylethoxy, WO 00/18723 PC'T/US99/22123 4-propylphenoxy. 4-propoxyphenoxy, thiophen-3-yl,tert -butoxy, 3-tert -butylphenoxy, 4-tent -butylphenoxy. 1,1.2,2-tetrafluoroethoxy, tetrahydrofuran-2-yl, 2-(5,6,7,8-tetrahydronaphthyloxy), thiazol-2-yl, thiazoi-4-yl, thiazol-5-yl, thiophen-2-yl, 2,2,2-trifluoroethoxy, 2,2,2-trifluoroethyl, 3,3,3-trifluoro-2-hydroxypropyl, trifluoromethoxy.
3-trifluoromethoxybenzyloxy, 4-trifluoromethoxybenzyloxy, 4-trifluoromethoxyphenoxy, 3-trifluoromethoxyphenoxy, trifluoromethyl, 3-trifluoromethylbenzyloxy, l,l-bis-trifluoromethyl-1-hydroxymethyl, 3-trifluoromethylbenzyl, 3,5-bis-trifluoromethylbenzyloxy, 10 4-trifluoromethylphenoxy.3-trifluoromethylphenoxy, 3-trifluoromethylphenyl, 2,3,4-trifluorophenoxy, 2,3,5-trifluorophenoxy, 3,4,~trimethylphenoxy, 3-difluoromethoxyphenoxy, 3-pentafluoroethylphenoxy. 3-( 1.1,2.2-tetrafluoroethoxy)phenoxy, 3-trifluoromethylthiophenoxy, 3-trifluoromethylthiobenzyloxy, and 15 trifluoromethylthio;
R6 is selected from the group consisting of chioro, fluoro, hydrido, pentafluoroethyl, 1,1,2,2-tetrafluoroethoxy, and trifluoromethyl:
R7 is selected from the Group consisting of hydrido, fluoro, and trifluoromethyl.

In an even more preferred specific embodiment of compounds of Formulas I-WOPA. I-WOHA, I-WOPC, and 1-WOHC, n is the integer 1;
Rl is selected from the Group consisting of trifluoromethyl, 25 chlorodifluoromethyl, and pentafluoroethyl;
R2 is hydrido, pentafluoroethyl, and trifluoromethyl;
R3 is selected from the group consisting of hydrido, methyl, trifluoromethyl, and difluoromethyl Y and Z are independently selected from the Group consisting of a 30 covalent single bond and methylene;
R4 and R8 are independently selected from the group consisting of hydrido and fluoro;
RS is selected from the group consisting of S-bromo-2-fluorophenoxy.
4-chloro-3-ethylphenoxy, cyclopentyl, 2,3-dichlorophenoxy, 3,4-dichlorophenoxy, 3-difluoromethoxyphenoxy, 3,S-dimethylphenoxy, 3.=1-dimethylphenoxy, 3-ethylphenoxy, 3-ethyl-S-methylphenoxy, 5 4-fluoro-3-methylphenoxy, 4-fluorophenoxy. 2-furyl, isobutyl, isopropoxy.
3-isopropylphenoxy, 3-methylphenoxy, pentafluoroethyl, 3-pentafluoroethylphenoxy, 3-tert -butylphenoxy, 1,1,2.2-tetrafluoroethoxy, 3-(1.1,2,2-tetrafluoroethoxy)phenoxy, 2-(x.6.7,8-tetrahydronaphthyloxy), trifluoromethoxy, 3-trifluoromethoxybenzyloxy,3-trifluoromethoxyphenoxy, 10 trifluoromethyl, 3-trifluoromethylbenzyloxy, 1,1-bis-trifluoromethyl-1-hydroxymethyl, trifluoromethylthio, and 3-trifluoromethylthiophenoxy;
R6 is selected from the group consisting of fluoro and hydrido;
R~ is selected from the group consisting of hydrido and fluoro.
15 In a preferred specific embodiment of compounds of Formulas I-WOPA and I-WOHA, A is selected from the group consisting of ethyl, 1-propenyl, propyl, isopropyl, butyl, 2-butenyl, 3-butenyl, 2-butynyl, sec-butyl, isobutyl, 2-methylpropenyi, 1-pentyl, 2-pentenyl, 3-pentenyl, 4-pentenyI, 2-pentynyl, 3-20 pentynyl, 2-pentyl, 1-methyl-2-butenyl, 1-methyl-3-butenyl, 1-methyl-2-butynyl, 3-pentyl, I-ethyl-2-propenyl, 2-methylbutyl, 2-methyl-2-butenyl, 2-methyl-3-butenyl. 2-methyl-3-butynyl. 3-methylbutyl, 3-methyl-2-butenyl, 3-methyl-3-butenyl, 1-hexyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 2-hexyl, 1-methyl-2-pentenyl. 1-methyl-3-25 pentenyl, 1-methyl-4-pentenyl, 1-methyl-2-pentynyl, 1-methyl-3-pentynyl, 3-hexyi, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 1-propyl-2-propenyl, 1-ethyl-2-butynyl, I-heptyl, 2-heptenyl, 3-heptenyl, 4--heptenyl, S-heptenyl, 6-heptenyl, 2-heptynyl. 3-heptynyl, 4--heptynyl, S-heptynyl, 2-heptyl, 1-methyl-2-hexenyl, 1-methyl-3-hexenyl, 1-methyl-4-hexenyl,'I-methyl-5-hexenyl, 1-methyl-2-30 hexynyl, 1-methyl-3-hexynyl, 1-methyl-4.-hexynyl, 3-heptyl. 1-ethyl-2-pentenyl, I-ethyl-3-pentenyl, 1-ethyl-4-pentenyl, I-butyl-2-propenyl, I-ethyt-2-pentynyl, 1-ethyl-3-pentynyl, i-octyl, 2-octenyl, 3-octenyl, 4.-octenyl, S-octenyl, 6-octenyl, 7-octenyl, 2-octynyl. 3-octynyl. 4--octynyl, S-octynyl, 6-octvnvl. 2-octvl, 1-methyl-2-heptenvl, 1-methyl-3-heptenvl. 1-methyl-4.-heptenyl. 1-methyl-~-heptenyl, 1-methyl-6-heptenyl, 1-methyl-2-heptynyl, 1-methyl-3-heptynyl. 1-methyl-4-heptenyl, 1-methyl-~-heptenyl, I-methyl-6-heptenyl, 1-methyl-2-heptenyl, 1-methyl-3-heptynyl, 1-methyl-:~-heptynyl, 1-methyl-5-heptynyl, 3-octyl, 1-ethyl-2-hexenyl, 1-ethyl-3-hexenyl, 1-ethyl-4-5 hexenyl, 1-ethyl-2-hexynyl, 1-ethyl-3-hexynyl, 1-ethyl-4-hexynyl, 1-ethyl-5-hexenyl, 1-pentyl-2-propenyl, 4-octyl, 1-propyl-2-pentenyl, 1-propyl-3-pentenyl, I-propyl-4-pentenyl, 1-butyl-2-butenyl, 1-propyl-2-pentynyl, 1-propyl-3-pentynyl, I-butyl-2-butynyl, 1-butyl-3-butenyl, 2,2-difluoropropyl.
4-trifluoromethyl-5,x,5-trifluoropentyl, 4-trifluoromethylpentyl, ~.~,6,6,6-10 pentafluorohexyl, 3,3,3-trifluoropropyl, 2-methoxyethyl, 2-ethoxyethyl, 2-propoxyethyl, 2-isopropoxyethyl, 2-butoxyethyl, 2-isobutoxyethyl, 2-sec-butoxyethyl, 2-pentoxyethyl, 2-hexoxyethyl, 3-methoxypropyl, 2-methoxyisopropyl. 3-ethoxypropyl. 2-ethoxyisopropyl, 3-propoxypropyl, 2-propoxyisopropyl. 3-isopropoxypropyl, 2-isopropoxyisopropyl, 3-15 butoxypropyl, 2-butoxyisopropyl, 3-isobutoxypropyl, 2-isobutoxyisopropyi, 3-pentoxypropyl, and 2-pentoxyisopropyl, wherein each member of group A
may be optionally substituted at any carbon up to and including 6 atoms from the point of attachment of A to Z with one or more of the group consisting of R33~ R34~ R35~ and R36 with the provisos that R33. R34, R3~~ and R36 20 must not be attached to the carbon directly linking A to Z and that R33, R35, and R36 must be selected from other than aryl and heteroaryl when substituting the carbon 2 atoms from Z wherein Z is a single covalent bond;
R33~ R34~ R3~~ and R36 are independently selected from the group consisting of cyano, hydroxy, 4-aminophenoxy, benzoyl, benzyl, benzyloxy, 25 S-bromo-2-fluorophenoxy, 4-bromo-3-fluorophenoxy, 4-bromo-2-nitrophenoxy, 3-bromobenzyloxy, 4-bromobenzyloxy, 4-bromophenoxy, ~-bromopyrid-2-yloxy, =4-butoxyphenoxy, chloro, 3-chlorobenzyt, 2-chlorophenoxy. 4-chlorophenoxy, 4-chloro-3-ethylphenoxy, 3-chloro-4-fluorobenzyl, 3-chloro-4-fluorophenyl, 30 3-chloro-2-fluorobenzyloxy, 3-chlorobenzyloxy, 4-chlorobenzyloxy, 4-chloro-3-methylphenoxy, 2-chloro-4-fluorophenoxy, 4-chloro-2-fluorophenoxy, 4-chlorophenoxy, 3-chloro-4-ethylphenoxy, 3-chloro-4-methylphenoxy, 3-chloro-4-fluorophenoxy, 4-chloro-3-fluorophenoxy, 4-chlorophenylamino, S-chloropyrid-3-yloxy.
2-cyanopyrid-3-yloxy, 4-cyanophenoxy, cyclobutoxy, cyclobutyl, cyclohexoxy, cyclohexylmethoxy, cyclopentoxy, cyclopentyl, cyclopentylcarbonyl, cyclopropyi, cyclopropyimethoxy, cyclopropoxy, 5 2,3-dichlorophenoxy, 2.4-dichlorophenoxy, 2,4-dichlorophenyl.
3,5-dichlorophenyl, 3,5-dichlorobenzyl, 3,4-dichlorophenoxy, 3,4-difluorophenoxy, 2,3-difluorobenzyloxy, 2,4-difluorobenzyloxy, 3,4-difluorobenzyloxy, 2,5-difluorobenzyloxy, 3,5-difluorophenoxy, 3,4-difluorophenyl. 3,5-difluorobenzyloxy, 4-difluoromethoxybenzyloxy, 10 2,3-difluorophenoxy, 2,4-difluorophenoxy, 2.5-difluorophenoxy, 3,5-dimethoxyphenoxy, 3-dimethylaminophenoxy, 3,5-dimethylphenoxy, 3,4-dimethylphenoxy, 3,4-dimethylbenzyl, 3,4-dimethylbenzyloxy, 3,5-dimethylbenzyloxy. 2,2-dimethylpropoxy, 1,3-dioxan-2-yl.
1,4-dioxan-2-yl, 1.3-dioxolan-2-yl, ethoxy, 4-ethoxyphenoxy, 15 4-ethylbenzyloxy, 3-ethylphenoxy, 4-ethylaminophenoxy, 3-ethyl-~-methyIphenoxy, fluoro, 4-fluoro-3-methylbenzyl, 4-fluoro-3-methylphenyl, 4-fluoro-3-methylbenzoyl, 4-fluorobenzyloxy, 2-fluoro-3-methylphenoxy, 3-fluoro-4-methylphenoxy, 3-fluorophenoxy, 3-fluoro-2-nitrophenoxy, 2-fluoro-3-trifluoromethylbenzyloxy, 20 3-fluoro-5-trifluoromethylbenzyloxy, 4-fluoro-2-trifluoromethylbenzyloxy, 4-fluoro-3-trifluoromethylbenzyloxy, 2-fluorophenoxy, 4-fluorophenoxy, 2-fluoro-3-trifluoromethylphenoxy, 2-fluorobenzyloxy, 4-fluorophenylamino. 2-fluoro-4-trifluoromethylphenoxy, 4-fluoropyrid-2-yloxy, 2-furyl, 3-furyl, heptafluoropropyl, 25 1,1,1,3,3,3-hexafluoropropyl, 2-hydroxy-3,3,3-trifluoropropoxy, 3-iodobenzyloxy, isobutyl, isobutylamino, isobutoxy, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, isopropoxy, isopropyl, 4-isopropylbenzyloxy, 3-isopropylphenoxy, 4-isopropylphenoxy, isopropylthio, =1-isopropyl-3-methylphenoxy, 3-isothiazolyl, 4-isothiazolyl, 30 5-isothiazolyl, 3-methoxybenzyl, 4-methoxycarbonylbutoxy, 3-methoxycarbonylprop-2-enyloxy, =1-methoxyphenyl, 3-methoxyphenylamino, 4-methoxyphenylamino, 3-methylbenzyloxy, 4-methylbenzyloxy, 3-methylphenoxy, 3-methyl-4-methylthiophenoxy, 4-methylphenoxy, 1-methylpropoxy, 2-methylpyrid-5-yloxy, 35 4-methylthiophenoxy, 2-naphthyloxy, 2-nitrophenoxy, 4-nitrophenoxy, 3-nitrophenyl. 4-nitrophenylthio. 2-oxazolyl. 4-o:cazoly. 5-oxazolyl.
pentatluoroethyl, pentafluoroethylthio, 2.2,3.3.3-pentailuoropropyl.
1,1,3,3,3-pentafluoropropyl, 1,1,2,2,3-pentafluoropropyl. phenoxv.
phenylamino, I-phenylethoxy, phenylsulfonyl, 4-propanoylphenow.
5 propoxy, :~-propylphenoxy, ~.-propoxyphenoxy, thiophen-3-yl, sic-butyl, ~-sec-butylphenoxy,tert -butoxy, 3-tort -butylphenoxy, =1-tort -butylphenow, -1,1.2,2-tetrafluoroethoxy, tetrahydrofuran-2-v1, -(~,6?,8-tetrahydronaphthyloxyj, thiazol-2-yl, thiazoi- r-yl. thiazol-5-yl.
thiopren-2-yl, 2,3.5-trit7uorobenzyloxy, 2,2.2-triflucrcethoxy.
10 2,2?-trifluoroethyl, 3,3,3-trifluoro-2-hydroxypropyl. triflueromethoxy, 3-trifluoromethoxvbenzyloxy, =4-trifluoromethoYybenzvloxv.
3-trifluoromethoxyphenoxy, 4-trifluoromethoxyphenoxy, trifluoromethyI, 3-trifluoromethylbenzyloxy, 4-trifluoromethylbenzvloxv.
2,4-.bis-trifluoromethylbenzyloxy, 1,1-bis-trifluoromethvl-1-hydroxymethyl.
15 3-trifluoromethylbenzyl, 3,~-bis-tritZuoromethylbenzyloxy, 4-trifluoromethylphenoxy, 3-trifluoromethylphenoxy, 3-trifluoromethylphenyl, 3-trifluoromethylthiobenzyloxy, 4-trifluoromethylthiobenzyloxy, 2,3,4-trifluorophenoxy, 2,3,4-trifluorophenyl, 2,3,5-trifluorophenoxy, 3,4,x-trimethylphenoxy, 20 3-difluoromethoxyphenoxy, 3-pentafluoroethylphenoxy.
3-(1,1,2,2-tetrafluoroethoxy)phenoxy, 3-trifluoromethylthiophenoYy, and trifluoromethvlthio.
In a preferred specific embodiment of compounds of Formulas I-25 WOPA and I-WOHA, A is selected from the group consisting of ethyl, 1-propenyl, propyl, isopropyl, butyl, 2-butenyl, 3-butenyl, sec-butyl, isobutvl, 2-methylpropenyl.
1-pentyl, 2-pentenyl. 3-pentenyl, 4-pentenyl, 2-pentyi. 1-methyl-2-butenyl. 1-methyl-3-butenyl, 3-pentyl, 1-ethyl-2-propenyl, 2-methylbutyl, 2-methyl-2-30 butenyl, 2-methyl-3-butenyl, 3-methylbutyl, 3-methyl ?-butenyl. 3-methyl-3-butenvl. 1-hexyl, 2-hexenyl, 3-hexenyl, 4-hexenyl. ~-hexenyl, 2-hexyl, 1-methyl-?-pentenyl, I-methyl-3-pentenyl, 1-methyl-4-pentenyl, 3-hexyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl. 1-propyl-2-propenyl. 1-heptyl, 2-heptenyl, 3-heptenyl, :~-heptenyl, 5-heptenyl. 6-heptenyl, ?-heptyl, i-methyl-2-hexenyl.
35 1-methyl-3-hexenyl, 1-methyl-4-hexenyl, 1-methyl-5-hexenyl.3-heptyl, I-ethyl-?-pentenyl, 1-ethyl-3-pcntr:nvl. 1-ethyl--I-pentem.l, 1-butt'-?-propenyl.
1-octyl, 2-octenyl, 3-octenyl. 4-octenyl. S-octenyl. 6-octenyl, 7-octenyl, 2-octyl, 1-methyl-2-heptenyl. 1-methyl-3-heptenyl. 1-methyl-:a-heptenyl, 1-methyi-5-heptenyl, 1-methyl-6-heptenyl, 1-methyl-.~-heptenyl, 1-methyl-6-heptenyt, 1-methyl-2-heptenyl, 3-octyl, 1-ethyl-2-hexenyt, 1-ethyl-3-hexenyl.
5 1-ethyl-4-hexenyl, 1-ethyl-S-hexenyl, 1-pentyl-2-propenyl, 4-octyl, 1-propyt-_ 2-pentenyl, 1-propyl-3-pentenyl, 1-propyt-4-pentenyl, 1-butyl-2-butenyl, 1-butyl-3-butenyl, 2,2-difluoropropyl, 4-trifluoromethyl-S,S,S-trifluoropentyl, ~1-trifluoromethylpentyl, S,S.6,6,6-pentafluorohexyl, and 3,3,3-trifluoropropyl, wherein each member of group A may be optionally 10 substituted at any carbon up to and including 6 atoms from the point of attachment of A to Z with one or more of the Group consisting of R33, R34 R3S, and R36 with the provisos that R33, R34, R3S. and R36 must not be attached to the carbon directly linking A to Z and that R33, R34, R3S, and R36 must be selected from other than aryl and heteroaryl when substituting the 15 carbon 2 atoms from Z wherein Z is a single covalent bond;
R33~ R34~ R3S~ and R36 are independently selected from the Group consisting of benzyloxy, S-bromo-2-fluorophenoxy, 4-bromo-3-fluorophenoxy, 3-bromobenzyloxy. 4-bromophenoxy,4-butoxyphenoxy, 3-chlorobenzyloxy, 20 2-chlorophenoxy, 4-chloro-3-ethylphenoxy, 4-chloro-3-methylphenoxy, 2-chloro-4-fluorophenoxy, 4-chtoro-2-fluorophenoxy, 4-chlorophenoxy, 3-chloro-4-ethylphenoxy, 3-chloro-4-methylphenoxy, 3-chloro-4-fluorophenoxy, 4-chloro-3-fluorophenoxy, 4-chlorophenylamino, 5-chloropyrid-3-yloxy, cyclobutoxy, cyclobutyl, cyclohexylmethoxy, 25 cyclopentoxy, cyclopentyl, cyclopentylcarbonyl, cyctopropylmethoxy, 2.3-dichlorophenoxy, 2,4-dichlorophenoxy, 2,4-dichlorophenyl, 3,S-dichiorophenyl, 3,S-dichlorobenzyl, 3.4-dichlorophenoxy, 3,4-difluorophenoxy,2.3-difluorobenzyloxy, 3,S-difluorobenzyloxy, difluoromethoxy, 3,S-difluorophenoxy, 3,4-difluorophenyl, 30 2,3-difluorophenoxy, 2,4-difluorophenoxy, 2,S-difluorophenoxy, 3,S-dimethoxyphenoxy,3-dimethylaminophenoxy, 3,4-dimethylbenzyloxy, 3,S-dimethylbenzyloxy, 3.S-dimethylphenoxy, 3,4-dimethylphenoxy, 1,3-dioxolan-2-yl, 3-ethylbenzyloxy, 3-ethylphenoxy, 4.-ethylaminophenoxy, 3-ethyl-5-methylphenoxy. 4-fluoro-3-methylbenzyl. :~-lluorobenzyloxy.
2-fluoro-3-methylphenoxy, 3-fluoro-4-methylphenoxy, 3-fluorophenoxy, 3-fluoro-2-nitrophenoxy, 2-fluoro-3-tritluoromethylbenzyioxy, 3-fluoro-~-trifluoromethylbenzyloxy, 2-fluorophenoxy, 4-fluorophenoxy.
5 2-fluoro-3-trifluoromethylphenoxy, 2-fluorobenzyloxy, 4-fluorophenylamino. 2-fluoro-.~-trifluoromethylphenoxy, 2-furyi, 3-furyl, heptafluoropropyl. 1,1,1,3,3,3-hexafluoropropyl, 2-hydroxy-3,3,3-trifluoropropoxy, isobutoxy, isobutyl. 3-isoxazolyl, 4-isoxazolyl, ~-isoxazolyl, isopropoxy. 3-isopropylbenzyloxy, IO 3-isopropylphenoxy, isopropylthio, ~.-isopropyl-3-methylphenoxy, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 3-methoxybenzyl, 4-methoxyphenylamino, 3-methylbenzyloxy, 4-methylbenxyIoxy, 3-methylphenoxy. 3-methyl-=1-methvithiophenoxv. .=1-methylphenoxy.
1-methylpropoxy. 2-methylpyrid-5-yloxy, 4-methylthiophenoxy, 15 2-naphthyloxy, 2-nitrophenoxy, 4-nitrophenoxy, 3-nitrophenyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, pentafluoroethyI, pentafluoroethylthio, 2,2,3,3,3-pentafluoropropyl, 1,1,3,3,3-pentafluoropropyl, 1,1,2,2.3-pentafluoropropyl, phenoxy, phenylamino, 1-phenylethoxy, 4-propylphenoxy, 4-propoxyphenoxy, thiophen-3-yl,tert -butoxy, 20 3-tent -butylphenoxy, 4-tert -butylphenoxy, 1,1,2.2-tetrafluoroethoxy, tetrahydrofuran-2-yl, 2-(5,6,7,8-tetrahydronaphthyloxy), thiazol-2-yl, thiazol-4-yl, thiazol-~-yl, thiophen-2-yl, 2,2,2-trifluoroethoxy, 2,2,2-trifluoroethyl, 3,3,3-trifluoro-2-hydroxypropyl, trifluoromethoxy, 3-trifluoromethoxybenzyloxy, 4-trifluoromethoxybenzyloxy, 25 4-trifluoromethoxyphenoxy, 3-trifluoromethoxyphenoxy, trifluoromethyl, 3-trifluoromethylbenzyloxy. 1,1-bis-trifluoromethyl-I-hydroxymethyl, 3-trifluoromethylbenzyl, 3,~-bis-trifluoromethylbenzyloxy, 4-trifluoromethylphenoxy, 3-trifluoromethylphenoxy.
3-trifluoromethylpheny(, 2,3.4-trifluorophenoxy, 2,3,5-trifluorophenoxy, 30 3,4,5-trimethylphenoxy, 3-difluoromethoxyphenoxy, 3-pentafluoroethy(phenoxy, 3-( 1,1.2.2-tet'rafluoroethoxy )phenoxy, 3-trifluoromethylthiophenoxy, 3-trifluoromethylthiobenzyloxy, and trifluoromethylthio.
35 In an even more preferred specific embodiment of compounds of Formulas I-WOPA and I-WOHA.
A is selected from the group consisting of 1-propenyi, propyl, isopropyl, butyl, 2-butenyl. 3-butenyl, sec-butyl, isobutyl, 2-methytpropenyl, 1-pentyt, 2-penteny, 3-penteny(, 4-pentenyl. 2-pentyl, 1-methyl-2-butenyl, 1-methyl-3-butenyl. 3-pentyl, I-ethyl-2-propenyl, 2-methylbutyl, 2-methyl-2-5 butenyl, 2-methyl-3-butenyl, 3-methylbutyl. 3-methyl-2-butenyl, 3-methyl-3-_ butenyl, 1-hexyl, 2-hexenyl, 3-hexenyl, 4-hexenyi, ~-hexenyl, 2-hexyl, 1-methyl-2-pentenyl. 1-methyl-3-pentenyl, 1-methyl-4-pentenyl.3-hexy(, I-ethyl-2-butenyl, 1-ethyl-3-butenyt, 1-propyl-2-propenyl. 1-ethyl-2-pentenyl.
1-ethyl-3-pentenyl. 1-ethyl-4-pentenyl, I-butyl-2-propenyl, 1-ethyl-2-hexenyl, ZO I-ethyl-3-hexenyl, I-ethyl-a-hexenyl, 1-ethyl-~-hexenyl, 1-pentyl-2-propenyl,l-propyl-2-pentenyl, 1-propyl-3-pentenyl, 1-propyl-4-pentenyl, I-butyl-2-butenyl, 1-butyl-3-butenyl, 2,2-difluoropropyt, 4-trifluoromethyl-~.~,5-trifluoropentyl. 4-trifluoromethylpentyl, ~.~,6.6,6-pentafluorohexyl, and 33.3-trifluoropropyl, wherein each member of group A may be optionally 15 substituted at any carbon up to and including 6 atoms from the point of attachment of A to Z with one or more of the group consisting of R33, R34~
R35, and R36 with the provisos that R33, R34, R35~ and R36 must not be attached to the carbon directly linking A to Z and that R33, R34, R3~, and R36 must be selected from other than aryl and heteroaryl when substituting the 20 carbon 2 atoms from Z wherein Z is a single covalent bond;
R33~ R34~ R35~ and R36 are independently selected from the group consisting of ~-bromo-2-fluorophenoxy, 4-chloro-3-ethylphenoxy, cyclopentyl, 2,3-dichlorophenoxy, 3,4-dichlorophenoxy, 3-difluoromethoxyphenoxy, 25 3,5-dimethylphenoxy, 3,4-dimethylphenoxy, 3-ethylphenoxy, 3-ethyl-5-methylphenoxy. 4-fluoro-3-methylphenoxy, 4-fluorophenoxy, 2-furyl, isobutyl, isopropoxy, 3-isopropylphenoxy, 3-methylphenoxy, pentafluoroethyi, 3-pentatluoroethylphenoxy, 3-tent -butylphenoxy, 1,1.2,2-tetrafl uoroethoxy, 3-( 1,1,2,2-tetrafl uoroethoxy jphenoxy, 30 2-(5,6,7,$-tetrahydronaphthyloxy),trifluoromethoxy, 3-trifluoromethoxybenzyloxy,3-trifluoromethoxyphenoxy, trifluoromethyl, 3-trifluoromethylbenzyloxy, 1,1-bis-trifluoromethyl-1-hydroxymethyl, trifluoromethytthio, and 3-trifluoromethylthiophenoxy.
In a preferred specific embodiment of compounds of Formulas f-WOHA and I-WOHC, DI, D2, Jl, J' and KI are independently selected from the group consistinj of C, N, O, S and a covalent bond to form the group consisting of 5 2-thienyl. 3-thienyl. 2-furyl. 3-furyl, 2-pyrrolvl. 3-pyrrolyl. 2-imidazolyl. ~l- ' imidazolyl, 3-pyrazolyl, 4-pyrazolyl, 1,2.=1-triazol-3-U, 1,2,=~-triazol-5-vl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-~-yl, 1,3,4-oxadiazol-3-yl, 1,3,=1-oxadiazol-~-yl, 3-isothiazolyl, ~-isothiazoiyl, ?-oxazolyl, 2-thiazolyl, 3-isoxazolyl, 5-isoxazolyl, 2-pyridyl, 3-pyridyi. :~-pyridyl, 2-pyrazinyi, 2-10 pyrimidinyl, 4-pyrimidinyl, s-pyrimidinyl, 3-pyridazinyl, .~-pyridazinyl, 1,3,5-triazin-2-yl, I.2.4-triazin-3-y(, 1.2,4-triazin-5-v. 1,2.4-triazin-6-yl.
1,2,3-triazin-4-yl, t-indolizinyl. 7-indolizinyl. I-isoquinolyl. and 2-quinolvl.
wherein a rind carbon atom adjacent to the carbon stem at the point of attachment may be optionally substituted with R4 or RS, a ring carbon atom 15 adjacent to the R4 position and two atoms from the point of attachment may be substituted with R~, a rind carbon atom adjacent to the R$ position and two atoms from the point of attachment may be substituted with R~. and a ring carbon atom three atoms from the point of attachment and adjacent to the R~
and R~ positions may be substituted with R6.

In a more preferred specific embodiment of compounds of Formulas I-WOHA and I-WOHC, Dl, D2, J l, J2 and Kl are independently selected from the group consisting of C. N, O, S and a covalent bond to form the group consisting of 25 2-thienyl. 3-thienyl, 2-furyi, 3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl. =1-imidazolyl, 3-pyrazolyl, 4-pyrazolyl, 2-oxazolyl. 2-thiazolyl, 3-isoxazolyl. ~-isoxazolyi, 2-pyridyl. 3-pyridyl. 4-pyridyl, 2-pyrazinyl, Z-pyrimidinyl, 4-pyrimidinyl, ~-pyrimidinyl. 3-pyridazinyl. 4-pyridazinyl. 1,3.x-triazin-2-yl.

indolizinyl, 7-indolizinyl, 1-isoquinolyl, and 2-quinolyl, wherein a rind carbon 30 atom adjacent to the carbon atom at the point of attachment may be optionally substituted with Ra or R~, a rind carbon atom adjacent to the R~ position and two atoms from the point of attachment may be substituted with R~, a rind carbon atom adjacent to the R8 position and two atoms from the point of attachment may be substituted with R-,, and a rind carbon atom three atoms from the point of attachment and adjacent to the R~ and R~ positions may be substituted with R6.
In an even more preferred specific embodiment of compounds of Formulas I-WOHA and I-WOHC, 10 Dl, D~, JI, J2 and K1 are independently selected from the group consisting of C, N, O, S and a covalent bond to form the group consisting of ?.-thienyl, 3-thienyl, 2-f uryl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, ~L-imidazolyl, 3-pyrazolyl, ~-pyrazolyl, 2-thiazolyl, 3-isoxazolyl, ~-isoxazolyl, ?-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrazinyl, 2-pyrirnidinyl, a-pyrimidinyl, 5-15 pyrimidinyl, 3-pyridazinyl, a.-pyridazinyl, and 1,3,5-triazin ~-yl, wherein a ring carbon atom adjacent to the carbon atom at the point of attachment may be optionally substituted with R~ or R8, a rind carbon atom adjacent to the R,~
position and two atoms from the point of attachment may be substituted with RS, a ring carbon atom adjacent to the R8 position and two atoms from the 2 0 point of attachment may be substituted with R~, and a rin, carbon atom three atoms from the point of attachment and adjacent to the R~ and R~ positions may be substituted with IZ6.
In a preferred specific embodiment of compounds of Formulas I-25 WOPC and 1-WOHC, A is selected from the Group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclopent-2-enyl, cyclopent-3-enyl, cyclohexyl, 4-methylcyclohexyl, ~-chloro-3-ethylphenoxycyclohexyl, 3-WO 00/1$723 PCT/US99/22123 trifluoromethoxypilenoxycyciohexy1. 3-trifluoromethylcyclohexyl. .~-trifluoromethylcyclohexyl, 3,~-bis-trifluoromethylcyclohexyl. adamantyl. 3-trilluoromethyladamantyl, norbornyl, 3-trifluoromethylnorbornyl, norbornenyl, 7-oxabicyclo[2.2.1 Jheptan-2-yl, bicyclo[3.1.0]hexan-6-yl, 5 cyclohex-2-enyl, evclohex-3-enyI, cycloheptyl, cyclohept-2-enyl, cyclohept-3=
enyi, cyclooctyl, cacloocl-2-enyl, cyclo~ct-3-enyl, cyc:luoc;l-=1-enyl, 2-morpholinyl, 3-morpholinyl, ~-+-morpholinyl, 1-piperazinyl. 2-piperazinyl, 1-piperidinyl, 2-piperidinyl. 3-piperidinyl. r-piperidinyl, 1-pyrrolidinyl. 2-pyrrolidinyl, 3-pyrrolidinyl. 2-dioxanyl. 2H-2-pyran y 1. 2H-3-pyranvl. 2H-4-10 pyranyl, 4H-2-pyranyl, 4H-3-pyranyl, 4H-~I-pyranyl. 2H-pyran-2-one-3-yl, 2H-pyran-2-one-~1-yl, 2H-pyran-2-one-~-yl, ~H-pyran-~I-one-2-yl, 4H-pyran-4-one-s-yl, 2-tetrahvdrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydropyranyl, 3-tetrahydropyranyl. .~-tetrahydropyranyl. 2-tetrahydrothienyl. and 3-tetrahydrothienyl, wherein each rind carbon may be optionally substituted with 15 R3~, a ring carbon other than the rind carbon at the point of attachment of A to Z may be optionall~~ substituted with oxo provided that no more than one ring carbon is substituted by oxo at the same time, rind carbon and nitrogen atoms adjacent to the carbon atom at the point of attachment may be optionally substituted with R9 or R13, a rind carbon or nitro?en atom adjacent to the Rg 2 0 position and two atoms from the point of attachment may be substituted with R1~, a rind carbon or nitrogen atom adjacent to the R13 position and two atoms from the point of attachment may be substituted with R12, a ring carbon or nitrogen atom three atoms from the point of attachment and adjacent to the Rl~ position may be substituted with R1 l, a ring carbon or nitrogen atom 25 three atoms from the point of attachment and adjacent to the R12 position may be substituted with R3', and a ring carbon or nitrogen atom four atoms from the point of attachment and adjacent to the R11 and R32 positions may be substituted with R31;
Rc~ and R13 are fluoro;
R1~ and RI' are independently selected from the Croup consisting of =l-aminophenoxy, benzoyl, benzyl. benzyloxy, ~-bromo-2-fluorophenoxy, G-bromo-3-fluorophenoxy, 4-bromo-2-nitrophenoxy. 3-bromobenzvloxy, 4-bromobenzyloxy. =1-bromophenoxy, 5-bromopyrid-2-yloxy, 5 4--butoxyphenoxy, chloro. 3-chlorobenzyl. 2-chlorophenoxy, 4-chlorophenoxy, 4-chloro-3-ethylphenoxy. 3-chloro-=1-fl uorobenzyl. 3-chioro-:l-fl uorophenyl.
3-chloro-2-fluorobenzyloxy, 3-chlorobenzyloxy, ~4--chlorobenzyloxy, 4-chloro-3-methylphenoxy, 2-chloro-~-fluorophenoxy, 10 4-chloro-2-fluorophenoxy, =1-chlorophenoxy, 3-chloro-.~.-ethylphenoxy, 3-chloro-=1-methylphenoxy, 3-chloro-4-fluorophenoxy, 4-chloro-3-fIuorophenoxy, a--chlorophenylamino, 5-chloropyrid-3-yloxy, 2-cyanopyrid-3-yloxy, 4-cyanophenoxy, cyclobutoxy, cyclobutyl, cyclohexoxy, cyclohexylmethoxy, cyclopentoxy, cyclopentyl, 15 cyclopentylcarbonyl, cyclopropyl, cyclopropylmethoxy, cyclopropoxy, 2,3-dichlorophenoxy, 2,4-dichlorophenoxy, 2,4-dichlorophenyl, 3,~-dichlorophenyl, 3,5-dichlorobenzyl, 3,4-dichlorophenoxy, 3,4-difluorophenoxy, 2,3-difluorobenzyioxy, 2,4-difluorobenzyloxy, 3,4-difluorobenzyloxy, 2,~-difluorobenzyloxy, 3,~-difluorophenoxy, 20 3,a.-difluorophenyl, 3,5-difluorobenzyloxy, 4-difiuoromethoxybenzyloxy, 2,3-difluorophenoxy, 2,4-difluorophenoxy, 2,5-difluorophenoxy, 3,~-dimethoxyphenoxy, 3-dimethylaminophenoxy, 3,5-dimethyiphenoxy, 3,4-dimethylphenoxy, 3,a-dimethylbenzyl, 3,4-dimethylbenzyloxy, 3,5-dimethylbenzyloxy, 2,2-dimethylpropoxy, 1.3-dioxan-2-yl, 25 1,4-dioxan-2-yl, 1,3-dioxolan-2-yl, ethoxy, 4-ethoxyphenoxy, 4-ethylbenzyloxy, 3-ethylphenoxy, 4--ethylaminophenoxy, 3-ethyl-~-methylphenoxy, fluoro, 4-fluoro-3-methylbenzyl, 4-fluoro-3-methylphenyl, 4.-fluoro-3-methy(benzoyl, 4-fluorobenzyloxy, 2-fluoro-3-methylphenoxy, 3-fluoro-=1-methylphenoxy. 3-fluorophenoxy, 30 3-fluoro-2-nitrophenoxy, 2-fluoro-3-trifluoromethylbenzyloxy, 3-fluoro-a-trifluoromethylbenzyloxy, 4--fluoro-2-trifluoromethylbenzyloxy, 4.-fluoro-3-trifluoromethylbenzyloxy, 2-fluorophenoxy, 4-fluorophenoxy, 2-fluoro-3-trifluoromethylphenoxy, 2-fluorobenzyloxy, 4-fluorophenylamino, 2-fluoro-4-trifluoromethylphenoxy, 35 4-fluoropyrid-2-yloxy, 2-furyl, 3-furyl, heptafluoropropyl, WO 00/1$723 PCT/US99/22123 1,1,1.3,3,3-hexafluoropropyl, 2-hydroxy-3,3,3-trifluoropropoxy, 3-iodobenzyloxy. isobutyl, isobutylamino, isobutoxy. 3-isoxazolyl.
4-isoxazolyl, ~-isoxazolyl, isopropoxy, isopropyl, 4-isopropylbenzyloxy, 3-isopropylphenoxy, :~-isopropylphenoxy, isopropylthio, 5 4-isopropyl-3-methylphenoxy, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 3-methoxybenzyl, 4-methoxycarbonylbutoxy.
3-methoxycarbonylprop-2-enyloxy, .~-methoxyphenyl, 3-methoxyphenylamino, 4-methoxyphenylamino. 3-methylbenzyloxy.
4-methylbenzyloxy, 3-methylphenoxy, 3-methyl-=i-methylthiophenoxy, 10 4-methylphenoxy, 1-methylpropoxy, 2-methylpyrid-5-yloxy, 4-methylthiophenoxy, 2-naphthyloxy, 2-nitrophenoxy. 4-.nitrophenoxy, 3-nitrophenyl, 4-nitrophenylthio. 2-oxazolyl, 4-oxazolyl. ~-oxazolyl, pentafluoroethyl, pentafluoroethylthio. 2.23.3.3-pentafluoropropyl.
1,1,3,3,3-pentafluoropropyl, 1,1,2.2,3-pentafluoropropyl, phenoxy, 15 phenylamino, 1-phenylethoxy, phenylsulfonyl, 4-propanoylphenoxy, propoxy, 4-propylphenoxy, 4-propoxyphenoxy, thiophen-3-yl, sec-butyl, 4-sec-butylphenoxy,tert -butoxy, 3-tort -butylphenoxy, =1-tort -butylphenoxy, 1,1,2,2-tetrafluoroethoxy, tetrahydrofuran-2-yl, 2-(5,6,7,8-tetrahydronaphthyloxy), thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, 20 thiophen-2-yl, 2,3,5-trifluorobenzyloxy, 2,2,2-trifluoroethoxy, 2,2,2-trifluoroethyl> 3,3,3-trifluoro-2-hydroxypropyl, trifluoromethoxy, 3-trifluoromethoxybenzyloxy, 4-trifluoromethoxybenzyloxy, 3-trifluoromethoxyphenoxy, 4-trifluoromethoxyphenoxy, trifluoromethyl, 3-trifluoromethylbenzyloxy, 4-trifluoromethylbenzyloxy, 25 2,4-bis-trifluoromethylbenzyioxy.l,l-bis-trifluoromethyl-1-hydroxymethyl>
3-trifluoromethylbenzyl, 3,5-bis-trifluoromethylbenzyloxy.
4-trifluoromethylphenoxy, 3-trifluoromethylphenoxy, 3-trifluoromethyiphenyl, 3-trifluoromethylthiobenzyloxy, .4-trifluoromethylthiobenzyloxy, 2,3,4-trifluorophenoxy, 30 2,3,4-trifluorophenyl, 2,3,5-trifluorophenoxy, 3,4,5-trimethylphenoxy, 3-difluoromethoxyphenoxy. 3-pentatluoro2thylphenoxy, 3-(1,1,2,2-tetrafluoroethoxy)phenoxy, 3-trifluoromethylthiophenoxy, and trifluoromethylthio;
R 11, R~ I , and R32 are independently selected from the Group consisting of chloro, fluoro, hydrido, pentafluoroethyl, 1,1,2,2-tetrafluoroethoxy, trifluoromethyl, and trifluoromethoxy:
R30 is selected from the group consisting of chloro, 5 ethoxy, ethyl, fluoro, heptaftuoropropyl, 1,1,1,3,3,3-hexafluoropropyl, isobutyl, isobutoxy, isopropoxy, isopropyl, isopropylthio, methyl, propyl, pentafluoroethyl.2,2,3,3,3-pentafluoropropyl, 1,1,3,3,3-pentafluoropropyl, 1,1,2,2.3-pentafluoropropyl, propoxy, sec-butyl, tort-butoxy, 1.1,2.2-tetrafluoroethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trifluoroethyl, 10 trifluoromethoxy, and trifluoromethyl.
In a more preferred specific embodiment of compounds of Formulas I-WOPC and I-WOHC, A is selected from the group consisting of cyclopropyl, cyclobutyl, 15 cyclopentyl, cyclohexyl, 4--methylcyclohexyl, 4-chloro-3-ethylphenoxycyclohexyl, 3-trifluoromethoxyphenoxycyclohexyl, 3-trifluoromethylcyclohexyl, 4-trifluoromethylcyclohexyl, 3,5-bis-trifluoromethylcyclohexyl, adamantyl, 3-trifluoromethyladamantyl, norbornyl, 3-trifluoromethylnorbornyl, norbornenyl, 7-oxabicyclo[2.2.1 )heptan-2-yl, 20 bicyclo[3.1.0]hexan-6-yl, cycloheptyl, cyclooctyl. 2-morpholinyl, 3-morpholinyl, 4-morpholinyl, 1-piperazinyl, 2-piperazinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyi, 2-dioxanyl, 4H-2-pyranyl, 4H-3-pyranyl, 4H-~l.-pyranyl, 4H-pyran-a-one-2-yl, 4H-pyran-4-one-3-yl, 2-tetrahydrofuranyl, 3-25 tetrahydrofuranyl, 2-tetrahydropyranyl, 3-tetrahydropyranyl, 4-tetrahydropyranyl, 2-tetrahydrothienyl, and 3-tetrahydrothienyl, wherein each ring carbon may be optionally substituted with R30, a ring carbon other than the ring carbon at the point of attachment of A to Z may be optionally substituted with oxo provided that no more than one ring carbon is substituted 30 by oxo at the same time, ring carbon and nitrogen atoms adjacent to the carbon atom at the point of attachment may be optionally substituted with Rc~ or R
13, a ring carbon or nitrogen atom adjacent to the R9 position and two atoms from the point of attachment may be substituted with RIp, a ring carbon or nitrogen atom adjacent to the R13 position and two atoms from the point of attachment may be substituted with R12, a ring carbon or nitrogen atom three atoms from the point of attachment and adjacent to the RIB position may be substituted 5 with R 1 l, a ring carbon or nitrogen atom three atoms from the point of attachment and adjacent to the R12 position may be substituted with R32, and a ring carbon or nitrogen atom four atoms from the point of attachment and adjacent to the R I l and R32 positions may be substituted with R31;
R9 and R13 are fluoro;
10 R10 and R12 are independently selected from the group consisting of benzyloxy, 5-bromo-2-fluorophenoxy, 4.-bromo-3-fluorophenoxy, 3-bromobenzyloxy, 4-bromophenoxy,4-butoxyphenoxy, 3-chIorobenzyloxy, 2-chlorophenoxy, 4-chloro-3-ethylphenoxy, 4-chloro-3-methylphenoxy, 2-chloro-4-fluorophenoxy, 4--chIoro-2-fluorophenoxy, 4-chlorophenoxy, 15 3-chloro-4-ethylphenoxy, 3-chIoro-4methylphenoxy, 3-chloro-4-fluorophenoxy, 4-chloro-3-fluorophenoxy..~-chlorophenylamino, S-chloropyrid-3-yloxy, cyclobutoxy, cyclobutyl, cyclohexylmethoxy.
cyclopentoxy, cyclopentyl. cyclopentylcarbonyl, cyclopropylmethoxy, 2,3-dichlorophenoxy, 2,4-dichlorophenoxy, 2.4-dichlorophenyl.
20 3,~-dichlorophenyl. 3,5-dichlorobenzyl, 3,4-dichlorophenoxy, 3,4-difluorophenoxy,2,3-difluorobenzyloxy, 3.~-difluorobenzyloxy, difluoromethoxy, 3,5-difluorophenoxy, 3,~1.-difluorophenyl, 2,3-difluorophenoxy, 2,4-difluorophenoxy, 2.5-difluorophenoxy, 3,5-dimethoxyphenoxy,3-dimethylaminophenoxy, 3,4-dimethylbenzyloxy, 25 3,5-dimethylbenzyloxy, 3,5-dimethylphenoxy, 3,.~-dimethylphenoxy, 1.3-dioxolan-2-yl, 3-ethylbenzyloxy. 3-ethyiphenoxy, 4-ethylaminophenoxy, 3-ethyl-5-methylphenoxy, 4-fluoro-3-methylbenzyl, 4-fluorobenzyloxy, 2-fluoro-3-methylphenoxy, 3-fluoro.-4-methylphenoxy, 3-fluorophenoxy, 3-fluoro-2-nitrophenoxy, 2-fluoro-3-trifluoromethylbenzyloxy, 3-fluoro-5-trifluoromethylbenzyloxy, 2-fluorophenoxy. 4-fluorophenoxy, 2-fluoro-3-trifluoromethylphenoxy. 2-tluorobenzyloxy, 4-fluorophenylamino, 2-fluoro-4-trifluoromethylphenoxy, 2-furyl, 3-furyl, heptafluoropropyl, 1,1,1,3,3,3-hexafluoropropyl, 5 2-hydroxy-3,3,3-trifluoropropoxy, isobutoxy. isobuty(. 3-isoxazolyl. _ 4-isoxazolyl, 5-isoxazolyl, isopropoxy, 3-isopropylbenzyloxy, 3-isopropylphenoxy, isopropylthio, 4-isopropyl-3-methylphenoxy, 3-isothiazolyl, 4-isothiazolyi, S-isothiazolyl, 3-methoxybenzyl, 4-methoxyphenylamino, 3-methylbenzyloxy. 4-methylbenxyloxy, 10 3-methylphenoxy, 3-methyl-4-methylthiophenoxy. 4-methylphenoxy, 1-methylpropoxy, 2-methylpyrid-~-yloxy, 4-methylthiophenoxy, 2-naphthyloxy, 2-nitrophenoxy, 4-nitrophenoxy, 3-nitrophenyl. 2-oxazolyl.
4-oxazolyl, 5-oxazolyl, pentafluoroethyh pentafluoroethylthio, 2,2,3,3,3-pentafluoropropyl, 1,1,3,3,3-pentafluoropropyl, 15 1,1,2,2,3-pentatluoropropyl, phenoxy, phenylamino, 1-phenylethoxy, 4-propylphenoxy, 4-propoxyphenoxy, thiophen-3-yi,tert -butoxy, 3-tert -butylphenoxy, 4-tert -butylphenoxy. 1,1,2,2-tetrafluoroethoxy, tetrahydrofuran-2-yl, 2-(5,6,7,8-tetrahydronaphthyloxy), thiazol-2-yl, thiazol-4-yl, thiazol-S-yl, thiophen-2-yl, 2,2,2-trifluoroethoxy, 20 2,2,2-trifluoroethyl, 3,3,3-trifluoro-2-hydroxypropyl, trifluoromethoxy, 3-trifluoromethoxybenzyloxy, 4-trifluoromethoxybenzyloxy, 4-trifluoromethoxyphenoxy, 3-trifluoromethoxyphenoxy, trifluoromethyl, 3-trifluoromethylbenzyloxy, 1,1-bis-trifluoromethyl-1-hydroxymethyl, 3-trifluoromethylbenzyl, 3,5-bis-trifluoromethylbenzyloxy, 25 4-trifluoromethylphenoxy, 3-trifluoromethylphenoxy, 3-trifluoromethylphenyl, 2,3.4-trifluorophenoxy, 2,3,x-trifluorophenoxy, 3,4,5-trimethylphenoxy, 3-difluoromethoxyphenoxy, 3-pentafluoroethylphenoxy, 3-(1,1,2,2-tetrafluoroethoxy)phenoxy, 3-trifluoromethylthiophenoxy, 3-trifluoromethylthiobenzyloxy, and 30 trifluoromethylthio;
R 11 ~ R31 ~ and R32 are independently selected from the b oup consisting of chloro, fluoro, hydrido, pentafluoroethyl, 1.1.2,2-tetrafluoroethoxy, and trifluoromethyl;
R3~ is selected from the group consisting of chloro, ethyl, fluoro, heptafluoropropyl, 1,1,1,3,3.3-hexafluoropropyl, isobutyl, isopropyl, methyl, pentafluoroethyl.2,2.3,3,3-pentafluoropropyl, 1,1,3.3.3-pentafluoropropyl.
1,1,2,2,3-pentafluoropropyl.propyl,.rec-butyl, 1.1,2,2-tetrafluoroethoxy.
5 2.2.2-trifluoroethoxy. 2,2,2-trifluoroethyl, trifluoromethoxy, and trifluoromethyl.
In an even more preferred specific embodiment of compounds of Formulas I-WOPC and I-WOHC, 10 A is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyI, 4-methylcyclohexyl, 4.-chloro-3-ethylphenoxycyclohexyl, 3-trifluoromethoxyphenoxycyclohexyl. 3-trifluoromethylcyclohexyl, 4-trifluoromethylcyclohexyl, 3,5-bis-trifluoromethylcyclohexyl, adamantyl, 3-trifluoromethyladamantyl, norbornyl, 15 3-trifluoromethylnorbornyl, norbornenyl, 7-oxabicyclo[2.2.1 ]heptan-2-yl, bicyclo[3.1.0]hexan-6-yl, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydropyranyl, 3-tetrahydropyranyl, 4-tetrahydropyranyl, 2-tetrahydrothienyl, and 3-tetrahydrothienyl, wherein a ring carbon other than the ring carbon at the point of attachment of A to Z may be optionally substituted 20 with oxo provided that no more than one ring carbon is substituted by oxo at the same time, ring carbon and nitrogen atoms adjacent to the carbon atom at the point of attachment may be optionally substituted with R9 or R13, a ring carbon or nitrogen atom adjacent to the R9 position and two atoms from the point of attachment may be substituted with Rl~, a ring carbon or nitrogen 25 atom adjacent to the R13 position and two atoms from the point of attachment may be substituted with R12, a rind carbon or nitrogen atom three atoms from the point of attachment and adjacent to the R10 position may be substituted with R1 l, a ring carbon or nitrogen atom three atoms from the point of attachment and adjacent to the R12 position may be substituted with R32, and a ring carbon or nitrogen atom four atoms from the point of attachment and adjacent to the R11 and R32 positions may be substituted with R31;
R9 and R 13 are fluoro;
R10 and R12 are independently selected from the Group consisting of 5 ~-bromo-2-fluorophenoxy, .4-chloro-3-ethylphenoxy, cyclopentyl, 2,3-dichlorophenoxy, 3,a.-dichlorophenoxy, 3-difluoromethoxyphenoxy, 3,5-dimethylphenoxy, 3,4-dimethylphenoxy, 3-ethylphenoxy, 3-ethyl-5-methylphenoxy, 4-fluoro-3-methylphenoxy, 4-fluorophenoxy, 2-furyl, isobutyl, isopropoxy, 3-isopropylphenoxy, 3-methylphenoxy, 10 pentafluoroethyl, 3-pentafluoroethylphenoxy, 3-tert -butylphenoxy, 1.1,2,2-tetrafluoroethoxy, 3-( l,1.2,2-tetrafluoroethoxy)phenoxy, 2-{~,6,7,8-tetrahydronaphthyloxy),trifluoromethoxy, 3-trifluoromethoxybenzyloxy,3-trifluoromethoxyphenoxy, trifluoromethyl, 3-trifluoromethyibenzyloxy, l,1-bis-trifluoromethyl-1-hydroxymethyl, 15 trifluoromethylthio, and 3-trifluoromethylthiophenoxy;
R11~ R31~ and R32 are independently selected from the group consisting of chloro, fluoro, hydrido, pentafluoroethyl, 1,1,2,2-tetrafluoroethoxy, and trifluoromethyl.
DEFINITIONS
20 The use of generic terms in the description of the compounds are herein defined for clarity.
Standard single letter elemental symbols are used to represent specific types of atoms unless otherwise defined. The symbol "C" represents a carbon atom.
The symbol "O" represents an oxygen atom. The symbol "N' represents a 25 nitrogen atom. The symbol ''P" represents a phosphorus atom. The symbol ''S"
represents a sulfur atom. The symbol ''H" represents a hydrogen atom. Double letter elemental symbols are used as defined for the elements of the periodical table (i.e., Cl represents chlorine, Se represents selenium, etc.).
As utilized herein, the term ''alkyl", either alone or within other terms such 30 as "haloalkyl" and "alkylthio", means an acyclic alkyl radical containing from 1 to about 10, preferably from 3 to about 8 carbon atoms and more preferably 3 to about 6 carbon atoms. Said alkyl radicals may be optionally substituted with groups as defined below. Examples of such radicals include methyl, ethyl, chloroethyl, hydroxyethyl, n-propyl, oxopropyl, isopropyl, n-butyl, cyanobutyl, isobutyl, sec-butyl, tent-butyl, pentyl, aminopentyl, iso-amyl, hexyl, octyl and the 5 like.
The term "alkenyl" refers to an unsaturated, acyclic hydrocarbon radical in so much as it contains at least one double bond. Such alkenyl radicals contain from about 2 to about 10 carbon atoms, preferably from about 3 to about 8 carbon atoms and more preferably 3 to about 6 carbon atoms. Said alkenyl radicals may be 10 optionally substituted with groups as defined below. Examples of suitable alkenyl radicals include propenyl, 2-chloropropenyl. buten-1-yl, isobutenyl, penten-1-yl, 2-2-methylbuten-1-yI, 3-methylbuten-1-yl, hexen-1-yl, 3-hydroxyhexen-1-yl, hepten-1-yl, and octen-1-yl. and the like.
The teml "alkynyl" refers to an unsaturated, acyclic hydrocarbon radical 15 in so much as it contains one or more triple bonds, such radicals containing about 2 to about 10 carbon atoms, preferably having from about 3 to about 8 carbon atoms and more preferably having 3 to about 6 carbon atoms. Said alkynyl radicals may be optionally substituted with groups as defined below.
Examples of suitable alkynyl radicals include ethynyl, propynyl, 20 hydroxypropynyl, butyn-1-yl, butyn-2-yl. pentyn-1-yl, pentyn-2-yl, 4-methoxypentyn-2-yl, 3-methylbutyn-1-yl, hexyn-1-yl, hexyn-2-y1, hexyn-3-yl, 3,3-dimethylbutyn-1-yl radicals and the like.
The term "hydrido" denotes a single hydrogen atom (H). This hydrido radical may be attached, for example, to an oxygen atom to form a "hydroxyl"
25 radical, one hydrido radical may be attached to a carbon atom to form a ''methine" radical (=CH-), or two hydrido radicals may be attached to a carbon atom to form a ''methylene" (-CH2-) radical.
The term ''carbon" radical denotes a carbon atom without any covalent bonds and capable of forming four covalent bonds.
30 The term ''cyano" radical denotes a carbon radical having three of four covalent bonds shared by a nitrogen atom.
The term "hydroxyalkyl" embraces radicals wherein any one or more of the alkyl carbon atoms is substituted with a hydroxyl as defined above.
Specifically embraced are monohydroxyalkyl, dihydroxyalkyl and 35 polyhydroxyalkyl radicals.

