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, I-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, 44347 (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. Biophvs.

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. Patent 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, 216- 220, (1990)) describe cholesteryl acetyl bromide as a CETP inhibitor. Morton and Zilversmit (J. Lipid Res., 35, 83647 (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 Sphenyl-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-l-amines. These are reported to be ß3- 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. Patent 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. Patent 2, 700, 686 further describes a process to prepare the N- (2-haloalkyl-2- hydroxyethyl) amines by reacting halogenated-1, 2-epoxyalkanes with the corresponding aliphatic amines and N-alkylanilines and their use as dye intermediates.

SUMMARY OF THE INVENTION The present invention provides 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 polycyclic aryl and heteroaryl tertiary-heteroalkylamines which are beneficial in the therapeutic and prophylactic treatment of coronary artery disease as given in Formula VII-H (also referred to herein as generic substituted polycyclic heteroaryl tertiary 2-heteroalkylamines) : or a pharmaceutically acceptable salt thereof, wherein ; n is an integer selected from 0 through 5 ; R1 is selected from the group consisting of haloalkyl, haloalkenyl, haloalkoxyalkyl, and haloalkenyloxyalkyl ; X is selected from the group consisting of O, H, F, S, S (O), NH, N (OH), N (alkyl), and N (alkoxy) ; R16 is selected from the group consisting of hydrido, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, alkoxyalkyl, alkenyloxyalkyl,

alkylthioalkyl, arylthioalkyl, aralkoxyalkyl, heteroaralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, heteroarylalkyl, monocarboalkoxyalkyl, monocarboalkoxy, dicarboalkoxyalkyl, monocarboxamido, monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl, acyl, aroyl, heteroaroyl, heteroaryloxyalkyl, dialkoxyphosphonoalkyl, trialkylsilyl, and a spacer selected from the group consisting of a covalent single bond and a linear spacer moiety having from 1 through 4 contiguous atoms linked to the point of bonding of an aromatic substituent selected from the group consisting of R4, R8, R9, R13, R14, and R15 to form a heterocyclyl ring having from 5 through 10 contiguous members with the provisos that said spacer moiety is other than a covalent single bond when R2 is alkyl and there is no R16 wherein X is H or F ; DI, D2, J1, J2 and K 1 are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more than one of D 1, D2, J 1, J2 and K l can be a covalent bond, no more than one of D1, D2, J 1, J2 and K1 can be O, no more than one of D 1, D2, J 1, J2 and K 1 can be S, one of D1, D2, J l f J2 and K1 must be a covalent bond when two of D1, D2, J1 J2 and K1 are O and S, and no more than four of D1, D2, J1 J2 and K1 can be N ; D3, D4, J3, J4 and K2 are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more than one of D3, D4, J3, J4 and K2 can be a covalent bond, no more than one of D3, D4, J3, J4 and K2 can be O, no more than one of D3, D4, J3, J4 and K2 can be S, one of D3, D4, J3, J4 and K2 must be a covalent bond when two of

D3, D4, J3, J4 and K2 are O and S, and no more than four of D3, D4, J3, J4 and K2 can be N ; R2 is independently selected from the group consisting of hydrido, hydroxy, hydroxyalkyl, amino, aminoalkyl, alkylamino. dialkylamino, alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkoxyalkyl, aryloxyalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, aralkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, heteroarylalkyl, heteroarylthioalkyl, heteroaralkylthioalkyl, monocarboalkoxyalkyl, dicarboalkoxyalkyl, <BR> <BR> monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl, alkylsulfinyl,<BR> <BR> <BR> alkylsulfonyl, alkylsulfinylalkyl, alkylsulfonylalkyl, haloalkylsulfinyl,<BR> <BR> <BR> haloalkylsulfonyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylalkyl, aralkylsulfinyl, aralkylsulfonyl, cycloalkylsulfinyl, cycloalkylsulfonyl, cycloalkylsulfinylalkyl, cycloalkylsufonylalkyl, heteroarylsulfonylalkyl, <BR> <BR> heteroarylsulfinyl, heteroarylsulfonyl, heteroarylsulfinylalkyl,<BR> <BR> <BR> aralkylsulfinylalkyl, aralkylsulfonylalkyl, carboxy, carboxyalkyl, carboalkoxy, carboxamide, carboxamidoalkyl, carboaralkoxy, dialkoxyphosphono, diaralkoxyphosphono, dialkoxyphosphonoalkyl, and diaralkoxyphosphonoalkyl ; R2 and R3 can be 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 6 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, and a heterocyclyl having from 4 through 8 contiguous members ; R2 and R 14 can be taken together to form a linear spacer moiety selected from the group consisting of a covalent bond and a linear spacer moiety having from 1 through 5 contiguous atoms to form a heterocyclyl ring having from 5 through 8 contiguous members with the proviso that said spacer group is other than-N= ;

R2 and R15 can be taken together to form a linear spacer moiety selected from the group consisting of a covalent bond and a linear spacer moiety having from 1 through 5 contiguous atoms to form a heterocyclyl ring having from 5 through 8 contiguous members with the proviso that said spacer group is other than-N= ; R2 and R19 can be taken together to form a linear spacer moiety selected from the group consisting of a covalent single bond and a linear moiety having from 1 through 5 contiguous atoms to form a ring selected from the group consisting of a cycloalkyl having from 3 through 8 contiguous members, a cycloalkylenyl having from 5 through 8 contiguous members, and a heterocyclyl having from 4 through 8 contiguous members ; R2 and R4, R2 and R8, R2 and Rg, and R2 and R13 can be independently selected to form spacer pairs wherein a spacer pair is taken together to form a linear spacer moiety wherein said linear spacer moiety is selected to form a heterocyclyl ring having from 5 through 10 contiguous members ; R3 is selected from the group consisting of hydrido, hydroxy, halo, cyano, aryloxy, hydroxyalkyl, amino, alkylamino, dialkylamino, acyl, sulfhydryl, acylamido, alkoxy, alkylthio, arylthio, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, alkoxyalkyl, heteroarylthio, aralkylthio, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, aroyl, heteroaroyl, aralkylthioalkyl, heteroaralkylthioalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, heteroarylalkyl, heteroarylthioalkyl, monocarboalkoxyalkyl, dicarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl, <BR> <BR> <BR> carboalkoxycyanoalkyl, alkylsulfinyl, alkylsulfonyl, haloalkylsulfinyl,<BR> <BR> <BR> <BR> <BR> haloalkylsulfonyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylalkyl,<BR> <BR> <BR> <BR> <BR> aralkylsulfinyl, aralkylsulfonyl, cycloalkylsulfinyl, cycloalkylsulfonyl, cycloalkylsulfinylalkyl, cycloalkylsufonylalkyl, heteroarylsulfonylalkyl, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylsulfinylalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl, carboxy, carboxyalkyl, carboalkoxy, carboxamide, carboxamidoalkyl, carboaralkoxy, dialkoxyphosphono,

diaralkoxyphosphono, dialkoxyphosphonoalkyl, and diaralkoxyphosphonoalkyl ; R3 and R14 can be taken together to form a linear spacer moiety selected from the group consisting of a covalent bond and a linear moiety having from 1 through 5 atoms to form a heterocyclyl ring having from 5 through 8 contiguous members ; R3 and R15 can be taken together to form a linear spacer moiety selected from the group consisting of a covalent bond and a linear moiety having from 1 through 5 atoms to form a heterocyclyl ring having from 5 through 8 contiguous members ; R3 and R4, R3 and Rg, R3 and Rg, and R3 and R13 can be independently selected to form spacer pairs wherein a spacer pair is taken together to form a linear spacer moiety wherein said linear spacer moiety is selected to form a heterocyclyl ring having from 5 through 10 contiguous members ; Y is selected from a group consisting of a covalent single bond, (C (R14) 2) q wherein q is an integer selected from 1 through 4 and (CH (R14)) g- W-(CH (R14)) p wherein g and p are integers independently selected from 0 through 2 ; R14 is independently selected from the group consisting of hydrido, hydroxy, halo, cyano, aryloxy, amino, alkylamino, dialkylamino, hydroxyalkyl, acyl, aroyl, heteroaroyl, heteroaryloxyalkyl, sulfhydryl, acylamido, alkoxy, alkylthio, arylthio, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, aralkoxyalkylalkoxy, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkoxythioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, heteroarylalkyl, heteroarylthioalkyl, heteroaralkylthioalkyl, monocarboalkoxyalkyl, dicarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl, <BR> <BR> alkylsulfinyl, alkylsulfonyl, haloalkylsulfinyl, haloalkylsulfonyl, arylsulfinyl,

arylsulfinylalkyl, arylsulfonyl, arylsulfonylalkyl, aralkylsulfinyl,<BR> <BR> <BR> aralkylsulfonyl, cycloalkylsulfinyl, cycloalkylsulfonyl, cycloalkylsulfinylalkyl,<BR> <BR> <BR> cycloalkylsufonylalkyl, heteroarylsulfonylalkyl, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylsulfinylalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl, carboxy, carboxyalkyl, carboalkoxy, carboxamide, carboxamidoalkyl, carboaralkoxy, dialkoxyphosphono, diaralkoxyphosphono, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, a spacer selected from a moiety having a chain length of 3 to 6 atoms connected to the point of bonding selected from the group consisting of Rg and R13 to form a ring selected from the group consisting of a cycloalkenyl ring having from 5 through 8 contiguous members and a heterocyclyl ring having from 5 through 8 contiguous members, and a spacer selected from a moiety having a chain length of 2 to 5 atoms connected to the point of bonding selected from the group consisting of R4 and R8 to form a heterocyclyl having from 5 through 8 contiguous members with the proviso that, when Y is a covalent bond, an R14 substituent is not attached to Y ; R14 and R15 can be taken together to form a spacer selected from a moiety having a chain length of 2 to 5 atoms to form a heterocyclyl ring having from 5 through 8 contiguous members ; R14 and R14, when bonded to the different atoms, can be taken together to form a group selected from the group consisting of a covalent bond, alkylene, haloalkylene, and a spacer selected from a group consisting of a moiety having a chain length of 2 to 5 atoms connected to form a ring selected from the group of a saturated cycloalkyl having from 5 through 8 contiguous members, a cycloalkenyl having from 5 through 8 contiguous members, and a heterocyclyl having from 5 through 8 contiguous members ; R14 and R14, when bonded to the same atom can be taken together to form a group selected from the group consisting of oxo, thiono, alkylene, haloalkylene, and a spacer selected from the group consisting of a moiety having a chain length of 3 to 7 atoms connected to form a ring selected from the group consisting of a cycloalkyl having from 4 through 8 contiguous members, a cycloalkenyl having from 4 through 8 contiguous members, and a heterocyclyl having from 4 through 8 contiguous members ;

W is selected from the group consisting of O, C (O), C (S), C (O) N (R14), C (S) N (R14), (R14) NC (O), (R14) NC (S), S, S (O), S (0) 2, S (0) 2N (R14) (R14) NS (O) 2, and N (R14) with the proviso that R14 is selected from other than halo and cyano : Z is independently selected from a group consisting of a covalent single bond, (C (R15) 2) q wherein q is an integer selected from I through 4, (CH (R15)) j-W-(CH (Rls)) k wherein j and k are integers independently selected from 0 through 2 with the proviso that, when Z is a covalent single bond, an R15 substituent is not attached to Z ; R15 is independently selected, when Z is (C (R15) 2) q wherein q is an integer selected from 1 through 4, from the group consisting of hydrido, hydroxy, halo, cyano, aryloxy, amino, alkylamino, dialkylamino, hydroxyalkyl, acyl, aroyl, heteroaroyl, heteroaryloxyalkyl, sulfhydryl, acylamido, alkoxy, alkylthio, arylthio, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkylthioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, heteroarylalkyl, heteroarylthioalkyl, heteroaralkylthioalkyl, monocarboalkoxyalkyl, dicarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl, alkylsulfinyl, alkylsulfonyl, haloalkylsulfinyl, haloalkylsulfonyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylalkyl, aralkylsulfinyl, aralkylsulfonyl, cycloalkylsulfinyl, cycloalkylsulfonyl, cycloalkylsulfinylalkyl, cycloalkylsufonylalkyl, heteroarylsulfonylalkyl, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylsulfinylalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl, carboxy, carboxyalkyl, carboalkoxy, carboxamide, <BR> <BR> <BR> carboxamidoalkyl, carboaralkoxy, dialkoxyphosphono, diaralkoxyphosphono, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, a spacer selected from a moiety having a chain length of 3 to 6 atoms connected to the point of bonding

selected from the group consisting of R4 and Rg to form a ring selected from the group consisting of a cycloalkenyl ring having from 5 through 8 contiguous members and a heterocyclyl ring having from 5 through 8 contiguous members, and a spacer selected from a moiety having a chain length of 2 to 5 atoms connected to the point of bonding selected from the group consisting of Rg and R13 to form a heterocyclyl having from 5 through 8 contiguous members ; R15 and R15, when bonded to the different atoms, can be taken together to form a group selected from the group consisting of a covalent bond, alkylene, haloalkylene, and a spacer selected from a group consisting of a moiety having a chain length of 2 to 5 atoms connected to form a ring selected from the group of a saturated cycloalkyl having from 5 through 8 contiguous members, a cycloalkenyl having from 5 through 8 contiguous members, and a heterocyclyl having from 5 through 8 contiguous members ; Ri< and R15, when bonded to the same atom can be taken together to form a group selected from the group consisting of oxo, thiono, alkylene, haloalkylene, and a spacer selected from the group consisting of a moiety having a chain length of 3 to 7 atoms connected to form a ring selected from the group consisting of a cycloalkyl having from 4 through 8 contiguous members, a cycloalkenyl having from 4 through 8 contiguous members, and a heterocyclyl having from 4 through 8 contiguous members ; R15 is independently selected, when Z is (CH (R15)) j-W-(CH (Rl5)) k wherein j and k are integers independently selected from 0 through 2, from the group consisting of hydride, halo, cyano, aryloxy, carboxyl, acyl, aroyl, heteroaroyl, hydroxyalkyl, heteroaryloxyalkyl, acylamido, alkoxy, alkylthio, arylthio, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, alkoxyalkyl, heteroaryloxyalkyl, aralkoxyalkyl, heteroaralkoxyalkyl, alkylsulfonylalkyl, alkylsulfinylalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, heteroarylalkyl, heteroarylthioalkyl, heteroaralkylthioalkyl, monocarboalkoxyalkyl, dicarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl,

carboalkoxycyanoalkyl, alkylsulfinyl, alkylsulfonyl, haloalkylsulfinyl, <BR> <BR> haloalkylsulfonyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylalkyl, aralkylsulfinyl, aralkylsulfonyl, cycloalkylsulfinyl, cycloalkylsulfonyl, <BR> <BR> cycloalkylsulfinylalkyl, cycloalkylsufonylalkyl, heteroarylsulfonylalkyl,<BR> <BR> <BR> heteroarylsulfinyl, heteroarylsulfonyl, heteroarylsulfinylalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl, carboxyalkyl, carboalkoxy, carboxamide, carboxamidoalkyl, carboaralkoxy, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, a spacer selected from a linear moiety having a chain length of 3 to 6 atoms connected to the point of bonding selected from the group consisting of R4 and R8 to form a ring selected from the group consisting of a cycloalkenyl ring having from 5 through 8 contiguous members and a heterocyclyl ring having from 5 through 8 contiguous members, and a spacer selected from a linear moiety having a chain length of 2 to 5 atoms connected to the point of bonding selected from the group consisting of Rg and R13 to form a heterocyclyl ring having from 5 through 8 contiguous members ; R4, R5, R6, R, R8, Rg, R 10, R 11, R 12, and R13 are independently selected from the group consisting of perhaloaryloxy, alkanoylalkyl, alkanoylalkoxy, alkanoyloxy, N-aryl-N-alkylamino, heterocyclylalkoxy, heterocyclylthio, hydroxyalkoxy, carboxamidoalkoxy, alkoxycarbonylalkoxy, alkoxycarbonylalkenyloxy, aralkanoylalkoxy, aralkenoyl, N-alkylcarboxamido, N-haloalkylcarboxamido, N-cycloalkylcarboxamido, N-arylcarboxamidoalkoxy, cycloalkylcarbonyl, cyanoalkoxy, heterocyclylcarbonyl, hydrido, carboxy, heteroaralkylthio, heteroaralkoxy, cycloalkylamino, acylalkyl, acylalkoxy, aroylalkoxy. heterocyclyloxy, aralkylaryl, aralkyl, aralkenyl, aralkynyl, heterocyclyl, perhaloaralkyl, aralkylsulfonyl, aralkylsulfonylalkyl, aralkylsulfinyl, aralkylsulfinylalkyl, halocycloalkyl, halocycloalkenyl, cycloalkylsulfinyl, cycloalkylsulfinylalkyl, <BR> <BR> cycloalkylsulfonyl, cycloalkylsulfonylalkyl, heteroarylamino,<BR> <BR> <BR> 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 proviso that there are one to five non- hydrido ring substituents R4, R5, R6, R7, and R8 present, that there are one to five non-hydrido ring substituents Rg, RIO, R11 s R12 and R13 present a R4, R5, R6, R7, R8, R9, R10, R11, R12, and R13 are each independently selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen ; R4 and R5, R5 and R6, R6 and R7, R7 and R8, Rg and Rlo, Rlo and R1 l, R11 and R12, and Rio and R13 can be independently selected to form spacer pairs wherein a spacer pair is taken together to form a linear moiety having from 3 through 6 contiguous atoms connecting the points of bonding of said spacer pair members to form a ring selected from the group consisting of a cycloalkenyl ring having 5 through 8 contiguous members, a partially saturated heterocyclyl ring having 5 through 8 contiguous members, a heteroaryl ring having 5 through 6 contiguous members, and an aryl with the provisos that no

more than one of the group consisting of spacer pairs R4 and R5, R5 and R6, R6 and R7, and R7 and R8, can be used at the same time and that no more than one of the group consisting of spacer pairs R9 and R 1 p, R 10 and R 11, R 11 and R 12, and R 12 and R 13 can be used at the same time ; R4 and Rg, R4 and R13, R8 and Rg, and R8 and R13 can be independently selected to form a spacer pair wherein said spacer pair is taken together to form a linear moiety wherein said linear moiety forms a ring selected from the group consisting of a partially saturated heterocyclyl ring having from 5 through 8 contiguous members and a heteroaryl ring having from 5 through 6 contiguous members with the proviso that no more than one of the group consisting of spacer pairs R4 and R9, R4 and R13, R8 and Rg, and R8 and R13 can be used at the same time ; R5 and R10, R5 and R12, R7 and RIO, and R7 and R12 can be independently selected to form a spacer pair wherein said spacer pair is taken together to form a linear moiety wherein said linear moiety forms a C8 to C13 heterocyclyl ring having from 8 through 13 contiguous members with the proviso that no more than one of the group consisting of spacer pairs R5 and R10, R5 and R 12, R7 and R109 and R7 and R12 can be used at the same time ; In another embodiment of compounds of Formula VII-H, D1, D2, J1, J2 and K1 are each carbon with the proviso that at least one of D3, D4, J3, J4 and K2 is selected from the group consisting of O, S, and N, wherein D3, D4, J3, J4 and K2 are independently selected from the group consisting of C, N, O, S and covalent bond with the provisos that no more than one of D3, D4, J3, J4 and K2 can be a covalent bond, no more than one of D3, D4, J3, J4 and K2 can be O, no more than one of D3, D4, J3, J4 and K2 can be S, one of D3, D4, J3, J4 and K2 must be a covalent bond when two of D3, D4,

