US20010018446A1

US20010018446A1 - Substituted N-Aliphatic-N-Aromatictertiary-Heteroalkylamines useful for inhibiting cholesteryl ester transfer protein activity

Info

Publication number: US20010018446A1
Application number: US09/760,627
Authority: US
Inventors: James Sikorski; Richard Durley; Margaret Grapperhaus; Deborah Mischke; Emily Reinhard; Barry Parnas; Melvin Rueppel
Original assignee: GD Searle LLC
Current assignee: GD Searle LLC
Priority date: 1999-09-23
Filing date: 2001-01-16
Publication date: 2001-08-30
Also published as: US20030191306A1; US6787570B2

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

FIELD OF THE INVENTION

This invention is in the field of treating cardiovascular disease, and specifically relates to compounds, compositions and methods for treating atherosclerosis and other coronary artery disease. More particularly, the invention relates to substituted N-Aliphatic-N-Aromatictertiary-Heteroalkylamine compounds that inhibit cholesteryl ester transfer protein (CETP), also known as plasma lipid transfer protein-1.

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 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 elevating 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 cause of morbidity and mortality in modem society. High LDL cholesterol (above 180 mg/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/LDL ratios. Inhibition of CETP by the subject compounds is shown to effectively modify plasma HDL/LDL ratios, and to check the progress and/or formation of these diseases.

CETP is a plasma protein that facilitates the movement of cholesteryl esters and triglycerides between the various lipoproteins in the blood (Tall, J. Lipid Res., 34, 1255-74 (1993)). The movement of cholesteryl 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, Medicinal Res. 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 (1989)) 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. Biophys. Acta 795, 743-480 (1984)), Morton et al. (J. Lipid Res. 35, 836-847 (1994)) and Tollefson et al. (Am. J. Physiol., 255, (Endocrinol. Metab. 18, E894-E902 (1988))) describe proteins from human plasma that inhibit CETP. U.S. Pat. No. 5,519,001, issued to Kushwaha et al., describes a 36 amino acid peptide derived from baboon apo C-1 that inhibits CETP activity. 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 Bioorg. Med. Chem. Lett., 8, 1277-80 (1998).

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 (1995)) describe cyclopropane-containing CETP inhibitors. Pietzonka et al. (Bioorg. Med. Chem. Lett, 6, 1951-54 (1996)) describe phosphonate-containing analogs of cholesteryl ester as CETP inhibitors. Coval et al. (Bioorg. Med. Chem. 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, 49, 693-96 (1996)) describe CETP inhibitors derived from an insect fungus. Busch et al. (Lipids, 25, 216220, (1990)) describe cholesteryl acetyl bromide as a CETP inhibitor. Morton and Zilversmit (J. Lipid Res., 35, 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 other cysteine modification reagents as CETP inhibitors. Xia et al. describe 1,3,5-triazines as CETP inhibitors (Bioorg. Med. Chem. Lett., 6,919-22 (1996)). Bisgaier et al. (Lipids, 29, 811-8 (1994)) describe 4-phenyl-5-tridecyl4H-1,2,4-triazole-thiol as a CETP inhibitor. Oomura et al. disclose non-peptidic tetracyclic and hexacyclic phenols as CETP inhibitors in Japanese Patent Application No. 10287662. In WO Patent Application No. 09914204, Sikorski describes 1,2,4-triazolylthiols useful as chlolesteryl ester transfer protein inhibitors.

Some substituted heteroalkylamine compounds are known. In European Patent Application No. 796846, Schmidt et al. describe 2-aryl-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 be β3-adrenergic receptor agonists useful for treating diabetes and other disorders. In Great Britain Patent Application No. 2305665, 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, Schmidt 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 protein inhibitors. In WO Patent Application No. 09839299, Muller-Gliemann et al. describe quinoline derivatives as cholesteryl ester transfer protein inhibitors. U.S. Pat. No. 2,700,686, issued to Dickey and Towne, describes N-(2-haloalkyl-2-hydroxyethyl)amines in which the amine is further substituted with either 1 to 2 aliphatic groups or one aromatic group and one aliphatic group. U.S. Pat. No. 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.

SUMMARY OF THE INVENTION

The present invention provides a class of compounds that can be used to inhibit cholesteryl ester transfer protein (CETP) activity and that have the general structure:

In another aspect, the present invention includes pharmaceutical 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 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 also be used to treat dyslipidemia (hypoalphalipoproteinemia), hyperlipoproteinaemia (chylomicronemia and hyperapobetalipoproteinemia), peripheral vascular disease, 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 developing 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 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 like.

DESCRIPTION OF THE INVENTION

The present invention relates to a class of compounds comprising substituted N-Aliphatic-N-Aromatictertiary-Heteroalkylamines which are beneficial in the therapeutic and prophylactic treatment of coronary artery disease as given in Formula I-WA (also referred to herein as “alicyclic/cyclic aryl/heteroaryl heteroalkylamines”):

or a pharmaceutically-acceptable salt thereof, wherein;

n is an integer selected from 1 through 4;

A and Q are independently selected from the group consisting of —CH ₂(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 —CH ₂(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 R ₃₃, R₃₄, R₃₅, and R₃₆is aryl or heteroaryl;

u and w are integers independently selected from 0 through 6;

A ₁is C(R₃₀);

D ₁, D₂, J₁, J₂and K₁are 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, J₂and K₁is a covalent bond, no more than one of D₁, D₂, J₁, J₂and K₁is O, no more than one of D₁, D₂, J₁J₂and K₁is S, one of D₁, D₂, J₁, J₂and K₁must be a covalent bond when two of D₁, D₂, J₁, J₂and K₁are O and S, and no more than four of D₁, D₂, J₁, J₂and K₁are N;

B ₁, B₂, D₃, D₄, J₃, J₄and K₂are 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, J₄and K₂are a covalent bond, no more than two of B_1,B₂, D₃, D₄, J₃, J₄and K₂are O, no more than two of B₁, B₂, D₃, D₄, J₃, J₄and K₂are S, no more than two of B₁, B₂, D₃, D₄, J₃, J₄and K₂are simultaneously O and S, and no more than two of B₁, B₂, D₃, D₄, J₃, J₄and K₂are N;

B ₁and D₃, D₃and J₃, J₃and K₂, K₂and J₄, J₄and D₄, and D₄and B₂are 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 can N═N unless the other spacer pairs is other than C(R₃₃)═C(R₃₅), O, N, and S;

R ₁₆is 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 R ₁₆wherein X is H or F;

R ₁is selected from the group consisting of haloalkyl, haloalkenyl, haloalkoxyalkyl, and haloalkenyloxyalkyl;

R ₂is selected from the group consisting of hydrido, aryl, aralkyl, alkyl, alkenyl, alkenyloxyalkyl, haloalkyl, haloalkenyl, halocycloalkyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy, halocycloalkoxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, dicyanoalkyl, and carboalkoxycyanoalkyl;

R ₃is selected from the group consisting of hydrido, hydroxy, cyano, aryl, aralkyl, acyl, alkoxy, alkyl, alkenyl, alkoxyalkyl, heteroaryl, alkenyloxyalkyl, haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, monocyanoalkyl, dicyanoalkyl, carboxamide, and carboxamidoalkyl;

Y is selected from a group consisting of a covalent single bond, (C(R ₁₄)₂)_qwherein q is an integer selected from 1 through 4 and (CH(R₁₄))_g—O—(CH(R₁₄))_pwherein g and p are integers independently selected from 0 through 2;

R ₁₄is selected from the group consisting of hydrido, hydroxy, cyano, hydroxyalkyl, acyl, alkoxy, alkyl, alkenyl, alkynyl, alkoxyalkyl, haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, monocarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl, carboalkoxy, carboxamide, carboxamidoalkyl;

Z is selected from the group consisting of covalent single bond, (C(R ₁₅)₂)_qwherein q is an integer selected from 1 through 2, and (CH(R₁₅))_j—O—(CH(R₁₅))_kwherein j and k are integers independently selected from 0 through 2;

R ₁₅is selected from the group consisting of hydrido, cyano, hydroxyalkyl, acyl, alkoxy, alkyl, alkenyl, alkynyl, alkoxyalkyl, haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, monocarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl, carboalkoxy, carboxamide, and carboxamidoalkyl;

R ₃₀is selected from the group consisting of hydrido, alkoxy, alkoxyalkyl, halo, haloalkyl, alkylamino, alkylthio, alkylthioalkyl, alkyl, alkenyl, haloalkoxy, and haloalkoxyalkyl with the proviso that R₃₀is selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen;

R ₃₀, when bonded to A₁, is taken together to form an intra-ring linear spacer connecting the A₁-carbon at the point of attachment of R₃₀to the point of bonding of a group selected from the group consisting of R₁₀, R₁₁, R₁₂, R₃₁, and R₃₂wherein 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;

R ₃₀, when bonded to A₁, is taken together to form an intra-ring branched spacer connecting the A₁-carbon at the point of attachment of R₃₀to the points of bonding of each member of any one of substituent pairs selected from the group consisting of subsitituent pairs R₁₀and R₁₁, R₁₀and R₃₁, R₁₀and R₃₂, R₁₀and R₁₂, R₁₁and R₃₁, R₁₁, and R₃₂, R₁₁, and R₁₂, R₃₁and R₃₂, R₃₁and R₁₂, and R₃₂and R₁₂and 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 contiguous members, and heterocyclyl having from 5 through 10 contiguous members;

R ₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₃₁, R₃₂, R₃₃, R₃₄, R₃₅, and R₃₆are 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 R₃₆are 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 R₃₃and R₃₄substituents are simultaneously selected from other than the group consisting of of hydrido and halo, and that no more than three of the R₃₅and R₃₆substituents are simultaneously selected from other than the group consistubg of hydrido and halo;

R ₉, R₁₀, R₁₁, R₁₂, R₁₃, R₃₁, and R₃₂are independently selected to be oxo with the provisos that B₁, B₂, D₃, D₄, J₃, J₄and K₂are independently selected from the group consisting of C and S, no more than two of R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₃₁, and R₃₂are simultaneously oxo, and that R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₃₁, and R₃₂are 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;

R ₄and R₅, R₅and R₆, R₆and R₇, R₇and R₈, R₉and R₁₀, R₁₀and R₁₁, R₁₁and R₃₁, R₃₁and R₃₂, R₃₂and R₁₂, and R₁₂and R₁₃are 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 R₄and R₅, R₅and R₆, R₆and R₇, and R₇and R₈, are used at the same time and that no more than one of the group consisting of spacer pairs R₉and R₁₀, R₁₀and R₁₁, R₁₁and R₃₁, R₃₁and R₃₂, R₃₂and R₁₂, and R₁₂and R₁₃are used at the same time;

R ₉and R₁₁, R₉and R₁₂, R₉and R₁₃, R₉and R₃₁, R₉and R₃₂, R₁₀and R₁₂, R₁₀and R₁₃, R₁₀and R₃₁, R₁₀and R₃₂, R₁₁and R₁₂, R₁₁and R₁₃, R₁₁and R₃₂, R₁₂and R₃₁, R₁₃and R₃₁, and R₁₃and R₃₂are 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 ring selected from the group consisting of a cycloalkyl having from 3 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;

R ₃₇and R₃₈are independently selected from the group consisting of hydrido, alkoxy, alkoxyalkyl, hydroxy, amino, thio, halo, haloalkyl, alkylamino, alkylthio, alkylthioalkyl, cyano, alkyl, alkenyl, haloalkoxy, and haloalkoxyalkyl.

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”):

or a pharmaceutically acceptable salt thereof, wherein;

R ₁₆is hydrido;

R ₁, R₂, R₃, n, A, Y, Q, and Z are defined as given above for Formula I-WA.

In a more specific embodiment of compounds of Formula I-WO, compounds have the Formula 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 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 R ₃₃, R₃₄, R₃₅, and R₃₆with the provisos that R₃₃, R₃₄, R₃₅, and R₃₆must not be attached to the carbon directly linking A to Z and that R₃₃, R₃₄, R₃₅, and R₃₆must be selected from other than aryl and heteroaryl when substituting the carbon 2 atoms from Z wherein Z is a single covalent bond;

R ₁is selected from the group consisting of haloalkyl and haloalkoxymethyl;

R ₂is selected from the group consisting of hydrido, aryl, alkyl, alkenyl, haloalkyl, haloalkoxy, haloalkoxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, and heteroaryl;

R ₃is 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;

R ₄and R₈are independently selected from the group consisting of hydrido and halo;

R ₅, R₆, and R₇are 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;

R ₄and R₅, R₅and R₆, R₆and R₇, and R₇and R₈are 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 R₄and R₅, R₅and R₆, R₆and R₇, and R₇and R₈, is used at the same time;

R ₃₃, R₃₄, R₃₅, and R₃₆are independently selected from the group group consisting of alkyl, halo, hydroxy, cyano, 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.

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

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 R ₃₀, 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 R₉or R₁₃, a ring carbon or nitrogen atom adjacent to the R₉position and two atoms from the point of attachment may be substituted with R₁₀, a ring carbon or nitrogen atom adjacent to the R₁₃position 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 R₁₀position may be substituted with R₁₁, a ring carbon or nitrogen atom three atoms from the point of attachment and adjacent to the R₁₂position may be substituted with R₃₂, and a ring carbon or nitrogen atom four atoms from the point of attachment and adjacent to the R₁₁and R₃₂positions may be substituted with R₃₁;

R ₁is selected from the group consisting of haloalkyl and haloalkoxymethyl;

R ₉and R₁₃is halo;

R ₁₀, R₁₁, R₁₂, R₃₁, and R₃₂are 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;

R ₃₀is 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, compounds have the Formula I-WOHA:

or a pharmaceutically acceptable salt thereof, wherein;

n is an integer selected from 1 through 2;

D ₁, D₂, J₁, J₂and K₁are 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, J₂and K₁is a covalent bond, no more than one of D₁, D₂, J₁, J₂and K₁is O, no more than one of D₁, D₂, J₁, J₂and K₁is S, one of D₁, D₂, J₁, J₂and K₁must be a covalent bond when two of D₁, D₂, J₁, J₂and K₁are O and S, and no more than four of D₁, D₂, J₁, J₂and K, are N;

R ₁is selected from the group consisting of haloalkyl and haloalkoxymethyl;

R ₃₃, R₃₄,R₃₅, and R₃₆are independently selected from the group group consisting of alkyl, halo, hydroxy, cyano, 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.

In still another more specific embodiment of compounds of Formula I-WO, compounds have the Formula I-WOHC:

or a pharmaceutically acceptable salt thereof, wherein;

n is an integer selected from 1 through 2;

D ₁, D₂, J₁, J₂and K₁are 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, J₂and K₁is a covalent bond, no more than one of D₁, D₂, J₁, J₂and K₁is O, no more than one of D₁, D₂, J₁, J₂and K₁is S, one of D₁, D₂, J₁, J₂and K₁must be a covalent bond when two of D₁, D₂, J₁, J₂and K₁are O and S, and no more than four of D₁, D₂, J₁, J₂and K₁are N;

R ₁is selected from the group consisting of haloalkyl and haloalkoxymethyl;

R ₉and R₁₃is halo;

In a preferred specific embodiment of compounds of Formulas I-WOPA, I-WOHA, I-WOPC, and I-WOHC,

n is the integer 1;

R ₁is selected from the group consisting of trifluoromethyl, 1,1,2,2-tetrafluoroethoxymethyl, trifluoromethoxymethyl, difluoromethyl, chlorodifluoromethyl, and pentafluoroethyl;

R ₂is 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;

R ₃is 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;

R ₄and R₈are independently selected from the group consisting of hydrido and fluoro;

R ₅is 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-fluorobenzyl, 3-chloro-4-fluorophenyl, 3-chloro-2-fluorobenzyloxy, 3-chlorobenzyloxy, 4-chlorobenzyloxy, 4-chloro-3-methylphenoxy, 2-chloro-fluorophenoxy, 4-chloro-2-fluorophenoxy, 4-chlorophenoxy, 3-chloro~ethylphenoxy, 3-chloro-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, 3,5dichlorophenyl, 3,5-dichlorobenzyl, 3,4-dichlorophenoxy, 3,4-difluorophenoxy, 2,3-difluorobenzyloxy, 2,4-difluorobenzyloxy, 3,4-difluorobenzyloxy, 2,5-difluorobenzyloxy, 3,5difluorophenoxy, 3,4-difluorophenyl, 3,5-difluorobenzyloxy, 4-difluoromethoxybenzyloxy, 2,3-difluorophenoxy, 2,4-difluorophenoxy, 2,5-difluorophenoxy, 3,-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-3-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-iodobenzyloxy, isobutyl, isobutylamnino, 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-pentafluoroethylphenoxy, 3-(1,1,2,2-tetrafluoroethoxy)phenoxy, 3-trifluoromethylthiophenoxy, and trifluoromethylthio;

R ₆is selected from the group consisting of chloro, fluoro, hydrido, pentafluoroethyl, 1,1,2,2-tetrafluoroethoxy, trifluoromethyl, and trifluoromethoxy;

R ₇is selected from the group consisting of hydrido, fluoro, and trifluoromethyl.

In a more preferred specific embodiment of compounds of Formulas I-WOPA, I-WOHA, I-WOPC, and I-WOHC,

n is the integer 1;

R ₂is 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; R₃is 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;

R ₅is 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-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-5methylphenoxy, 4-fluoro-3-methylbenzyl, 4-fluorobenzyloxy, 2-fluoro-3-methylphenoxy, 3-fluoro-3-trimethylphenoxy, 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-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-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, 3,4,5trimethylphenoxy, 3-difluoromethoxyphenoxy, 3-pentafluoroethylphenoxy, 3-(1,1,2,2-tetrafluoroethoxy)phenoxy, 3-trifluoromethylthiophenoxy, 3-trifluoromethylthiobenzyloxy, and trifluoromethylthio;

R ₆is selected from the group consisting of chloro, fluoro, hydrido, pentafluoroethyl, 1,1,2,2-tetrafluoroethoxy, and trifluoromethyl;

In an even more preferred specific embodiment of compounds of Formulas I-WOPA, I-WOHA, I-WOPC, and I-WOHC,

n is the integer 1;

R ₁is selected from the group consisting of trifluoromethyl, chlorodifluoromethyl, and pentafluoroethyl;

R ₂is hydrido, pentafluoroethyl, and trifluoromethyl;

R ₃is selected from the group consisting of hydrido, methyl, trifluoromethyl, and difluoromethyl

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

R ₅is 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;

R ₆is selected from the group consisting of fluoro and hydrido;

R ₇is selected from the group consisting of hydrido and fluoro.

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-methylpropenyl, 1-pentyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-pentynyl, 3-pentynyl, 2-pentyl, 1-methyl-2-butenyl, 1-methyl-3-butenyl, 1-methyl-2-butynyl, 3-pentyl, 1-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-pentenyl, 1-methyl~pentenyl, 1-methyl-2-pentynyl, 1-methyl-3-pentynyl, 3-hexyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 1-propyl-2-propenyl, 1-ethyl-2-butynyl, 1-heptyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 5-heptynyl, 2-heptyl, 1-methyl-2-hexenyl, 1-methyl-3-hexenyl, 1-methyl-5-hexenyl, 1-methyl-5-hexenyl, 1-methyl-2-hexynyl, 1-methyl-3-hexynyl, 1-methyl-4-hexynyl, 3-heptyl, 1-ethyl-2-pentenyl, 1-ethyl-3-pentenyl, 1-ethyl-4-pentenyl, 1-butyl-2-propenyl, 1-ethyl-2-pentynyl, 1-ethyl-3-pentynyl, 1-octyl, 2-octenyl, 3-octenyl, 4-octenyl, 5-octenyl, 6-octenyl, 7-octenyl, 2-octynyl, 3-octynyl, 4-octynyl, 5-octynyl, 6-octynyl, 2-octyl, 1-methyl-2-heptenyl, 1-methyl-3-heptenyl, 1-methyl-4-heptenyl, 1-methyl-5-heptenyl, 1-methyl-6-heptenyl, 1-methyl-2-heptynyl, 1-methyl-3-heptynyl, 1-methyl-4-heptenyl, 1-methyl-5-heptenyl, 1-methyl4-heptenyl, 1-methyl-2-heptenyl, 1-methyl-3-heptynyl, 1-methyl-4-heptynyl, 1-methyl-5-heptynyl, 3-octyl, 1-ethyl-2-hexenyl, 1-ethyl-3-hexenyl, 1-ethyl-5-hexenyl, 1-ethyl-2-hexynyl, 1-ethyl-3-hexynyl, 1-ethyl4-hexynyl, 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-propyl-2-pentynyl, 1-propyl-3-pentynyl, 1-butyl-2-butynyl, 1-butyl-3-butenyl, 2,2-difluoropropyl, 4-trifluoromethyl-5,5,5-trifluoropentyl, 4-trifluoromethylpentyl, 5,5,6,6,6-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-butoxypropyl, 2-butoxyisopropyl, 3-isobutoxypropyl, 2-isobutoxyisopropyl, 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 R ₃₃, R₃₄, R₃₅, and R₃₆with the provisos that R₃₃, R₃₄, R₃₅, and R₃₆must not be attached to the carbon directly linking A to Z and that R₃₃, R₃₄, R₃₅, and R₃₆must be selected from other than aryl and heteroaryl when substituting the carbon 2 atoms from Z wherein Z is a single covalent bond;

R ₃₃, R₃₄, R₃₅, and R₃₆are independently selected from the group consisting of cyano, hydroxy, 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-fluorophenoxy, 4-chloro-2-fluorophenoxy, 4-chlorophenoxy, 3-chloro4-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-fluoro4-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-4yl, 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-pentafluoroethylphenoxy, 3-(1,1,2,2-tetrafluoroethoxy)phenoxy, 3-trifluoromethylthiophenoxy, and trifluoromethylthio.