The term "alkanoyl" embraces radicals wherein one or more of the terminal alkyl carbon atoms are substituted with one or more carbonyl radicals as defined below. Specifically embraced are monocarbonyialkyl and dicarbonylalkyl radicals. Examples of monocarbonylalkyl radicals include 5 formyl, acetyl, and pentanoyl. Examples of dicarbonylall.-yl radicals include_ oxalyl, malonyl, and succinyl.
The term "allylene'' radical denotes linear or branched radicals having from 1 about 10 carbon atoms and having attachment points for two or more covalent bonds. Examples of such radicals are methylene, ethylene.
10 ethylidene, methylethylene, and isopropylidene.
The term "alkenylene" radical denotes linear or branched radicals having from 2 to about 10 carbon atoms, at least one double bond, and having attachment points for two or more covalent bonds. Examples of such radicals are 1,1-vinylidene (CH.,=C), 1,2-vinylidene (-CH=CH-), and 1.=1-butadienyl 15 (-CH=CH-CH=CH-).
The term "halo" means halogens such as fluorine, chlorine, bromine or iodine atoms.
The term "haloalkyl" embraces radicals wherein any one or more of the alkyl carbon atoms is substituted with halo as defined above. Specifically 20 embraced are monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals. A
monohaioalkyl radical, for one example, may have either a bromo, chloro or a fluoro atom within the radical. Dihalo radicals may have two or more of the same halo atoms or a combination of different halo radicals and polyhaloalhyl radicals may have more than two of the same halo atoms or a combination of 25 different halo radicals. More preferred haloalkyl radicals ire "lower haloalkyl"
radicals having one to about six carbon atoms. Examples of such haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, trifluoroethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, 30 difluoropropyl, dichloroethyl and dichloropropyl.
The term "hydroxyhaloalkyl" embraces radicals wherein any one or more of the haloalkyl carbon atoms is substituted with hydroxy as defined above. Examples of "hydroxyhaloalkyl" radicals include hexafluorohydoxypropyl.

The term "haloalkylene radical" denotes alkylene radicals wherein am one or more of the alkylene carbon atoms is substituted with halo as defined above. Dihalo alkylene radicals may have two or more of the same halo atoms or a combination of different halo radicals and polyhaloallylene radicals may have more than two of the same halo atoms or a combination of different halo-radicals. More preferred haloalkylene radicals are "lower haloalkylene"
radicals having one to about six carbon atoms. Examples of ''haloalkylene"
radicals include difluoromethylene, tetraf(uoroethylene, tetrachloroethylene.
alkyl substituted monofluoromethylene, and aryl substituted trifluoromethylene.
The term ''haloalkenyl" denotes linear or branched radicals having from I to about 10 carbon atoms and having one or more double bonds wherein any one or more of the alkenyl carbon atoms is substituted with halo as defined above. Dihaloalkenyl radicals may have two or more of the same halo atoms or a combination of different halo radicals and polyhaloalkenyl radicals may have more than two of the same halo atoms or a combination of different halo radicals.
The terms "alkoxy" and "alkoxyallyl" embrace linear or branched oxy containing radicals each having alkyl portions of one to about ten carbon atoms, such as methoxy radical. The teml "alkoxyalkyl" also embraces alkyl radicals having one or more alkoxy radicals attached to the alkyl radical, that is, to form monoalkoxyalkyl and dialkoxyalkyl radicals. More preferred alkoxy radicals are "lower alkoxy" radicals having one to six carbon atoms. Examples of such radicals include methoxy, ethoxy, propoxy, butoxy, isopropoxy and ten-butoxy alkyls. The "alkoxy" radicals may be further substituted with one or more halo atoms, such as ff uoro, chloro or bromo, to provide "haloalkoxy"
and "haloalkoxyalkyl" radicals. Examples of such haloalkoxy radicals include fluoromethoxy, chloromethoxy, trifluoromethoxy, difluoromethoxy, trifluoroethoxy, fluoroethoxy, tetrafluoroethoxy, pentafluoroethoxy, and fluoropropoxy. Examples of such . haloalkoxyallyl radicals include fluoromethoxymethyl, chloromethoxyethyl, trifluoromethoxymethyl, difluoromethoxyethyl, and trifluoroethoxymethyl.
The terms "alkenyloxy" and "alkenyloxyalkyl" embrace linear or branched oxy-containing radicals each having alkenyl portions of two to about ten carbon atoms, such as ethenyioxy or propenyloxy radical. The term "alkenyloxyalkyl" also embraces alkenyl radicals having one or more WO 00/18723 PC'T/US99/22123 alkenyloxy radicals attached to the alkyl radical, that is, to form monoalkenyloxyalkyl and diaikenyloxyalkyl radicals. More preferred alkenyloxy radicals are "lower aikenyloxy" radicals having two to six carbon atoms. Examples of such radicals include ethenyioxy, propenyloxy, butenyloxy, and isopropenyloxy alkyls. The "alkenyioxy" radicals may be_ further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide "haloalkenyloxy" radicals. Examples of such radicals include trifluoroethenyloxy, fluoroethenyloxy, difluoroethenyhloxy, and fiuoropropenyloxy.
The term "haloalkoxyalkyl" also embraces alkyl radicals having one or more haloalkoxy radicals attached to the alkyl radical, that is, to form monohaIoalkoxyalkyl and dihaloalkoxyalkyl radicals. The term "haloallcenyloxy" also embraces oxygen radicals having one or more haloalkenyloxy radicals attached to the oxygen radical, that is, to form monohaioalkenyloxy and dihaloalkenyloxy radicals. The term "haloaikenyloxyalkyl" also embraces alkyl radicals having one or more haloalkenyloxy radicals attached to the alkyl radical, that is, to form monohaloalkenyloxyalkyi and dihaloalkenyloxyalkyl radicals.
The term "alkylenedioxy" radicals denotes alkylene radicals having at least two oxygens bonded to a single aikylene group. Examples of "aikylenedioxy" radicals include methylenedioxy, ethylenedioxy, alkylsubstituted methylenedioxy, and arylsubstituted methylenedioxy. The term "haloalkylenedioxy" radicals denotes haioalkylene radicals having at least two oxy groups bonded to a single haloaIkyl group. Examples of "haloalkyienedioxy" radicals include difluoromethylenedioxy, tetrafluoroethylenedioxy, tetrachloroethylenedioxy, alkylsubstituted monofluoromethylenedioxy, and arylsubstituted monofluoromethylenedioxy.
The term "aryl", alone or in combination, means a carbocyclic aromatic system containing one, two or three rings wherein such rings may be attached together in a pendant manner or may be fused. The temp "fused" means that a ' second ring is present (ie, attached or formed) by having two adjacent atoms in common (ie, shared) with the first ring. The term "fused" is equivalent to the term ''condensed". The term "aryl" embraces aromatic radicals such as phenyl, naphthyl, tetrdhydronaphthyl, indane and biphenyl.

The term "perhaloaryl" embraces aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indane and biphenyl wherein the aryl radical is substituted with 3 or more halo radicals as defined below.
The term "heterocyclyl" embraces saturated and partially saturated 5 heteroatom-containing ring-shaped radicals having from ~ through 15 ring_ members selected from carbon, nitrogen, sulfur and oxygen, wherein at least one ring atom is a heteroatom. Heterocyclyl radicals may contain one, two or three rings wherein such rings may be attached in a pendant manner or may be fused. Examples of saturated heterocyclic radicals include saturated 3 to 6-10 membered heteromonocylic group containing 1 to 4 nitrogen atoms(e.g.
pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc.]; saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g. morpholinyl, etc.]: saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen 15 atoms [e.g., thiazolidinyi, etc.]. Examples of partially saturated heterocyclyl radicals include dihydrothiophene, dihydropyran, dihydrofuran and dihydrothiazole. Non-limiting examples of heterocyclic radicals include 2 pyrrolinyl, 3-pyrrolinyl, pyrralindinyl, 1,3-dioxolanyl, 2H-pyranyl, 4H
pyranyl, piperidinyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl, 20 thiomorpholinyl, and the like.
The term "heteroaryl" embraces fully unsaturated heteroatom-containing ring-shaped aromatic radicals having from 5 through 15 ring members selected from carbon, nitrogen, sulfur and oxygen, wherein at least one rind atom is a heteroatom. Heteroaryl radicals may contain one, two or three rings wherein 25 . such rings may be attached in a pendant manner or may be fused. Examples of "heteroaryl" radicals, include unsaturated ~ to 6 membered heteromonocyclyl group containing 1 to 4 nitrogen atoms, for example. pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl. 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl [e.g., 4H-1,2,4--triazolyl, 1H-1,2,3-triazolyl, ZH-1,2,3-30 triazolyl, etc.] tetrazolyl [e.g. 1H-tetrazolyl, 2H-tetrazolyl, etc.], etc.;
unsaturated condensed heteroc~rclic group' containing 1 to 5 nitrogen atoms, for example, indolyl, isoindolyl, indoliziny(, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolapyridazinyl [e.g., tetrazolo [1,5-b]pyridazinyl, etc.], etc.; unsaturated 3 to 6-membered heteromonocyclic 35 Group containing an oxygen atom, for example, pyranyl, 2-furyl, 3-furyl, etc.;
unsaturated 5 to 6-membered heteromonocvciic Group containing a sulfur atom, WO 00/18723 PCT/US99/2212.3 for example, 2-thienyl, 3-thienyt. etc.: unsaturated ~- to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms auJ 1 to 3 llitro~en atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl, 1,3,=l-oxadiazolyl, 1.2,x-oxadiazolyl, etc.] ete.; unsaturated condensed 5 heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nilro~en atoms_ [e.a. benzoxazolyl, bCClzUxadlaGUlyl, etc.]; unsaturated 5 to 6-membere~3 heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl, thiadiazoly! [e.Q., 1.2.=I- thiadiazolvl.
1,3.;.-thiadiazolyl, 1.?.5-thiadiazolyl. etc.) etc.; unsaturated condensed heterocyclic 10 group containinc 1 to 2 sulfur atoms and 1 to 3 nitro;en atoms [e.g., benzothiazolyl, benzothiadiazolyl, etc.] and the like. The term also embraces radicals where heterocyclic radicals are fused with aryl radicals. Examples of such fused bicyclic radicals include benzofuran. benzothiopliene, and the like.
Said "heterocyclyl'' group may have 1 to 3 substituents as defined below.
15 Preferred heterocyclic radicals include five to twelve membered fused or unfused radicals. Non-limiting examples of heteroaryl radicals include pyrrolyl, pyridinyl, pyridyloxy, pyrazolyl, triazolyl, pyrimidinyl, pyridazinyl, oxazolyl, thiazolyl, imidazolyl, indoiyl, thiophenyl, furanyl, tetrazolyl, 2-imidazolinyl, imidazolidinyl, 2-pyrazolinyl, pyrazolidinyl, isoxazolyl, 20 isothiazolyl, 1,2,3-oxadiazolyl, 1,2 ,3-triazolyl, I,3.4-thiadiazolyl, pyrazinyl, piperazinyl, 1,3,5-triazinyl, 1,3,5-trithianyl, benzo(b)thiophenyl, benzimidazoyl, quinolinyl, tetraazolyl, and the like.
The term "sulfonyl", whether used alone or linked to other terms such as alkylsulfonyl, denotes respectively divalent radicals -S4~-.
"Alkylsulfonyl", 25 embraces alkyl radicals attached to a sulfonyl radical, where alkyl is defined as above. "Alkylsulfonylalkyl", embraces alkylsulfonyl radicals attached to an alkyl radical, where alkyl is defined as above. "Haloalkylsulfonyl", embraces haloalkyl radicals attached to a sulfonyl radical, where haloal),yl is defined as above. "Haloalkylsulfonylalkyl", embraces haloallylsulfonyl radicals attached 30 to an alkyl radical, where alkyl is defined as above. The term "aminosulfonyl"
denotes an amino radical attached to a sulfonyl radical.
The term "sulfinyl", whether used alone or linked to other terms such as alkylsulfinyl, denotes respectively divalent radicals -S(O)-.
"Alkylsulfinyl", embraces alkyl radicals attached to a sulfinyl radical, where allyl is defined as 35 above. "Alkylsulfinylalkyl", embraces alkylsulflnyl radicals attached to an alkyl radical, where alkyl is defined as above. "Haloalkylsulfinyl", embraces haloalkyl radicals attached to a sulfinyl radical, where haloalkyl is defined as above. "Haloalkyisulfinylallyl", embraces haloalkylsulfinyl radicals attached to an alkyl radical, where alkyl is defined as above.
5 The term "aralkyl" embraces aryl-substituted alkyl radicals. Preferable aralkyl radicals are "lower aralkyl" radicals havin; aryl radicals attached to alkyl radicals having one to six carbon atoms. Examples of such radicals include benzyl, diphenylmethyl, triphenylmethyl, phenylethyl and diphenylethyl. The terms benzyl and phenylmethyl are interchangeable.
10 The term "heteroaralkyl" embraces heteroaryl-substituted alkyl radicals wherein the heteroaralkyl radical may be additionally substituted with three or more substituents as defined above for araikyl radicals. The term "perhaloaralkyl" embraces aryl-substituted alkyl radicals wherein the aralkyl radical is substituted with three or more halo radicals as defined above.
15 The term "aralkylsulfinyl", embraces aralkyl radicals attached to a sulf nyl radical, where aralkyl is defined as above. "Aratkylsulfinylalkyl", embraces aralkylsulfinyl radicals attached to an alkyl radical, where alkyl is defined as above.
The term "aralkylsulfonyl", embraces aralkyl radicals attached to a 20 sulfonyl radical, where aralkyl is defined as above.
"Aralkylsulfonylalkyl", embraces arallcylsulfonyl radicals attached to an alkyl radical, where alkyl is defined as above.
The term "cycloalkyl" embraces radicals having from 3 through 15 carbon atoms. Cycloalkyl radicals may contain one, two, three, or four rings 25 wherein such rings may be attached in a pendant manner or may be fused.
Examples of cycloalkyl radicals having two or more rings inctude adamantyl, norbornyl, and 7-oxabicyclo[2.2.1 ]heptanyl. More preferred cycloalkyl radicals are "lower cycloalkyl" radicals having from 3 through 8 carbon atoms.
Examples include radicals such as cyclopropyl, cyclobutyl, cyclopentyl, 30 cyclohexyl and cycloheptyl. The term "cycloalkyl" also embraces radicals ' where cycloalkyl radicals are fused with aryl radicals or heterocyclyl radicals.
The term "cycloalkylalkyl" embraces cycloalkyl-substituted alkyl radicals.
Preferable cycloalkylalkyl radicals are "lower cycloalkylalkyl" radicals having cycloalkyl radicals attached to alkyl radicals having from one through six 35 carbon atoms. Examples of such radicals include cyclohexylhexyl. The term "cycloalkenvl" embraces radicals havin~ three to fifteen carbon atoms and one or more carbon-carbon double bonds. Cycloalkenyl radicals may contain one, two, three, or four rings wherein such rings may be attached in a pendant manner or may be fused. Examples of cycloalkenyl radicals having two or more rings include norbornenyI. Preferred cycloalkenyl radicals are "lower cycloalkenyl" radicals having three to seven carbon atoms. Examples include radicals such as cyclobutenyl, cyclopentenyl, cyclohexenyl and cyclohepteny~.
The term "halocycloallyl" embraces radicals wherein any one or more of the cycloalkyl carbon atoms is substituted with halo as defined above.
Specifically embraced are monohalocycloalkyl, dihalocycloalkyl and polyhalocycloaIkyl radicals. A monohalocycloalkyl radical, for one example, may have either a bromo, chloro or a fluoro atom within the radical. Dihalo radicals may have two or more of the same halo atoms or a combination of different halo radicals and polyhalocycloalkyl radicals may have more than two of the same halo atoms or a combination of different halo radicals. More preferred halocycloalkyl radicals are "lower halocycloalkyl" radicals having three to about eight carbon atoms. Examples of such halocycloalkyl radicals include fluorocyclopropyl, difluorocyclobutyl, trifluorocyclopentyl, tetrafluorocyclohexyl, and dichlorocyclopropyl. The term "halocycloalkenyl"
embraces radicals wherein any one or more of the cycloalkenyl carbon atoms is substituted with halo .as defined above. Specifically embraced are monohalocycloalkenyl, dihalocycloalkenyl and polyhalocycloalkenyl radicals.
The term "cycloalkoxy" embraces cycloalkyl radicals attached to an oxy radical. Examples of such radicals includes cyclohexoxy and cyclopentoxy.
The term "cycloalkoxyalkyl" also embraces alkyl radicals having one or more cycloalkoxy radicals attached to the alkyl radical, that is, to form monocycloalkoxyalkyl and dicycloalkoxyalkyl radicals. Examples of such radicals include cyclohexoxyethyl. The "cycloalkoxy" radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide "halocycloalkoxy" and ''halocycloalkoxyalkyl" radicals.
3 0 The term "cycloalkylalkoxy" embraces cycloalkyl radicals attached to an alkoxy radical. Examples of such radicals includes cyclohexylmethoxy and cyclopentylmethoxy.
The term "cycloalkenyloxy" embraces cycloalkenyl radicals attached to an oxy radical. Examples of such radicals includes cyclohexenyloxy and cyclopentenyloxy. The term "cycloalkenyloxyalkyl" also embraces alkyl radicals having one or more cycloalkenylo~cy radicals attached to the alkyl radical, that is, to form monocycloalkenyloxyalkyl and dicycloalkenyloxyalkyl radicals. Examples of such radicals include cyclohexenyloxyethyl. The "cycloalkenyloxy" radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide "halocycloalkenyloxy" and ''halocycloalkenyloxyalkyl" radicals.
The term "cycloalkylenedioxy" radicals denotes cycloalkylene radicals having at least two~oxygens bonded to a single cycloalkylene group. Examples of ''alkylenedioxy" radicals include 1,2-dioxycyclohexylene.
The term "cycloalkylsulfinyl", embraces cycloalkyl radicals attached to a sulfinyl radical, where cycloalkyl is defined as above.
"Cycloalkylsulfinylalkyl", embraces cycloalkylsulfinyl radicals attached to an alkyl radical, where alkyl is defined as above. The term "Cycioalkylsulfonyl", embraces cycloalkyi radicals attached to a sulfonyi radical. where cycloalkyl is defined as above. "Cycloalkylsulfonylalkyl", embraces cycloalkylsulfonyl radicals attached to an alkyl radical, where alkyl is defined as above.
The term "cycloalkylaikanoyl" embraces radicals wherein one or more of the cycloalkyl carbon atoms are substituted with one or more carbonyl radicals as defined below. Specifically embraced are monocarbonylcycloallyl and dicarbonylcycloalkyl radicals. Examples of monocarbonylcycloalkyl radicals include cyclohexylcarbonyl, cyclohexylacetyl, and cyclopentylcarbonyl. Examples of dicarbonylcycloalkyl radicals include 1,2-dicarbonylcyclohexane..
The term "alkylthio" embraces radicals containing a linear or branched alkyl radical, of one to ten carbon atoms, attached to a divalent sulfur atom.
More preferred alkylthio radicals are ''lower alkylthio" radicals having one to six carbon atoms. An example of "lower alkylthio" is methylthio (CH3-S-).
The "alkylthio" radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide "haloalkylthio" radicals.
Examples of such radicals include fluoromethylthio, chloromethyithio, trifluoromethylthio, difl,uoromethylthio, trifluoroethylthio, fluoroethylthio, tetrafluoroethylthio, pentafluoroethylthio, and fluoropropylthio.
The term "alkyl aryl amino" embraces radicals containing a linear or branched alkyl radical, of one to ten carbon atoms, and one aryl radical both attached to an amino radical. Examples include N-methyl.-methoxyaniline, N-ethyl-4-methoxyaniline, and N-methyl-4-tritluoromethoxyaniline.

WO 00/18723 PC'f/US99/22123 The terms alkylamino denotes "monoalkylamino" and ''dialkylamino"
containing one or two alkyl radicals, respectively, attached to an amino radical.
The terms arylamino denotes "monoarylamino" and "diarylamino"
containing one or two aryl radicals, respectively, attached to an amino radical.
Examples of such radicals include N-phenylamino and N-naphthylamino. _ The term "aralkylamino", embraces aralkyl radicals attached to an amino radical, where aralkyl is defined as above. The term arallylamino denotes ''monoaralkylamino" and "diaralkylamino" containing one or two aralkyl radicals, respectively, attached to an amino radical. The term aralkylamino further denotes ''monoaralkyl monoalkylamino" containing one aralkyl radical and one alkyl radical attached to an amino radical.
The term "arylsulfinyl" embraces radicals containing an aryl radical, as defined above, attached to a divalent S(=O) atom. The teen "arylsulfinylalkyl"
denotes arylsulfinyl radicals attached to a linear or branched alkyl radical, of one to ten carbon atoms.
The term "arylsulfonyl", embraces aryl radicals attached to a sulfonyl radical, where aryl is defined as above. "arylsulfonylaIkyl", embraces arylsulfonyl radicals attached to an alkyl radical, where alkyl is defined as above. The term "heteroarylsulfinyl" embraces radicals containing an heteroaryl radical, as defined above, attached to a divalent S(=O) atom. The term "heteroarylsulfmylalkyl" denotes heteroarylsulfinyi radicals attached to a linear or branched alkyl radical, of one to ten carbon atoms. The term "Heteroarylsulfonyl", embraces heteroaryl radicals attached to a suifonyl radical, where heteroaryl is defined as above. "Heteroarylsulfonylalkyl", 2 5 embraces heteroarylsulfonyl radicals attached to an alkyl radical, where alkyl is defined as above.
The term "aryloxy" embraces aryl radicals, as defined above, attached to an oxygen atom. Examples of such radicals include phenoxy, 4-chloro-3-ethylphenoxy, 4-chloro-3-methylphenoxy, 3-chloro-4-ethylphenoxy, 3,4-dichlorophenoxy, 4-methylphenoxy, 3-trifluoromethoxyphenoxy, 3-trifluoromethylphenoxy, 4-fluorophenoxy, 3,4-dimethylphenoxy, 5-bromo-2-fluorophenoxy, 4-bromo-3-fluorophenoxy, 4-fluoro-3-methylphenoxy, 5,6,7,8-tetrahydronaphthyloxy, 3-isopropylphenoxy, 3-cyclopropylphenoxy, 3-ethylphenoxy, 4-tort -butylphenoxy. 3-pentafluoroethylphenoxy, and 3-(1,1,2,2-tetrafluoroethoxy)phenoxy, 54 _ The term "aroyl" embraces aryl radicals, as defined above, attached to an carbonyl radical as defined abov e. Examples of such radicals include benzoyl and toluoyl.

The term "aralkanoyl" embraces aralkyl radicals, as defined herein, attached to an carbonyl radical as defined above. Examples of such radicals_ include, for example, phenylacetyl.

The term "aralkoxy" embraces oxy-containing aralkyl radicals attached through an oxygen atom to other radicals. More preferred aralkoxy radicals are "lower aralkoxy" radicals having phenyl radicals attached to lower alkoxy radical as described above. Examples of such radicals include benzyloxy, 1-phenylethoxy, 3-trifluoromethoxybenzyloxy, 3-trifluoromethylbenzyloxy, 3,5-difluorobenyloxy, 3-bromobenzyloxy. 4-propylbenzyloxy, 2-fluoro-3-trifluoromethylbenzyloxy, and 2-phenylethoxy.

The term "aryloxyalkyl" embraces aryloxy radicals, as defined above, attached to an alkyl group. Examples of such radicals include phenoxymethyl.

The term "haloaryloxyalkyl" embraces aryloxyalkyl radicals, as defined above, wherein one to five halo radicals are attached to an aryloxy group.

The term "heteroaroyl" embraces heteroaryl radicals, as defined above, attached to an carbonyl radical as defined above. Examples of such radicals 2 0 include furoyl and nicotinyl.

The term "heteroaralkanoyl" embraces heteroaralkyl radicals, as defined herein, attached to an carbonyl radical as defined above. Examples of such radicals include, for example, pyridylacetyl and furylbutyryl.

The term "heteroaralkoxy" embraces oxy-containing heteroaralkyl radicals attached through an oxygen atom to other radicals.
More preferred heteroaralkoxy radicals are "lower heteroaralkoxy"
radicals having heteroaryl radicals attached to lower alkoxy radical as described above.

The term "haloheteroaryloxyalkyl" embraces heteroaryloxyalkyl radicals, as defined above, wherein one to four halo radicals are attached to an heteroaryloxy group.

The term "heteroarylamino" embraces heterocyclyl radicals, as defined above, attached to an amino Group. Examples of such radicals include pyridylamino.

The term "heteroarylaminoalkyl" embraces heteroarylamino radicals, as defined above, attached to an alkyl group. Examples of such radicals include pvridvlmethvlamino.

The term "heteroaryloxy" embraces heterocyclyt radicals, as defined above, attached to an oxy Group. Examples of such radicals include 2-thiophenyloxy, 2-pyrimidyloxy, 2-pyridyloxy, 3-pyridyloxy, and ~:l-pyridyloxy.
5 The term ''heteroaryloxyalkyl" embraces heteroaryloxy radicals, a.~
defined above, attached to an alkyl Group. Examples of such radicals include 2-pyridyloxymethyl, 3-pyridyloxyethyl, and 4-pyridyloxymethyl.
The term "arylthio" embraces aryl radicals, as defined above, attached to an sulfur atom. Examples of such radicals include phenylthio.
10 The term "arylthioalkyl" embraces arylthio radicals, as defined above, attached to an alkyl group. Examples of such radicals include phenylthiomethyl.
The term "alkylthioalkyl" embraces alkylthio radicals, as defined above.
attached to an alkyl group. Examples of such radicals include 15 methylthiomethyl. The term "alkoxyalkyl" embraces alkoxy radicals, as defined above, attached to an alkyl group. Examples of such radicals include methoxymethyl.
The term "carbonyl" denotes a carbon radical having two of the four covalent bonds shared with an oxygen atom. The term ''carboxy" embraces a 2 0 hydroxyl radical, as defined above, attached to one of two unshaved bonds in a carbonyl group. The term ''carboxamide" embraces amino, monoalkylamino, dialkylamino, monocycloalkylamino, alkylcycloalkylamino, and dicycloalkylamino radicals, attached to one of two unshaved bonds in a carbonyl group. The term ''carboxamidoalkyl" embraces carboxamide radicals, as defined above, attached to 2 5 an alkyl group. The term "carboxyalkyl" embraces a carboxy radical, as defined above, attached to an alkyl group. The term "carboalkoxy" embraces alkoxy radicals, as defined above, attached to one of two unshaved bonds in a carbonyl group. The term "carboaralkoxy" embraces aralkoxy radicals, as defined above, attached to one of two unshaved bonds in a carbonyl group. The term 30 ''monocarboalkoxyalkyl" embraces one carboalkoxy radical, as defined above, ', attached to an alkyl group. The term ''dicarboalkoxyalkyl" embraces two carboalkoxy radicals, as defined above, attached to an alkylene group. The term ''monocyanoalkyl" embraces one cyano radical, as defined above, attached to an alkyl group. The term ''dicyanoalkylene" embraces two cyano radicals, as defined 35 above, attached to an alkyl group. The term ''carboalkoxycyanoalkyl"
embraces one cyano radical, as defined above, attached to an carboalkoxyalkyl Group.

The term "acyl", alone or in combination, means a carbonyl or thionocarbonyl group bonded to a radical selected from, for example, hydrido, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkoxyalkyl, haloalkoxy, aryl, heterocyclyl, heteroaryl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkyl, cycloalkyl, 5 cycloalkylalkyl, cycloalkenyl, alkylthio, ary(thio, amino, alkylamino, dialkylamino, aralkoxy, arylthio, and alkylthioalkyl. Examples of "acyl" are formyl, acetyl, benzoyl, trifluoroacetyl, phthaloyl, malonyl, nicotinyl, and the like.
The term "haloalkanoyl" embraces one or more halo radicals, as defined herein, attached to an alkanoyl radical as defined above. Examples of such radicals 10 include, for example, chloroacetyl, trifluoroacetyl, bromopropanoyl, and heptafluorobutanoyl. The term "diacyl", alone or in combination, means having two or more carbonyl or thionocarbonyl groups bonded to a radical selected from, for example, alkylene, alkenylene, alkynylene, haloalkylene, alkoxyalkylene.
aryl, heterocyclyl, heteroaryl, aralkyl, cycloalkyl, cycloalkylalkyl, and cycloalkenyl.
15 Examples of ''diacyl" are phthaloyl, malonyl, succinyl, adipoyl, and the like.
The term ''benzylidenyl" radical denotes substituted and unsubstituted benzyl groups having attachment points for two covalent bonds. One attachment point is through the methylene of the benzyl group with the other attachment point through an ortho carbon of the phenyl ring. The methylene group is designated for 20 attached to the lowest numbered position. Examples include the base compound benzylidene of structure:
The term "phenoxylidenyl" radical denotes substituted and unsubstituted phenoxy groups having attachment points for two covalent bonds. One attachment 25 point is throw the oxy of the phenoxy group with the other attachment point through an ortho carbon of the phenyl ring. The oxy group is designated for attached to the lowest numbered position. Examples include the base compound phenoxylidene of structure:

H
H
The term "phosphono'' embraces a pentavalent phosphorus attached with two covalent bonds to an oxygen radical. The term "dialkoxyphosphono" denotes two alkoxy radicals, as defined above, attached to a phosphono radical with two 5 covalent bonds. The term "diaralkoxyphosphono" denotes two aralkoxy radicals, as defined above, attached to a phosphono radical with two covalent bonds. The term "dialkoxyphosphonoalkyl" denotes dialkoxyphosphono radicals, as defined above, attached to an alkyl radical. The term "diaralkoxyphosphonoalkyt"
denotes diaralkoxyphosphono radicals, as defined above, attached to an alkyl radical.
10 Said "alkyl", "alkenyl", "alhynyl". "alkanoyl", ''alkylene", "alkenylene", "benzylidenyl", "phenoxylidenyl", ''hydroxyalkyl", "haloalkyl", "haloalkylene", "haloalkenyl", "alkoxy", "alkenyloxy", "alkenyloxyalkyl", "alkoxyalkyl", ''aryl", ''perhaloaryl", "haioalkoxy", "haloalkoxyalkyl", "haloalkenyloxy", "haloalkenyloxyalkyl", ''alkylenedioxy", ''haloalkylenedioxy", "heterocyclyl", 15 "heteroaryl", ''hydroxyhaloalkyl", "alkylsulfonyl", "haloalkylsulfonyl", ''alkylsulfonylalkyl". ''haloalkylsulfonylalkyl", "alkylsulfinyl", ''alkylsulfinylalkyl", "haloalkylsulfinylalkyl", "aralkyl", "heteroaralkyl", ''perhaloaralkyl", ''aralkylsulfonyl", "aralkylsulfonylalkyl", ''aralkylsuifinyl", ''aralkylsulfinylalkyl", ''cycloalkyl", "cycloalkylalkanoyl", "cycloalkylalkyl", 20 "cycloalkenyl", ''halocycloalkyl", "halocycloalkenyl", "cycloalkylsulfinyl", ''cycloalkylsulfinylalkyl", ''cycloalkylsulfonyl", "cycloalkylsulfonylalkyl", "cycloalkoxy", "cycloalkoxyalkyl", "cycloalkylalkoxy", "cycloalkenyloxy", "cycloalkenyloxyalkyl", ''cycloalkylenedioxy", "halocycloalkoxy", ''halocycloalkoxyalkyl", "halocycloalkenyloxy", ''halocycloalkenyloxyalkyl", 25 ''alkylthio", "haloalkylthio", ''alkylsulfinyl", ''amino", "oxy", ''thio", ''alkylamino", ''arylamino", "aralkylamino'", "arylsulfinyl", "arylsulfinylalkyl", "arylsulfonyl", "arylsulfonylalkyl", "heteroarylsulfinyl", "heteroarylsulfinylalkyl", "heteroarylsulfonyl", "heteroarylsulfonylalkyl", "heteroarylamino", "heteroarylaminoalkyl'', "heteroaryloxy", "heteroaryloxylalkyl", "aryloxy", WO 00/18?23 PCT/US99/22123 ''aroyl", ''aralkanoyl", ''aralkoxy", ''aryloxyalkyl". "haloaryloxyalkyl".
"heteroaroyl", "heteroaralkanoyl", "heteroaralkoxy". "heteroaralkoxyalkyl", "arylthio", "arylthioalkyl", "alkoxyalkyl", "acyl" and "diacyl" groups defined above may optionally have 1 to 5 non-hydrido substituents such as perhaloaralkyl, 5 aralkylsulfonyl, araikylsulfonylaIkyl, aralkylsulfinyl, aralkylsulfinylalkyl, _ halocycloalkyl, halocycloalkenyl, cycloaIkylsulfinyl, cycloalkylsulfinylalkyl, cycloalkylsulfonyl, cycloalkylsulfonylalkyl, heteroarylamino. N-heteroarylamino-N-alkylamino, heteroarylaminoalkyl, heteroaryloxy. heteroaryloxylalkyl, haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl, haloalkoxylalkyl, heteroaralkoxy, 10 cycloalkoxy, cycloalkenyloxy, cycloalkoxyalkyl, cycloalkylalkoxy, cycloatkenyloxyalkyl, cycloalkylenedioxy, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxy, halocycloalkenyloxyalkyl, hydroxy, amino, thin, nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, arylthioalkyl, heteroaralkoxyalkyl, alkytsulfinyl, alkylsulfinylalkyl, 15 arylsulfinylalkyl, arylsulfonylalkyl, heteroarylsultinylalkyl, heteroarylsulfonylalkyl, alkylsulfonyl, alkylsulfonylalkyi, haloalkylsulfinylalkyl, haloalkylsulfonylalkyt, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, monoarylamidosulfonyl, arylsulfonamido, diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, 20 arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl, alkynyl, alkenyloxy, alkenyloxyalky, alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkylalkanoyl, cycloalkenyl, lower cycloalkylalkyl, lower cycloalkenylaikyl, halo, haloalkyl, haloalkenyl, haloalkoxy, 25 hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, hydoxyheteroaralkyl, haloalkoxyalkyl, aryl, aralkyl, aryloxy, aralkoxy, aryloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, carboxyalkyl, carboalkoxy, alkoxycarbonyl, carboaralkoxy, carboxamido, 30 carboxamidoalkyl, cyano, carbohaloalkoxy, phosphono, phosphonoalkyl, diaralkoxyphosphono, and diaralkoxyphosphonoalkyl.
The term "spacer" may include a covalent bond, a linear moiety having a backbone of 1 to 7 continous atoms, and a branched moiety having three branches connecting to a common atom with a total of from 1 through 8 atoms.
35 The spacer may have 1 ko 7 atoms of a univalent or multi-valent chain.
Univalent chains may be constituted by a radical selected from =C(H)-.