J3, J4 and K2 are O and S, and no more than four of D3, D4, J3, J4 and K2 can be N ; DI, , D2, J1, J2 and K1 can be selected from the group consisting of C, O, S, N and covalent bond with the provisos that D3, D4, J3, J4 and K2 are each carbon and at least one of D 1 s D2 J1 J2 and K 1 is selected from the group consisting of O, S, and N wherein, when Dl, D2 J19 J2 and Kl are selected from the group consisting of C, O, S, covalent bond, and N, no more than one of Di, Do, Ji, Jo and Kl can be a covalent bond. no more than one of DI, , D2, J 1, J2 and K1 can be O, no more than one of D 1, D2, J 1, J2 and K1 can be S, one of Di, Do, Ji, Jo and Kl must be a covalent bond when two of D1, D2, J 1, J2 and K I are 0 and S, and no more than four of D 1, D2, J 1, J2 and K1 can be N ; n is an integer selected from 1 through 4 ; X is oxy ; R16 is selected from the group consisting of hydrido, acyl, aroyl, and trialkylsilyl ; R1 is selected from the group consisting of haloalkyl, haloalkyl, haloalkenyl, haloalkoxyalkyl, and haloalkenyloxyalkyl ; R2 is selected from the group consisting of hydrido, hydroxy, aryl, aralkyl, alkyl, alkenyl, alkenyloxyalkyl, haloalkyl, haloalkenyl, halocycloalkyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy, halocycloalkoxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, dicyanoalkyl, and carboalkoxycyanoalkyl ; R3 is 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 the group consisting of covalent single bond and (C (R14) 2) q wherein q is an integer selected from 1 through 2 ; R14 is selected from the group consisting of hydrido, cyano, <BR> <BR> <BR> hydroxyalkyl, acyl, alkoxy, alkyl, alkenyl, alkoxyalkyl, haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, monocyanoalkyl, dicyanoalkyl, carboxamide, and carboxamidoalkyl ; Z is selected from the group consisting of covalent single bond, (C (R15) 2) q wherein q is an integer selected from 1 through 2, and (CH (R15)) j- W-(CH (R15)) k wherein j and k are integers independently selected from 0 through 2 ; W is oxy ; R15 is selected from the group consisting of hydrido, cyano, hydroxyalkyl, acyl, alkoxy, alkyl, alkenyl, alkoxyalkyl, haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, monocyanoalkyl, dicyanoalkyl, carboxamide, and carboxamidoalkyl ; R4, R8, Rg, and R13 are independently selected from the group consisting of hydrido, halo, haloalkyl, and alkyl ; R5, R6, R7, R1o, R1 l, and R12 are independently selected from the group consisting of perhaloaryloxy, alkanoylalkyl, alkanoylalkoxy, alkanoyloxy, N-aryl-N-alkylamino, heterocyclylalkoxy, heterocyclylthio, hydroxyalkoxy, carboxamidoalkoxy, alkoxycarbonylalkoxy, alkoxycarbonylalkenyloxy, aralkanoylalkoxy, aralkenoyl, N-alkylcarboxamido, N-haloalkylcarboxamido, N-cycloalkylcarboxamido, N- arylcarboxamidoalkoxy, cycloalkylcarbonyl, cyanoalkoxy, heterocyclylcarbonyl, hydrido, carboxy, heteroaralkylthio, heteroarylsulfonyl, heteroaralkoxy, cycloalkylamino, acylalkyl, acylalkoxy, aroylalkoxy, heterocyclyloxy, aralkylaryl, aralkyl, aralkenyl, aralkynyl, heterocyclyl, haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl, cycloalkoxy, cycloalkylalkoxy, hydroxy, amino, thio, nitro, lower alkylamino, alkylthio, arylamino, aralkylamino, arylthio, arylthioalkyl, alkylsulfonyl. alkylsulfonamido, monoarylamidosulfonyl, arylsulfonyl, heteroarylthio, heterocyclylsulfonyl, heterocyclylthio, alkanoyl, alkenoyl, aroyl, alkyl, alkenyl, alkynyl, alkenyloxy, alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkylalkanoyl, halo,

haloalkyl, haloalkoxy, hydroxyhaloalkyl, hydroxyalkyl, aryl, aralkyl, aryioxy, aralkoxy, saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkyl, heteroarylalkyl, arylaikenyl, carboalkoxy, alkoxycarboxamido, alkylamidocarbonylamido, arylamidocarbonylamido, carboalkoxyalkyl, carboalkoxyalkenyl, carboxamido, carboxamidoalkyl, and cyano ; R4 and R5, Rs and R6, R6 and R7, R7 and R8, R9 and R 10, R 10 and R1 l, R1 l and R12, and R 12 and R 13 spacer pairs can be independently selected from the group consisting of alkylene, alkenylene, alkylenedioxy, aralkylene, diacyl, haloalkylene, and aryloxylene with the provisos that no more than one of the group consisting of spacer pairs R4 and R5, R5 and R6, R6 and R7, and R7 and R8 can be used at the same time and that no more than one of the group consisting of spacer pairs R9 and R10, R10 and R1 l R11 and Rio, and R12 and R 13 can be used at the same time.

In an even more specific embodiment of compounds of Formula VII-H, D1 D2, JI, J2 and K1 are each carbon ; D3, D4, J3, J4 and K2 are independently selected from the group consisting of C, N, O, S and covalent bond with the provisos that at least one of D3, D4, J3, J4 and K2 is selected from the group consisting of O, S, and N, wherein no more than one of D3, D4, J3, J4 and K2 can be a covalent bond, no more than one of D3, D4, J3, J4 and K2 can be O, no more than one of D3, D4, J3, J4 and K2 can be S, one of D3, D4, J3, J4 and K2 must be a covalent bond when two of D3, D4, J3, J4 and K2 are O and S, and no more than four of D3, D4, J3, J4 and K2 can be N ; n is an integer selected from 1 to 3 ; X is oxy ;

R1 is selected from the group consisting of trifluoromethyl, 1, 1, 2, 2-tetrafluoroethoxymethyl, trifluoromethoxymethyl, chloromethyl, fluoromethyl, difluoromethyl, chlorodifluoromethyl, pentafluoroethyl, 2, 2, 3, 3, 3-pentafluoropropyl, and heptafluoropropyl ; R16 is selected from the group consisting of acetyl, benzoyl, dimethyl tert-butylsilyl, hydrido, and trimethylsilyl ; R2 is selected from the group consisting of hydrido, hydroxy, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, vinyl, phenyl, trifluoromethyl, 4-trifluoromethylphenyl, 1, 1, 2, 2-tetrafluoroethoxymethyl, chloromethyl, trifluoromethoxymethyl, fluoromethyl, difluoromethyl, chlorodifluoromethyl, pentafluoroethyl, 2, 2, 3, 3, 3-pentafluoropropyl, and heptafluoropropyl, pentafluorophenyl, and pentafluorophenoxymethyl ; R3 is selected from the group consisting of hydrido, hydroxy, cyano, acetyl, methoxy, ethoxy, methyl, ethyl, propyl, vinyl, phenyl, methoxymethyl, 4-trifluoromethylphenyl, trifluoromethyl, 1, 1, 2, 2-tetrafluoroethoxymethyl, trifluoromethoxymethyl, chloromethyl, fluoromethyl, difluoromethyl, chlorodifluoromethyl, pentafluoroethyl, 2, 2, 3, 3, 3-pentafluoropropyl, heptafluoropropyl, pentafluorophenyl, and pentafluorophenoxymethyl.

In a more specific embodiment of compounds of Formula VII-H, D3, D4, J3, J4 and K2 are each carbon ; D D2, J1 J2 and Kl are independently selected from the group consisting of C, N, O, S and covalent bond with the provisos that at least one of DI, D2, J1 J2 and K1 is selected from the group consisting of O, S, and N, wherein no more than one of D1, D2, J1 J2 and K1 can be a covalent bond, no more than one of D 1, D2, J 1, J2 and K 1 can be O, no more than one of D 1, D2, J 1, J2 and K1 can be S, one of D I, D2, J 1, J2 and K 1 must be a covalent bond when two of D l, D2, J 1, J2 and Kl are O and S, and no more than four of D1, D2, J 1, J2 and K1 can be N ;

n is an integer selected from 1 to 3 ; X is oxy ; R1 is selected from the group consisting of trifluoromethyl, 1, 1, 2, 2-tetrafluoroethoxymethyl, trifluoromethoxymethyl, chloromethyl, fluoromethyl, difluoromethyl, chlorodifluoromethyl, pentafluoroethyl, 2, 2, 3, 3, 3-pentafluoropropyl, and heptafluoropropyl ; R16 is selected from the group consisting of acetyl, benzoyl, dimethyl tert-butylsilyl, hydrido, and trimethylsilyl ; R2 is selected from the group consisting of hydride, hydroxy, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, vinyl, phenyl, trifluoromethyl, 4-trifluoromethylphenyl, 1, 1, 2, 2-tetrafluoroethoxymethyl, chloromethyl, trifluoromethoxymethyl, fluoromethyl, difluoromethyl, chlorodifluoromethyl, pentafluoroethyl, 2, 2, 3, 3, 3-pentafluoropropyl, and heptafluoropropyl, pentafluorophenyl, and pentafluorophenoxymethyl ; R3 is selected from the group consisting of hydrido, hydroxy, cyano, acetyl, methoxy, ethoxy, methyl, ethyl, propyl, vinyl, phenyl, methoxymethyl, 4-trifluoromethylphenyl, trifluoromethyl, 1, 1, 2, 2-tetrafluoroethoxymethyl, trifluoromethoxymethyl, chloromethyl, fluoromethyl, difluoromethyl, chlorodifluoromethyl, pentafluoroethyl, 2, 2, 3, 3, 3-pentafiuoropropyl, heptafluoropropyl, pentafluorophenyl, and pentafluorophenoxymethyl.

In a preferred embodiment of compounds of Formula VII-H, the compounds correspond to the Formula VII (also referred to herein as generic phenyl tertiary 2-heteroalkylamines) :

or a pharmacuetically acceptable salt thereof, wherein ; n is an integer selected from 0 through 4 ; X is selected from the group consisting of O, H, F, S, S (O), NH, N (OH), N (alkyl), and N (alkoxy) ; R16 is selected from the group consisting of hydride, alkyl, acyl, aroyl, heteroaroyl, trialkylsilyl, and a spacer selected from the group consisting of a covalent single bond and a linear spacer moiety having a chain length of 1 to 4 atoms linked to the point of bonding of any aromatic substituent selected from the group consisting of R4, R8, Rg, and R13 to form a heterocyclyl ring having from 5 through 10 contiguous members with the proviso that said linear spacer moiety is other than covalent single bond when R2 is alkyl ; R1 is selected from the group consisting of haloalkyl, haloalkenyl, haloalkoxyalkyl, and haloalkenyloxyalkyl ; R2 is selected from the group consisting of hydride, hydroxy, hydroxyalkyl, aryl, aralkyl, alkyl, alkenyl, aralkoxyalkyl, aryloxyalkyl,

alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, cycloalkyl, cycloalkylalkyl,<BR> <BR> <BR> cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl. haloalkyl, haloalkenyl halocycloalkyl, halocycloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, heteroarylalkyl, monocyanoalkyl, and dicyanoalkyl, carboalkoxycyanoalkyl ; R3 is selected from the group consisting of hydrido, hydroxy, halo, cyano, hydroxyalkyl, aryl, aralkyl, acyl, alkoxy, alkyl, alkenyl, alkoxyalkyl, aroyl, heteroaroyl, alkenyloxyalkyl, haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, monocarboalkoxyalkyl, dicarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl, carboxamide, and carboxamidoalkyl ; Y is selected from the group consisting of covalent single bond and (C (R14) 2) q wherein q is an integer selected from 1 through 2 ; R14 is selected from the group consisting of hydrido, hydroxy, cyano, hydroxyalkyl, acyl, alkoxy, alkyl, alkenyl, alkynyl, alkoxyalkyl, haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, monocarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl, carboalkoxy, carboxamide, carboxamidoalkyl ; Z is selected from the group consisting of covalent single bond, (C (R15) 2) q wherein q is an integer selected from 1 through 2, and (CH (R15)) j- W- (CH (R15)) k wherein j and k are integers independently selected from 0 through 2 ; W is selected from the group consisting of O, C (O), C (S), C (O) N (R14), C (S) N (R14), (R14) NC (O), (R14) NC (S), S, S (O), S (O) 2, S (O) 2N (R14), (R14) NS (O) 2, and N (RI4) with the proviso that R 14 is other than cyano ; R15 is 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 ; R4, are independently selected from the group consisting of hydrido, halo, haloalkyl, and alkyl ; R5, R6, R7, Rlo, R11, and R12 are independently selected from the group consisting of perhaloaryloxy, alkanoylalkyl, alkanoylalkoxy, alkanoyloxy, N-aryl-N-alkylamino, heterocyclylalkoxy, heterocyclylthio, hydroxyalkoxy, carboxamidoalkoxy, alkoxycarbonylalkoxy, <BR> <BR> <BR> alkoxycarbonylalkenyloxy, aralkanoylalkoxy, aralkenoyl, N-alkylcarboxamido, N-haloalkylcarboxamido, N-cycloalkylcarboxamido, N- arylcarboxamidoalkoxy, cycloalkylcarbonyl, cyanoalkoxy, heterocyclylcarbonyl, 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, <BR> <BR> <BR> alkylsulfinyl, alkylsulfinylalkyl, arylsulfinylalkyl, arylsulfonylalkyl,<BR> <BR> <BR> <BR> <BR> 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 <BR> <BR> <BR> cycloalkenylalkyl, halo, haloalkyl, haloalkenyl, haloalkoxy, hydroxyhaloalkyl,

hydroxyaralkyl, hydroxyalkyl, hydoxyheteroaralkyl, haloalkoxyalkyl, aryl, heteroaralkynyl, aryloxy, aralkoxy, aryloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, heteroaralkyl, arylalkenyl, heteroarylalkenyl, carboxyalkyl, carboalkoxy, alkoxycarboxamido, alkylamidocarbonylamido, arylamidocarbonylamido, carboalkoxyalkyl, carboalkoxyalkenyl, carboaralkoxy, carboxamido, carboxamidoalkyl, cyano, carbohaloalkoxy, phosphono, phosphonoalkyl, diaralkoxyphosphono, and diaralkoxyphosphonoalkyl ; R4 and R5, R5 and R6, R6 and R7, R7 and R8, R9 and R 10, R 10 and R 11, R11 and R12, and R12 and R13 can be independently selected to form spacer pairs wherein a spacer pair is taken together to form a linear moiety having from 3 through 6 contiguous atoms connecting the points of bonding of said spacer pair members to form a ring selected from the group consisting of a cycloalkenyl ring having 5 through 8 contiguous members, a partially saturated heterocyclyl ring having 5 through 8 contiguous members, a heteroaryl ring having 5 through 6 contiguous members, and an aryl with the provisos that no more than one of the group consisting of spacer pairs R4 and R5, R5 and R6, R6 and R7, and R7 and R8, can be used at the same time and that no more than one of the group consisting of spacer pairs R9 and Rlo, Rlo and R11, R1 l and R12 and R12 and R13 can be used at the same time.

In a preferred embodiment of compounds of Formula VII, compounds have the Formula VII-2 :

wherein ; n is an integer selected from 1 through 4 ; R16 is selected from the group consisting of hydrido, acyl, aroyl, and trialkylsilyl ; Ri is selected from the group consisting of haloalkyl, haloalkenyl, haloalkoxyalkyl, and haloalkenyloxyalkyl ; R2 is selected from the group consisting of hydrido, hydroxy, aryl, aralkyl, alkyl, alkenyl, alkenyloxyalkyl, haloalkyl, haloalkenyl, halocycloalkyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl. halocycloalkoxy, halocycloalkoxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, dicyanoalkyl, and carboalkoxycyanoalkyl ; R3 is 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 the group consisting of covalent single bond and (C (R14) 2) q wherein q is an integer selected from 1 through 2 ; R14 is selected from the group consisting of hydrido, cyano, hydroxyalkyl, acyl, alkoxy, alkyl, alkenyl, alkoxyalkyl, haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, monocyanoalkyl, dicyanoalkyl, carboxamide, and carboxamidoalkyl ; Z is selected from the group consisting of covalent single bond, (C (R wherein q is an integer selected from 1 through 2, and (CH (R15)) j- W- (CH (Rl5)) k wherein j and k are integers independently selected from 0 through 2 ; W is oxy ; R15 is selected from the group consisting of hydrido, cyano, hydroxyalkyl, acyl, alkoxy, alkyl, alkenyl, alkoxyalkyl, haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, monocyanoalkyl, dicyanoalkyl, carboxamide, and carboxamidoalkyl ; R4, R8, Rg, and R13 are independently selected from the group consisting of hydrido, halo, haloalkyl, and alkyl ; R5, R6, R7, RIO, R11, and R12 are independently selected from the group consisting of perhaloaryloxy, alkanoylalkyl, alkanoylalkoxy, alkanoyloxy, N-aryl-N-alkylamino, heterocyclylalkoxy, heterocyclylthio, hydroxyalkoxy, carboxamidoalkoxy, alkoxycarbonylalkoxy, alkoxycarbonylalkenyloxy, aralkanoylalkoxy, aralkenoyl, N-alkylcarboxamido, N-haloalkylcarboxamido, N-cycloalkylcarboxamido, N- arylcarboxamidoalkoxy, cycloalkylcarbonyl, cyanoalkoxy, heterocyclylcarbonyl, hydrido, carboxy, heteroaralkylthio, heteroarylsulfonyl, heteroaralkoxy, cycloalkylamino, acylalkyl, acylalkoxy, aroylalkoxy, heterocyclyloxy, aralkylaryl, aralkyl, aralkenyl, aralkynyl, heterocyclyl, haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl, cycloalkoxy, cycloalkylalkoxy, hydroxy, amino, thio, nitro, lower alkylamino, alkylthio, arylamino, aralkylamino, arylthio, arylthioalkyl, alkylsulfonyl, alkylsulfonamido, monoarylamidosulfonyl, arylsulfonyl, heteroarylthio, heterocyclylsulfonyl,

heterocyclylthio, alkanoyl, alkenoyl, aroyl, alkyl, alkenyl, alkynyl, alkenyloxy, alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkylalkanoyl, halo, <BR> <BR> haloalkyl, haloalkoxy, hydroxyhaloalkyl, hydroxyalkyl, aryl, aralkyl, aryloxy, aralkoxy, saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, carboalkoxy, alkoxycarboxamido, alkylamidocarbonylamido, arylamidocarbonylamido, carboalkoxyalkyl, carboalkoxyalkenyl, carboxamido, carboxamidoalkyl, and cyano ; R4 and R5, R5 and R6, R6 and R7, R7 and R8, R9 and R1o, Rlo and Ri 1, Rl l and R12, and R12 and R13 spacer pairs can be independently selected from the group consisting of alkylene, alkenylene, alkylenedioxy, aralkylene, diacyl, haloalkylene, and aryloxylene with the provisos that no more than one of the group consisting of spacer pairs R4 and R5, R5 and R6, R6 and R7, and R7 and R8 can be used at the same time and that no more than one of the group consisting of spacer pairs R9 and Rlo, Rlo and R, R11 and R12, and R 12 and R13 can be used at the same time.