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, 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-4-pentenyl, 3-hexyl, 1-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-3-pentenyl, 1-ethyl-4-pentenyl, 1-butyl-2-propenyl, 1-octyl, 2-octenyl, 3-octenyl, 4-octenyl, 5octenyl, 6octenyl, 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-methyl4-heptenyl, 1-methyl-2-heptenyl, 3-octyl, 1-ethyl-2-hexenyl, 1-ethyl-3-hexenyl, 1-ethyl-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-trifluoromethylpentyl, 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 R ₃₃, R₃₄, R₃₅, and R₃₆with the provisos that R₃₃, R₃₄, R₃₅, and R₃₆must not be attached to the carbon directly linking A to Z and that R₃₃, R₃₄, R₃₅, and R₃₆must be selected from other than aryl and heteroaryl when substituting the carbon 2 atoms from Z wherein Z is a single covalent bond;

R ₃₃, R₃₄, R₃₅, and R₃₆are 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-chloromethylphenoxy, 3-chloro-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-fluoro4-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-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-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-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.

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-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-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-ethyl4-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-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 R ₃₃, R₃₄, R₃₅, and R₃₆with the provisos that R₃₃, R₃₄, R₃₅, and R₃₆must not be attached to the carbon directly linking A to Z and that R₃₃, R₃₄, R₃₅, and R₃₆must be selected from other than aryl and heteroaryl when substituting the carbon 2 atoms from Z wherein Z is a single covalent bond;

R ₃₃, R₃₄, R₃₅, and R₃₆are 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.

In a preferred specific embodiment of compounds of Formulas I-WOHA and I-WOHC,

D ₁, D₂, J₁, J₂and K₁are 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, 4-imidazolyl, 3-pyrazolyl, 4-pyrazolyl, 1,2,4-triazol-3-yl, 1, 2, 4-triazol-5yl, 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-triazintyl, 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 R₄or R₈, a ring carbon atom adjacent to the R₄position and two atoms from the point of attachment may be substituted with R5, a ring carbon atom adjacent to the R₈position 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 R₅and R₇positions may be substituted with R₆.

In a more preferred specific embodiment of compounds of Formulas I-WOHA and I-WOHC,

D ₁, D₂, J₁, J₂and K₁are 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, 4-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 ,Striazin-2-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 R₄or R₈, a ring carbon atom adjacent to the R₄position and two atoms from the point of attachment may be substituted with R₅, a ring carbon atom adjacent to the R₈position 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 R₅and R₇positions may be substituted with R₆.

In an even more preferred specific embodiment of compounds of Formulas I-WOHA and I-WOHC,

D ₁, D₂, J₁, J₂and K₁are 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, 4-imidazolyl, 3-pyrazolyl, 4-pyrazolyl, 2-thiazolyl, 3-isoxazolyl, 5-isoxazolyl, 2-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 R₄or R₈, a ring carbon atom adjacent to the R₄position and two atoms from the point of attachment may be substituted with R₅, a ring carbon atom adjacent to the R₈position 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 R₅and R₇positions may be substituted with R₆.

In a preferred specific embodiment of compounds of Formulas I-WOPC and I-WOHC,

A is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclopent-2-enyl, cyclopent-3-enyl, cyclohexyl, 4-methylcyclohexyl, 4-chloro-3-ethyiphenoxycyclohexyl, 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, cycloocl-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-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 R ₃₀, 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 R₉or R₁₃, a ring carbon or nitrogen atom adjacent to the R₉position and two atoms from the point of attachment may be substituted with R₁₀, a ring carbon or nitrogen atom adjacent to the R₁₃position 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 R₁₀position may be substituted with R₁₁, a ring carbon or nitrogen atom three atoms from the point of attachment and adjacent to the R₁₂position may be substituted with R₃₂, and a ring carbon or nitrogen atom four atoms from the point of attachment and adjacent to the R₁₁and R₃₂positions may be substituted with R₃₁;

R ₉and R₁₃are fluoro;

R ₁₀and R₁₂are 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-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-4fluorophenoxy, 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-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-methylmethylthiophenoxy, 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-pentafluoroethylphenoxy, 3-(1,1,2,2-tetrafluoroethoxy)phenoxy, 3-trifluoromethylthiophenoxy, and trifluoromethylthio;

R ₁₁, R₃₁, and R₃₂are independently selected from the group consisting of chloro, fluoro, hydrido, pentafluoroethyl, 1,1,2,2-tetrafluoroethoxy, trifluoromethyl, and trifluoromethoxy;

R ₃₀is selected from the group consisting of chloro, ethoxy, ethyl, fluoro, heptafluoropropyl, 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, tert-butoxy, 1,1,2,2-tetrafluoroethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trifluoroethyl, 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, 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 be optionally substituted with R ₃₀, 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 R₉or R₁₃, a ring carbon or nitrogen atom adjacent to the R₉position and two atoms from the point of attachment may be substituted with R₁₀, a ring carbon or nitrogen atom adjacent to the R₁₃position 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 R₁₀position may be substituted with R₁₁, a ring carbon or nitrogen atom three atoms from the point of attachment and adjacent to the R₁₂position may be substituted with R₃₂, and a ring carbon or nitrogen atom four atoms from the point of attachment and adjacent to the R₁₁and R₃₂positions may be substituted with R₃₁;

R ₉and R₁₃are fluoro;

R ₁₀and R₁₂are 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-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, 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-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;

R ₁₁, R₃₁, and R₃₂are independently selected from the group consisting of chloro, fluoro, hydrido, pentafluoroethyl, 1,1,2,2-tetrafluoroethoxy, and trifluoromethyl;

R ₃₀is 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.

In an even more preferred specific embodiment of compounds of Formulas I-WOPC and I-WOHC,

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 R ₉or R₁₃, a ring carbon or nitrogen atom adjacent to the R₉position and two atoms from the point of attachment may be substituted with R₁₀, a ring carbon or nitrogen atom adjacent to the R₁₃position 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 R₁₀position may be substituted with R₁₁, a ring carbon or nitrogen atom three atoms from the point of attachment and adjacent to the R₁₂position may be substituted with R₃₂, and a ring carbon or nitrogen atom four atoms from the point of attachment and adjacent to the R₁₁and R₃₂positions may be substituted with R₃₁;

R ₉and R₁₃are fluoro;

R ₁₀and R₁₂are 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;

R ₁₁, R₃₁, and R₃₂are independently selected from the group consisting of chloro, fluoro, hydrido, pentafluoroethyl, 1,1,2,2-tetrafluoroethoxy, and trifluoromethyl.

DEFINITIONS

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 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 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, tert-butyl, pentyl, aminopentyl, iso-amyl, hexyl, octyl and the 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 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-yl, 3-methylbuten-1-yl, hexen-1-yl, 3-hydroxyhexen-1-yl, hepten-1-yl, and octen-1-yl, and the like.

The term “alkynyl” refers to an unsaturated, acyclic hydrocarbon radical 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, 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-yl, 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” 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” (—CH ₂—) radical.

The term “carbon” radical denotes a carbon atom without any covalent bonds and capable of forming four covalent bonds.

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 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 monocarbonylalkyl and dicarbonylalkyl radicals. Examples of monocarbonylalkyl radicals include formyl, acetyl, and pentanoyl. Examples of dicarbonylalkyl radicals include oxalyl, malonyl, and succinyl.

The term “alkylene” 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, 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 ₂═C), 1,2-vinylidene (—CH═CH—), and 1,4-butadienyl (—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 embraced are monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals. A monohaloalkyl 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 polyhaloalkyl radicals may have more than two of the same halo atoms or a combination of different halo radicals. More preferred haloalkyl radicals are “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, 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 any 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 polyhaloalkylene 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, tetrafluoroethylene, tetrachloroethylene, alkyl substituted monofluoromethylene, and aryl substituted trifluoromethylene.

The term “haloalkenyl” denotes linear or branched radicals having from 1 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 “alkoxyalkyl” embrace linear or branched oxy-containing radicals each having alkyl portions of one to about ten carbon atoms, such as methoxy radical. The term “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 tent-butoxy alkyls. The “alkoxy” radicals may be further substituted with one or more halo atoms, such as fluoro, 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 haloalkoxyalkyl 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 ethenyloxy or propenyloxy radical. The term “alkenyloxyalkyl” also embraces alkenyl radicals having one or more alkenyloxy radicals attached to the alkyl radical, that is, to form monoalkenyloxyalkyl and dialkenyloxyalkyl radicals. More preferred alkenyloxy radicals are “lower alkenyloxy” radicals having two to six carbon atoms. Examples of such radicals include ethenyloxy, propenyloxy, butenyloxy, and isopropenyloxy alkyls. The “alkenyloxy” 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 fluoropropenyloxy.

The term “haloalkoxyalkyl” also embraces alkyl radicals having one or more haloalkoxy radicals attached to the alkyl radical, that is, to form monohaloalkoxyalkyl and dihaloalkoxyalkyl radicals. The term “haloalkenyloxy” also embraces oxygen radicals having one or more haloalkenyloxy radicals attached to the oxygen radical, that is, to form monohaloalkenyloxy and dihaloalkenyloxy radicals. The term “haloalkenyloxyalkyl” also embraces alkyl radicals having one or more haloalkenyloxy radicals attached to the alkyl radical, that is, to form monohaloalkenyloxyalkyl and dihaloalkenyloxyalkyl radicals.

The term “alkylenedioxy” radicals denotes alkylene radicals having at least two oxygens bonded to a single alkylene group. Examples of “alkylenedioxy” radicals include methylenedioxy, ethylenedioxy, alkylsubstituted methylenedioxy, and arylsubstituted methylenedioxy. The term “haloalkylenedioxy” radicals denotes haloalkylene radicals having at least two oxy groups bonded to a single haloalkyl group. Examples of “haloalkylenedioxy” 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 term “fused” means that a second ring is present (i.e., attached or formed) by having two adjacent atoms in common (i.e., shared) with the first ring. The term “fused” is equivalent to the term “condensed”. The term “aryl” embraces aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, 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 heteroatom-containing ring-shaped radicals having from 5 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-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 6membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., thiazolidinyl, etc.]. Examples of partially saturated heterocyclyl radicals include dihydrothiophene, dihydropyran, dihydrofuran and dihydrothiazole. Non-limiting examples of heterocyclic radicals include 2-pyrrolinyl, 3-pyrrolinyl, pyrrolindinyl, 1,3-dioxolanyl, 2H-pyranyl, 4H-pyranyl, piperidinyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl, 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 ring atom is a heteroatom. Heteroaryl radicals may contain one, two or three rings wherein such rings may be attached in a pendant manner or may be fused. Examples of “heteroaryl” radicals, include unsaturated 5 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, 2H-1,2,3-triazolyl, etc.] tetrazolyl [e.g. 1H-tetrazolyl, 2H-tetrazolyl, etc.], etc.; unsaturated condensed heterocyclic group containing 1 to 5 nitrogen atoms, for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl [e.g., tetrazolo [1,5-b]pyridazinyl, etc.], etc.; unsaturated 3 to 6-membered heteromonocyclic group containing an oxygen atom, for example, pyranyl, 2-furyl, 3-furyl, etc.; unsaturated 5 to 6membered heteromonocyclic group containing a sulfur atom, for example, 2-thienyl, 3-thienyl, etc.: unsaturated 5 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl [e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.] etc.; unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g. benzoxazolyl, benzoxadiazolyl, etc.]; unsaturated 5 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl, thiadiazolyl [e.g., 1,2,4- thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.] etc.; unsaturated condensed heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen 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, benzothiophene, and the like.

Said “heterocyclyl” group may have 1 to 3 substituents as defined below. 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, indolyl, thiophenyl, furanyl, tetrazolyl, 2-imidazolinyl, imidazolidinyl, 2-pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,3-triazolyl, 1,3,4-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 —SO ₂—. “Alkylsulfonyl”, 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 haloalkyl is defined as above. “Haloalkylsulfonylalkyl”, embraces haloalkylsulfonyl radicals attached 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 alkyl is defined as above. “Alkylsulfinylalkyl”, embraces alkylsulfinyl 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. “Haloalkylsulfinylalkyl”, embraces haloalkylsulfinyl radicals attached to an alkyl radical, where alkyl is defined as above.

The term “aralkyl” embraces aryl-substituted alkyl radicals. Preferable aralkyl radicals are “lower aralkyl” radicals having 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.

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 aralkyl radicals. The term “perhaloaralkyl” embraces aryl-substituted alkyl radicals wherein the aralkyl radical is substituted with three or more halo radicals as defined above.

The term “aralkylsulfinyl”, embraces aralkyl radicals attached to a sulfinyl radical, where aralkyl is defined as above. “Aralkylsulfinylalkyl”, embraces aralkylsulfinyl radicals attached to an alkyl radical, where alkyl is defined as above.

The term “aralkylsulfonyl”, embraces aralkyl radicals attached to a sulfonyl radical, where aralkyl is defined as above. “Aralkylsulfonylalkyl”, embraces aralkylsulfonyl 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 wherein such rings may be attached in a pendant manner or may be fused. Examples of cycloalkyl radicals having two or more rings include 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, 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 carbon atoms. Examples of such radicals include cyclohexylhexyl. The term “cycloalkenyl” embraces radicals having 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 norbornenyl. Preferred cycloalkenyl radicals are “lower cycloalkenyl” radicals having three to seven carbon atoms. Examples include radicals such as cyclobutenyl, cyclopentenyl, cyclohexenyl and cycloheptenyl. The term “halocycloalkyl” 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 polyhalocycloalkyl 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.

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 cycloalkenyloxy 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 “Cycloalkylsulfonyl”, embraces cycloalkyl radicals attached to a sulfonyl radical, where cycloalkyl is defined as above. “Cycloalkylsulfonylalkyl”, embraces cycloalkylsulfonyl radicals attached to an alkyl radical, where alkyl is defined as above.

The term “cycloalkylalkanoyl” 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 monocarbonylcycloalkyl 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 (CH ₃—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, chloromethylthio, trifluoromethylthio, difluoromethylthio, 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-methyltmethoxyaniline, N-ethyl-4-methoxyaniline, and N-methyl-4-trifluoromethoxyaniline.

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 aralkylamino 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 term “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. “arylsulfonylalkyl”, 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 “heteroarylsulfinylalkyl” denotes heteroarylsulfinyl radicals attached to a linear or branched alkyl radical, of one to ten carbon atoms. The term “Heteroarylsulfonyl”, embraces heteroaryl radicals attached to a sulfonyl radical, where heteroaryl is defined as above. “Heteroarylsulfonylalkyl”, 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-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-tert-butylphenoxy, 3-pentafluoroethylphenoxy, and 3-(1,1,2,2-tetrafluoroethoxy)phenoxy.

The term “aroyl” embraces aryl radicals, as defined above, attached to an carbonyl radical as defined above. 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 include furyl 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 pyridylmethylamino.

The term “heteroaryloxy” embraces heterocyclyl radicals, as defined above, attached to an oxy group. Examples of such radicals include 2-thiophenyloxy, 2-pyrimidyloxy, 2-pyridyloxy, 3-pyridyloxy, and 4-pyridyloxy.

The term “heteroaryloxyalkyl” embraces heteroaryloxy radicals, as 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.

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 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 hydroxyl radical, as defined above, attached to one of two unshared bonds in a carbonyl group. The term “carboxamide” embraces amino, monoalkylamino, dialkylamino, monocycloalkylamino, alkylcycloalkylamino, and dicycloalkylamino radicals, attached to one of two unshared bonds in a carbonyl group. The term “carboxamidoalkyl” embraces carboxamide radicals, as defined above, attached to 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 unshared bonds in a carbonyl group. The term “carboaralkoxy” embraces aralkoxy radicals, as defined above, attached to one of two unshared bonds in a carbonyl group. The term “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 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, cycloalkylalkyl, cycloalkenyl, alkylthio, arylthio, 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 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. 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 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 point is through 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:

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 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 “diaralkoxyphosphonoalkyl” denotes diaralkoxyphosphono radicals, as defined above, attached to an alkyl radical.

Said “alkyl”, “alkenyl”, “alkynyl”, “alkanoyl”, “alkylene”, “alkenylene”, “benzylidenyl”, “phenoxylidenyl”, “hydroxyalkyl”, “haloalkyl”, “haloalkylene”, “haloalkenyl”, “alkoxy”, “alkenyloxy”, “alkenyloxyalkyl”, “alkoxyalkyl”, “aryl”, “perhaloaryl”, “haloalkoxy”, “haloalkoxyalkyl”, “haloalkenyloxy”, “haloalkenyloxyalkyl”, “alkylenedioxy”, “haloalkylenedioxy”, “heterocyclyl”, “heteroaryl”, “hydroxyhaloalkyl”, “alkylsulfonyl”, “haloalkylsulfonyl”, “alkylsulfonylalkyl”, “haloalkylsulfonylalkyl”, “alkylsulfinyl”, “alkylsulfinylalkyl”, “haloalkylsulfinylalkyl”, “aralkyl”, “heteroaralkyl”, “perhaloaralkyl”, “aralkylsulfonyl”, “aralkylsulfonylalkyl”, “aralkylsulfinyl”, “aralkylsulfinylalkyl”, “cycloalkyl”, “cycloalkylalkanoyl”, “cycloalkylalkyl”, “cycloalkenyl”, “halocycloalkyl”, “halocycloalkenyl”, “cycloalkylsulfinyl”, “cycloalkylsulfinylalkyl”, “cycloalkylsulfonyl”, “cycloalkylsulfonylalkyl”, “cycloalkoxy”, “cycloalkoxyalkyl”, “cycloalkylalkoxy”, “cycloalkenyloxy”, “cycloalkenyloxyalkyl”, “cycloalkylenedioxy”, “halocycloalkoxy”, “halocycloalkoxyalkyl”, “halocycloalkenyloxy”, “halocycloalkenyloxyalkyl”, “alkylthio”, “haloalkylthio”, “alkylsulfinyl”, “amino”, “oxy”, “thio”, “alkylamino”, “arylamino”, “aralkylamino”, “arylsulfinyl”, “arylsulfinylalkyl”, “arylsulfonyl”, “arylsulfonylalkyl”, “heteroarylsulfinyl”, “heteroarylsulfinylalkyl”, “heteroarylsulfonyl”, “heteroarylsulfonylalkyl”, “heteroarylamino”, “heteroarylaminoalkyl”, “heteroaryloxy”, “heteroaryloxylalkyl”, “aryloxy”, “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, aralkylsulfonyl, aralkylsulfonylalkyl, aralkylsulfinyl, aralkylsulfinylalkyl, halocycloalkyl, halocycloalkenyl, cycloalkylsulfinyl, cycloalkylsulfinylalkyl, cycloalkylsulfonyl, cycloalkylsulfonylalkyl, heteroarylamino, N-heteroarylamino-N-alkylamino, heteroarylaminoalkyl, heteroaryloxy, heteroaryloxylalkyl, 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, 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, aralkyl, aryloxy, aralkoxy, aryloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, carboxyalkyl, carboalkoxy, alkoxycarbonyl, carboaralkoxy, carboxamido, 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. The spacer may have 1 to 7 atoms of a univalent or multi-valent chain. Univalent chains may be constituted by a radical selected from ═C(H)—, ═C(R ₁₇)—, —O—, —S—, —S(O)—, —S(O)₂—, —NH—, —N(R₁₇)—, —N═, —CH(OH)—, ═C(OH)—, —CH(OR₁₇)—, ═C(OR₁₇)—, and —C(O)— wherein R₁₇is selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, aryloxyalkyl, alkoxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkoxyalkyl, perhaloaralkyl, heteroarylalkyl, heteroaryloxyalkyl, heteroarylthioalkyl, and heteroarylalkenyl. Multi-valent chains may consist of a straight chain of 1 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 5 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. 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)—, —OCH₂O—, —O(CH₂)₂O—, —NHCH₂—, —OCH(R₁₇)O—, —O(CH₂CHR₁₇)O—, —OCF₂O—, —O(CF₂)₂O—, —S—, —S(O)—, —S(O)₂—, —N(R)—, —N(H)O—, —N(R₁₇)O—, —N(R₁₇)—, —C(O)—, —C(O)NH—, —C(O)NR₁₇—, —N═, —OCH₂—, —SCH₂—, S(O)CH₂—, —CH₂C(O)—, —CH(OH)—, ═C(OH)—, —CH(OR₁₇)—, ═C(OR₁₇)—, S(O)₂CH₂—, and —NR₁₇CH₂— 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, aralkylsulfinyl, aralkylsulfinylalkyl, halocycloalkyl, halocycloalkenyl, cycloalkylsulfinyl, cycloalkylsulfinylalkyl, cycloalkylsulfonyl, cycloalkylsulfonylalkyl, heteroarylamino, N-heteroarylamino-N-alkylamino, heteroarylaminoalkyl, heteroaryloxy, heteroaryloxylalkyl, 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, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl, alkynyl, alkenyloxy, alkenyloxyalky, alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkenyl, 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, heteroarylalkyl, 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, including cis- and trans-geometric isomers, E- and Z-geometric isomers, R- and S-enantiomers, diastereomers, d-isomers, 1-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.