=C{RI7)-~ -Ow -S-~ -S(O)-. -S(O)2-, -NH-, -N(Rl~)-, -N=, -CH(OH)-, =C(OH)-, -CH(ORI~)-, =C(ORI~)-, and -C(O)- wherein R1~ is selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, aryloxyalkyl, alkoxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, 5 haloalkenyl, haloalkoxyalkyl, perhaloaralkyl, heteroarylalkyl, heteroaryloxyalkyl, heteroarylthioalkyl, and heteroarylalkenyl. Multi-valent chains may consist of a straight chain of I or 2 or 3 or 4 or 5 or 6 or 7 atoms, a straight chain of 1 or 2 or 3 or 4 or S or 6 atoms with a side chain, or a branched chain made up of 1 or 2 or 3 or 4 atoms in each of the three branches.
10 The chain may be constituted of one or more radicals selected from: lower alkylene, lower alkenyl, -O-, -O-CH2-, -S-CH2-, -CH2CH2-, ethenyl, -CH=CH(OH)-, -OCH20-, -O(CH2)20-, -NHCH2-, -OCH(R1~)O-, -O(CH2CHR1~)O-, -OCF20-, -O(CF2)20-, -S-, -S(O)-, -S(O)2-, -N(H)-, -N(H)O-, -N(Rf~)O-, -N(R1~)-. -C(O)-, -C(O)NH-, -C(O)NR1~-, -N=, 15 -OCH2-, -SCH2-, S(O)CH2-, -CH2C(O)-> -CH(OH)-, =C(OH)-, -CH{OR1~)-, =C(ORl~)-, S(O)2CH2-, and -NRl~CH2- and many other radicals defined above or generally known or ascertained by one of skill-in-the art. Side chains may include substituents such as 1 to 5 non-hydrido substituents such as perhaloaralkyl, aralkylsulfonyl, aralkylsulfonylalkyl, 2 0 aralkylsulfinyl, aralkylsulfinylalkyl, halocycloalkyl, halocycloalkenyl, cycloalkylsulfinyl, cycloalkylsulfinylalkyl, cycloalkylsulfonyl, cycloalkylsulfonylalkyl, heteroarylamino, N-heteroaryiamino-N-alkylamino, heteroarylaminoalkyl, heteroaryloxy, heteroaryloxylalkyl, haloalkyithio, alkanoyloxy, alkoxy, alkoxyalkyl, haloalkoxylalkyl, heteroaralkoxy, 25 cycloalkoxy, cycloalkenyloxy, cycloalkoxyalkyl, cycloalkylalkoxy, cycloalkenyloxyalkyl, cycloalky(enedioxy, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxy, halocycloalkenyloxyalkyl, hydroxy, amino, thio, vitro, tower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, arylthioalkyl, heteroaralkoxyalkyl, 30 alkylsulfinyl, alkylsulfinylalkyl, aryisulfmylalkyl, arylsulfonylalkyl, heteroarylsulftnylalkyl, heteroarylsulfonylalkyl, alkylsulfonyl.
alkyisulfonylalkyl, haloaikylsulfinylalkyi, haloalkylsulfonylalkyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, monoarylamidosulfonyl, 5 arylsulfonamido, diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, _ arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl, alkynyl, alkenyloxy, alkenyloxyalky, alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkenyl, 10 lower cycloalkylalkyl, lower cycloalkenylalkyl, halo, haloalkyl, haloalkenyl, haloalkoxy, hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, hydoxyheteroaralkyl, haloalkoxyalkyl, aryl, aralkyl, aryloxy, aralkoxy, aryloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkyl, heteroarylaikyl, 15 arylalkenyl, heteroarylalkenyl, carboxyalkyl, carboalkoxy, carboaralkoxy, carboxamido, carboxamidoalkyl, cyano, carbohaloalkoxy, phosphono, phosphonoalkyl, diaralkoxyphosphono, and diaralkoxyphosphonoalkyl.
Compounds of the present invention can exist in tautomeric, geometric or stereoisomeric forms. The present invention contemplates all such compounds, 20 including cis- and traps-Geometric isomers, E- and Z-geometric isomers, R-and S-enantiomers, diastereomers, d-isomers, l-isomers, the racemic mixtures thereof and other mixtures thereof, as fallinG within the scope of the invention.
Pharmaceutically acceptable sales of such tautomeric, geometric or stereoisomeric forms are also included within the invention.
25 The terms "cis" and "traps" denote a form of geometric isomerism in which two carbon atoms connected by a double bond will each have a hydrogen atom on the same side of the double bond ("cis'') or on opposite sides of the double bond (''traps").
Some of the compounds described contain alkenyi Groups, and are 30 meant to include both cis and traps or "E" and "Z" Geometric forms.
Some of the compounds described contain one or more stereocenters and are meant to include R, S, and mixtures of R and S forms for each stereocenter present.
Some of the compounds described herein may contain one or more 35 ketonic or aldehydic carbonyl groups or combinations thereof alone or as part of a heterocyclic rinG system. Such carbonyl groups may exist in part or principally in the "keto" form and in part or principally as one or more ''enoI"
forms of each aldehyde and ketone Group present. Compounds of the present invention having aldehydic or ketonic carbonyl groups are meant to include both "keto' and ''enol" tautomeric forms.
Some of the compounds described herein may contain one or more _ amide carbonyl groups or combinations thereof alone or as part of a heterocyclic ring system. Such carbonyl groups may exist in part or principally in the ''keto" form and in part or principally as one or more "enol" forms of each amide group present. Compounds of the present invention having amidic carbonyl groups are meant to include both ''keto" and "enol" tautomeric forms.
Said amide carbonyl groups may be both oxo (C=O) and thiono (C=S) in type.
Some of the compounds described herein may contain one or more imine or enamine groups or combinations thereof. Such groups may exist in part or principally in the "imine" form and in part or principally as one or more "enamine" forms of each group present. Compounds of the present invention having said imine or enamine groups are meant to include both "imine" and ''enamine" tautomeric forms.
The following general synthetic sequences are useful in making the present invention. Abbreviations used in the schemes are as follows: "AA"
represents amino acids, "BINAP" represents 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, "Boc" represents tert-butyloxycarbonyl, "BOP" represents benzotriazol-1-yl-oxy-tris-(dimethylamino), "bu" represents butyl, ''dba"
represents dibenzylideneacetone, ''DCC" represents 1,3-dicyclohexylcarbodiimide, "DIBAH" represents diisobutylaluminum hydride, "DIPEA" represents diisopropylethyIamine, "DMF" represents dimethylformamide, "DMSO" represents dimethylsulfoxide, "Fmoc"
represents 9-fluorenylmethoxycarbonyl, ''LDA" represents lithium diisopropylamide, "PHTH" represents a phthaloyl group, "pnZ" represents 4-nitrobenzyloxycarbonyl, "PTC" represents a phase transfer catalyst, "p-TsOH"
represents paratoluenesulfonic acid, "TBAF' represents tetrabutylammonium fluoride, "TBTU" represents 2-(1H-benzotriozole-1-yl)-1,1,3,3-tetramethyl uronium tetrafluoroborate, "TEA" represents triethylamine, "TFA" represents trifluoroacetic acid, ''THF' represents tetrahydrofuran, ''TMS" represents trimethylsilyl, and "Z" represents benzyloxycarbonyl.

PHARMACEUTICAL UTILITY AND COMPOSITION
The present invention comprises a pharmaceutical composition comprising a therapeutically-effective amount of a compound of Formulas VII-5 H, VII, VII-2, VII-3, VI1-4, and Cyclo-VII, in association with at least one pharmaceutically-acceptable carrier, adjuvant or diluent.
The present invention also comprises a treatment and prophylaxis of coronary artery disease and other CIJTP-mediated disorders in a subject, comprising administering to the subject having such disorder a therapeutically-10 effective amount of a compound of Formula I-WA:
R 16\
R15\z/A

R2 n Yi R3 R 14 ( I -WA ) wherein R1, R2, R3, n, R14, R15, Ri6~ A~ Q~ X, Y, and Z are as defined above for the compounds of Formula I-WA;
15 or a pharmaceutically-acceptable salt thereof.
As a further embodiment, compounds of the present invention of Formulas I-WA, I-WO, I-WOHA, I-WOPC, I-WOHA, and i-WOHC, or a pharmaceutically-acceptable salt thereof as defined above and further comprise 20 a treatment and prophylaxis of coronary artery disease and other CETP-mediated disorders in a subject, comprising administering to the subject having such disorder a therapeutically-effective amount of compounds of Formulas I-WA, I-WO, I-WOHA, I-WOPC, I-WOHA, and I-WOHC, of the present invention or a pharmaceutically-acceptable salt thereof.
25 Compounds of Formulas I-WA, I-WO, I-WOHA, I-WOPC, I-WOHA, and I-WOHC are capable of inhibiting activity of cholesteryl ester transfer protein (CETP), and thus could be used in the manufacture of a medicament, a method for the prophylactic or therapeutic treatment of diseases mediated by CETP, such as peripheral vascular disease, hyperlipidaemia, hypercholesterolemia, and other diseases attributable to either high LDL and low HDL or a combination of both, or a procedure to study the mechanism of action of the cholesteryl ester transfer protein (CETP) to enable the design of better inhibitors. The compounds of Formulas I-WA. I-WO, I-WOHA, I-5 WOPC, I-WOHA, and I-WOHC would be also useful in prevention of cerebral vascular accident (CVA) or stroke.
Also included in the family of compounds of Formulas I-WA, I-WO, I-WOHA, I-WOPC, I-WOHA, and I-WOHC are the pharmaceutically-acceptable salts thereof. The term "pharmaceutically-acceptable salts" embraces salts 10 commonly used to form alkali metal salts and to form addition salts of free acids or free bases. The nature of the salt is not critical, provided that it is pharmaceutically acceptable. Suitable pharmaceutically-acceptable acid addition salts of compounds of Formula I-WA may be prepared from inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, 15 hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid.
Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucoronic, malefic, fumaric, 20 pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, salicylic, p-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethylsulfonic, benzenesulfonic, sulfanilic, stearic, cyclohexylaminosulfonic, algenic, galacturonic acid. Suitable pharmaceutically-acceptable base addition salts of compounds of Formula I-WA include metallic salts made from 25 aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from N,N'-dibenzylethyleneldiamine, choline, chloroprocaine, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procain. All of these salts may be prepared by conventional means from the corresponding compounds of Formulas I-WA, I-30 WO, I-WOHA, I-WOPC, I-WOHA, and I-WOHC by reacting, for example, the appropriate acid or base with the compounds of Formulas I-WA, I-WO, I-WOHA, I-WOPC, I-WOHA, and I-WOHC.
Also embraced within this invention is a class of pharmaceutical compositions comprising the active compounds of Formula I-WA in 35 association with one or more non-toxic, pharmaceutically-acceptable earners and/or diluents and/or adjuvants (collectively referred to herein as "carrier"

materials) and, if desired, other active ingredients. The active compounds of the present invention may be administered by any suitable route, preferably in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended. The active compounds and composition 5 may, for example, be administered orally, intravascularly, intraperitoneally, _ subcutaneously, intramuscularly or topically.
For oral administration, the pharmaceutical composition may be in the form of, for example, a tablet, capsule, suspension or liquid. The pharmaceutical composition is preferably made in the form of a dosage unit 10 containing a particular amount of the active ingredient. Examples of such dosage units are tablets or capsules. The active ingredient may also be administered by injection as a composition wherein, for example, saline, dextrose or water may be used as a suitable carrier.
The amount of therapeutically active compounds which are 15 administered and the dosage regimen for treating a disease condition with the compounds and/or compositions of this invention depends on a variety of factors, including the age, weight, sex and medical condition of the subject, the severity of the disease, the route and frequency of administration, and the particular compound employed, and thus may vary widely.
2 0 The pharmaceutical compositions may contain active ine edients in the range of about 0.1 to 2000 mg, and preferably in the range of about 0.5 to 500 mg. A daily dose of about 0.01 to 100 mGIkG body weight, and preferably between about 0.5 and about 20 mGIkG body weight, may be appropriate. The daily dose can be administered in one to four doses per day.
25 The compounds may be formulated in topical ointment or cream, or as a suppository, containing the active ingredients in a total amount of, for example, 0.075 to 30% w/w, preferably 0.2 to 20% wlw and most preferably 0.4 to 15% w/w. When formulated in an ointment, the active ingredients may be employed with either paraffinic or a water-miscible ointment base.
30 Alternatively, the active ingredients may be formulated in a cream with an oil-in-water cream base. If desired, the aqueous phase of the cream base may include, for example at least 30% w/w of a polyhydric alcohol such as propylene Glycol, butane-1,3-diol, mannitol, sorbitol, glycerol, polyethylene Glycol and mixtures thereof. The topical formulation may desirably include a 35 compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethylsulfoxide and related analogs. The compounds of this invention can also be administered by a transdermal device. Preferably topical administration will be accomplished using a patch either of the reservoir and porous membrane type or of a solid matrix variety. In either case, the 5 active agent is delivered continuously from the reservoir or microcapsules through a membrane into the active agent permeable adhesive, which is in contact with the skin or mucosa of the recipient. If the active agent is absorbed through the skin, a controlled and predetermined flow of the active agent is administered to the recipient. In the case of microcapsules, the encapsulating 10 agent may also function as the membrane.
The oily phase of the emulsions of this invention may be constituted from known ingredients in a known manner. While the phase may comprise merely an emulsifier, it may comprise a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier 15 is included together with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both an oil and a fat. Together, the emulsifiers) with or without stabilizers) make-up the so-called emulsifying wax, and the wax together with the oil and fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations. Emulsifiers 20 and emulsion stabilizers suitable for use in the formulation of the present invention include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate, among others.
The choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties, since the solubility of the active 25 compound in most oils likely to be used in pharmaceutical emulsion formulations is very low. Thus, the cream should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers. Straight or branched chain, mono- or dibasic alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol diester of 30 coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters may be used. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils can be used.
35 For therapeutic purposes, the active compounds of this combination invention are ordinarily combined with one or more adjuvants appropriate to the indicated route of administration. If administered per os, the compounds may be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, 5 gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone, andlor polyvinyl _ alcohol, and then tableted or encapsulated for convenient administration. Such capsules or tablets may contain a controlled-release formulation as may be provided in a dispersion of active compound in hydroxypropylmethyl cellulose. Formulations for parenteral administration may be in the form of 10 aqueous or non-aqueous isotonic sterile injection solutions or suspensions.
These solutions and suspensions may be prepared from sterile powders or granules having one or more of the carriers or diluents mentioned for use in the formulations for oral administration. The compounds may be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, 15 peanut oil, sesame oil, benzyl alcohol, sodium chloride, and/or various buffers. Other adjuvants and modes of administration are well and widely known in the pharmaceutical art.
AlI mentioned references are incorporated by reference as if here written.
20 Although this invention has been described with respect to specific embodiments, the details of these embodiments are not to be construed as limitations.
GENERAL SYNTHETIC PROCEDURES

The compounds of the present invention can be synthesized, for example, according to the following procedures of Schemes 1 through 14 below, wherein the substituents are as defined for Formulas I-WA, I-WO, I-WOHA, I-WOPC, I-WOHA, and I-WOHC above except where further noted.
30 Synthetic Scheme 1 shows the preparation of compounds of formula XIIIA-H ("Secondary Heteroaryl Amines") which are intermediates in the preparation of the compounds of the present invention corresponding to Formula I-WO ("Alicyclic/Cyclic Aryl/Heteroaryl Aminoalcohols") and Formula I-WA ("Alicyclic/Cyciic Aryl/Heteroaryl tertiary Heteroalkylamines") 35 wherein one substituent (A or Q) on the nitrogen is AQ-1 which can be independently selected from the group consisting of aryl and heteroary(, which are preferably substituted with one or more Groups, and another substituent (A
or Q) on the nitrogen is AQ-2 which can be independently selected from the group consisting of AQ-2 and -CHZ(CR3~R38)~ (CR33R34)u-T-5 (CR3~R36)w H. AQ-2 and -CHZ(CR37R38w'(CR33R34.)u-T-(CR35R36)rv H can be independently selected from the group consisting of C3-C8 alkyl, C3-C8 alkenyl, C3-C8 alkynyl, C3-C8 haloalkyl, C3-C8 haloalkenyl, C3-C6 alkoxy C1-C2 alkyl, C3-C8 hydroxyhaloalkyl, C3-C10 cycloalkyl, CS-CIO
cycloalkenyl, C4-C9 saturated heterocyclyl, and C4-C9 partially saturated 10 heterocyclyl, wherein said group may be optionally substituted.
Schemes 1 through 14, taken together, prepare tertiary heteroalkylamine compounds of the present invention by addition of a halogenated, heteroatom (for example, oxygen, sulfur, or nitrogen) containing precursor to a resulting secondary amine to introduce a heteroatom containing 15 alkyl group wherein one of the two groups making up the secondary amine is aromatic groups and the other is aliphatic (for example, C3-C8 alkyl, C3-C8 alkenyl, C3-C8 alkynyl, C3-C8 haloalkyl, C3-C8 haloalkenyl, C3-C6 alkoxy Cl-C2 alkyl, C3-C8 hydraxyhaloalkyl, C3-C10 cycloaikyl, CS-C10 cycloalkenyl), C4-C9 saturated heterocyclyl, and C4-C9 partially saturated 2 0 heterocyclyl.
The "Heteroaryl Imines" corresponding to Formulas XII-AH, CXII-AH, CKXII-AH can be prepared through dehydration techniques generally known in or adaptable from the art by reacting "Heteroaryl Amine" of Formula X-AH or a "Heteroaryl Carbonyl" of Formula XI-AH with a suitable an 25 aliphatic, saturated heterocyclic, or partially saturated heterocyclic amine or carbonyl compound as shown in Schemes 1, 3, 4, 5, 6, 12, and subsequent specific examples. For example in Scheme 3, the two reactants (AQ-2A and XI-AH) react by refluxing them in an aprotic solvent, such as hexane, toluene, cyclohexane, benzene, and the like, using a Dean-Stark type trap to remove 30 water. After about 2-8 hours or until the removal of water is complete, the aprotic solvent is removed in vacuo to yield the "Heteroaryl Imine'' of Formula XII-AH.
The "Secondary Cyclic Heteroaryl Amines" of Formula XIIIA-H can be prepared from the corresponding "Generic (mine" of Formula XII, "Cyclic Heteroaryl Imine" of Formulas XII-AH, CXII-AH, and CKXII-AH can be prepared in several ways. For example, in one synthetic scheme (Reduction Method-1), the "Generic Imine" of Formula XII-AH is partially or completely dissolved in presence of a lower alcohol containing sufficient organic or 5 mineral acid, as described in WO Patent Application No. 9738973, Swiss Patent CH 441366 and U. S. Patent Nos. 3359316 and 3334017, which are incorporated herein by reference, and then hydrogenated at 0-100°C, more preferably 20-50°C, and most preferably between 20-30°C and pressures of 10-200 psi hydrogen or more preferably between .50-70 psi hydrogen in the 10 presence of a noble metal catalyst such as Pt02.
In another synthetic scheme (Reduction Method-2), the "Cyclic Heteroaryl Imine" of Formulas XII-AH, CXII-AH, and CKXII-AH is slurried in a lower alcohol such as ethanol, methanol or like solvent at 0-10°C
and solid sodium borohydride is added in batches over S-10 minutes at 0-10°C with 15 stirring. The reaction mixture is stirred below 10°C for 30-90 minutes and then is warmed gradually to 15-30°C. After about 1-10 hours, the mixture is cooled and acid is added until the aqueous layer was just acidic (pH 5-7).
In yet another synthetic scheme (Reduction Method-3), which is preferred when Z is an oxygen, the "Cyclic Heteroaryl Imine" of Formulas 2 0 XII-AH, CXII-AH, and CKXII-AH is slurried in a lower alcohol solvent at 0-10°C and acidified to a pH less than 4 and sodium cyanoborohydride is added in batches over 30-90 minutes at 0-20°C with stirring and addition of a suitable organic or mineral acid to keep the pH at or below 4. The reaction mixture is stirred and warmed gradually to about 20-25°C. After about 1-10 hours, the 25 mixture is cooled and base added until the mixture was just slightly alkaline.
The ''Secondary Cyclic Heteroaryl Amines" of Formulas XIII-AH, CXIIIA-H, and CKXIII-AH can also be prepared, according to Schemes 1 and 3, by an alkylation procedure based on the nucleophilic substitution of bromides by amines. In one synthetic alkylation scheme (Alkylation Method-30 1), a "Cyclic Amine" of Formula AQ-2A or a ''Generic Amine-1" of Formula X
is reacted with a "Heteroaryl Bromide" of Formula XXI-AH or "Generic Bromide" of Formula XXI as described in Vogel's Textbook of Practical Organic Chemistry, Fifth Edition, 1989, pages 902 to 905 and references cited therein all of which are incorporated herein by reference. In an alternate synthetic alkylation scheme exemplified in Scheme 1, an "Amine" of Formula 5 XXII is reacted with a "Heteroaryl Bromide" in a method employing palladium.
catalyzed carbon-nitrogen bond formation. Suitable procedures for this conversion are described in Wagaw and Buchwald, J. Orj. Chem.( 1996), 61, 7240-7241, Wolfe, Wagaw and Buchwald, J. Am. Chem. Soc. (1996), 118, 7215-7216, and Wolfe and Buchwald, Tetrahedron Letters ( I997), 38(36), 10 6359-6362 and references cited therein all of which are incorporated herein by reference.
The "Generic Secondary Amine", "Heteroaryl Amine", ''Cyclic Amine", "Alicyclic Amine", and "Heteoaryl Hydroxylamine" amines and hydroxylamines, the "Generic Carbonyl", "Heteroaryl Carbonyl", ''Cyclic 15 Carbonyl", and "Cyclic Ketone" aldehydes and ketones, and ''Generic Bromide-1", Generic Bromide-2", "Heteroaryl Bromide", and the like halides, tosylates, mesylates, triflates, and precursor alcohols required to prepare the "Secondary Cyclic Heteroaryl Amine" compounds are available from commercial sources or can be prepared by one skilled in the art from published 20 procedures. Commercial sources include but are not limited to Aldrich Chemical, TCI-America, Lancaster-Synthesis, Oakwood Products, Acros Organics, and Maybridge Chemical. Disclosed procedures for "Generic Amine" amines, hydroxylamines, and hydrazines include Sheradsky and Nov, J. Chem. Soc., Perkin Trans.l ( 1980), ( 12), 2781-6; Marcoux, Doye, and 25 Buchwald, J. Am. Chem. Soc. (1997), 1 I9, 1053-9; Sternbach and Jamison, Tetrahedron Lett. ( 1981 ), 22(35), 3331-4; U. S. Patent No. 5306718; EP No.
314435; WO No. 9001874; WO No. 9002113; JP No. 05320117; WO No.
9738973; Swiss Patent No. CH 441366; U. S. Patents Nos. 3359316 and 3334017; and references cited therein which are incorporated herein by 3 0 reference.
Synthetic Schemes 2, IO and 11 show the preparation of the class of compounds of the present invention corresponding to Formula I-WO
("Alicyclic/Cyclic Aryl/Heteroaryl Aminoalcohols") and Formula I-WA
("Alicyclic/Cyclic Aryl/Heteroaryl tertiary Heteroalkylamines").
35 Derivatives of "AlicycliclCyclic Aryl/Heteroaryl Aminoalcohols" or "Alicyclic/Cyclic Aryl/Heteroaryl tertiary Heteroalkylamines", in which the ", CA 02345108 2001-03-22 ' 70 heteroatom (O, N, or S) is attached to an alkyl group removed from the amine by two or more carbons are readily prepared by anion chemistry using the method of Scheme 2. The anion of "Secondary Amine" amines and hydroxylamines of Formula XIII are readily formed by dissolving the specific amine, hydroxylamine, or hydrazine in an aprotic solvent, such as _ tetrahydrofuran, toluene, ether, dimethylformamide, and dimethylformamide, under anhydrous conditions. The solution is cooled to a temperature between -78 and 0°C, preferably between -78 and -60°C and the anion formed by the addition of at least one equivalent of a strong, aprotic, non-nucleophillic base such as NaH or n-butyllithium under an inert atmosphere for each acidic group present. Maintaining the temperature between -78 and 0°C, preferably between -78 and -60°C> with suitable cooling, an appropriate alkyl halide, alkyl benzenesulfonate such as a alkyl tosylate, alkyl mesylate, alkyl triflate or similar alkylating reagent of the general structure:
Ris\
X

R1 I ~(CH)n M (XXX) where m is zero, X can be RN, O, and S, and M is a readily displaceable group such as chloride, bromide, iodide, tosylate, triflate, and mesylate. After allowing the reaction mixture to warm to room temperature, the reaction product is added to water, neutralized if necessary, and extracted with a water-2 0 immiscible solvent such as diethyl ether or methylene chloride. The combined aprotic solvent extract is washed with saturated brine, dried over drying agent such as anhydrous MgSO~ and concentrated in vacuo to yield crude Formula I-WO ("Alicyclic/Cyclic Aryl/Heteroaryl Aminoalcohols") and Formula I-WA
("Alicyclic/Cyclic Aryl/Heteroaryl tertiary Heteroalkylamines"). This material is purified, for example, by eluting through silica gel with a medium polar solvent such as ethyl acetate in a non-polar solvent such as hexanes to yield purified Formula (-WA and Formula I-WO. Products are structurally confirmed by low and high resolution mass spectrometry and NMR.

Compounds of Formula (XXX), which can be used to prepare I-WA, I-WO, I-WOPA, I-WOPC, I-WOHA, and I-WOHC, are given in Table 2.
Reagents la and 2a in Table 2 are prepared from the corresponding alcohols.
The tosylates are readily obtained by reacting the corresponding alcohol with 5 tosyl chloride using procedures found in House's Modern Synthetic Reactions, Chapter 7, W. A. Benjamin, Inc., Shriner, Fuson, and Curtin in The Systematic Indentification of Organic Compounds, 5th Edition, John Wiley &
Sons, and Fieser and Fieser in Reagents for Organic Synthesis, Volume 1, John Wiley & Sons, which are incorporated herein by reference.
10 A preferred procedure for Formula I-WO ("Alicyclic/Cyclic Aryl/Heteroaryl Aminoalcohols") and Formula I-WA ("AlicycliclCyclic Aryl/Heteroaryl tertiary Heteroalkylamines" compounds is Method A of Schemes 2, 10, 11, and 14. Oxirane reagents useful in Method A are exemplified, but not limited to those in Table 1. Formula I-WO
15 ("AIicyclic/Cyclic Aryl/Heteroaryl 1-Amino-2-alcohol") and Formula I-WA
("Alicyclic/Cyclic Aryl/Heteroaryl tertiary 2-Heteroalkylamine") compounds are prepared by using "Secondary Cyclic Heteroaryl Amine" and "Alicyclic Heteroaryl Amine" amines and hydroxylamines of Formulas XIIIA-H, CXIIIA-H, CKXIII-AH, ACXIIIA-H, and RACXIIIA-H prepared above with 20 oxiranes of the type listed in Table 1 and represented by the general structure:

(RIC) In some cases, the oxiranes are prepared by reaction of epoxidation reagents such as MCPBA and similar type reagents readily selectable by a person of skill-in-the-art with alkenes. Fieser and Fieser in Reagents for Organic 25 Synthesis, John Wiley & Sons'provides, along with cited references, numerous suitable epoxidation reagents and reaction conditions, which are incorporated herein by reference.
Formula I-WA ("Alicyclic/Cyclic Aryl/Heteroaryl tertiary 2 Heteroalkylamine") compounds, wherein the 2-hetero group is an amino, 30 substituted amino, or thiol,-can be prepared by using appropriate aziridines and thirranes according to Method A of Scheme 2. Aziridine and thiirane reagents 72 _ useful in Method A are exemplified, but not limited to those in Table 1. These Formula I-WA ("Alicyclic/Cyclic Aryl/I-Ieteroaryl tertiary 2-Heteroalkylamine"j compounds, wherein the 2-hetero b oup is an amino, substituted amino, or thiol, can be prepared by using "Secondary Cyclic Heteroaryl Amine" and 5 ''Alicyclic Heteroaryl Amine" amines and hydroxylamines of Formulas XIIIA=
H, CXIIIA-H, CKXIII-AH, ACXIIIA-H, and RACXIIIA-H prepared above with aziridines and thiiranes of the type listed in Table 1 and represented by the General structure:
Rig X H
(XX) wherein X is selected from N and S and R16 10 is hydrogen or another suitable group when X is N.

Table 1. Structure of Oxirane, Aziridine, and Thiirane Reagents.

i (XX) No :

I ______ O CF H H

2 ______ O CCl H H

3 ______ O CF3 CH3 H

______ O CF3CF2 H H

______ O CF3CF2CF2 H H

7 ______ O CF3CH2 H H

g ______ O CF3 CHF2 H

9 ___-__ O CF3 H CF3 10 ______ O CF3 CF3 H

I1 ______ O CF3 C6H5 H

12 ______ O CCl3 C6H$ H

13 ------ O CCI CyclopropylH

______ ~ CCl3 CH3 H

IS ______ ~ CCl3 (CH3) 2CH H

16 _----- O CHCI2 H H

18 ______ O CF3 H CH3 --i 9 H N CF CF H

Table 1. (continued) Structure of Oxirane, Aziridine, and Thiirane Reagents.

No. - - -2l Benzyl N CF H H

24 Benzyloxy N CF H H

25 ______ S CF H H

26 ______ -S CF3CF2 H H

27 __-___ ~ CCl3CH2 H H

28 ------ O CBr3CH2 H H

29 ------ 0 CHBr2CH2 H H

30 ______ ~ CBrCl2 H H

31 ______ 0 _ CClF2 H H
-32 ______ 0 CCl2F H H

33 ------ O CC~3CCl2 H H

43 ______ 0 FCH H H

______ O = (CH ) CF3 R2+R3 2 47 ______ O CF3--_. _- R2+R3 =
(CH2)4 48 ______ O -- CHF2-_ R2+R3 _ (CH2)4 56 ------ O CgrF2CC1FCH2 H H

N

~

O O
M

O O
'. ~t r.

O _ y", U O
U
v C c,: c~
~ N

O O
~

_ O
O I
~

s~

O ~
I'' O O
.-~ .
' .~..

O ~ ..C
~

~U

s c g .
U .
Ad :

..
L L
L" c~
r c ~a a~

a ~a u~ Uz ~o v V ~ ~ 04 x x M

.. ~ ~ ~ z ~~

Q x ~ O O

~ N

~ Ci M M
U ~ I

lfl f--i N

-i (~

~3 M N

cs Li.
:

_' ~ U U

a U
L

y (V y Q

H x z A mixture of a "Secondary Amine" amine or hydroxylamine and an oxirane of Formula XX are stirred and heated to 40-90°C for 5 to 48 hours in a tightly capped or contained reaction vessel. A Lewis acid such as ytterbium triflate in acetonitrile may be added to speed up reaction and improve yield.
5 When a Lewis acid is used, the reaction should be carried out under inert, anhydrous conditions using a blanket of dry nitrogen or argon gas. After cooling to room temperature and testing the reaction mixture for complete reaction by thin layer chromatography or high pressure liquid chromatography (hplc), the reaction product is added to water and extracted with a water 10 immiscible solvent such as diethyl ether or methylene chloride. (Note: If the above analysis indicates that reaction is incomplete, heating should be resumed until complete with the optional addition of more of the oxirane). The combined aprotic solvent extract is washed with saturated brine, dried over drying agent such as anhydrous MgSO~ and concentrated in vacuo to yield 15 crude Formula I-WO ("Alicyclic/Cyclic Aryl/Heteroaryl Aminoalcohols") and Formula I-WA ("Alicyclic/Cyclic Aryl/Heteroaryl tertiary Heteroalkylamines") compounds. This material is purified by eluting through silica gel with 5~0°l0 of a medium polar solvent such as ethyl acetate in a non-polar solvent such as hexanes to yield the Formula I-WO ("Alicyclic/Cyclic AryI/Heteroaryl 20 Aminoaicohols") and Formula I-WA ("Alicyclic/Cyclic Aryl/Heteroaryl tertiary Heteroalkylamines") compounds. Products are tested for purity by HPLC. If necessary, the Formula I-WO ("Alicyclic/Cyclic Aryl/Heteroaryl Aminoalcohols") and Formula I-WA ("Alicyclic/Cyclic AryIIHeteroaryl tertiary Heteroalkylamines") compounds are purified by additional chromatography or 25 recrystallization. Products are structurally confirmed by low and high resolution mass spectrometry and NMR. Examples of specific Formula VII
Formula I-WO ("Alicyclic/Cyclic Aryl/Heteroaryl Aminoalcohols") and Formula I-WA ("Alicyclic/Cyclic Aryl/Heteroaryl tertiary Heteroalkylamines") prepared are summarized in the Examples and Example Tables 1 through 7.
30 Specific Formula I-WO ("Alicyclic/Cyclic Aryl/Heteroaryl Aminoalcohols") and Formula I-WA ("Alicyclic/Cyclic Aryl/Heteroaryl tertiary Heteroalkylamines") analogs of the Formula I-WO ("Alicyclic/Cyclic Ary1/Heteroaryl Aminoalcohols") and Formula I-WA ("AlicycliclCyclic Aryl/Heteroaryl tertiary Heteroalkylamines") compounds summarized in the 35 Examples and Example Tables 1 through 7, wherein the hydroxyl or oxy group are replaced with an amino, substituted amino, aza, or thiol, can be prepared by using the appropriate aziridine reagents or thiirane reagents readily by adapting the procedures in the numerous specific Examples and Schemes disclosed in the present invention. Similarly, intermediates, in which the hydroxyl or oxy group of said intermediates are replaced with an amino, substituted amino, aza, 5 or thiol, can be converted using the numerous specific Examples and Schemes disclosed in the present invention to other Formula I-WO
("Alicyclic/Cyclic Aryl/Heteroaryl Aminoalcohols") and Formula I-WA
("Alicyclic/Cyclic Aryl/Heteroaryl tertiary HeteroaIkylamines") compounds.
Formula I-WO ("Alicyclic/Cyclic Aryl/Heteroaryl Aminoalcohols") and 10 Formula I-WA ("Alicyclic/Cyclic Aryl/Heteroaryl tertiary Heteroalkylamines") compounds can further be prepared in an alternate manner to procedures disclosed above and in Schemes 1, 2, and 3. Schemes 12 and 13 detail such procedures to prepare compounds of the present invention by initial formation of an halogenated, oxygen containing primary alkylamine XL ("Generic 15 Substituted Alkylamine"). Said halogenated, oxygen containing primary alkylamine XL, formed in Scheme 12, is itself converted to secondary amine LX-H ("Heteroaryl Alkyl Amine) using procedures disclosed above. Primary alkylamine XL is first reacted with an aldehydic or ketonic carbonyl compound, XI-AH ("Heteroaryl Carbonyl") with azeotropic distillation to form 20 imines, L-H ("Heteroaryl Imine"). Said imine L-H are then reduced with or without prior isolation by Reduction Methods 1, 2 or 3 as disclosed above and in Scheme 1 to yield secondary amines LX-H ("Heteroaryl Alkyl Amine). Said secondary amine LX-H can be converted according to Scheme 14 to Formula I-WO ("Alicyclic/Cyclic Aryl/Heteroaryl Aminoalcohols").
2 5 Formula I-WO ("Alicyclic/Cyclic Aryl/Heteroaryl Aminoalcohols") and Formula I-WA ("Alicyc(ic/Cyclic Aryl/Heteroaryl tertiary Heteroalkylamines") compounds can further be prepared in an alternate manner to procedures disclosed above and in additional Schemes.
Formula I-WO ("Alicyclic/Cyclic Aryl/Heteroaryl Aminoalcohols") are 30 alternately referred to as Formula I-WO ("Alicyclic/Cyclic Ary1/Heteroaryl hydroxyalkylamines").
Formula I-WO ("Alicyclic/Cyciic Aryl/Heteroaryl Aminoalcohols") and Formula I-WA ("Alicyclic/Cyclic Aryl/Heteroaryl tertiary Heteroalkylamines") compounds can themselves serve as intermediates for conversion to additional 35 compounds of this invention. Compounds of the present invention useful as intermediates include those in which the R; or R~ position substituent in Formula I-WO ("Alicyclic/Cyclic Aryl/Heteroaryl Aminoalcohols") and Formula I-WA ("Alicyclic/Cyclic Aryl/Heteroaryl tertiary Heteroalkylamines") compounds is a bromo group, hydroxyl group, sulfhydryl group, bromomethyl or other bromoalkyl groups, vitro group, amino group, methoxy 5 carbonyl or other alkoxy carbonyl groups, cyano group, or acyl groups. Other preferred compounds of the present invention useful as intermediates include those in which the Rio position substituent in Formulas I-WA or I-WO is a bromo group, hydroxyl group, sulfhydryl group, bromomethyl or other bromoalkyl groups, vitro group, amino group, methoxy carbonyl or other 10 alkoxy carbonyl groups, cyano group, or acyl groups. Other compounds of Formulas I-WA or I-WO and the present invention useful as intermediates include those in which one or more of R6, R~ ~ , and R~., substituents in Formulas I-WA or I-WO is a bromo group, hydroxyl croup, sulfhydryl group, bromomethyl or other bromoalkyl groups, vitro group, amino group, methoxy 15 carbonyl or other alkoxy carbonyl groups, cyano group, or acyl groups.
Formula I-WO ("AlicycIic/Cyclic Aryl/Heteroaryl Aminoalcohols") are alternately referred to as Formula I-WO ("Alicyclic/Cyclic ArylIHeteroaryl Tertiary 2-hydroxyalkylamines").
A 3-bromo substituent at the R~ position in Formula I-WO
20 ("Alicyclic/Cyclic 3-Bromoaryl Tertiary 2-Hydroxyalkylamines") can be reacted with a phenol to afford 3-phenoxy compounds of the present invention of Formula I-WO ("Alicyclic/Cyclic 3-Phenoxyaryl Tertiary 2-Hydroxyalkylamines").
A 3-bromo substituent at the R5 position in Formula I-WO
25 ("Alicyclic/Cyclic 3-Bromoheteroaryl Tertiary 2-hydroxyalkylamine") can, be reacted, for example, with a phenol to afford additional compounds of the present invention of Formula I-WO ("Alicyclic/Cyclic 3-Aryloxyaryl, 3-Heteroaryloxyaryl, 3-Heteroaryloxyheteroaryl, and 3-Aryloxyheteroaryl Tertiary 2-Hydroxyalkylamines").
30 A 3-bromo substituent at the R; position in Formula I-WO
("AlicycIic/Cyclic 3-Bromoaryl Tertiary 2-hydroxyalkylamine") can be reacted with a phenol to afford additional compounds of the present invention of Formula I-WO ("Alicyclic/Cyclic 3-Phenylaryl Tertiary 2-Hydroxyalkylamine").

Conversion of a 3-bromo substituent at the R5 position in Formula l-WO ("Alicyclic/Cyclic 3-Bromoaryl Tertiary 2-hydroxyalkylamine") by reaction with a primary or secondary amine can afford additional compounds of the present invention of Formula 1-WO ("Alicyclic/Cyclic 3- R.,.,aminoaryl 5 Tertiary 2-Hydroxyalkylamine"). _ Conversion of a 3-bromo substituent at the RS position in Formula I-WO ("Alicyclic/Cyclic 3-Bromoaryl Tertiary 2-hydroxyalkylamine") by reaction with an aryl borinate can afford additional compounds of the present invention of Formula I-WO ("Alicyclic/Cyclic 3-Phenylaryl Tertiary 2-20 Hydroxyalkylamine").
Conversion of a 3-bromo substituent at the R~ position in Formula I-WO ("Alicyclic/Cyclic 3-Bromoaryl Tertiary 2-hydroxyalkylamine") by reaction with a heteroaryl dibutyl tin compound can afford additional compounds of the present invention of Formula I-WO ("Alicyclic/Cyclic 3-15 Heteroarylaryl Tertiary 2-Hydroxyalkylamine").
Conversion of a 3-bromomethyl substituent at the RS position in Formula I-WO ("Alicyclic/Cyclic 3-Bromomethylaryl Tertiary 2-hydroxyalkylamine") by reaction with an aryl borinate can afford additional compounds of the present invention of Formula I-WO ("Alicyclic/Cyclic 3-20 Arylmethylaryl Tertiary 2-Hydroxyalkylamine").
Conversion of a 3-hydroxyl substituent at the RS position in Formula I-WO ("Alicyclic/Cyclic 3-Hydroxyheteroaryl Tertiary 2-hydroxyalkylamine") by reaction with an aryl bromide or heteroaryl bromide can afford additional compounds of the present invention of Formula I-WO ("AlicycIic/Cyclic 3-25 Aryloxyaryl, 3-Heteroaryloxyaryl, 3-Heteroaryloxyheteroaryl, and 3-Aryloxyheteroaryl Tertiary 2-Hydroxyalkylamines").
Conversion of a 3-hydroxyl substituent at the R~ position in Formula I-WO ("Alicyclic/Cyclic 3-Hydroxyaryl Tertiary 2-hydroxyalkylamine") by reaction with an aryl bromide can afford additional compounds of the present 30 invention of Formula I-WO ("Alicyclic/Cyclic 3-Phenoxyaryl Tertiary 2-Hydroxyalkylamine").
Conversion of a 3-hydroxyl substituent at the RS position in Formula I-WO ("Alicyclic/Cyclic 3-Hydroxyheteroaryl Tertiary 2-hydroxyalkylamine") by reaction with an aralkyl bromide or heteroaralkyl bromide can afford additional compounds of the present invention of Formula I-WO
("Alicyclic/Cyclic 3-Aralkyloxyaryl, 3-Heteroaralkyloxyaryl, 3-Heteroaralkyloxyheteroaryl, and 3-Aralkyloxyheteroaryl Tertiary 2-Hydroxyalkylamines").
5 Conversion of a 3-hydroxyl substituent at the R~ position in Formula I
WO ("Alicyclic/Cyclic 3-Hydroxyaryl Tertiary 2-hydroxyalkylamine") by reaction with an aralkyl bromide can afford additional compounds of the present invention of Formula I-WO ("AlicycliclCyclic 3-Aralkyloxyaryl Tertiary 2-Hydroxyalkylamine").
10 Conversion of a 3-hydroxyl substituent at the R; position in Formula 1-WO ("Alicyclic/Cyclic Polycyclic 3-Hydroxyaryl Tertiary 2-hydroxyalkylamine") by reaction with a displaceable organo bromide can afford additional compounds of the present invention of Formula I-WO
("Alicyclic/Cyclic 3-Organooxyaryl Tertiary 2-Hydroxyalkylamine").
15 Conversion of a 3-thio substituent at the R5 position in Formula I-WO
("AlicycIic/Cyclic 3-thioaryl Tertiary 2-hydroxyalkylamine") by reaction with a displaceable organo bromide can afford additional compounds of the present invention of Formula I-WO ("Alicyclic/Cyclic 3-Organothiaaryl Tertiary 2-Hydroxyalkylamine"). "Alicyctic/Cyclic 3-Organothiaaryl Tertiary 2-2 0 Hydroxyalkylamines" can be oxidized to sulfonyl compounds of 3-Organosulfonylaryl Tertiary 2-Hydroxyalkylamine").
Conversion of a 3-vitro substituent at the R5 position in Formula I-WO
("AlicycliclCyclic 3-Nitroaryl Tertiary 2-hydroxyalkylamine") .by hydrogenation can afford additional compounds of the present invention of 25 Formula I-WO ("Alicyclic/Cyclic 3-Aminoaryl Tertiary 2-Hydroxyalkylamine"). Formula I-WO ("Alicyclic/Cyclic 3-Aminoaryl Tertiary 2-Hydroxyalkylamines") can be acylated to acyl amide compounds of Formula I-WO ("AlicycliclCyclic 3-Acylaminoaryl Tertiary 2-Hydroxyalkylamine").
Conversion of a 3-amino substituent at the RS position in Formula I-30 WO ("AlicycIic/Cyclic 3-Aminoaryl Tertiary 2-hydroxyalkylamine") by reaction with carbonyl compounds can afford additional compounds of the present invention of Formula I-WO ("Alicyclic/Cyclic 3-(Saturated Nitrogen Heterocycl-lyl)aryl Tertiary 2-Hydroxyalkylamine" and "AlicycliclCyclic 3-(Unsaturated Nitrogen Heterocycl-lyl)aryl Tertiary 2-Hydroxyalkylamine").

Conversion of a 3-methoxycarbonyl substituent at the R~ position in Formula I-WO ("Alicyclic/Cyclic 3-Carbomethoxyaryl Tertiary 2-hydroxyalkylamine") by reaction with amination reagents can afford additional compounds of the present invention of Formula I-WO ("Alicyclic/Cyclic 3-5 Carboxamidoaryl Tertiary 2-Hydroxyalkylamine").
Conversion of a 3-cyano substituent at the R5 position in Formula I-WO ("AiicycIic/Cyclic 3-Cyanoaryl Tertiary 2-hydroxyalkylamine") by reaction with organometaIlic reagents can afford additional compounds of the present invention of Formula I-WO ("Alicyclic/Cyclic 3-Acylaryl Tertiary 2-10 Hydroxyalkylamine"). Said "Alicyclic/Cyclic 3-Acylaryl Tertiary 2-Hydroxyalkylamines", can be reduced to hydroxyl compounds of Formula I-WO ("Alicyclic/Cyclic 3-Hydroxysubstitutedmethylaryl Tertiary 2-Hydroxyalkylamine").
Conversion of a 3-methoxycarbonyl substituent at the Ri ~ position in 15 Formula I-WO ("Alicyclic/Cyclic 3-Carbomethoxyaryl Tertiary 2-hydroxyalkylamine") by reaction with amination reagents can afford additional compounds of the present invention of Formula I-WO ("Alicyclic/Cyclic 3-Carboxamidoaryl Tertiary 2-Hydroxyalkylamine").
Conversion of a 3-methoxycarbonyl substituent at the R1 o position in 20 Formula I-WO ("Alicyciic/Cyclic 3-Carbomethoxyaryl Tertiary 2-hydroxyalkylamine") by reaction with an organometallic reagent can afford additional compounds of the present invention of Formula I-WO
("Alicyclic/Cyclic 3-(bis-Organohydroxymethyl)aryl Tertiary 2-Hydroxyalkylamine").
25 Conversion of a 3-methoxycarbonyl substituent at the R1 o position in Formula I-WO ("Alicyclic/Cyclic 3-Carbomethoxyaryl Tertiary 2-hydroxyalkylamine") by reaction with lithium aluminum hydride can afford additional compounds of the present invention of Formula I-WO
("Alicyclic/Cyclic 3-Hydroxymethylaryl Tertiary 2-Hydroxyalkylamine").
30 Conversion of a 3-methoxycarbonyl substituent at the R~ o position in Formula I-WO ("Alicyclic/Cyclic 3-Carbomethoxyaryl Tertiary 2-hydroxyalkylamine") by reaction with an alkylation reagent can afford additional compounds of the present invention of Formula I-WO
("Alicyclic/Cyclic 3-(bis-Organo-hydroxymethyl)aryl Tertiary 2-35 Hydroxyalkylamine").