In a more preferred embodiment of compounds of Formula VII-2, n is an integer selected from 1 through 2 ; R1 is selected from the group consisting of haloalkyl and haloalkoxyalkyl ; R16 is hydrido ; R2 is selected from the group consisting of hydrido, aryl, alkyl, alkenyl, haloalkyl, haloalkoxy, haloalkoxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, and heteroaryl ; R3 is selected from the group consisting of hydrido, aryl, alkyl, alkenyl, haloalkyl, and haloalkoxyalkyl ; Y is selected from the group consisting of a covalent single bond and alkylene ; Z is selected from the group consisting of a covalent single bond and alkylene ;

R14 is selected from the group consisting of hydrido, alkyl, and haloalkyl ; R15 is selected from the group consisting of hydrido, alkyl, and haloalkyl ; R4, Rg, Rg, and R13 are independently selected from the group consisting of hydrido and halo ; R5, R6, R7, RIO, Ru 1, and R12 are independently selected from the group consisting of perhaloaryloxy, N-aryl-N-alkylamino, heterocyclylalkoxy, heterocyclylthio, hydroxyalkoxy, carboxamidoalkoxy, alkoxycarbonylalkoxy, alkoxycarbonylalkenyloxy, aralkanoylalkoxy, aralkenoyl, N-arylcarboxamidoalkoxy, cycloalkylcarbonyl, cyanoalkoxy, heterocyclylcarbonyl, 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.

In an even more preferred embodiment of compounds of Formula VII-2, n is the integer 1 ; R16 is hydrido ; R, is haloalkyl ; R2 is selected from the group consisting of hydrido, alkyl, haloalkyl, aryl, and haloalkoxy ; R3 is selected from the group consisting of hydrido, alkyl, and haloalkyl ; Y is alkylene ; Z is covalent single bond ; R14 is hydrido ; R4, R8, Rg, and R13 are independently selected from the group consisting of hydrido and halo ;

R5, R6, R7, RIO, Pi i. and R12 are independently selected from the group consisting of perhaloaryloxy, N-aryl-N-alkylamino, heterocyclylalkoxy, heterocyclylthio, hydroxyalkoxy, aralkanoylalkoxy, aralkenoyl, cycloalkylcarbonyl, cyanoalkoxy, heterocyclylcarbonyl, hydrido, alkyl, halo, haloalkyl, haloalkoxy, aryl, alkylthio, arylamino, arylthio, aroyl, arylsulfonyl, aryloxy, aralkoxy, heteroaryloxy, alkoxy, aralkyl, cycloalkoxy, cycloalkylalkoxy, cycloalkylalkanoyl, heteroaryl, cycloalkyl, haloalkylthio, hydroxyhaloalkyl, heteroaralkoxy, and heteroaryloxyalkyl.

In an embodiment of compounds of Formula VII-2, n is an integer selected from 1 to 3 ; R1 is selected from the group consisting of trifluoromethyl, 1, 1, 2, 2-tetrafluoroethoxymethyl, trifluoromethoxymethyl, chloromethyl, fluoromethyl, difluoromethyl, chlorodifluoromethyl, pentafluoroethyl, 2, 2, 3, 3, 3-pentafluoropropyl, and heptafluoropropyl ; R16 is selected from the group consisting of acetyl, benzoyl, dimethyl tert-butylsilyl, hydrido, and trimethylsilyl ; R2 is selected from the group consisting of hydrido, hydroxy, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, vinyl, phenyl, trifluoromethyl, 4-trifluoromethylphenyl, 1, 1, 2, 2-tetrafluoroethoxymethyl, chloromethyl, trifluoromethoxymethyl, fluoromethyl, difluoromethyl, chlorodifluoromethyl, pentafluoroethyl, 2, 2, 3, 3, 3-pentafluoropropyl, and heptafluoropropyl, pentafluorophenyl, and pentafluorophenoxymethyl ; R3 is selected from the group consisting of hydrido, hydroxy, cyano, acetyl, methoxy, ethoxy, methyl, ethyl, propyl, vinyl, phenyl, methoxymethyl, 4-trifluoromethylphenyl, trifluoromethyl, 1, 1, 2, 2-tetrafluoroethoxymethyl, trifluoromethoxymethyl, chloromethyl, fluoromethyl, difluoromethyl, chlorodifluoromethyl, pentafluoroethyl, 2, 2, 3, 3, 3-pentafluoropropyl, heptafluoropropyl, pentafluorophenyl, and pentafluorophenoxymethyl.

In a preferred embodiment of compounds of Formula VII-2, n is the integer 1 ; R16 is hydrido ;

Ri is selected from the group consisting of trifluoromethyl, 1, 1, 2, 2- tetrafluoroethoxymethyl, trifluoromethoxymethyl, difluoromethyl, chlorodifluoromethyl, and pentafluoroethyl ; R2 is selected from the group consisting of hydrido, methyl, ethyl, propyl, butyl, vinyl, phenyl, 4-trifluoromethylphenyl, trifluoromethyl, 1, 1, 2, 2- tetrafluoroethoxymethyl, trifluoromethoxymethyl, difluoromethyl, chlorodifluoromethyl, pentafluoroethyl, 2, 2, 3, 3, 3-pentafluoropropyl. and heptafluoropropyl ; R3 is selected from the group consisting of hydrido, phenyl, 4 trifluoromethylphenyl, methyl, ethyl, vinyl, methoxymethyl, trifluoromethyl, trifluoromethoxymethyl, difluoromethyl, chlorodifluoromethyl, and pentafluoroethyl.

In a even more preferred embodiment of compounds of Formula VII-2, n is the integer 1 ; Ri is selected from the group consisting of trifluoromethyl, 1, 1, 2, 2- tetrafluoroethoxymethyl, trifluoromethoxymethyl, difluoromethyl, chlorodifluoromethyl, and pentafluoroethyl ; R16 is hydrido ; R2 is selected from the group consisting of hydrido, methyl, ethyl, phenyl, 4trifluoromethylphenyl, trifluoromethyl, trifluoromethoxymethyl, 1, 1, 2, 2-tetrafluoroethoxymethyl, difluoromethyl, chlorodifluoromethyl, pentafluoroethyl, 2, 2, 3, 3, 3-pentafluoropropyl, and heptafluoropropyl ; R3 is selected from the group consisting of hydrido, phenyl, 4-trifluoromethylphenyl, methyl, trifluoromethyl, difluoromethyl, and chlorodifluoromethyl.

In a most preferred embodiment of compounds of Formula VII-2, n is the integer 1 ; R1 is selected from the group consisting of trifluoromethyl and pentafluoroethyl :

R16 is hydrido ; R2 is selected from the group consisting of hydride, phenyl, and trifluoromethyl ; R3 is selected from the group consisting of hydride, methyl, trifluoromethyl, and difluoromethyl.

In another embodiment of compounds of Formula VII, compounds have the formula Cyclo-VII : (Cyclo-VII)

wherein : R16 is taken together with R4, Rg, Rg, or R13 to form a spacer selected from the group consisting of a covalent single bond and a linear spacer moiety having a chain length of 1 to 4 atoms to form a heterocyclyl ring having from 5 through 10 contiguous members with the proviso that said linear spacer moiety is other than covalent single bondwhen R2 is alkyl ; n is an integer selected from 1 through 3 ; X is selected from the group consisting of O, S, NH, N (alkyl), and N (alkoxy) ;

Ri is selected from the group consisting of haloalkoxyalkyl, and haloalkenyloxyalkyl ; R2 is selected from the group consisting of hydrido, hydroxy, hydroxyalkyl, aryl, aralkyl, alkyl, alkenyl, aralkoxyalkyl, aryloxyalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, heteroarylalkyl, monocyanoalkyl, and dicyanoalkyl, carboalkoxycyanoalkyl ; R3 is selected from the group consisting of hydrido, hydroxy, halo, cyano, hydroxyalkyl, aryl, aralkyl, acyl, alkoxy, alkyl, alkenyl, alkoxyalkyl, aroyl, heteroaroyl, alkenyloxyalkyl, haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, monocarboalkoxyalkyl, dicarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl, carboxamide, and carboxamidoalkyl ; Y is selected from the group consisting of covalent single bond and (C (R14) 2) q wherein q is an integer selected from 1 through 2 ; R14 is selected from the group consisting of hydrido, hydroxy, cyano, hydroxyalkyl, acyl, alkoxy, alkyl, alkenyl, alkynyl, alkoxyalkyl, haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, monocarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl, carboalkoxy, carboxamide, carboxamidoalkyl ; Z is selected from the group consisting of covalent single bond, (C (R15) 2) q wherein q is an integer selected from 1 through 2, and (CH (R15)) j- W-(CH (R15)) k wherein j and k are integers independently selected from 0 through 2 ; W is selected from the group consisting of O. C (O), S, S (O), and S (O) 2 ; R15 is selected from the group consisting of hydrido, cyano, hydroxyalkyl, acyl, alkoxy, alkyl, alkenyl, alkynyl, alkoxyalkyl, haloalkyl,

haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, <BR> <BR> monocarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl, carboalkoxy, carboxamide, and carboxamidoalkyl ; R4, R8, Rg, and R13 are independently selected from the group consisting of hydrido, halo, haloalkyl, and alkyl ; R5, R6, R7, R1o, R1 l, and R12 are independently selected from the group consisting of perhaloaryloxy, alkanoylalkyl, alkanoylalkoxy, alkanoyloxy, N-aryl-N-alkylamino, heterocyclylalkoxy, heterocyclylthio, hydroxyalkoxy, carboxamidoalkoxy, alkoxycarbonylalkoxy, alkoxycarbonylalkenyloxy, aralkanoylalkoxy, aralkenoyl, N-alkylcarboxamido, N-haloalkylcarboxamido, N-cycloalkylcarboxamido, N- arylcarboxamidoalkoxy, cycloalkylcarbonyl, cyanoalkoxy, heterocyclylcarbonyl, 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, heteroaralkyl, arylalkenyl, heteroarylalkenyl, carboxyalkyl, carboalkoxy, alkoxycarboxamido, alkylamidocarbonylamido, arylamidocarbonylamido, carboalkoxyalkyl, carboalkoxyalkenyl, carboaralkoxy, carboxamido, carboxamidoalkyl, cyano, carbohaloalkoxy, phosphono, phosphonoalkyl, diaralkoxyphosphono, and diaralkoxyphosphonoalkyl ; R5 and R6, R6 and R7, R7 and Rg, Rg and R10 R10 and R11 R11 and R 12, and Ri and R13 can be 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 R5 and R6, R6 and R7, and R7 and R8, can be used at the same time and that no more than one of the group consisting of spacer pairs Rg and R10 R10 and R1 l, R1 l and R12 and R12 and R13 can be used at the same time.

In an embodiment of compounds of Formula Cyclo-VII, n is the integer 1 ; X is selected from the group consisting of O, NH, and S ; R16 is taken together with R4, R8, Rg, or R13 to form a spacer selected from the group consisting of a covalent single bond, CH2, CH (CH3), CF2, C (O), C (S), and SO2 ; R1 is selected from the group consisting of trifluoromethyl, 1, 1, 2, 2- tetrafluoroethoxymethyl, trifluoromethoxymethyl, difluoromethyl, chlorodifluoromethyl, and pentafluoroethyl ; R2 is selected from the group consisting of hydrido, phenyl,

4-trifluoromethylphenyl, vinyl, trifluoromethyl, pentafluoroethyl, 1, 1, 2, 2-tetrafluoroethoxymethyl, trifluoromethoxymethyl, difluoromethyl, chlorodifluoromethyl, 2, 2, 3, 3, 3-pentafluoropropyl, and heptafluoropropyl ; R3 is selected from the group consisting of hydrido, methyl, ethyl, <BR> <BR> <BR> <BR> vinyl, phenyl. 4-trifluoromethylphenyl, methoxymethyl, trifluoromethyl, trifluoromethoxymethyl, difluoromethyl, chlorodifluoromethyl, and pentafluoroethyl.

In another embodiment of compounds of Formula Cyclo-VII, compounds have the formula :

n is the integer 1 ; X is oxy ; R16 is taken together with R4, Rg, Rg, or R13 to form a covalent single bond ; Ri is selected from the group consisting of trifluoromethyl, 1, 1, 2, 2- tetrafluoroethoxymethyl, trifluoromethoxymethyl, difluoromethyl, chlorodifluoromethyl, and pentafluoroethyl ; R2 is selected from the group consisting of hydrido, phenyl, 4-trifluoromethylphenyl, vinyl, trifluoromethyl, pentafluoroethyl,

1, 1, 2, 2-tetrafluoroethoxymethyl, trifluoromethoxymethyl, difluoromethyl, chlorodifluoromethyl, 2, 2, 3, 3, 3-pentafluoropropyl, and heptafluoropropyl ; R3 is selected from the group consisting of hydrido, methyl, ethyl, vinyl, phenyl, 4-trifluoromethylphenyl, methoxymethyl, trifluoromethyl, trifluoromethoxymethyl, difluoromethyl, chlorodifluoromethyl, and pentafluoroethyl.

In another embodiment of compounds of Formula VII. compounds have the Formula VII-3 : or a pharmaceutically acceptable salt thereof, wherein : R1 is selected from the group consisting of haloalkyl, haloalkenyl, haloalkoxyalkyl and haloalkenyloxyalkyl ; R2 is hydroxyalkyl ; Y is selected from the group consisting of covalent single bond and (C (R 14) 2) q wherein q is an integer selected from 1 through 2 ; R14 is selected from the group consisting of hydrido, cyano, hydroxyalkyl, acyl, alkoxy, alkyl, alkenyl, alkoxyalkyl, haloalkyl, haloalkenyl,

haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, monocyanoalkyl, dicyanoalkyl, carboxamide, and carboxamidoalkyl ; Z is selected from the group consisting of covalent single bond, (C (R15) 2) q wherein q is an integer selected from 1 through 2, and (CH (R15)) g- W- (CH (R wherein j and k are integers independently selected from 0 through 2 ; W is oxy ; R15 is selected from the group consisting of hydrido, cyano, hydroxyalkyl, acyl, alkoxy, alkyl, alkenyl, alkoxyalkyl, haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, monocyanoalkyl, dicyanoalkyl, carboxamide, and carboxamidoalkyl ; R4, R8, Rg, and R13 are independently selected from the group consisting of hydrido, halo, haloalkyl, and alkyl ; R5, R6, R7, RIO, R, 1, and R12 are independently selected from the group consisting of perhaloaryloxy, alkanoylalkyl. alkanoylalkoxy, alkanoyloxy, N-aryl-N-alkylamino, heterocyclylalkoxy, heterocyclylthio, hydroxyalkoxy, carboxamidoalkoxy, alkoxycarbonylalkoxy, alkoxycarbonylalkenyloxy, aralkanoylalkoxy, aralkenoyl, N-alkylcarboxamido, N-haloalkylcarboxamido, N-cycloalkylcarboxamido, N- arylcarboxamidoalkoxy, cycloalkylcarbonyl, cyanoalkoxy, heterocyclylcarbonyl, hydrido, carboxy, heteroaralkylthio, heteroarylsulfonyl, heteroaralkoxy, cycloalkylamino, acylalkyl. acylalkoxy, aroylalkoxy, heterocyclyloxy, aralkylaryl, aralkyl, aralkenyl, aralkynyl, heterocyclyl, haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl, cycloalkoxy, cycloalkylalkoxy, hydroxy, amino, thio, nitro, lower alkylamino, alkylthio, arylamino, aralkylamino, arylthio, arylthioalkyl, alkylsulfonyl, alkylsulfonamido, monoarylamidosulfonyl, arylsulfonyl, heteroarylthio, heterocyclylsulfonyl, heterocyclylthio, alkanoyl, alkenoyl, aroyl, alkyl. alkenyl, alkynyl, alkenyloxy, alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkylalkanoyl, halo, haloalkyl, haloalkoxy, hydroxyhaloalkyl, hydroxyalkyl, aryl, aralkyl, aryloxy, aralkoxy, saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, carboalkoxy, alkoxycarboxamido, alkylamidocarbonylamido, arylamidocarbonylamido, carboalkoxyalkyl, carboalkoxyalkenyl, carboxamido, carboxamidoalkyl, and cyano ;

R4 and R5, Rs and R6, R6 and R7, R7 and R8, R9 and R 10, R 10 and Ri 1 R1 l and R12, and Ri and R13 spacer pairs can be independently selected from the group consisting of alkenylene, alkylenedioxy, aralkylene, diacyl, haloalkylene, and aryldioxylene with the provisos that no more than one of the group consisting of spacer pairs R4 and R5, R5 and R6, R6 and R7, and R7 and R8 can be used at the same time and that no more than one of the group consisting of spacer pairs R9 and R 10, R 10 and R 11, R 11 and R 12, and R 12 and R13 can be used at the same time.