The terms “cis” and “trans” 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 (“trans”).

Some of the compounds described contain alkenyl groups, and are meant to include both cis and trans 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 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 “enol” 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 diisopropylethylamine, “DMF” represents dimethylformamide, “DMSO” represents dimethylsulfoxide, “Fmoc” represents 9-fluorenylmethoxycarbonyl, “LDA” represents lithium diisopropylamide, “PHTH” represents a phthaloyl group, “pnZ” represents 4-nitrobenzyloxycarbonyl, “PTFC” 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-H, VII, VII-2, VII-3, VII-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 CETP-mediated disorders in a subject, comprising administering to the subject having such disorder a therapeutically-effective amount of a compound of Formula I-WA:

wherein R ₁, R₂, R₃, n, R₁₄, R₁₅, R₁₆, A, Q. X, Y, and Z are as defined above for the compounds of Formula I-WA;

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 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.

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 (CEFP), 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-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 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, 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, maleic, fumaric, 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 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-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 association with one or more non-toxic, pharmaceutically-acceptable carriers 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 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 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 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.

The pharmaceutical compositions may contain active ingredients 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 mg/kg body weight, and preferably between about 0.5 and about 20 mg/kg body weight, may be appropriate. The daily dose can be administered in one to four doses per day.

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% w/w 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. 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 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 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 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 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 emulsifier(s) with or without stabilizer(s) 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 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 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 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.

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, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone, and/or 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 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, 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.

All mentioned references are incorporated by reference as if here written.

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.

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/Cyclic Aryl/Heteroaryl tertiary Heteroalkylamines”) wherein one substituent (A or Q) on the nitrogen is AQ-1 which can be independently selected from the group consisting of aryl and heteroaryl, 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 —CH ₂(CR₃₇R₃₈)_v—(CR₃₃R₃₄)_u-T-(CR₃₅R₃₆)_w—H. AQ-2 and —CH₂(CR₃₇R₃₈)_v—(CR₃₃R₃₄)_u-T-(CR₃₅R₃₆)_w—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, C5-C10 cycloalkenyl, C4C9 saturated heterocyclyl, and C4C9 partially saturated 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 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 C1-C2 alkyl, C3-C8 hydroxyhaloalkyl, C3-C10 cycloalkyl, C5-C10 cycloalkenyl), C4-C9 saturated heterocyclyl, and C4C9 partially saturated 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 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 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 Imine” 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 mineral acid, as described in WO Patent Application No. 9738973, Swiss Patent CH 441366 and U.S. Pat. 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 presence of a noble metal catalyst such as PtO ₂.

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 5-10 minutes at 0-10° C. with 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 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 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-1), a “Cyclic Amine” of Formula AQ-2A or a “Generic Amine-I” 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 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. Org. Chem.(1996), 61, 7240-7241, Wolfe, Wagaw and Buchwald, J. Am. Chem. Soc. (1996), 118, 7215-7216, and Wolfe and Buchwald, Tetrahedron Letters (1997),38(36), 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 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 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.1 (1980), (12), 2781-6; Marcoux, Doye, and Buchwald, J.Am. Chem. Soc. (1997), 119, 1053-9; Sternbach and Jamison, Tetrahedron Lett. (1981), 22(35), 3331-4; U.S. Pat. No. 5306718; EP No. 314435; WO No. 9001874; WO No. 9002113; JP No. 05320117; WO No. 9738973; Swiss Patent No. CH 441366; U.S. Pat. Nos. 3359316 and 3334017; and references cited therein which are incorporated herein by reference.

Synthetic Schemes 2, 10 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”).

Derivatives of “Alicyclic/Cyclic Aryl/Heteroaryl Aminoalcohols” or “Alicyclic/Cyclic Aryl/Heteroaryl tertiary Heteroalkylamines”, in which the 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:

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-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 ₄and 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 I-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 1 a and 2a in Table 2 are prepared from the corresponding alcohols. The tosylates are readily obtained by reacting the corresponding alcohol with 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.

A preferred procedure for Formula I-WO (“Alicyclic/Cyclic Aryl/Heteroaryl Aminoalcohols”) and Formula I-WA (“Alicyclic/Cyclic 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 (“Alicyclic/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 oxiranes of the type listed in Table I and represented by the general structure:

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 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, substituted amino, or thiol, can be prepared by using appropriate aziridines and thirranes according to Method A of Scheme 2. Aziridine and thiirane reagents useful in Method A are exemplified, but not limited to those in Table 1. These Formula I-WA (“Alicyclic/Cyclic Aryl/Heteroaryl tertiary 2-Heteroalkylamine”) compounds, wherein the 2-hetero group is an amino, substituted amino, or thiol, can be 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 aziridines and thiiranes of the type listed in Table 1 and represented by the general structure:

wherein X is selected from N and S and R ₁₆is hydrogen or another suitable group when X is N.

TABLE 1


Structure of Oxirane, Aziridine, and Thiirane Reagents.

	(XX)

Rgnt
No.	R₁₆	X	R₁	R₂	R₃

1	—	O	CF₃	H	H
2	—	O	CCl₃	H	H
3	—	O	CF₃	CH₃	H
4	—	O	CF₃CF₂	H	H
5	—	O	CF₃CF₂CF₂	H	H
6	—	O	CF₃OCF₂CF₂	H	H
7	—	O	CF₃CH₂	H	H
8	—	O	CF₃	CHF₂	H
9	—	O	CF₃	H	CF₃
10	—	O	CF₃	CF₃	H
11	—	O	CF₃	C₆H₅	H
12	—	O	CCl₃	C₆H₅	H
13	—	O	CCl₃	Cyclopropyl	H
14	—	O	CCl₃	CH₃	H
15	—	O	CCl₃	(CH₃)₂CH	H
16	—	O	CHCl₂	H	H
17	—	O	CHCl₂	Cl	H
18	—	O	CF₃	H	CH₃
19	H	N	CF₃	CF₃	H
20	H	N	CF₃	H	H
21	Benzyl	N	CF₃	H	H
22	CH₃O	N	CF₃	H	H
23	CH₃	N	CF₃	H	H
24	Benzyloxy	N	CF₃	H	H
25	—	S	CF₃	H	H
26	—	S	CF₃CF₂	H	H
27	—	O	CCl₃CH₂	H	H
28	—	O	CBr₃CH₂	H	H
29	—	O	CHBr₂CH₂	H	H
30	—	O	CBrCl₂	H	H
31	—	O	CClF₂	H	H
32	—	O	CCl₂F	H	H
33	—	O	CCl₃CCl₂	H	H
43	—	O	FCH₂	H	H

46	—	O	CF₃	R₂+ R₃= (CH₂)₃
47	—	O	CF₃	R₂+ R₃= (CH₂)₄
48	—	O	CHF₂	R₂+ R₃= (CH₂)₄

56	—	O	CBrF₂CClFCH₂	H	H
57	—	O	HCF₂CF₂OCH₂	H	H

TABLE 2


Structure and Source of Alcohol and Glycol Reagents.

	(XXX)

Reagent
Number	R₁	n	M	R₂	R₃	X-R₁₆	Source of Reagent

1A	CF₃	3	OTs	H	H	OH	Chiral separation and then tosylation of alcohol from Justus
							Liebigs Ann. Chem. (1969), 720, 81-97.
2A	CF₃CH₂CH₂	3	OTs	H	H	OH	Chiral separation and then tosylation of alcohol from Z.
							Naturforsch., B: Chem. Sci. (1997), 52 (3). 413-418

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. 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 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 ₄and concentrated in vacuo to yield 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 5-40% 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 Aryl/Heteroaryl Aminoalcohols”) 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 Aryl/Heteroaryl tertiary Heteroalkylamines”) compounds are purified by additional chromatography or 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.

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 Aryl/Heteroaryl Aminoalcohols”) and Formula I-WA (“Alicyclic/Cyclic Aryl/Heteroaryl tertiary Heteroalkylamines”) compounds summarized in the 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, 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 1-WA (“Alicyclic/Cyclic Aryl/Heteroaryl tertiary Heteroalkylamines”) compounds.

Formula I-WO (“Alicyclic/Cyclic Aryl/Heteroaryl Aminoalcohols”) and Formula 1-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 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 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”).

Formula I-WO (“Alicyclic/Cyclic Aryl/Heteroaryl Aminoalcohols”) and Formula I-WA (“Alicyclic/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 alternately referred to as Formula I-WO (“Alicyclic/Cyclic Aryl/Heteroaryl 2-hydroxyalkylamines”).

Formula I-WO (“Alicyclic/Cyclic Aryl/Heteroaryl Aminoalcohols”) and Formula I-WA (“Alicyclic/Cyclic Aryl/Heteroaryl tertiary Heteroalkylamines”) compounds can themselves serve as intermediates for conversion to additional compounds of this invention. Compounds of the present invention useful as intermediates include those in which the R ₅or R₇position 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, nitro group, amino group, methoxy 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 R₁₀position substituent in Formulas I-WA or I-WO is a bromo group, hydroxyl group, sulfhydryl group, bromomethyl or other bromoalkyl groups, nitro group, amino group, methoxy carbonyl or other 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, R₁₁, and R₁₂substituents in Formulas I-WA or I-WO is a bromo group, hydroxyl group, sulfhydryl group, bromomethyl or other bromoalkyl groups, nitro group, amino group, methoxy carbonyl or other alkoxy carbonyl groups, cyano group, or acyl groups.

Formula I-WO (“Alicyclic/Cyclic Aryl/Heteroaryl Aminoalcohols”) are alternately referred to as Formula I-WO (“Alicyclic/Cyclic Aryl/Heteroaryl Tertiary 2-hydroxyalkylamines”).

A 3-bromo substituent at the R ₅position in Formula I-WO (“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 R ₅position in Formula I-WO (“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”).

A 3-bromo substituent at the R ₅position in Formula I-WO (“Alicyclic/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 R ₅position in Formula I-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 I-WO (“Alicyclic/Cyclic 3- R₂₂aminoaryl Tertiary 2-Hydroxyalkylamine”).

Conversion of a 3-bromo substituent at the R ₅position 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-Hydroxyalkylamine”).

Conversion of a 3-bromo substituent at the R ₅position 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-Heteroarylaryl Tertiary 2-Hydroxyalkylamine”).

Conversion of a 3-bromomethyl substituent at the R ₅position 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-Arylmethylaryl Tertiary 2-Hydroxyalkylamine”).

Conversion of a 3-hydroxyl substituent at the R ₅position 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 (“Alicyclic/Cyclic 3-Aryloxyaryl, 3-Heteroaryloxyaryl, 3-Heteroaryloxyheteroaryl, and 3-Aryloxyheteroaryl Tertiary 2-Hydroxyalkylamines”).

Conversion of a 3-hydroxyl substituent at the R ₅position in Formula I-WO (“Alicyclic/Cyclic 3-Hydroxyaryl Tertiary 2-hydroxyalkylamine”) by reaction with an aryl bromide can afford additional compounds of the present invention of Formula I-WO (“Alicyclic/Cyclic 3-Phenoxyaryl Tertiary 2-Hydroxyalkylamine”).

Conversion of a 3-hydroxyl substituent at the R ₅position 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”).

Conversion of a 3-hydroxyl substituent at the R ₅position 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 (“Alicyclic/Cyclic 3-Aralkyloxyaryl Tertiary 2-Hydroxyalkylamine”).

Conversion of a 3-hydroxyl substituent at the R ₅position in Formula I-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”).

Conversion of a 3-thio substituent at the R ₅position in Formula I-WO (“Alicyclic/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”). “Alicyclic/Cyclic 3-Organothiaaryl Tertiary 2-Hydroxyalkylamines” can be oxidized to sulfonyl compounds of 3-Organosulfonylaryl Tertiary 2-Hydroxyalkylamine”).

Conversion of a 3-nitro substituent at the R ₅position in Formula l-WO (“Alicyclic/Cyclic 3-Nitroaryl Tertiary 2-hydroxyalkylamine”) by hydrogenation can afford additional compounds of the present invention of Formula I-WO (“Alicyclic/Cyclic 3-Amninoaryl Tertiary 2-Hydroxyalkylamine”). Formula I-WO (“Alicyclic/Cyclic 3-Aminoaryl Tertiary 2-Hydroxyalkylamines”) can be acylated to acyl amide compounds of Formula I-WO (“Alicyclic/Cyclic 3-Acylaminoaryl Tertiary 2-Hydroxyalkylamine”).

Conversion of a 3-amino substituent at the R ₅position in Formula I-WO (“Alicyclic/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-1yl)aryl Tertiary 2-Hydroxyalkylamine” and “AlicyclictCyclic 3-(Unsaturated Nitrogen Heterocycl-1yl)aryl Tertiary 2-Hydroxyalkylamine”).

Conversion of a 3-methoxycarbonyl substituent at the R ₅position 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-Carboxamidoaryl Tertiary 2-Hydroxyalkylamine”).

Conversion of a 3-cyano substituent at the R ₅position in Formula I-WO (“Alicyclic/Cyclic 3-Cyanoaryl Tertiary 2-hydroxyalkylamine”) by reaction with organometallic reagents can afford additional compounds of the present invention of Formula I-WO (“Alicyclic/Cyclic 3-Acylaryl Tertiary 2-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 R ₁₀position 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 l-WO (“Alicyclic/Cyclic 3-Carboxamidoaryl Tertiary 2-Hydroxyalkylamine”).

Conversion of a 3-methoxycarbonyl substituent at the R ₁₀position in Formula I-WO (“Alicyclic/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”).

Conversion of a 3-methoxycarbonyl substituent at the R ₁₀position 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”).

Conversion of a 3-methoxycarbonyl substituent at the R ₁₀position 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-Hydroxyalkylamine”).

Conversion of a 3-methoxycarbonyl substituent at the R ₁₀position in Formula I-WO (“Alicyclic/Cyclic 3-Carbomethoxyaryl Tertiary 2-hydroxyalkylamine”) by reaction initially with an amidation reagent and then an organometallic reagent can afford additional compounds of the present invention of Formula I-WO (“Alicyclic/Cyclic 3-(Organo-carbonyl)aryl Tertiary 2-Hydroxyalkylamine”).

Formula I-WO (“Alicyclic/Cyclic Aryl/Heteroaryl Aminoalcohols”) and Formula I-WA (“Alicyclic/Cyclic Aryl/Heteroaryl tertiary Heteroalkylamines”) and other compounds of this invention posssessing hydroxyl, thiol, and amine functional groups can be converted to a wide variety derivatives. The hydroxyl group X, wherein R ₁₆is 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 acylating reagent such as an aliphatic acid 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, 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 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 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 sodium hydroxide. Suitable procedures and methods for preparing these derivatives can be found in House's Modern Synthetic Reactions, 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. Reagents of a wide variety that can be used to derivatize hydroxyl, thiol, and amines of compounds of Formulas I-WA, I-WO, and other compounds of the present invention are available from commercial sources or 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”) 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 R ₁₆is 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 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 carried out using an alkoxide forming reagent such as sodium hydride, potassium t-butoxide, sodium amide, lithium amide, and n-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 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, I-WO, and other compounds that have at least one primary, secondary or tertiary amine group present can be 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 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 found in House's Modern Synthetic Reactions, 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. Perfluoroalkyl derivatives can be prepared as described by DesMarteau in J. Chem. Soc. Chem. Commun. 2241 (1998). Reagents of a wide variety that can be used to derivative hydroxyl, thiol, and amines of compounds of Formulas I-WA, I-WO, and the like are available from commercial sources or the references cited above, which are incorporated herein by reference.

The following examples are provided to illustrate the present invention and 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.

The following examples are provided to illustrate the present invention and are not intended to limit the scope thereof. Without further elaboration, it 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 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 following specific examples, which have been or may be properly characterized by ¹H NMR and mass spectrometry. These compounds also may be formed in The following examples contain detailed descriptions of the methods of preparation of compounds of Formula V-H. These detailed descriptions fall 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 temperatures are Degrees centigrade unless otherwise indicated.

EXAMPLE 1

[0307]

3-[(4-methylcyclohexyl)[[(3-trifluoromethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol

EX-1A) 4-Methylcyclohexylamine (1.15 g, 10 mmol, 97%, mixture of cis and trans 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, MS m/z=269 [M[0308] ⁺]. The oil was dissolved in methanol, and after cooling to 0° 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 1N HCl solution. After neutralizing to pH 7.5 with 2.5N sodium hydroxide, the mixture was extracted with diethyl ether (3×20 mL). The organic layer was washed with brine and water, then dried over anhydrous MgSO₄, 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-1A (1.08 g, 4 mmol) and 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 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 MgSO[0309] ₄. 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-[(4-methyl-cyclohexyl)[[(3-trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol product as a light amber oil, 99% pure by HPLC analysis. HRMS calculated for C₁₈H₂₃F₆NO: 384.1762 [M+H]⁺, found: 384.1754. ¹H NMR (CDCl₃) δ0.92 (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, 1H), 3.94 (s, 1H), 7.45-7.60 (m, 4H). ¹⁹F NMR (CDCl₃) δ−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. [0310]

Example Table 1. Substituted 3-[(N-alkyl and N-cycloalkyl)[aryl]methyl]amino-1,1,1 -trifluoro-2-propanols.