Conversion of a 3-methoxycarbonyl substituent at the R~ ~ position in Formula I-WO ("Alicyclic/Cyclic 3-Carbomethoxyaryl Tertiary 2-hydroxyalkylamine") by reaction intially with an amidation reagent and then an organometallic reagent can afford additional compounds of the present 5 invention of Formula I-WO ("Alicyclic/Cyclic 3-(Organo-carbonyi)aryl Tertiary 2-Hydroxyalkylamine").
Formula I-WO ("Alicyclic/Cyclic Aryl/Heteroaryl Aminoalcohols") and Formula I-WA ("AlicycliclCyclic Aryl/Heteroaryl tertiary Heteroalkylamines") and other compounds of this invention posssessing hydroxyl, thiol, and amine 10 functional groups can be converted to a wide variety derivatives. The hydroxyl group X, wherein RI6 is a hydrogen, of compounds of the present invention can be readily converted to esters of carboxylic, sulfonic, carbamic, phosphonic, and phosphoric acids. Acylation to form a carboxylic acid ester is readily effected using a suitable acytating reagent such as an aliphatic acid I5 anhydride or acid chloride. The corresponding aryl and heteroaryl acid anhydrides and acid chlorides can also be used. Such reactions are generally carried out using an amine catalyst such as pyridine in an inert solvent. In like manner, compounds that have at least one hydroxyl group present in the form of an alcohol or phenol can be acylated to its corresponding esters.
Similarly, 20 carbamic acid esters (urethans) can be obtained by reacting any hydroxyl group with isocyanates and carbamoyl chlorides. Sulfonate, phosphonate, and phosphate esters can be prepared using the corresponding acid chloride and similar reagents. Compounds that have at least one thiol group present can be converted to the corresponding thioesters derivatives analogous to those of 25 alcohols and phenols using the same reagents and comparable reaction conditions. Compounds of Formulas I-WA, I-WO, and other compounds of the present invention that have at least one primary or secondary amine group present can be converted to the corresponding amide derivatives. Amides of carboxylic acids can be prepared using the appropriate acid chloride or 30 anhydrides with reaction conditions analogous to those used with alcohols and phenols. Ureas of the corresponding primary or secondary amine can be prepared using isocyanates directly and carbamoyl chlorides in the presence of an acid scavenger such as triethylamine or pyridine. Sulfonamides can be prepared from the corresponding sulfonyl chloride in the presence of aqueous 35 sodium hydroxide. Suitable procedures and methods for preparing these derivatives can be found in House's Modern Synthetic Reactions, W. A.

WO 00/18723 PC'T/US99/22123-Benjamin, Inc., Shriner, Fuson, and Curtin in The Systematic lndentification of Organic Compounds, Sth Edition, John Wiley & Sons, and Fieser and Fieser in Reagents for Organic Synthesis, Volume 1, John Wiley & Sons.
Reagents of a wide variety that can be used to derivatize hydroxyl, thiol, and 5 amines of compounds of Formulas I-WA, I-WO, and other compounds of the present invention are available from commerical sources ar the references cited-above, which are incorporated herein by reference.
Formula I-WO ("Alicyclic/Cyclic Aryl/Heteroaryl Aminoalcohols") and Formula I-WA ("Alicyclic/Cyclic Aryl/Heteroaryl tertiary Heteroalkylamines") 10 and other compounds of this invention posssessing hydroxyl, thiol, and amine functional groups can be alkylated to a wide variety derivatives. The hydroxyl group X, wherein R16 is a hydrogen, of compounds of Formulas I-WA, I-WO, and other compounds of the present invention can be readily converted to ethers. Alkylation to form an ether is readily effected using a suitable 15 alkylating reagent such as an alkyl bromide, alkyl iodide or alkyl sulfonate.
The corresponding aralkyl, heteroaralkyl, alkoxyalkyl, aralkyloxyalkyl, and heteroaralkyloxyalkyl bromides, iodides, and sulfonates can also be used.
Such reactions are generally carned out using an alkoxide forming reagent such as sodium hydride, potassium t-butoxide, sodium amide, lithium amide, and n-20 butyl lithium using an inert polar solvent such as DMF, DMSO, THF, and similar, comparable solvents. amine catalyst such as pyridine in an inert solvent. In like manner, compounds of Formulas I-WA, I-WO, and the like that have at least one hydroxyl group present in the form of an alcohol or phenol can be alkylated to their corresponding ethers. Compounds of Formulas 25 I-WA, I-WO, and other compounds that have at least one thiol group present can be converted to the corresponding thioether derivatives analogous to those of alcohols and phenols using the same reagents and comparable reaction conditions. Compounds of Formulas I-WA,1-WO, and other compounds that have at least one primary, secondary or tertiary amine group present can be 30 converted to the corresponding quaternary ammonium derivatives. Quaternary ammonium derivatives can be prepared using the appropriate bromides, iodides, and sulfonates analogous to those used with alcohols and phenols.
Conditions involve reaction of the amine by warming it with the alkylating reagent with a stoichiometric amount of the amine (i.e., one equivalent with a 35 tertiary amine, two with a secondary, and three with a primary). With primary and secondary amines, two and one equivalents, respectively, of an acid scavenger are used concurrently. Tertiary amines can be prepared from the corresponding primary or secondary amine by reductive alkylation with aldehydes and ketones using reduction methods 1, 2, or 3 as shown in Scheme 1. Suitable procedures and methods for preparing these derivatives can be 5 found in House's Modern Synthetic Reactions, W. A. Benjamin, Inc.>
Shriner, Fuson, and Curtin in The Systematic indentification of Organic Compounds, Sth Edition, John Wiley & Sons, and Fieser and Fieser in Reagents for Organic Synthesis, Volume 1, John Wiiey & Sons.
Perfluoroalkyl derivatives can be prepared as described by DesMarteau in J.
10 Chem. Soc. Chem. Commun. 2241 (1998). Reagents of a wide variety that can be used to derivatize hydroxyl, thiol, and amines of compounds of Formulas I-WA, I-WO, and the like are available from commerical sources or the references cited above, which are incorporated herein by reference.
The following examples are provided to illustrate the present invention and 15 are not intended to limit the scope thereof. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds.

$5 A SG~lf'II~IE' _ i R15 Z + ~ ~ -H20 A

NHZ R14~ ~Q heat , Generic Imine Generic Amine-1 Generic Carbonyl R15 (x) Compound (xII) (xI; Y - C) N
'Y

Akylation R Reduction 114 Method-1:
Method-1: Reduction Y H2/ Pt02 Method-3:
Br/ ~Q 20°COH Reduction NaCNBH3 Generic Bromide-1 g0 psi Method-2: 20°C
(xxI; Y = CH) NaBH4 pH < 4 NaHCO
0-20°C
Solvent A
R15 ~ ~ Generic Secondary 14 ~ N\ Y Amine Y / ~Q (xI II ) Generic Amine-2 ( xx I I ; Y = CH ) ~Ylation Method-2 + Pd2(dba)3 + Base A -Br Generic Bromide-2 (xxIII) Scheme 2 A
Generic _ R15 ~ Secondary Amine /N\Y (XIII) I~ \Q

Method B:
Method A:
Z. NaH or n-BuLi R1 H Aprotic Solvent, -78°C
(RR) 2. R2 R3 I
R2 R3 R1- i - (CHjn M
60-90°C/THF/Lewis Aci R16-. X ( XRIC ) 'A

R16 X ~ / N\
(CHjn Y Q
R

I-WA (X = O, S, NH), I-WO, I-WOPA, I -WOPC , I -WOHA, and I -WOHC ( X = O in others ) Scheme 3 AQ-2 A: Cyclic Amine R11' % 31 Heteroaryl Carbonyl _ J3-K~ ( X I -AH ) R4 R10"'~ ~ y iR32 1 3 ~ 4 O~Y D1 /R5 /B1 D4~ ~ ~ II
R9 ~ ~ R12 R14 ~D2~ ~K1..
/Al-B\ R8 12 R6 heat R4 (XII-AH) : Cyclic I Ra Heteroaryl Imine Br ~Y ~ 1~J ~5 R5w .K1.. ~R7 R ~ II J1 J2 14 ~D2 ~ ~Kl~ ~ II
R8 12 R6 R ~D1~2\R R10 '1 R ~ Rll Heteroaryl Bromide R14 ~ ~ iD3~
(XXI-AH) ~~ ~ 1 J3 Akylation N Al K2-'R31 Method-1: \ /
Solvent B21 iJ4 R31 NaHC03 / ,4 \R32 ~ /R32 R31 R12 Rll /K2~ Reduction ~J3 J; Method-1: Reduction D -,..R12 H2 /Pt02 Method-2 _--D 4 C2H50H NaBH4 R10 \B -' / 2\ 2 0°C CH3aC
1 A1 R13 60 psi ~-20 R Reduction N 14 Method-3:
D R NaCNBH3 1~J ~ 5 CH30H/20°C/pH <a_ R14 /D2. -K1.

R Secondary Cyclic Heteroaryl Amine ( XI I IA-H ) Scheme 4 R11\ /R31 R10\ ~J3 K2~ ~R32 H2N R _ I 3 I 4 ~Y /Dl~ J ~R5 /B1 ~D4~~. R ~ ~ n i Rg W R12 14 ~D2: ~Ki_ Al- ~ R8 t 2 R6 O heat Heteroaryl Amine AQ-2C: Cyclic (X-Ag) Carbonyl R

R5\ iKiw ~R7 (CXII-AH): Cyclic i1 t~2 Heteroaryl Imine /D1 w D2, Reduction R10 Method-1: R14 H2/Pt02 ' R \B iD3~,J 11 2 0°C \~ i K2-"-R31 60 psi ~ ~ /
R31 1 R15 ~B2~D4~J4v R
R32 Reduction R31 ~ 32 Ril~ rK2~J4 Method-2: R12 J3 ~ NaBH4 I D4'Rl CH30H
_---D
R10 \ ~ 0-20°C Reduction B ' /B2~ Method-3:
/ i Al R13 NaCNBH3 R , R CH30H/20°C/pH <4 g CHI 1 R ~ ~ D1 /R5 / i R14 ~D2 ' ; ~Ki' I
R~
Secondary Cyclic Heteroaryl Amine(CXIIIA-H) ~ c ~h eme 5 Rll' % 31 AQ-2CR: Cyclic Ketone J3_K2 R4 R10\ ~ \ iR32 I
3 ~ q H2N\Y % 1\ /R5 J
/B1 D~~ R, ~ ~ II1 R9 ~ ~ R12 jq /D2.' ~K1_ // 1-B\ R8 12 R6 heat Heteroaryl Amine (XI-AH) I
R5\ ~Klw ~R7 (CRXII-AH) : Cyclic I I( Heteroaryl Imine Rq~Dl~ 2~R8R10 R ~ R11 R1 q Y ~ iD 3-~.
gl J3 (CRXIII-AH):
N p, K2-R31 Secondary Cyclic Heteroaryl Reduction g /Jq Method-1: ~ ~~D4 ~R
R31 R H2/Pt02 R ~ 32 R11\ /K2_J~ 32 CoH50H 31 R12 J3 \ 20 C Reduction D ~R12 60 psi Method-2:
.D q NaBHq R10 ~ ~ CH30H
B1~.. ~2w 0-20°C
Al R13 ~ Reduction R9 ~ Method-3:
Rq NaCNBH3 N~ I CH30H/20°C/pH <4 ~D1~ ~R5 J

R14 /D2 '~ ~K1..
Re J2 R6 I
R~

Scheme 6 R11\ /R31 AQ-2A: Cyclic _ Amine R10\ ~ \ .~R32 I
3 ~ 4 0\ C D1 /R5 \J
/B1 4~ ~ ~ 111 R9 ~A1_B ~ R12 C1 R ~D2 ~~J ~K1,R
\ $ ,2 s H2N R13 ~ R~
TEA Heteroaryl Carbonyl Solvent Chloride ( CCRI -AH ) I
R5\ i{lw ~R7 (CAXII-AH) : Cyclic i 1 ~; 2 Heteroaryl Amide /D1 ~ D2 R4 ~ ~t8 R1 R9\ ~11 ~'D3w LiAlH4 \

0-20°C \
R31 B2w ~4 R11~ / 2'~ J~R32 R / ' 4 \R32 'K
J3 \ 31 R12 D4'R12 R10~D3 j /B2~ ( XI I IA-H ) : Cyclic 1 A1 R13 Heteroaryl Amine NCH ' /Dlw /R5 2~ J1 I l R /D2~~J ~K1~R
g 12 6 Scheme 7 NH2-CH2(CR3~R38)v-(CR33R34)u-T-(CR35R36~w H
AQ-2 AA: Alicyclic Amine -~D1~ ~R5 TEA

THF
R8 J2 R6 0-20°C
R~
Heteroaryl Carbonyl Chloride(CCXI-AH) I
R5\ ~Klw ~R7 g /D1 ~D2wR

O=C ( RAC7CI I-AH ) :Alicyclic Heteroaryl Amide HN CH2(CR3~R38~v'(CR33R34~u-T-(CR35R36)w-H

I
R5\ ~K1~ ~R7 /D1 ~/DZ~

CH2 (RACRIIIA-H) :Alicyclic Heteroaryi Amine HN CH2(CR3~R38)v-(CR33R34~u-T-(CR35R36~w H

SC~PI~II~: $
HO-C(CR3~R38)v-(CR33R34)u T-(CR35R36)w-H
AQ-2CCA: Alicyclic Carboxylic Acid O i /D1~ /R5 J DCC
~~ 1 THF
R14 /D2 ~~ ~K1.
R8 J2 R6 0-20°C
I Acetonitrile R~
Heteroaryl Amine ( IC -AH ) I
R5\ i~lw iR7 I1 (12 ,/D1 ~D2w R4 ' Re R14- (ACXII-AH) :Alicyclic Heteroaryl Amide HN C(CR3~R38)v-(CR33R34)u-T-(CR35R36)r~ H

R6 LiAlH4 I THF
R5\T K1~ 'R~ 0-20°C

/D1 ~ D2~
R4 ~ R8 R14- (19~CRIIIA-H) :Alicyclic Heteroaryl Amine HN CHZ(CR3~R38~v-(CR33R34)u-T-(CR35R36)w-H

Scheme 9 NH2 CH2(CR37R38)v-(CR33R34)u-T-(CR35R36)w-H
AQ-2AA: Alicyclic Amine O
~D1~ /R5 TEA
Cl ~~ THF

R8/D2~J2 K1~R6 0-20°C
I

Heteroaryl Carbonyl Chloride ( ccxl -AH ) I
R5\ ~Kl~ ~R7 il i2 /D1 ~ D2~
R4 ~ R8 O= ( RACXI I-AH ) :Alicyclic Heteroaryl Amide HN CH2 (CR3~R38 )v-(CR33R34 )u-T-(CR35R36 )~a H

I
R5\ iKl~ ~R7 I II
/D1 ~2w R4 ( R8 CHZ ( RACR I I IA-H ) : A1 icyclic Heteroaryl Amine HN CH2(CR3~R38)~-(CR33R34)u-T-(CR35R36)ra H

Scheme 10 I
R5\ ~Klw ~R7 I il /D1~D2\ ( I-'n10/I-WOPA/I-WOHA) :Alicyclic R4 I Rg Aryl/Heteroaryl Aminoalcoholcs H CH2(CR37R38)v-(CR33R34)u-T-(CR35R36)w H
HO

R2 Method A:

(XX) R6 60-90°C/THF/Lewis Acid I (X = O) R5\ ~Klw ~R7 I II
/D1 ~2~
R4 ~ R8 HN CH2(CR3~R38)v-(CR33R34)u-T-(CR35R36)~a H
( RACXI I IA-H ) :Alicyclic Heteroaryl Amine S C ~"~. ~ I~fl ~

R1 l ~ /K2~ J~ _ '~ 3 \
D4'R12 R10''~\ I (I-WO/I-WOPC/I-WOHC):Cyclic /B 1 ~B2~ Aryl/Heteroaryl Aminoalcoholcs i A1 R13 Rg N I
R3 ~ / lw /--5 J
R2 ~ ~ 1 ~ 1 X14 /'D2.' iKl R1 Re J2 R6 OH ~ I
R~
Method A:

(XX) R11\ /K2_""J/ 32 60-90°C/THF/Lewis Acid J3 \ (X - O) I D4'R12 Rl p~D3 Bl~", ~B2~
Al R13 Rg I
N~ ~ 1 ~ ~R5 J

R ~2 J ~K1~R

Secondary Cyclic Heteroaryl Amine (XIIIA-H) Scheme 12 R1 Rz R3 Heteroaryl Alkyl Amine ( LX-H ) _ I
/Y~D1~ /R5 R14 '' ~~~ J1 /D2'' ~K1.

R~ Reduction Method 1, 2 or 3 Heteroaryl Carbonyl R1 Rz R3 o ( RI -AH ) Heteroaryl I 4 R16-X ~ Imine ( L-H ) /yYDi /R5 CHIN
R14 IJi ~) R4 R /D2:J ~K1~R ~y~Dl~ /R5 R7 _H20 R /D2 J ~K1.R
XL : ( Generic Azeotropic 8 1 z 6 Substituted Distillation R7 Alkylamine) R ~ CH2NHZ 1. NaCN/DMF R1 H
is x 2 . LiAlH4 ( gR ) R1 R R3 Ether Solvent Rz R

1. Br2/H2S04 (X = O; R16 = H) 2. NaBH4/H20 Ref: 3. NaCN/EtOH-H20 J. Med. Chem. 4.LiAlH4/Ether O
Vol. 18, 1975 pages 1106-10 R1 CH2R3 Scheme 13 R1 R2 R3 Heteroaryl Alkyl 8111 /R31 R16-X Amine (LX-H) R10\ ~J3 K2~ ~32 CH2~H D3 J4 I By D
/Y ~ 1~ /RS R9/ ~A -B ~ 4~R12 /D2; ~K1, C1 R13 Re 12 R6 O
R7 AQ-2CCC: Cyclic CarbonylChloride l.Protect by R 11 ~ 'R 3I
Silylatio /n 2 . TEA/THF R10\ ~ \ ~R32 0-2 0"C
R /B1\ /D4~R
R1 R2 R3 9 Al-82 12 _ ~~~~~ R 13 R16 X CH2N O I-WA, I-WO, LiAl R4 I-WOPC, and THF ~ ( D R I-WOHC Amides ~Y ~ 1~ / 5 0-20F'C R ~ J1 /D2: ~K1.
R
Rll R3 R8 1 2 6 / R~
R10\ ~J3 K2~ iR32 B D
R9/ 1~ / 4~i2 Rl R2 R3 Al 82 Rl6rX CH2~ I-WA ( X = O, S, NH ) I-WO, R4 I-WOPC, and I-WOHC
I (X = O in others) /Y~Dy /R5 YI J

Re/D2~ J ~K1_R

R~

Scheme 14 I
~NH ~D1\ /R5 Heteroaryl Hydroxylamine OH ~ J1 (XI-AH-OX) I I
/D2 , _Kl Rg i 2 _R6 R~
l.NaH, DMF or THF
2 . Br-CH2 ( CR37R38 ) v- ( CR33R34 ) u-T ( CR35R36 )ca H

I
R5\ /D1 NH
Jl ~ \O-CH2 ( CR37R38 ) v- ( CR33R34 ) u-T- ( CR35R36 ) w-H
/K1~ ~~D2~ Alicyclic Hydroxylamine(VLXX-AO) R6 ~2 RS
.. R7 R1 X H
(XX) 60-90°C
Acetonitrile Lewis Acid ~ R

~R16 R4 , ~X

J1 1~~ \O-CH2 ( CR37R3-8) ~- ( CR33R34 ) u-T- ( CH35R36 ) w'H
R ~Kl J ~D2wR I-WA (X = O, S, NH), I-WO, I-WOPA, 6 2 g and I-WOHA (X = O in others) R~

g9 The following examples are provided to illustrate the present invention and are not intended to limit the scope thereof. Without further elaboration, it 5 is believed that one skilled in the art can, using the preceding descriptions, utilize the present invention to its fullest extent. Therefore the following preferred specific embodiments are to be construed as merely illustrative and not limitative of the remainder of the disclosure in any way whatsoever.
Compounds containing multiple variations of the structural modifications 10 illustrated in the preceding schemes or the following Examples are also contemplated. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds.
One skilled in the art may use these generic methods to prepare the 15 following specific examples, which have been or may be properly characterized by ' H NMR and mass spectrometry. These compounds also may be formed in vivo.
The following examples contain detailed descriptions of the methods of preparation of compounds of Formula V-H. These detailed descriptions fall 20 within the scope and are presented for illustrative purposes only and are not intended as a restriction on the scope of the invention. All parts are by weight and temperahires are Decrees centigrade uness otherwise indicated.

WO 00/18723 PC'T/US99/22123 OH CF3 _ F3C ~ N
3-[(4-methylcyclohexyl)[[(3-trifluoromethyl)phenyl]methyl)amino]-1,1,1-trifluoro-2-propanol 10 EX-lA) 4-Methylcyclohexylamine (1.I5 g, 10 mmol, 97%, mixture of cis and traps isomers) and 3-trifluoromethylbenzaldehyde (1.74 g, 10 mmol) were dissolved in anhydrous chloroform (25 mL) and heated under reflux for 4 h using a Dean-Stark trap to remove water. The volatile components were removed in vacuo to give the desired imine (2.69 g) product quantitatively as a colorless oil, 15 MS m/z = 269 [M+]. The oil was dissolved in methanol, and after cooling to °C, solid sodium borohydride was added (0.64 g, 17 mmol). The mixture was allowed to warm to room temperature and stirred for 2 h. then acidified with 1 N
HCl solution. After neutralizing to pH 7.5 with 2.5 N sodium hydroxide, the mixture was extracted with diethyl ether (3 x 20 mL). The organic layer was 20 washed with brine and water, then dried over anhydrous MgS04, and evaporated to give 1.96 g (68.4%) of the desired N (4-methylcyclohexyl)[[3-(trifluoromethyl)-phenyl]methyl]amine product as a colorless oil, which was greater than 90% pure by reverse phase' HPLC analysis. MS m/z = 271 [M+].
EX-1B) The benzylamine product from EX-lA (1.08 g, 4 mmol) and 25 3,3,3-trifluoro-1,2-epoxypropane (0.67 g, 6 mmol) were dissolved in 1.0 mL
of acetonitrile. Ytterbium (III) trifluoromethanesulfonate (0.21 g, 0.33 mmol) was added, and the stirred solution was warmed to 50 °C for 2 h under an atmosphere 5 of nitrogen, at which time HPLC analysis indicated that no amine starting material remained. The reaction was quenched with water and extracted with ether. The ether layer was washed with water and brine, then dried over anhydrous MgS04.
The crude product was purified by flash column chromatography on silica gel eluting with ethyl acetate in hexane ( 1:12) to give 1.18 g (77%) of the desired 3 10 [(4-methyl-cyclohexyl)[[(3-trifluoromethyf)phenyl]-methyl]amino]-l,l,l-trifluoro-2-propanol product as a light amber oil. 99% pure by HPLC analysis.
HRMS calculated for C18H23F6N0: 384.1762 [M+H]+, found: 384.1754. 1H
NMR (CDC13) S 0.92 (dd, 3H), 1.17-1.81 (m, 8H), 1.93 (m, 1H), 2.48 (m, 1H), 2.80 (m, 2H), 3.76 (d, 2H), 3.79 (m, 1 H), 3.94 (s, 1 H), 7.45-7.60 (m, 4H).

15 NMR (CDC13) 8 -79.2 (d, 3F), -63.1 (s, 3F).
Additional substituted 3-[(N alkyl and N cycloalkyl)[aryl]methyl]amino-1,1,1-trifluoro-2-propanols can be prepared by one skilled in the art using similar methods, as shown in Example Table 1.

5 Example Table 1. Substituted 3-[(N alkyl and N cycloalkyl)[aryl]methyl]amino-I ,1,1-trifluoro-2-propanols.
OH RsuB~
~RsuB2 -C
R CalculatedObserved No. '1JUB1 SUB2 Mass Mass + +
M+H jMH~

2 cyclopropyl4-OCF; 344.1085 344.1086 3 isopropyl 4-OCF3 346.1242 346.1245 4 cyclopropyl3-OCF; 344.108 344.1085 5 isopropyl 3-OCF3 346.1242 346.1239 6 n-propyl 3-OCF3 346.1242 346.1252 7 cyclopentyl3-OCF; 372.1398 372.1409 OH
~ 'N
F3C/ v w to 3-[(3-methyl-2-butenyl)[(3-(trifluoromethoxy)phenyl]
araino]-1,1,1-trifluoro-2-propanol EX-8A) 3-Trifluoromethoxy aniline (23.81 g, 134.4 mmol) and 3,3,3-15 trifluoro-i,2-epoxypropane (3.76 g, 33.6 mmol) were placed into a sealed tube and heated at 80 °C for 24 h. The excess aniline was removed by distillation (70 °C at 80 tort). The resulting residue contained 8.6 g (>95%) of the desired 3-[[(trifluoromethoxy)phenyl]-amino]-1,1,1-trifluoro-2-propanol product as a light yellow oil. IH NMR (CDC13) 8 3.29-3.37 (m, IH), 3.55 (dd, 1H), 4.20 (m, iFI), 6.48-6.63 (m, 3H), 7.12 (t, I H). I9F NMR (CDC13) b -79.36 (s, 3F), -58.44 (s, 3F).
EX-8B) The 3-[[(trifluoromethoxy)phenyl]amino]-I.1,1-trifluoro-2-propanol product from EX-8A (18.68 g, 64.6 mmol) and imidazole (10.99 g, 0.162 mmol) were dissolved in dimethylformamide (40.0 mL) and t-butyldimethylsilylchloride ( 11.69 g, 77.6 mmol) was added in 3.0 g portions over 15 min. The reaction was stirred at 23 °C for 18 h. The resulting solution was diluted with ethyl acetate and washed with water and brine. The organic layer was dried (MgS04) and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with 25% ethyl acetate in hexane to afford 17.088 of the desired silylated product as a light golden oil. FABMS
m/z =
404 [M+H]+' 1H NMR (CDCl3) b 0.042 (s, 3H), 0.085 (s, 3H), 0.91 (s, 9H), 3.25-3 .3 5 (m, 1 H), 3.50 (dd, 1 H), 4.10 (m, 1 H), 6.40 (bs, 1 H), 6.50 (dd, 1 H), 6.59 (d, 1 H), 7.17 (t, 1 H).
EX-8C) The silylated product from EX-8B (0.15 g, 0.372 mmol ) was dissolved in THF (0.5 mL) in a 2-dram glass vial with stir bar and cooled to 0 °C
2 5 in an ice bath. KOtBu ( 1 M in THF, 1.2 eq, 0.446 mmol, 0.446 mL) was added to the cold solution in one portion. The reaction mixture was stirred at 0 °C for 5 min, then 1-chloro-3-methyl-2-butene (38.9 mg, 0.372 mmol) in 0.5 mL of THF
was added in one portion to the cold reaction mixture. The ice bath was removed, and the reaction was stirred at 23 °C for 18 h. The resulting solution was diluted with ethyl acetate and washed with water and brine. The organic layer was dried 5 (MgS04) and concentrated under a nitrogen stream. The crude residue was dissolved in 2.0 mL of THF and treated with tetrabutylammonium fluoride ( 1 M
in THF, 1.2 eq, 0.446 mmol, 0.446 mL). The reaction mixture was stirred at 23 °C
for 3 h. The reaction was diluted with ethyl acetate and washed with water and brine. T'he organic layer wad dried (MgS04) and concentrated under a nitrogen 10 stream. The crude residue was purified using 0.~ g of silica gel eluting with hexane { 100%) followed by 30% ethyl acetate in hexane to give 59.1 mg (44.4%
yield) of the desired 3-[{3-methyl-2-butenyl)[(3-(trifluoromethoxy)-phenyl]amino]- 1,1,1-trifluoro-2-propanol product as a golden oil. FABMS m/z = 358 [M+H] .
15 Additional examples of substituted 3-[(N alkyl, N alkenyl and N alkynyl)-[(trifluoromethoxy)phenyl] amino]-1,1,1-trifluoro-2-propanols can be prepared by one skilled in the art using similar methods, as shown in Example Table 2.

5 Example Table 2. 3-[(N alkyl, N alkenyl and N
alkynyl)[(trifluoromethoxy)phenyl] amino]-1,1,1-trifluoro-2-propanols.

OH
~ /N
F C' v \R

~SUB1 CalculatedObserved No. [ Mol. Wt. Mass M+H]+

9 2,3-octenyl 399 400 10 2,3-propynyl 327 328 11 3-methyl-butyl 359 360 12 2-(carbomethoxy)-2-propenyl387 388 13 3-(carbomethoxy)-2-propenyl387 388 14 4-methoxy-2-butenyl 373 374 F

H
1,1'-((Phenylmethyl)imino]bis[3,3,3-trifluoro-2-propanol[
Benzylamine ( 1.5 eq, 2.88 g, 2.94 mL, 26.8 mmol) was combined with 3,3,3-trifluoro-1,2-epoxypropane (2.0 g, 17.86 mmol) in a sealed glass tube and heated at 80 °C for 18 h. Upon cooling to room temperature, the reaction mixture formed a slushy white solid. The solid was collected by filtration and washed with diethyl ether. The mother liquor was concentrated in vacuo to give 1.71 g (43%) of the desired 1,1'-[(phenyl-methyl)imino)bis[3,3,3-trifluoro-2-_ propanol) product as a colorless oil. FABMS miz = 332 [M+H)+. 1H NMR
(CDCl3) 8 2.85-2.96 (m, 4H) , 3.94 (s, 2H), 3.94-3.97 (m, 2H}, 7.24- 7.37 (m, 5H).
Additional examples of substituted l,1'-[(phenylmethyl)imino)bis[3,3,3-tri-fluoro-2-propanols) can be prepared by one skilled in the art using similar methods, as shown in Example Table 3.
Example Table 3. Substituted 1,1'-((phenylmethyl)imino)bis[3,3,3-trifluoro-2-propanols) Rsua2 OH
F C~ N H

'17UB2 Calculated Observed Mass N-'' Mass [M+H[+ M+H +

16 3-trifluoromethyl400.0959 400.0923 ' 17 4-trifluoromethoxy416.0908 416.0905 ~2CH3 CI

3-[[3-(4-chloro-3-ethylphenoxy)phenyl] [3-cyclohexylmethyl]amino]-1,1,1-trifluoro-2-propanol EX-18A) To a solution of 1,3-dinitrobenzene (16.8 g, 0.1 mol) and 4-chloro-3-ethylphenol (15.6 g, 0.1 mol) in 200 mL of dimethylsulfoxide was added cesium carbonate (65 g, 0.2 mol). The reaction mixture was heated at 100 °C
under nitrogen overnight then cooled to room temperature. The reaction mixture was filtered through celite then rinsed with diethyl ether and a small amount of water. The filtrate was extracted several times with diethyl ether. The organic layers were combined, washed with water and brine, dried over MgS04, and concentrated in vacuo to give 21.8 g (78%) of the desired 3-(4-chloro-3-ethylphenoxy)-1-nitrobenzene product as a dark orange oil, which was greater than 90% pure by reverse phase HPLC analysis. HRMS calcd. for 2 0 C 14H 12C1N03: 295.0849 [M+NI-14~+, found 295.0862.
EX-18B) To a solution of 3-(4-chloro-3-ethylphenoxy)-1-nitrobenzene (10 g, 0.036 mol) from EX-18A in 400 mL of glacial acetic acid and 1 mL of water was added zinc metal (20 g, 0.305 mol) at room temperature, and the resultant mixture was stirred for 1 h. The reaction mixture was filtered through celite.
The filtrate was neutralized with ammonium hydroxide and extracted with diethyl ether. The organic layer was washed with water and brine, dried over MgS04, WO 00/18723 PCT/US99/22123.

5 and concentrated in vacuo to give 10 g ( 100%) of the desired 3-(4-chloro-3-ethylphenoxy)aniline product as a dark orange oil. which was greater than 90%
pure by reverse phase HPLC analysis. HRMS calcd. for C 14H 14C1N0: 248.0842 [M+H] , found: 248.0833.
EX-18C) The 3-(4-chloro-3-ethylphenoxy)aniline (0.45 g, 0.002 mol) 10 product from EX-18B was mixed with neat 3,3,3-trifluoro-1,2-epoxypropane (0.220 g, 0.002 mol) in a pressurized vial. The resulting mixture was heated at 90 °C for 18 h, cooled, and the excess 3,3,3-trifluoro-1,2-epoxypropane was removed in vacuo. The crude product was purified by flash column chromatography on silica gel eluting with 1:4 ethyl acetate in hexane to give 0.254 15 g (35%) ofthe desired 3-[[3-(4-chloro-3-ethyl-phenoxy)phenylJamino]-1,1,1-trifluoro-2-propanol product as a pure orange oil. Anal calcd. for C17H17NOF3Cl: C, 56.75; H, 4.76; N, 3.89. Found: C, 56.72; H, 4.70; N, 3.85.
HRMS calcd.: 360.0978 [M+H]+, found: 360.0969. 1H NMR (CDCl3) 8 1.50 (t, 3H), 2.72 (m, 2H), 3.36 (m, 1 H), 3.54 (m, 1 H), 4.20 (m, 1 H), 6.42 (m, 2H), 2 0 6.81 (dd, 1 H), 6.94 (d, 1 H), 7.18 (d, 1 H), 7.25 (m, 2H).
The 3-[[3-(4-chloro-3-ethylphenoxy)phenylJamino]-1,1,1-trifluoro-2-propanol product from EX-18C was dissolved in 12 mL of tetrahydrofuran. To this stirred solution was added cyclohexanecarboxaldehyde (0.032 g, 0.285 mmol), followed by sodium tri-acetoxyborohydride (0.079 g, 0.370 mmol and 2 5 concentrated acetic acid (0.020 g, 0.325 mmol). The resulting mixture was stirred at room temperature for 18 h. Additional, cyclohexanecarboxaldehyde (0.032 g, 0.285 mmol) was added and the mixture was allowed to stir at room temperature for another 18 h. The reaction was quenched with saturated sodium bicarbonate and extracted with methylene chloride. The organic layers were combined, dried 30 over MgS04 and concentrated to an orange/brown oil. The crude product was 5 purified by flash column chromatography on silica gel eluting with 1:4 ethyl acetate in hexane to give 0.080 g (61%) of the desired 3-[[3-(4-chloro-3 ethylphenoxy)phenyl] [3-cyclohexylmethyl] amino]- I ,1,1-trifluoro-2-propanol product as a yellow-orange oiI (>95% pure by HPLC). HRMS calcd.: 456.117 [M+H]+, found: 456.1942. 1H NMR (CDC13) b 0.82-I.OI (m, 2H), I.22-I.27 10 (m, 3H), 1.73-1.76 (m, SH), 2.74 (dd, 2H), 3.15 (dd, 2H), 3.23 (dd, 1H), 3.52 (m, 1 H), 3.80 (dd, 1 H), 4.28 (m, 1 H), 6.34 (d, 2H), 6.42 (d, 1 H), 6.83 (dd, 1 H), 6.98 (d, 1 H), 7.19 (t, 1 H), 7.29 (d, 1 H). 19F NMR (CDC13) b -79.06 (d, 3F).
Based on the preceding procedures, additional substituted 3-[(N-alkyl)-[[aryl]methyl]amino]-1,1,1-trifluoro-2-propanols and 3-[(N-cycloalkyl)-15 [[aryl]methyl]-amino]-halo-2-propanols are prepared by one skilled in the art using similar methods, as shown in Example Tables 4 and 5. Similarly, substituted 3-[(N aryl)[[cycloalkyl]-methyl]amino]-halo-2-propanols and substituted 3-[(N
aryl)[[haloalkyl]methyl]amino]-halo-2-propanols are prepared by one skilled in the art using analogous methods, as shown in Example Tables 6 and 7.

Example Table 4. 3-[(N-alkyl)([aryl Jmethyl Jamino J-1,1,1-trifluoro-2-propanols.
OH
F C' v N
3 y,!/
RsuB
Ex. _ _ Ex.
No. ~~ No.

4-OCFg 38 3-(2-thienyl) 20 3_OCF2CF2H 39 3-cyclopropyl 21 2_F, 5-CF3 44 4-F, 3-(2-furyl) 22 2_F, 4-CF3 41 3_(3-CF3-phenoxy) 23 3-CF3~ 4-F 42 3,(OCF2CF20) 24 3_CF3CF2 _- 43 3-OCFZCF3 25 3-cyclopentyl 44 3-cyclopentoxy 26 3-isopropoxy 45 3-(cyclopropyl)methoxy 27 3-SCF3 '~ 3-OCH2CH(OH) CF3 28 3-sec-butoxy 47 3-CF3 29 3-C(CF3)2pH 48 4-CF3 30 3-(2-furyl) 49 3-CHZCF2CF3 31 3-(3-furyl) 50 3-CH2CF3 32 3-isobutyl 51 3_CH(CF3)2 33 3-isobutoxy 52 3-CF2CF2CF3 34 3-ethoxy 53 3-phenoxy 35 3_OCH2CF3 54 3-phenyl 36 3-propoxy 55 3-(tetrahydro-2-furyl) 37 3-tert-butoxy 56 isoamyl Example Table 4. (cont.) 3-[(N-alkyl)[[arylJmethyl)aminoJ-1,1,1-trifluoro-2 propanols.
OH
FaC

Ex. Ex.

No ~~ No . .

57 3-OCF3 76 3-(2-thienyl) 58 3-OCF2CF2H 77 3-cyclopropyl 59 2-F, 5-CF3 78 4-F, 3-(2-furyl) 2-F, 4-CF3 79 3-(3-CF3-phenoxy) 61 3-CF3, 4-F 80 3,4-(OCF2CF20) 62 3-CF3CF2 81 3_OCF2CF3 63 3-cyclopentyl 82 3-cyclopentoxy 64 3-isopropoxy 83 3-(cyclopropyl)methoxy 65 3_SCF3 84 3-OCH2CH(OH) CFg 66 3-sec-butoxy 85 3-CF3 67 3-C(CF3)20H 86 4-CF3 68 3-(2-fury!) 87 3-CH2CF2CF3 69 3_(3_furyp. 88 3-CH2CF3 70 3-isobutyl 89 3-CH(CF3)2 71 3-isobutoxy 90 3-CF2CF2CF3 72 3-ethoxy 91 3-phenoxy 73 3-OCH2CF3 ' 92 3-phenyl 74 3-propoxy 93 3-(tetrahydro-2-furyl) 75 3-ten-butoxy 94 isoamyl IO

Example Table 4. (cont.) 3-((N-alkyl)[[aryl[96methyljamino]-1,1,1-trifluoro-2 propanols.
O ~ OCF3 OH
F C "V N

RSUB
Ex. Ex.

N ~~ N ~1~
o o . .

gs 3-OCF 114 3-(2-thienyl) 96 3_OCF CF H 115 3-cyclopropyl 97 2_F, 5-CF 116 4-F, 3-(2-furyl) 98 2-F, 4-CF3 117 3_(3-CF3-phenoxy) 3-CF3, 4-F 118 3~(OCF2CF20) 1~ 3-CF3CF2 119 3_OCFZCF3 101 3-cyclopentyl 120 3-cyc(opentoxy 102 3-isopropoxy 121 3-(cyclopropyl)methoxy 103 3-SCF3 122 3_OCH2CH(OH) CF3 104 3-sec-butoxy 123 3_CF3 105 3-C(CF3)20H 124 4-CF3 106 3-(2-furyl) 125 107 3-(3-furyl) 126 3_CH2CF3 108 3-isobutyl 127 3-CH(CF3)2 109 3-isobutoxy 128 3_CF2CF2CFg 110 3-ethoxy 129 3-phenoxy 111 3-OCH2CF3 130 3-phenyl 112 3-propoxy 131 3-(tetrahydro-2-furyl) 113 3-ten-butoxy 132 isoamyl Example Table 4. (cont.) 3-[(N-alkyl)([aryl Jmethyl [amino]-1,1.1-trifluoro-2 propanols.
O
OH H
F C~ N
\ ~Rsu B
E E
~c. u.

No. ~~ No.

_ 133 3-OCF 1S2 ~ 3-(2-thienyl) 134 3_OCF2CF2H IS3 3-cyclopropyl 13S 2-F, S-CF3 IS4 4-F, 3-(2-fury() 136 2-F, 4-CF3 1SS 3-(3-CF3-phenoxy) 137 3-CF3, 4-F 1 3,(OCF2CF20) 138 3-CF3CF2 1S7 3_pCF2CF3 139 3-cyclopentyl 1S8 3-cyclopentoxy 140 3-isopropoxy 1S9 3-(cyclopropyl)methoxy 141 3-SCF3 160 3_pCH2CH(OH) CF3 142 3-sec-butoxy 161 3-CF3 143 3-C(CF3)20H 162 4-CF3 144 3-(2-fury() 163 3-CH2CF2CF3 14S 3-(3-fury() 1~ 3-CH2CF3 14b 3-isobutyl 16S 3-CH(CF3)2 147 3-isobutoxy 166 3_CF2CF2CF3 148 3-ethoxy 167 3-phenoxy 149 3_OCH CF 168 3-phenyl 1S0 3-propoxy 169 3-(tetrahydro-2-fury() 1S1 3-tent-butoxy 170 isoamyl ExampleTable4. (cont.) 3-[(N-alkyl)[[aryl)methyl)amino]-1,1,1-trifluoro-2 propanols.
O
F
OH ~F
F C' 'J N i "5UB
Ex. R Ex.

R
N ---sue N

o o . .

171 3_~F3 190 3-(2-thienyl) 172 3_OCF2CF2H 191 3-cyclopropy 173 192 4-F, 3-(2-furyl) 2-F, 5-CF3 174 2_F, CF3 - 193._ _ 3-(3-CF3-phenoxy) 175 3-CF3, 4-F 194 3,(pCF2CF20) 176 3_CF3CF2 _ _ _ 195 3-OCFZCF3 177 3-cyclopentyl 196 3-cyclopentoxy 178 3-isopropoxy 197 3-(cyclopropyl)methoxy 179 3-SCF3 198 3_OCH2CH(OH) CF3 180 3-sec-butoxy 1~ 3-CF3 181 3-C(CF3)2OH 2~ CF3 182 3-(2-furylj - 201 3-CH2CF2CF3 183 3-(3-furyl) 202 3-CH2CF3 184 3-isobutyi 203 3-CH(CF3)2 185 3-isobutoxy 2~ 3-CF2CF2CF3 186 3-ethoxy 205 3-phenoxy 187 3_OCH2CF3 _ __ 2~ 3_phenyl 188 3-propoxy 207 3-(tetrahydro-2-furyl) 189 3-tent-butoxy 208 isoamyl WO 00/1$723 PCT/US99/22123 Example Table 5. 3-[(N-cycloafkyl)[[aryl jmethyl )amino]-1,1,1-trio uoro-2 propanols.
OH
F C' v N
~ \~
RSUB
Ex. R Ex.

N --s~ N --o o . .

209 3-tent-butoxy 228 3-(2-thienyl) 210 3-OCF2CF2H 229 3-cyclopropyl 211 230 4-F, 3-(2-furyl) 2-F, 5-CFg 212 2-F, 4-CF3 231 3-(3_CF3-phenoxy) 213 3-CF3, 4-F 232 3,(pCF2CF20) 214 3_CF3CF2 233 3-OCF2CF3 215 3-cyclopentyl 234 3-cyclopentoxy 216 3-isopropoxy 235 3-(cyclopropyl)methoxy 217 3-SCFg 236 3-OCH2CH(OH) CF3 218 3-sec-butoxy 237 3-CF3 219 3_C(CF3)ZOH 238 CF3 220 3-(2-furyl) 239 3-CH2CF2CF3 221 3-(3-furylj 2'~ 3-CH2CF3 222 3-isobutyl 241 3-CH(CFgy~

223 3-isobutoxy 242 3_CF2CF2CF3 224 3-ethoxy 243 3-phenoxy 225 3_pCH2CF3 2'14 3-phenyl 226 3-propoxy 245 3-(tetrahydro-2-furyl) 227 3-(2-pyridyl) 246 isoamyl Example Table 5. (cont.). 3-[(N-cycloalkyl)[[aryl[methyl]amino]-halo-2-propanols.
OH
N
F3C~ - i Rs ue Ex. R Ex.

No. --$~ No. -247 ~CF3 266 3-(2-thienyl) 2~ 3-OCF2CF2H 267 3-cyclopropyl 249 2_F~ 5-CF3 268 4-F, 3-(2-fury!) 250 2-F, 4-CF3 269 3_(3-CFg-phenoxy) 251 3-CF3, 4-F 270 3,(OCF2CF20) 253 3-cyclopentyl 272 3-cyclopentoxy 254 3-isopropoxy 273 3-(cyclopropyl)methoxy 255 3-SCFg 274 3_OCH2CH(OH) CF3 256 3-sec-butoxy 275 3-CF3 257 3_C(CF3)2OH 276 4-CFg 258 3-(2-fury!) 277 3-CH2CF2CF3 259 3-(3-fury!) 278 3-CH2CF3 260 3-isobutyl 279 3-CH(CF3)2 261 3-isobutoxy 280 3_CF2CF2CF3 262 3-ethoxy 281 3-phenoxy 263 3_pCH2CF3 282 3-phenyl 264 3-propoxy 283 3-(tetrahydro-2-fury!) 265 3-ten-butoxy 284 isoamyl Example Table 5. (cont.). 3-[(N-cycloalkyl)[[aryl]methyl]amino)-halo-2-propanols.
OH
F C' v N

RSUB
Ex. Ex.

No ~~ N

. o.