In an embodiment of compounds of Formula VII-3, R1 is selected from the group consisting of trifluoromethyl, 1, 1, 2, 2- tetrafluoroethoxymethyl, chloromethyl, trifluoromethoxymethyl, fluoromethyl, difluoromethyl, chlorodifluoromethyl, pentafluoroethyl, 2, 2, 3, 3, 3- pentafluoropropyl, heptafluoropropyl, and pentafluorophenoxymethyl ; R2 is hydroxymethyl, 1-hydroxyethyl, and 1, 2-dihydroxyethyl.

In another embodiment of compounds of Formula VII, compounds have the Formula VII4 :

wherein ; X is oxy ; Ri is selected from the group consisting of haloalkyl and haloalkoxyalkyl ; Rl6 is hydride ; R2 and R3 are 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 6 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, and a heterocyclyl having from 4 through 8 contiguous members ; Y is selected from the group consisting of a covalent single bond and alkylene ; Z is selected from the group consisting of a covalent single bond and alkylene ;

R14 is selected from the group consisting of hydrido, alkyl, and haloalkyl ; R15 is selected from the group consisting of hydrido, alkyl, and haloalkyl ; R4, R8, R9, and R13 are independently selected from the group consisting of hydrido and halo ; R5, R6, R7, R1o, R1 l, and R12 are independently selected from the group consisting of perhaloaryloxy, N-aryl-N-alkylamino, heterocyclylalkoxy, heterocyclylthio, hydroxyalkoxy, carboxamidoalkoxy, alkoxycarbonylalkoxy, alkoxycarbonylalkenyloxy, aralkanoylalkoxy, aralkenoyl, N-arylcarboxamidoalkoxy, cycloalkylcarbonyl, cyanoalkoxy, heterocyclylcarbonyl, 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.

In an embodiment of compounds of Formula VII-4, X is oxy ; R16 is hydrido ; R1 is selected from the group consisting of trifluoromethyl, 1, 1, 2, 2- tetrafluoroethoxymethyl, trifluoromethoxymethyl, difluoromethyl, chlorodifluoromethyl, and pentafluoroethyl ; R2 and R3 spacer pair is selected from the group consisting of -CH2SCH2-,-CH2OCH2-,-CH2CH (R17)-, -CH=C(R17)-, -CH2S (0) 2CH2-,-CH2CH2CH (R17)-,.-CH2CH(R17)CH2-, -CH2CH=C (R17)-, -CH(R17)CH=CH-, -CH2C(R17)=CH-, -CH (R17) C (O) N (R 17)-,-C (O) N (RI7) CH (R17)-, -CH(R17) C (O) NHCH2-,

-CH2C (O) NHCH (R17)-, -CH(R17) CH (RI7) C (O) NH-, -C (O) NHCH (RI7) CH (R17)-, -CH2CH(R17)CH2CH2-, -CH (R17) CH2CH2CH2-,-CH2CH=CHCH2-,-CH=CHCH2CH2-, -CH=CHCH=CH-,-CH2CH2CH2CH2CH2-,-CH2CH2CH=CHCH2-, -(CH2)2O-, -(CH2CHR17)O-, -(CF2)2O-, -SCH2CH2-, -S(O)CH2CH2-, -CH2S (O) CH2-,-CH2S (O) CH2CH2-,-S (O) 2CH2-,-CH2N (R 7) 0-, -CH2CH2C (O)-,-CH2C (O) NRl-, and-CH2NR17CH2-wherein R17 is selected from the group consisting of H, CH3, OCH3, CF3, CH2CH3, F, Cl, CH2OH, and OH.

In an embodiment of compounds of Formulas VII-H, VII, VII-2, VII-3, VII-4, and Cyclo-VII, Y is selected from the group consisting of a covalent single bond, methylene, 2-fluoroethylidene, ethylidene, 2, 2-difluoroethylidene, and 2, 2, 2- trifluoroethylidene ; Z is group selected from the group consisting of covalent single bond, oxy, methyleneoxy, methylene, ethylene, ethylidene, 2-fluoroethylidene, 2, 2- difluoroethylidene, and 2, 2, 2-trifluoroethylidene ; R4, R8, Rg, and R13 are independently selected from the group consisting of hydrido and fluoro ; R5 and R1o are independently selected from the group consisting of acetoxy, 3-acetamidophenoxy, 3-acetylphenoxy, 4-acetylphenylsulfonyl, amino, 4-acetylphenylthio, acetylthio, 3-aminobenzyloxy, 4-aminobenzyloxy, 4- aminophenoxy, 3-aminophenyl, benzoyl, benzoylamido, benzoylmethoxy, <BR> <BR> benzyl, N-benzylamidocarbonyl, benzylamino, 3-benzylimidazol4-ylmethoxy, N-benzyl-N-methylamidocarbonyl, benzyloxy, 4-benzyloxybenzyloxy, 4- benzylphenoxy, 4-benzylpiperidinyl, bromo, 5-bromo-2-fluorophenoxy, 4- bromo-3-fluorophenoxy, bromomethyl, 4-bromo-2-nitrophenoxy, 2- bromobenzyloxy, 3-bromobenzyloxy, 4-bromobenzyloxy, 4-bromophenoxy, 5- bromopyrid-2-yloxy, 4-bromothiophen-3-ylthio, butoxy, 4-butoxyphenoxy, N- butylylcarboxamido, N-butyl-N-methylcarboxamido,

N-butyl-4-ethoxycarbonylphenylamino, 4-butylphenoxy, carboxy, carboxamidomethoxy, 3-carboxybenzyloxy, 4-carboxybenzyloxy, 4-carboxyphenyl, 5-carboxypyrid-3-yloxy, chloro, 3-chlorobenzyl, 2-chlorobenzyloxy, 3-chlorobenzyloxy, 4-chlorobenzyloxy, 2-chlorophenoxy, 4-chlorophenoxy, 4-chloro-3-ethylphenoxy, 3-chloro-4-fluorobenzyl, 3-chloro-4-fluorophenyl, 3-chloro-2-fluorobenzyloxy, 3-chloro-2- hydroxypropoxy, 4-chloro-3-methylphenoxy, 4-chloro-3-methylbenzyl, 2-chloro-4-fluorophenoxy, 4-chlorophenoxy, 3-chloro-4-ethylphenoxy, 3-chloro4-methylphenoxy, 3-chloro4-fluorophenoxy, 4-chloro-3-fluorophenoxy, 4-chloro-2-fluorophenoxy, <BR> <BR> 3-chloro-4-fluorophenylsulfonylamido, 4-chlorophenyl,<BR> <BR> <BR> 3-chlorophenylamino, 4-chlorophenylamino,<BR> <BR> <BR> 5-chlorophenylthiophen-3-ylmethoxy, 5-chloropyrid-3-yloxy, 4-chlorothiophen-2-ylmethylthio, cyano, 3-cyanobenzyloxy, 4-cyanobenzyloxy, 4- (2-cyano-2-ethoxycarbonylacetyl) phenylamino, N- (2-cyanoethyl)-4-methylphenylamino, 2-cyanopyrid-3-yloxy, 4-cyanophenoxy, 4-cyanophenyl, 3-cyanophenylamino, 4-cyanophenylamino, 3-cyanopropoxy, cyclobutoxy, cyclobutyl, cyclohexylamidocarbonyl, cyclohexoxy, cyclohexylmethoxy, cyclopentoxy, cyclopentyl, N- cyclopentylamidocarbonyl, cyclopentylcarbonyl, 4-cyclopentylphenxoy, cyclopropyl, cyclopropylmethoxy, cyclopropoxy, 3, 5-dichlorobenzyloxy, 3, 5-dichloro4-methylphenoxy, 2, 3-dichlorophenoxy, 2, 4-dichlorophenoxy, 3, 5-dichlorophenoxy, 2*4-dichlorophenyl, 3, 5-dichlorophenyl, 3, 5-dichloro4-methoxyphenyl, 3, 5-dichlorobenzyl, 3, 4-dichlorophenoxy, 3, 4-dichlorophenyl, 3, 4-difluorophenoxy, 2, 4-difluorobenzyloxy, 2, 5-difluorobenzyloxy, 3, 5-difluorobenzyloxy, 2, 6- difluorobenzyloxy, 3, 5-difluorophenoxy, 3, 4-difluorophenyl, 4-difluoromethoxybenzyloxy, 2, 3-difluorophenoxy, 2, 4-difluorophenoxy, 2, 3- difluorobenzyloxy, 3, 4-difluorobenzyloxy, difluoromethoxy, 2, 5-difluorophenoxy, 3, 5-difluorophenylamino, 3, 5-dimethoxyphenoxy, dimethylamino, N, N-dimethylcarboxamido, 2- (N, N-dimethylamino) ethoxy, 3-dimethylaminophenoxy, 3, 4-dimethylbenzyloxy, 3, 5-dimethylbenzyloxy, 3, 5-dimethylphenoxy, 3, 4-dimethylphenoxy, 3, 5-dimethyl4 (N, N-dimethylamino) phenyl, 3, 4-dimethoxyphenylamino, 3, 4- dimethylbenzyl, 3, 4-dimethylbenzyloxy, 1, 1-dimethylhydroxymethyl, 3, 3-dimethyl-2-oxobutoxy, 2, 2-dimethylpropoxy, 1, 3-dioxan-2-yl, 1, 4-dioxan- 2-yl, 1, 3-dioxolan-2-yl, ethoxy, ethoxycarbonyl,

3-ethoxycarbonylphenylamino, 4-ethoxycarbonylphenylamino, 1-ethoxycarbonylbutoxy, 4-ethoxyphenoxy, ethyl, 4, 4-ethylenedioxypiperidinyl, N-ethyl-N-methylcarboxamido, 3-ethylphenoxy, 4-ethylaminophenoxy, 4-ethylbenzyloxy, 3-ethyl-5-methylphenoxy, N-ethyl-3-methylphenylamino, N-ethyl-4-methoxyphenylamino, fluoro, 4-fluorobenzylamino, 4-fluoro-3-methylbenzyl, 2-fluoro-3-methylbenzyloxy, 4-fluoro-3-methylphenyl, 4-fluorobenzoyl, 4-fluoro-3-methylbenzoyl, 3-fluorobenzyloxy, 4-fluorobenzyloxy, 2-fluoro-3-methylphenoxy, 3-fluoro-4- methylphenoxy, 3-fluorophenoxy, 3-fluoro-2-nitrophenoxy, 2-fluoro-3- <BR> <BR> trifluoromethylbenzyloxy, 4-fluoro-2-trifluoromethylbenzyloxy,<BR> <BR> <BR> 4-fluoro-3-trifluoromethylbenzyloxy, 5-fluoro-3-trifl uoromethylbenzyloxy, 2-fluorophenoxy, 4-fluorophenoxy, 2-fluoro-3-trifluoromethylphenoxy, 2-fluorobenzyloxy, 4-fluorophenylamidocarbonylamido, 4-fluorophenylamino, 4-fluorobenzoylamido, 4-fluorobenzylamidocarbonyl, 2- fluoro-4-trifluoromethylphenoxy, 4-fluoro-2-trifluoromethylphenoxy, 2-fluoro-4-chloromethylphenoxy, 4-fluoropyrid-2-yloxy, 2-furyl, 3-furyl, N- (2, 2, 3, 3, 4, 4, 4-heptafluorobutyl) amidocarbonyl, heptafluoropropyl, 1, 1, 1, 3, 3, 3-hexafluoropropyl, hydrazinocarbonyl, hydrido, hydroxy, 2- hydroxyethoxy, 1-hydroxyisobutyl, 3-hydroxy-2, 2-dimethylpropoxy, hydroxymethyl, 3-hydroxymethylphenoxy, 4-hydroxyphenoxy, 3- hydroxypropoxy, 2-hydroxy-3, 3, 3-trifluoropropoxy, 4-imidazol-1-yl-phenoxy, indol-5-yloxy, iodo, 3-iodobenzyloxy, isobutylamino, isobutoxy, N-isobutoxycarbonylamido, isobutyl, isobutyryl, isobutyrylamido, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, isopropoxy, isopropyl, isopropylamidocarbonyl, isopropylamidocarbonylamido, 4-isopropylbenzyloxy, N-isopropyl-N-methylamino, 3-isopropylphenoxy, 4-isopropylphenoxy, isopropylthio, 4-isopropyl-3-methylphenoxy, isopropylsulfonyl, isopropylsulfonylamido, isoquinolin-3-yloxy, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, methoxy, 3-methoxybenzoylamido, 3-methoxybenzyl, methoxycarbonyl, 4-methoxycarbonylbutoxy, 3-methoxycarbonylbenzyloxy, 4-methoxycarbonylbenzyloxy, 2-methoxyethoxy, 3-methoxycarbonylmethoxy, 3-methoxycarbonylprop-2-enyloxy, methoxymethyl, N-methoxy-N-methylcarboxamido, 3-methoxyphenoxy, 4-methoxyphenoxy, 4-methoxy-3-methylphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-methoxyphenylamino,

4-methoxyphenylamino, 3-methoxyphenylamidocarbonylamido, 4-methoxyphenylthio, methyl, N-methyl-4-methoxyphenylamino, 4-methylbenzyl, 3-methylbutyl, 3-methylphenoxy, 4-methylsulfonylphenyl, <BR> <BR> 3-methylXmethylthiophenoxy, 3-methylbenzyloxy, 4-methylbenzyloxy,<BR> <BR> <BR> 2-methyl-3-nitrophenoxy, 2-methyl-5-nitrophenoxy, 4-methylphenoxy,<BR> <BR> <BR> 4-methylphenyl, N-methyl-N-phenylamidocarbonyl, N-methyl-N-propylcarboxamido, 4- (5- (4-methylphenyl)-1, 3, 4-oxadiazol-2-yl) phenylamino, 3-methylphenylsulfonylamido, 4-methylpiperazin-1-ylcarbonyl, 1-methylpropoxy, 3-methylbut-2-enyloxy, 2-methylpyrid-6-yl, 3-methylpyrid-2-yl, 2-methylpyrid-3-yloxy, 2-methylpyrid-5-yloxy, N- methylpyrrol-2-yl, Smethylsulfonylphenylsulfonyl, 4-methylsulfonylphenylthio, 4-methylthiophenoxy, 4-methylthiophenyl, 4-methylthiobenzyl, morpholin-4-ylcarbonyl, 2-naphthyloxy, N-neopentylamidocarbonyl, nitro, 3-nitrobenzyl, 3-nitrobenzyloxy, 4-nitrobenzyloxy, 2-nitrophenoxy, 3-nitrophenoxy, 4-nitrophenoxy, 3-nitrophenyl, 4-nitrophenylsulfonyl, 3-nitrophenylsulfonylamido, 4-nitrophenylthio, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 2-oxobutoxy, 5-oxohexoxy, N-oxypyrid-3-ylmethylsulfonyl, 2, 3, 4, 5, 6- pentafluorobenzyloxy, pentafluoroethyl, pentafluoroethylthio, 4- (2, 3, 4, 5, 6-pentafluorophenyl)-2, 3, 5, 6-tetrafluorophenoxy, 2, 2, 3, 3, 3-pentafluoropropyl, 1, 1, 3, 3, 3-pentafluoropropyl, 1, 1, 2, 2, 3-pentafluoropropyl, phenoxy, 3-phenoxybenzyloxy, phenyl, phenylamidocarbonylamido, l-(N-phenylcarboxamido) ethoxy, phenylamino, 4- phenylbenzyloxy, 1-phenylethoxy, phenylhydroxymethyl, 3-phenylphenoxy, 4-phenylphenoxy, phenylsulfonyl, phenylsulfonylamido, 2-phenylsulfonylethoxy, phenylthio, 1-piperidinyl, piperidin-4-ylcarbonyl, piperidin-4-ylsulfonyl, piperidin-4-ylthio, hexahydropyran-4-yioxy, 4-propanoyl, 4-propanoylphenoxy, propoxy, 4-propylphenoxy, 4-propylphenylamino, 4-propoxyphenoxy, pyrid-2-yl, pyrid-3-yl, pyrid-3-ylcarboxamido, pyrid-2-ylmethoxy, pyrid-3-ylmethoxy, pyrid-4-ylmethoxy, pyrid-2-yloxy, pyrid-3-yloxy, pyrid-2-ylmethylthio, pyrid- 4-ylthio, pyrimid-2-yl, pyrimid-2-yloxy, pyrimid-5-yloxy, pyrrolin-1-ylcarbonyl, 2-(pyrrolidin-1-yl) ethoxy, thiophen-3-yl, sec-butyl, 4-sec-butylphenoxy, tert-butoxy, N-tert-butylamidocarbonyl, 4-tert-butylbenzyl, 4-tert-butylbenzyloxy, 3-tert-butylphenoxy,

4-tert-butylphenoxy, 4-tert-butylphenyl, tetrazol-5-yl, 3- (1, 1, 2, 2-tetrafluoroethoxy) benzylamino, 1, 1, 2. 2-tetrafluoroethoxy, 2, 3, 5, 6-tetrafluoro-4-methoxybenzyioxy, 2, 3, 5, 6-tetrafluoro-4-trifluoromethylbenzyloxy, tetrahydrofuran-2-yl, 2- (5, 6, 7, 8-tetrahydronaphthyloxy), thiazol-2-yi, thiazol-4-yl, thiazol-5-yl, thiol, 4-thiophenoxy, thiophen-2-yl, 2, 3, 5-trifluorobenzyloxy, 2, 4, 6-trifluorobenzyloxy, N- (4, 4, 4-trifluorobutyl)-4-methoxyphenylamino, 2, 2, 2-trifluoroethoxy, 2, 2, 2-trifluoroethyl, 3, 3, 3-trifluoro-2-hydroxypropyl, N- (2, 2, 2-trifluoroethyl) amidocarbonyl, trifluoromethoxy, 3-trifluoromethoxybenzyloxy, 3-trifluoromethoxybenzylamidocarbonyl, 3-trifluoromethoxybenzylamidocarbonylhydrazinocarbonyl, 4-trifluoromethoxybenzyloxy, 3-trifluoromethoxyphenoxy, 4-trifluoromethoxyphenoxy, 4-trifluoromethoxyphenylamino, trifluoromethyl, 3-trifluoromethylbenzylamine, 3-trifluoromethylbenzyloxy, 4-trifluoromethylbenzyloxy, 2, 4-bis-trifluoromethylbenzyloxy, 3, 4-bis-trifluoromethylbenzyloxy, 1, 1-bis-trifluoromethyl-1-hydroxymethyl, 3, 5-bis-trifluoromethylphenyl, 3-trifluoromethylbenzyl, 3, 5-bis-trifluoromethylbenzyloxy, 4-trifluoromethylphenoxy, 3-trifluoromethylphenoxy, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 3-trifluoromethylphenylamidocarbonylamido, 4-trifluoromethylphenylamino, 3- trifluoromethylphenylsulfonylamido, 3-trifluoromethylthiobenzyloxy, 4-trifluoromethylthiobenzyloxy, 2, 3, 4-trifluorophenoxy, 2, 3, 4-trifluorophenyl, 2, 3, 5-trifluorophenoxy, 3*4, 5-trimethylphenoxy, 3, 4, 5-trimethoxyphenylamino, 3-trifluoromethylpyrid-2-yl, 3-trifluoromethylpyrid-2-yloxy, 5-trifluoromethylpyrid-2-yloxy, 3-difluoromethoxyphenoxy, 3-pentafluoroethylphenoxy, 3- (1, 1, 2, 2-tetrafluoroethoxy) phenoxy, 3-trifluoromethylthiophenoxy, and trifluoromethylthio ; R6 and R1 l are independently selected from the group consisting of acetoxy, benzyloxy, bromo, butoxy, butoxycarbonyl, chloro, 4-chlorophenyl, 3, 4-dichlorophenoxy, cyano, 2-cyanophenyl, difluoromethoxy, ethoxy, fluoro, hydrido, hydroxy, methoxy, methoxycarbonyl, methyl, methylsulfonyl, morpholin-4-yl, nitro, octyl, phenoxy, phenyl, phenylethenyl, phenylethynyl, propoxy, thiophen-2-yl, trifluoromethyl, pentafluoroethyl, 1, 1, 2, 2- tetrafluoroethoxy, and trifluoromethoxy ;