			Calculated	Observed
Ex.			Mass	Mass
No.	R_SUB1	R_SUB2	[M + H]⁺	[M + H]⁺

2	cyclopropyl	4-OCF₃	344.1085	344.1086
3	isopropyl	4-OCF₃	346.1242	346.1245
4	cyclopropyl	3-OCF₃	344.1085	344.1085
5	isopropyl	3-OCF₃	346.1242	346.1239
6	n-propyl	3-OCF₃	346.1242	346.1252
7	cyclopentyl	3-OCF₃	372.1398	372.1409

EXAMPLE 8

[0312]

3-[(3-methyl-2-butenyl)[(3-(trifluoromethoxy)phenyl] amino]-1,1,1-trifluoro-2-propanol

EX8A) 3-Trifluoromethoxy aniline (23.81 g, 134.4 mmol) and 3,3,3-trifluoro-1,2-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 torr). 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. [0313] ¹H NMR (CDCl₃) δ3.29-3.37 (m, 1H), 3.55 (dd, 1H), 4.20 (m, 1H), 6.48-6.63 (m, 3H), 7.12 (t, 1H). ¹⁹F NMR (CDCl₃) δ−79.36 (s, 3F), −58.44 (s, 3F).
EX-8B) The 3-[[(trifluoromethoxy)phenyl]amino]-1,1,1-trifuoro-2-propanol product from EX8A (18.68 g, 64.6 mmol) and imidazole (10.99 g, 0.162 mmol) were dissolved in dimethylfornamide (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 (MgSO[0314] ₄) and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with 25% ethyl acetate in hexane to afford 17.08 g of the desired silylated product as a light golden oil. FABMS m/z= 404 [M+H]⁺. ¹H NMR (CDCl₃) δ 0.042 (s, 3H), 0.085 (s, 3H), 0.91 (s, 9H), 3.25-3.35 (m, 1H), 3.50 (dd, 1H), 4.10 (m, 1H), 6.40 (bs, 1H), 6.50 (dd, 1H), 6.59 (d, 1H), 7.17 (t, 1H).
EX-8C) The silylated product from EX8B (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. in an ice bath. KOtBu (1M 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 (MgSO[0315] ₄) and concentrated under a nitrogen stream. The crude residue was dissolved in 2.0 mL of THF and treated with tetrabutylammonium fluoride (1M 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. The organic layer wad dried (MgSO₄) and concentrated under a nitrogen stream. The crude residue was purified using 0.5 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]⁺.
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. [0316]

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

Ex.		Calculated	Observed
No.	R_SUB1	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-pro-	387	388
	penyl
13	3-(carbomethoxy)-2-pro-	387	388
	penyl
15	4-methoxy-2-butenyl	373	374

EXAMPLE 15

[0318]

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 m/z=332 [M+H][0319] ⁺. ¹H NMR (CDCl₃) δ 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 1,1′-[(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. [0320]

Example Table 3. Substituted 1,1′-[(phenylmethyl)imino]bis[3,3,3-trifluoro-2-propanols]

[0321]

Ex. Calculated Observed Mass

No. R_SUB2 Mass [M + H]⁺ [M + H]⁺

16 3-trifluoromethyl 400.0959 400.0923

17 4-trifluoromethoxy 416.0908 416.0905

EXAMPLE 18

[0322]

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 MgSO[0323] ₄, 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 C₁₄H ₁₂ClNO₃: 295.0849 [M+NH₄]⁺, 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 MgSO[0324] ₄, 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 C₁₄H₁₄ClNO: 248.0842 [M+H]⁺, found: 248.0833.
EX-18C) The 3-(4-chloro-3-ethylphenoxy)aniline (0.545 g, 0.002 mol) 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 g (35%) of the desired 3-[[3-(4-chloro-3-ethyl-phenoxy)phenyl]amino]-1,1,1-trifluoro-2-propanol product as a pure orange oil. Anal calcd. for C[0325] ₁₇H₁₇NOF₃Cl: 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. H NMR (CDCl₃) δ 1.50 (t, 3H), 2.72 (m, 2H), 3.36 (m, 1H), 3.54 (m, 1H), 4.20 (m, 1H), 6.42 (m, 2H), 6.81 (dd, 1H), 6.94 (d, 1H), 7.18 (d, 1H), 7.25 (m, 2H).
The 3-[[3-(4-chloro-3-ethylphenoxy)phenyl]amino]-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 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 over MgSO[0326] ₄and concentrated to an orange/brown oil. The crude product was 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]-1,1,1 -trifluoro-2-propanol product as a yellow-orange oil (>95% pure by HPLC). HRMS calcd.: 456.1917 [M+H]⁺, found: 456.1942. ¹H NMR (CDCl₃) δ 0.82-1.01 (m, 2H), 1.22-1.27 (m, 3H), 1.73-1.76 (m, 5H), 2.74 (dd, 2H), 3.15 (dd, 2H), 3.23 (dd, 1H), 3.52 (m, 1H), 3.80 (dd, 1H), 4.28 (m, 1H), 6.34 (d, 2H), 6.42 (d, 1H), 6.83 (dd, 1H), 6.98 (d, 1H), 7.19 (t, 1H), 7.29 (d, 1H). ¹⁹F NMR (CDCl₃) δ −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)-[ [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. [0327]

Example Table 4. 3-[(N-alkyl)[[aryl]methyl]amino]- 1,1,1 -trifluoro-2-propanols.



Ex.
No.	R_SUB

19	4-OCF₃
20	3-OCF₂CF₂H
21	2-F, 5-CF₃
22	2-F, 4-CF₃
23	3-CF₃, 4-F
24	3-CF₃CF₂
25	3-cyclopentyl
26	3-isopropoxy
27	3-SCF₃
28	3-sec-butoxy
29	3-C(CF₃)₂OH
30	3-(2-furyl)
31	3-(3-furyl)
32	3-isobutyl
33	3-isobutoxy
34	3-ethoxy
35	3-OCH₂CF₃
36	3-propoxy
37	3-tert-butoxy
38	3-(2-thienyl)
39	3-cyclopropyl
40	4-F, 3-(2-furyl)
41	3-(3-CF₃-phenoxy)
42	3,4-(OCF₂CF₂O)
43	3-OCF₂CF₃
44	3-cyclopentoxy
45	3-(cyclopropyl)methoxy
46	3-OCH₂CH(OH)CF₃
47	3-CF₃
48	4-CF₃
49	3-CH₂CF₂CF₃
50	3-CH₂CF₃
51	3-CH(CF₃)₂
52	3-CF₂CF₂CF₃
53	3-phenoxy
54	3-phenyl
55	3-(tetrahydro-2-furyl)
56	isoamyl


57	3-OCF₃
58	3-OCF₂CF₂H
59	2-F, 5-CF₃
60	2-F, 4-CF₃
61	3-CF₃, 4-F
62	3-CF₃CF₂
63	3-cyclopentyl
64	3-isopropoxy
65	3-SCF₃
66	3-sec-butoxy
67	3-C(CF₃)₂OH
68	3-(2-furyl)
69	3-(3-furyl)
70	3-isobutyl
71	3-isobutoxy
72	3-ethoxy
73	3-OCH₂CF₃
74	3-propoxy
75	3-tert-butoxy
76	3-(2-thienyl)
77	3-cyclopropyl
78	4-F, 3-(2-furyl)
79	3-(3-CF₃-phenoxy)
80	3,4-(OCF₂CF₂O)
81	3-OCF₂CF₃
82	3-cyclopentoxy
83	3-(cyclopropyl)methoxy
84	3-OCH₂CH(OH)CF₃
85	3-CF₃
86	4-CF₃
87	3-CH₂CF₂CF₃
88	3-CH₂CF₃
89	3-CH(CF₃)₂
90	3-CF₂CF₂CF₃
91	3-phenoxy
92	3-phenyl
93	3-(tetrahydro-2-furyl)
94	isoamyl

95	3-OCF₃
96	3-OCF₂CF₂H
97	2-F, 5-CF₃
98	2-F, 4-CF₃
99	3-CF₃, 4-F
100	3-CF₃CF₂
101	3-cyclopntyl
102	3-isopropoxy
103	3-SCF₃
104	3-sec-butoxy
105	3-C(CF₃)₂OH
106	3-(2-furyl)
107	3-(3-furyl)
108	3-isobutyl
109	3-isobutoxy
110	3-ethoxy
111	3-OCH₂CF₃
112	3-propoxy
113	3-tert-butoxy
114	3-(2-thienyl)
115	3-cyclopropyl
116	4-F, 3-(2-furyl)
117	3-(3-CF₃-phenoxy)
118	3,4-(OCF₂CF₂O)
119	3-OCF₂CF₃
120	3-cyclopentoxy
121	3-(cyclopropyl)methoxy
122	3-OCH₂CH(OH)CF₃
123	3-CF₃
124	4-CF₃
125	3-CH₂CF₂CF₃
126	3-CH₂CF₃
127	3-CH(CF₃)₂
128	3-CF₂CF₂CF₃
129	3-phenoxy
130	3-phenyl
131	3-(tetrahydro-2-furyl)
132	isoamyl

133	3-OCF₃
134	3-OCF₂CF₂H
135	2-F, 5-CF₃
136	2-F, 4-CF₃
137	3-CF₃, 4-F
138	3-CF₃CF₂
139	3-cyclopentyl
140	3-isopropoxy
141	3-SCF₃
142	3-sec-butoxy
143	3-C(CF₃)₂OH
144	3-(2-furyl)
145	3-(3-furyl)
146	3-isobutyl
147	3-isobutoxy
148	3-ethoxy
149	3-OCH₂CF₃
150	3-propoxy
151	3-tert-butoxy
152	3-(2-thienyl)
153	3-cyclopropyl
154	4-F, 3-(2-furyl)
155	3-(3-CF₃-phenoxy)
156	3,4-(OCF₂CF₂O)
157	3-OCF₂CF₃
158	3-cyclopentoxy
159	3-(cyclopropyl)methoxy
160	3-OCH₂CH(OH)CF₃
161	3-CF₃
162	4-CF₃
163	3-CH₂CF₂CF₃
164	3-CH₂CF₃
165	3-CH(CF₃)₂
166	3-CF₂CF₂CF₃
167	3-phenoxy
168	3-phenyl
169	3-(tetrahydro-2-furyl)
170	isoamyl

171	3-OCF₃
172	3-OCF₂CF₂H
173	2-F, 5-CF₃
174	2-F, 4-CF₃
175	3-CF₃, 4-F
176	3-CF₃CF₂
177	3-cyclopentyl
178	3-isopropoxy
179	3-SCF₃
180	3-sec-butoxy
181	3-C(CF₃)₂OH
182	3-(2-furyl)
183	3-(3-furyl)
184	3-isobutyl
185	3-isobutoxy
186	3-ethoxy
187	3-OCH₂CF₃
188	3-propoxy
189	3-tert-butyoxy
190	3-(2-thienyl)
191	3-cyclopropyl
192	4-F, 3-(2-furyl)
193	3-(3-CF₃-phenoxy)
194	3,4-(OCF₂CF₂O)
195	3-OCF₂CF₃
196	3-cyclopenoxy
197	3-(cyclopropyl)methoxy
198	3-OCH₂CH(OH)CF₃
199	3-CF₃
200	4-CF₃
201	3-CH₂CF₂CF₃
202	3-CH₂CF₃
203	3-CH(CF₃)₂
204	3-CF₂CF₂CF₃
205	3-phenoxy
206	3-phenyl
207	3-(tetrahydro-2-furyl)
208	isoamyl

Example Table 5. (cont.). 3-[(N-cycloalkyl)[[aryl]methyl]amino]-halo-2-propanols.



Ex.
No.	R_SUB

209	3-tert-butoxy
210	3-OCF₂CF₂H
211	2-F, 5-CF₃
212	2-F, 4-CF₃
213	3-CF₃, 4-F
214	3-CF₃CF₂
215	3-cyclopentyl
216	3-isopropoxy
217	3-SCF₃
218	3-sec-butoxy
219	3-C(CF₃)₂OH
220	3-(2-furyl)
221	3-(3-furyl)
223	3-isobutoxy
224	3-ethoxy
225	3-OCH₂CF₃
226	3-propoxy
227	3-(2-pyridyl)
228	3-(2-thienyl)
229	3-cyclopropyl
230	4-F, 3-(2-furyl)
231	3-(3-CF₃-phenoxy)
232	3,4-(OCF₂CF₂O)
233	3-OCF₂CF₃
234	3-cyclopentoxy
235	3-(cyclopropyl)methoxy
236	3-OCH₂CH(OH)CF₃
237	3-CF₃
238	4-CF₃
239	3-CH₂CF₂CF₃
240	3-CH₂CF₃
241	3-CH(CF₃)₂
242	3-CF₂CF₂CF₃
243	3-phenoxy
244	3-phenyl
245	3-(tetrahydro-2-furyl)
246	isoamyl

247	4-OCF₃
248	3-OCF₂CF₂H
249	2-F, 5-CF₃
250	2-F, 4-CF₃
251	3-CF₃CF₂
252	3-CF₃CF₂
253	3-cyclopentyl
254	3-isopropoxy
255	3-SCF₃
256	3-sec-butoxy
257	3-C(CF₃)₂OH
258	3-(2-furyl)
259	3-(3-furyl)
260	3-isobutyl
261	3-isobutoxy
262	3-ethoxy
263	3-OCH₂CF₃
264	3-propoxy
265	3-tert-butoxy
266	3-(2-thienyl)
267	3-cyclopropyl
268	4-F, 3-(2-furyl)
269	3-(3-CF₃-phenoxy)
270	3,4-(OCF₂CF₂O)
271	3-OCF₂CF₃
272	3-cyclopentoxy
273	3-(cyclopropyl)methoxy
274	3-OCH₂CH(OH)CF₃
275	3-CF₃
276	4-CF₃
277	3-CH₂CF₂CF₃
278	3-CH₂CF₃
279	3-CH(CF₃)₂
280	3-CF₂CF₂CF₃
281	3-phenoxy
282	3-phenyl
283	3-(tetrahydro-2-furyl)
284	isoamyl

285	3-OCF₃
286	3-OCF₂CF₂H
287	2-F, 5-CF₃
288	2-F, 4-CF₃
289	3-CF₃, 4-F
290	3-CF₃CF₂
291	3-cyclopentyl
292	3-isopropoxy
293	3-SCF₃
294	3-sec-butoxy
295	3-C(CF₃)₂OH
296	3-(2-furyl)
297	3-(3-furyl)
298	3-isobutyl
299	3-isobutyl
300	3-ethoxy
301	3-OCH₂CF₃
302	3-propoxy
303	3-tert-butoxy
304	3-(2-thienyl)
305	3-cyclopropyl
306	4-F, 3-(2-furyl)
307	3-(3-CF₃-phenoxy)
308	3,4-(OCF₂CF₂O)
309	3-OCF₂CF₃
310	3-cyclopentoxy
311	3-(cyclopropyl)methoxy
312	3-OCH₂CH(OH)CF₃
313	3-CF₃
314	4-CF₃
315	3-CH₂CF₂CF₃
316	3-CH₂CF₃
317	3-CH(CF₃)₂
318	3-CF₂CF₂CF₃
319	3-phenoxy
320	3-phenyl
321	3-(tetrahydro-2-furyl)
322	isoamyl

324	3-OCF₃
324	3-OCF₂CF₂H
325	2-F, 5-CF₃
326	2-F, 4-CF₃
327	3-CF₃, 4-F
328	3-CF₃CF₂
329	3-cyclopentyl
330	3-isopropoxy
331	3-SCF₃
332	3-sec-butoxy
333	3-C(CF₃)₂OH
334	3-(2-furyl)
335	3-(3-furyl)
336	3-isobutyl
337	3-isobutoxy
338	3-ethoxy
339	3-OCH₂CF₃
340	3-propoxy
341	3-tert-butoxy
342	3-(2-thienyl)
343	3-cyclopropyl
344	4-F, 3-(2-furyl)
345	3-(3-CF₃-phenoxy)
346	3,4-(OCF₂CF₂O)
347	3-OCF₂CF₃
348	3-cyclopentoxy
349	3-(cyclopropyl)methoxy
350	3-OCH₂CH(OH)CF₃
351	3-CF₃
352	4-CF₃
353	3-CH₂CF₂CF₃
354	3-CH₂CF₃
355	3-CH(CF₃)₂
356	3-CF₂CF₂CF₃
357	3-phenoxy
358	3-phenyl
359	3-(tetrahydro-2-furyl)
360	isoamyl

361	3-OCF₃
362	3-OCF₂CF₂H
363	2-F, 5-CF₃
364	2-F, 4-CF₃
365	3-OCF₃, 4-F
366	3-CF₃CF₂
367	3-cyclopentyl
368	3-isopropoxy
369	3-SCF₃
370	3-sec-butoxy
371	3-C(CF₃)₂OH
372	3-(2-furyl)
373	3-(3-furyl)
374	3-isobutyl
375	3-isobutoxy
376	3-ethoxy
377	3-OCH₂CF₃
378	3-propoxy
379	3-tert-butoxy
380	3-(2-thienyl)
381	3-cyclopropyl
382	4-F, 3-(2-furyl)
383	3-(3-CF₃phenoxy)
384	3,4-OCF₂CF₂O)
385	3-OCF₂CF₃
386	3-cyclopentoxy
387	3-(cyclopropyl)methoxy
388	3-OCH₂CH(OH)CF₃
389	3-CF₃
390	4-CF₃
391	3-CH₂CF₂CF₃
392	3-CH₂CF₃
393	3-CH(CF₃)₂
394	3-CF₂CF₂CF₃
395	3-phenoxy
396	3-phenyl
397	3-(tetrahydro-2-furyl)
398	isoamyl

399	3-OCF₃
400	3-OCF₂CF₂H
401	2-F, 5-CF₃
402	2-F, 4-CF₃
403	3-CF₃, 4-F
404	3-CF₃CF₂
405	3-cyclopentyl
406	3-isopropoxy
407	3-SCF₃
408	3-sec-butoxy
409	3-C(CF₃)₂OH
410	3-(2-furyl)
411	3-(3-furyl)
412	3-isobutyl
413	3-isobutoxy
414	3-ethoxy
415	3-OCH₂CF₃
416	3-propoxy
417	3-tert-butoxy
418	3-(2-thienyl)
419	3-cyclopropyl
420	4-F, 3-(2-furyl)
421	3-(3-CF₃-phenoxy)
422	3,4-(OCF₂CF₂O)
423	3-OCF₂CF₃
424	3-cyclopentoxy
425	3-(cyclopropyl)methoxy
426	3-OCH₂CH(OH)CF₃
427	3-CF₃
428	4-CF₃
429	3-CH₂CF₂CF₃
430	3-CH₂CF₃
431	3-CH(CF₃)₂
432	3-CF₂CF₂CF₃
433	3-phenoxy
434	3-phenyl
435	3-(tetrahydro-2-furyl)
436	isoamyl

437	3-OCF₃
438	3-OCF₂CF₂H
439	2-F, 5-CF₃
440	2-F, 4-CF₃
441	3-CF₃, 4-F
442	3-CF₃CF₂
443	3-cyclopentyl
444	3-isopropoxy
445	3-SCF₃
446	3-sec-butoxy
447	3-C(CF₃)₂OH
448	3-(2-furyl)
449	3-(3-furyl)
450	3-isobutyl
451	3-isobutoxy
452	3-ethoxy
453	3-OCH₂CF₃
454	3-propoxy
455	3-tert-butoxy
456	3-(2-thienyl)
457	3-cyclopropyl
458	4-F, 3-(2-furyl)
459	3-(3-CF₃-phenoxy)
460	3,4-(OCF₂CF₂O)
461	3-OCF₂CF₃
462	3-cyclopentoxy
463	3-(cyclopropyl)methoxy
464	3-OCH₂CH(OH)CF₃
465	3-CF₃
466	4-CF₃
467	3-CH₂CF₂CF₃
468	3-CH₂CF₃
469	3-CH(CF₃)₂
470	3-CF₂CF₂CF₃
471	3-phenoxy
472	3-phenyl
473	3-(tetrahydro-2-furyl)
474	isoamyl


475	3-OCF₃
476	3-OCF₂CF₂H
477	2-F, 5-CF₃
478	2-F, 4-CF₃
479	3-CF₃, 4-F
480	3-CF₃CF₂
481	3-cyclopentyl
482	3-isopropoxy
483	3-SCF₃
484	3-sec-butoxy
485	3-C(CF₃)₂OH
486	3-(2-furyl)
487	3-(3-furyl)
488	3-isobutyl
489	3-isobutoxy
490	3-ethoxy
491	3-OCH₂CF₃
492	3-propoxy
493	3-tert-butoxy
494	3-(2-thienyl)
495	3-cyclopropyl
496	4-F, 3-(2-furyl)
497	3-(3-CF₃-phenoxy)
498	3,4-(OCF₂CF₂O)
499	3-OCF₂CF₃
500	3-cyclopentoxy
501	3-(cyclopropyl)methoxy
502	3-OCH₂CH(OH)CF₃
503	3-CF₃
504	4-CF₃
505	3-CH₂CF₂CF₃
506	3-CH₂CF₃
507	3-CH(CF₃)₂
508	3-CF₂CF₂CF₃
509	3-phenoxy
510	3-phenyl
511	3-(tetrahydro-2-furyl)
512	isoamyl

513	3-OCF₃
514	3-OCF₂CF₂H
515	2-F, 5-CF₃
516	2-F, 4-CF₃
517	3-CF₃, 4-F
518	3-CF₃CF₂
519	3-cyclopentyl
520	3-isopropoxy
521	3-SCF₃
522	3-sec-butoxy
523	3-C(CF₃)₂OH
524	3-(2-furyl)
525	3-(3-furyl)
526	3-isobutyl
527	3-isobutoxy
528	3-ethoxy
529	3-OCH₂CF₃
530	3-propoxy
531	3-tert-butoxy
532	3-(2-thienyl)
533	3-cyclopropyl
534	4-F, 3-(2-furyl)
535	3-(3-CF₃-phenoxy)
536	3,4-(OCF₂CF₂O)
537	3-OCF₂CF₃
538	3-cyclopentoxy
539	3-(cyclopropyl)methoxy
540	3-OCH₂CH(OH)CF₃
541	3-CF₃
542	4-CF₃
543	3-CH₂CF₂CF₃
544	3-CH₂CF₃
545	3-CH(CF₃)₂
546	3-CF₂CF₂CF₃
547	3-phenoxy
548	3-phenyl
549	3-(tetrahydro-2-furyl)
550	isoamyl