285 3-OCF 304 3-(2-thienyl) 286 3-OCF2CF2H 305 3-cyclopropyl 287 3~ 4-F, 3-(2-furyl) 2-F, 5-CF3 288 2-F, 4-CF3 307 3_{3-CF3-phenoxy) 289 3_CF3, F - _ 308 3~(OCF2CF20) 290 3-CF3CF2-. 3~ 3_OCF2CF3 291 3-cyclopentyl 310 3-cyclopentoxy 292 3-isopropoxy 311 3-(cyclopropyl)methoxy 293 3_SCF3 312 3_OCH2CH(OH)CF3 294 3-sec-butoxy 313 3_CF3 295 3-C(CF3)20H 314 -__. CF3 _ 296 3-(2-f ryl) _ 315 3-CH2CF2CF3 297 3-(3-furyl) 316 3-CH2CF3 298 3-isobutyl 317 3-CH(CF3)2 299 3-isobutoxy 318 3-CF2CF2CF3 300 3-efhoxy 319 3-phenoxy 301 3-OCH2CF3 320 3-phenyl 302 3-propoxy 321 3-(tetrahydro-2-furyl) 303 3-tent-butoxy 322 isoamyl Example Table 5. (cont.). 3-[(N-cycloalkyl)[[aryl Jmethyl)amino)-halo-2-F
Rsue Ex. Ex.
No ~~ No . .

323 3-pCF3 342 3-(2-thienyl) 324 3-OCF2CF2H 343 3-cyclopropyl 325 344 4-F, 3-(2-furyl) 2-F, 5-CF3 326 2-F, 4-CFg 345 3_(3-CF3-phenoxy) 327 3-CF3, 4-F 3~ 3,4-(OCF2CF20) 328 3-CFgCF2 347 3-OCF2CF3 329 3-cyclopentyl 348 3-cyclopentoxy 330 3-isopropoxy 349 3-(cyclopropyl)methoxy 331 3-SCFg 350 3-OCH2CH(OH) CF3 332 3-sec-butoxy 351 3-CF3 333 3-C(CF3)20H 352 4-CF3 334 3-(2-furyl) 353 3_CH2CF2CF3 335 3-(3-furyl) 354 3-CHZCF3 336 3-isobutyl 355 3-CH(CFg)2 337 3-isobutoxy 356 3_CF2CFZCF3 338 3-ethoxy 357 3-phenoxy 339 3-pCH2CF3 358 3-phenyl 340 3-propoxy 359 3-(tetrahydro-2-furyi) 341 3-tent-butoxy 360 isoamyl i0 propanols.

WO 00/18723 PC'T/US99/22123 Example Table 5. (coat.). 3-[(N-cycloalkyl)I [aryl (methyl (amino]-halo-2-propanols.

OH CI
F C~ N
RsuB
Ex. R Ex.

No -s~ N -. o.

361 3-OCF3 380 3-(2-thienyl) 362 3-pCF2CF2H 381 3-cyclopropyl 363 382 4-F, 3-(2-fury() 2-F, 5-CF3 3~ 2-F, 4-CF3 383 3-(3_CF3-phenoxy) 365 3_CF3, 4-F 384 3,(OCF2CF20) 3~ 3-CFgCF2 385 3_pCF2CF3 367 3-cyclopentyl 386 3-cyclopentoxy 368 3-isopropoxy 387 3-(cyclopropyl)methoxy 369 3-SCF3 388 3-OCH2CH(OH) CF3 370 3-sec-butoxy 389 3-CF3 371 3-C(CF3)2OH 3~ 4-CF3 372 3-(2-fury() 391 3_CH2CF2CF3 373 3-(3-fury() 392 3-CH2CF3 374 3-isobutyl 393 3-CH(CF3)2 375 3-isobutoxy 3~ 3-CF2CF2CF3 376 3-ethoxy 395 3-phenoxy 377 3-OCH2CFg 3~ 3-phenyl 378 3-propoxy 397 3-(tetrahydro-2-fury( j 379 3-tent-butoxy 398 isoamyl Example Table 5. (cont.). 3-((N-cycloalkyl)( [aryl methyl )amino]-halo-2-propanols.
0 ~ OC F3 i~
OH
F C~N
3 \
"5U B
Ex. R Ex.

No --S~ N -. o.

3~ 3-OCF3 418 3-(2-thienyl) 3-OCF2CF2H 419 3-cyclopropyl 401 420 4-F, 3-(2-furyl) 2-F, 5-CF3 ~2 2-F, 4-CF3 __ 42l 3_(3_CFg-phenoxy) ~3 3-CF3, 4-F _ 422 3,(pCF2CF20) 3-CF3CF2 423 3_OCFZCF3 405 3-cyclopentyl 424 - 3-cyclopentoxy 406 3-isopropoxy 425 3-(cyclopropyl)methoxy 3-SCF3 426 3_~1..12CH(OH) CF3 408 3-sec-butoxy _ 427 _. 3_CF3 3-C(CF3)20H 428 _ ~CF3 -410 3-(2-furyl) 429 3-CH2CF2CF3 411 3-(3-furyl) 430 3-CH2CF3 412 3-isobutyl 431 3-CH(CF3)2 413 3-isobutoxy 432 3-CF2CF2CF3 414 3-ethoxy 433 3-phenoxy 415 3-OCH2CF3 434 3-phenyl 416 3-propoxy 435 3-(tetrahydro-2-furyl) 417 3-tent-butoxy 436 isoamyl Example Table S. (cont.). 3-~(N-cycloalkyl)([aryl (methyl (amino]-halo-2-propanols.

OH
~ JN
F C
RsuB
Ex. Ex.
No. ~~ No.

437 3-OCF3 4S6 3-(2-thienyl) 438 3_OCF2CF2H 4S7 3-cyclopropyl 439 458 4-F, 3-(2-furyl) 2-F, S-CF3 2-F, 4-CF3 4S9 3-(3-CF3-phenoxy) ~l 3-CFg, 4-F ~ 3,4-(OCF2CF20) 442 3_CF3CF2 '~l 3-OCF2CF3 443 3-cyclopentyl 4b2 3-cyclopentoxy 444 3-isopropoxy 463 3-(cyclopropyl)methoxy 3-SCF3 ~' 3-OCH2CH(OH) CF3 446 3-sec-butoxy 46S 3-CF3 44.7 3-C(CF3)20H ~6 4-CF3 448 3-(2-furyl) ~7 3_CH2CF2CF3 449 3-(3-furyl) '~8 3-CH2CF3 4S0 3-isobutyl ~9 3-CH(CF3)2 4S 3-isobutoxy 470 3_CF2CF2CF3 452 3-ethoxy 471 3-phenoxy 453 3-OCH2CF3 472 3-phenyl ~

4S4 3-propoxy 473 3-(tetrahydro-2-furyl) 4S5 3-tent-butoxy 474 isoamyl WO 00/18723 PCTlUS99/22123 Example Table 5. (cont.). 3-[(N-cycloalkyl)((aryl]methyl)amino]-halo-2-propanols.

OH
C IF2 C' RsuB
Ex. _ Ex.

No ~~ No . .

475 3-pCF3 494 3-(2-thienyl) 476 3_OCFZCF2H 495 3-cyclopropyl 477 2-F, 5-CF3 496 F, 3-(2-fury!) 478 2-F, CF3 497 3-(3_CF3-phenoxy) 479 3_CF3, 4-F 498 3,(pCF2CF20) 480 _ 3-CF3CF2 4~ 3-OCF2CF3 481 3-cyciopentyl 500 3-cyclopentoxy 482 3-isopropoxy 501 3-(cyclopropyl)methoxy 483 3-SCF3 502 3_pCH2CH(OH) CF3 484 3-sec-butoxy 503 3-CF3 485 3_C(CF3)20H 5~ 4-CF3 486 3-(2-furyl) 505 3-CH2CFZCF3 487 3-(3-furyl) 5~ 3-CH2CF3 488 3-isobutyl 507 3-CH(CF3)2 489 3-isobutoxy 508 3_CF2CF2CF3 490 - 3-ethoxy 509 3-phenoxy 491 3_OCH2CF3 510 3-phenyl 492 3-propoxy 511 3-(tetrahydro-2-furyl) 493 3-ten-butoxy 512 isoamyl lz3 Example Table 5. (cont.). 3-[(N-cycloalkyl)~(aryl ~methyl)amino]-halo-2-propanols.

OH
F CF C' 'uN

RSUB
Ex. R Ex. '-No. -s~ No. R

513 3-OCF3 532 3-(2-thienyl) 514 3_OCF2CF2H 533 3-cyclopropyl 515 2_F, S-CF3 534 4-F, 3-(2-furyl) 516 2-F, 4-CF3 535 3-(3-CF3-phenoxy) 517 3-CF3, 4-F 536 3~4...(OCF2CF20) 519 3-cyclopentyf 538 3-cyclopentoxy 520 3-isopropoxy 539 3-(cyclopropyl)methoxy 521 3-SCF3 5~ 3-OCH2CH(OH) CF3 522 3-sec-butoxy 541 3-CF3 523 _ 3-C(CF3)2OH 542 CF3 524 3-(2-furyl) 543 3-CH2CF2CF3 525 - 3-(3-furyl) 5~ 3-CH2CF3 526 3-isobutyl 545 3-CH(CF3)2 527 3-isobutoxy 5~ 3-CF2CF2CF3 528 3-ethoxy 547 3-phenoxy 529 3_pCH2CF3 548 3-phenyl 530 3-propoxy 549 3-(tetrahydro-2-furyl) 53l 3-tent-butoxy 550 isoamyl Example Table S. (cont.). 3-[(N-cycloalkyl)~[aryl~methylpamino)-halo-2-propanols.

OH
F3C~ - i RS~
E -'-'-' x. E R
x.

No. -s~ No.

SS 3-OCF S70 3-(2-thienyl) SS2 3_OCF2CF2H S71 3-cyclopropyl SS3 2-F, S-CF3 S72 4-F, 3-(2-furyl) SS4 2-F, 4-CF3 S73 3-(3-CF3-phenoxy) SSS 3-CF3, 4-F S74 3,~.(OCF2CF20) SS7 3-cyclopentyl S76 3-cyclopentoxy SS8 3-isopropoxy S77 3-(cyclopropyl)methoxy SS9 3-SCF3 578 3-OCH2CH(OH) CF3 S60 3-sec-butoxy S79 3-CF3 S61 3-C(CF3)ZOH S80 CF3 562 3-(2-furyl) S81 3_CH2CF2CF3 563 3-(3-furyl) S82 3-CH2CF3 5~ 3-isobutyl S83 3-CH(CF3)2 S6S 3-isobutoxy S84 3-CF2CF2CF3 S66 3-ethoxy S8S 3-phenoxy S67 3-OCH CF ' S86 3-phenyl S68 3-propoxy S87 3-(tetrahydro-2-furyl) S69 3-ten-butoxy S88 isoamyl Example Table 5. (cont.). 3-[(N-cycloalkyl)[[aryl)methylJamino)-halo-2-propanols.
FsC C F3 OH
N
F3C~ - i RsuB
Ex. Ex.

No ~~ N

. o .

589 3-OCF3 608 3-(2-thienyl) 3-OCFZCF2H ~9 3-cyclopropyl 591 2-F, 5-CF3 610 4-F, 3-(2-furyl) 592 2-F, 4-CFg 611 3_(3-CF3-phenoxy) 593 3-CF3, 4-F 612 3,q_(OCFZCF20) 595 3-cyclopentyl 614 3-cyclopentoxy 596 3-isopropoxy 615 3-(cyclopropyl)methoxy 3-SCF3 616 3_pCH2CH(OH) CF3 598 3-sec-butoxy 617 3-CF3 599 3-C(CF3 )20H 618 4-CF3 600 3-(2-furyl) 619 3-CH2CF2CF3 601 3-(3-furyl) 620 3-CH2CF3 602 3-isobutyl 621 3-CH(CF3)2 603 3-isobutoxy 622 3_CF2CF2CF3 604 3-ethoxy 623 3-phenoxy 3-OCHZCF3 624 3-phenyl 606 3-propoxy 625 3-(tetrahydro-2-furyl) 607 3-tent-butoxy 626 isoamyl Example Table 5. (cont.). 3-((N-cycloalkyl)[[aryl[methyl]amino]-halo-2-propanols.
OH
F C' v N
3 \
RSU B
Ex. R ~ Ex.

N --S~ N
o o . .

627 ~ 3-OCF3 646 3-(2-thienyl) 628 3-OCF2CF2H ~7 3-cyclopropyi 629 2-F, 5-CF3 648 4-F, 3-(2-furyl) 630 2-F, 4-CF3 ~9 3-(3-CF3-phenoxy) 631 3_CF3, 4-F 650 3~(OCF2CF20) 632 3_CF3CF2 651 3-pCF2CF3 633 3-cyclopentyl 652 3-cyclopentoxy 634 3-isopropoxy 653 3-(cyclopropyl)methoxy 635 3-SCF3 654 3-OCH2CH(OH) CF3 636 3-sec-butoxy 655 3-CF3 637 3-C(CF3)20H 656 4-CF3 638 3-(2-furyl) 657 3-CHZCF2CF3 639 3-(3-furyl) 658 3-CH2CF3 640 3-isobutyl 659 3-CH(CF3)2 641 3-isobutoxy ~ 3-CF2CF2CF3 642 3-ethoxy 661 3-phenoxy 3-OCH2CF3 662 3-phenyl 644 3-propoxy 663 3-(tetrahydro-2-furyl) 645 3-ten-butoxy 664 isoamyl Example Table S. (cont.). 3-((N-cycloalkyl)[[ary![methyl)amino)-halo-2-propanols.
O
OH
F C~ N
'RSUB
Ex. R Ex.

N -SUB N --sUB
o o . .

665 3-OCF3 684 3-(2-thienyf) 666 3-OCF2CF2H 685 3-cyclopropyl 2-F, 5-CF3 686 4-F, 3-(2-furyl) ~8 2-F, 4-CF3 687 3-(3-CF3-phenoxy) 669 3-CF3, F 688 3,q_(OCF2CF20) 670 3-CF3CF2 689 3-OCF.,CF3 671 3-cyclopentyl 690 3-cyclopentoxy 672 3-isopropoxy 691 3-(cyclopropyl)methoxy 673 3-SCF3 692 3-OCH2CH(OH) CF3 674 3-sec-butoxy 693 3-CF3 675 3_C(CF3)20H 694 4-CF3 676 3-(2-furyl) 695 3-CH2CF2CF3 677 3-(3-furyl) 696 3-CH2CF3 678 3-isobutyl 697 3-CH(CF3)2 679 3-isobutoxy 698 3-CF2CF2CF3 680 3-ethoxy 699 3-phenoxy 681 3-OCH2CF3 700 3-phenyl 682 3-propoxy 701 3-(tetrahydro-2-furyl j 683 3-tent-butoxy 702 isoamyl 12$
Example Table 5. (cont.). 3-[(N-cycloalkyl)~[aryl~methyl)amino~-halo-2-. propanols.

OH
FsC v N i Rsu a Ex. Ex.

No. ~~ No.

703 3-OCF3 722 3-(2-thienyl) 3-OCF2CF2H 723 3-cyclopropyl 705 724 4-F, 3-(2-fury!) 2-F, 5-CF3 2-F, 4-CF3 725 3-(3-CF3-phenoxy) 707 3-CF3, F 726 3,(OCF2CF20) 708 3=CF3CF2 727 3_OCF2CF3 709 3-cyclopentyl 728 3-cyclopentoxy 710 3-isopropoxy 729 3-(cyclopropyl)methoxy 711 3-SCF3 730 3-OCH2CH(OH) CF3 712 3-sec-butoxy 731 3-CF3 713 3_C(CF3)20H 732 CF3 714 3-(2-fury!) 733 3_CH2CFZCF3 715 3-(3-fury!) 734 3_CH2CF3 716 3-isobutyl 735 3-CH(CF3)2 717 3-isobutoxy 736 3_CF2CF2CF3 718 3-ethoxy 737 3-phenoxy 719 3-pCH2CF3 738 3-phenyl 720 3-propoxy 739 3-(tetrahydro-2-fury!) 721 3-ten-butoxy 740 isoamyl Example Table 5. (cont.). 3-((N-cycloalkyl)[[aryl~methyl~amino]-halo-2-propanols.
OC H(C H3)2 OH
I N

, Rsu a Ex. _ R Ex.

No -S~ No ~I1B
. .

741 3-OCF3 760 3-(2-thienyl) 742 3_OCF2CF2H 761 3-cyclopropyl 743 2-F, 5-CF3 762 4-F, 3-(2-fury!) 2-F, 4-CFg 763 3-(3-CF3-phenoxy) 745 3-CF3, 4-F 7~, 3,4-(OCF2CF20) 746 3-CF3CF2 765 3-pCF2CF3 74? 3-cyclopentyl 766 3-cyclopentoxy 748 3-isopropoxy 767 3-(cyclopropyl)methoxy 749 3-SCF3 768 3-OCHZCH(OH) CF3 750 3-sec-butoxy 769 3-CF3 751 3-C{CF3)20H 770 4-CF3 752 3-(2-fury!) 771 3-CH2CF2CF3 753 3-(3-fury!) 772 3-CH2CF3 754 3-isobutyl 773 3-CH{CF3)2 755 3-isobutoxy 774 3-CFZCF2CF3 756 3-ethoxy 775 3-phenoxy 757 - 3_~1..12CF3 776 3-phenyl 758 3-propoxy 777 3-(tetrahydro-2-fury!) 759 3-tent-butoxy 778 isoamyl Example Table 5. (cont.). 3-[(N-cycloalkyl)[[aryl]methyl]amino]-halo-2-propanols.
oCH2 ' w OH
1 ~N CFs R sue Ex. Ex.

No ~~ N

. o.

779 _ 798 3-(2-thienyl) 780 3-OCF2CF2H 799 3-cyclopropyl 781 _ 8~ 4-F, 3-(2-furyl) 2-F, 5-CF3 782 2-F, 4-CF3 801 3-(3-CF3-phenoxy) 783 3-CF3, F 802 3,(OCF2CF20) 784 3-CF3CF2 803 3_pCF2CF3 785 3-cyclopentyl 804 3-cyclopentoxy 786 3-isopropoxy 805 3-(cyclopropyl)methoxy 787 3-SCF3 8~ 3-OCH2CH(OH) CF3 788 3-sec-butoXy 807 3-CF3 789 3-C(CF3)20H 808 4-CF3 790 3-(2-furyl) 809 3-CH2CF2CF3 791 3-(3-furyl) 810 3-CH2CFg 792 3-isobutyl 811 3_CH(CF3)2 793 3-isobutoxy 812 3-CF2CF2CF3 794 3-ethoxy 813 3-phenoxy 795 3-OCH2CF3 814 3-phenyl 796 3-propoxy 815 3-(tetrahydro-2-furyl) 797 3-tert-butoxy 816 isoamyl Example Table 5. (cont.). 3-[(N-cycloalkyl)(~aryl~methyl)amino~-halo-2-propanols.
OH
F3CI \
sue Ex. Ex.

No. ~~ No.

OCF3 834 (2-thienyl) 818 pCF2CFZH 835 cyclopropyl 2 3 836 (3-CF3-phenoxy) 820 CH2CF3 837 cyclopentoxy 821 CF3 838 (cyclopropyl)methoxy 822 CFgCF2 839 OCH2CH(OH) CF3 823 cyclopentyl- 8'~ CH2CF2CF3 824 isopropoxy 841 CH(CF3)2 825 SCF3 _ 842 CH(CF3)2 826 sec-butoxy 843 CF2CF2CF3 827 C(CF3)2OH 844 phenoxy 828 (2-furyl) 845 phenyl 829 (3-furylj 846 (tetrahydro-2-furyl) 830 isobutyl 847 isoamyl 831 - isobutoxy 848 propoxy 832 ethoxy 849 tent-butoxy 833 OCH2CF3 850 (2-pyridyl) WO 00!18723 PCT/US99/22123 Example Table 5. (coat. ). 3-[(N-cycloalkyl )[ [aryl [methyl amino]-halo-2-propanols.

OH Rsua F3C~N
N
Ex. _ Ex.

No. ~~ No.

851 OCF3 868 (2-thienyl) 852 pCF2CF2H 869 cyclopropyl 853 ~F2CF3 870 (3-CF3-phenoxy) 854 CH2CF3 871 cyclopentoxy 855 CF - - 872 (cyclopropyl)methoxy 856 CF3CF2 873 OCH2CH(OH) CF3 857 cyclopentyl 874 CH2CF2CF3 858 isopropoxy 875 CH(CF3)2 859 _ SCF3 876 CH{CF3)2 860 sec-butoxy 877 CF2CF2CF3 861 C{CF3)20H 878 phenoxy 862 (2-fury!) 879 phenyl 863 (3-fury!) 880 (tetrahydro-2-fury!) 864 isobutyl 881 isoamyl 865 isobutoxy 882 propoxy 866 ethoxy 883 ten-butoxy 867 OCH2CF3 _ 884 (2-pyridyl) Example Table 6. 3-[(.v aryl)[[cycloalkyl]methylJamino]-halo-2-propanols.
\ ~ ~ Rsua2 RsuB~
/ /
OH OH
F3C~N F C~N

_ X1 ~SUBI ~

0 ~ ,SUB2 .

885 3-isopropyl ~9 3-CF30-benzyloxy 886 2-CI, 3-Ct 910 3_CF3-benzyloxy 3-CF O 911 3-F, 5-F-benzyloxy 4-F 9I2 cyclohexylmethyleneoxy 4-CH 913 benzyloxy 890 2-F, 5-Br 914 3-CF3, S-CF3-benzyloxy 891 ~Cl, 3-CH3CH2 915 4-CF30-benzyloxy 892 3-CH3CH2 916 4-CH3CH2-benzyloxy 893 3-CH3, 5-CH3 917 isopropoxy 894 3_(CH3lgC 918 3-CF3-benzyl 89~ 4-F, 3-CH3 919 isopropylthio 896 3-CI, 4-CI 920 cvclopentoxy 8~ 3.4-(CH2)q, 921 3-CI-~-pyridinyloxy 898 3-HCF2CF20 922 3-CF3S-benzyloxy 8~ 3-CHF20 ~~ 3-CH3, 4-CH3-benzyloxy 900 3-(CH3)21V 924 ,, -F. 3-CF3-benzyloxy 901 3-cyclopropyl 92~ 3_F, ~-CF3-benzyloxy 902 3-(2-furyl) 926 (CH3)2CH-benzyloxy 3-CF3CF2 ~2~ I-phenylethoxy 4-NH2 9~ 4-F, 3-CH3-benzoyl 905 ~_CH3, 4-CH3. >-CH3 929 3_CF3_phenyl 4-CH3CH2CH20 930 4-CHgO-phenylamino -~ ~ ~

, ,SUB2 3-CF 931 cyclopropoxy 2-N02 932 4-NO~-phenylthio Example Table 6 (cont.). 3-[(N aryl)[[cycloalkylJmethyl]amino]-halo-?-propanols.
O ~ ~ ~ Rsue2 ~ Rsus, / /
OH OH
FC' vN FC- vN

~! ~SUB1 ~ ~
o SUB2 . , 933 3-isopropyl 957 3-CF30-benzyloxy 934 2-Cl, 3-Cl 9~ 3-CF3-benzyloxy 935 3-CF30 959 3-F, 5-F-benzyloxy 936 4-F 960 c ~clohexv(meth leneoxv 937 4-CH3 961 benzyloxy 938 2-F, S-Br ~'2 3-CF3, 5-CF3-benzyloxy 939 Cl, 3-CH3GH2 963 ,~CF30-benzyioxy 3-CH3CH2 ~ 4-CH3CH2-benzyloxy 941 3-CH3, 5-CH3 ~5 isopropoxy 942 3-(CH3)3C ~ 3-CF3-benzyl 943 4_F, 3-CHg 967 isopropylthio 944 3-Cl, 4-Cl 968 c clo entox 945 3,4_(CH2)~ ' 3-Cl-5-pyridinyloxy 3-HCF2CF20 97~ 3-CF3S-benzyloxy 3-CHF20 971 3-CH3, 4-CH3-benzyloxy 3-(CH3)2N ~2 2-F, 3-CF3-benzyloxy 949 3-cyclopropyl 973 3-F,~-CF3-benzyloxy _.-______ .. ... ._._..___ ___._____ ___._...______._..
.__.._. ____ 1 3~

~

l SUB! ~ SUB' o.

950 3-(2-furyl) 974 ;~-~CH3)2CH-benzyloxy 9~1 3-CF3CF2 ~S 1-phenylethoxy 952 4-NH2 ~6 4-F, 3-CHI-benzoyl 9~3 3_CH;, 4-CH3, 5-CH3 9~~ ~-CF;-phenyl 4-CH3CH~CH20 9~8 4-CH30-phenylamino 3-CFA ~9 cyclopropoxy 2-~02 _ 980 ,~_~,~p2_phenylthio Example Table 6 (cont.l. 3-[(V=aryll[[cycloalkylJmethylJaminoJ-halo-?-propanols.
-l RsuB, ~ w OH OH
FsC- " N F C ~ N

' ~SU81 ~ ~SUB2 j~o ,-981 3-isopropyl 1005 3-CF30-benzyloxy 982 2-Cl, 3-Cl l~ 3-CF3-benzyloxy 3-CF30 l~ 3-F, ~-F-benzyloxy i 984 4-F 1008 cyclohexylmethyleneoxy 98~ 4-CH 1009 benzyloxy 986 2-F, ~-Br 1010 3_CF3, ~-CF3-benzyloxy 4-F, 3-CF3 1011 4-CF30-henzyloxy 3-CH3CH2 1012 4-CH3CH2-benzyloxy 3-CHI, ~-CHI 1013 isopropoxy 3-lCH3)3C _ 1014 _;_CF3_benzyl 4-F, 3-CH3 1015 isopropylthio ~SUB1 B
SG'B2 ~,~ .

992 ~ 3-Cl, 4-Cl 1016 cyclopentoxy 3,4-(CH2)~ 1017 3-Cl-5-pyridinyioxy 3-HCF2CF20 1018 3_CF3S-benzyloxy 995 3-CHF20 ~ 1019 3-CH3.4-CH3-benzyloxy 3-(CH3)2N 1020 2-F.3-CF3-benzyloxy 997 3-cyclopropyl 1021 3_F. ~-CF;-benzyloxy 998 3-(2-furyi) 1022 4_(CH;)2CH-benzyloxy ~ ~

3-CF3 CF2 1023 1-phenylethoxy 1~ 4-NH2 ~ 102. 4_F.3-CH3-benzoyl 1001 ~-CH3, 4-CH3, 5-CH3 1025 3-CF3-phenyl 1002 ,~-CH3CH2CH20 1026 4-CH30-phenylamino 1~~ 3-CF3 1027 cyclopropoxy l~ 2-N02 1028 N02-phenylthio Example Table 6 (cont.). 3-[(V'-aryl}([cycloalk-yl]methyl]amino]-halo-2-propanols.
O ~ Rsu~
Rsue~

F3C ~ N F C~ N

WUBI ~ _~UB2 1029 3-isopropyl 103 3-CF30-benzyloxy 1030 2-C1.3-CI 1054 3-CF3-benzyloxy 1031 3-CF3O 10 3-F, ~-F-benzyloxy 1032 ~l-F 10_'i6cyclohexylmethyleneoxy 1033 4-CH3 1~~ _ ~nzyloxy _ ~.~c. E
N ~SUB1 ~ SUB' o. ~"

1034 2-F. ~-Br- 108 ;-CF;. ~-CF3-benzyloxv -103 4_CI, 3-CHzCH~ IO~g :~-CFzO-benzyloxy 10~6 3-CH;CH~ 1~0 -1-CH;CH~-benzylory 1037 3-CH3, S-CH3 1061 ~ isopropoxy 1038 3-(CH3)3C 1~2 3-CFz-benzyl 1039 4-F, 3-CH3 1063 isoprvpylthio 1040 3-Ct.4-Cl 1064 cyclopentoxy 1041 3,4-(CH2)4 106 3-Cl-~-pyridinyloxy 1042 3_HCF2CF20 1~ 3-CF;S-benzyloxy 1043 3-CHF~O 1~7 3-CH3.4-CH3-benzvlorv_ 1~ 3-(CH3)~N 1~g 2-F.3-CF3-benzyloxy 1045 3-cyclopropyl 1069 3_F, ~-CF3-benzyloxy 1046 3-(2-furyl) 1070 4-(CH3)~CH-benzyloxy 1047 3-CF3CF2 1071 1-phenylethoxy 1048 4-NH2 1072 ~-F' 3-CH3-benzoyl 1049 3-CH3, 4-('H3, 10'73 3-CF3-phenyl -~-CH3 100 ,~CH3CH~CH20 1074 4_CH30-phenylamino IOSl 3-CF 107 cyclopropoxy 1052 2-NO~ 1076 ~NO~-phenylthio WO 00/18723 PCT'/US99/22123 Example Table 6 (coat. ). 3-[(h! aryl)[(cycloalkvl]methyl]amino]-halo-'' propanols.
\ ~ Rsus2 Rsue~
/ /
OH OH
F3C~ N C F F C' v N
3 3 C Fg ~iTBI ~

1077 3-isopropyl 1101 3_CF30-benzyloxy 1078 ?-Cl, 3-CI 1102 3-CF3_benzyloxv 1079 3-CF30 1103 3-F,S-F-benzyloxy 1080 4-F 1104 cyclohexylmethyleneoxy 1081 4-CH 1105 benzyloxy 1082 2-F, 5-Br 1106 3-CF3. 5-CF3-benzyloxy 1083 4-Cl, 3-CH;CH2 1I07~q_CF~O-benzyloxy 1084 3-CH3CH2 1108 4_CH3CH2-benzyloxy 1085 3-CH3.5-CH3 1109 isopropoxy 1086 3-(CH3)3C 1110 3-CF3-benzyl 1087 4_F, 3-CH3 1111 isopropylthio 1088 3-C1, 4-C1 1112 cyclopentoxy 1089 3~~(CH2)4 1113 3-Cl-~-pyridinyloxy l~ 3-HCF2CF20 111. 3-CF3S-benzyloxy 1091 3-CHF~O 111 3-CH3, 4-CH3-benzvloxy 3-(CH3)2N 1116 ?-F, 3-CF;-benzyloxy 1093 3-cyclopropyl 1117 3-F, S-CFg-benzyloxv 1094 3-(2-furyl) 1118 ~~CH3)2CH-benzyloxy 1095 3-CF3CF2 1119 1-phenylethoxy 1096 ~NH2_ 1120 4-F, 3-C1-fg-benzoyl 1~ 3-CH3, 4-CH3, 5-CH3 1121 3-CF3-phenyl ~ ' SUBI

, SUB

1098 4-CH3CH2CH20 1122 4_CH30-phenylamino ~

3-CF3 1 t23 cyclopropoxy 1100 2-NO? 1124 :~N02-phenylthio Example Table 6 (cont.). ~-((~?4'-aryl)[[cycloaikyl]methyl]amino]-halo-?-prapanols.
O \ ~ RsuB2 Rsue~
OH OH
F3C~N F C~N

~SSUBl ~ B

, 1125 3-isopropyl 1149 3_CF~O-benzyloxy 1126 2-Cl, 3-Cl 1150 3-CF3-benzyloxy 1127 3-CF3U 1151 3-F, ~-F-benzyloxy 1128 4-F 1152 cyclohexylmethyleneoxy 1129 4-CH 1153 benzyloxy 1130 2-F, 5-Br 1154 3-CF3, 5-CF3-benzyloxy 1131 ~Cl, 3-CH3CH2 11~~ 4_CF30-benzyloxy 1132 3-CH3CH~ 11x' 4-CH3CH~-benzyloxy 1133 3-CH3, 5-CH3 1157 - isopropoxy 1134 3-(CH3)3C 1158 3-CF3-~nzyl 1135 4-F, 3-CH3 ~ isopropylthio 1136 3-Cl, 4-Cl 1160 cyclopentoxy 1137 3_~(CH214 1161 3-Cl-5-py~ridinyloxy 1138 3-HCF2CFO0 1162 3_CF3S-benzyloxy ~ 3-CHF20 1 3_CH3, 4-CH3-benzyloxy 1=10 _ _ ~UB1 '~ ~

B

11-103-(CH3)2N 116'x'2-F, 3-CF3-benzyloxy l 3-cyclopropyl 1 t6~ 3-F. ~-CF3-benzyloxy 14!

1142 3-(2-furyl) 1166 ,~1C1..13~2CH-benzyloxy 1143 3-CF3CF2 1167 1-phenylethoxy ~

1114 ~NH' - 1168 .~_F.3-CH3-benzoyl 1145 3-CH3, 4-CHI, 5-CH; I I69 3-CF;-phenyl - -1146 ~-CH3CH2CH20 1170 :~-CH30-phenylamino ~

1147 3-CF3 1171 cyclopropoxy 1148 2-NO~ 1172 4-N02-phenylthio Example Table 6 (cont.). 3-[(~~=aryl)[[cycloail:yl]methyl]amino]-halo-?-propanols.
RsuB2 RsuB~
OH OH
F3C " N ~ F C~ N

--, X1 ~SUB1 ~ ~SUB2 , 1173 3-isopropyl 1197 3_CF30-benzyloxy 1174 2-Cl, 3-Cl ~ I 3-CF3-benzyloxy ~

117 3-C~;30 1199 3-F, 5-F-benzyloxy 1176 4-F 1200 cyclohexylrnethyleneoxy 1177 4-CH3 ~ 1201 benzyloxy 1178 2-F, 5-Br 1202 3-CF;, ~-CF3-benzyloxy 1179 4_Cl, 3-CH3CH2 ~1203 ;~,CF3abenzyloxy ~

1180 3-CHzCH2 12~' =7.-CH3CH2-benzyloxy 1181 3-CH3, 5-CHI 1205 isopropoxy F~ _ E g~
N ~SUB1 x. ~SUB

o. iVo, 2 1182 3-(CH3)3C 1206 ~ ;-CF3_- benzyl 1183 .~-F, 3-CH3 1207 isopropylthio 118. 3-Cl, 4-Cl 1208 cyclopentoxy 118 3'4-(CH?)4 109 3-CI-5-pyridinylox"

1186 3-HCF2CF~0 1'10 3-CF;S-benzyloxy 1187 3-CHF20 1211 3-CH;, 4-CH3-benzyloxy I

1188 3-(CH31~N 1212 ~-F, 3-CF3-benzyloxy l 3-cyciopropyl 1213 3_F, 5-CF3-benzyloxy 1190 3-(2-furyl) 1214 ~(C1..;3)~CH-benzyloxy 1191 3-CF3CF~ 1215 1-phenylethoxy 119. NH~ 1216 ~.-F_ 3-CH3-benzoyl 1193 3-CH3, 4-CH3, 5-CH3 1217 3-CF3-phenyl 1194 ,~CH3CH2CH20 1218 ..~-CH30-phenylamino 119 3-CF3 1219 cyclopropoxy 2-N02 1220 ~~~~-phenylthio Example Table 6 (cont.). :i-[(.V-aylj[[cycloalkyl]methyl]amino]-halo-2-propanols.
O \ RsuBz w'~ Rsue~
/ /

C F3 , FsC FaC
~,SUBI ~SUB2 1221 3-isopropyl 124 3-CFgO-benzyloxy 1222 2-Cl, 3-CI 1246 3-CF3-benzyloxy ~SUB1 ~ ~
SLrB~

~o, , 1223 3-CF30 1247 3-F. ~-F-benzyloxy 1224 4-F 1248 cyclohexylmethyleneoxy 1225 4_CH3 1249 benzyloxy 1226 2-F, ~-Br 1250 3_CF3. ~-CF3-benzyloxy 1227 4_Cl, 3-CH3CH2 1251 4-CF30-benzylex:~

1228 3_CH3CH2 1252 4-CH3CH~-benzyloxy 1229 1253 isopropoxy ~ 3-CHz. ~-CH3 1230 3-(CH3)3C 12~'a'3_CF3-benzyl 1231 4-F, 3-CH3 125 isopropylthio 1232 3-Cl, 4-CI 1256 cyclopentoxy 1233 3~4._(CH2)4 j-~7 - ~_Cl-~~yridinyloxy I''343-HCF~CF20 1258 3-CF3S-benzyloxv 1~~ 3-CHF20 129 3_CH3, 4-CH3-benzyloxy 12'363-(CH3)2N 1260 2_F, 3-CF3-benzyloxy 1237 3-cyclopropyl 1261 3_F, ~-CF3-benzyloxy 1238 3-(2-furylj 1262 ~(CH3)2CH-bcnzyloxy 1239 3-CF3CF2 1263 1-phenylethoxy 1240 4-NH2 126 4-F, '~-CH3_benzovl y 1241 3_CH3, 4-CH3, 5-CH3 126 3-CF3-phenvi 1242 4_CH3CH2CH20 12~ 4-CH30-phenylamino 1243 3-CFA 1267 cyclopropoxy 1244 2-NO2 i.'~ - N02-phenylthio E~cample Table 6 (cont.). 3-[(.'V aryl)[[cycloalkvl]methyl]amino]-halo-2 propanols.

\ RSUB1 ' \
/ /

F3C~ N F C~ N

~~1 ~ .. UB2 1269 3-isopropyl 1293 3-CF30-benzyloxy 1270 2-Cl, 3-CI 1294 3-CF3_benzyloxy 1271 3-CF30 129 3-F, 5-F-benzyioxy 1272 1 4-F ' 1296 cyc(ohexylmethyleneoxy 1273 4-CH 1297 benzyloxy 1274 2-F, 5-Br 1298 3_CF3, 5-CF3-benzyloxy 1275 4_Cl, 3-CH3CH2 1299 4_CF30-benzyloxy 1276 3-CH3CH2 13~ 4-CH3CH2-benzyloxy 1277 ~_CH3, ~_CH3 1301 isopropoxy 1278 3_(CH3)3C 1302 3_CF3_benzyl ~

1279 4_F, 3-CH3 1303 isopropylthio 1280 3-Cl, 4-Cl 1304 cyclopentoxy 1281 3.4_(CH2)4 1305 3-Cl-S-pyridinyloxy 1282 3-HCF~CF20 13~ 3-CF3S-benzylo~y 1~ 3-CHF20 1307 3_CH3, 4-CH3-benzyloxy l~ 3-(CH3)2N ~ 1308 2-F.3-CF3-benzyloxy 1285 3-cyciopropyl ~ 3-F. 5-CF3-benzyloxy 1286 3-(2-furyl) 1310 ~(C1..13)2CH-benzyloxy 1287 3-CF3CF' 1311 1-phenylethoxy 1288 4-NHS 1312 4_F.3-CH3-benzoyl 1289 3-Cl"13, 4_CH3, 1313 3-CF3-phenyl ~-CH3 1=J4 r.
~SUB1 ~ __ No, ~ UB2 1290 4-CH3CH2CH20 1314 4-CH~O-phenylamino ~

1291 3-CF3 1315 cs~ciopropoxy 1292 ~-N~' ' 1316 ~0,~-phenylthio Example Table 6 (cons.). 3-[(w-aryl j[[c;ycloalkyljmethyl]amino]-halo-2-propanols.
O v ~ ~ Rsus2 Rsuei / /
OH OH
F3C~ N F C~ N

1 SUBI N ~
~ SUB2 ~.- . , 1317 3-isopropyl 1341 3-CF30-benzyloxy 1318 2-Cl, 3-Ci 1342 3-CF3-benzyloxy 1319 3-CF30 1343 3-F, ~-F-benzyloxy 1320 4-F 1344 cyciohexylmethyleneoxy 1321 ~CH3 1345 benzyloxy 1322 2-F, ~-Br 1346 3_CF3. 5-CF3-benzyloxy 132'34-Cl, 3-CH3CH2 1347-_ ~CF30-benzyloxy 1324 3-~.H3CH2 13~ 4-CH3CH2-. . . bemyloxy 1325 3_CH3, S-CH3 1349 isopropoxy 1325 3_(CH3)3C 13''U3-CF3-benzyl 1327 4_F~ 3-CHg 1351 isopropylthio 1328 3-C1.4-CI 132 cyclopentoxy 1329 3,4_(CH2),~ 1353 3-Cl-~-pyridinyloxy 1330 3-I-ICF2CF20 13'x'13-CF3S-benzyloxy 1331 3-CHF20 13~~ 3-CHI, 4-CH3-benzyloxy B
~S

No. 2 U

1332 3-(CH3)2N 136 2-F, 3-CF3-benzyloxy 1333 3-cyclopropyl 137 3_F, S-CF3-benzyloxy 1334 3-(2-furyl) 1358 :~-( CH3 )ZCH-benzyloxy 133 3-CF3CF2 1359 1-phenylethoxy 1336 Nli~ 1360 4_F, 3-CHg-benzoyl 1337 3_CH3, 4-CHg, 5-CH3 1'61 3_CF3-phenyl 1338 4-CH3CH2CH20 1362 ,~CH30-phenylamino 1339 3-CF3 1363 - cyclopropoxy 1340 2-NOZ _13~ -NO?-phenylthio Example Table 6 (cont.). 3-[(~V-aryl)[[cycloalkyl]methyl]amino]-halo-2-propanols.
O ~~ RsuB2 w Rsue~
OH OH
F3C- " N O F C~ N O

~SUBI ~ ~SUBZ

1~,_ 1365 3-isopropyl . 1389 3-CF30-benzyloxy 1366 2-Cl, 3-CI 1390 3-CF3-benzyloxy 1367 3-CF30 1391 3-F, 5-F-benzyloxy 1368 4-F 1392 cyclohexylmethyleneoxy 1369 ~CH3 ~ benzyloxy 1370 2-F, ~-Br 1394 3-CF3, 5-CF3-benzyloxy 1371 4-CI, 3-CH3CH2 1395 4_CF~O-benzyloxy 1372 3_CH3CH2 1396 4-CH3CH2-benzyloxy L373 3_CH3, 5-CH3 1397 isopropoxy Tw ~SUBt ~ .. ~

o . SUB2 1374 3-(CH3)3C 1398 3-CF3-benzyl 1375 .~_F, 3-CH 1399 isopropylthio 1376 3-C1.4-CI 1400 cyclopentoxy 1377 3,4_~CH'~4 1401 3-Cl-5-pyridinyloxy 1378 3_HCFZCF20 1'~2 3-CF3S-benzyloxy 1379 3-CHFZO 1''~33-CH3.4-CH3-benzyloxy 1380 3_(CH3)2N 1~ 2-F.3-CF3-benzyloxy .

1381 3-cyclopropyl 1=~~ 3-F, 5-CF3-benzyloxy 1382 3-(2-furyl) 1'~ ~~CH3)ZCH-benzyloxy 1383 3-CF3CF~ 1407 1-phenylethoxy ' 1384 4-NH2 1'~8 4-F, 3-CH3-benzoyl 1385 3-CH3, ~,-CH3, 1'4093-CFg-phenyl ~-CH3 1386 4_CH3CH~CH~O 1410 4-CH30-phenylamino 1387 3-CF3 1411 cyclopropoxy 138$ ~-N~2 1412 ~N02-phenylthio Example Table 6 (cont.). 3-[(N aryl)[[cycloalkyl]methyl]amino]-halo-2-propanols.
Rs~s2 Rsua~
OH
F3C~N
O
1~ ~SUBt ~ ~
S
B

. , U

1413 3-isopropyl '14373_CF30-benzyloxy 1414 2-CI, 3-Cl 1438 3_CF3_benzyloxy 1415 3-CF O 1439 3-F, 5-F-ben~yloxy ~' ~SUBI-. ~ ~

o. ,o, 1416 4-F 1:L~0cyclohexyimethyleneoxy 1=I174-CH 1'I'IIbenzyloxy 1418 2-F, 5-Br 1'~'~23_CF3, 5-CF3-benzyloxy 1419 I 4-Cl, 3-CH3CH~ 1'1'13-4-CF30-benzyloxy 1420 3-CH3CH2 1'I"I'14-CH3CH~-benzyloxy 1421 3_CH3, 5-CH3 1'I'l~isopropoxy , 1422 3-(CH3)3C 1'~' 3-CF3-benzyl I4~ 4-F.3-CH3 1':1'17isopropyithio 1424 3-Cl, 4-Cl 1448 cyclopentoxy 142 3,4-(CHZ)4 1=1=193-Cl-~-pyridinyloxy 1426 3-HCF2CF20 1'l~ 3-CF3S-benzyioxy 14'7 3-CHF20 1'~~I3-CH3, 4-CH3-benzvloxy 1428 3-(CH3)ZN 1'12 2-F.3-CF3-benzyloxy 1429 3-cyclopropyl I'1~33-F, ~-CF3-benzyloxy 1430 3-(2-furyl) 14~ ~~CH3)'CH-benzyloxy 1=1313_CF3CF~_ 1'1 1-phenylethoxy 1432 4-NH2 1'~~ 4_F, 3-CH3-benzoyl 1433 3-CH3, 4-CH3. 5-CH3 1457 3-CF3-phenyl 1434 ,~-CH3CH2CH20 1'l~ 4-CH30-phenylamino 143 3-CF 14>9 cyclopropoxy 1436 2-N02 I'~ 4-N02-phenylthio Example Table 7. 3-[(l~'-arvl)[[haloaIkvIJmethvlJaminoJ-halo-?-propanols.
° \ ,~ ~ RsuB2 Rsus, °H OH ~ .
F3C " N CF F C~N CF

~SllB 0 $
' j~o. t 1 SUB

1461 3-isopropyl l~~ 3-CF30-benzyloxy 1=1622-Cl, 3-Cl 1-1863-CF3-benzyloxy 1~-~ 3-CF3C 1=1873-F, 5-F-benzyloxy 1464 4-F 1:183cyclohexylmethyteneoxy 1~~ ~CH3 1489 benzyloxy 1466 2-F, 5-Br t'~~ 3-CF3, 5-CFg-benzyloxy 1467 q.-Cl, 3-CH3CH2 1=1914-CF30-benzyloxy l~ 3-CHgCH2 1492 4-CH3CH2-benzyloxy 1469 3-CH3, ~-CH3 t493 isopropoxy 1470 3-(CH3)3C 1-t~ 3-CF3-benzyl 1471 4-F, 3-CH3 149 isopropylthio 1472 3-Cl, :~-Cl 1496 cyclopentoxy 1473 3,4-1CH2)4 1497 3-Cl-5-pyridinyloxy 1474 3_HCF2CF20 1498 3-CF3S-benzyloxy 1475 3-CHF20~ 1'~~ 3-CH3, 4-CH3-benzyloxy 1476 3-(CH~)2N 1~ 2-F, 3-CF3-benzyloxy 14~'i3-cyclupropyl 1501 3_F, 5-CF3-benzyloxy 1478 3-(2-furyl> 102 ~C1..13)2CH-benzyloxy 1479 3-CF3CF~ 1 1-phenylethoxy ~3 1~ 4-NH2 l~ 4-F, 3-CH3-benzoyl 1481 3_CH3, 4-CH3, S-CH3 1505 3-CF3-phenyl 1482 ~CHzCH2CH2U l~' 4-CHgO-phenylamino ~~1 No. ~SUB2 1483 3-CF 1507 cyclopropoxy 3 ~

l~ 2-NO~ l =1-IV02-pheny lthio ~8 Example Table 7 (cont.). 3-[(:V-a~~l)~[haioalkyl]methviJamino]-halo-?-propanols.
Rsue~ \ Rsus (/
OH
_ FzC F3 F3C- V N C FzC F3 SUBI ~ ~
~

, UB2 1509 3-isopropyl 1533 3-CF30-benzyloxy 1510 2-Cl, 3-Cl 1534 3-CF3-benzyloxy 1511 3-CF30 153 3-F,5-F-benzyloxy 1512 4-F 1536 cyclohexyimethyleneoxy ~ ~

1513 4-CHI 1537 benzyloxy 1514 2-F, 5-Br 1538 3-CF3, ~-CF3-benzyloxy 1515 4_Cl, 3-CH3CH~ 1539 4-CF30-benzyloxy ~ ~

1516 3-CH3CH2 1~ .~_CH3CH~-benzyloxy 1517 3_CH3.5-CH3 1~1 isopropoxy 1518 3-(CH3)3C 1542 3-CF3_benzyl 1519 ~F, 3-CH3 1543 isopropylthio 1520 3-Cl, 4-Cl 154 - cyclopentoxy ~

1521 3,4-(CH?)4 1545 3-Cl-5-pyridinyloxy 1522 3-HCF2CF24 1~ 3-CF3S-benzyloxy 1~~ 3-CHF20 1~7 3-CH3, 4-CH3-benzyloxy 1524 3-(CH3)'y 1~ 2-F.3-CF3-benzyloxy 1525 3-cyciopropyl 149 3-F, 5-CF3-benzyloxy 1526 3-(2-furyll 1550 ~(CH3)2CH-benzyloxy WO 00/18723 PCT/US99/22123.