R7 and R12 are independently selected from the group consisting of benzyloxy, hydrido, fluoro, hydroxy, methoxy, and trifluoromethyl : R5 and R6 can be taken together to form a spacer group selected from the group consisting of benzylidene, 5-bromobenzylidene, ethylene-1, 2-dioxy, tetrafluoroethylene-1, 2-dioxy, 1, 4-butadienyl, methylene-1, 1-dioxy, phenoxylidene. and propylene-1, 3-dioxy ; R6 and Ry can be taken together to form a spacer group selected from the group consisting of benzylidene, 5-bromobenzylidene, ethylene-1, 2-dioxy, tetrafluoroethylene-1, 2-dioxy, 1, 4-butadienyl, methylene-1, 1-dioxy, phenoxylidene. and propylene-1, 3-dioxy ; R1o and Ri j can be taken together to form a spacer group selected from the group consisting of benzylidene, ethylene-1, 2-dioxy, methylene-l, l-dioxy, phthaloyl, and tetrafluoroethylene-1, 2-dioxy ; Ri 1 and Rio can be taken together to form a spacer group selected from the group consisting of benzylidene, ethylene-1, 2-dioxy, methylene-1, 1-dioxy, phthaloyl, and tetrafluoroethylene-1, 2-dioxy ; R12 can be the spacer group 1, 4-butadienyl.

In a preferred embodiment of compounds of Formulas VII-H, VII, VII-2, VII-3, VII-4, and Cyclo-VII, Y is selected from the group consisting of methylene, ethylene, and ethylidene ; Z is covalent single bond ; R4, R8, Rg, and R13 are independently selected from the group consisting of hydrido and fluoro ; R5 and RIO are independently selected from the group consisting of 4-aminophenoxy, benzoyl, benzyl, benzyloxy, 5-bromo-2-fluorophenoxy, 4-bromo-3-fluorophenoxy, 4-bromo-2-nitrophenoxy, 3-bromobenzyloxy, 4-bromobenzyloxy, 4-bromophenoxy, 5-bromopyrid-2-yloxy, 4-butoxyphenoxy, chloro, 3-chlorobenzyl, 2-chlorophenoxy, 4-chlorophenoxy, 4-chl oro-3-ethyl phenoxy, 3-chloro-4-fluorobenzyl, 3-chloro4-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, <BR> <BR> 3-chloro4-methylphenoxy, 3-chloro4-fluorophenoxy,<BR> <BR> <BR> 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-methylXmethylthiophenoxy, 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 and R1 l are independently selected from the group consisting of chloro, fluoro, hydrido, pentafluoroethyl, 1, 1, 2, 2-tetrafluoroethoxy, trifluoromethyl, and trifluoromethoxy ; R7 and R12 are independently selected from the group consisting of hydrido, fluoro, and trifluoromethyl.

In an even more preferred embodiment of compounds of Formulas VII-H, VII, VII-2, VII-3, VII-4, and Cyclo-VII, Y is methylene ; Z is covalent single bond ; R4, R8, Rg, and R13 are independently selected from the group consisting of hydrido and fluoro ;

R5 and RIO are independently selected from the group consisting of benzyloxy, 5-bromo-2-fluorophenoxy, 4-bromo-3-fluorophenoxy, 3-bromobenzyloxy, 4-bromophenoxy, 4-butoxyphenoxy, 3-chlorobenzyloxy, 2-chlorophenoxy, 4-chloro-3-ethylphenoxy, 4-chloro-3-methylphenoxy, <BR> <BR> <BR> 2-chloro-4-fluorophenoxy, 4-chloro-2-fluorophenoxy, 4-chlorophenoxy.<BR> <BR> <BR> <BR> <BR> <P>3-chloro-4-ethylphenoxy, 3-chloro-4-methylphenoxy,<BR> <BR> <BR> <BR> <BR> 3-chloro4-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, <BR> <BR> <BR> 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, <BR> <BR> <BR> 2-fluoro-3-trifluoromethylphenoxy, 2-fluorobenzyloxy, 4-fluorophenylamino,<BR> <BR> <BR> <BR> <BR> 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, thiazolXyl, 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 and R1 l are independently selected from the group consisting of chloro, fluoro, hydrido, pentafluoroethyl, 1, 1, 2, 2-tetrafluoroethoxy, and trifluoromethyl ; R7 and R12 are independently selected from the group consisting of hydrido, fluoro, and trifluoromethyl.

In a most preferred embodiment of compounds of Formulas VII-H, VII, VII-2, VII-3, VII-4, and Cyclo-VII, Y is methylene ; Z is covalent single bond ; R4, R8, Rg, and R13 are independently selected from the group consisting of hydrido and fluoro ; R5 is selected from the group consisting of 4-chloro-3-ethylphenoxy, 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, 3-isopropylphenoxy, 3-methylphenoxy, 3-pentafluoroethylphenoxy, 3-tert-butylphenoxy, 3- (1, 1, 2, 2-tetrafluoroethoxy) phenoxy, 2- (5, 6, 7, 8-tetrahydronaphthyloxy), 3-trifluoromethoxybenzyloxy, 3-trifluoromethoxyphenoxy, 3-trifluoromethylbenzyloxy, and 3-trifluoromethylthiophenoxy ; RIO is selected from the group consisting of cyclopentyl,

1, 1, 2. 2-tetrafluoroethoxy, 2-furyl, 1, 1-bis-trifluoromethyl-1-hydroxymethyl, pentafluoroethyl, trifluoromethoxy, trifluoromethyl, and trifluoromethylthio ; R6 and Ri l are independently selected from the group consisting of fluoro and hydrido ; R7 and R12 are independently selected from the group consisting of hydrido and fluoro.

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 I to about 10, preferably from 1 to about 8 carbon atoms and more preferably 1 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 tenm"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 2 to about 8 carbon atoms and more preferably 2 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-I-yl, hepten- 1-yl, and octen-I-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 2 to about 8

carbon atoms and more preferably having 2 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, <BR> <BR> <BR> 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" (-CH2-) 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 to 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 (CH2=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, <BR> <BR> 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 tert-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 (ie, attached or formed) by having two adjacent atoms in common (ie, shared) with the first ring. The term"fused"is equivalent to the term"condensed". The term"aryl"embraces aromatic radicals such as phenyl, naphthyl, 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, partially saturated and unsaturated 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 6-membered 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.

Examples of unsaturated heterocyclic radicals, also termed"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 le. g., 4H-1, 2, 4-triazolyl, lH-1, 2, 3-triazolyl, 2H-1, 2, 3-triazolyl, etc.] tetrazolyl le. g.

IH-tetrazolyl, 2H-tetrazolyl, etc.], etc. ; unsaturated condensed heterocyclic group containing 1 to 5 nitrogen atoms, for example, indolyl, isoindolyl, <BR> <BR> indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl [e. g., tetrazol [1, 5-bjpyridazinyl, etc.], etc. ; unsaturated 3 to 6-membered heteromonocyclic group containing an oxygen atom, for example, pyranyl, 2-furyl, 3-furyl, etc. ; unsaturated 5 to 6-membered 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 le. 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. l ; 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 heterocyclic radicals include pyrrolyl, pyridinyl, pyridyloxy, pyrazolyl, triazolyl, pyrimidinyl, pyridazinyl, oxazolyl, thiazolyl, imidazolyl, indolyl, thiophenyl, furanyl, tetrazolyl, 2- pyrrolinyl, 3-pyrrolinyl, pyrrolindinyl, 1, 3-dioxolanyl, 2-imidazolinyl, imidazolidinyl, 2-pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, 1, 2, 3- oxadiazolyl, 1, 2, 3-triazolyl, 1, 3, 4-thiadiazolyl, 2H-pyranyl, 4H-pyranyl, piperidinyl, 1, 4-dioxanyl, morpholinyl, 1, 4-dithianyl, thiomorpholinyl, 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-SO2-."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 three to ten carbon atoms. More preferred cycloalkyl radicals are"lower cycloalkyl"radicals having three to seven carbon atoms. Examples include radicals such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. The term"cycloalkylalkyl" embraces cycloalkyl-substituted alkyl radicals. Preferable cycloalkylalkyl radicals are"lower cycloalkylalkyl"radicals having cycloalkyl radicals attached to alkyl radicals having one to six carbon atoms. Examples of such radicals include cyclohexylhexyl. The term"cycloalkenyl"embraces radicals having three to ten carbon atoms and one or more carbon-carbon double bonds. 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 (CH3-S-). The "alkylthio"radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide"haloalkylthio"radicals. Examples of such radicals include fluoromethylthio, 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-methyl-4-methoxyaniline, N- ethyl-4-methoxyaniline, and N-methyl-4-trifluoromethoxvaniline.

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 monoal kyl amino"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-4-ethylphenoxy, 3, 4- dichlorophenoxy, 4-methylphenoxy, 3-trifluoromethoxyphenoxy, 3- trifluoromethylphenoxy, 4-fluorophenoxy, 3, 4-dimethylphenoxy, 5-bromo-2- fluorophenoxy, 4-bromo-3-fluorophenoxy, 4-fluoro-3-methylphenoxy, 5, 6, 7, 8- tetrahydronaphthyloxy, 3-isopropylphenoxy, 3-cyclopropylphenoxy, 3- ethylphenoxy, 4-tert-butylphenoxy, 3-pentafluoroethylphenoxy, and 3- (1, 1, 2, 2-tetrafl uoroethoxy) 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-propylbenzyioxy, 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 furoyl and nicotinyl.

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

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

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

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

The term"heteroarylaminoalkyl"embraces heteroarylamino radicals, as defined above, attached to an alkyl group. Examples of such radicals include 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, hydride, 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","alken ylene", "benzylidenyl","phenoxylidenyl","hydroxyalkyl","haloalkyl"," haloalkylene", <BR> <BR> "haloalkenyl","alkoxy","alkenyloxy","alkenyloxyalkyl","alkox yalkyl","aryl", "perhaloaryl","haloalkoxy","haloalkoxyalkyl","haloalkenyloxy ",

"haloalkenyloxyalkyl","alkylenedioxy","haloalkylenedioxy","h eterocyclyl",<BR> <BR> <BR> "heteroaryl","hydroxyhaloalkyl","alkylsulfonyl","haloalkylsu lfonyl", "alkylsulfonylalkyl","haloalkylsulfonylalkyl","alkylsulfinyl ","alkylsulfinylalkyl", "haloalkylsulfinylalkyl","aralkyl","heteroaralkyl","perhaloa ralkyl", <BR> <BR> "aralkylsulfonyl","aralkylsulfonylalkyl","aralkylsulfinyl"," aralkylsulfinylalkyl", "cycloalkyl","cycloalkylalkanoyl","cycloalkylalkyl","cycloal kenyl", "halocycloalkyl","halocycloalkenyl","cycloalkylsulfinyl", "cycloalkylsulfinylalkyl","cycloalkylsulfonyl","cycloalkylsu lfonylalkyl", "cycloalkoxy","cycloalkoxyalkyl","cycloalkylalkoxy","cycloal kenyloxy", "cycloalkenyloxyalkyl","cycloalkylenedioxy","halocycloalkoxy ", "halocycloalkoxyalkyl","halocycloalkenyloxy","halocycloalken yloxyalkyl", "alkylthio","haloalkylthio","alkylsulfinyl","amino","oxy","t hio","alkylamino", <BR> <BR> "arylamino","aralkylamino","arylsulfinyl","arylsulfinylalkyl ","arylsulfonyl",<BR> <BR> <BR> "arylsulfonylalkyl","heteroarylsulfinyl","heteroarylsulfinyl alkyl", "heteroarylsulfonyl","heteroarylsulfonylalkyl","heteroarylam ino", <BR> <BR> "heteroarylaminoalkyl","heteroaryloxy","heteroaryloxylalkyl" ,"aryloxy","aroyl", "aralkanoyl","aralkoxy","aryloxyalkyl","haloaryloxyalkyl","h eteroaroyl", "heteroaralkanoyl","heteroaralkoxy","heteroaralkoxyalkyl","a rylthio", "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, <BR> <BR> 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, <BR> <BR> alkylsulfinyl, alkylsulfinylalkyl, arylsulfinylalkyl, arylsulfonylalkyl,<BR> <BR> <BR> 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"can include a covalent bond and a linear moiety having a backbone of 1 to 7 continous 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 (R17)-,-O-,-S-,-S (O)-,-S (O) 2-,-NH-,-N (R17)-, -N=,-CH (OH)-, =C (OH)-,-CH (OR17)-, =C (OR17)-, and-C (O)- wherein R17 is 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 or a straight chain of 1 or 2 or 3 or 4 or 5 or 6 atoms with a side chain. 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-, -OCF20-,-O (CF2) 2°--S-,-S (O)-,-S (O) 2-,-N (H)-,-N (H) O-,-N (R17)O-, -N (R 17)--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, <BR> <BR> 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'- <BR> <BR> binaphthyl,"Boc"represents tert-butyloxycarbonyl,"BOP"represents<BR> <BR> <BR> 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,"PTC"represents a phase transfer catalyst,"p-TsOH"

represents paratoluenesulfonic acid,"TBAF'represents tetrabutylammonium fluoride,"TBTU"represents 2-(1 H-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 VII-H : wherein R 1, R2, R3, R4, R5, R6, R7, R8, Rg, R 10, R 11, R 12, R 13, R14, R15, R16, X, Y, and Z are as defined above for the compounds of Formula VII-H ;

or a pharmaceutically-acceptable salt thereof.

As a further embodiment, compounds of the present invention of Formulas VII-H, VII, VII-2, VII-3, VII-4, and Cyclo-VII, or a pharmaceutically-acceptable salt thereof as defined above and further including those, wherein R16 is a covalent single bond linked to a point of bonding of R4 or R8 when R2 is alkyl, R2 and R14 are taken together to form a-N= spacer group, are taken together to form a-N= spacer group, 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 VII-H, VII, VII-2, VII-3, VII-4, and Cyclo-VII, of the present invention or a pharmaceutically-acceptable salt thereof.

Compounds of Formulas VII-H, VII, VII-2, VII-3, VII-4, and Cyclo- VII including those, wherein R16 is a covalent single bond linked to a point of bonding of R4 or R8 when R2 is alkyl, R2 and R 14 are taken together to form a -N= spacer group, and R2 and R15 are taken together to form a-N= spacer group, are capable of inhibiting activity of cholesteryl ester transfer protein (CETP), and thus could be used in the manufacture of a medicament, a method for the prophylactic or therapeutic treatment of diseases mediated by CETP, such as peripheral vascular disease, hyperlipidaemia, hypercholesterolemia, and other diseases attributable to either high LDL and low HDL or a combination of both, or a procedure to study the mechanism of action of the cholesteryl ester transfer protein (CETP) to enable the design of better inhibitors. The compounds of Formulas VII-H, VII, VII-2, VII-3, VII-4, and Cyclo-VII would be also useful in prevention of cerebral vascular accident (CVA) or stroke.

Also included in the family of compounds of Formulas VII-H, VII, VII- 2, VII-3, VII-4, and Cyclo-VII 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 VII-H 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, glycol, 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 VII-H 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 VII-H, VII, VII-2, VII-3, VII-4, and Cyclo-VII by reacting, for example, the appropriate acid or base with the compounds of Formulas VII-H, VII, VII-2, VII-3, VII-4, and Cyclo-VII.

Also embraced within this invention is a class of pharmaceutical compositions comprising the active compounds of Formula VII-H 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% wiw, 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 15 below, wherein the substituents are as defined for Formulas VII-H, VII, VII-2, VII-3, VII-4, and Cyclo-VII 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 VII ("Generic Substituted Polycyclic Aryl tertiary-2-hydroxyalkylamines") and Formula VII-H (Generic Substituted Polycyclic Heteroaryl tertiary 2- Heteroalkylamines or"Generic Substituted Polycyclic Heteroaryl tertiary-2- hydroxyalkylamines") wherein the heteroaryl amine (X-AH), Heteroaryl Bromide (XXI-AH), and Heteroaryl Carbonyl (XI-AH) can independently be both aryl and heteroaryl in type. Schemes 1 through 3, 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 secondary amine to introduce a heteroatom containing alkyl group wherein the two groups making up the secondary amine both are made up of aromatic groups or both groups contain aromatic rings wherein said aromatic rings maybe 0 to 2 aryl rings and 0 to 2 heteroaryl rings.

The"Diheteroaryl Imine"corresponding to Formula XII-AH can be prepared through dehydration techniques generally known in or adaptable from the art by reacting"Heteroaryl Amine"of Formula X-AH with the"Heteroaryl Carbonyl"of Formula XI-AH in Scheme 1 and subsequent specific examples.