551	3-OCF₃
552	3-OCF₂CF₂H
553	2-F, 5-CF₃
554	2-F, 4-CF₃
555	3-CF₃, 4-F
556	3-CF₃CF₂
557	3-cyclopentyl
558	3-isopropoxy
559	3-SCF₃
560	3-sec-butoxy
561	3-C(CF₃)₂OH
562	3-(2-furyl)
563	3-(3-furyl)
564	3-isobutyl
565	3-isobutoxy
566	3-ethoxy
567	3-OCH₂CF₃
568	3-propoxy
569	3-tert-butoxy
570	3-(2-thienyl)
571	3-cyclopropyl
572	4-F, 3-(2-furyl)
573	3-(3-CF₃phenoxy)
574	3,4-(OCF₂CF₂O)
575	3-OCF₂CF₃
576	3-cyclopentyl
577	3-(cyclopropyl)methoxy
578	3-OCH₂CH(OH)CF₃
579	3-CF₃
580	4-CF₃
581	3-CH₂CF₂CF₃
582	3-CH₂CF₃
583	3-CH(CF₃)₂
584	3-CF₂CF₂CF₃
585	3-phenoxy
586	3-phenyl
587	3-(tetrahydro-2-furyl)
588	isoamyl

589	3-OCF₃
590	3-OCF₂CF₂H
591	2-F, 5-CF₃
592	2-F, 4-CF₃
593	3-CF₃, 4-F
594	3-CF₃CF₂
595	3-cyclopentyl
596	3-isopropoxy
597	3-SCF₃
598	3-sec-butoxy
599	3-C(CF₃)₂OH
600	3-(2-furyl)
601	3-(3-furyl)
602	3-isobutyl
603	3-isobutoxy
604	3-ethoxy
605	3-OCH₂CF₃
606	3-propoxy
607	3-tert-butoxy
608	3-(2-thienyl)
609	3-cyclopropyl
610	4-F, 3-(2-furyl)
611	3-(3-CF₃-phenoxy)
612	3,4-(OCF₂CF₂O)
613	3-OCF₂CF₃
614	3-cyclopentoxy
615	3-(cyclopropyl)methoxy
616	3-OCH₂CH(OH)CF₃
617	3-CF₃
618	4-CF₃
619	3-CH₂CF₂CF₃
620	3-CH₂CF₃
621	3-CH(CF₃)₂
622	3-CF₂CF₂CF₃
623	3-phenoxy
624	3-phenyl
625	3-(tetrahydro-2-furyl)
626	isoamyl

627	3-OCF₃
628	3-OCF₂CF₂H
629	2-F, 5-CF₃
630	2-F, 4-CF₃
631	3-CF₃, 4-F
632	3-CF₃CF₂
633	3-cyclopentyl
634	3-isopropoxy
635	3-SCF₃
636	3-sec-butoxy
637	3-C(CF₃)₂OH
638	3-(2-furyl)
639	3-(3-furyl)
640	3-isobutyl
641	3-isobutoxy
642	3-ethoxy
643	3-OCH₂CF₃
644	3-propoxy
645	3-tert-butoxy
646	3-(2-thienyl)
647	3-cyclopropyl
648	4-F, 3-(2-furyl)
649	3-(3-CF₃-phenoxy)
650	3,4-(OCF₂CF₂O)
651	3-OCF₂CF₃
652	3-cyclopentoxy
653	3-(cyclopropyl)methoxy
654	3-OCH₂CH(OH)CF₃
655	3-CF₃
656	4-CF₃
657	3-CH₂CF₂CF₃
658	3-CH₂CF₃
659	3-CH(CF₃)₂
660	3-CF₂CF₂CF₃
661	3-phenoxy
662	3-phenyl
663	3-(tetrahydro-2-furyl)
664	isoamyl

665	3-OCF₃
666	3-OCF₂CF₂H
667	2-F, 5-CF₃
668	2-F, 4-CF₃
669	3-CF₃, 4-F
670	3-CF₃CF₂
671	3-cyclopentyl
672	3-isopropoxy
673	3-SCF₃
674	3-sec-butoxy
675	3-C(CF₃)₂OH
676	3-(2-furyl)
677	3-(3-furyl)
678	3-isobutyl
679	3-isobutoxy
680	3-ethoxy
681	3-OCH₂CF₃
682	3-propoxy
683	3-tert-butoxy
684	3-(2-thienyl)
685	3-cyclopropyl
686	4-F, 3-(2-furyl)
687	3-(3-CF₃-phenoxy)
688	3,4-(OCF₂CF₂O)
689	3-OCF₂CF₃
690	3-cyclopentoxy
691	3-(cyclopropyl)methoxy
692	3-OCH₂CH(OH)CF₃
693	3-CF₃
694	4-CF₃
695	3-CH₂CF₂CF₃
696	3-CH₂CF₃
697	3-CH(CF₃)₂
698	3-CF₂CF₂CF₃
699	3-phenoxy
700	3-phenyl
701	3-(tetrahydro-2-furyl)
702	isoamyl

703	3-OCF₃
704	3-OCF₂CF₂H
705	2-F, 5-CF₃
706	2-F, 4-CF₃
707	3-CF₃, 4-F
708	3-CF₃CF₂
709	3-cyclopentyl
710	3-isopropoxy
711	3-SCF₃
712	3-sec-butoxy
713	3-C(CF₃)₂OH
714	3-(2-furyl)
715	3-(3-furyl)
716	3-isobutyl
717	3-isobutoxy
718	3-ethoxy
719	3-OCH₂CF₃
720	3-propoxy
721	3-tert-butoxy
722	3-(2-thienyl)
723	3-cyclopropyl
724	4-F, 3-(2-furyl)
725	3-(3-CF₃-phenoxy)
726	3,4-(OCF₂CF₂O)
727	3-OCF₂CF₃
728	3-cyclopentyl
729	3-(cyclopropyl)methoxy
730	3-OCH₂CH(OH)CF₃
731	3-CF₃
732	4-CF₃
733	3-CH₂CF₂CF₃
734	3-CH₂CF₃
735	3-CH(CF₃)₂
736	3-CF₂CF₂CF₃
737	3-phenoxy
738	3-phenyl
739	3-(tetrahydro-2-furyl)
740	isoamyl

741	3-OCF₃
742	3-OCF₂CF₂H
743	2-F, 5-CF₃
744	2-F, 4-CF₃
745	3-CF₃, 4-F
746	3-CF₃CF₂
747	3-cyclopentyl
748	30isopropoxy
749	3-SCF₃
750	3-sec-butoxy
751	3-C(CF₃)₂OH
752	3-(2-furyl)
753	3-(3-furyl)
754	3-isobutyl
755	3-isobutoxy
756	3-ethoxy
757	3-OCH₂CF₃
758	3-propoxy
759	3-tert-butoxy
760	3-(2-thienyl)
761	3-cyclopropyl
762	4-F, 3-(2-furyl)
763	3-(3-CF₃-phenoxy)
764	3,4-(OCF₂CF₂O)
765	3-OCF₂CF₃
766	3-cyclopentyl
767	3-(cyclopropyl)methoxy
768	3-OCH₂CH(OH)CF₃
769	3-CF₃
770	4-CF₃
771	3-CH₂CF₂CF₃
772	3-CH₂CF₃
773	3-CH(CF₃)₂
774	3-CF₂CF₂CF₃
775	3-phenoxy
776	3-phenyl
777	3-(tetrahydro-2-furyl)
778	isoamyl

779	3-OCF₃
780	3-OCF₂CF₂H
781	2-F, 5-CF₃
782	2-F, 4-CF₃
783	3-CF₃, 4-F
784	3-CF₃CF₂
785	3-cyclopentyl
786	3-isopropoxy
787	3-SCF₃
788	3-sec-butoxy
789	3-C(CF₃)₂OH
790	3-(2-furyl)
791	3-(3-furyl)
792	3-isobutyl
793	3-isobutoxy
794	3-ethoxy
795	3-OCH₂CF₃
796	3-propoxy
797	3-tert-butoxy
798	3-(2-thienyl)
799	3-cyclopropyl
800	4-F, 3-(2-furyl)
801	3-(3-CF₃-phenoxy)
802	3,4-(OCF₂CF₂O)
803	3-OCF₂CF₃
804	3-cyclopentyl
805	3-(cyclopropyl)methoxy
806	3-OCH₂CH(OH)CF₃
807	3-CF₃
808	4-CF₃
809	3-CH₂CF₂CF₃
810	3-CH₂CF₃
811	3-CH(CF₃)₂
812	3-CF₂CF₂CF₃
813	3-phenoxy
814	3-phenyl
815	3-(tetrahydro-2-furyl)
816	isoamyl

817	OCF₃
818	OCF₂CF₂H
819	OCF₂CF₃
820	CH₂CF₃
821	CF₃
822	CF₃CF₂
823	cyclopentyl
824	isopropoxy
825	SCF₃
826	sec-butoxy
827	C(CF₃)₂OH
828	(2-furyl)
829	(3-furyl)
830	isobutyl
831	isobutoxy
832	ethoxy
833	OCH₂CF₃
834	(2-thienyl)
835	cyclopropyl
836	(3-CF₃-phenoxy)
837	cyclopentoxy
838	(cyclopropyl)methoxy
839	OCH₂CH(OH)CF₃
840	CH₂CF₂CF₃
841	CH(CF₃)₂
842	CH(CF₃)₂
843	CF₂CF₂CF₃
844	phenoxy
845	phenyl
846	(tetrahydro-2-furyl)
847	isoamyl
848	propoxy
849	tert-butoxy
850	(2-pyridyl)

852	OCF₃
852	OCF₂CF₂H
853	OCF₂CF₃
854	CH₂CF₃
855	CF₃
856	CF₃CF₂
857	cyclopentyl
858	isopropoxy
859	SCF₃
860	sec-butoxy
861	C(CF₃)₂OH
862	(2-furyl)
863	(3-furyl)
864	isobutyl
865	isobutoxy
866	ethoxy
867	OCH₂CF₃
868	(2-thienyl)
869	cyclopropyl
870	(3-CF₃-phenoxy)
871	cyclopentoxy
872	(cyclopropyl)methoxy
873	OCH₂CH(OH)CF₃
874	CH₂CF₂CF₃
875	CH(CF₃)₂
876	CH(CF₃)₂
877	CF₂CF₂CF₃
878	phenoxy
879	phenyl
880	(tetrahydro-2-furyl)
881	isoamyl
882	propoxy
883	tert-butoxy
884	(2-pyridyl)

Example Table 6. 3-[(N-aryl)[[cycloalkyl]methyl]amino]-halo-2-propanols.

Ex.		Ex.
No.	R_SUB1	No.	R_SUB2

885	3-isopropyl	909	3-CF₃O-benzyloxy
886	2-Cl, 3-Cl	910	3-CF₃O-benzyloxy
887	3-CF₃O	911	3-F, 5-F-benzyloxy
888	4-F	912	cyclohexylmethylebeoxy
889	4-CH₃	913	benzyloxy
890	2-F, 5-Br	914	3-CF₃, 5-CF₃-benzyloxy
891	4-Cl, 3-CH₃CH₂	915	4-CF₃O-benzyloxy
892	3-CH₃CH₂	916	4-CH₃CH₂-benzyloxy
893	3-CH₃, 5-CH₃	917	isopropoxy
894	3-(CH₃)₃C	918	3-CF₃-benzyl
895	4-F, 3-CH₃	919	isopropylthio
896	3-Cl, 4-Cl	920	cyclopentoxy
897	3,4-(CH₂)₄	921	3-Cl-5-pyridinyloxy
898	3-HCF₂CF₂O	922	3-CF₃S-benzyloxy
899	3-CHF₂O	923	3-CH₃, 4-CH₃-benzyloxy
900	3-(CH₃)₂N	924	2-F, 3-CF₃-benzyloxy
901	3-cyclopropyl	925	3-F, 5-CF₃-benzyloxy
902	3-(2-furyl)	926	4-(CH₃)₂CH-benzyloxy
903	3-CF₃CF₂	927	1-phenylethoxy
904	4-NH₂	928	4-F, 3-CH₃-benzoyl
905	3-CH₃, 4-CH₃, 5-CH₃	929	3-CF₃-phenyl
906	4-CH₃CH₂CH₂O	930	4-CH₃O-phenylamino
907	3-CF₃	931	cyclopropoxy
908	2-NO₂	932	4-NO₂-phenylthio

933	3-isopropyl	957	3-CF₃O-benzyloxy
934	2-Cl, 3-Cl	958	3-CF₃-benzyloxy
935	3-CF₃O	959	3-F, 5-F-benzyloxy
936	4-F	960	cyclohexylmethyleneoxy
937	4-CH₃	961	benzyloxy
938	2-F, 5-Br	962	3-CF₃, 5-CF₃-benzyloxy
939	4-Cl, 3-CH₃CH₂	963	4-CF₃O-benzyloxy
940	3-CH₃CH₂	964	4-CH₃CH₂-benzyloxy
941	3-CH₃, 5-CH₃	965	isopropoxy
942	3-(CH₃)₃C	966	3-CF₃-benzyl
943	4-F, 3-CH₃	967	isopropylthio
944	3-Cl, 4-Cl	968	cyclopentoxy
945	3,4-(CH₂)₄	969	3-Cl-5-pyridinyloxy
946	3-HCF₂CF₂O	970	3-CF₃S-benzyloxy
947	3-CHF₂O	971	3-CH₃, 4-CH₃-benzyloxy
948	3-(CH₃)₂N	972	2-F, 3-CF₃-benzyloxy
949	3-cyclopropyl	973	3-F, 5-CF₃-benzyloxy
950	3-(2-furyl)	974	4-(CH₃)₂CH-benzyloxy
951	3-CF₃CF₂	975	1-phenylethoxy
952	4-NH₂	976	4-F, 3-CH₃-benzoyl
953	3-CH₃, 4-CH₃, 5-CH₃	977	3-CF₃-phenyl
954	4-CH₃CH₂CH₂O	978	4-CH₃O-phenylamino
955	3-CF₃	979	cyclopropoxy
956	2-NO₂	980	4-NO₂-phenylthio

981	3-isopropyl	1005	3-CF₃O-benzyloxy
982	2-Cl, 3-Cl	1006	3-CF₃-benzyloxy
983	3-CF₃O	1007	3-F, 5-F-benzyloxy
984	4-F	1008	cyclohexylmethyleneoxy
985	4-CH₃	1009	benzyloxy
986	2-F, 5-Br	1010	3-CF₃, 5-CF₃-benzyloxy
987	4-F, 3-CF₃	1011	4-CF₃O-benzyloxy
988	3-CH₃CH₂	1012	4-CH₃CH₂-benzyloxy
989	3-CH₃, 5-CH₃	1013	isopropoxy
990	3-(CH₃)₃C	1014	3-CF₃-benzyl
991	4-F, 3-CH₃	1015	isopropylthio
992	3-Cl, 4-Cl	1016	cyclopentoxy
993	3,4-(CH₂)₄	1017	3-Cl-5-pyridinyloxy
994	3-HCF₂CF₂O	1018	3-CF₃S-benzyoxy
995	3-CHF₂O	1019	3-CH₃, 4-CH₃-
			benzyloxy
996	3-(CH₃)₂N	1020	2-F, 3-CF₃-benzyloxy
997	3-cyclopropyl	1021	3-F, 5-CF₃-benzyloxy
998	3-(2-furyl)	1022	4-(CH₃)₂CH-benzyloxy
999	3-CF₃CF₂	1023	1-phenylethoxy
1000	4-NH₂	1024	4-F, 3-CH₃-benzoyl
1001	3-CH₃, 4-CH₃, 5-CH₃	1025	3-CF₃-phenyl
1002	4-CH₃CH₂CH₂O	1026	4-CH₃O-phenylamino
1003	3-CF₃	1027	cyclopropoxy
1004	2-NO₂	1028	4-NO₂-phenylthio

1029	3-isopropyl	1053	3-CF₃O-benzyloxy
1030	2-Cl, 3-Cl	1054	3-CF₃-benzyloxy
1031	3-CF₃O	1055	3-F, 5-F-benzyloxy
1032	4-F	1056	cyclohexylmethyleneoxy
1033	4-CH₃	1057	benzyloxy
1034	2-F, 5-Br	1058	3-CF₃, 5-CF₃-benzyloxy
1035	4-Cl, 3-CH₃CH₂	1059	4-CF₃O-benzyloxy
1036	3-CH₃CH₂	1060	4-CH₃CH₂-benzyloxy
1037	3-CH₃, 5-CH₃	1061	isopropoxy
1038	3-(CH₃)₃C	1062	3-CF₃-benzyl
1039	4-F, 3-CH₃	1063	isopropylthio
1040	3-Cl, 4-Cl	1064	cyclopentoxy
1041	3,4-(CH₂)₄	1065	3-Cl-5-pyridinyloxy
1042	3-HCF₂CF₂O	1066	3-CF₃S-benzyloxy
1043	3-CHF₂O	1067	3-CH₃, 4-CH₃-benzyloxy
1044	3-(CH₃)₂N	1068	2-F, 3-CF₃-benzyloxy
1045	3-cyclopropyl	1069	3-F, 5-CF₃-benzyloxy
1046	3-(2-furyl)	1070	4-(CH₃)₂CH-benzyloxy
1047	3-CF₃CF₂	1071	1-phenylethoxy
1048	4-NH₂	1072	4-F, 3-CH₃-benzoyl
1049	3-CH₃, 4-CH₃, 5-CH₃	1073	3-CF₃-phenyl
1050	4-CH₃CH₂CH₂O	1074	4-CH₃OO-phenylamino
1051	3-CF₃	1075	cyclopropoxy
1052	2-NO₂	1076	4-NO₂-phenylthio

1077	3-isopropyl	1101	3-CF₃O-benzyloxy
1078	2-Cl, 3-Cl	1102	3-CF₃-benzyloxy
1079	3-CF₃O	1103	3-F, 5-F-benzyloxy
1080	4-F	1104	cyclohexylmethyleneoxy
1081	4-CH₃	1105	benzyloxy
1082	2-F, 5-Br	1106	3-CF₃, 5-CF₃-benzyloxy
1083	4-Cl, 3-CH₃CH₂	1107	4-CF₃O-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-Cl, 4-Cl	1112	cyclopentoxy
1089	3,4-(CH₂)₄	1113	3-Cl-5-pyridinyloxy
1090	3-HCF₂CF₂O	1114	3-CF₃S-benzyloxy
1091	3-CHF₂O	1115	3-CH₃, 4-CH₃-benzyloxy
1092	3-(CH₃)₂N	1116	2-F, 3-CF₃-benzyloxy
1093	3-cyclopropyl	1117	3-F, 5-CF₃-benzyloxy
1094	3-(2-furyl)	1118	4-(CH₃)₂CH-benzyloxy
1095	3-CF₃CF₂	1119	1-phenylethoxy
1096	4-NH₂	1120	4-F, 3-CH₃-benzoyl
1097	3-CH₃, 4-CH₃, 5-CH₃	1121	3-CF₃-phenyl
1098	4-CH₃CH₂CH₂O	1122	4-CH₃O-phenylamino
1099	3-CF₃	1123	cyclopropoxy
1100	2-NO₂	1124	4-NO₂-phenylthio

1125	3-isopropyl	1149	3-CF₃O-benzyloxy
1126	2-Cl, 3-Cl	1150	3-CF₃-benzyloxy
1127	3-CF₃O	1151	3-F, 5-F-benzyloxy
1128	4-F	1152	cyclohexylmethyleneoxy
1129	4-CH₃	1153	benzyloxy
1130	2-F, 5-Br	1154	3-CF₃, 5-CF₃-benzyloxy
1131	4-Cl, 3-CH₃CH₂	1155	4-CF₃O-benzyloxy
1132	3-CH₃CH₂	1156	4-CH₃CH₂-benzyloxy
1133	3-CH₃, 5-CH₃	1157	isopropoxy
1134	3-(CH₃)₃C	1158	3-CF₃-benzyl
1135	4-F, 3-CH₃	1159	isopropylthio
1136	3-Cl, 4-Cl	1160	cyclopentoxy
1137	3,4-(CH₂)₄	1161	3-Cl-5-pyridinyloxy
1138	3-HCF₂CF₂O	1162	3-CF₃S-benzyloxy
1139	3-CHF₂O	1163	3-CH₃, 4-CH₃-benzyloxy
1140	3-(CH₃)₂N	1164	2-F, 3-CF₂-benzyloxy
1141	3-cyclopropyl	1165	3-F, 5-CF₃-benzyloxy
1142	3-(2-furyl)	1166	4-(CH₃)₂CH-benzyloxy
1143	3-CF₃CF₂	1167	1-phenylethoxy
1144	4-NH₂	1168	4-F, 3-CH₃-benzoyl
1145	3-CH₃, 4-CH₃, 5-CH₃	1169	3-CF₃-phenyl
1146	4-CH₃CH₂CH₂O	1170	4-CH₃O-phenylamino
1147	3-CF₃	1171	cyclopropoxy
1148	2-NO₂	1172	4-NO₂-phenylthio