~UBI ~ ~
T

,SL

127 ~ 3-CF3CF2 1551 1-phenylethoxy 128 4-NH2 152 4-F, 3-CH3-benzoyU

1529 3.CH~, 4-CH3, 5-CH3 1553 3-CFA-phenyl 1530 4-CH3CH2CH20 15~ 4-CH30-phenylaminu I

1531 3-CF3 1555 cyclopropoxy 152 2-N02 1556 NO2-phenylthio Example Table 7 (cont.). 3-[(N-aryl)[[haloalkyl]methyl]amino]-halo-2-propanols.
RsuB?
RsuB~
/ /
OH OH
F C~N~C~CF3)a F C~N~WCF~s $SUB1 ~ ~SUB2 1557 3-isopropyl 1581 3-CF30-benzyloxy 1558 2-Cl, 3-Cl 1582 3-CF3-benzyloxy 1559 3-CF30 1~ 3-F, 5-F-benzyloxy 1560 ~-F 1584 cyclohexylmethyleneoxy 1561 CH 1585 benzyloxy 1562 2-F, ~-Br 1586 3-CF3, 5_CF3-benzyloxy 1563 4-Cl, 3-CH3CH2 1 4-CF30-benzyloxy ~7 1~4 3-CH3CH2 1~ 4-CH3CH2-benzyloxy 1'~~ 3-CH3, 5-CH3 1589 isopropoxy 1 ~ 3-(CH3)3C ' 3-CF3-benzyl ~~

1567 4-F, 3-CH3 1591 isopropylthio 1568 3-Cl, 4-Cl 1592 cyclopentoxy 1569 ~,~(CH 1593 3-Cl-5-pyridinyioxy 2)4 1570 _ 1594 3_CF3S-benzyioxy ~suBi ~; B

h suB2 1571 3_CHFZp 1 ';_CH3, ~-CH3-benzyloxy J9~

1572 3_(CH3)2N l~~ 2-F.3-CF3-benzyloxy 1573 3-cyclopropyl 1597 3_F,~_CF~-benzyloxy 1574 3-(2-furyl) ~ 198 ~(CH3)2CH-benzyloxy ~

1575 3-CF~CF2 l~~ 1-phenylethoxy 1576 4-NHS _~ 16~ 4-F.3-CH;-benzoyl 1577 3-CH3, 4-CH,. ~-CH3 1601 ~-CF3-phenyl 1578 4_CH3CH2CH~0 l~' 4-CH30-phenylanuno 1579 3-CF3 1603 cyclopropoxy 1~ 2-~.p2 1~ ~N02-phenylthio Example Table 7 (cont.). 3-[(~~=aryl)[[haloalkyl]methyl]amino]-halo-2-propanols.
O ~ . ~ RsuB2 RsuB~

F C~N CN F C~N CN
s CF3 s CF3 ~~1 _ _ ~
_ ~2 1605 3-isopropyl 1629 3_CF30-benzyloxy 1606 2-Cl, 3-Cl 1630 3-CF3-benzyloxy 1607 3-CF3p 1631 3-F.5-F-benzyloxy 1608 4-F 1632 cyclohexyimethyleneoxy 1609 4-CH 1633 benayloxy 1610 2-F. 5-Br 1634 3_CF3, ~-CF3-benzyloxy 1611 4_Cl, 3-CH3CH~ 163 4_CF30-beazyloxy 1612 3-CH3CH2 1636 4-CH3CH2_benzylaxy 1613 3_CH3. 5-CH3 1637 isopropoxy ~

WO 00/18723 PCTNS99/22123 _ ~UB1 ~ ~

161-13-(CH3)3C 1638 3-CFA-benzyl 161 4_F, 3-CH3 1639 isopropylthio 1616 ~ 3-C1, 4-Cl 1640 cyclopentoxy 1617 3,,~_(CH~)4 1641 3-CI-5-pyridinyloxy 1618 3_HCF~CF20 16'1'23-CF~S-benzyloxy 1619 ~-CHF20 1643 3_CH;, 4-CH;-benzyloxy 1620 3-(CH3)'N 1~ 2-F, 3-C F3-benzyloxy 1621 3-cyclopropyl 1~~ 3-F, 5-CF3-benzyloxy 1622 3-(2-furyl) l~ .:1-(CH3)2CH-benzyloxy 1623 3-CF3CF2 1~'7 1-phenylethoxy 1624 4-NH2 1~ 4-F, 3-CH3-benzoyl 162 3_CH3, 4-CH3, ~-CH3 1649 3-CF3-phenyl 1626 ~CH3CH2CH20 16~ 4-CH30-phenylamino 1627 3-CF3 161 cyclopropoxy 1628 2-N~2 162 4_Np2_phenylthio BIOASSAYS
CETP Activity In Vitro ASSAY OF CETP INHIBITION USING PURIFIED COMPONENTS
(RECONSTITUTED BUFFER ASSAY) The ability of compounds to inhibit CETP activity was assessed using an in vitro assay that measured the rate of transfer of radiolabeled cholesteryl ester ([3H]CE) from HDL donor particles to LDL acceptor particles. Details of the assay are provided by Glenn, K. C. et al. (Glenn and Melton, "Quantification of ' 10 Cholesteryl Ester Transfer Protein (CETP): A) CETP Activity and B) Immunochemical Assay of CETP Protein," Meth. Enzymol., 263, 339-351 ( 1996)). Human recombinant CETP can be obtained from the serum-free conditioned medium of CHO cells transfected with a cDNA for CETP and purified as described by Wang, S. et al. (J. Biol. Chem. 267, 17487-17490 (1992)). To measure CETP activity, [3H]CE-labeled-HDL, LDL, CETP and assay buffer (50 mM tris(hydroxymethyl)aminomethane, pH 7.4; 150 mM
sodium chloride; 2 mM ethylenediamine-tetraacetic acid (EDTA); I % bovine serum albumin) were incubated in a final volume of 200 lcL, for 2 hours at 37 in 96 well plates. Inhibitors were included in the assay by diluting from a 10 mM
2 0 DMSO stock solution into 16% (v/v) aqueous DMSO so that the final concentration of inhibitor was 800 ~cM. The inhibitors were then diluted 1:1 with CETP in assay buffer, and then 25 lcL of that solution was mixed with 175 ~L
of lipoprotein pool for assay. Following incubation, LDL was differentially precipitated by the addition of 50 BL of 1 % (w/v) dextran sulfate/0.5 M
magnesium chloride, mixed by vortex, and incubated at room temperature for 10 minutes. A potion of the solution (200 ~L) was transferred to a filter plate (Millipore). After filtration, the radioactivity present in the precipitated LDL was measured by liquid scintillation counting. Correction for non-specific transfer or precipitation was made by including samples that do not contain CETP. The rate of [3H~CE transfer using this assay was linear with respect to time and CETP
concentration, up to 25-30% of [3H]CE transferred.
The potency of test compounds was determined by performing the above described assay in the presence of varying concentrations of the test compounds and determining the concentration required for 50% inhibition of transfer of ~3H~CE from HDL to LDL. This value was defined as the IC50. The IC50 values determined from this assay are accurate when the IC50 is greater than nM. In the case where compounds have greater inhibitory potency, accurate measurements of IC50 may be determined using loner incubation times (up to I8 hours) and lower final concentrations of CETP (< 50 nM).
Examples of IC50 values determined by these methods are summarized in Table 3.

Table 3. Inhibition of CETP Activity by Examples in Reconstituted Buffer Assay.
Ex. ICso No.

l8 ll l 15 ll 45 l4 55 6 >100.0 5 >100.0 15 >100.0 3 not tested

Claims (23)

What we claim is:
1. The compound having the formula of:

or a pharmaceutically acceptable salt thereof, wherein;
n is an integer selected from 1 through 2;
A and Q are independently selected from the group consisting of -CH2(CR37R38)v-(CR33R34)u-T-(CR35R36)w-H.

with the provisos that one of A and Q must be AQ-1 and that one of A and Q
must be selected from the group consisting of AQ-2 and -CH2(CR37R38)v-(CR33R34)u-T-(CR35R36)W-H

T is selected from the Group consisting of a single covalent bond, O, S, S(O), S(O)2, C(R33)=C(R35), and C~C;
v is an integer selected from 0 through 1 with the proviso that v is 1 when any one of R33, R34, R35, and R36 is ant or heteroaryl;
a and w are integers independently selected from 0 through 6;

A1 is C(R30);
D1, D2, J1, J2 and K1 are independently selected from the croup consisting of C, N, O, S and a covalent bond with the provisos that no more than one of D1, D2, J1, J2 and K1 is a covalent bond, no more than one of D1, D2, J1, J2 and K1 is O, no more than one of D1, D2, J1, J2 and K1 is S, one of D1, D2, J1, J2 and K1 must be a covalent bond when two of D1, D2, J1, J2 and K1 are O and S, and no more than four of D1, D2, J1, J2 and K1 are N;
B1, B2, D3, D4, J3, J4 and K2 are independently selected from the Group consisting of C, C(R30), N, O, S and a covalent bond with the provisos that no more than 5 of B1, B2, D3, D4, J3, J4 and K2 are a covalent bond, no more than two of B1, B2, D3, D4, J3, J4 and K2 are O, no more than two of B1, B2, D3, D4, J3, J4 and K2 are S, no more than two of B1, B2, D3, D4, J3, J4 and K2 are simultaneously O and S, and no more than two of B1, B2, D3, D4, J3, J4 and K2 are N;
B1 and D3, D3 and J3, J3 and K2, K2 and J4, J4 and D4, and D4 and B2 are independently selected to form an in-ring spacer pair wherein said spacer pair is selected from the croup consisting of C(R33)=C(R35) and N=N
with the provisos that AQ-2 must be a ring of at least five contiguous members, that no more than two of the group of said spacer pairs are simultaneously C(R33 )=C(R35), and that no more than one of the group of said spacer pairs is N=N unless the other spacer pairs are other than C(R33)=C(R35), O. N, and S:

R1 is selected from the group consisting of haloalkyl and haloalkoxymethyl;
R2 is selected from the group consisting of hydrido, aryl, alkyl, alkenyl, haloalkyl, haloalkoxy, haloalkoxyalkyl. perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, and heteroaryl;
R3 is selected from the group consisting of hydrido, aryl, alkyl, alkenyl, haloalkyl, and haloalkoxyalkyl;
Y is selected from the group consisting of a covalent single bond, (CH2)q wherein q is an integer selected from 1 through 2, and (CH2)j-O-(CH2)k wherein j and k are integers independently selected from 0 through 1;
Z is selected from the group consisting of covalent single bond, (CH2)q wherein q is an integer selected from 1 through 2, and (CH2)j-O-(CH2)k wherein j and k are integers independently selected from 0 through 1;
R7, R8, R9, and R13 are independently selected from the group consisting of hydrido, halo, haloalkyl, and alkyl ;
R30 is selected from the group consisting of hydrido, alkoxy, alkoxyalkyl, halo, haloalkyl, alkylamino, alkylthio, alkylthioalkyl, alkyl, alkenyl, haloalkoxy, and haloalkoxyalkyl with the proviso that R30 is selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen:
R30, when bonded to A1, is taken together to form an intra-ring linear spacer connecting the A1-carbon at the point of attachment of R30 to the point of bonding of a group selected from the group consisting of R10, R11, R12, R31, and R32 wherein said intra-ring linear spacer is selected from the group consisting of a covalent single bond and a spacer moiety having from 1 through 6 contiguous atoms to form a ring selected from the group consisting of a cycloalkyl having from 3 through 10 contiguous members, a cycloalkenyl having from 5 through 10 contiguous members, and a heterocyclyl having from 5 through 10 contiguous members;

R30, when bonded to A1, is taken to ether to form an intra-ring branched spacer connecting the A 1-carbon at the point of attachment of R30 to the points of bonding of each member of any one of substituent pairs selected from the group consisting of subsitituent pairs R10 and R11, R10 and R31, R10 and R32, R10 and R12, R11 and R31, R11 and R32, R11 and R12, R31 and R32, R31 and R12, and R32 and R12 and wherein said intra-ring branched spacer is selected to form two rinds selected from the group consisting of cycloalkyl having from 3 through 10 continuous members.
cycloalkenyl having from 5 through 10 contiguous members, and heterocyclyl having from 5 through 10 contiguous members;
R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R31, R32, R33, R34, R35, and R36 are independently selected from the group consisting of hydrido, carboxy, heteroaralkylthio, heteroaralkoxy, cycloalkylamino, acyclakyl, acylalkoxy, aroylalkoxy, heterocyclyloxy, aralkylaryl, aralkyl, aralkenyl, aralkynyl, heterocyclyl, perhaloaralkyl, aralkylsulfonyl, aralkylsulfonylalkyl, aralkylsulfinyl, aralkylsulfinylalkyl, halocycloalkyl, halocycloalkenyl, cycloalkylsulfinyl, cycloalkylsulfinylalkyl, cycloalkylsulfonyl, cycloalkylsulfonylalkyl, heteroarylamino, N-heteroarylamino-N-alkylamino, heteroarylaminoalkyl,haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl, haloalkoxylalkyl, heteroaralkoxy.
cycloalkoxy, cycloalkenyloxy, cycloalkoxyalkyl, cycloalkylalkoxy, cycloalkenyloxyalkyl, cycloalkylenedioxy, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxy, halocycloalkenyloxyalkyl, hydroxy, amino, thio, nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, arylthioalkyl, heteroaralkoxyalkyl, alkylsulfinyl, alkylsulfinylalkyl, arylsulfinylalkyl, arylsulfonylalkyl, heteroarylsulfinylalkyl, heteroarylsulfonylalkyl, alkylsulfonyl, alkylsulfonylalkyl, haloalkylsulfinylalkyl, haloalkylsulfonylalkyl.

alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, monoarylamidosulfonyl, arylsulfonamido, diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl.
arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, heterocyclylsulfonyl, heterocyclylthio, alkanoyl, alkenoyl-aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl, alkynyl, alkenyloxy, alkenyloxyalky, alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkylalkanoyl, cycloalkenyl, lower cycloalkylalkyl, lower cycloalkenylalkyl, halo, haloalkyl, haloalkenyl, haloalkoxy, hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, hydoxyheteroaralkyl, haloalkoxyalkyl, aryl, heteroaralkynyl, aryloxy, aralkoxy, aryloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkenyl, heteroarylalkenyl, carboxyalkyl, carboalkoxy, alkoxycarboxamido, alkylamidocarbonylamido, arylamidocarbonylamido, carboalkoxyalkyl, carboalkoxyalkenyl, carboaralkoxy, carboxamido, carboxamidoalkyl, cyano, carbohaloalkoxy, phosphono, phosphonoalkyl, diaralkoxyphosphono, and diaralkoxyphosphonoalkyl with the provisos that R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R31, R32, R33, R34, R35, and R36 are each independently selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen, that no more than three of the R33 and R34 substituents are simultaneously selected from other than the group consisting of of hydrido and halo, and that no more than three of the R35 and R36 substituents are simultaneously selected from other than the group consisting of of hydrido and halo;
R9, R10, R11, R12, R13, R31, and R32 are independently selected to be oxo with the provisos that B1, B2, D3, D4, J3, J4 and K2 are independently selected from the group consisting of C and S, no more than two of R9, R10, R11, R12, R13, R31, and R32 are simultaneously oxo, and that R9, R10, R11, R12, R13, R31, and R32 are each independently selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen;
R4 and R5, R5 and R6, R6 and R7, R7 and R8, R9 and R10, R10 and R11, R11 and R31, R31 and R32, R32 and R12, and R12 and R13 are independently selected to form spacer pairs wherein a spacer pair is taken together to form a linear moiety having from 3 through 6 contiguous atoms connecting the points of bonding of said spacer pair members to form a ring selected from the group consisting of a cycloalkenyl ring having 5 through 8 contiguous members, a partially saturated heterocyclyl ring having 5 through 8 contiguous members, a heteroaryl ring having 5 through 6 contiguous members, and an aryl with the provisos that no more than one of the group consisting of spacer pairs R4 and R5, R5 and R6, R6 and R7, and R7 and R8, is used at the same time and that no more than one of the group consisting of spacer pairs R9 and R10, R10 and R11, R11 and R31, R31 and R32, R32 and R12, and R12 and R13 is used at the same time;
R9 and R11, R9 and R12, R9 and R13, R9 and R31, R9 and R32, R10 and R12, R10 and R13, R10 and R31, R10 and R32, R11 and R12, R11 and R13, R11 and R32, R12 and R31, R13 and R31, and R13 and R32 are independently selected to form a spacer pair wherein said spacer pair is taken together to form a linear spacer moiety selected from the group consisting of a covalent single bond and a moiety having from 1 through 3 contiguous atoms to form a rind selected from the group consisting of a cycloalkyl having from through 8 contiguous members, a cycloalkenyl having from 5 through 8 continuous members, a saturated heterocyclyl having from 5 through 8 contiguous members and a partially saturated heterocyclyl having from 5 through 8 continuous members with the provisos that no more than one of said group of spacer pairs is used at the same time;
R37 and R38 are independently selected from the group consisting of hydrido, alkoxy, alkoxyalkyl, hydroxy, amino, thio, halo, haloalkyl, alkylamino, alkylthio, alkylthioalkyl, cyano, alkyl, alkenyl, haloalkoxy, and haloalkoxyalkyl.
2. The compound as recited in Claim 1 having the formula of:

or a pharmaceutically acceptable salt thereof, wherein;
n is an integer selected from 1 through 2;
A and Q are independently selected from the group consisting of -CH2(CR37R38)v -(CR33R34)u-T-(CR35R36)w -H, with the provisos that one of A and Q must be AQ-1P and that one of A and Q
must be selected from the group consisting of AQ-2 and -CH2(CR37R38)v -(CR33R34)u-T-(CR35R36)w-H;

T is selected from the group consisting of a single covalent bond, O, S, S(O), S(O)2, C(R33)=C(R35), and C=C;
v is an integer selected from 0 through 1 with the proviso that v is 1 when any one of R33, R34, R35, and R36 is aryl or heteroaryl;

a and w are integers independently selected from 0 through 6;
A1 is C(R30);
B1, B2, D3, D4, J3, J4 and K2 are independently selected from the group consisting of C, C(R30), N, O, S and a covalent bond with the provisos that no more than 5 of B1, B2, D3, D4, J3, J4 and K4 are a covalent bond, no more than two of B1, B2, D3, D4, J3, J4 and K2 are O, no more than two of B1, B2, D3, D4, J3, J4 and K2 are S, no more than two of B1, B2, D3, D4, J3, J4 and K2 are simultaneously O and S, and no more than two of B1, B2, B3, D4, J3, J4 and K2 are N;
B1 and D3, D3 and J3, J3 and K2, K2 and J4, J4 and D4, and D4 and B2 are independently selected to form an in-ring spacer pair wherein said spacer pair is selected from the croup consisting of C(R33)=C(R35) and N=N
with the provisos that AQ-2 must be a ring of at least five contiguous members, that no more than two of the group of said spacer pairs are simultaneously C(R33)=C(R35), and that no more than one of the group of said spacer pairs is N=N unless the other spacer pairs are other than C(R33)=C(R35), O, N, and S;
R1 is selected from the group consisting of haloalkyl and haloalkoxymethyl;
R2 is selected from the group consisting of hydrido, aryl, alkyl, alkenyl, haloalkyl, haloalkoxy, haloalkoxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, and heteroaryl;
R3 is selected from the group consisting of hydrido, aryl, alkyl, alkenyl, haloalkyl, and haloalkoxyalkyl;

Y is selected from the group consisting of a covalent single bond, (CH2)q wherein q is an integer selected from 1 through 2, and (CH2)j-O-(CH2)k wherein j and k are integers independently selected from 0 through 1;
Z is selected from the group consisting of covalent single bond, (CH2)q wherein q is an integer selected from 1 through 2, and (CH2)j-O-(CH2)k wherein j and k are integers independently selected from 0 through 1:
R30 is selected from the group consisting of hydrido, alkoxy, alkoxyalkyl, halo, haloalkyl, alkylamino, alkylthio, alkylthioalkyl, alkyl, alkenyl, haloalkoxy, and haloalkoxyalkyl with the proviso that R30 is selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen;
R30, when bonded to A1, is taken together to form an intra-ring linear spacer connecting the A1-carbon at the point of attachment of R30 to the point of bonding of a group selected from the group consisting of R10, R11, R12, R31, and R32 wherein said intra-ring linear spacer is selected from the group consisting of a covalent single bond and a spacer moiety having from 1 through 6 contiguous atoms to form a ring selected from the group consisting of a cycloalkyl having from 3 through 10 contiguous members, a cycloalkenyl having from 5 through 10 contiguous members, and a heterocyclyl having from 5 through 10 contiguous members;
R30, when bonded to A1, is taken together to form an intra-ring branched spacer connecting the A 1-carbon at the point of attachment of R30 to the points of bonding of each member of any one of substituent pairs selected from the group consisting of subsitituent pairs R10 and R11, R10 and R31, R10 and R32, R10 and R12, R11 and R31, R11 and R32, R11 and R12, R31 and R32, R31 and R12, and R32 and R12 and wherein said intra-rind branched spacer is selected to form two rims selected from the group consisting of cycloalkyl having from 3 through 10 continuous members, cycloalkenyl having from 5 through 10 contiguous members, and heterocyclyl having from 5 through 10 contiguous members;

R4, R5, R6. R7, R8, R9, R10, R11, R12, R13, R31, R32, R33, R34, R35, and R36 are independently selected from the group consisting of hydrido, carboxy, heteroaralkylthio, heteroaralkoxy, cycloalkylamino.
acylalkyl, acylalkoxy, aroylalkoxy, heterocyclyloxy, aralkylaryl, aralkyl, aralkenyl, aralkynyl, heterocyclyl, perhaloaralkyl, aralkylsulfonyl, aralkylsulfonylalkyl, aralkylsulfinyl, aralkylsulfinylalkyl, halocycloalkyl, halocycloalkenyl, cycloalkylsulfinyl, cycloalkylsulfinylalkyl, cycloalkylsulfonyl, cycloalkylsulfonylalkyl, heteroarylamino, N-heteroarylamino-N-alkylamino, heteroarylaminoalkyl,haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl, haloalkoxylalkyl, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy, cycloalkoxyalkyl, cycloalkylalkoxy, cycloalkenyloxyalkyl, cycloalkylenedioxy, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxy, halocycloalkenyloxyalkyl, hydroxy, amino, thio, nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, arylthioalkyl, heteroaralkoxyalkyl, alkylsulfinyl, alkylsulfinylalkyl, arylsulfinylalkyl, arylsulfonylalkyl, heteroarylsulfinylalkyl, heteroarylsulfonylalkyl, alkylsulfonyl, alkylsulfonylalkyl, haloalkylsulfinylalkyl, haloalkylsulfonylalkyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, monoarylamidosulfonyl, arylsulfonamido, diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, heterocyclylsulfonyl, heterocyclylthio, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl, alkynyl, alkenyloxy, alkenyloxyalky, alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkylalkanoyl, cycloalkenyl, lower cycloalkylalkyl, lower cycloalkenylalkyl, halo, haloalkyl, haloalkenyl, haloalkoxy, hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, hydoxyheteroaralkyl, haloalkoxyalkyl, aryl, heteroaralkynyl, aryloxy, aralkoxy, aryloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkenyl, heteroarylalkenyl, carboxyalkyl, carboalkoxy, alkoxycarboxamido, alkylamidocarbonylamido, arylamidocarbonylamido, carboalkoxyalkyl, carboalkoxyalkenyl, carboaralkoxy, carboxamido, carboxamidoalkyl, cyano, carbohaloalkoxy, phosphono, phosphonoalkyl, diaralkoxyphosphono, and diaralkoxyphosphonoalkyl with the provisos that R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R31, R32, R33, R34, R35, and R36 are each independently selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen, that no more than three of the R33 and R34 substituents are simultaneously selected from other than the group consisting of of hydrido and halo, and that no more than three of the R35 and R36 substituents are simultaneously selected from other than the group consistubg of hydrido and halo;
R9, R10, R11, R12, R13, R31, and R32 are independently selected to be oxo with the provisos that B1, B2, D3, D4, J3, J4 and K2 are independently selected from the group consisting of C and S, no more than two of R9, R10, R11, R12, R13, R31, and R32 are simultaneously oxo, and that R9, R10, R11, R12, R13, R31, and R32 are each independently selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen;

R4 and R5, R5 and R6, R6 and R7, R7 and R8, R9 and R10, R10 and R11, R11 and R31, R31 and R32, R32 and R12, and R12 and R13 are independently selected to form spacer pairs wherein a spacer pair is taken together to form a linear moiety having from 3 through 6 contiguous atoms connecting the points of bonding of said spacer pair members to form a ring selected from the group consisting of a cycloalkenyl ring having 5 through 8 contiguous members, a partially saturated heterocyclyl ring having 5 through 8 contiguous members, a heteroaryl ring having 5 through 6 contiguous members, and an aryl with the provisos that no more than one of the group consisting of spacer pairs R4 and R5, R5 and R6, R6 and R7, and R7 and R8, is used at the same time and that no more than one of the group consisting of spacer pairs R9 and R10, R10 and R11, R11 and R31, R31 and R32, R32 and R12, and R12 and R13 is used at the same time;
R9 and R11, R9 and R12, R9 and R13, R9 and R31, R9 and R32, R10 and R12, R10 and R13, R10 and R311 R10 and R32, R11 and R12, R11 and R13, R11 and R32, R12 and R31, R13 and R31, and R13 and R32 are independently selected to form a spacer pair wherein said spacer pair is taken together to form a linear spacer moiety selected from the broup consisting of a covalent single bond and a moiety having from 1 through 3 continuous atoms to form a rind selected from the group consisting of a cycloalkyl having from through 8 contiguous members, a cycloalkenyl having from 5 through 8 continuous members, a saturated heterocyclyl having from 5 through 8 contiguous members and a partially saturated heterocyclyl having from 5 through 8 contiguous members with the provisos that no more than one of said group of spacer pairs is used at the same time;
R37 and R38 are independently selected from the group consisting of hydrido, alkoxy, alkoxyalkyl, hydroxy, amino, thio, halo, haloalkyl, alkylamino, alkylthio, alkylthioalkyl, cyano, alkyl, alkenyl, haloalkoxy, and haloalkoxyalkyl.
3. The compound as recited in Claim 2 having the formula of:

or a pharmaceutically acceptable salt thereof, wherein:
n is an integer selected from 1 through 2;
A is selected from the group consisting of C3-C10 cycloalkyl, C5-C10 cycloalkenyl, C4-C9 saturated heterocyclyl, and C4-C9 partially saturated heterocyclyl, wherein each ring carbon may be optionally substituted with R30, a ring carbon other than the rind carbon at the point of attachment of A to Z
may be optionally substituted with oxo provided that no more than one rind carbon is substituted by oxo at the same time, rind carbon and nitrogen atoms adjacent to the carbon atom at the point of attachment may be optionally substituted with R9 or R13, a ring carbon or nitrogen atom adjacent to the R9 position and two atoms from the point of attachment may be substituted with R10, a rind carbon or nitrogen atom adjacent to the R13 position and two atoms from the point of attachment may be substituted with R12, a ring carbon or nitrogen atom three atoms from the point of attachment and adjacent to the R10 position may be substituted with R11, a ring carbon or nitrogen atom three atoms from the point of attachment and adjacent to the R12 position may be substituted with R32, and a rind carbon or nitrogen atom four atoms from the point of attachment and adjacent to the R11 and R32 positions may be substituted with R31;
R1 is selected from the group consisting of haloalkyl and haloalkoxymethyl;
R2 is selected from the group consisting of hydrido, aryl, alkyl, alkenyl, haloalkyl, haloalkoxy, haloalkoxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, and heteroaryl;
R3 is selected from the group consisting of hydrido, aryl, alkyl, alkenyl, haloalkyl, and haloalkoxyalkyl;
Y and Z are independently selected from the group consisting of a covalent single bond, oxy and alkylene;
R4 and R8 are independently selected from the group consisting of hydrido and halo;
R9 and R13 are halo;
R5, R6, and R7 are independently selected from the group consisting of hydrido, alkyl, halo, haloalkyl, haloalkoxy, aryl, alkylthio, arylamino, arylthio, aroyl, arylsulfonyl, aryloxy, aralkoxy, heteroaryloxy, alkoxy, aralkyl, cycloalkoxy, cycloalkylalkoxy, cycloalkylalkanoyl, heteroaryl, cycloalkyl, haloalkylthio, hydroxyhaloalkyl, heteroaralkoxy, heterocyclyloxy, aralkylaryl, heteroaryloxyalkyl, heteroarylthio, and heteroarylsulfonyl;
R4 and R5, R5 and R6, R6 and R7, and R7 and R8 are independently selected to force spacer pairs wherein a spacer pair is taken together to form a linear moiety having from 3 through 6 contiguous atoms connecting the points of bonding of said spacer pair members ho fore a ring selected from the group consisting of a cycloalkenyl ring having 5 through 8 contiguous members, a partially saturated heterocyclyl ring having 5 through 8 contiguous members, a heteroaryl ring having 5 through 6 contiguous members, and an aryl with the proviso that no more than one of the group consisting of spacer pairs R4 and R5, R5 and R6, R6 and R7, and R7 and R8, is used at the same time;
R10, R11, R12, R31, and R32 are independently selected from the group group consisting of alkyl, halo, haloalkyl, haloalkoxy, aryl, alkylthio, arylamino, arylthio, aroyl, arylsulfonyl, aryloxy, aralkoxy, heteroaryloxy, alkoxy, aralkyl, cycloalkoxy, cycloalkylalkoxy, cycloalkylalkanoyl, heteroaryl, cycloalkyl, haloalkylthio, hydroxyhaloalkyl, heteroaralkoxy, heterocyclyloxy, aralkylaryl, heteroaryloxyalkyl, heteroarylthio, and heteroarylsulfonyl;

R30 is selected from the group consisting of alkoxy, alkoxyalkyl, halo, haloalkyl, alkylamino, alkylthio, alkylthioalkyl, alkyl, alkenyl, haloalkoxy, and haloalkoxyalkyl.
4. The compound as recited in Claim 3 or a pharmaceutically acceptable salt thereof, wherein;
n is the integer 1;
A is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclopent-2-enyl, cyclopent-3-enyl, cyclohexyl, 4-methylcyclohexyl, 4-chloro-3-ethylphenoxycyclohexyl, 3-trifluoromethoxyphenoxycyclohexyl, 3-trifluoromethylcyclohexyl, 4-trifluoromethylcyclohexyl, 3,5-bis-trifluoromethylcyclohexyl, adamantyl, 3-trifluoromethyladamantyl, norbornyl, 3-trifluoromethylnorbornyl, norbornenyl, 7-oxabicyclo[2.2.1]heptan-2-yl, bicyclo[3.1.0]hexan-6-yl, cyclohex-2-enyl, cyclohex-3-enyl, cycloheptyl, cyclohept-2-enyl, cyclohept-3-enyl, cyclooctyl, cyclooct-2-enyl, cyclooct-3-enyl, cyclooct-4-enyl, 2-morpholinyl, 3-morpholinyl, 4-morpholinyl, 1-piperazinyl, 2-piperazinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-dioxanyl, 2H-2-pyranyl, 2H-3-pyranyl, 2H-4-pyranyl, 4H-2-pyranyl, 4H-3-pyranyl, 4H-4-pyranyl, 2H-pyran-2-one-3-yl, 2H-pyran-2-one-4.-yl, 2H-pyran-2-one-5-yl, 4H-pyran-4-one-2-yl, 4H-pyran-4-one-3-yl, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydropyranyl, 3-tetrahydropyranyl, 4-tetrahydropyranyl, 2-tetrahydrothienyl, and 3-tetrahydrothienyl, wherein each ring carbon may be optionally substituted with R30, a ring carbon other than the ring carbon at the point of attachment of A
to Z may be optionally substituted with oxo provided that no more than one ring carbon is substituted by oxo at the same time, rind carbon and nitrogen atoms adjacent to the carbon atom at the point of attachment may be optionally substituted with R9 or R13, a rind carbon or nitrogen atom adjacent to the R9 position and two atoms from the point of attachment may be substituted with R10, a ring carbon or nitrogen atom adjacent to the R13 position and two atoms from the point of attachment may be substituted with R12, a rind carbon or nitrogen atom three atoms from the point of attachment and adjacent to the R10 position may be substituted with R11, a ring carbon or nitrogen atom three atoms from the point of attachment and adjacent to the R12 position may be substituted with R32, and a ring carbon or nitrogen atom four atoms from the point of attachment and adjacent to the R11 and R32 positions may be substituted with R31;
R1 is selected from the group consisting of trifluoromethyl, 1,1,2,2-tetrafluoroethoxymethyl, trifluoromethoxymethyl, difluoremethyl, chlorodifluoromethyl, and pentafluoroethyl;
R2 is selected from the group consisting of hydrido, methyl, ethyl, propyl, butyl, vinyl, phenyl, 4-trifluoromethylphenyl, 1,1,2,2-tetrafluoroethoxymethyl, trifluoromethoxymethyl, difluoromethyl, pentafluoroethyl, trifluoromethyl, and 2,2,3,3,-pentafluoropropyl;
R3 is selected from the group consisting of hydrido, phenyl, 4-trifluoromethylphenyl, methyl, ethyl, vinyl, trifluoromethyl, trifluoromethoxymethyl, difluoromethyl, chlorodifluoromethyl, and pentafluoroethyl;

Y and Z are independently selected from the group consisting of a covalent single bond, oxy, and methylene with the proviso that only one of Y
and Z are simultaneously oxy;
R4 and R8 are independently selected from the group consisting of hydrido and fluoro;
R9 and R13 are fluoro;
R5, R10 and R12 are independently selected from the group consisting of 4-aminophenoxy, benzoyl, benzyl, benzyloxy, 5-bromo-2-fluorophenoxy, 4-bromo-3-fluorophenoxy, 4-bromo-2-nitrophenoxy, 3-bromobenzyloxy, 4-bromobenzyloxy, 4-bromophenoxy, 5-bromopyrid-2-yloxy, 4-butoxyphenoxy, chloro, 3-chlorobenzyl, 2-chlorophenoxy, 4-chlorophenoxy, 4-chloro-3-ethylphenoxy, 3-chloro-4-fluorobenzyl, 3-chloro-4-fluorophenyl, 3-chloro-2-fluorobenzyloxy, 3-chlorobenzyloxy, 4-chlorobenzyloxy, 4-chloro-3-methylphenoxy, 2-chloro-4-fluorophenoxy, 4-chloro-2-fluorophenoxy, 4-chlorophenoxy, 3-chloro-4-ethylphenoxy, 3-chloro-4-methylphenoxy, 3-chloro-4-fluorophenoxy, 4-chloro-3-fluorophenoxy, 4-chlorophenylamino, 5-chloropyrid-3-yloxy, 2-cyanopyrid-3-yloxy, 4-cyanophenoxy, cyclobutoxy, cyclobutyl, cyclohexoxy, cyclohexylmethoxy, cyclopentoxy, cyclopentyl, cyclopentylcarbonyl, cyclopropyl, cyclopropylmethoxy, cyclopropoxy, 2,3-dichlorophenoxy, 2,4-dichlorophenoxy, 2,4-dichlorophenyl, 3,5-dichlorophenyl. 3,5-dichlorobenzyl, 3,4-dichlorophenoxy.
3,4-difluorophenoxy, 2,3-difluorobenzyloxy, 2,4-difluorobenzyloxy, 3,4-difluorobenzyloxy, 2,5-difluorobenzyloxy, 3,5-difluorophenoxy, 3,4-difluorophenyl, 3,5-difluorobenzyloxy, 4-difluoromethoxybenzyloxy, 2,3-difluorophenoxy, 2,4-difluorophenoxy, 2,5-difluorophenoxy, 3,5-dimethoxyphenoxy, 3-dimethylaminophenoxy, 3,5-dimethylphenoxy, 3,4-dimethylphenoxy. 3,4-dimethylbenzyl, 3,4-dimethylbenzyloxy, 3,5-dimethylbenzyloxy, 2,2-dimethylpropoxy, 1,3-dioxan-2-yl, 1,4-dioxan-2-yl, 1,3-dioxolan-2-yl, ethoxy, 4-ethoxyphenoxy, 4-ethylbenzyloxy, 3-ethylphenoxy, 4-ethylaminophenoxy, 3-ethyl-5-methylphenoxy, fluoro, 4-fluoro-3-methylbenzyl, 4-fluoro-3-methylphenyl, 4-fluoro-3-methylbenzoyl, 4-fluorobenzyloxy, 2-fluoro-3-methylphenoxy, 3-fluoro-4-methylphenoxy, 3-fluorophenoxy, 3-fluoro-2-nitrophenoxy, 2-fluoro-3-trifluoromethylbenzyloxy, 3-fluoro-5-trifluoromethylbenzyloxy, 4-fluoro-2-trifluoromethylbenzyloxy, 4-fluoro-3-trifluoromethylbenzyloxy, 2-fluorophenoxy, 4-fluorophenoxy, 2-fluoro-3-trifluoromethylphenoxy, 2-fluorobenzyloxy-, 4-fluorophenylamino,-2-fluoro-4-trifluoromethylphenoxy, 4-fluoropyrid-2-yloxy, 2-furyl, 3-furyl, heptafluoropropyl, 1,1,1,3,3,3-hexafluoropropyl.
2-hydroxy-3,3,3-trifluoropropoxy, 3-iodobenzylory, isobutyl, isobutylamino.
isobutoxy, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, isopropoxy, isopropyl, 4-isopropylbenzyloxy, 3-isopropylphenoxy, 4-isopropylphenoxy, isopropylthio, 4-isopropyl-3-methylphenoxy, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 3-methoxybenzyl, 4-methoxycarbonylbutoxy.
3-methoxycarbonylprop-2-enyloxy, 4-methoxyphenyl, 3-methoxyphenylamino, 4-methoxyphenylamino, 3-methylbenzyloxy, 4-methylbenzyloxy, 3-methylphenoxy, 3-methyl-4-methylthiophenoxy, 4-methylphenoxy, 1-methylpropoxy, 2-methylpyrid-5-yloxy, 4-methylthiophenoxy, 2-naphthyloxy, 2-nitrophenoxy, 4-nitrophenoxy, 3-nitrophenyl, 4-nitrophenylthio, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, pentafluoroethyl, gentafluoroethylthio, 2,2,3,3,3-pentafluoropropyl, 1,1,3,3,3-pentafluoropropyl, 1,1,2,2,3-pentafluoropropyl, phenoxy, phenylamino, 1-phenylethoxy, phenylsulfonyl, 4-propanoylphenoxy, propoxy, 4-propylphenoxy, 4-propoxyphenoxy, thiophen-3-yl, sec-butyl, 4-sec-butylphenoxy,tert -butoxy, 3-tert -butylphenoxy, 4-tert -butylphenoxy, 1,1,2.2-tetrafluoroethoxy, tetrahydrofuran-2-yl, 2-(5,6,7,8-tetrahydronaphthyloxy), thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, thiophen-2-yl, 2,3,5-trifluorobenzyloxy, 2,2,2-trifluoroethoxy, 2,2,2-trifluoroethyl, 3,3,3-trifluoro-2-hydroxypropyl, trifluoromethoxy, 3-trifluoromethoxybenzyloxy, 4-trifluoromethoxybenzyloxy, 3-trifluoromethoxyphenoxy, 4-trifluoromethoxyphenoxy, trifluoromethyl, 3-trifluoromethylbenzyloxy, 4-trifluoromethylbenzyloxy, 2,4-bis-trifluoromethylbenzyloxy, 1.1-bis-trifluoromethyl-1-hydroxymethyl.
3-trifluoromethylbenzyl, 3,5-bis-trifluoromethylbenzyloxy, 4-trifluoromethylphenoxy, 3-trifluoromethylphenoxy, 3-trifluoromethylphenyl, 3-trifluoromethylthiobenzyloxy, 4-trifluoromethylthiobenzyloxy, 2,3,4-trifluorophenoxy.