For example, when Z is a covalent bond, methylene, methine substituted with another subsitutent, ethylene, or another subsituent as defined in Formula V-H, the two reactants (X-AH 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 "Diheteroaryl Imine"of Formula XII-AH. Alternately, when Z is an oxygen, the "Diheteroaryl Imine"is an oxime derivative. Oxime type"Diheteroaryl Imine" compounds are readily prepared from the corresponding 0-substituted

hydroxylamine and the appropriate aldehyde or ketone type"Heteroaryl Carbonyl". Alternately, when Z is a nitrogen, the"Diheteroaryl Imine"is a hydrazone derivative. Hydrazone type"Diheteroaryl Imine"compounds are readily prepared from the corresponding hydrazine and the appropriate aldehyde or ketone type"Heteroaryl Carbonyl". Suitable procedures for forming oxime and hydrazone imines are also described by Shriner, Fuson, and Curtin in The Systematic Indentification of Organic Compounds, 5th Edition, John Wiley & Sons, and by Fieser and Fieser in Reagents for Organic Synthesis, Volume l, John Wiley & Sons, which are incorporated herein by reference.

The"Secondary Heteroaryl Amines"of Formula XIIIA-H can be prepared from the corresponding"Diheteroaryl Imine"of Formula XII-AH in several ways. For example, in one synthetic scheme (Reduction Method-1), which is preferred when Z is a nitrogen, the"Generic Imine"hydrazone 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. Patent Nos.

3359316 and 3334017, which are incorporated herein by reference, and then hydrogenated at 0-100°C, more preferrably 20-50°C, and most preferrably between 20-30°C and pressures of 10-200 psi hydrogen or more preferrably between 50-70 psi hydrogen in the presence of a noble metal catalyst such as pro2.

In another synthetic scheme (Reduction Method-2), which is preferred when Z is a single bond or carbon, the"Diheteroaryl Imine"of Formula XII-AH is slurred 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 preferrred when Z is an oxygen, the"Diheteroaryl Imine"oxime of Formula XII-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 Heteroaryl Amines"of Formula XIII-AH can also be prepared, according to Scheme 1, by an alkylation procedure based on the nucleophilic substitution of bromides by amines. In one synthetic alkylation scheme (Alkylation Method-1), a"Heteroaryl Amine"of Formula X-AH is reacted with a"Heteroaryl Bromide-"of Formula XXIII-AH 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 10, a"Heteroaryl Amine"of 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"Secondary Heteroaryl Amine"amines, hydroxylamines, and hydrazines, the"Heteroaryl Carbonyl"aldehydes, ketones, hydrazones, and oximes, and"Heteroaryl Bromide"halides, tosylates, mesylates, triflates, and precursor alcohols required to prepare the"Secondary 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. l (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. Patent No. 5306718 ; EP No. 314435 ; WO No. 9001874 ; WO No. 9002113 ; JP No.

05320117 ; WO No. 9738973 ; Swiss Patent No. CH 441366 ; U. S. Patents Nos. 3359316 and 3334017 ; and references cited therein which are incorporated herein by reference.

Synthetic Scheme 2 shows the preparation of the class of compounds of the present invention corresponding to Formula VII ("Generic Substituted Polycyclic Aryl tertiary-2-hydroxyalkylamines") and Formula VII-H (Generic

Substituted Polycyclic Heteroaryl tertiary 2-Heteroalkylamines or"Generic Substituted Polycyclic Heteroaryl tertiary-2-hydroxyalkylamines").

Derivatives of"Generic Substituted Polycyclic Aryl tertiary-2- hydroxyalkylamines"or"Generic Substituted Polycyclic Heteroaryl tertiary-2- hydroxyalkylamines", in which the heteroatom (-O-) 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 Heteroaryl Amine"amines, hydroxylamines, and hydrazines of Formula XIIIA- H 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, preferrably 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, preferrably 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 MgS04 and concentrated in vacuo to yield crude Formula VII ("Generic Substituted Polycyclic Aryl tertiary-2-hydroxyalkylamines"or Formula VII-H "Generic Substituted Polycyclic Heteroaryl tertiary-2-hydroxyalkylamines",").

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 VII-H and Formula VII. Products are structurally confirmed by low and high resolution mass spectrometry and NMR.

Compounds of Formula (XXX), which can be used to prepare the "Generic Substituted Polycyclic Heteroaryl and Aryl tertiary hydroxyalkylamines"compounds in Tables 3 and 4, are given in Table 2.

Reagents la and 2a in Table 2 are prepared from the corresponding alcohols.

The tosylates are readily obtained by reacting the corresponding alcohol with 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 VII ("Generic Substituted Polycyclic Aryl tertiary-2-hydroxyalkylamines") and Formula VII-H (Generic Substituted Polycyclic Heteroaryl tertiary 2-Heteroalkylamines or"Generic Substituted Polycyclic Heteroaryl tertiary-2-hydroxyalkylamines") compounds is Method A of Scheme 3. Oxirane reagents useful in Method A are exemplified, but not limited to those in Table 1. Formula VII ("Generic Substituted Polycyclic Aryl tertiary-2-hydroxyalkylamines") and Formula VII-H (Generic Substituted Polycyclic Heteroaryl tertiary 2-Heteroalkylamines or"Generic Substituted Polycyclic Heteroaryl tertiary-2-hydroxyalkylamines") compounds are prepared by using"Secondary Heteroaryl Amine"amines, hydroxylamines, and hydrazines of Formula XIIIA-H prepared above with oxiranes of the type listed in Table 1 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 VII ("Generic Substituted Polycyclic Aryl tertiary-ff- heteroalkylamines") and Formula VII-H ("Generic Substituted Polycyclic Heteroaryl tertiary 2-Heteroalkylamines") 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 3.

Aziridine and thiirane reagents useful in Method A are exemplified, but not limited to those in Table 1. These Formula VII ("Generic Substituted Polycyclic Aryl tertiary 2-heteroalkylamine") and Formula VII-H ("Generic Substituted Polycyclic Heteroaryl tertiary-2-heteroalkylamines") compounds, wherein the 2- hetero group is an amino, substituted amino, or thiol, can be prepared by using "Secondary Heteroaryl Amine"amines, hydroxylamines, and hydrazines of Formula XIIIA-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 Ra 6 is

hydrogen or another suitable group when X is N.

Table 1. Structure of Oxirane, Aziridine, and Thiirane Reagents. Rgnt X R16 R1 R2 R3 No. 1 ------ O H H CF3 2 ------ O H H CCl3 3 ------ O CH3 H CF3 4 ------ O H H CF3CF2 5 ------ O H H CF3CF2CF2 6 ------ O H H CF3OCF2CF2 7 ------ O H H CF3CH2 8 ------ O H CF3 CHF2 9 ------ O H CF3 CF3 10 ------ O H CF3 CF3 11 ------ O H CF3 C6H5 12 ------ O H CCl3 C6H5 13 ------ O Cyclopropyl H CCl3 14 ------ O H CCl3 CH3 15 ------ O H CCl3 (CH3)2CH 16 ------ O H H CHCl2 17 ------ O Cl H CHCl2 18 ------ O H CF3 CH3 19 H N H CF3 CF# 20 H N H H CF3 Table 1. (continued) Structure of Oxirane, Aziridine, and Thiirane Reagents. Rgnt X R16 R1 R2 R3 No. 21 Benzyl N H H CH3O CF3 23 N H H CH3 CF3 24 Benzyloxy N H H CF3 25 ------ S H H CF3 26 ------ S H H CF3CF2 27 ------ O H H CCl3CH2 28 ------ O H H CBr3CH2 29 ------ O H H CHBr2CH2 30 ------ O H H CBrCl2 31 ------ O H H CClF2 32 ------ O H H CCl2F 33 ------ O H H CCl3CCl2 43 ------ O H H FCH2 46 ------ O CF3 R2+R3 = (CH2)3 47 ------ O CF3 R2+R3 = (CH2)4 48 ------ O CHF2 R2+R3 = (CH2)4 56 ------ O H H CBrF2CClFCH2 57 ------ O H H HCF2CF2OCH2 Table 2. Structure and Source of Alcohol and Glycol Reagentds. Reagent M Source of Reagent n R1 R2 R3 X-R16 Number 1A 3 OTs H H OH Chiral separation and then tosylation of alcohol from Justus CF3 Liebigs Ann. Chem. (1969), 720, 81-97. 2A 3 OTs H H OH Chiral separation and then tosylation of alcohol from Z. CF3CH2CH2 Naturforsch., B: Chem. Sci. (1997), 52 (3). 413-418 Table 3. Structure of Substituted Phenyl tertiary- omega-Hydroxyalkylamines<BR> (Y is CH; R8, R9, R12, R13, and R14 are each H; Z is covalent bond and R15 is absent). Inhibitor Number n R1 R2 R3 R4 R5 R6 R7 R10 R11 Column1+Column 2 Reagent Reagent 1A 1N 3 H H H H H H CF3 C6H5O OCF2CF2H 1A 2N 3 H H H H H H CF3 OCF3 OCF2CF2H Table 3 (Continued). Structure of Substituted Phenyl tertiary- omega-Hydroxyalkylamines<BR> (Y is CH; R8, R9, R12, R13, and R14 are each H; Z is covalent bond and R15 is absent). INhibitor Number n R1 R2 R3 R4 R5 R6 R7 R10 R11 Column1+Column 2 Reagent Reagent 1A 3N 3 H H F H H F H CF3 OCF2CF2H 1A 4N 3 H H H F H H H CF3 OCF2CF2H 1A 5N 3 H H H H H H CF3 C6H5O OCF3 1A 6N 3 H H H H H H CF3 OCF3 OCF3 1A 7N 3 H H H H phenyl H H CF3 OCF3 1A 8N 3 H H H phenyl H H H CF3 OCF3 1A 9N 3 H H H H H H H CF3 OCF3 1A 10N 3 H H H Br H H H CF3 OCF3 1A 11N 3 H H H F H H CF3 CF3 1A 12N 3 H H H H H H CF3 CH3 CF3 1A 13N 3 H H H H H H CF3 CF3 CF3 1A 14N 3 H H H H H H CF3 CH3 OCF3 Table 3 (Continued). Structure of Substituted Phenyl tertiary- omega-Hydroxyalkylamines<BR> (Y is CH; R8, R9, R12, R13, and R14 are each H; Z is covalent bond and R15 is absent). Inhibitor Number n R1 R2 R3 R4 R5 R6 R7 R10 R11 Column1+Column 2 Reagent Reagent 1A 15N 3 H H H F F H H CF3 OCF3 1A 16N 3 H H H Br H H H CF3 CF3 1A 17N 3 H H H F H H CF3 CF3 OCF3 1A 18N 3 H H H F H H H CF3 OCF3 1A 19N 3 H H H Cl H H H CF3 OCF3 1A 20N 3 H H H F H H H CF3 CF3 1A 21N 3 H H H F F H H CF3 CF3 1A 22N 3 H H H Cl H H H CF3 CF3 1A 23N 3 H H H F H H PHENOXY H CF3 1A 24N 3 H H H Cl H BH CF3 CF3 CH3 1A 25N 3 H H H F H H CF3 CF3 CH3 1A 26N 3 H H H H H H H CF3 CF3 Table 3 (Continued). Structure of Substituted Phenyl tertiary- omega-Hydroxyalkylamines<BR> (Y is CH; R8, R9, R12, R13, and R14 are each H; Z is covalent bond and R15 is absent). Inhibitor Number n R1 R2 R3 R4 R5 R6 R7 R10 R11 Column1+Column 2 Reagent Reagent 1A 27N 3 H H F F H H H CF3 CF3 1A 28N 3 H H H H H H CF3 OCH3 CF3 1A 29N 3 H H H F F H H CF3 CH3 1A 30N 3 H H H H H H CF3 OCH3 CH3 1A 31N 3 H H H H H H H CF3 CH3 1A 32N 3 H H H Cl H H H H CF3 1A 33N 3 H H H F H H F H CF3 1A 34N 3 H H H H H H CF3 OCH3 CH3 1A 35N 3 H H H H H H H H CF3 1A 36N 3 H H H H H H CF3 CH3 CH3 1A 37N 3 H H H H Cl H H H CF3 1A 38N 3 H H H F H H H CF3 3-CF3- Table 3 (Continued). Structure of Substituted Phenyl tertiary- omega-Hydroxyalkylamines<BR> (Y is CH; R8, R9, R12, R13, and R14 are each H; Z is covalent bond and R15 is absent). Inhibitor Number n R1 R2 R3 R4 R5 R6 R7 R10 R11 Column1+Column 2 Reagent Reagent phenoxy 1A 39N 3 H H H F H H H CF3 4-CH3O- phenoxy 1A 40N 3 H H H F H H 4-Cl- H phenoxy 1A 41N 3 H H H F H H H H CF3 1A 42N 3 H H H F H H H CF3 CH3 1A 43N 3 H H H F H F H CF3 CH3 1A 44n 3 H H F F H H H CF3 CH3 1A 45N 3 H H H Cl H H H CF3 CH3 1A 46N 3 H H H H H H CF3 CH3 CH3 1A 48N 3 H H H H H H CF3 CH3 CF3 1A 51N 3 H H H H H F H CF3 CH3 Table 3 (Continued). Structure of Substituted Phenyl tertiary- omega-Hydroxyalkylamines<BR> (Y is CH; R8, R9, R12, R13, and R14 are each H; Z is covalent bond and R15 is absent). Inhibitor Number n R1 R2 R3 R4 R5 R6 R7 R10 R11 Column1+Column 2 Reagent Reagent 1A 52N 3 H H H H H F H CF3 CF3 1A 53N 3 H H H H H H CF3 CF3 CH3 1A 54N 3 H H H H H H CF3 OCH3 CF3 1A 56N 3 H H H H H H CF3 CH3 CF3 1A 57N 3 H H H H H H CF3 C6H5O OCF3 1A 58N 3 H H H H H H H CF3 OCF3 1A 59N 3 H H H H H H CF3 OCF3 OCF3 1A 60N 3 H H H F H H CF3 CF3 CF3 1A 61N 3 H H H H H H CF3 OCH3 CF3 1A 62N 3 H H H H H H CF3 CH3 CF3 1A 63N 3 H H H Cl H H H CF3 CF3 1A 64N 3 H H H H H H CF3 CF3 OCF3 Table 3 (Continued). Structure of Substituted Phenyl tertiary- omega-Hydroxyalkylamines<BR> (Y is CH; R8, R9, R12, R13, and R14 are each H; Z is covalent bond and R15 is absent). Inhibitor Number n R1 R2 R3 R4 R5 R6 R7 R10 R11 Column1+Column 2 Reagent Reagent 1A 65N 3 H H H F H H H CF3 OCF3 1A 66N 3 H H H F H F H CF3 OCF3 1A 67N 3 H H H Br H H H CF3 OCF3 1A 68N 3 H H H Cl H H H CF3 OCF3 1A 69N 3 H H H F F H H CF3 OCF3 1A 70N 3 H H H F H H H phenyl CF3 1A 71N 3 H H H H H H CF3 CH3 OCF3 1A 72N 3 H H H F F H H CF3 CF3 1A 73N 3 H H H Cl H H H CF3 CH3 1A 74N 3 H H H H H H CF3 OCH3 CH3 1A 75N 3 H H H F H H H CF3 CH3 1A 76N 3 H H F F H H H CF3 OCF3 Table 3 (Continued). Structure of Substituted Phenyl tertiary- omega-Hydroxyalkylamines<BR> (Y is CH; R8, R9, R12, R13, and R14 are each H; Z is covalent bond and R15 is absent). Inhibitor Number n R1 R2 R3 R4 R5 R6 R7 R10 R11 Column1+Column 2 Reagent Reagent 1A 78N 3 H H H H H H CF3 OCH3 CH3 1A 79N 3 H H H H H H CF3 CH3 CH3 1A 80N 3 H H H H H H CF3 CH3 CH3 1A 82N 3 H H H F F H H CF3 CH3 1A 83N 3 H H H F H F H CF3 CH3 1A 84N 3 H H F F H H H CF3 CH3 1A 85N 3 H H F H H H CF3 CF3 CH3 1A 86N 3 H H H H H H CF3 CH3 CF3 1A 88N 3 H H H H H H CF3 CF3 CH3 1A 90N 3 H H H H H H CF3 CF3 CH3 1A 92N 3 H H H F H H CF3 CF3 CH3 Table 4. Structure of Substituted Phenyl tertiary- omega-Hydroxyalkylamines<BR> (Y and Z are CH; R8, R9, R12, R13, R14, and R15 are each H; Z is covalent R15 is absent). Inhibitor Number n R1 R2 R3 R4 R5 R6 R7 R10 R11 Column1+Column 2 Reagent Reagent 1A 1DB 3 H H H H H H CF3 OCF3 1A 2DB 3 H H H Cl H H H CF3 CF3 Table 4 (Continued). Structure of Substituted Phenyl tertiary- omega-Hydroxyalkylamines<BR> (Y and Z are CH; R8, R9, R12, R13, R14, and R15 are each H; Z is covalent R15 is absent). Inhibitor Number n R1 R2 R3 R4 R5 R6 R7 R10 R11 Column1+Column 2 Reagent Reagent 1A 3DB 3 H H H Br H H H CF3 OCF3 1A 4DB 3 H H H Cl H H H CF3 OCF3 1A 5DB 3 H H H Cl H H H CF3 CF3 1A 6DB 3 H H H H Cl H H CF3 CF3 1A 7DB 3 H H H F H H H CF3 OCF3 1A 8DB 3 H H H H Cl H H Cf3 CF3 1A 9DB 3 H H H F H H H CF3 CF3 1A 10DB 3 H H H H F H H CF3 CF3 1A 11DB 3 H H F H H H H CF3 CF3 1A 12DB 3 H H H Cl H H H CF3 CF3 1A 13DB 3 H H H H Cl H H CF3 CF3 1A 14DB 3 H H Cl H H H H CF3 CF3 Table 4 (Continued). Structure of Substituted Phenyl tertiary- omega-Hydroxyalkylamines<BR> (Y and Z are CH; R8, R9, R12, R13, R14, and R15 are each H; Z is covalent R15 is absent). Inhibitor Number n R1 R2 R3 R4 R5 R6 R7 R10 R11 Column1+Column 2 Reagent Reagent 1A 15DB 3 H H H F H H H CF3 CH3 1A 16DB 3 H H H H F H H CF3 CH3 1A 17DB 3 H H H F H H H CF3 CH3 1A 18DB 3 H H F H H H H CF3 CH3 1A 19DB 3 H H H H F H H CF3 CH3 1A 20DB 3 H H F H H H H CF3 CH3 1A 21DB 3 H H F H H H H CF3 CF3 1A 22DB 3 H H Cl H H H H CF3 CF3 1A 23DB 3 H H H F H H H CF3 CF3 1A 24DB 3 H H H H F H H CF3 CF3 1A 25DB 3 H H H F H H H CF3 CF3 1A 26DB 3 H H H H F H H CF3 CF3 Table 4 (Continued). Structure of Substituted Phenyl tertiaryl- omega-Hydroxyalkylamines<BR> (Y and Z are CH; R8, R9, R12, R13, R14, and R15 are each H; Z is covalent R15 is absent). Inhibitor Number n R1 R2 R3 R4 R5 R6 R9 R10 R11 Column 1+Column 2 Reagent Reagent 1A 27DB 3 H H H H H H CF3 OCF3 OCF3

A mixture of a"Secondary Heteroaryl Amine"amine, hydroxylamine, or hydrazine of Formula XIIIA-H 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 MgSO4 and concentrated in vacuo to yield crude Formula VII ("Generic Substituted Polycyclic Aryl tertiary 2-hydroxyalkylamine") and Formula VII-H ("Generic Substituted Polycyclic Heteroaryl tertiary-2-hydroxyalkylamine") compounds. This material is purified by eluting through silica gel with 540% of a medium polar solvent such as ethyl acetate in a non-polar solvent such as hexanes to yield the Formula VII ("Generic Substituted Polycyclic Aryl tertiary 2-hydroxyalkylamine") and Formula VII-H ("Generic Substituted Polycyclic Heteroaryl tertiary-2-hydroxyalkylamine"). Products are tested for purity by HPLC. If necessary, the Formula VII ("Generic Substituted Polycyclic Aryl tertiary 2-hydroxyalkylamine") and Formula VII-H ("Generic Substituted Polycyclic Heteroaryl tertiary-2-hydroxyalkylamine") 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 ("Generic Substituted Polycyclic Aryl tertiary 2- hydroxyalkylamine") compounds prepared are summarized in the Examples and Example Tables 1 through 54.