1173	3-isopropyl	1197	3-CF₃O-benzyloxy
1174	2-Cl, 3-Cl	1198	3-CF₃-benzyloxy
1175	3-CF₃O	1199	3-F, 5-F-benzyloxy
1176	4-F	1200	cyclohexylmethyleneoxy
1177	4-CH₃	1201	benzyloxy
1178	2-F, 5-Br	1202	3-CF₃, 5-CF₃-benzyloxy
1179	4-Cl, 3-CH₃CH₂	1203	4-CF₃O-benzyloxy
1180	3-CH₃CH₂	1204	4-CH₃CH₂-benzyloxy
1181	3-CH₃, 5-CH₃	1205	isopropoxy
1182	3-(CH₃)₃C	1206	3-CF₃-benzyl
1183	4-F, 3-CH₃	1207	isopropylthio
1184	3-Cl, 4-Cl	1208	cyclopentoxy
1185	3,4-(CH₂)₄	1209	3-Cl-5-pyridinyloxy
1186	3-HCF₂CF₂O	1210	3-CF₃S-benzyloxy
1187	3-CHF₂O	1211	3-CH₃, 4-CH₃-benzyloxy
1188	3-(CH₃)₂N	1212	2-F, 3-CF₃-benzyloxy
1189	3-cyclopropyl	1213	3-F, 5-CF₃-benzyloxy
1190	3-(2-furyl)	1214	4-(CH₃)₂CH-benzyloxy
1191	3-CF₃CF₂	1215	1-phenylethoxy
1192	4-NH₂	1216	4-F, 3-CH₃-benzoyl
1193	3-CH₃, 4-CH₂, 5-CH₃	1217	3-CF₃-phenyl
1194	4-CH₃CH₂CH₂O	1218	4-CH₃O-phenylamino
1195	3-CF₃	1219	cyclopropxy
1196	2-NO₂	1220	4-NO₂-phenylthio

1221	3-isopropyl	1245	3-CF₃O-benzyloxy
1222	2-Cl, 3-Cl	1246	3-CF₃-benzyloxy
1223	3-CF₃O	1247	3-F, 5-F-benzyloxy
1224	4-F	1248	cyclohexylmethyleneoxy
1225	4-CH₃	1249	benzyloxy
1226	2-F, 5-Br	1250	3-CF₃, 5-CF₃-benzyloxy
1227	4-Cl, 3-CH₃CH₂	1251	4-CF₃O-benzyloxy
1228	3-CH₃CH₂	1252	4-CH₃CH₂-benzyloxy
1229	3-CH₃, 5-CH₃	1253	isopropoxy
1230	3-(CH₃)₃C	1254	3-CF₃-benzyl
1231	4-F, 3-CH₃	1255	isopropylthio
1232	3-Cl, 4-Cl	1256	cyclopentoxy
1233	3,4-(CH₂)₄	1257	3-Cl-5-pyridinyloxy
1234	3-HCF₂CF₂O	1258	3-CF₃S-benzyloxy
1235	3-CHF₂O	1259	3-CH₃, 4-CH₃-benzyloxy
1236	3-(CH₃)₂N	1260	2-F, 3-CF₃-benzyloxy
1237	3-cyclopropyl	1261	3-F, 5-CF₃-benzyloxy
1238	3-(2-furyl)	1262	4-(CH₃)₂CH-benzyloxy
1239	3-CF₃CF₂	1263	1-phenylethoxy
1240	4-NH₂	1264	4-F, 3-CH₃-benzoyl
1241	3-CH₃, 4-CH₃, 5-CH₃	1265	3-CF₃-phenyl
1242	4-CH₃CH₂CH₂O	1266	4-CH₃O-phenylamino
1243	3-CF₃	1267	cyclopropoxy
1244	2-NO₂	1268	4-NO₂-phenylthio

1269	3-isopropyl	1293	3-CF₃O-benzyloxy
1270	2-Cl, 3-Cl	1294	3-CF₃-benzyloxy
1271	3-CF₃O	1295	3-F, 5-F-benzyloxy
1272	4-F	1296	cyclohexylmethyleneoxy
1273	4-CH₃	1297	benzyloxy
1274	2-F, 5-Br	1298	3-CF₃, 5-CF₃-benzyloxy
1275	4-Cl, 3-CH₃CH₂	1299	4-CF₃O-benzyloxy
1276	3-CH₃CH₂	1300	4-CH₃CH₂-benzyloxy
1277	3-CH₃, 5-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-5-pyridinyloxy
1282	3-HCF₂CF₂O	1306	3-CF₃S-benzyloxy
1283	3-CHF₂O	1307	3-CH₃, 4-CH₃-benzyloxy
1284	3-(CH₃)₂N	1308	2-F, 3-CF₃-benzyloxy
1285	3-cyclopropyl	1309	3-F, 5-CF₃-benzyloxy
1286	3-(2-furyl)	1310	4-(CH₃)₂CH-benzyloxy
1287	3-CF₃CF₂	1311	1-phenylethoxy
1288	4-NH₂	1312	4-F, 3-CH₃-benzoyl
1289	3-CH₃, 4-CH₃, 5-CH₃	1313	3-CF₃-phenyl
1290	4-CH₃CH₂CH₂O	1314	4-CH₃O-phenylamino
1291	3-CF₃	1315	cyclopropoxy
1292	2-NO₂	1316	4-NO₂-phenylthio

1317	3-isopropyl	1341	3-CF₃O-benzyloxy
1318	2-Cl, 3-Cl	1342	3-CF₃-benzyloxy
1319	3-CF₃O	1343	3-F, 5-F-benzyloxy
1320	4-F	1344	cyclohexylmethyleneoxy
1321	4-CH₃	1345	benzyloxy
1322	2-F, 5-Br	1346	3-CF₃, 5-CF₃-benzyloxy
1323	4-Cl, 3-CH₃CH₂	1347	3-CF₃, 5-CF₃-benzyloxy
1324	3-CH₃CH₂	1348	4-CH₃CH₂-benzyloxy
1325	3-CH₃, 5-CH₃	1349	siopropoxy
1326	3-(CH₃)₃C	1350	3-CF₃-benzyl
1327	4-F, 3-CH₃	1351	isopropylthio
1328	3-Cl, 4-Cl	1352	cyclopentoxy
1329	3,4-(CH₂)₄	1353	3-Cl-5-pyridinyloxy
1330	3-HCF₂CF₂O	1354	3-CF₃S-benzyloxy
1331	3-CHF₂O	1355	3-CH₃, 4-CH₃-benzyloxy
1332	3-(CH₃)₂N	1356	2-F, 3-CF₃-benzyloxy
1333	3-cyclopropyl	1357	3-F, 5-CF₃-benzyloxy
1334	3-(2-furyl)	1358	4-(CH₃)₂CH-benzyloxy
1335	3-CF₃CF₂	1359	1-phenylethoxy
1336	4-NH₂	1360	4-F, 3-CH₃-benzoyl
1337	3-CH₃, 4-CH₃, 5-CH₃	1361	3-CF₃-phenyl
1338	4-CH₃CH₂CH₂O	1362	4-CH₃O-phenylamino
1339	3-CF₃	1363	cyclopropoxy
1340	2-NO₂	1364	4-NO₂-phenylthio

1365	3-isopropyl	1389	3-CF₃O-benzyloxy
1366	2-Cl, 3-Cl	1390	3-CF₃-benzyloxy
1367	3-CF₃O	1391	3-F, 5-F-benzyloxy
1368	4-F	1392	cyclohexylmethyleneoxy
1369	4-CH₃	1393	benzyloxy
1370	2-F, 5-Br	1394	3-CF₃, 5-CF₃-benzyloxy
1371	4-Cl, 3-CH₃CH₂	1395	4-CF₃O-benzyloxy
1372	3-CH₃CH₂	1396	4-CH₃CH₂-benzyloxy
1373	3-CH₃, 5-CH₃	1397	isopropoxy
1374	3-(CH₃)₃C	1398	3-CF₃-benzyl
1375	4-F, 3-CH₃	1399	isopropylthio
1376	3-Cl, 4-Cl	1400	cyclopentoxy
1377	3,4-(CH₂)₄	1401	3-Cl-5-pyridinyloxy
1378	3-HCF₂CF₂O	1402	3-CF₃S-benzyloxy
1379	3-CHF₂O	1403	3-CH₃, 4-CH₃-benzyloxy
1380	3-(CH₃)₂N	1404	2-F, 3-CF₃-benzyloxy
1381	3-cyclopropyl	1405	3-F, 5-CF₃-benzyloxy
1382	3-(2-furyl)	1406	4-(CH₃)₂CH-benzyloxy
1383	3-CF₃CF₂	1407	1-phenylethoxy
1384	4-NH₂	1408	4-F, 3-CH₃-benzoyl
1385	3-CH₃, 4-CH₃, 5-CH₃	1409	3-CF₃-phenyl
1386	4-CH₃CH₂CH₂O	1410	4-CH₃O-phenylamino
1387	3-CF₃	1411	cyclopropoxy
1388	2-NO₂	1412	4-NO₂-phenylthio

1413	3-isopropyl	1437	3-CF₃O-benzyloxy
1414	2-Cl, 3-Cl	1438	3-CF₃-benzyloxy
1415	3-CF₃O	1439	3-F, 5-F-benzyloxy
1416	4-F	1440	cyclohexylmethyleneoxy
1417	4-CH₃	1441	benzyloxy
1418	2-F, 5-Br	1442	3-CF₃, 5-CF₃-benzyloxy
1419	4-Cl, 3-CH₃CH₂	1443	4-CF₃O-benzyloxy
1420	3-CH₃CH₂	1444	4-CH₃CH₂-benzyloxy
1421	3-CH₃, 5-CH₃	1445	isopropoxy
1422	3-(CH₃)₃C	1446	3-CF₃-benzyl
1423	4-F, 3-CH₃	1447	isopropylthio
1424	3-Cl, 4-Cl	1448	cyclopentoxy
1425	3,4-(CH₂)₄	1449	3-Cl-5-pyridinyloxy
1426	3-HCF₂CF₂O	1450	3-CF₃S-benzyloxy
1427	3-CHF₂O	1451	3-CH₃, 4-CH₃-benzyloxy
1428	3-(CH₃)₂N	1452	2-F, 3-CF₃-benzyloxy
1429	3-cyclopropyl	1453	3-F, 5-CF₃-benzyloxy
1430	3-(2-furyl)	1454	4-(CH₃)₂CH-benzyloxy
1431	3-CF₃CF₂	1455	1-phenylethoxy
1432	4-NH₂	1456	4-F, 3-CH₃-benzoyl
1433	3-CH₃, 4-CH₃, 5-CH₃	1457	3-CF₃-phenyl
1434	4-CH₃CH₂CH₂O	1458	4-CH₃O-phenylamino
1435	3-CF₃	1459	cyclopropoxy
1436	2-NO₂	1460	4-NO₂phenylthio

Example Table 7. 3-[(N-aryl)[[haloalkyl]methyl]amino]-halo-2-propanols.

Ex.		Ex.
No.	R_SUB1	No.	R_SUB2

1461	3-isopropyl	1485	3-CF₃O-benzyloxy
1462	2-Cl, 3-Cl	1486	3-CF₃-benzyloxy
1463	3-CF₃O	1487	3-F, 5-F-benzyloxy
1464	4-F	1488	cyclohexylmethyleneoxy
1465	4-CH₃	1489	benzyloxy
1466	2-F, 5-Br	1490	3-CF₃, 5-CF₃-benzyloxy
1467	4-Cl, 3-CH₃CH₂	1491	4-CF₃O-benzyloxy
1468	3-CH₃CH₂	1492	4-CH₃CH₂-benzyloxy
1469	3-CH₃, 5-CH₃	1493	isopropoxy
1470	3-(CH₃)₃C	1494	3-CF₃-benzyl
1471	4-F, 3-CH₃	1495	isopropylthio
1472	3-Cl, 4-Cl	1496	cyclopentoxy
1473	3,4-(CH₂)₄	1497	3-Cl-5-pyridinyloxy
1474	3-HCF₂CF₂O	1498	3-CF₃S-benzyloxy
1475	3-CHF₂O	1499	3-CH₃, 4-CH₃-benzyloxy
1476	3-(CH₃)₂N	1500	2-F, 3-CF₃-benzyloxy
1477	3-cyclopropyl	1501	3-F, 5-CF₃-benzyloxy
1478	3-(2-furyl)	1502	4-(CH₃)₂CH-benzyloxy
1479	3-CF₃CF₂	1503	1-phenylethoxy
1480	4-NH₂	1504	4-F, 3-CH₃-benzoyl
1481	3-CH₃, 4-CH₃, 5-CH₃	1505	3-CF₃-phenyl
1482	4-CH₃CH₂CH₂O	1506	4-CH₃O-phenylamino
1483	3-CF₃	1507	cyclopropoxy
1484	2-NO₂	1508	4-NO₂-phenylthio

1509	3-isopropyl	1533	3-CF₃O-benzyloxy
1510	2-Cl, 3-Cl	1534	3-CF₃-benzyloxy
1511	3-CF₃O	1535	3-F, 5-F-benzyloxy
1512	4-F	1536	cyclohexylmethyleneoxy
1513	4-CH₃	1537	benzyloxy
1514	2-F, 5-Br	1538	3-CF₃, 5-CF₃-benzyloxy
1515	4-Cl, 3-CH₃CH₂	1539	4-CF₃O-benzyloxy
1516	3-CH₃CH₂	1540	4-CH₃CH₂-benzyloxy
1517	3-CH₃, 5-CH₃	1541	isopropoxy
1518	3-(CH₃)₃C	1542	3-CF₃-benzyl
1519	4-F, 3-CH₃	1543	isopropylthio
1520	3-Cl, 4-Cl	1544	cyclopentoxy
1521	3,4-(CH₂)₄	1545	3-Cl-5-pyridinyloxy
1522	3-HCF₂CF₂O	1546	3-CF₃S-benzyloxy
1523	3-CHF₂O	1547	3-CH₃, 4-CH₃-benzyloxy
1524	3-(CH₃)₂N	1548	2-F, 3-CF₃-benzyloxy
1525	3-cyclopropyl	1549	3-F, 5-CF₃-benzyloxy
1526	3-(2-furyl)	1550	4-(CH₃)₂CH-benzyloxy
1527	3-CF₃CF₂	1551	1-phenylethoxy
1528	4-NH₂	1552	4-F, 3-CH₃-benzoyl
1529	3-CH₃, 4-CH₃, 5-CH₃	1553	3-CF₃-phenyl
1530	4-CH₃CH₂CH₂O	1554	4-CH₃O-phenylamino
1531	3-CF₂	1555	cyclopropoxy
1532	2-NO₂	1556	4-NO₂-phenylthio

1557	3-isopropyl	1581	3-CF₃O-benzyloxy
1558	2-Cl, 3-Cl	1582	3-CF₃-benzyloxy
1559	3-CF₃O	1583	3-F, 5-F-benzyloxy
1560	4-F	1584	cyclohexylmethyleneoxy
1561	4-CH₃	1585	benzyloxy
1562	2-F, 5-Br	1586	3-CF₃, 5-CF₃-benzyloxy
1563	4-Cl, 3-CH₃CH₂	1587	4-CF₃O-benzyloxy
1564	3-CH₃CH₂	1588	4-CH₃CH₂-benzyloxy
1565	3-CH₃, 5-CH₃	1589	isopropoxy
1566	3-(CH₃)₃C	1590	3-CF₃-benzyl
1567	4-F, 3-CH₃	1591	isopropylthio
1568	3-Cl, 4-Cl	1592	cyclopentoxy
1569	3,4-(CH₂)₄	1593	3-Cl-5-pyridinyloxy
1570	3-HCF₂CF₂O	1594	3-CF₃S-benzyloxy
1571	3-CHF₂O	1595	3-CH₃, 4-CH₃-benzyloxy
1572	3-(CH₃)₂N	1596	2-F, 3-CF₃-benzyloxy
1573	3-cyclopropyl	1597	3-F, 5-CF₃-benzyloxy
1574	3-(2-furyl)	1598	4-(CH₃)₂CH-benzyloxy
1575	3-CF₃CF₂	1599	1-phenylethoxy
1576	4-NH₂	1600	4-F, 3-CH₃-benzoyl
1577	3-CH₃, 4-CH₃, 5-CH₃	1601	3-CF₃-phenyl
1578	4-CH₃CH₂CH₂O	1602	4-CH₃O-phenylamino
1579	3-CF₃	1603	cyclopropoxy
1580	2-NO₂	1604	4-NO₂-phenylthio

1605	3-isopropyl	1629	3-CF₃O-benzyloxy
1606	2-Cl, 3-Cl	1630	3-CF₃-benzyloxy
1607	3-CF₃O	1631	3-F, 5-F-benzyloxy
1608	4-F	1632	cyclohexylmethyleneoxy
1609	4-CH₃	1633	benzyloxy
1610	2-F, 5-Br	1634	3-CF₃, 5-CF₃-benzyloxy
1611	4-Cl, 3-CH₃CH₂	1635	4-CF₃O-benzyloxy
1612	3-CH₃CH₂	1636	4-CH₃CH₂-benzyloxy
1613	3-CH₃, 5-CH₃	1637	isopropoxy
1614	3-(CH₃)₃C	1638	3-CF₃-benzyl
1615	4-F, 3-CH₃	1639	isopropylthio
1616	3-Cl, 4-Cl	1640	cyclopentoxy
1617	3,4-(CH₂)₄	1641	3-Cl-5-pyridinyloxy
1618	3-HCF₂CF₂O	1642	3-CF₃S-benzyloxy
1619	3-CHF₂O	1643	3-CH₃, 4-CH₃-benzyloxy
1620	3-(CH₃)₂N	1644	2-F, 3-CF₃-benzyloxy
1621	3-cyclopropyl	1645	3-F, 5-CF₃benzyloxy
1622	3-(2-furyl)	1646	4-(CH₃)₂CH-benzyloxy
1623	3-CF₃CF₂	1647	1-phenylethoxy
1624	4-NH₂	1648	4-F, 3-CH₃-benzoyl
1625	3-CH₃, 4-CH₃, 5-CH₃	1649	3-CF₃-phenyl
1626	4-CH₃CH₂CH₂O	1650	4-CH₃O-phenylamino
1627	3-CF₃	1651	cyclopropyl
1628	2-NO₂	1652	4-NO₂-phenylthio

BIOASSAYS

CETP Activity In Vitro [0332]
ASSAY OF CETP INHIBITION USING PURIFIED COMPONENTS (RECONSTITUTED BUFFER ASSAY) [0333]
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 ([[0334] 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 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); 1% bovine serum albumin) were incubated in a final volume of 200 μL, for 2 hours at 37° C. in 96 well plates. Inhibitors were included in the assay by diluting from a 10 mM DMSO stock solution into 16% (v/v) aqueous DMSO so that the final concentration of inhibitor was 800 μM. The inhibitors were then diluted 1:1 with CETP in assay buffer, and then 25 μL of that solution was mixed with 175 μL of lipoprotein pool for assay. Following incubation, LDL was differentially precipitated by the addition of 50 μL of 1% (w/v) dextran sulfate/0.5M magnesium chloride, mixed by vortex, and incubated at room temperature for 10 minutes. A potion of the solution (200 μL) 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 [[0335] ³H]CE from HDL to LDL. This value was defined as the IC₅₀. The IC₅₀values determined from this assay are accurate when the IC₅₀is greater than 10 nM. In the case where compounds have greater inhibitory potency, accurate measurements of IC₅₀may be determined using longer incubation times (up to 18 hours) and lower final concentrations of CETP (<50 nM).
Examples of IC[0336] ₅₀values determined by these methods are summarized in Table 3.

Table 3. Inhibition of CETP Activity by Examples in Reconstituted Buffer Assay.