2,3,4.-tritluorophenyl, 2,3,5-trifluorophenoxy, 3,4,5-trimethylphenoxy, 3-difluoromethoxyphenoxy, 3-pentatluoroethylphenoxy, 3-(1,1,2,2-tetrafluoroethoxy)phenoxy, 3-trifluoromethylthiophenoxy, and trifluoromethylthio;
R6, R11, R31, and R32 are independently selected from the group consisting of chloro, fluoro, hydrido, pentafluoroethyl, 1,1,2,2-tetrafluoroethoxy, trifluoromethyl, and trifluoromethoxy;
R7 is selected from the group consisting of hydrido, fluoro, and trifluoromethyl;
R30 is selected from the group consisting of chloro, ethoxy, ethyl, fluoro, heptafluoropropyl, 1,1,1,3,3,3-hexafluoropropyl, isobutyl, isobutoxy, isopropoxy, isopropyl, isopropylthio, methyl pentafluoroethyl, 2,2,3,3,3-pentafluoropropyl, 1,1,3,3,3-gentafluoropropyl, 1,1,2,2,3-pentafluoropropyl, propoxy, propyl, sec-butyl, tert-butoxy, 1,1,2,2-tetrafluoroethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trifluoroethyl, trifluoromethoxy, and trifluoromethyl.
5. The compound as recited in Claim 4 or a pharmaceutically acceptable salt thereof, wherein;
n is the integer i;
A is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4-methylcyclohexyl, 4-chloro-3-ethylphenoxycyclohexyl, 3-trifluoromethoxyphenoxycyclohexyl, 3-trifluoromethylcyclohexyl, 4-trifluoromethylcyclohexyl, 3,5-bis-trifluoromethylcyclohexyl, adamantyl, 3-tritluoromethyladamantyl, norbomyl, 3-trifluoromethylnorbomyl, norbomenyl, 7-oxabicyclo[2.2.]heptan-2-yl, bicyclo[3.1.0¦hexan-6-yl, cycloheptyl, cyclooctyl, 2-morpholinyl, 3-morpholinyl. 4-morpholinyl. 1-piperazinyl. 2-piperazinyl 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4.-piperidinyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-dioxanyl, 4H-2-pyranyl, 4H-3-pyranyl, 4H-4-pyranyl, 4H-pyran-4-one-2-yl, 4H-pyran-4-one-3-yl, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydropyranyl, 3-tetrahydropyranyl, 4-tetrahydropyranyl, 2-tetrahydrothienyl, and 3-tetrahydrothienyl, wherein each ring carbon may be optionally substituted with R30, a ring carbon other than the ring carbon at the point of attachment of A to Z may be optionally substituted with oxo provided that no more than one ring carbon is substituted by oxo at the same time, ring carbon and nitrogen atoms adjacent to the carbon atom at the point of attachment ma Y be optionally substituted with R9 or R13, a ring carbon or nitrogen atom adjacent to the R9 position and two atoms from the point of attachment may be substituted with R10, a ring carbon or nitrogen atom adjacent to the R13 position and two atoms from the point of attachment may be substituted with R12, a ring carbon or nitrogen atom three atoms from the point of attachment and adjacent to the R10 position may be substituted with R11, a rind carbon or nitrogen atom three atoms from the point of attachment and adjacent to the R12 position may be substituted with R32, and a ring carbon or nitrogen atom four atoms from the point of attachment and adjacent to the R11 and R32 positions may be substituted with R31;
R1 is selected from the group consisting of trifluoromethyl, 1,1,2,2-tetrafluoroethoxymethyl, trifluoromethoxymethyl, difluoromethyl, chlorodifluoromethyl, and pentafluoroethyl;
R2 is selected from the group consisting of hydrido, methyl, ethyl, phenyl, 4-trifluoromethylphenyl, trifluoromethoxymethyl, 1,1,2,2-tetrafluoroethoxymethyl, difluoromethyl, pentafluoroethyl, trifluvromethyl and 2,2,3,3,3-pentafluoropropyl;
R3 is selected from the group consisting of hydrido, phenyl.
.4-.trifluoromethylphenyl, methyl, trifluoromethyl, difluoromethyl, and chlorodifluoromethyl;
Y and Z are independently selected from a covalent single bond and methylene;

R4 and R8 are independently selected from the group consisting of hydrido and fluoro;
R9 and R13 are fluoro;
R5, R10 and R12 are independently selected from the group consisting of benzyloxy, 5-bromo-2-fluorophenoxy, 4-bromo-3-fluorophenoxy, 3-bromobenzyloxy, 4-bromophenoxy,4-butoxyphenoxy, 3-chlorobenzyloxy, 2-chlorophenoxy, 4-chloro-3-ethylphenoxy, 4-chloro-3-methylphenoxy, 2-chloro-4-fluorophenoxy, 4-chloro-2-fluorophenoxy, 4-chlorophenoxy, 3-chloro-4-ethylphenoxy, 3-chloro-4-methylphenoxy, 3-chloro-4-fluorophenoxy, 4-chloro-3-fluorophenoxy, 4-chlorophenylamino, 5-chloropyrid-3-yloxy, cyclobutoxy, cyclobutyl, cyclohexylmethoxy, cyclopentoxy, cyclopentyl, cyclopentylcarbonyl, cyclopropylmethoxy, 2,3-dichlorophenoxy, 2,4-dichlorophenoxy, 2,4-dichlorophenyl, 3,5-dichlorophenyl, 3,5-dichlorobenzyl, 3,4-dichlorophenoxy, 3,4-difluorophenoxy,2,3-difluorobenzyloxy, 3,5-difluorobenzyloxy, difluoromethoxy, 3,5-difluorophenoxy, 3,4-difluorophenyl, 2,3-difluorophenoxy, 2,4-difluorophenoxy. 2,5-difluorophenoxy, 3,5-dimethoxyphenoxy,3-dimethylaminophenoxy, 3,4-dimethylbenzyloxy, 3,5-dimethylbenzyloxy, 3.5-dimethylphenoxy, 3,4-dimethylphenoxy, 1,3-dioxolan-2-yl, 3-ethylbenzyloxy. 3-ethylphenoxy, 4-ethylaminophenoxy, 3-ethyl-5-methylphenoxy, 4-fluoro-3-methylbenzyl, 4-fluorobenzyloxy, 2-fluoro-3-methylphenoxy, 3-fluoro-4.-methylphenoxy, 3-fluorophenoxy.
3-fluoro-2-nitrophenoxy, 2-fluoro-3-trifluoromethylbenzyloxy, 3-fluoro-2-trifluoromethylbenzyloxy, 2-fluorophenoxy, 4-fluorophenoxy, 2-fluoro-3-trifluoromethylphenoxy, 2-fluorobenzyloxy, 4-fluorophenylamino, 2-fluoro-4-trifluoromethylphenoxy, 2-furyl, 3-furyl, heptafluoropropyl, 1,1,1,3,3,3-hexafluoropropyl, 2-hydroxy-3,3,3-trifluoropropoxy, isobutoxy, isobutyl; 3-isoxazolyl.
4-isoxazolyl. 5-isoxazolyl, isopropoxy, 3-isopropylbenzyloxy, 3-isopropylphenoxy, isopropylthio, 4-isopropyl-3-methylphenoxy.
3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 3-methoxybenzyl, 4-methoxyphenylamino, 3-methylbenzyloxy, 4-methylbenxyloxy, 3-methylphenoxy, 3-methyl-4-methylthiophenoxy, 4-methylphenoxy.

1-methylpropoxy, 2-methylpyrid-5-yloxy, 4-methylthiophenoxy, 2-naphthyloxy, 2-nitrophenoxy, 4-nitrophenoxy, 3-nitrophenyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, pentafluoroethyl, pentafluoroethylthio.
2,2,3,3,3-pentafluoropropyl, 1,1 x,3,3-pentafluoropropyl, 1,1,2,2,3-pentafluoropropyl, phenoxy, phenylamino, 1-phenylethoxy, 4-propylphenoxy, 4-propoxyphenoxy, thiophen-3-yl,tert-butoxy.
3-tert -butylphenoxy, 4-tent -butylphenoxy, 1,1,2,2-tetrafluoroethoxy.
tetrahydrofuran-2-yl, 2-(5,6,7,8-tetrahydronaphthyloxy), thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, thiophen-2-yl, 2,2,2-trifluoroethoxy, 2,2,2-trifluoroethyl, 3,3,3-trifluoro-2-hydroxypropyl, trifluoromethoxy, 3-trifluoromethoxybenzyloxy, 4-trifluoromethoxybenzyloxy, 4-trifluoromethoxyphenoxy, 3-trifluoromethoxyphenoxy, trifluoromethyl, 3-trifluoromethylbenzyloxy, 1,1-bis-trifluoromethyl-1-hydroxymethyl, 3-trifluoromethylbenzyl, 3,5-bis-trifluoromethylbenzyloxy, 4-trifluoromethylphenoxy, 3-trifluoromethylphenoxy, 3-trifluoromethylphenyl, 2,3,4-trifluorophenoxy, 2,3,5-trifluorophenoxy, 3,4,5-trimethylphenoxy, 3-difluoromethoxyphenoxy, 3-pentafluoroethylphenoxy, 3-(1,1,2,2-tetrafluoroethoxy)phenoxy, 3-trifluoromethylthiophenoxy, 3-trifluoromethylthiobenzyloxy, and trifluoromethylthio;
R6, R11, R31, and R32 are independently selected from the group consisting of chloro, fluoro, hydrido, pentafluoroethyl, 1,1,2,2-tetrafluoroethoxy, and trifluoromethyl;
R7 is selected from the group consisting of hydrido, fluoro, and trifluoromethyl;
R30 is selected from the group consisting of chloro, ethyl, methyl.
propyl, fluoro, heptafluoropropyl, 1,1,1,3,3.3-hexafluoropropyl, isobutyl, isopropyl, pentafluoroethyl, 2,2.3,3,3-pentafluoropropyl, 1,1,3,3.3-pentafluoropropyl, 1,1.2.2,3-pentafluorepropyl, sec-butyl.
1,1,2,2-tetrafluoroethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trifluoroethyl, trifluoromethoxy, and trifluoromethyl.
6. The compound as recited in Claim 5 or a pharmaceutically acceptable salt thereof, wherein;
n is the integer 1:

A is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4-methylcyclohexyl, 4-chloro-3-ethylphenoxycyclohexyl, 3-trifluoromethoxyphenoxycyclohexyl, 3-trifluoromethylcycfohexyl, 4-trifluoromethylcyclohexyl, 3,5-bis-trifluoromethylcyclohexyl, adamantyl, 3-trifluoromethyladamantyl, norbornyl, 3-trifluoromethylnorbornyl, norbornenyl, 7-oxabicyclo[2.2.1]heptan-2-yl, bicyclo[3.1.0]hexan-6-yl, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydropyranyl, 3-tetrahydropyranyl, 4-tetrahydropyranyl, 2-tetrahydrothienyl, and 3-tetrahydrothienyl, wherein a ring carbon other than the ring carbon at the point of attachment of A to Z may be optionally substituted with oxo provided that no more than one ring carbon is substituted by oxo at the same time, ring carbon and nitrogen atoms adjacent to the carbon atom at the point of attachment may be optionally substituted with R9 or R 13, a ring carbon or nitrogen atom adjacent to the R9 position and two atoms from the point of attachment may be substituted with R10, a ring carbon or nitrogen atom adjacent to the R13 position and two atoms from the point of attachment may be substituted with R12, a ring carbon or nitrogen atom three atoms from the point of attachment and adjacent to the R10 position may be substituted with R11, a ring carbon or nitrogen atom three atoms from the point of attachment and adjacent to the R12 position may be substituted with R32, and a ring carbon or nitrogen atom four atoms from the point of attachment and adjacent to the R11 and R32 positions may be substituted with R31;
R1 is selected from the group consisting of trifluoromethyl, chlorodifluoromethyl, and pentafluoroethyl;

R2 is hydrido, pentafluoroethyl, and trifluoromethyl;
R3 is selected from the group consisting of hydrido, methyl, trifluoromethyl, and difluoromethyl Y is methylene;
Z is a covalent single bond;
R4 and R8 are independently selected from the group consisting of hydrido and fluoro:
R9 and R13 are fluoro;
R5, R10 and R12 are independently selected from the group consisting of 5-bromo-2-fluorophenoxy, 4-chloro-3-ethylphenoxy, cyclopentyl, 2,3-dichlorophenoxy, 3,4-dichlorophenoxy, 3-difluoromethoxyphenoxy, 3,5-dimethylphenoxy, 3,4-dimethylphenoxy, 3-ethylphenoxy, 3-ethyl-5-methylphenoxy, 4-fluoro-3-methylphenoxy, 4-fluorophenoxy, 2-furyl, isobutyl, isopropoxy, 3-isopropylphenoxy, 3-methylphenoxy, pentafluoroethyl, 3-pentafluoroethylphenoxy, 3-tert-butylphenoxy, 1,1,2,2-tetrafluoroethoxy; 3-(1,1,2,2-tetrafluoroethoxy)phenoxy, 2-(5,6,7,8 tetrahydronaphthyloxy),trifluoromethoxy, 3-trifluoromethoxybenzyloxy,3-trifluoromethoxyphenoxy, trifluoromethyl, 3-trifluoromethylbenzyloxy, 1,1-bis-trifluoromethyl-1-hydroxymethyl, trifluoromethylthio, and 3-trifluoromethylthiophenoxy;

R6, R11, R31, and R32 are independently selected from the group consisting of chloro, fluoro, hydrido, pentafluoroethyl, 1,1,2,2-tetrafluoroethoxy, and trifluoromethyl;
R7 is selected from the group consisting of hydrido and fluoro.
7. The compound as recited in Claim 5 or a pharmaceutically acceptable salt thereof, wherein;
n is the integer 1;

A is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4-methylcyclohexyl, 4-chloro-3-ethylphenoxycyclohexyl, 3-trifluoromethoxyphenoxycyclohexyl, 3-trifluoromethylcyclohexyl, 4-trifluoromethylcyclohexyl, 3,5-bis-trifluoromethylcyclohexyl, adamantyl, 3-trifluoromethyladamantyl, norbornyl,-3-trifluoromethylnorbornyl, norbornenyl, 7-oxabicyclo[2.2.1]heptan-2-yl, bicyclo(3.1.0)hexan-6-yl, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydropyranyl, 3-tetrahydropyranyl, 4-tetrahydropyranyl, 2-tetrahydrothienyl, and 3-tetrahydrothienyl, wherein a ring carbon other than the ring carbon at the point of attachment of A to Z may be optionally substituted with oxo provided that no more than one ring carbon is substituted by oxo at the same time, ring carbon and nitrogen atoms adjacent to the carbon atom at the point of attachment may be optionally substituted with R9 or R13, a ring carbon or nitrogen atom adjacent to the R9 position and two atoms from the point of attachment may be substituted with R10, a ring carbon or nitrogen atom adjacent to the R13 position and two atoms from the point of attachment may be substituted with R12, a ring carbon or nitrogen atom three atoms from the point of attachment and adjacent to the R10 position may be substituted with R11, a ring carbon or nitrogen atom three atoms from the point of attachment and adjacent to the R12 position may be substituted with R32, and a ring carbon or nitrogen atom four atoms from the point of attachment and adjacent to the R11 and R32 positions may be substituted with R31;
R1 is selected from the group consisting of trifluoromethyl, chlorodifluoromethyl, and pentatluoroethyl;
R2 is hydrido, pentafluoroethyl, and trifluoromethyl;
R3 is selected from the group consisting of hydrido, methyl, trifluoromethyl, and difluoromethyl Y is a covalent single bond;
Z is methylene;
R4 and R8 are independently selected from the group consisting of hydrido and fluoro;
R9 and R13 are fluoro:
R5, R10 and R12 are independently selected from the group consisting of 5-bromo-2-fluorophenoxy, 4-chloro-3-ethylphenoxy, cyclopentyl, 2,3-dichlorophenoxy, 3,4-dichlorophenoxy, 3-difluoromethoxyphenoxy, 3,5-dimethylphenoxy, 3,4-dimethylphenoxy, 3-ethylphenoxy, 3-ethyl-5-methylphenoxy, 4-fluoro-3-methylphenoxy, 4-fluorophenoxy, 2-furyl, isobutyl, isopropoxy, 3-isopropylphenoxy, 3-methylphenoxy, pentafluoroethyl, 3-pentafluoroethylphenoxy, 3-tert-butylphenoxy, 1,1,2,2-tetrafluoroethoxy, 3-(1,1,2,2-tetrafluoroethoxy)phenoxy, 2-(5,6,7,8-tetrahydronaphthyloxy),trifluoromelhoxy, 3-trifluoromethoxybenzyloxy,3-trifluoromethoxyphenoxy, trifluoromethyl, 3-trifluoromethylbenzyloxy, 1,1-bis-trifluoromethyl-1-hydroxymethyl, trifluoromethylthio, and 3-trifluoromethylthiophenoxy;

R6, R11, R31, and R32 are independently selected from the group consisting of chloro, fluoro, hydrido, pentafluoroethyl, 1,1,2,2-tetrafluoroethoxy, and trifluoromethyl;

R7 is selected from the group consisting of hydrido and fluoro.
8. The compound as recited in Claim 2 having the formula of:

or a pharmaceutically acceptable salt thereof wherein;
n is an integer selected from 1 through 2;
A is selected from the group consisting of C3-C8 alkyl, C3-C8 alkenyl, C3-C8 alkynyl, C3-C8 haloalkyl, C3-C8 haloalkenyl, C3-C6 alkoxy C1-C2 alkyl, and C3-C8 hydroxyhaloalkyl. wherein each member of group A
may be optionally substituted at any carbon up to and including 6 atoms from the point of attachment of A to Z with one or more of the group consisting of R33, R34, R35, and R36 with the provisos that R33, R34, R35, and R36 must not be attached to the carbon directly linking A to Z and that R33, R34, R35, and R36 must be selected from other than aryl and heteroaryl when substituting the carbon 2 atoms from Z wherein Z is a single covalent bond;
R1 is selected from the group consisting of haloalkyl and haloalkoxymethyl R2 is selected from the group consisting of hydrido, aryl, alkyl, alkenyl, haloalkyl, haloalkoxy, haloalkoxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl and heteroaryl;
R3 is selected from the group consisting of hydrido, aryl, alkyl, alkenyl, haloalkyl, and haloalkoxyalkyl;

Y and Z are independently selected from the group consisting of a covalent single bond, oxy and alkylene;

R4 and R8 are independently selected from the group consisting of hydrido and halo;
R5, R6, R7, R33. R34, R35, and R36 are independently selected from the croup consisting of hydrido, alkyl, halo, haloalkyl, haloalkoxy, aryl, alkylthio, arylamino, arylthio. aroyl, arylsulfonyl, aryloxy, aralkoxy, heteroaryloxy, alkoxy, aralkyl, cycloalkoxy, cycloalkylalkoxy, cycloalkylalkanoyl, heteroaryl, cycloalkyl, haloalkylthio, hydroxyhaloalkyl, heteroaralkoxy, heterocyclyloxy, aralkylaryl, heteroaryloxyalkyl, heteroarylthio, and heteroarylsulfonyl;
R4 and R5, R5 and R6, R6 and R7, and R7 and R8 are independently selected to form spacer pairs wherein a spacer pair is taken together to form a linear moiety having from 3 through 6 contiguous atoms connecting the points of bonding of said spacer pair members to form a ring selected from the group consisting of a cycloalkenyl ring having 5 through 8 continuous members, a partially saturated heterocyclyl ring having 5 through 8 contiguous members, a heteroaryl ring having 5 through 6 continuous members, and an aryl with the proviso that no more than one of the group consisting of spacer pairs R4 and R5, R5 and R6, R6 and R7, and R7 and R8, is used at the same time;
9. The compound as recited in Claim 8 or a pharmaceutically acceptable salt thereof, wherein;
n is the integer 1;
A is selected from the group consisting of ethyl, 1-propenyl, propyl, isopropyl, butyl, 2-butenyl, 3-butenyl, see-butyl, isobutyl, 2-methylpropenyl, 1-pentyl, 2-pentenyl, 3-pentenyl, 4-pentenyl. 2-pentyl, 1-methyl-2-butenyl, 1-methyl-3-butenyl, 3-pentyl, 1-ethyl-2-propenyl, 2-methylbutyl, 2-methyl-2-butenyl, 2-methyl-3-butenyl, 3-methylbutyl, 3-methyl-2-butenyl, 3-methyl-3-butenyl, 1-hexyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-hexyl, 1-methyl-2-pentenyl, 1-methyl-3-pentenyl, 1-methyl-4-pentenyl, 3-hexyl, l-ethyl-2-butenyl, 1-ethyl-3-butenyl, 1-propyl-2-propenyl, 1-heptyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, 2-heptyl, 1-methyl-2-hexenyl, 1-methyl-3-hexenyl, 1-methyl-4-hexenyl, 1-methyl-5-hexenyl, 3-heptyl, 1-ethyl-2-pentenyl, 1-ethyl-4-pentenyl, 1-ethyl-4-pentenyl, 1-butyl-2-propenyl, 1-octyl, 2-octenyl, 3-octenyl, 4-octenyl, 5-octenyl, 6-octenyl, 7-octenyl, 2-octyl, 1-methyl-2-heptenyl, 1-methyl-3-heptenyl, 1-methyl-4-heptenyl, 1-methyl-5-heptenyl, 1-methyl-6-heptenyl, 1-methyl-4-heptenyl, 1-methyl-6-heptenyl, 1-methyl-2-heptenyl, 3-octyl, 1-ethyl-2-hexenyl, 1-ethyl-3-hexenyl, 1-ethyl-4-hexenyl, 1-ethyl-5-hexenyl, 1-pentyl-2-propenyl, 4-octyl, 1-propyl-2-pentenyl, 1-propyl-3-pentenyl, 1-propyl-4-pentenyl, 1-butyl-2-butenyl, 1-butyl-3-butenyl, 2,2-difluoropropyl, 4-trifluoromethyl-5,5,5-trifluoropentyl, 4-trifluoromethyipentyl, 5,5,6,6,6-pentafluorohexyl and 3,3,3-trifluoropropyl, wherein each member of group A may be optionally substituted at any carbon up to and including 6 atoms from the point of attachment of A to Z with one or more of the group consisting of R33, R34, R35, and R36 with the provisos that R33, R34, R35, and R36 must not be attached to the carbon directly linking A to Z and that R33, R34, R35, and R36 must be selected from other than aryl and heteroaryl when substituting the carbon 2 atoms from Z wherein Z is a single covalent bond;
R1 is selected from the group consisting of trifluoromethyl, 1,1.2,2-tetrafluoroethoxymethyl, trifluoromethoxymethyl, difluoromethyl, chlorodifluoromethyl, and pentafluoroethyl;
R2 is selected from the group consisting of hydrido, methyl, ethyl, phenyl, 4-trifluoromethylphenyl, trifluoromethoxymethyl, 1,1,2,2-tetrafluoroethoxymethyl, difluoromethyl, pentafluoroethyl, trifluoromethyl, and 2,2,3,3,3-pentafluoropropyl;
R3 is selected from the group consisting of hydrido, phenyl, 4-trifluoromethylphenyl, methyl, trifluoromethyl, difluoromethyl, and chlorodifluoromethyl;
Y and Z are independently selected from a covalent single bond and methylene;

R4 and R8 are independently selected from the group consisting of hydrido and fluoro;
R5, R33, R34, R35, and R36 are independently selected from the group consisting of benzyloxy, 5-bromo-2-fluorophenoxy, 4-bromo-3-fluorophenoxy, 3-bromobenzyloxy, 4-bromophenoxy, 4-butoxyphenoxy, 3-chlorobenzyloxy, 2-chlorophenoxy, 4-chloro-3-ethylphenoxy, 4-chloro-3-methylphenoxy, 2-chloro-4-fluorophenoxy, 4-chloro-2-fluorophenoxy, 4-chlorophenoxy, 3-chloro-4-ethylphenoxy, 3-chloro-4-methylphenoxy, 3-chloro-4-fluorophenoxy, 4-chloro-3-fluorophenoxy, 4-chlorophenylamino, 5-chloropyrid-3-yloxy, cyclobutoxy, cyclobutyl, cyclohexylmethoxy, cyclopentoxy, cyclopentyl, cyclopentylcarbonyl, cyclopropylmethoxy, 2,3-dichlorophenoxy, 2,4-dichlorophenoxy, 2,4-dichlorophenyl.
3,5-dichlorophenyl, 3,5-dichlorobenzyl, 3,4-dichlorophenoxy, 3,4-difluorophenoxy,2,3-difluorobenzyloxy, 3,5-difluorobenzyloxy, difluoromethoxy, 3,5-difluorophenoxy, 3,4-difluorophenyl, 2,3-difluorophenoxy, 2,4-difluorophenoxy, 2,4-difluorophenoxy, 3,5-dimethoxyphenoxy.3-dimethylaminophenoxy, 3,4-dimethylbenzyloxy, 3,5-dimethylbenzyloxy, 3,5-dimethylphenoxy, 3,4-dimethylphenoxy, 1,3-dioxolan-2-yl, 3-ethylbenzyloxy, 3-ethylphenoxy, 4-ethylaminophenoxy, 3-ethyl-2-methylphenoxy, 4-fluoro-3-methylbenzyl, 4-fluorobenzyloxy, 2-fluoro-3-methylphenoxy, 3-fluoro-4-methylphenoxy, 3-fluorophenoxy, 3-fluoro-2-nitrophenoxy, 2-fluoro-3-trifluoromethylbenzyloxy, 3-fluoro-5-trifluoromethylbenzyloxy, 2-fluorophenoxy, 4-fluorophenoxy, 2-fluoro-3-trifluoromethylphenoxy, 2-fluorobenzyloxy, 4-fluorophenylamino, 2-fluoro-4-trifluoromethylphenoxy, 2-furyl, 3-furyl, heptafluoropropyl, 1,1,1,3,3,3-hexafluoropropyl, 2-hydroxy-3,3,3-trifluoropropoxy, isobutoxy, isobutyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, isopropoxy, 3-isopropylbenzyloxy, 3-isopropylphenoxy, isopropylthio, 4-isopropyl-3-methylphenoxy, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 3-methoxybenzyl, 4-methoxyphenylamino, 3-methylbenzyloxy, 4-methylbenxyloxy, 3-methylphenoxy, 3-methyl-4-methylthiophenoxy, 4-methylphenoxy, 2-naphthyloxy, 2-nitrophenoxy, 4-nitrophenoxy, 3-nitrophenyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, pentafluoroethyl, pentafluoroethylthio, 2,2,3,3,3-pentafluoropropyl, 1,1,3,3,3-pentafluoropropyl, 1,1,2,2,3-pentafluoropropyl, phenoxy, phenylamino, 1-phenylethoxy, 4-propylphenoxy, 4-propoxyphenoxy, thiophen-3-yl,tert -butoxy, 3-tent -butylphenoxy, 4-tert -butylphenoxy, 1,1,2,?-tetrafluoroethoxy, tetrahydrofuran-2-yl, 2-(5,6,7,8-tetrahydronaphthyloxy), thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, thiophen-2-yl, 2,2,2-trifluoroethoxy, 2,2,2-trifluoroethyl, 3,3,3-trifluoro-2-hydroxypropyl, trifluoromethoxy, 3-trifluoromethoxybenzyloxy, 4-trifluoromethoxybenzyloxy, 4-trifluoromethoxyphenoxy, 3-trifluoromethoxyphenoxy. trifluoromethyl, 3-trifluoromethylbenzyloxy, 1.1-bis-trifluoromethyl-1-hydroxymethyl, 3-trifluoromethylbenzyl, 3,5-bis-trifluoromethylbenzyloxy, 4-trifluoromethylphenoxy, 3-trifluoromethylphenoxy, 3-trifluoromethylphenyl, 2,3,4-trifluorophenoxy, 2,3,5-trifluorophenoxy, 3,4,5-trimethylphenoxy, 3-difluoromethoxyphenoxy, 3-pentafluoroethylphenoxy, 3-(1,1,2,2-tetrafluoroethoxy)phenoxy, 3-trifluoromethyithiophenoxy, 3-trifluoromethylthiobenzyloxy, and trifluoromethylthio;
R6 is selected from the group consisting of chloro, fluoro, hydrido, pentafluoroethyl, 1,1,2,2-tetrafluoroethoxy, and trifluoromethyl;
R7 is selected from the group consisting of hydrido, fluoro, and trifluoromethyl.
10. The compound as recited in Claim 9 or a pharmaceutically acceptable salt thereof, wherein;
n is the integer 1;
A is selected from the group consisting of 1-propenyl, propyl, isopropyl, butyl, 2-butenyl, 3-butenyl, sec-butyl, isobutyl, 2-methylpropenyl, 1-pentyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-pentyl, 1-methyl-2-butenyl, 1-methyl-3-butenyl; 3-pentyl, 1-ethyl-2-propenyl, 2-methylbutyl, 2-methyl-2-butenyl, 2-methyl-3-butenyl, 3-methylbutyl, 3-methyl-2-butenyl, 3-methyl-3-butenyl, l-hexyl, 2-hexenyl, 3-hexenyl. 4-hexenyl, 5-hexenyl, 2-hexyl, 1-methyl-2-pentenyl, 1-methyl-3-pentenyl, 1-methyl-4-pentenyl, 3-hexyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 1-propyl-2-propenyl, 1-ethyl-2-pentenyl, 1-ethyl-3-pentenyl, 1-ethyl-4-pentenyl, 1-butyl-2-propenyl, 1-ethyl-2-hexenyl, 1-ethyl 3-hexenyl, 1-ethyl-4-hexenyl, 1-ethyl-5-hexenyl, 1-pentyl-2-propenyl,1-propyl-2-pentenyl, 1-propyl-3-pentenyl, 1-propyl-4-pentenyl, 1-butyl-2-butenyl. 1-butyl-3-butenyl, 2,2-difluoropropyl, 4-trifluoromethyl-5,5,5-trifluoropentyl, 4-trifluoromethylpentvl, 5,5,6,6,6-pentafluorohexyl, and 3,3,3-trifluoropropyl, wherein each member of group A may be optionally substituted at any carbon up to and including 6 atoms from the point of attachment of A to Z with one or more of the group consisting of R33, R34, R35, and R36 with the provisos that R33, R34, R35, and R36 must not be attached to the carbon directly linking A to Z and that R33, R34, R35, and R36 must be selected from other than aryl and heteroaryl when substituting the carbon 2 atoms from Z wherein Z is a single covalent bond;
R1 is selected from the group consisting of trifluoromethyl, chlorodifluoromethyl, and pentafluoroethyl;
R2 is hydrido, pentafluoroethyl, and trifluoromethyl;
R3 is selected from the group consisting of hydrido, methyl, trifluoromethyl, and difluoromethyl Y is a covalent sine bond;
Z is methylene;
R4 and R8 are independently selected from the group consisting of hydrido and fluoro;
R5, R33, R34, R35, and R36 are independently selected from the group consisting of 5-bromo-2-fluorophenoxy, 4-chloro-3-ethylphenoxy, cyclopentyl, 2.3-dichlorophenoxy, 3.4-dichlorophenoxy, 3-difluoromethoxyphenoxy, 3,5-dimethylphenoxy, 3,4-dimethylphenoxy, 3-ethylphenoxy, 3-ethyl-5-methylphenoxy, 4-fluoro-3-methylphenoxy, 4-fluorophenoxy, 2-furyl, isobutyl, isopropoxy, 3-isopropylphenoxy, 3-methylphenoxy, pentafluoroethyl, 3-pentafluoroethylphenoxy, 3-tert -butylphenoxy, 1,1,2,2-tetrafluoroethoxy, 3-(1,1,2,2-tetrafluoroethoxy)phenoxy, 2-(5,6,7,8-tetrahydronaphthyloxy) , trifluoromethoxy, 3-trifluoromethoxybenzyloxy,3-trifluoromethoxyphenoxy, -trifluoromethyl. 3-trifluoromethylbenzyloxy. 1,1 -bis-trifluoromethyl-1-hydroxymethyl, trifluoromethylthio, and 3-trifluoromethylthiophenoxy;
R6 is selected from the group consisting of fluoro and hydrido;
R7 is selected from the group consisting of hydrido and fluoro.
11. The compound as recited in Claim 9 or a pharmaceutically acceptable salt thereof, wherein;
n is the integer 1;
A is selected from the group consisting of 1-propenyl, propyl, isopropyl, butyl, 2-butenyl, 3-butenyl, sec-butyl, isobutyl, 2-methylpropenyl, 1-pentyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-pentyl, 1-methyl-2-butenyl, 1-methyl-3-butenyl, 3-pentyl, 1-ethyl-2-propenyl, 2-methylbutyl, 2-methyl-2-butenyl, 2-methyl-3-butenyl, 3-methylbutyl, 3-methyl-2-butenyl, 3-methyl-3-butenyl, 1-hexyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-hexyl, 1-methyl-2-pentenyl, 1-methyl-3-pentenyl, 1-methyl-2-pentenyl, 3-hexyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 1-propyl-2-propenyl, 1-ethyl-2-pentenyl, 1-ethyl-3-pentenyl, 1-ethyl-4-pentenyl, 1-butyl-2-propenyl, 1-ethyl-2-hexenyl, 1-ethyl-3-hexenyl, 1-ethyl-4-hexenyl, 1-ethyl-5-hexenyl, 1-pentyl-2-propenyl,1-propyl-2-pentenyl, 1-propyl-3-pentenyl, 1-propyl-4-pentenyl, 1-butyl-2-butenyl, 1-butyl-3-butenyl, 2,2-difluoropropyl, 4-trifluoromethyl-5,5,5-trifluoropentyl, 4-trifluoromethylpentyl, 5,5,6,6,6-pentafluorohexyl, and 3,3,3-trifluorupropyl, wherein each member of Group A may be optionally substituted at any carbon up to and including 6 atoms from the point of attachment of A to Z with one or more of the group consisting of R33, R34, R35, and R36 with the provisos that R33, R34, R35, and R36 must not be attached to the carbon directly linking A to Z and that R33, R34, R35, and R36 must be selected from other than aryl and heteroaryl when substituting the carbon 2 atoms from Z wherein Z is a single covalent bond;
R1 is selected from the group consisting of trifluoromethyl, chlorodifluoromethyl, and pentafluoroethyl;
R2 is hydrido, pentafluoroethyl, and trifluoromethyl;
R3 is selected from the group consisting of hydrido, methyl, trifluoromethyl, and difluoromethyl Y is methylene;
Z is a covalent single bond;
R4 and R8 are independently selected from the group consisting of hydrido and fluoro;
R5, R33, R34, R35, and R36 are independently selected from the group consisting of 5-bromo-2-fluorophenoxy, 4-chloro-3-ethylphenoxy, cyclopentyl, 2,3-dichlorophenoxy, 3,4-dichlorophenoxy, 3-difluoromethoxyphenoxy, 3,5-dimethylphenoxy, 3,4-dimethylphenoxy, 3-ethylphenoxy, 3-ethyl-5-methylphenoxy, 4-fluoro-3-methylphenoxy, 4-fluorophenoxy, 2-furyl, isobutyl, isopropoxy. 3-isopropylphenoxy, 3-methylphenoxy, pentafluoroethyl, 3-pentafluoroethylphenoxy, 3-tert -butylphenoxy, 1,1,2,2-tetrafluoroethoxy, 3-(1,1,2,2-tetrafluoroethoxy)phenoxy, 2-(5,6,7,8-tetrahydronaphthyloxy), trifluoromethoxy, 3-trifluoromethoxybenzyloxy,3-trifluoromethoxyphenoxy, trifluoromethyl, 3-trifluoromethylbenzyloxy, 1,1-bis-trifluoromethyl-1-hydroxymethyl, trifluoromethylthio, and 3-trifluoromethylthiophenoxy;
R6 is selected from the group consisting of fluoro and hydrido;
R7 is selected from the group consisting of hydrido and fluoro.
12. The compound as recited in Claim 1 having the formula of:
or a pharmaceutically acceptable salt thereof, wherein;
n is an integer selected from 1 through 2;
A and Q are independently selected from the group consisting of -CH2(CR37R38)v-(CR33R34)u -T-(CR3R36)w -H
with the provisos that one of A and Q must be AQ-1H and that one of A and Q
must be selected from the group consisting of AQ-2 and -CH2(CR37R38)v-(CR33R34)u -T-(CR3R36)w -H;
T is selected from the group consisting of a single covalent bond. O, S.
S(O). S(O)2. C(R33)=C(R36), and C~C;
v is an integer selected from 0 through 1 with the proviso that v is 1 when any one of R33, R34, R35, and R36 is aryl or heteroaryl;
u and w are integers independently selected from 0 through 6;
A1 is C(R30);

D1, D2, J1, J2 and K1 are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more than one of D1, D2, J1, J2 and K1 is a covalent bond, no more than one of D1, D2, J1, J2 and K1 is O, no more than one of D1, D2, J1, J2 and K1 is S, one of D1, D2, J1, J2 and K1 must be a covalent bond when two of D1, D2, J1, J2 and K1 are O and S, and no more than four of D1, D2, J1, J2 and K1 are N;
B1, B2, D3, D4, J3, J4 and K2 are independently selected from the group consisting of C, C(R30), N, O, S and a covalent bond with the provisos that no more than 5 of B1, B2, D3, D4, J3, J4 and K2 are a covalent bond, no more than two of B1, B2, D3, D4, J3, J4 and K2 are O, no more than two of B1, B2, D3, D3, J3, J4 and K2 are S, no more than two of B1, B2, D3, D4, J3, J4, and K2 are simultaneously O and S. and no more than two of B1, B2, D3, D4, J3, J4 and K2 are N:
B1 and D3, D3 and J3, J3 and K2, K2 and J4, J4 and D4, and D4 and B2 are independently selected to form an in-ring spacer pair wherein said spacer pair is selected from the group consisting of C(R33)=C(R35) and N=N
with the provisos that AQ-2 must be a ring of at least five contiguous members, that no more than two of the group of said spacer pairs are simultaneously C(R33)=C(R35), and that no more than one of the group of said spacer pairs is N=N unless the other spacer pairs are other than C(R33)=C(R35), O, N, and S;

R1 is selected from the group consisting of haloalkyl and haloalkoxymethyl;
R2 is selected from the group consisting of hydrido, aryl, alkyl, alkenyl, haloalkyl, haloalkoxy, haloalkoxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, and heteroaryl;
R3 is selected from the group consisting of hydrido, aryl, alkyl, alkenyl, haloalkyl, and haloalkoxyalkyl;
Y is selected from the group consisting of a covalent single bond, (CH2)q wherein q is an integer selected from 1 through 2, and (CH2)j-O-(CH2)k wherein j and k are integers independently selected from 0 through 1;
Z is selected from the group consisting of covalent single bond, (CH2)q wherein q is an integer selected from 1 through 2, and (CH2)j-O-(CH2)k wherein j and k are integers independently selected from 0 through 1;
R30 is selected from the group consisting of hydrido, alkoxy, alkoxyalkyl, halo, haloalkyl, alkylamino, alkylthio, alkylthioalkyl, alkyl, alkenyl, haloalkoxy, and haloalkoxyalkyl with the proviso that R30 is selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen;
R30, when bonded to A1, is taken together to form an intra-ring linear spacer connecting the A1-carbon at the point of attachment of R30 to the point of bonding of a group selected from the group consisting of R10, R11, R12, R31, and R32 wherein said intra-ring linear spacer is selected from the group consisting of a covalent single bond and a spacer moiety having from 1 through 6 contiguous atoms to form a ring selected from the group consisting of a cycloalkyl having from 3 through 10 contiguous members, a cycloalkenyl having from 5 through 10 contiguous members, and a heterocyclyl having from 5 through 10 contiguous members;

R30, when bonded to A1, is taken together to form an intra-ring branched spacer connecting the A1-carbon at the point of attachment of R30 to the points of bonding of each member of any one of substituent pairs selected from the group consisting of subsitituent pairs R10 and R11, R10 and R31, R10 and R32. R10 and R12, R11 and R31, R11 and R32, R11 and R12, R31 and R32, R31 and R12, and R32 and R12 and wherein said intra-ring branched spacer is selected to form two rings selected from the group consisting of cycloalkyl having from 3 through 10 contiguous members, cycloalkenyl having from 5 through 10 continuous members, and heterocyclyl having from 5 through 10 contiguous members;
R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R31, R32 , R33, R34, R35, and R36 are independently selected from the group consisting of hydrido, carboxy, heteroaralkylthio, heteroaralkoxy, cycloalkylamino, acylalkyl, acylalkoxy, aroylalkoxy, heterocyclyloxy, aralkylaryl, aralkyl, aralkenyl, aralkynyl, heterocyclyl, perhaloaralkyl, aralkylsulfonyl, aralkylsulfonylalkyl, aralkylsulfinyl, aralkylsulfinylalkyl, halocycloalkyl, halocycloalkenyl, cycloalkylsulfinyl, cycloalkylsulfinylalkyl, cycloalkylsulfonyl, cycloalkylsulfonylalkyl, heteroaryamino, N-heteroarylamino-N-alkylamino, heteroarylaminoalkyl,haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl, haloalkoxylalkyl, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy, cycloalkoxyalkyl, cycloalkylalkoxy, cycloalkenyloxyalkyl, cycloalkylenedioxy, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxy, halocycloalkenyloxyalkyl, hydroxy, amino, thin, vitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkyiamino, arylthio, arylthioalkyl, heteroaralkoxyalkyl, alkylsulfinyl, alkylsulfinylalkyl, arylsulfinylalkyl, arylsulfonylalkyl, heteroarylsulfinylalkyl, heteroarylsulfonylalkyl, alkylsulfonyl, alkyisulfonylalkyl, haloalkylsulfinylalkyl, haloalkylsulfonylalkyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, monoarylamidosulfonyl, arylsulfonamido, diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, heterocyclylsulfonyl, heterocyclylthio, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl, alkynyl, alkenyloxy, alkenyloxyalky, alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkylalkanoyl, cycloalkenyl, lower cycloalkylalkyl, lower cycloalkenylalkyl, halo, haloalkyl, haloalkenyl, haloalkoxy, hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, hydoxyheteroaralkyl, haloalkoxyalkyl, aryl, heteroaralkynyl, aryloxy, aralkoxy, aryloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkenyl, heteroarylalkenyl, carboxyalkyl, carboalkoxy, alkoxycarboxamido, alkylamidocarbonylamido, arylamidocarbonylamido, carboalkoxyalkyl. carboalkoxyalkenyl, carboaralkoxy, carboxamido.
carboxamidoalkyl, cyano, carbohaloalkoxy, phosphono, phosphonoalkyl, diaralkoxyphosphono, and diaralkoxyphosphonoalkyl with the provisos that R4, R5, R6, R7, R8, R9, R10, R11, R12. R13, R31, R32, R33, R34, R35, and R36 are each independently selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen, that no more than three of the R33 and R34 substituents are simultaneously selected from other than the group consisting of of hydrido and halo, and that no more than three of the R35 and R36 substituents are simultaneously selected from other than the group consistubg of hydrido and halo;
R9, R10, R11, R12, R13, R31, and R32 are independently selected to be oxo with the provisos that B1, B2. D3. D4, J3, J4 and K2 are independently selected from the group consisting of C and S, no more than two of R9, R10, R11, R12, R13, R31, and R32 are simultaneously oxo, and that R9, R10, R11, R12, R13, R31, and R32 are each independently selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen;

R4 and R5, R5 and R6, R6 and R7, R7 and R8, R9 and R10, R10 and R11, R11 and R31, R31 and R32. R32 and R12, and R12 and R13 are independently selected to form spacer pairs wherein a spacer pair is taken together to form a linear moiety having from 3 through 6 continuous atoms connecting the points of bonding of said spacer pair members to form a ring selected from the group consisting of a cvcloalkenyl ring having 5 through 8 contiguous members, a partially saturated heterocyclyl ring having a through 8 contiguous members, a heteroaryl ring having 5 throuch 6 contiguous members, and an aryl with the provisos that no more than one of the group consisting of spacer pairs R4 and R5, R6 and R6. R6 and R7, and R7 and R8, is used at the same time and that no more than one of the group consisting of spacer pairs R9 and R10, R10 and R11, R11 and R31, R31 and R32, R32 and R12, and R12 and R13 is used at the same time;
R9 and R11, R12 and R12, R9 and R13, R9 and R31, R9 and R32, R10 and R12, R10 and R13, R10 and R31, R10 and R32, R11 and R 12, R11 and R13, R11 and R32, R12 and R31, R13 and R31, and R13 and R32 are independently selected to form a spacer pair wherein said spacer pair is taken together to form a linear spacer moiety selected from the group consisting of a covalent single bond and a moiety having from 1 through 3 continuous atoms to form a ring selected from the group consisting of a cycloalkyl having from through 8 contiguous members, a cycloalkenyl having from 5 through 8 contiguous members, a saturated heterocyclyl having from 5 through 8 contiguous members and a partially saturated heterocyclyl having from 5 through 8 contiguous members with the provisos that no more than one of said group of spacer pairs is used at the same time;
R37 and R38 are independently selected from the group consisting of hydrido, alkoxy, alkoxyalkyl, hydroxy, amino, thio, halo, haloalkyl, alkylamino, alkylthio, alkylthioalkyl, cyano, alkyl. alkenyl, haloalkoxy, and haloalkoxyalkyl.
13. The compound as recited in Claim 12 having the formula of:

or a pharmaceutically acceptable salt thereof, wherein;
n is an integer selected from 1 through 2;
A is selected from the group consisting of C3-C10 cycloalkyl, C5-C10 cycloalkenyl, C4-C9 saturated heterocyclyl, and C4-C9 partially saturated heterocyclyl, wherein each ring carbon may be optionally substituted with R30, a ring carbon other than the ring carbon at the point of attachment of A to Z
may be optionally substituted with oxo provided that no more than one ring carbon is substituted by oxo at the same time, ring carbon and nitrogen atoms adjacent to the carbon atom at the point of attachment may be optionally substituted with R9 or R13, a ring carbon or nitrogen atom adjacent to the R9 position and two atoms from the point of attachment may be substituted with R10, a ring carbon or nitrogen atom adjacent to the R13 position and two atoms from the point of attachment may be substituted with R12, a ring carbon or nitrogen atom three atoms from the point of attachment and adjacent to the R10 position may be substituted with R11, a ring carbon or nitrogen atom three atoms from the point of attachment and adjacent to the R12 position may be substituted with R32, and a ring carbon or nitrogen atom four atoms from the point of attachment and adjacent to the R11 and R32 positions may be substituted with R31;

D1, D2, J1, J2 and K1 are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more than one of D1, D2, J1, J2 and K1 is a covalent bond, no more than one of D1, D1, J1, J2 and K1 is O, no more than one of D1, D2, J1, J2 and K1 is S, one of D1, D2, J1, J2 and K1 must be a covalent bond when two of D1, D2, J1, J2 and K1 are O and S, and no more than four of D1, D2, J1, J2 and K1 are N;

R1 is selected from the group consisting of haloalkyl and haloalkoxymethyl;

R2 is selected from the group consisting of hydrido, aryl, alkyl, alkenyl, haloalkyl, haloalkoxy, haloalkoxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, and heteroaryl;

R3 is selected from the group consisting of hydrido, aryl, alkyl, alkenyl, haloalkyl, and haloalkoxyalkyl;

Y and Z are independently selected from the group consisting of a covalent single bond, oxy and alkylene;

R4 and R8 are independently selected from the group consisting of hydrido and halo;

R9 and R13 are halo;

R5, R6, and R7 are independently selected from the group consisting of hydrido, alkyl, halo, haloalkyl, haloalkoxy, aryl, alkylthio, arylamino, arylthio, aroyl, arylsulfonyl, aryloxy, aralkoxy, heteroaryloxy, alkoxy, aralkyl, cycloalkoxy, cycloalkylalkoxy, cycloalkylalkanoyl, heteroaryl, cycloalkyl, haloalkylthio, hydroxyhaloalkyl, heteroaralkoxy, heterocyclyloxy, aralkylaryl, heteroaryloxyalkyl, heteroarylthio, and heteroarylsulfonyl;

R4 and R5, R5 and R6, R6 and R7, and R7 and R8 are independently selected to form spacer pairs wherein a spacer pair is taken together to form a linear moiety having from 3 through 6 contiguous atoms connecting the points of bonding of said spacer pair members to form a ring selected from the group -consisting of a cycloalkenyl ring having 5 through 8 contiguous members, a partially saturated heterocyclyl ring having 5 through 8 contiguous members, a heteroaryl ring having 5 through 6 contiguous members, and an aryl with the proviso that no more than one of the group consisting of spacer pairs R4 and R5, R5 and R6, R6 and R7, and R7 and R8, is used at the same time;

R10, R11, R12, R31, and R32 are independently selected from the group group consisting of alkyl, halo, haloalkyl, haloalkoxy, aryl, alkylthio, arylamino, arylthio, aroyl, arylsulfonyl, aryloxy, aralkoxy, heteroaryloxy, alkoxy, aralkyl, cycloalkoxy, cycloalkylalkoxy, cycloalkylalkanoyl, heteroaryl.
cycloalkyl, haloalkylthio, hydroxyhaloalkyl, heteroaralkoxy, heterocyclyloxy, aralkylaryl, heteroaryloxyalkyl, heteroarylthio, and heteroarylsulfonyl;