Specific Formula VII ("Generic Substituted Polycyclic Aryl tertiary 2- hydroxyalkylamine") and Formula VII-H ("Generic Substituted Polycyclic Heteroaryl tertiary-2-hydroxyalkylamine") analogs of the"Polycyclic Aryl tertiary-2-hydroxyalkylamine"compounds summarized in the Examples and Example Tables I through 54, 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 VII ("Generic Substituted Polycyclic Aryl tertiary 2-hydroxyalkylamine") and Formula VII-H ("Generic Substituted Polycyclic Heteroaryl tertiary-2-hydroxyalkylamine") analogs of the"Polycyclic Aryl tertiary-2-hydroxyalkylamine"compounds.

Formula VII ("Generic Substituted Polycyclic Aryl tertiary-2- hydroxyalkylamines") and Formula VII-H ("Generic Substituted Polycyclic Heteroaryl tertiary-2-hydroxyalkylamines") can further be prepared in an alternate manner to procedures disclosed above and in Schemes 1, 2, and 3.

Schemes 9 and 10 detail such procedures to prepare tertiary oxyalkylamine compounds of the present invention by initial formation of an halogenated, oxygen containing primary alkylamine XVL ("Generic Substituted Alkylamine"). Said halogenated, oxygen containing primary alkylamine XVL, formed in Scheme 9, is itself converted to secondary amine VLX-H ("Heteroaryl Alkyl Amine) using procedures disclosed above. Primary alkylamine XVL is first reacted with an aldehydic or ketonic carbonyl compound, XI-AH ("Heteroaryl Carbonyl") with azeotropic distillation to form imines, VL-H ("Heteroaryl Imine"). Said imine VL-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 VLX-H ("Heteroaryl Alkyl Amine).

Said secondary amine VLX-H can be converted according to Scheme 10 to VII-H ("Generic Substituted Polycyclic Heteroaryl Tertiary 2- hydroxyalkylamines"). Using similar schemes, VLX can be converted to VII ("Generic Substituted Polycyclic Phenyl Tertiary 2-hydroxyalkylamines").

Compounds of this invention in which one aromatic substituent is aryl and the other aromatic substitutent is heteroaryl can be readily prepared by reacting VLX-H with an aryl bromide or aralkyl bromide instead of using an heteroaryl bromide or heteroaralkyl bromide. Similarly, compounds of this invention in which one aromatic substituent is aryl and the other aromatic substitutent is heteroaryl can be readily prepared by reacting the aryl analog of VLX-H with an heteroaryl bromide or heteroaralkyl bromide instead of using an aryl bromide or aralkyl bromide.

Formula VII ("Generic Substituted Polycyclic Aryl tertiary-2- hydroxyalkylamines") and Formula VII-H ("Generic Substituted Polycyclic Heteroaryl tertiary-2-hydroxyalkylamines") can further be prepared in an alternate manner to procedures disclosed above and in Schemes 1, 2, 3, 9, and 10. Schemes 13, 14, and 15 detail alternate procedures to prepare tertiary oxyalkylamine compounds of the present invention by initial formation of an halogenated, oxygen containing secondary alkylamines VLX and VLXX ("Phenyl Alkylamines") and VLXX-O ("Phenyl Oxy Alkylamines"). Said secondary alkylamines VLX and VLXX ("Phenyl Alkylamines") and VLXX-O ("Phenyl Oxy Alkylamines") can be converted according to Schemes 13, 14 and 15 to VII ("Generic Substituted Polycyclic Aryl Tertiary 2- hydroxyalkylamines") and VII-H ("Generic Substituted Polycyclic Heteroaryl Tertiary 2-hydroxyalkylamines") by reaction with appropriate aromatic halides such as aryl bromides and heteroaryl bromides as desired.

Formula VII ("Generic Substituted Polycyclic Aryl tertiary-2- hydroxyalkylamines") and Formula VII-H ("Generic Substituted Polycyclic Heteroaryl tertiary-2-hydroxyalkylamines") can further be prepared in an alternate manner to procedures disclosed above and in Schemes 1, 2, 3, 9, 10, 13, 14, and 15. Another alternate procedure to prepare tertiary oxyalkylamine compounds of the present invention by reacting secondary amine XIIIA-H ("Secondary Heteroaryl Amine") with a diazo ester. The intermediate glycinate tertiary amine can then be reduced, partially reoxidized to an aldehyde, and converted using a perfluoroalkyl trimethylsilyl compound (for example, trifluoromethyl-TMS) to the desired product, VII ("Generic Substituted Polycyclic Aryl Tertiary 2-hydroxyalkylamines") and VII-H ("Generic Substituted Polycyclic Heteroaryl Tertiary 2-hydroxyalkylamines").

A particularly useful procedure to prepare Formula VII ("Generic Substituted Polycyclic Aryl tertiary-2-hydroxyalkylamines") and Formula VII- H (Generic Substituted Polycyclic Heteroaryl tertiary 2-Heteroalkylamines or "Generic Substituted Polycyclic Heteroaryl tertiary-2-hydroxyalkylamines") compounds of the present invention in which the heteroaryl group is directly bonded is disclosed in Schemes 11 and 12. An halogenated, oxygen containing primary alkylamine XVL ("Generic Substituted Alkylamine") formed according to Scheme 9 is itself converted by reaction with LXXI-AH ("Heteroaryl Halide") to afford secondary amine VLXX-H ("Heteroaryl Secondary Amine) using procedures disclosed in Scheme 11 and above.

VLXX-H is converted to VII-H ("Generic Substituted Polycyclic Phenyl

Heteroaryl Tertiary 2-hydroxyalkylamine") by alkylation chemistry with an aralkyl bromide or aralkyloxyalkyl bromide using either of two procedures disclosed in Scheme 12. Isolation and purification is effected as disclosed previously.

Formula VII ("Generic Substituted Polycyclic Aryl tertiary-2- hydroxyalkylamines") and Formula VII-H (Generic Substituted Polycyclic Heteroaryl tertiary 2-Heteroalkylamines or"Generic Substituted Polycyclic Heteroaryl tertiary-2-hydroxyalkylamines") can themselves serve as intermediates for conversion to additional compounds of this invention.

Compounds of Formula VII-H, Formula VII and the present invention useful as intermediates include those in which the R7 position substituent in Formula VII ("Generic Substituted Polycyclic Aryl tertiary-2-hydroxyalkylamines") 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 Formula VII-H, Formula VII and the present invention useful as intermediates include those in which the R 0 position substituent in Formula VII 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 Formula VII-H, Formula VII and the present invention useful as intermediates include those in which one or more of R6, R7, R) j, and Rl 2 substituents in Formula VII-H and Formula VII 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.

A 3-bromo substituent at the R7 position in Formula VII ("Generic Substituted Polycyclic 3-Bromoaryl Tertiary 2-hydroxyalkylamine") can be reacted with a phenol to afford, as described in Examples, 3-phenoxy compounds of the present invention of Formula VII ("Generic Substituted Polycyclic 3-Phenoxyaryl Tertiary 2-Hydroxyalkylamine").

A 3-bromo substituent at the R7 position in Formula VII-H ("Generic Substituted Polycyclic 3-Bromoheteroaryl Tertiary 2-hydroxyalkylamine") can, as shown in Scheme 4, be reacted with a phenol to afford, as described in Examples, additional compounds of the present invention of Formula VII-H

("Generic Substituted Polycyclic 3-Aryloxyaryl, 3-Heteroaryloxyaryl, 3- Heteroaryloxyheteroaryl, and 3-Aryloxyheteroaryl Tertiary 2- Hydroxyalkylamines").

A 3-bromo substituent at the R7 position in Formula VII ("Generic Substituted Polycyclic 3-Bromoaryl Tertiary 2-hydroxyalkylamine") can, as shown in Scheme 7, be reacted with a phenol to afford, as described in Examples, additional compounds of the present invention of Formula VII ("Generic Substituted Polycyclic 3-Phenylaryl Tertiary 2- Hydroxyalkylamine").

Conversion of a 3-bromo substituent at the R7 position in Formula VII ("Generic Substituted Polycyclic 3-Bromoaryl Tertiary 2-hydroxyalkylamine") by reaction with a primary or secondary amine can, as shown in Scheme 8, afford, as described in Examples, additional compounds of the present invention of Formula VII ("Generic Substituted Polycyclic 3-R22aminoaryl Tertiary 2-Hydroxyalkylamine").

Conversion of a 3-bromo substituent at the Rl o position in Formula VII ("Generic Substituted Polycyclic 3-Bromoaryl Tertiary 2-hydroxyalkylamine") by reaction with an aryl borinate can afford, as described in Examples, additional compounds of the present invention of Formula VII ("Generic Substituted Polycyclic 3-Phenylaryl Tertiary 2-Hydroxyalkylamine").

Conversion of a 3-bromo substituent at the R 0 position in Formula VII ("Generic Substituted Polycyclic 3-Bromoaryl Tertiary 2-hydroxyalkylamine") by reaction with a heteroaryl dibutyl tin compound can afford, as described in Examples, additional compounds of the present invention of Formula VII ("Generic Substituted Polycyclic 3-Heteroarylaryl Tertiary 2- Hydroxyalkylamine").

Conversion of a 3-bromomethyl substituent at the R7 position in Formula VII ("Generic Substituted Polycyclic 3-Bromomethylaryl Tertiary 2- hydroxyalkylamine") by reaction with an aryl borinate can afford, as described in Examples, additional compounds of the present invention of Formula VII ("Generic Substituted Polycyclic 3-Arylmethylaryl Tertiary 2- Hydroxyalkylamine").

Conversion of a 3-hydroxyl substituent at the R7 position in Formula VII-H ("Generic Substituted Polycyclic 3-Hydroxyheteroaryl Tertiary 2-

hydroxyalkylamine") by reaction with an aryl bromide or heteroaryl bromide can afford, as described in Examples, additional compounds of the present invention of Formula VII-H ("Generic Substituted Polycyclic 3-Aryloxyaryl, 3-Heteroaryloxyaryl, 3-Heteroaryloxyheteroaryl, and 3-Aryloxyheteroaryl Tertiary 2-Hydroxyalkylamines").

Conversion of a 3-hydroxyl substituent at the R7 position in Formula VII ("Generic Substituted Polycyclic 3-Hydroxyaryl Tertiary 2- hydroxyalkylamine") by reaction with an aryl bromide can afford, as described Scheme 5 and in Examples, additional compounds of the present invention of Formula VII ("Generic Substituted Polycyclic 3-Phenoxyaryl Tertiary 2- Hydroxyalkylamine").

Conversion of a 3-hydroxyl substituent at the R7 position in Formula VII-H ("Generic Substituted Polycyclic 3-Hydroxyheteroaryl Tertiary 2- hydroxyalkylamine") by reaction with an aralkyl bromide or heteroaralkyl bromide can afford, as described in Examples, additional compounds of the present invention of Formula VII-H ("Generic Substituted Polycyclic 3- Aralkyloxyaryl, 3-Heteroaralkyloxyaryl, 3-Heteroaralkyloxyheteroaryl, and 3- Aralkyloxyheteroaryl Tertiary 2-Hydroxyalkylamines").

Conversion of a 3-hydroxyl substituent at the R7 position in Formula VII ("Generic Substituted Polycyclic 3-Hydroxyaryl Tertiary 2- hydroxyalkylamine") by reaction with an aralkyl bromide can afford, as described in Examples, additional compounds of the present invention of Formula VII ("Generic Substituted Polycyclic 3-Aralkyloxyaryl Tertiary 2- Hydroxyalkylamine").

Conversion of a 3-hydroxyl substituent at the R7 position in Formula VII ("Generic Substituted Polycyclic 3-Hydroxyaryl Tertiary 2- hydroxyalkylamine") by reaction with an RI 7-bromide can afford, as described in Examples, additional compounds of the present invention of Formula VII ("Generic Substituted Polycyclic 3-Rl 7-oxyaryl Tertiary 2- Hydroxyalkylamine").

Conversion of a 3-thio substituent at the R7 position in Formula VII ("Generic Substituted Polycyclic 3-thioaryl Tertiary 2-hydroxyalkylamine") by reaction with an Rl 7-bromide can afford, as described in Examples,

additional compounds of the present invention of Formula VII ("Generic Substituted Polycyclic 3-Rl7thiaaryl Tertiary 2-Hydroxyalkylamine").

"Generic Substituted Polycyclic 3-Rl 7thiaaryl Tertiary 2- Hydroxyalkylamines"can be oxidized to sulfonyl compounds of Formula VII ("Generic Substituted Polycyclic 3-R7sulfonylaryl Tertiary 2- Hydroxyalkylamine").

Conversion of a 3-nitro substituent at the R7 position in Formula VII ("Generic Substituted Polycyclic 3-Nitroaryl Tertiary 2-hydroxyalkylamine") by hydrogenation can afford, as described in Examples, additional compounds of the present invention of Formula VII ("Generic Substituted Polycyclic 3-Aminoaryl Tertiary 2-Hydroxyalkylamine")."Generic Substituted Polycyclic 3-Aminoaryl Tertiary 2-Hydroxyalkylamines"can be acylated to acyl amide compounds of Formula VII ("Generic Substituted Polycyclic 3- Acylaminoaryl Tertiary 2-Hydroxyalkylamine").

Conversion of a 3-amino substituent at the R7 position in Formula VII ("Generic Substituted Polycyclic 3-Aminoaryl Tertiary 2-hydroxyalkylamine") by reaction with carbonyl compounds can afford, as described in Examples, additional compounds of the present invention of Formula VII ("Generic Substituted Polycyclic 3- (Saturated Nitrogen Heterocycl-lyl) aryl Tertiary 2- Hydroxyalkylamine"and"Generic Substituted Polycyclic 3- (Unsaturated Nitrogen Heterocycl-lyl) aryl Tertiary 2-Hydroxyalkylamine").

Conversion of a 3-methoxycarbonyl substituent at the R7 position in Formula VII ("Generic Substituted Polycyclic 3-Carbomethoxyaryl Tertiary 2- hydroxyalkylamine") by reaction with amination reagents can afford, as described in Examples, additional compounds of the present invention of Formula VII ("Generic Substituted Polycyclic 3-Carboxamidoaryl Tertiary 2- Hydroxyalkylamine").

Conversion of a 3-cyano substituent at the R7 position in Formula VII ("Generic Substituted Polycyclic 3-Cyanoaryl Tertiary 2-hydroxyalkylamine") by reaction with organometallic reagents can afford, as described in Examples, additional compounds of the present invention of Formula VII ("Generic Substituted Polycyclic 3-Acylaryl Tertiary 2-Hydroxyalkylamine").

Said"Generic Substituted Polycyclic 3-Acylaryl Tertiary 2- Hydroxyalkylamines", can be reduced to hydroxyl compounds of Formula VII

("Generic Substituted Polycyclic 3-Hydroxysubstitutedmethylaryl Tertiary 2- Hydroxyalkylamine").

Conversion of a 3-methoxycarbonyl substituent at the Rl o position in Formula VII ("Generic Substituted Polycyclic 3-Carbomethoxyaryl Tertiary 2- hydroxyalkylamine") by reaction with amination reagents can afford, as described in Examples, additional compounds of the present invention of Formula VII ("Generic Substituted Polycyclic 3-Carboxamidoaryl Tertiary 2- Hydroxyalkylamine").

Conversion of a 3-methoxycarbonyl substituent at the RIO position in Formula VII ("Generic Substituted Polycyclic 3-Carbomethoxyaryl Tertiary 2- hydroxyalkylamine") by reaction with an organometallic reagent can afford, as described in Examples, additional compounds of the present invention of Formula VII ("Generic Substituted Polycyclic 3-(bis-R20-hydroxymethyl) aryl Tertiary 2-Hydroxyalkylamine").

Conversion of a 3-methoxycarbonyl substituent at the Rl o position in Formula VII ("Generic Substituted Polycyclic 3-Carbomethoxyaryl Tertiary 2- hydroxyalkylamine") by reaction with lithium aluminum hydride can afford, as described in Examples, additional compounds of the present invention of Formula VII ("Generic Substituted Polycyclic 3-Hydroxymethylaryl Tertiary 2- Hydroxyalkylamine").

Conversion of a 3-methoxycarbonyl substituent at the R 0 position in Formula VII ("Generic Substituted Polycyclic 3-Carbomethoxyaryl Tertiary 2- hydroxyalkylamine") by reaction with an alkylation reagent can afford, as described in Examples, additional compounds of the present invention of Formula VII ("Generic Substituted Polycyclic 3-(bis-R2 l-hydroxymethyl) aryl Tertiary 2-Hydroxyalkylamine").

Conversion of a 3-methoxycarbonyl substituent at the RIO position in Formula VII ("Generic Substituted Polycyclic 3-Carbomethoxyaryl Tertiary 2- hydroxyalkylamine") by reaction intially with an amidation reagent and then an R20-organometallic reagent can afford, as described in Examples, additional compounds of the present invention of Formula VII ("Generic Substituted Polycyclic 3-(R20-carbonyl) aryl Tertiary 2-Hydroxyalkylamine").