	Ex.	IC₅₀
	No.	(μM)

	18	11
	1	15
	16	15
	9	18
	4	20
	11	45
	8	45
	10	50
	14	55
	12	60
	17	60
	13	80
	7	100
	2	100
	6	>100.0
	5	>100.0
	15	>100.0
	3	not tested

Claims

What we claim is:

1. A compound having the formula:

or a pharmaceutically-acceptable salt thereof, wherein;

n is an integer selected from 1 through 4;

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 R₃₆is aryl or heteroaryl;

u and w are integers independently selected from 0 through 6;

A₁is C(R₃₀);

D₁, D₂, J₁, J₂and K₁are 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, J₂and K₁is a covalent bond, no more than one of D₁, D₂, J₁, J₂and K₁is O, no more than one of D₁, D₂, J₁, J₂and K, is S, one of D₁, D₂, J₁, J₂and K₁must be a covalent bond when two of D₁, D₂, J₁, J₂and K₁are O and S, and no more than four of D₁, D₂, J₁, J₂and K₁are N;

B₁, B₂, D₃, D₄, J₃, J₄and K₂are 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, 13, 14 and K₂are a covalent bond, no more than two of B₁, B₂, D₃, D₄, J₃, J₄and K₂are O, no more than two of B₁, B₂, D₃, D₄, J₃, J₄and K₂are S, no more than two of B₁, B₂, D₃, D₄, J₃, J₄and K₂are simultaneously O and S, and no more than two of B₁, B₂, D_3,D₄, J₃, J₄and K₂are N;

B₁and D₃, D₃and J₃, J₃and K₂, K₂and J₄, J₄and D₄, and D₄and B₂are 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 can N═N unless the other spacer pairs is other than C(R₃₃)═C(R₃₅), O, N, and S:

R₁₆is 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 R₁₆wherein X is H or F;

R₁is selected from the group consisting of haloalkyl, haloalkenyl, haloalkoxyalkyl, and haloalkenyloxyalkyl;

R₂is selected from the group consisting of hydrido, aryl, aralkyl, alkyl, alkenyl, alkenyloxyalkyl, haloalkyl, haloalkenyl, halocycloalkyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy, halocycloalkoxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, dicyanoalkyl, and carboalkoxycyanoalkyl;

R₃is selected from the group consisting of hydrido, hydroxy, cyano, aryl, aralkyl, acyl, alkoxy, alkyl, alkenyl, alkoxyalkyl, heteroaryl, alkenyloxyalkyl, haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, monocyanoalkyl, dicyanoalkyl, carboxamide, and carboxamidoalkyl;

Y is selected from a group consisting of a covalent single bond, (C(R₁₄)₂)_qwherein q is an integer selected from 1 through 4 and (CH(R₁₄))_g—O—(CH(R₁₄))_pwherein g and p are integers independently selected from 0 through 2;

R₁₄is selected from the group consisting of hydrido, hydroxy, cyano, hydroxyalkyl, acyl, alkoxy, alkyl, alkenyl, alkynyl, alkoxyalkyl, haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, monocarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl, carboalkoxy, carboxamide, carboxamidoalkyl;

Z is selected from the group consisting of covalent single bond, (C(R₁₅)₂)_qwherein q is an integer selected from 1 through 2, and (CH(R₁₅))_j—O—(CH(R₁₅)) wherein j and k are integers independently selected from 0 through 2;

R₁₅is selected from the group consisting of hydrido, cyano, hydroxyalkyl, acyl, alkoxy, alkyl, alkenyl, alkynyl, alkoxyalkyl, haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, monocarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl, carboalkoxy, carboxamide, and carboxamidoalkyl;

R₃₀is selected from the group consisting of hydrido, alkoxy, alkoxyalkyl, halo, haloalkyl, alkylamino, alkylthio, alkylthioalkyl, alkyl, alkenyl, haloalkoxy, and haloalkoxyalkyl with the proviso that R₃₀is 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 R₃₀to the point of bonding of a group selected from the group consisting of R₁₀, R₁₁, R₁₂, R₃₁, and R₃₂wherein 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 R₃₀to the points of bonding of each member of any one of substituent pairs selected from the group consisting of subsitituent pairs R₁₀and R₁₁, R₁₀and R₃₁, R₁₀and R₃₂, R₁₀and R₁₂, R₁₁and R₃₁, R₁₁and R₃₂, R ₁₁and R₁₂, R₃₁and R₃₂, R₃₁and R₁₂, and R₃₂and R₁₂and 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 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 R₃₆are 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, halocycloal kenyloxy, halocycioalkenyloxyalkyl, hydroxy, amino, thio, nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, arylthioalkyl, heteroaralkoxyalkyl, alkylsulfinyl, alkylsulfinylalkyl, arylsulfinylalkyl, arylsulfonylalkyl, heteroarylsulfinylalkyl, heteroarylsulfonylalkyl, alkylsulfonyl, alkylsulfonylalkyl, haloalkylsulfinylalkyl, haloalkylsulfonylalkyl, alkylsulfonaniido, 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 R₃₆are 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 R₃₃and R₃₄substituents are simultaneously selected from other than the group consisting of of hydrido and halo, and that no more than three of the R₃₅and R₃₆substituents are simultaneously selected from other than the group consisting of of hydrido and halo:

R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₃₁, and R₃₂are independently selected to be oxo with the provisos that B₁, B₂, D₃, D₄, J₃, J₄and K₂are independently selected from the group consisting of C and S, no more than two of R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₃₁, and R₃₂are simultaneously oxo, and that R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₃₁, and R₃₂are 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;

R₄and R₅, R₅and R₆, R₆and R₇, R₇and R₈, R₉and R₁₀, R₁₀and R₁₁, R₁₁and R₃₁, R₃₁and R₃₂, R₃₂and R₁₂, and R₁₂and R₁₃are 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 R₄and R₅, R₅and R₆, R₆and R₇, and R₇and R₈, are used at the same time and that no more than one of the group consisting of spacer pairs R₉and R₁₀, R₁₀and R₁₁, R₁₁and R₃₁, R₃₁and R₃₂, R₃₂and R₁₂, and R₁₂and R₁₃are used at the same time;

R₉and R₁₁, R₉and R₁₂, R₉and R₁₃, R₉and R₃₁, R₉and R₃₂, R₁₀and R₁₂, R₁₀and R₁₃, R₁₀and R₃₁, R₁₀and R₃₂, R₁₁and R₁₂, R₁₁and R₁₃, R₁₁and R₃₂, R₁₂and R₃₁, R₁₃and R₃₁, and R₁₃and R₃₂are 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 ring selected from the group consisting of a cycloalkyl having from 3 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;

R₃₇and R₃₈are 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;

u and w are integers independently selected from 0 through 6;

A₁is C(R₃₀);

D₁, D₂, J₁, J₂and K₁are 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, J₂and K₁is a covalent bond, no more than one of D₁, D₂, J₁, J₂and K₁is O, no more than one of D₁, D₂, J₁, J₂and K₁is S, one of D₁, D₂, J₁, J₂and K₁must be a covalent bond when two of D₁, D₂, J₁, J₂and K₁are O and S, and no more than four of D₁, D₂, J₁, J₂and K₁are N;

B₁, B₂, D₃, D₄, J₃, J₄and K₂are 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, J₄and K₂are a covalent bond, no more than two of B₁, B₂, D₃, D₄, J₃, J₄and K₂are O, no more than two of B₁, B₂, D₃, D₄, J₃, J₄and K₂are S, no more than two of B₁, B₂, D₃, D₄, J₃, J₄and K₂are simultaneously O and S, and no more than two of B₁, B₂, D₃, D₄, J₃, J₄and K₂are N;

B₁and D₃, D₃and J₃, J₃and K₂, K₂and J₄, J₄and D₄, and D₄and B₂are 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;

R₁is selected from the group consisting of haloalkyl and haloalkoxymethyl;

R₂is selected from the group consisting of hydrido, aryl, alkyl, alkenyl, haloalkyl, haloalkoxy, haloalkoxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, and heteroaryl;

R₃is 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)_qwherein q is an integer selected from 1 through 2, and (CH₂)_j—O—(CH₂)_kwherein j and k are integers independently selected from 0 through 1;

Z is selected from the group consisting of covalent single bond, (CH₂)_qwherein q is an integer selected from 1 through 2, and (CH₂)_j—O—(CH₂)_kwherein j and k are integers independently selected from 0 through 1:

R₄, R₈, R₉, and R₁₃are independently selected from the group consisting of hydrido, halo, haloalkyl, and alkyl;

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 R₃₀to the points of bonding of each member of any one of substituent pairs selected from the group consisting of subsitituent pairs R₁₀and R₁₁, R₁₀and R₃₁.

R₁₀and R₃₂, R₁₀and R₁₂, R₁₁and R₃₁, R₁₁and R₃₂, R₁₁and R₁₂, R₃₁and R₃₂, R₃₁and R₁₂, and R₃₂and R₁₂and 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 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 R₃₆are 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 R₃₆are 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 R₃₃and R₃₄substituents are simultaneously selected from other than the group consisting of of hydrido and halo, and that no more than three of the R₃₅and R₃₆substituents are simultaneously selected from other than the group consistubg of hydrido and halo;

R₄and R₅, R₅and R₆, R₆and R₇, R₇and R₈, R₉and R₁₀, R₁₀and R₁₁, R₁₁and R₃₁, R₃₁and R₃₂, R₃₂and R₁₂, and R₁₂and R₁₃are 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 R₄and R₅, R₅and R₆, R₆and R₇, and R₇and R₈, is used at the same time and that no more than one of the group consisting of spacer pairs R₉and R₁₀, R₁₀and R₁₁, R₁₁and R₃₁, R₃₁and R₃₂, R₃₂and R₁₂, and R₁₂and R₁₃is used at the same time;

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;

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;

v is an integer selected from 0 through 1 with the proviso that v is 1 when any one of R₃₃, R₃₄, R₃₅, and R₃₆is aryl or heteroaryl:

u and w are integers independently selected from 0 through 6;

A₁is C(R₃₀);

R₁is selected from the group consisting of haloalkyl and haloalkoxymethyl;

Z is selected from the group consisting of covalent single bond, (CH₂)_qwherein q is an integer selected from 1 through 2, and (CH₂)_j—O—(CH₂)_kwherein j and k are integers independently selected from 0 through 1;

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 R₃₀to the points of bonding of each member of any one of substituent pairs selected from the group consisting of subsitituent pairs R₁₀and R₁₁, R₁₀and R₃₁, R₁₀and R₃₂, R₁₀and R₁₂, R₁₁and R₃₁, R₁₁and R₃₂, R₁₁and R₁₂, R₃₁and R₃₂, R₃₁and R₁₂, and R₃₂and R₁₂and 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 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 R₃₆are 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 nionoaryl 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 R₃₆are 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 R₃₃and R₃₄substituents are simultaneously selected from other than the group consisting of of hydrido and halo, and that no more than three of the R₃₅and R₃₆substituents are simultaneously selected from other than the group consistubg of hydrido and halo;

R₉and R₁₁, R₉and R₁₂, R₉and R₁₃, R₉and R₃₁, R₉and R₃₂, R₁₀and R₁₂, R₁₀and R₁₃, R₁₀and R₃₁, R₁₀and R₃₂, R₁₁and R₁₂, R₁₁and R₁₃, R₁₁and R₃₂, R₁₂and R₃₁, R₁₃and R₃₁, and R₁₃and R₃₂are 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 I through 3 contiguous atoms to form a ring selected from the group consisting of a cycloalkyl having from 3 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;

4. The compound as recited in

claim 3

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 C4C9 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 R₉or R₁₃, a ring carbon or nitrogen atom adjacent to the R₉position and two atoms from the point of attachment may be substituted with R₁₀, a ring carbon or nitrogen atom adjacent to the R₁₃position 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 R₁₀position may be substituted with R₁₁, a ring carbon or nitrogen atom three atoms from the point of attachment and adjacent to the R₁₂position may be substituted with R₃₂, and a ring carbon or nitrogen atom four atoms from the point of attachment and adjacent to the R₁₁and R₃₂positions may be substituted with R₃₁;

R₁is selected from the group consisting of haloalkyl and haloalkoxymethyl;

R₄and R₈are independently selected from the group consisting of hydrido and halo;

R₉and R₁₃are halo;

R₅, R₆, and R₇are 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;

R₄and R₅, R₅and R₆, R₆and R₇, and R₇and R₈are 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 R₄and R₅, R₅and R₆, R₆and R₇, and R₇and R₈, is used at the same time;

R₁₀, R₁₁, R₁₂, R₃₁, and R₃₂are 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;

R₃₀is selected from the group consisting of alkoxy, alkoxyalkyl, halo, haloalkyl, alkylamino, alkylthio, alkylthioalkyl, alkyl, alkenyl, haloalkoxy, and haloalkoxyalkyl.

5. The compound as recited in

claim 4

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, norbomenyl, 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-pyranyl, 2H-pyran-2-one-3-yl, 2H-pyran-2-one-4yl, 2H-pyran-2-one-5yl, 4H-pyran-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 R₉or R₁₃, a ring carbon or nitrogen atom adjacent to the R₉position and two atoms from the point of attachment may be substituted with R₁₀, a ring carbon or nitrogen atom adjacent to the R₁₃position 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 R₁₀position may be substituted with R₁₁, a ring carbon or nitrogen atom three atoms from the point of attachment and adjacent to the R₁₂position may be substituted with R₃₂, and a ring carbon or nitrogen atom four atoms from the point of attachment and adjacent to the R₁₁and R₃₂positions may be substituted with R₃₁;

R₁is selected from the group consisting of trifluoromethyl, 1,1,2,2-tetrafluoroethoxymethyl, trifluoromethoxymethyl, difluoromethyl, chlorodifluoromethyl, and pentafluoroethyl;

R₂is 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;

R₃is selected from the group consisting of hydrido, phenyl, 4-trifluoromethylphenyl, methyl, ethyl, vinyl, trifluoromethyl, trifluoromethoxymethyl, difluoromethyl, chlorodifluoromethyl, and pentafluoroethyl;

R₄and R₈are independently selected from the group consisting of hydrido and fluoro;

R₉and R₁₃are fluoro;

R₅, R₁₀and R₁₂are 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-chloro4-fluorobenzyl, 3-chloro4-fluorophenyl, 3-chloro-2-fluorobenzyloxy, 3-chlorobenzyloxy, 4-chlorobenzyloxy, 4-chloro-3-methylphenoxy, 2-chloro-4-fluorophenoxy, 4-chloro-2-fluorophenoxy, -chlorophenoxy, 3-chloro-4-ethylphenoxy, 3-chloro-4-methylphenoxy, 3-chloro-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-fluoro4-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-pentafluoroethylphenoxy, 3-(1,1,2,2-tetrafluoroethoxy)phenoxy, 3-trifluoromethylthiophenoxy, and trifluoromethylthio;

R₆, R₁₁, R₃₁, and R₃₂are independently selected from the group consisting of chloro, fluoro, hydrido, pentafluoroethyl, 1,1,2,2-tetrafluoroethoxy, trifluoromethyl, and trifluoromethoxy;

R₇is selected from the group consisting of hydrido, fluoro, and trifluoromethyl;

R₃₀is 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-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-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, 4-H-4-pyranyl, 4H-pyran-4-one-2-yl, 4-H-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 R₉or R₁₃, a ring carbon or nitrogen atom adjacent to the R₉position and two atoms from the point of attachment may be substituted with R₁₀, a ring carbon or nitrogen atom adjacent to the R₁₃position 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 R₁₀position may be substituted with R₁₁, a ring carbon or nitrogen atom three atoms from the point of attachment and adjacent to the R₁₂position may be substituted with R₃₂, and a ring carbon or nitrogen atom four atoms from the point of attachment and adjacent to the R₁₁and R₃₂positions may be substituted with R₃₁;

R₂is 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;

R₃is 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;

R₉and R₁₃are fluoro:

R₅, R₁₀and R₁₂are 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-dimethylaminopbenoxy, 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-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, 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-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 R₃₂are independently selected from the group consisting of chloro, fluoro, hydrido, pentafluoroethyl, 1,1,2,2-tetrafluoroethoxy, and trifluoromethyl;

R₃₀is 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-pentafluoropropyl, sec-butyl, 1,1,2,2-tetrafluoroethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trifluoroethyl, trifluoromethoxy, and trifluoromethyl.

7. The compound as recited in

claim 6

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 R₉or R₁₃, a ring carbon or nitrogen atom adjacent to the R₉position and two atoms from the point of attachment may be substituted with R₁₀, a ring carbon or nitrogen atom adjacent to the R₁₃position 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 R₁₀position may be substituted with R₁₁, a ring carbon or nitrogen atom three atoms from the point of attachment and adjacent to the R₁₂position may be substituted with R₃₂, and a ring carbon or nitrogen atom four atoms from the point of attachment and adjacent to the R₁₁and R₃₂positions may be substituted with R₃₁;

R₁is selected from the group consisting of trifluoromethyl, chlorodifluoromethyl, and pentafluoroethyl;

R₂is hydrido, pentafluoroethyl, and trifluoromethyl;

R₃is selected from the group consisting of hydrido, methyl, trifluoromethyl, and difluoromethyl

Y is methylene;

Z is a covalent single bond;

R₉and R₁₃are fluoro;

R₅, R₁₀and R₁₂are 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;

R₇is selected from the group consisting of hydrido and fluoro.

8. The compound as recited in

claim 6

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-6yl, 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 R₉or R₁₃, a ring carbon or nitrogen atom adjacent to the R₉position and two atoms from the point of attachment may be substituted with R₁₀, a ring carbon or nitrogen atom adjacent to the R₁₃position 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 R₁₀position may be substituted with R₁₁, a ring carbon or nitrogen atom three atoms from the point of attachment and adjacent to the R₁₂position may be substituted with R₃₂, and a ring carbon or nitrogen atom four atoms from the point of attachment and adjacent to the R₁₁and R₃₂positions may be substituted with R₃₁:

R₂is hydrido, pentafluoroethyl, and trifluoromethyl;

Y is a covalent single bond;

Z is methylene;

R₉and R₁₃are fluoro;

R₇is selected from the group consisting of hydrido and fluoro.

9. The compound as recited in

claim 3

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 R₃₆with the provisos that R₃₃, R₃₄, R₃₅, and R₃₆must not be attached to the carbon directly linking A to Z and that R₃₃, R₃₄, R₃₅, and R₃₆must be selected from other than aryl and heteroaryl when substituting the carbon 2 atoms from Z wherein Z is a single covalent bond;

R₁is selected from the group consisting of haloalkyl and haloalkoxymethyl;

R₅, R₆, R₇, R₃₃, R₃₄, R₃₅, and R₃₆are 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;

R₅, and R₅, R₅and R₆, R₆and R₇, and R₇and R₈are 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 R₄and R₅, R₅and R₆, R₆and R₇, and R₇and R₈, is used at the same time;

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 ethyl, 1-propenyl, propyl, isopropyl, butyl, 2-butenyl, 3-butenyl, 2-butynyl, sec-butyl, isobutyl, 2-methylpropenyl, 1-pentyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-pentynyl, 3-pentynyl, 2-pentyl, 1-methyl-2-butenyl, 1-methyl-3-butenyl, 1-methyl-2-butynyl, 3-pentyl, 1-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-pentenyl, 1-methyltpentenyl, 1-methyl-2-pentynyl, 1-methyl-3-pentynyl, 3-hexyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 1-propyl-2-propenyl, 1-ethyl-2-butynyl, 1-heptyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 5-heptynyl, 2-heptyl, 1-methyl-2-hexenyl, 1-methyl-3-hexenyl, 1-methyl-4-hexenyl, 1-methyl-5-hexenyl, 1-methyl-2-hexynyl 1-methyl-3-hexynyl, 1-methyl-4-hexynyl, 3-heptyl, 1-ethyl-2-pentenyl, 1-ethyl-3-pentenyl, 1-ethyl pentenyl, 1-butyl-2-propenyl, 1-ethyl-2-pentynyl, 1-ethyl-3-pentynyl, 1-octyl, 2-octenyl, 3-octenyl, 4-octenyl, 5-octenyl, 6-octenyl, 7-octenyl, 2-octynyl, 3-octynyl, 4-octynyl, 5-octynyl, 1-octynyl, 2-octyl, 1-methyl-2-heptenyl, 1-methyl-3-heptenyl, 1-methyl-4-heptenyl, 1-methyl-5-heptenyl, 1-methyl-6-heptenyl, 1-methyl-2-heptynyl, 1-methyl-3-heptynyl, 1-methyl-4-heptenyl, 1-methyl-5-heptenyl, 1-methyl-6-heptenyl, 1-methyl-2-heptenyl, 1-methyl-3-heptynyl, 1-methyl-4-heptynyl, 1-methyl-5-heptynyl, 3-octyl, 1-ethyl-2-hexenyl, 1-ethyl-3-hexenyl, 1-ethyl-4-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, 1-propyl-4-pentenyl, 1-butyl-2-butenyl, 1-propyl-2-pentynyl, 1-propyl-3-pentynyl, 1-butyl-2-butynyl, 1-butyl-3-butenyl, 2,2-difluoropropyl, 4-trifluoromethyl-5,5,5-trifluoropentyl, 4-trifluoromethylpentyl, 5,5,6,6,6-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-butoxypropyl, 2-butoxyisopropyl, 3-isobutoxypropyl, 2-isobutoxyisopropyl, 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 R₃₆with the provisos that R₃₃, R₃₄, R₃₅, and R₃₆must not be attached to the carbon directly linking A to Z and that R₃₃, R₃₄, R₃₅, and R₃₆must be selected from other than aryl and heteroaryl when substituting the carbon 2 atoms from Z wherein Z is a single covalent bond:

R₅, R₃₃, R₃₄, R₃₅, and R₃₆are 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-chloro4-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-methyl benzoyl, 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-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-trifluoromethyl benzyloxy, 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-pentafluoroethylphenoxy, 3-(1,1,2,2-tetrafluoroethoxy)phenoxy, 3-trifluoromethylthiophenoxy, and trifluoromethylthio;

R₃₃, R₃₄, R₃₅, and R₃₆are independently selected from the group consisting of cyano and hydroxy;

R₆is selected from the group consisting of chloro, fluoro, hydrido, pentafluoroethyl, 1,1,2,2-tetrafluoroethoxy, trifluoromethyl, and trifluoromethoxy;

R₇is selected from the group consisting of hydrido, fluoro, and trifluoromethyl.