R30 is selected from the group consisting of alkoxy, alkoxyalkyl, halo, haloalkyl, alkylamino, alkylthio, alkylthioalkyl, alkyl, alkenyl, haloalkoxy, and haloalkoxyalkyl.
14. The compound as recited in Claim 13 or a pharmaceutically acceptable salt thereof, wherein;

n is the integer 1;

A is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclopent-2-enyl, cyclopent-3-enyl, cyclohexyl, 4-methylcyclohexyl, 4-chloro-3-ethylphenoxycyclohexyl, 3-trifluoromethoxyphenoxycyclohexyl, 3-trifluoromethylcyclohexyl, 4-trifluoromethylcyclohexyl, 3,5-bis-trifluoromethylcyclohexyl, adamantyl, 3-trifluoromethyladamantyl, norbornyl, 3-trifluoromethylnorbornyl, norbornenyl, 7-oxabicyclo[2.2.1]heptan-2-yl, bicyclo[3.1.0)hexan-6-yl, cyclohex-2-enyl, cyclohex-3-enyl, cycloheptyl, cyclohept-2-enyl, cyclohept-3-enyl, cyclooctyl, cyclooct-2-enyl, cyclooct-3-enyl, cyclooct-4-enyl, 2-morpholinyl, 3-morpholinyl, 4-morpholinyl, 1-piperazinyl, 2-piperazinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-dioxanyl, 2H-2-pyranyl, 2H-3-pyranyl, 2H-4-pyranyl, 4H-2-pyranyl, 4H-3-pyranyl, 4H-4-pyranyl, 2H-pyran-2-one-3-yl, 2H-pyran-2-one-4-yl, 2H-pyran-2-one-5-yl, 4H-pyran-4-one-2-yl, 4H-pyran-4-one-3-yl, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydropyranyl, 3-tetrahydropyranyl, 4-tetrahydropyranyl, 2-tetrahydrothienyl, and 3-tetrahydrothienyl, wherein each ring carbon may be optionally substituted with R30, a ring carbon other than the ring carbon at the point of attachment of A
to Z may be optionally substituted with oxo provided that no more than one ring carbon is substituted by oxo at the same time, ring carbon and nitrogen atoms adjacent to the carbon atom at the point of attachment may be optionally substituted with R9 or R13, a ring carbon or nitrogen atom adjacent to the R9 position and two atoms from the point of attachment may be substituted with R10, a ring carbon or nitrogen atom adjacent to the R13 position and two atoms from the point of attachment may be substituted with R12, a ring carbon or nitrogen atom three atoms from the point of attachment and adjacent to the R10 position may be substituted with R11, a ring carbon or nitrogen atom three atoms from the point of attachment and adjacent to the R12 position may be substituted with R32, and a ring carbon or nitrogen atom four atoms from the point of attachment and adjacent to the R11 and R32 positions may be substituted with R31;

D1, D2, J1,J2 and K1 are independently selected from the group consisting of C, N, O, S and a covalent bond to form the group consisting of 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, imidazolyl, 3-pyrazolyl, 4-pyrazolyl, 1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,3,4-oxadiazol-3-yl, 1,3,4-oxadiazol-5-yl, 3-isothiazolyl, 5-isothiazolyl, 2-oxazolyl, 2-thiazolyl, 3-isoxazolyl, 5-isoxazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl,4-pyridazinyl, 1,3,5-triazin-2-yl, 1,2,4-triazin-3-yl, 1,2,4-triazin-5-yl, 1,2,4-triazin-6-yl, 1,2,3-triazin-4-yl, 1-indolizinyl, 7-indolizinyl, 1-isoquinolyl, and 2-quinolyl, wherein a ring carbon atom adjacent to the carbon atom at the point of attachment may be optionally substituted with R4 or R8, a rind carbon atom adjacent to the R4 position and two atoms from the point of attachment may be substituted with R5, a ring carbon atom adjacent to the R8 position and two atoms from the point of attachment may be substituted with R7, and a ring carbon atom three atoms from the point of attachment and adjacent to the R5 and R7 positions may be substituted with R6;

R1 is selected from the group consisting of trifluoromethyl, 1,1.2.2-tetrafluoroethoxymethyl, trifluoromethoxymethyl, difluoromethyl, chlorodifluoromethyl, and pentafluoroethyl;

R2 is selected from the group consisting of hydrido, methyl, ethyl, propyl, butyl, vinyl, phenyl, 4-trifluoromethylphenyl, 1,1,2,2-tetrafluoroethoxymethyl, trifluoromethoxymethyl, difluoromethyl, pentafluoroethyl, trifluoromethyl, and 2,2,3,3.3-pentafluoropropyl;

R3 is selected from the group consisting of hydrido, phenyl, 4-trifluoromethylphenyl, methyl, ethyl, vinyl, trifluoromethyl, trifluoromethoxymethyl, difluoromethyl, chlorodifluoromethyl, and pentafluoroethyl;

Y and Z are independently selected from the group consisting of a covalent single bond, oxy, and methylene with the proviso that only one of Y
and Z arc simultaneously oxy;

R4 and R8 are independently selected from the group consisting of hydrido and fluoro;

R9 and R13 are fluoro;

R5, R10 and R12 are independently selected from the group consisting of 4-aminophenoxy, benzoyl, benzyl, benzyloxy, 5-bromo-2-fluorophenoxy, 4-bromo-3-fluorophenoxy, 4-bromo-2-nitrophenoxy, 3-bromobenzyloxy, 4-bromobenzyloxy.
4-bromophenoxy, 5-bromopyrid-2-yloxy, 4-butoxyphenoxy, chloro, 3-chlorobenzyl, 2-chlorophenoxy,4-chlorophenoxy, 4-chloro-3-ethylphenoxy, 3-chloro-4-fluorobenzyl, 3-chloro-4-fluorophenyl, 3-chloro-2-fluorobenzyloxy, 3-chlorobenzyloxy, 4-chlorobenzyloxy, 4-chloro-3-methylphenoxy, 2-chloro-4-fluorophenoxy, 4-chloro-2-fluorophenoxy, 4-chlorophenoxy, 3-chloro-4-ethylphenoxy, 3-chloro-4-methylphenoxy, 3-chloro-4-fluorophenoxy, 4-chloro-3-fluorophenoxy, 4-chlorophenylamino,5-chloropyrid-3-yloxy, 2-cyanopyrid-3-yloxy, 4-cyanophenoxy, cyclobutoxy, cyclobutyl, cyclohexoxy, cyclohexylmethoxy, cyclopentoxy, cyclopentyl, cyclopentylcarbonyl, cyclopropyl, cyclopropylmethoxy,cyclopropoxy, 2,3-dichlorophenoxy, 2,4-dichlorophenoxy, 2,4-dichlorophenyl, 3,5-dichlorophenyl, 3,5-dichlorobenzyl, 3,4-dichlorophenoxy, 3,4-difluorophenoxy, 2,3-difluorobenzyloxy, 2,4-difluorobenzyloxy, 3,4-difluorobenzyloxy, 2,5-difluorobenzyloxy, 3,5-difluorophenoxy, 3,4-difluorophenyl, 3,5-difluorobenzyloxy, 4-difluoromethoxybenzyloxy, 2,3-difluorophenoxy, 2,4-difluorophenoxy, 2,5-difluorophenoxy, 3,5-dimethoxyphenoxy, 3-dimethylaminophenoxy, 3,5-dimethylphenoxy, 3,4-dimethylphenoxy, 3,4-dimethylbenzyl, 3,4-dimethylbenzyloxy, 3,5-dimethylbenzyloxy, 2,2-dimethylpropoxy, 1,3-dioxan-2-yl, 1,4-dioxan-2-yl, 1,3-dioxolan-2-yl, ethoxy, 4-ethoxyphenoxy, 4-ethylbenzyloxy, 3-ethylphenoxy, 4-ethylaminophenoxy, 3-ethyl-5-methylphenoxy, fluoro, 4-fluoro-3-methylbenzyl, 4-fluoro-3-methylphenyl, 4-fluoro-3-methylbenzoyl, 4-fluorobenzyloxy, 2-fluoro-3-methylphenoxy, 3-fluoro-4-methylphenoxy, 3-fluorophenoxy, 3-fluoro-2-nitrophenoxy, 2-fluoro-3-trifluoromethylbenzyloxy, 3-fluoro-S-trifluoromelhylbenzyloxy, 4-fluoro-2-trifluoromethylbenzyloxy, 4-fluoro-3-trifluoromethylbenzyloxy, 2-fluorophenoxy, 4-fluorophenoxy, 2-fluoro-3-trifluoromethylphenoxy, 2-fluorobenzyloxy, 4-fluorophenylamino, 2-fluoro-4-trifluoromethylphenoxy, 4-fluoropyrid-2-yloxy, 2-furyl, 3-furyl, heptafluoropropyl, 1,1,1,3,3,3-hexafluoropropyl, 2-hydroxy-3,3,3-trifluoropropoxy, 3-iodobenzyloxy, isobutyl, isobutylamino, isobutoxy, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, isopropoxy, isopropyl, -4-isopropylbenzyloxy, 3-isopropylphenoxy, 4-isopropylphenoxy, isopropylthio, 4-isopropyl-3-methylphenoxy, 3-isothiazolyl. 4-isothiazolyl, 5-isothiazolyl, 3-methoxybenzyl, 4-methoxycarbonylbutoxy, 3-methoxycarbonylprop-2-enyloxy, 4-methoxyphenyl, 3-methoxyphenylamino, 4-methoxyphenylamino, 3-methylbenzyloxy, 4-methylbenzyloxy, 3-methylphenoxy, 3-methyl-4-methylthiophenoxy, 4-methylphenoxy, 1-methylpropoxy, 2-methylpyrid-5-yloxy, 4-methylthiophenoxy, 2-naphthyloxy, 2-nitrophenoxy, 4-nitrophenoxy, 3-nitrophenyl, 4-nitrophenylthio, 2-oxazolyl. 4-oxazolyl, 5-oxazolyl, pentafluoroethyl, pentafluoroethylthio, 2,2,3,3,3-pentafluoropropyl, 1,1,3,3,3-pentafluoropropyl, 1,1,2,2,3-pentafluoropropyl, phenoxy, phenylamino, 1-phenylethoxy, phenylsulfonyl, 4-propanoylphenoxy, propoxy, 4-propylphenoxy, 4-propoxyphenoxy, thiophen-3-yl, sec-butyl, 4-sec-butylphenoxy,tert -butoxy, 3-tert -butylphenoxy, 4-tert -butylphenoxy, 1,1,2,2-tetrafluoroethoxy, tetrahydrofuran-2-yl.
2-(5,6,7,8-tetrahydronaphthyloxy), thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, thiophen-2-yl, 2,3,5-trifluorobenzyloxy, 2,2,2-trifluoroethoxy, 2,2,2-trifluoroethyl, 3,3,3-trifluoro-2-hydroxypropyl, trifluoromethoxy, 3-trifluoromethoxybenzyloxy, 4-trifluoromethoxybenzyloxy, 3-trifluoromethoxyphenoxy, 4-trifluoromethoxyphenoxy, trifluoromethyl, 3-trifluoromethylbenzyloxy, 4-trifluoromethylbenzyloxy, 2,4-bis-trifluoromethylbenzyloxy, 1,1-bis-trifluoromethyl-1-hydroxymethyl, 3-trifluoromethylbenzyl, 3,5-bis-trifluoromethylbenzyloxy, 4-trifluoromethylphenoxy, 3-trifluoromethylphenoxy, 3-trifluoromethylphenyl, 3-trifluoromethylthiobenzyloxy, 4-trifluoromethylthiobenzyloxy, 2,3,4-trifluorophenoxy, 2,3,4-trifluorophenyl, 2,3,5-trifluorophenoxy. 3,4,5-trimethylphenoxy, 3-difluoromethoxyphenoxy, 3-pentatluoroethylphenoxy, 3-(1,1,2,2-tetrafluoroethoxy)phenoxy, 3-trifluoromethylthiophenoxy, and trifluoromethylthio;

R6, R11, R31, and R32 are independently selected from the group consisting of chloro, fluoro, hydrido, pentafluoroethyl, 1,1,2,2-tetrafluoroethoxy, trifluoromethyl, and trifluoromethoxy;
R7 is selected from the group consisting of hydrido, fluoro, and trifluoromethyl;
R30 is selected from the group consisting of chloro, ethoxy, ethyl, fluoro, heptafluoropropyl, 1,1,1,3,3,3-hexafluoropropyl, isobutyl, isobutoxy, isopropoxy, isopropyl, isopropylthio, methyl, pentafluoroethyl, 2,2,3,3,3-pentafluoropropyl, 1,1,3,3,3-pentafluoropropyl, 1,1,2,2,3-pentafluoropropyl, propoxy, propyl, sec-butyl, tert-butoxy, 1,1,2,2-tetratluoroethoxy, 2,2,2-trifluoroethoxy, 2.2,2-trifluoroethyl, trifluoromethoxy, and trifluoromethyl.
15. The compound as recited in Claim 14 or a pharmaceutically acceptable salt thereof, wherein;
n is the integer 1;
A is selected from the Group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4-methylcyclohexyl, 4-chloro-3-ethylphenoxycyclohexyl, 3-trifluoromethoxyphenoxycyclohexyl, 3-trifluoromethylcyclohexyl, 4-trifluoromethylcyclohexyl, 3,5-bis-trifluoromethylcyclohexyl, adamantyl, 3-trifluoromethyladamantyl, norbornyl, 3-trifluoromethylnorbornyl, norbornenyl, 7-oxabicyclo[2.2.1]heptan-2-yl, bicyclo[3.1.0]hexan-6-yl, cycloheptyl, cyclooctyl, 2-morpholinyl, 3-morpholinyl, 4-morpholinyl, 1-piperazinyl, 2-piperazinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-dioxanyl, 4H-2-pyranyl, 4H-3-pyranyl, 4H-4-pyranyl, 4H-pyran-4-one-2-yl, 4H-pyran-4-one-3-yl, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydropyranyl, 3-tetrahydropyranyl, 4-tetrahydropyranyl, 2-tetrahydrothienyl, and 3-tetrahydrothienyl, wherein each ring carbon may he optionally substituted with R30, a ring carbon other than the ring carbon at the point of attachment of A to Z may be optionally substituted with oxo provided that no more than one ring carbon is substituted by oxo at the same time, ring carbon and nitrogen atoms adjacent to the carbon atom at the point of attachment may be optionally substituted with R9 or R13, a ring carbon or nitrogen atom adjacent to the R9 position and two atoms from the point of attachment may be substituted with R10, a ring carbon or nitrogen atom adjacent to the R13 position and two atoms from the point of attachment may be substituted with R12, a ring carbon or nitrogen atom three atoms from the point of attachment and adjacent to the R10 position may be substituted with R11, a ring carbon or nitrogen atom three atoms from the point of attachment and adjacent to the R12 position may be substituted with R12, and a ring carbon or nitrogen atom four atoms from the point of attachment and adjacent to the R11 and R32 positions may be substituted with R31;
D1, D2. J1, J2 and K1 are independently selected from the group consisting of C, N, O, S and a covalent bond to form the group consisting of 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, imidazolyl, 3-pyrazolyl, 4-pyrazolyl, 2-oxazolyl. 2-thiazolyl, 3-isoxazolyl, 5-isoxazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 1,3,5-triazin-2-yl, indolizinyl, 7-indolizinyl, 1-isoquinolyl, and 2-quinolyl, wherein a ring carbon atom adjacent to the carbon atom at the point of attachment may be optionally substituted with R4 or R8, a ring carbon atom adjacent to the R4 position and two atoms from the point of attachment may be substituted with R5, a ring carbon atom adjacent to the R8 position and two atoms from the point of attachment may be substituted with R7, and a ring carbon atom three atoms from the point of attachment and adjacent to the R5 and R7 positions may be substituted with R6;
R1 is selected from the group consisting of trifluoromethyl, 1,1,2,2-tetratluoroethoxymethyl, trifluoromethoxymethyl, difluoromethyl, chlorodifluoromethyl, and pentafluoroethyl;
R2 is selected from the group consisting of hydrido, methyl, ethyl, phenyl, 4-trifluoromethylphenyl, trifluoromethoxymethyl, 1,1,2,2-tetrafluoroethoxymethyl, difluoromethyl. pentafluoroethyl, trifluoromethyl, and 2,23,3,3-pentafluoropropyl;
R3 is selected from the group consisting of hydrido, phenyl, 4-trifluoromethylphenyl, methyl, trifluoromethyl, difluoromethyl, and chlorodifluoromethyl;
Y and Z are independently selected from a covalent single bond and methylene;
R4 and R8 are independently selected from the group consisting of hydrido and fluoro;
R9 and R13 are fluoro;
R5, R10 and R12 are independently selected from the group consisting of benzyloxy, 5-bromo-2-fluorophenoxy, 4-bromo-3-fluorophenoxy, 3-bromobenzyloxy, 4-bromophenoxy,4-butoxyphenoxy, 3-chlorobenzyloxy, 2-chlorophenoxy, 4-chloro-3-ethylphenoxy, 4-chloro-3-methylphenoxy, 2-chloro-4-fluorophenoxy, 4-chloro-2-fluorophenoxy, 4-chlorophenoxy, 3-chloro-4-ethylphenoxy, 3-chloro-4-methylphenoxy, 3-chloro-4-fluorophenoxy, 4-chloro-3-fluorophenoxy, 4-chlorophenylamino, 5-chloropyrid-3-yloxy, cyclobutoxy, cyclobutyl, cyclohexylmethoxy, cyclopentoxy, cyclopentyl, cyclopentylcarbonyl, cyclopropylmethoxy, 2.3-dichlorophenoxy, 2,4-dichlorophenoxy, 2,4-dichlorophenyl, 3,5-dichlorophenyl, 3,5-dichlorobenzyl, 3,4-dichlorophenoxy, 3,4-difluorophenoxy,2,3-difluorobenzyloxy, 3,5-difluorobenzyloxy, difluoromethoxy, 3,5-difluorophenoxy, 3,4-difluorophenyl, 2,3-difluorophenoxy, 2,4-difluorophenoxy. 2,5-difluorophenoxy, 3,5-dimethoxyphenoxy,3-dimethylaminophenoxy, 3,4-dimethylbenzyloxy, 3.3-dimethylbenzyloxy, 3,5-dimethylphenoxy, 3,4-dimethylphenoxy, 1,3-dioxolan-2-yl, 3-ethylbenzyloxy, 3-ethylphenoxy, 4-ethylaminophenoxy.
3-ethyl-5-methylphenoxy, 4-fluoro-3-methylbenzyl, 4-fluorobenzyloxy, 2-fluoro-3-methylphenoxy, 3-fluoro-4-methylphenoxy. 3-fluorophenoxy, 3-fluoro-2-nitrophenoxy, 2-fluoro-3-trifluoromethyl benzyloxy, 3-fluoro-5-trifluoromethylbenzyloxy, 2-fluorophenoxy, 4-fluorophenoxy, 2-fluoro-3-trifluoromethylphenoxy, 2-fluorobenzyloxy, 4-fluorophenylamino, 2-fluoro-4-trifluoromethylphenoxy. 2-furyl, 3-furyl, heptafluoropropyl, 1,1.1.3,3,3-hexafluoropropyl, 2-hydroxy-3,3.3-trifluoropropoxy, isobutoxy, isobutyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, isopropoxy, 3-isopropylbenzyloxy, 3-isopropylphenoxy, isopropylthio, 4-isopropyl-3-methylphenoxy, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 3-methoxybenzyl, 4-methoxyphenylamino, 3-melhylbenzyloxy, 4-methylbenxyloxy, 3-methylphenoxy, 3-methyl-4-methylthiophenoxy, 4-methylphenoxy, 1-methylpropoxy, 2-methylpyrid-5-yloxy, 4-methylthiophenoxy, 2-naphthyloxy, 2-nitrophenoxy. 4-nitrophenoxy. 3-nitrophenyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, pentafluoroethyl, pentafluoroethylthio, 2,2,3,3,3-pentafluoropropyl, 1,1,3,3,3-pentafluoropropyl, 1,1,2,2,3-pentafluoropropyl, phenoxy, phenylamino, 1-phenylethoxy, 4-propylphenoxy. 4-propoxyphenoxy, thiophen-3-yl,tert -butoxy, 3-tert-butylphenoxy, 4-tert -butylphenoxy, 1,1,2,2-tetrafluoroethoxy, tetrahydrofuran-2-yl, 2-(5,6,7,8-tetrahydronaphthyloxy), thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, thiophen-2-yl, 2,2,2-trifluoroethoxy, 2,2,2-trifluoroethyl, 3,3,3-trifluoro-2-hydroxypropyl, trifluoromethoxy, 3-trifluoromethoxybenzyloxy, 4-trifluorocnethoxybenzyloxy, 4-trifluoromethoxyphenoxy, 3-trifluoromethoxyphenoxy, trifluoromethyl, 3-trifluoromethylbenzyloxy, 1,1-bis-trifluoromethyl-1-hydroxymethyl.
3-trifluoromethylbenzyl, 3,5-bis-trifluoromethylbenzyloxy, 4-trifluoromethylphenoxy. 3-trifluoromethylphenoxy, 3-trifluoromethylphenyl, 2.3,4-trifluorophenoxy, 2,3,5-trifluorophenoxy, 3,4,5-trimethylphenoxy, 3-difluoromethoxyphenoxy, 3-pentafluoroethylphenoxy, 3-(1,1,2,2-tetrafluoroethoxy)phenoxy, 3-trifluoromethylthiophenoxy, 3-trifluoromethylthiobenzyloxy, and trifluoromethylthio;
R6, R11, R31, and R32 are independently selected from the group consisting of chloro, fluoro, hydrido, pentafluoroethyl. 1,1,2,2-tetrafluoroethoxy, and trifluoromethyl;
R7 is selected from the group consisting of hydrido, fluoro, and trifluoromethyl:
R30 is selected from the group consisting of chloro, ethyl, fluoro, heptafluoropropyl, 1,1,1,3,3,3-hexafluoropropyl, isobutyl, isopropyl, methyl, pentafluoroethyl, 2,2,3,3,3-pentafluoropropyl, 1,1,3,3,3-pentafluoropropyl.
1,1,2,2,3-pentafluoropropyl, propyl, sec-butyl, 1,1,2,2-tetrafluoroethoxy, 2.2,2-trifluoroethoxy, 2,2,2-trifluoroethyl, trifluoromethoxy, and trifluoromethyl.
16. The compound as recited in Claim 15 or a pharmaceutically acceptable salt thereof, wherein:
n is the integer 1;
A is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4-methylcyclohexyl, 4-chloro-3-ethylphenoxycyclohexyl, 3-trifluoromethoxyphenoxycyclohexyl, 3-trifluoromethylcyclohexyl, 4-trifluoromethylcyclohexyl, 3,5-bis-trifluoromethylcyclohexyl, adamantyl, 3-trifluoromethyladamantyl, norbornyl, 3-trifluoromethylnorbornyl, norbornenyl, 7-oxabicyclo(2,2,1]heptan-2-yl, bicyclo[3.1.0)hexan-6-yl, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydropyranyl, 3-tetrahydropyranyl, 4-tetrahydropyranyl, 2-tetrahydrothienyl, and 3-tetrahydrothienyl, wherein a ring carbon other than the ring carbon at the point of attachment of A to Z may be optionally substituted with oxo provided that no more than one rind carbon is substituted by oxo at the same time, ring carbon and nitrogen atoms adjacent to the carbon atom at the point of attachment may be optionally substituted with R9 or R 13, a ring carbon or nitrogen atom adjacent to the R9 position and two atoms from the point of attachment may be substituted with R10, a ring carbon or nitrogen atom adjacent to the R13 position and two atoms from the point of attachment may be substituted with R12, a ring carbon or nitrogen atom three atoms from the point of attachment and adjacent to the R10 position may be substituted with R11, a ring carbon or nitrogen atom three atoms from the point of attachment and adjacent to the R12 position may be substituted with R32, and a ring carbon or nitrogen atom four atoms from the point of attachment and adjacent to the R11 and R32 positions tray be substituted with R31;
D1, D2, J1, J2 and K1 are independently selected from the group consisting of C, N, O, S and a covalent bond to form the group consisting of 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, imidazolyl, 3-pyrazolyl, 4-pyrazolyl, 2-thiazolyl, 3-isoxazolyl, 5-isoxazolyl, pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, and 1,3,5-triazin-2-yl, wherein a ring carbon atom adjacent to the carbon atom at the point of attachment may be optionally substituted with R4 or R8, a ring carbon atom adjacent to the R4 position and two atoms from the point of attachment may be substituted with R5, a ring carbon atom adjacent to the R8 position and two atoms from the point of attachment may be substituted with R7, and a ring carbon atom three atoms from the point of attachment and adjacent to the R5 and R7 positions may be substituted with R6;
R1 is selected from the group consisting of trifluoromethyl, chlorodifluoromethyl, and pentafluoroethyl;
R2 is hydrido, pentafluoroethyl, and trifluoromethyl;

R3 is selected from the group consisting of hydrido, methyl, trifluoromethyl, and difluoromethyl Y is a covalent single bond:
Z is methylene;
R4 and R8 are independently selected from the group consisting of hydrido and fluoro:
R9 and R13 are fluoro;
R5, R10 and R12 are independently selected from the group consisting of 5-bromo-2-fluorophenoxy, 4-chloro-3-ethylphenoxy, cyclopentyl, 2,3-dichlorophenoxy, 3,4-dichlorophenoxy, 3-difluoromethoxyphenoxy, 3,5-dimethylphenoxy, 3,4-dimethylphenoxy, 3-ethylphenoxy, 3-ethyl-5-methylphenoxy, 4-fluoro-3-methylphenoxy, 4-fluorophenoxy, 2-furyl, isobutyl, isopropoxy, 3-isopropylphenoxy, 3-methylphenoxy, pentafluoroethyl, 3-pentafluoroethylphenoxy, 3-tert -butylphenoxy, 1,1,2,2-tetrafluoroethoxy, 3-(1,1,2,2-tetrafluoroethoxy)phenoxy, 2-(5,6,7,8-tetrahydronaphthyloxy),trifluoromethoxy, 3-trifluoromethoxybenzyloxy,3-trifluoromethoxyphenoxy, trifluoromethyl, 3-trifluoromethylbenzyloxy, 1,1-bis-trifluoromethyl-1-hydroxymethyl, trifluoromethylthio, and 3-trifluoromethylthiophenoxy;
R6, R11, R31, and R32 are independently selected from the group consisting of chloro, fluoro, hydrido, pentafluoroethyl, 1,1,2,2-tetrafluoroethoxy, and trifluoromethyl;
R7 is selected from the group consisting of hydrido and fluoro.
17. The compound as recited in Claim 15 or a pharmaceutically acceptable salt thereof, wherein;
n is the integer 1;
A is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 3-methylcyclohexyl, 4-chloro-3-ethylphenoxycyclohexyl, 3-trifluoromethoxyphenoxycyclohexyl, 3-trifluoromethylcyclohexyl, 4-trifluoromethylcyclohexyl, 3,5-bis-trifluoromethylcyclohexyl, adamantyl, 3-trifluoromethyladamantyl, norbornyl.
3-trifluoromethylnorbornyl, norbornenyl, 7-oxabicyclo[2.2.1]heptan-2-yl, bicyclo[3.1.0]hexan-6-yl, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydropyranyl, 3-tetrahydropyranyl, 4-tetrahydropyranyl, 2-tetrahydrothienyl, and 3-tetrahydrothienyl, wherein a ring carbon other than the ring carbon at the point of attachment of A to Z may be optionally substituted with oxo provided that no more than one ring carbon is substituted by oxo at the same time, ring carbon and nitrogen atoms adjacent to the carbon atom at the point of attachment may be optionally substituted with R9 or R13, a ring carbon or nitrogen atom adjacent to the R9 position and two atoms from the point of attachment may be substituted with R10, a ring carbon or nitrogen atom adjacent to the R13 position and two atoms from the point of attachment may be substituted with R12, a ring carbon or nitrogen atom three atoms from the point of attachment and adjacent to the R10 position may be substituted with R11, a ring carbon or nitrogen atom three atoms from the point of attachment and adjacent to the R12 position may be substituted with R32, and a ring carbon or nitrogen atom four atoms from the point of attachment and adjacent to the R11 and R32 positions may be substituted with R31;
D1, D2, J1, J2 and K1 are independently selected from the a group consisting of C, N, O, S and a covalent bond to form the group consisting of 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, imidazolyl, 3-pyrazolyl, 4-pyrazolyl, 2-thiazolyl, 3-isoxazolyl, 5-isoxazolyl, pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, and 1,3,5-triazin-2-yl, wherein a ring carbon atom adjacent to the carbon atom at the point of attachment may be optionally substituted with R4 or R8, a ring carbon atom adjacent to the R4 position and two atoms from the point of attachment may be substituted with R5, a ring carbon atom adjacent to the R8 position and two atoms from the point of attachment may be substituted with R7, and a ring carbon atom three atoms from the point of attachment and adjacent to the R5 and R7 positions may be substituted with R6;
R1 is selected from the group consisting of trifluoromethyl, chlorodifluoromethyl, and pentafluoroethyl;
R2 is hydrido, pentafluoroethyl, and trifluoromethyl;
R3 is selected from the group consisting of hydrido, methyl, trifluoromethyl, and difluoromethyl Y is methylene;
Z is a covalent single bond;
R4 and R8 are independently selected from the group consisting of hydrido and fluoro;
R9 and R13 are fluoro;
R5, R10 and R12 are independently selected from the group consisting of 5-bromo-2-fluorophenoxy, 4-chloro-3-ethylphenoxy, cyclopentyl, 2,3-dichlorophenoxy, 3,4-dichlorophenoxy. 3-difluoromethoxyphenoxy, 3,5-dimethylphenoxy, 3,4-dimethylphenoxy, 3-ethylphenoxy, 3-ethyl-5-methylphenoxy, 4-fluoro-3-methylphenoxy, 4-fluorophenoxy, 2-furyl, isobutyl, isopropoxy, 3-isopropylphenoxy, 3-methylphenoxy, pentafluoroethyl, 3-pentafluoroethylphenoxy. 3-tert -butylphenoxy, 1,1,2,2-tetrafluoroethoxy, 3-(1,1,2,2-tetrafluoroethoxy)phenoxy, 2-(5,6,7,8-tetrahydronaphthyloxy),trifluoromethoxy, 3-trifluoromethoxybenzyloxy,3-trifluoromethoxyphenoxy, trifluoromethyl, 3-trifluoromethylbentyloxy, 1,1-bis-trifluoromethyl-1-hydroxymethyl, trifluoromethylthio, and 3-trifluoromethylthiophenoxy;

R6, R11, R31, and R32 are independently selected from the group consisting of chloro, fluoro, hydrido, pentafluoroethyl, 1,1,2,2-tetrafluoroethoxy, and trifluoromethyl;
R7 is selected from the group consisting of hydrido and fluoro.
18. A compound as recited in Claim 1, or a pharmaceutically acceptable salt thereof, wherein said compound is selected from the group consisting of:
3-[[3-(4-chloro-3-ethylphenoxy)phenyl](cyclohexylmethyl)amino]-1,1,1-trifluoro-2-propanol;
3-[(3-(4-chloro-3-ethylphenoxy)phenyl](cyclopentylmethyl)amino]-1,1,1-trifluoro-2-propanol;
3-[[3-(4-chloro-3-ethylphenoxy)phenyl](cyclopropylmethyl)amino]-1,1,1-trifluoro-2-propanol;
3-[[3-(4-chloro-3-ethylphenoxy)phenyl][(3-trifluoromethyl)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;
3-[[3-(4-chloro-3-ethylphenoxy)phenyl][(3-pentafluoroethyl)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;
3-[[3-(4-chloro-3-ethylphenoxy)phenyl][(3-trifluoromethoxy)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;
3-[[3-(4-chloro-3-ethylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)cyclo-hexylmethyl]amino]-1,1,1-trifluoro-2-propanol;
3-[[3-(3-trifluoromethoxyphenoxy)phenyl](cyclohexylmethyl)amino)-1,1,1-trifluoro-2-propanol;
3-[[3-(3-trifluoromethoxyphenoxy)phenyl](cyclopentylmethyl)amino]-1,1,1-trifluoro-2-propanol;
3-[[33-trifluoromethoxyphenoxy)phenyl](cyclopropylmethyl)amino]-1,1,1-trifluoro-2-propanol;
3-[[3-(3-trifluoromethoxyphenoxy)phenyl][(3-trifluoromethyl)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;

3-((3-(3-trifluoromethoxyphenoxy)phenyl[[(3-pentafluoroethyl)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;
3-[[3-(3-trifluoromethoxyphenoxy)phenyl][(3-trifluoromethoxy)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;
3-[[3-(3-trifluoromethoxyphenoxy)phenyl][[3-(1,1,2,2 tetrafluoroethoxy)cyclo-hexylmethyl]amino]-1,1,1-trifluoro-2-propanol;
3-[[3-(3-isopropylphenoxy)phenyl](cyclohexylmethyl)amino]-1,1,1-trifluoro-2-propanol;
3-[[3-(3-isopropylphenoxy)phenyl](cyclopentylmethyl)amino]-1,1,1-trifluoro-2-propanol;
3-[[3-(3-isopropylphenoxylphenyl](cyclopropylmethyl)amino]-1,1,1-trifluoro-2-propanol;
3-[[3-(3-isopropylphenoxy)phenyl][(3-trifluoromethyl)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;
3-[[3-(3-isopropylphenoxy)phenyl][(3-pentafluoroethyl)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;
3-[[3-(3-isopropylphenoxy)phenyl][(3-trifluoromethoxy)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;
3-([3-(3-isopropylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)cyclo-hexyl]methyl]amino]-1,1,1-trifluoro-2-propanol;
3-[[3-(2,3-dichlorophenoxy)phenyl](cyclohexylmethyl)amino]-1,1,1-trifluoro-2-propanol;
3-[[3-(2,3-dichlorophenoxy)phenyl](cyclopentylmethyl)amino]-1,1,1-trifluoro-2-propanol;
3-[[3-(2,3-dichlorophenoxy)phenyl](cyclopropylmethyl)amino]-1,1,1-trifluoro-2-propanol;
3-[[3-(2,3-dichlorophenoxy)phenyl][(3-trifluoromethyl)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;
3-[[3-(2,3-dichlorophenoxy)phenyl][(3-pentafluoroethyl)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;
3-[(3-(2,3-dichlorophenoxy)phenyl][(3-trifluoromethoxy)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;
3-[[3-(2,3-dichlorophenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)cyclo-hexylmethyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(4-fluorophenoxy)phenyl((cyclohexylmethyl)amino]-1,1,1-trifluoro-2-propanol;
3-[[3-(4-fluorophenoxy)phenyl](cyclopentylmethyl)amino]-1,1,1-trifluoro-2-propanol;
3-[[3-(4-fluorophenoxy)phenyl](cyclopropylmethyl)amino]-1,1,1-trifluoro-2-propanol;
3-([3-(4-fluorophenoxy)phenyl]((3-trifluoromethyl)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;
3-((3-(4-fluorophenoxy)phenyl][(3-pentafluoroethyl)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;
3-[(3-(4-fluorophenoxy)phenyl][(3-trifluoromethoxy)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;
3-[[3-(4-fluorophenoxy)phenyl][(3-(1,1,2,2-tetrafluoroethoxy)cyclo-hexylmethyl]amino]-1,1,1-trifluoro-2-propanol;
3-[[3-(3-trifluoromethoxybenzyloxy)phenyl](cyclohexylmethyl)amino]-1,1,1-trifluoro-2-propanol;
3-[[3-(3-trifluoromethoxybenzyloxy)phenyl](cyclopentylmethyl)amino]-1,1,1-trifluoro-2-propanol;
3-[[3-(3-trifluoromethoxybenzyloxy)phenyl](cyclopropylmethyl)amino]-1,1,1-trifluoro-2-propanol;
3-[[3-(3-trifluoromethoxybenzyloxy)phenyl][(3-trifluoromethyl)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;
3-[[3-(3-trifluoromethoxybenzyloxy)phenyl)[(3-pentafluoroethyl)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;
3-[[3-(3-trifluoromethoxybenzyloxy)phenyl][(3-trifluoromethoxy)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;
3-[[3-(3-trifluoromethoxybenzyloxy)phenyl][[3-(1,1,2,2 tetrafluoroethoxy)-cyclohexylmethyl]amino]-1,1,1-trifluoro-2-propanol;
3-[[3-(3-trifluoromethylbenzyloxy)phenyl](cyclohexylmethyl)amino]-1,1,1-trifluoro-2-propanol;
3-[[3-(3-trifluoromethylbenzyloxy)phenyl](cyclopentylmethyl)amino]-1,1,1-trifluoro-2-propanol;
3-[[3-(3-trifluoromethylbenzyloxy)phenyl](cyclopropylmethyl)amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(3-trifluoromethylbenzyloxy)phenyl][[(3-trifluoromethyl)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;
3-[(3-(3-trifluoromethylbenzyloxy)phenyl][(3-pentafluoroethyl)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;
3-[[3-(3-trifluoromethylbenzyloxy)phenyl][(3-trifluoromethoxy)cyclohexyl-methyl]amino)-1,1,1-trifluoro-2-propanol:
3-[[3-(3-trifluoromethylbenzyloxy)phenyl][[3-(1,1,2,2 tetrafluoroethoxy)cyclo-hexylmethyl]amino)-1,1,1-trifluoro-2-propanol;
3-[[[(3-trifluoromethyl)phenyl]methyl](cyclohexyl)amino]-1,1,1-trifluoro-2-propanol;
3-[[[(3-pentafluoroethyl)phenyl]methyl)(cyclohexyl)amino]-1,1,1-trifluoro-2-propanol;
3-[[[(3-trifluoromethoxy)phenyl methyl](cyclohexyl)amino]-1,1,1-trifluoro-2-propanol;
3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl](cyclohexyl)amino]-1,1,1-trifluoro-2-propanol;
3-[[[(3-trifluoromethyl)phenyl]methyl](4-methylcyclohexyl)amino]-1,1,1-trifluoro-2-propanol;
3-[[[(3-pentafluoroethyl)phenyl]methyl](4-methylcyclohexyl)amino]-1,1,1-trifluoro-2-propanol;
3-[[[(3-trifluoromethoxy)phenyl]methyl](4-methylcyclohexyl)amino]-1,1,1-trifluoro-2-propanol;
3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl](4-methylcyclohexyl)amino]-1,1,1-trifluoro-2-propanol 3-[[[(3-trifluoromethyl)phenyl]methyl](3-trifluoromethylcyclohexyl)amino]-1,1,1-trifluoro-2-propanol;
3-[[[(3-pentafluoroethyl)phenyl]methyl](3-trifluoromethylcyclohexyl)amino]-1,1,1-trifluoro-2-propanol;
3-[[[(3-trifluoromethoxy)phenyl]methyl](3-trifluoromethylcyclohexyl)amino]-1,1,1-trifluoro-2-propanol;
3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl](3-trifluoromethylcyclo-hexyl)amino]-1,1,1-trifluoro-2-propanol;
3-[[[(3-trifluoromethyl)phenyl)methyl](3-(4-chloro-3-ethylphenoxy)cyclo-hexyl)amino]-1,1,1-trifluoro-2-propanol;

3-[[[(3-pentafluoroethyl)phenyl]methyl]]3-(4-chloro-3-ethylphenoxy)cyclo-hexyl]amino]-1,1,1-trifluoro-2-propanol;
3-[[[(3-trifluoromethoxy)phenyl]methyl](3-(4-chloro-3-ethylphenoxy)cyclo-hexyl]amino]-1,1,1-trifluoro-2-propanol;
3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-(4-chloro-3-ethylphenoxy)-cyclohexyl]amino]-1,1,1-trifluoro-2-propanol;
3-[[[(3-trifluoromethyl)phenyl]methyl](3-phenoxycyclohexyl)amino]-1.1,1-trifluoro-2-proganol;
3-[[[(3-pentafluoroethyl)phenyl]methyl](3-phenoxycyclohexyl)amino]-1,1,1-trifluoro-2-propanol;
3-[[[(3-trifluoromethoxy)phenyl]methyl](3-phenoxycyclohexyl)amino]-1,1,1-trifluoro-2-propanol:
3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl](3-phenoxycyclohexyl)amino]-1,1,1-trifluoro-2-propanol;
3-[[[(3-trifluoromethyl)phenyl]methyl](3-isopropoxycyclohexyl)amino]-1,1,1-trifluoro-2-propanol;
3-[[[(3-pentafluoroethyl)phenyl]methyl)(3-isopropoxycyclohexyl)amino]-1,1,1-trifluoro-2-propanol;
3-[[[(3-trifluoromethoxy)phenyl]methyl](3-isopropoxycyclohexyl)amino]-1,1,1-trifluoro-2-propanol;
3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl](3-isopropoxycyclohexyl)-amino]-1,1,1-trifluoro-2-propanol;
3-[(((,3-trifluoromethyl)phenyl]methyl](3-cyclopentyloxycyclohexyl)amino)-1,1,1-trifluoro-2-propanol:
3-[[[(3-pentafluoroethyl)phenyl]methyl](3-cyclopentyloxycyclohexyl)amino]-1,1,1-trifluoro-2-propanol;
3-[[[(3-trifluoromethoxy)phenyl]methyl](3-cyclopentyloxycyclohexyl)amino]-1,1,1-trifluoro-2-propanol;
3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl](3-cyclopentyloxycyclohcxyl)-amino]-1,1,1-trifluoro-2-propanol;
3-[[[(2-trifluoromethyl)pyrid-6-yl]methyl](3-isopropoxycyclohexyl)amino]-1,1,1-trifluoro-2-propanol;
3-[[[(2-trifluoromethyl)pyrid-6-yl]methyl](3-cyclopentyloxycyclohexyl)-amino]-1,1,1-trifluoro-2-propanol;

3-[[[(2-trifluoromethyl)pyrid-6-yl]methyl](3-phenoxycyclohexyl)amino]-1,1,1-trifluoro-2-propanol;
3-[[[(2-trifluoromethyl)pyrid-6-yl]methyl](3-trifluoromethylcyclohexyl)amino]-1,1,1-trifluoro-2-propanol;
3-[[[(2-trifluoromethyl)pyrid-6-yl]methyl][3-(4-chloro-3-ethylphenoxy)cyclo-hexyl]amino]-1,1,1-trifluoro-2-propanol;
3-[[[(2-trifluoromethyl)pyrid-6-yl]methyl][3-(1,1,2,2 tetrafluoroethoxy)cyclo-hexyl]amino]-1,1,1-trifluoro-2-propanol;
3-[[[(2-trifluoromethyl)pyrid-6-yl]methyl](3-pentafluoroethylcyclohexyl)-amino]-1,1,1-trifluoro-2-propanol;
3-[[[(2-trifluoromethyl)pyrid-6-yl]methyl](3-trifluoromethoxycyclohexyl)-amino]-1,1,1-trifluoro-2-propanol:
3-[[[(3-trifluoromethyl)phenyl]methyl][3-(4-chloro-3-ethylphenoxy)propyl]-amino]-1,1,1-trifluoro-2-propanol;
3-[[[(3-pentafluoroethyl)phenyl]methyl][3-(4-chloro-3-ethylphenoxy)propyl]-amino]-1,1,1-trifluoro-2-propanol;
3-[[[(3-trifluoromethoxy)phenyl]methyl][3-(4-chloro-3-ethylphenoxy)propyl]-amino]-1,1,1-trifluoro-2-propanol;
3-[[(3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-(4-chloro-3-ethylphenoxy)-propyl]amino]- 1,1,1-trifluoro-2-propanol;
3-[[[(3-trifluoromethyl)phenyl]methyl][3-(4-chloro-3-ethylphenoxy)-2,2,-di-fluroropropyl]amino]-1,1,1-trifluoro-2-propanol;
3-[[[(3-pentafluoroethyl)phenyl]methyl][3-(4-chloro-3-ethylphenoxy)-2,2,-di-fluroropropyl]amino]-1,1,1-trifluoro-2-propanol;
3-[[[(3-trifluoromethoxy)phenyl]methyl][3-(4-chloro-3-ethylphenoxy)-2,2,-di-fluroropropyl]amino]-1,1,1-trifluoro-2-propanol;
3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-(4-chloro-3-ethylphenoxy)-2,2,-difluroropropyl]amino]-1,1,1-trifluoro-2-propanol;
3-[[[(3-trifluoromethyl)phenyl]methyl][3-(isopropoxy)propyl]amino]-1,1,1-trifluoro-2-propanol;
3-[[[(3-pentafluoroethyl)phenyl]methyl][3-(isopropoxy)propyl]amino]-1,1,1-trifluoro-2-propanol;
3-[[[(3-trifluoromethoxy)phenyl]methyl][3-(isopropoxy)propyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[[(3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]]3-(isopropoxy)propyl]amino]-1,1,1-trifluoro-2-propanol; and 3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-(phenoxy)propyl]amino]-1,1,1-trifluoro-2-propanol.
19. A pharmaceutical composition comprising a compound of one of claims 1 through 18 together with a pharmaceutically acceptable carrier.
20. A method of treating coronary artery disease or other CETP-mediated disorders in a subject by administering a therapeutically effective amount of a compound of one of claims 1 through 18.
21. A method of preventing coronary artery disease or other CETP-mediated disorders in a subject by administering a therapeutically effective amount of a compound of one of claims 1 through 18.
22. A method of treating or preventing cerebral vascular accident (CVA) or other CETP-mediated disorders in a subject by administering a therapeutically effective amount of a compound of one of claims 1 through 18.
23. A method of treating or preventing dyslipidemia and other CETP-mediated disorders in a subject by administering a therapeutically effective amount of a compound of one of claims 1 through 18.
CA002345108A 1998-09-25 1999-09-23 Substituted n-aliphatic-n-aromatic tertiary-heteroalkylamines useful for inhibiting cholesteryl ester transfer protein activity Abandoned CA2345108A1 (en)

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