11. The compound as recited in

claim 10

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, 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 pentenyl, 3-hexyl, 1-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-3-pentenyl, 1-ethyl-4-pentenyl, 1-butyl-2-propenyl, 1-octyl, 2-octenyl, 3-octenyl, 4-octenyl, 5octenyl. 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-trifluoromethylpentyl, 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 R₃₆with the provisos that R₃₃, R₃₄, R₃₅, and R₃₆must not be attached to the carbon directly linking A to Z and that R₃₃, R₃₄, R₃₅, and R₃₆must be selected from other than aryl and heteroaryl when substituting the carbon 2 atoms from Z wherein Z is a single covalent bond;

R₃is 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;

R₅, R₃₃, R₃₄, R₃₅, and R₃₆are 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-fluorophenoxy, 4-chloro-2-fluorophenoxy, 4-chlorophenoxy, 3-chloro-4-ethylphenoxy, 3-chloro4-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-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, 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-telrahydronaphthyloxy), 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, 2-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;

R₆is selected from the group consisting of chloro, fluoro, hydrido, pentafluoroethyl, 1,1,2,2-tetrafluoroethoxy, and trifluoromethyl;

12. The compound as recited in

claim 11

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-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 hexenyl, 1-ethyl--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-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 R₃₆with the provisos that R₃₃, R₃₄, R₃₅, and R₃₆must not be attached to the carbon directly linking A to Z and that R₃₃, R₃₄, R₃₅, and R₃₆must be selected from other than aryl and heteroaryl when substituting the carbon 2 atoms from Z wherein Z is a single covalent bond;

R₂is hydrido, pentafluoroethyl, and trifluoromethyl;

R₃is selected from the group consisting of hydrido, methyl. trifluoromethyl, and difluoromethyl

Y is a covalent single bond;

Z is methylene;

R₅, R₃₃, R₃₄, R₃₅, and R₃₆are 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-tetrahydronaplithyloxy), trifluoromethoxy, 3-trifluoromethoxybenzyloxy,3-trifluoromethoxyphenoxy, trifluoromethyl, 3-trifluoromethylbenzyloxy, 1,1-bis-trifluoromethyl-1-hydroxymethyl, trifluoromethylthio, and 3-trifluoromethylthiophenoxy;

R₆is selected from the group consisting of fluoro and hydrido;

R₇is selected from the group consisting of hydrido and fluoro.

13. The compound as recited in

claim 11

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-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-trifluoromethylpentyl, 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, R₃₄R₃₅, and R₃₆with the provisos that R₃₃, R₃₄, R₃₅, and R₃₆must not be attached to the carbon directly linking A to Z and that R₃₃, R₃₄, R₃₅, and R₃₆must be selected from other than aryl and heteroaryl when substituting the carbon 2 atoms from Z wherein Z is a single covalent bond;

R₂is hydrido, pentafluoroethyl, and trifluoromethyl;

Y is methylene;

Z is a covalent single bond;

R₅, R₃₃, R₃₄, R₃₅, and R₃₆are 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;

R₆is selected from the group consisting of fluoro and hydrido;

R₇is selected from the group consisting of hydrido and fluoro.

14. 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;

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-(CR₃₅R₃₆)_w—H;

u and w are integers independently selected from 0 through 6;

A₁is C(R₃₀);

B₁, B₂, D₃, D₄, J₃, J₄and K₂are 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, J₄and K₂are a covalent bond, no more than two of B₁, B₂, D₃, D₄, J₃, J₄and K₂are O, no more than two of B₁, B₂, D₃, D₄, J₃, J₄and K₂are ,no more than two of B₁, B₂,D₃, D₄, J₃, J₄and K₂are simultaneously O and S, and no more than two of B₁, B₂, D₃, D₄, J₃, J₄and K₂are N;

R₁is selected from the group consisting of haloalkyl and haloalkoxymethyl;

Y is selected from the group consisting of a covalent single bond, (CH₂)_qwherein q is an integer selected from 1 through 2, and (CH₂)_g—O—(CH₂)_kwherein j and k are integers independently selected from 0 through 1:

Z is selected from the group consisting of covalent single bond, (CH₂)_qwherein q is an integer selected from 1 through 2, and (CH₂)_j—O—CH₂)_kwherein i and k are integers independently selected from (0 through 1;

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 R₃₀to the points of bonding of each member of any one of substituent pairs selected from the group consisting of subsitituent pairs R₁₀and R₁₁, R₁₀and R₃₁, R₁₀and R₃₂, R₁₀and R₁₂, R₁₁and R₃₁, R₁₁and R₃₂, R₁₁and R₁₂, R₃₁and R₃₂, R₃₁and R₁₂, and R₃₂and R₁₂and 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 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 R₃₆are independently selected from the group consisting of hydrido, carboxy, heteroaralkylthio, heteroaralkoxy, cycloalkylaimino, acylalkyl, acylalkoxy, aroylalkoxy, heterocyclyloxy, aralkiylaryl, 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, alkoxycarboxamiido, 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 R₃₆are 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 R₃₃and R₃₄substituents are simultaneously selected from other than the group consisting of of hydrido and halo, and that no more than three of the R₃₅and R₃₆substituents are simultaneously selected from other than the group consistubg, of hydrido and halo;

R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₃₁, and R₃₂are independently selected to be oxo with the provisos that B₁, B₂, D₃, D₄, J₃, J₄and K₂are independently selected from the group consisting of C and S, no more than two of R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₃₁, and R₃₂are simultaneously oxo, and that R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₃₁, and R₃₂are 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:

R₉and R₁₁, R₉and R₁₂, R₉and R₁₃, R₉and R₃₁, R₉and R₃₂, R₁₀and R₁₂, R₁₀and R₁₃, R₁₀and R₃₁, R₁₀and R₃₂, R₁₃and R₁₂, R₁₁and R₁₃, R₁₁and R₃₂, R₁₂and R₃₁, R₁₃and R₃₁and R₁₃and R₃₂are 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 ring selected from the group consisting of a cycloalkyl having from 3 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;

15. The compound as recited in

claim 14

having the formula of:

or a pharmaceutically acceptable salt thereof, wherein;

n is an integer selected from 1 through 2;

R₁is selected from the group consisting of haloalkyl and haloalkoxymethyl;

R₃₃, R₃₄, R₃₅, and R₃₆are independently selected from the group group consisting of alkyl, halo, hydroxy, cyano, 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.

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 ethyl, 1-propenyl, propyl, isopropyl, butyl, 2-butenyl, 3-butenyl, 2-butynyl, sec-butyl, isobutyl, 2-methylpropenyl, 1-pentyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-pentynyl, 3-pentynyl, 2-pentyl, 1-methyl-2-butenyl, 1-methyl-3-butenyl, 1-methyl-2-butynyl, 3-pentyl, 1-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-pentenyl, 1-methyl-4-pentenyl, 1-methyl-2-pentynyl, 1-methyl-3-pentynyl, 3-hexyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 1-propyl-2-propenyl, 1-ethyl-2-butynyl, 1-heptyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 5-heptynyl, 2-heptyl, 1-methyl-2-hexenyl, 1-methyl-3-hexenyl, 1-methyl-4-hexenyl, 1-methyl-5-hexenyl, 1-methyl-2-hexynyl, 1-methyl-3-hexynyl, 1-methyl-4-hexynyl, 3-heptyl, 1-ethyl-2-pentenyl, 1-ethyl-3-pentenyl, 1-ethyl-pentenyl, 1-butyl-2-propenyl, 1-ethyl-2-pentynyl, 1-ethyl-3-pentynyl, 1-octyl, 2-octenyl, 3-octenyl, 4-octenyl, 5-octenyl, 6-octenyl, 7-octenyl, 2-octynyl, 3-octynyl, 4-octynyl, 5-octynyl, 6-octynyl, 2-octyl, 1-methyl-2-heptenyl, 1-methyl-3-heptenyl, 1-methyl-4-heptenyl, 1-methyl-5-heptenyl, 1-methyl-6-heptenyl, 1-methyl-2-heptynyl, 1-methyl-3-heptynyl, 1-methyl-4-heptenyl, 1-methyl-5-heptenyl, 1-methyl-6-heptenyl, 1-methyl-2-heptenyl, 1-methyl-3-heptynyl, 1-methyl-4-heptynyl, 1-methyl-5-heptynyl, 3-octyl, 1-ethyl-2-hexenyl, 1-ethyl-3-hexenyl, 1-ethyl-4-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, 1-propyl-4-pentenyl, 1-butyl-2-butenyl, 1-propyl-2-pentynyl, 1-propyl-3-pentynyl, 1-butyl-2-butynyl, 1-butyl-3-butenyl, 2,2-difluoropropyl, 4-trifluoromethyl-5,5,5-trifluoropentyl, 4-trifluoromethylpentyl, 5,5,6,6,6-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-propoxylsopropyl, 3-isopropoxypropyl, 2-isopropoxylsopropyl, 3-butoxypropyl, 2-butoxyisopropyl, 3-isobutoxypropyl, 2-isobutoxyisopropyl, 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 R₃₆with the provisos that R₃₃, R₃₄, R₃₅, and R₃₆must not be attached to the carbon directly linking A to Z and that R₃₃, R₃₄, R₃₅, and R₃₆must be selected from other than aryl and heteroarl when substituting the carbon 2 atoms from Z wherein Z is a single covalent bond:

D₁, D₂, J₁, J₂and K₁are 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, 4-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 R₄or R₈, a ring carbon atom adjacent to the R₄position and two atoms from the point of attachment may be substituted with R5, a ring carbon atom adjacent to the R₈position 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 R₅and R₇positions may be substituted with R₆;

R₅, R₃₃, R₃₄, R₃₅, and R₃₆are 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-chloro4-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-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-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-pentafluoroethylphenoxy, 3-(1,1,2,2-tetrafluoroethoxy)phenoxy, 3-trifluoromethylthiophenoxy, and trifluoroniethylthio;

17. The compound as recited in

claim 16

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, 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-4-pentenyl, 3-hexyl, 1-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-3-pentenyl, 1-ethylpentenyl, 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-methylthephenyl, 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-trifluoromethylpentyl, 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 R₃₆with the provisos that R₃₃, R₃₄, R₃₅, and R₃₆must not be attached to the carbon directly linking A to Z and that R₃₃, R₃₄, R₃₅, and R₃₆must 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, J₁, J₂and K₁are 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, 4-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, 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 R₄or R₈, a ring carbon atom adjacent to the R₄position and two atoms from the point of attachment may be substituted with R₅, a ring carbon atom adjacent to the R₈position 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 R₅and R₇positions may be substituted with R₆;

R₁is selected from the group consisting of trifluoromethyl. 1,1,2,2-tetrafluoroethoxymethyl, trifluoromethoxymethyl, difluoromethyl, chlorodifluoromethyl, and pentafluoroethyl;

R₂is 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:

Y and Z are independently selected from a covalent single bond and methylene;

R₅, R₃₃, R₃₄, R₃₅, and R₃₆are 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-chloro4-methylphenoxy, 3-chloro-4-fluorophenioxy, 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-5-trifluoromethylbenzyloxy, 2-fluorophenoxy, 4-fluorophenoxy, 2-fluoro-3-trifluoromethylphenoxy, 2-fluorobenzyloxy, 4-fluorophenylamino, 2-fluoro-4-trifluoromethylphenoxy, 2-furyl, 3-furyl, heptafluioropropyl, 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, 1,1,3,3,3-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, 5-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;

18. The compound as recited in

claim 17

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-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-trifluoromethylpentyl, 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 R₃₆with the provisos that R₃₃, R₃₄, R₃₅, and R₃₆must not be attached to the carbon directly linking A to Z and that R₃₃, R₃₄, R₃₅, and R₃₆must 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, J₁, J₂and K₁are 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, 4-imidazolyl, 3-pyrazolyl, 4-pyrazolyl, 2-thiazolyl, 3-isoxazolyl, 3-isoxazolyl, 2-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 R₄or R₈, a ring carbon atom adjacent to the R₄position and two atoms from the point of attachment may be substituted with R5, a ring carbon atom adjacent to the R₈position 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 R₅and R₇positions may be substituted with R₆;

R₂is hydrido, pentafluoroethyl, and trifluoromethyl;

Y is a covalent single bond;

Z is methylene;

R₅, R₃₃, R₃₄, R₃₅, and R₃₆are 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;

R₆is selected from the group consisting of fluoro and hydrido;

R₇is selected from the group consisting of hydrido and fluoro.

19. The compound as recited in

claim 17

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-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-ethylthexenyl, 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-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 R₃₆with the provisos that R₃₃, R₃₄, R₃₅and R₃₆must not be attached to the carbon directly linking A to Z and that R₃₃, R₃₄, R₃₅, and R₃₆must 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, J₁, J₂and K₁are 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, 4-imidazolyl, 3-pyrazolyl, 4-pyrazolyl, 2-thiazolyl, 3-isoxazolyl, -5-isoxazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, and 1,3,5triazin-2-yl, wherein a ring carbon atom adjacent to the carbon atom at the point of attachment may be optionally substituted with R₄or R₈, a ring carbon atom adjacent to the R₄position and two atoms from the point of attachment may be substituted with R5, a ring carbon atom adjacent to the R₈position 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 R₅and R₇positions may be substituted with R₆;

R₂is hydrido, pentafluoroethyl, and trifluoromethyl;

Y is methylene;

Z is a covalent single bond;

R₅, R₃₃, R₃₄, R₃₅, and R₃₆are 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-isopropyiphenoxy, 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;

R₆is selected from the group consisting of fluoro and hydrido;

R₇is selected from the group consisting of hydrido and fluoro.

20. The compound as recited in

claim 14

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 R₉or R₁₃, a ring carbon or nitrogen atom adjacent to the R₉position and two atoms from the point of attachment may be substituted with R₁₀, a ring carbon or nitrogen atom adjacent to the R₁₃position 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 R₁₀position may be substituted with R₁₁, a ring carbon or nitrogen atom three atoms from the point of attachment and adjacent to the R₁₂position may be substituted with R₃₂, and a ring carbon or nitrogen atom four atoms from the point of attachment and adjacent to the R₁₁and R₃₂positions may be substituted with R₃₁;

R₁is selected from the group consisting of haloalkyl and haloalkoxymethyl;

R₉and R₁₃are halo;

21. The compound as recited in

claim 20

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 R₉or R₁₃, a ring carbon or nitrogen atom adjacent to the R₉position and two atoms from the point of attachment may be substituted with R₁₀, a ring carbon or nitrogen atom adjacent to the R₁₃position 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 R₁₀position may be substituted with R₁₁, a ring carbon or nitrogen atom three atoms from the point of attachment and adjacent to the R₁₂position may be substituted with R₃₂, and a ring carbon or nitrogen atom four atoms from the point of attachment and adjacent to the R₁₁and R₃₂positions may be substituted with R₃₁;

D₁, D₂, J₁, J₂and K₁are 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, 4-imidazolyl, 3-pyrazolyl, 4-pyrazolyl, 1,2,4-triazol-3-yl, 1,2,4-triazol-5yl, 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-5yl, 1,2,4-triazin-6-yl, 1,2,3-triazin4-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 R₄or R₈, a ring carbon atom adjacent to the R₄position and two atoms from the point of attachment may be substituted with R5, a ring carbon atom adjacent to the R₈position 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 R₅and R₇positions may be substituted with R₆;

R₉and R₁₃are fluoro;

R₅, R₁₀and R₁₂are 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, 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-difluorobenzyoxy, 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-methylphenoxy, 3-fluorophenoxy, 3-fluoro-2-nitrophenoxy, 2-fluoro-3-trifluoromethylbenzyloxy, 3-fluoro-5-trifluoromethylbenzyloxy, -fluoro-2-trifluoromethylbenzyloxy, 4-fluoro-3-trifluoromethylbenzyloxy, 2-fluorophenoxy, 4-fluorophenoxy, 2-fluoro-3-trifluoromethylphenoxy, 2-fluorobenzyloxy, 4-fluorophenylamino, 2-fluoro-4-trifuoromethylphenoxy, 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-trifluoromethyl benzyloxy, 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-pentafluoroethylphenoxy, 3-(1,1,2,2-tetrafluoroethoxy)phenoxy, 3-trifluoromethylthiophenoxy, and trifluoromethylthio;

R₃₀is 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-tetrafluoroethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trifluoroethyl, trifluoromethoxy, and trifluoromethyl.

22. The compound as recited in

claim 21

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 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 R₉or R₁₃, a ring carbon or nitrogen atom adjacent to the R₉position and two atoms from the point of attachment may be substituted with R₁₀, a ring carbon or nitrogen atom adjacent to the R₁₃position 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 R₁₀position may be substituted with R₁₁, a ring carbon or nitrogen atom three atoms from the point of attachment and adjacent to the R₁₂position may be substituted with R₃₂, and a ring carbon or nitrogen atom four atoms from the point of attachment and adjacent to the R₁₁and R₃₂positions may be substituted with R₃₁;

D₁, D₂, J₁, J₂and K₁are 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, 4-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, 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 R₄or R₈, a ring carbon atom adjacent to the R₄position and two atoms from the point of attachment may be substituted with R5, a ring carbon atom adjacent to the R₈position 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 R₅and R₇positions may be substituted with R₆;

Y and Z are independently selected from a covalent single bond and methylene;

R₉and R₁₃are fluoro;

R₅, R₁₀and R₁₂are 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-dimethylbenzyioxy, 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-fluoro4-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-fluorotrifluoromethylphenoxy, 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-oxazoyl, 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-5yl, 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-difluorometboxyphenoxy, 3-pentafluoroethylphenoxy, 3-(1,1,2,2-tetrafluoroethoxy)phenoxy, 3-trifluoromethylthiophenoxy, 3-trifluoromethylthiobenzyloxy, and trifluoromethylthio;

R₃₀is 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.

23. The compound as recited in

claim 22

or a pharmaceutically acceptable salt thereof, wherein;

n is the integer 1;

D₁, D₂, J₁, J₂and K₁are 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, 4-imidazolyl, 3-pyrazolyl, 4-pyrazolyl, 2-thiazolyl, 3-isoxazolyl, 5-isoxazolyl, 2-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 R₄or R₈, a ring carbon atom adjacent to the R₄position and two atoms from the point of attachment may be substituted with R5, a ring carbon atom adjacent to the R₈position 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 R₅and R₇positions may be substituted with R₆;

R₂is hydrido, pentafluoroethyl, and trifluoromethyl;

Y is a covalent single bond;

Z is methylene;

R₉and R₁₃are fluoro;

R₅, R₁₀and R₁₂are 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;

R₇is selected from the group consisting of hydrido and fluoro.

24. The compound as recited in

claim 22

or a pharmaceutically acceptable salt thereof, wherein;

n is the integer 1;

R₂is hydrido, pentafluoroethyl, and trifluoromethyl;

Y is methylene;

Z is a covalent single bond:

R₉and R₁₃are fluoro;

R₅, R₁₀and R₁₂are 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;

R₇is selected from the group consisting of hydrido and fluoro.

25. A compound as recited in any one of claims 1 or 2, 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-[[3-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-isopropylphenoxy)phenyl](cyclopropylmethyi)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)phenylmethyl](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-trifluoromethylcycloohexyl)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-propanol;

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-[[[(3-4-fluoromethyl)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-cyclopentyloxycyclohexyl)-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-6yl]methyl](3-trifluoromethylcyclohexyl)amino]-1,1,1-trifluoro-2-propanol;

3-[[[(2-trifluoromethyl)pyrid6-yl]methyl][3-(4-chloro-3-ethylphenoxy)cyclo-hexyl] amino]-1,1,1-trifluoro-2-propanol;

3-[[[(2-trifluoromethyl)pyrid-6-yl]methyl][3-(1,2-tetrafluoroethoxy)cyclo-hexyl] amino]-1,1,1 -trifluoro-2-propanol;

3-[[[(2-trifluoromethyl)pyrid-6yl]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.

26. A pharmaceutical composition comprising a compound of one of claims 1 through 25 together with a pharmaceutically acceptable carrier.

27. 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 25.

28. 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 25.

29. 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 25.

30. 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 25.