Formula VII ("Generic Substituted Polycyclic Aryl tertiary-2- hydroxyalkylamines"), Formula VII-H ("Generic Substituted Polycyclic

Heteroaryl tertiary-2-hydroxyalkylamines") 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 Rl6 is a hydrogen, of compounds of Formulas VII, VII-H, and other 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 of Formulas VII, VII-H, and Cyclo-VII 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 of Formulas VII, VII-H, and Cyclo-VII 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 VII, VII-H, and Cyclo-VII 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 VII, VII-H, and Cyclo-VII are available from

commerical sources or the references cited above, which are incorporated herein by reference.

Formula VII ("Generic Substituted Polycyclic Aryl tertiary-2- hydroxyalkylamines"), Formula VII-H ("Generic Substituted Polycyclic Heteroaryl tertiary-2-hydroxyalkylamines") 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 Ri is a hydrogen, of compounds of Formulas VII, VII-H 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 VII, VII-H, and Cyclo-VII 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 VII, VII-H, and Cyclo-VII 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 VII, VII-H, and Cyclo-VII 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 preparedfrom 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 derivatize hydroxyl, thiol, and amines of compounds of Formulas VII, VII-H, and Cyclo-VII are available from commerical sources or the references cited above, which are incorporated herein by reference.

Formula VII ("Generic Substituted Polycyclic Aryl tertiary-2- hydroxyalkylamines"), Formula VII-H ("Generic Substituted Polycyclic Heteroaryl tertiary-2-hydroxyalkylamines") and certain other compounds of this invention can be converted, according to Scheme 6, to the corresponding cyclic derivatives represented by the general designation"Tricyclic tertiary- oxyalkylamines"exmplified by Formula Cyclo-VII ("Substituted Tricyclic Phenyl tertiary-2-oxyalkylamines"). The hydroxyl group X, wherein R16 is a hydrogen of compounds of Formulas VII and VII-H can be cyclized to corresponding cyclic ethers. Compounds suitable for cyclization will normally have at least one leaving group within 5 to 10 continuous atoms of the hydroxyl group X wherein R16 is a hydrogen. Most preferrably the leaving group will be within 5 to 7 atoms of the hydroxyl group X so as to form a 5 to 7 membered ring heteroatom containing ring. When the leaving group is part of an aromatic ring system, the leaving group will be preferrably in an ortho position. Suitable leaving groups generally include halides, sulfates, sulfonates, trisubsituted amino, disubstituted sulfonium, diazonium, and like, and, in the case of aromatic systems, also includes nitro, alkoxy, aryloxy, heteroaryloxy, and alkylthio. When X-R16 is a thiol, amino, or substituted amino, the corresponding analogous sulfur and nitrogen analogs, Cyclo-VII ("Substituted Tricyclic Phenyl tertiary-2-thioalkylamines and tertiary-2- azaalkylamines"), of Formula Cyclo-VII ("Substituted Tricyclic Phenyl tertiary-2-oxyalkylamines") can be obtained.

The cyclization reaction to form"Tricyclic tertiary-oxyalkylamines"can be accomplished by aromatic and aliphatic nucleophilic substitution reactions such as those disclosed in March's Advanced Organic Chemistry, 4th Edition, John Wiley & Sons, especially at pages 293-412 and 649-658 and the references cited therein, which are incorporated herein by reference. Hydroxyl containing suitably

substituted compounds can be converted to a cyclic analog by heating a suitably substituted compound under anhydrous conditions in a suitable solvent, such as dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone, tetraglyme, or hexamethylphosphoramide, in the presence of a suitable base such as potassium carbonate, cesium carbonate, sodium hydroxide, potassium tertiary-butoxide, or lithium diisopropylamide. Alternately, sodium amide in anhydrous ammonia solvent can be used. Temperatures in the range of-20 °C to 200 °C can be used for time periods of 30 minutes to more than 24 hours. The preferred temperature can be selected by standard synthetic chemical technique balancing maximum yield, maximum purity, cost, ease of isolation and operation, and time required. Isolation of the"Tricyclic tertiary-oxyalkylamines"can be effected as described above for <BR> <BR> <BR> othertertiary-oxyalkylamines. Representative"Tricyclictertiary-oxyalkylamines" prepared using the methodology described above are included in Table 5.

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.

Table 5. Structure of Substituted Tricyclictertiary-2-oxyalkylamines. XCF3 H Cyclo-VII q l \" a-N/Rlo Y 2* K K 2R1 R6, 1 H 1 R6 R 13 \ R5 R12 R5 K1-R6 R10 K2-R11 R12 R13 Y Z 4-chloro-3-ethylphenoxy C-H H H H CH2 C-CF3 - 4-chloro-3-ethylphenoxy N H H H CH2 C-CF3 4-chloro-3-ethylphenoxy C-H H C- H H CH2 CF3 - 4-chloro-3-ethylphenoxy N H C- H H CH2 CF3 - Table 5. (cont.) Structure of Substituted Tricyclic tertiary-2-oxyalkylamines. R5 K1-R6 R10 K2-R11 R12 R13 Y Z 4-chloro-3-ethylphenoxy C-H H N H CH2 CF3 - 4-chloro-3-ethylphenoxy C-H H H H C-CF3 - - 4-chloro-3-ethylphenoxy N H H H C-CF3 - - 4-chloro-3-ethylphenoxy C-H H C- H H CF3 - - 4-chloro-3-ethylphenoxy N H C- H H CF3 - 4-chloro-3-ethylphenoxy C-H H N H CF3 - - Table 5. (cont.) Structure of Substituted Tricyclic tertiary-2-oxyalkylamines. CAF3 H i F3 2 R5 f1 1 Z . * Cyclo-VII l---R6 I-,'K, Ru R10 R7 R7 K1-R6 R10 K2-R11 R5 R6 Y Z 4-chloro-3-ethylphenoxy C-H C- H H H CH2 OCF2CF2H - 4-chloro-3-ethylphenoxy N C- H H H CH3 OCF2CF2H - 4-chloro-3-ethylphenoxy C-H N H H CH2 OCF2CF2H - phenoxy C-H C- H H H CH2 OCF2CF2H - Table 5. (cont.) Structure of Substituted Tricyclic tertiary-2-oxyalkylamines. R7 K1-R6 R10 K2-R11 R5 R8 Y Z phenoxy N C- H H H CH2 OCF2CF2H - phenoxy C-H N H H CH2 OCF2CF2H - 4-chloro-3-ethylphenoxy C-H C- H H H CH2 CF2CF3 - 4-chloro-3-ethylphenoxy C-H C- H H H CH2 CF2CF3 - 4-chloro-3-ethylphenoxy N C- H H H CH2 CF2CF3 phenoxy C-H N H H CH2 CF2CF3 phenoxy N C- H H H CH2 CF2CF3 - - phenoxy C-H N H H CH2 CF2CF3 4-chloro-3-ethylphenoxy C-H C- H H H CH2 CF3 - 4-chloro-3-ethylphenoxy N C- H H H CH2 CF3 - 4-chloro-3-ethylphenoxy C-H N H H CH2 CF3 - Table 5. (cont.) Structure of Substituted Tricyclic tertiary-2-oxyalkylamines. R7 K1-R6 R10 K2-R11 R5 R8 Y Z phenoxy C-H C- H H H CH2 CF3 - phenoxy N C- H H H CH2 CF3 - phenoxy C-H N H H CH2 CF3 -0 4-chloro-3-ethylphenoxy C-H C- H F CH2 OCF2CF2H - 4-chloro-3-ethylphenoxy N C- H F CH2 OCF2CF2H - 4-chloro-3-ethylphenoxy C-H N H F CH2 OCF2CF2H - 4-chloro-3-ethylphenoxy C-H 2-furyl C- H H H CH2 - 4-chloro-3-ethylphenoxy N 2-furyl C- H H H CH2 - 4-chloro-3-ethylphenoxy C-H 2-furyl N H H CH2 4-chloro-3-ethylphenoxy C-H C- H H H CH2 SCF3 - 4-chloro-3-ethylphenoxy N C- H H H CH2 - SCF3 Scheme 1 Heteroaryl Carbonyl Heteroaryl Amine (X-AH) (XI-AH) R6 R9 1 0 R5-, j IR7 4,,, RIO 2 J4 J2 J1/I J4 I in R14 R4 R13 i 3 11 R15-z-H20 R12 beat rus NH2 R I Rg \ ! Br I I I / D2 D1 R14/-I I I 4 R4/ \R8 I I R4 r R13 i 3 11 15 I R9 13 J3 1 Heteroaryl Bromide J4 (XXI-AH)/R14 zD Akylation J3 2R Method-1 : Solvent R12 NaHC03 Diheteroaryl Imine Reduction (XII-AH) Redaction Method-1 : R6 H/pto Reduction Method-2 : Rl IR7 C2H50H NABH J2 200C 4 II 60 psi CH30H t 60/CH30H/ 4 R4 f 8 // R15-Z Rg/Reduction Method-3 : N N oD4 oRlo/NaCNBH3 H y J4 CH30H/20OC/pH <4 / .. r R14/D3 : K2 R13 J3 R R12 Secondary Heteroaryl Amine (XIIIA-H) VII-H/VII : (Generic Polycyclic Aryl and Heteroaryl Tertiary OmegaHydroxyalkylamines) R6 'Scheme 2 2 1 J2 11 /D2 D1 8 R15 ? Rg Method B : Step 1 : \y/4 10 J4 NaH or n-BuLi vil R--J."Rn \ Aprotic Solvent R12 Step 2 : Secondary R16-,, 16 \ X R Heteroaryl Amine (XIIIA-H)/ /C (CH) n-M Re i/ / (/xi) R5 iKlw R7 R2 11 x R3 I I 21 P4)"8 X R, 1 3 I 4/R10 J 'C- (CH) n/ R14 i Ri R14 D I I R2' R12 Scheme 3 R6 R5\,, R1 oR7 R5\ iKlw 7 Secondary D D1 Heteroaryl Amine 2w 1 R4 t IIIA-H) R-Z Rg D4/R10 /Y--T I1 4 R14 11 R13 J3 11 1 Method A : R12 R1 t H Method : (XX) 1. NaH or n-BuLi Aprotic Solvent 2 \-78°C 60-90°C 2. Acetonitrile R1 A H Lewis Acid R6 (XX) 6 R3 I R2 R J2 R3 I IN J2 J1 R15-z Rg Rl5- ? Rg \ I4/10 J 114 Rl R2 R3 R14/D3 : K2 R13 i 3 11 Ri R3 j Rl3"3 Pll R12 VII-H/VII : (Generic Substituted Polycyclic Heteroaryl and Aryl Tertiary 2-Hydroxyalkylamine) R R4/R5 D2J2 Rl 6 (K1 R6 I/X-Kl-R6 )))/ R '2 IJ1 R7 /D2 D1\R 8 Rj) 8 X = and S R15-l Rg I I Rl6-0 D, , /au', '4 1 R2 R3 R14/D3 : K2 13"3 Pll R12 Cu2 (triflate) 2'Benzene 2 equivalents of Aryl-OH, Aryl-SH, Heteroaryl-OH, or Heteroaryl-SH R6 2. 5 eqv. Cs2C03 R Br 2. 5 eqv. 1-Naphthoic Acid R5 Ki Br J2 J1 4A Molecular Sieves '''Dimethylacetamide/toluene R4,-D2 D"'R8 105 OC/10-14 Days R15-l Rg I R16-0 P4/Rlo y J4 114 Ri R2 R3 R14 zD3 _K2 Rl3"3 Pll R12 Scheme 4 VII-H/VII : (Generic Substituted Polycyclic 3-Aryloxyaryl, 3-Heteroaryloxyaryl, 3-Heteroaryloxyheteroaryl, 3-Aryloxyheteroaryl, 3-Arylthioaryl, 3-Heteroarylthioaryl, 3-Heteroarylthioheteroaryl, 3-Arylthioheteroaryl, Tertiary 2-Hydroxyalkylamine) vii-H/vn : (Generic Substituted Polycyclic 3-Bromoheteroaryl and 3-Bromoaryl Tertiary 2-Hydroxyalkylamine) Scheme 5 VII-H/VII : (Generic Substituted Polycyclic 3-Aryloxyaryl, 3-Heteroaryloxyaryl 3-Aryloxyheteroaryl, or 3-Heteroaryloxyheteroaryl Tertiary 2-Hydroxyalkylamine) R /". R4 \/R5 R K6 /1R6 I 0-'K-R6 v R zD2 R R7 R4 ? 8 I R15 I R9 I Pi R Rl 4 11 J i1 4 R1 R2 R3 R14/D3 : oK2 T3 11 R12 Cu2 (triflate) 2 Benzene 1 equiv. of aryl bromide or heteroaryl bromide 6 R 1. 4 eqiuv. Cs2C03 R K OH -' R5J2K1\J1OH Ethyl acetate/toluene 105 °C/3-10 Days 2"1- 8 Ris- ? Ra R15-l Rg I I 4/R10 J It Rl R2 R3 R14/D3 : K2 R13 i 3 11 R12 VII-H/VII : (generic suDstitutea Polycyclic 3-Hydroxyheteroaryl and 3-Hydroxyaryl Tertiary 2-Hydroxyalkylamine) Scheme 6 R6 R5 R4---R8 R15 Z Rg t i !'\ R I Rl R2 R3 1 R \ VII : (Generic Substituted 13 11 Polycyclic Aryl Tertiary R12 2-Hydroxyalkylamine) (Rl6- R6 LDA/DMF 5 7 or NaNH2/NH3 x 8-4 X \ 8 R5 R9 10 R1 R2 \ "2'T3 R3 R3 R14 4R R13 Ril R12 Ri2 Phenyl Cyclo-VII : Substituted Tricyclic Phenyl tertiary-2-oxyalkylamines NOTE : Use of VII-H will afford mono-and di-heteroaryl analogs of Cyclo-VII.

Scheme 7 VII : (Generic Substituted Polycyclic 3-Arylaryl Tertiary 2-Hydroxyalkylamine) R5 ruz j *L Re j T R4 R R8 I R4 R8 R4-| R8 R15 Rg R <g ll 14 11 R13 R12 LiCl Heat Pd (Ph3P) 4 PdCl2 (Ph3P) 2 Aryl-B (OH) 2 Aryl-B (OH) 2 Aryl-Sn (n-Bu) 4 Toluène Toluene R6 2 M Na2C03 Ethanol I R4 x8 R4 _ | 8 R15 Rg 10 R2 R R14 R R14 wS 3gRlo R12 VII : (Generic Substituted Polycyclic 3-Bromoaryl Tertiary 2-Hydroxyalkylamine) NOTE : Use of Heteroaryl-B (OH) 2 will give the heteroarylmethyl analog of VII. Scheme 8 6 N Rs @ (R22) 2 1 VII : (Generic Substituted Polycyclic 3-R22-aminoaryl R4 8 z Tertiary 2-Hydroxyalkylamine) R15 10 R14 R. Rz R3 \ 11 R13 R12 R22-primary or secondary amine Pd (dba) 3/R- (+)-BINAP 2. 5 eqiuv. Cs 2C03 Toluene/100 °C/1-2 Days R6 R5 Br V I I : (Generic Substituted Polycyclic 3-Bromoaryl R4 T-R8 Tertiary 2-Hydroxyalkylamine) I Rl5-Z Rg R16-X *R 10 R e RR14 + Z R R14 1 R2 R3 R I R12 R22 is selected independently from any one or two of the following groups : hydride, hydroxy, aryloxy, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, alkoxyalkyl, aralkoxyalkyl, alkylsulfinylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkoxy, halocycloalkoxyalkyl, arylsulfinylalkyl, arylsulfonylalkyl, alkylamino cycloalkylsulfinylalkyl, cycloalkylsufonylalkyl, heteroarylsulfonylalkyl, heteroarylsulfinylalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl, hydroxyalkyl, amino, alkoxy, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkylthioalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, heteroaryl, halocycloalkenyloxyalkyl, heteroarylalkyl, halocycloalkenyl, and heteroarylthioalkyl.

Scheme 9 R1 R2 R3 Heteroaryl Alkyl Amine (VLX-H) R ~ X 16 NH R16--X NA syHt « D4 \ oR1 o J R14 D IJ4 /D3.. K2 Rl4 f R14 11 I R12 Reduction Method \1, 2 or 3 Heteroaryl Carbonyl R1 R2 R3 0 (XI-AH) Heteroaryl R-X Imine (VL-8) I R16-N 4/Ri0 N R R J4 1 R14 I 114 II I D3 : K2 R/Y 4 /R10 R13 J3 R11 14 II R12 _g2p R/D3 J sK2R 13 3 11 XVL : (Generic/Azeotropic Substituted Distillation R12 Alkylamine) X Excess Liquid NH3 gg) Ri R2 R3 R2 R3 1. NaN3/DMF 2. X = O)

Scheme 10 Ri R2 R3 Heteroaryl Alkyl Amine (VLX-H) R16-X NH Rg R14 D 11 J R14 It4 /D3.. IC2 R13/J3 2 R12 , R6 Pd (dba) 3/R- (+)-BINAP 2. 2. 5 eqiuv. Cs2C03 2 1 Toluene D D R4 r R8 100 °C/1-2 Days Ber \ R5/R6 J2=Kl R4-D2\"J1 R7 D, D1 ru R2 R3 N R8 R16 X 9 Rg YH « D4/1O J I 4 R14 l IJ4 D, K R13/i3 2 R t R12 VII-H : (Generic Substituted Polycyclic Heteroaryl Tertiary 2-hydroxyalkylamine) NOTE : Use of a heteroaryl alkyl amine with an aryl bromide or an aryl alkyl amine analog of VLX-H with an aryl bromide will afford mono or di aryl analogs of VII-H.

Scheme 11 R1 R2 R3 R9 R16-x I NH. D , Heteroaryl Secondary | J4 Amine (VLXX-H)/D3 Xi-H I R12 /Pd (dba) 3/R- (+)-BINAP /2. 5 eqiuv. Cs2C03 /Toluene 100 100 °C/1-20 Days NH,, R16-X NH2 R XVL : (Generic M 4\ 10 Substituted R3 Alkylamine) Rl6-H) R13 i 3 Rl l R12 2 equiv. NaH or n-BuLi\ Heteroaryl Halide Aprotic Solvent (LXXI-AH) -78, then up to 150 °C M = Br or Cl ; D3 or D4 = O, N, or S R, R2 R3 Rg R16-x R-X P4/-Rlo NHD , Heteroaryl Secondary Amine (VLXX-H) D 2l t I R12 Scheme 12 R1 R2 R3 Rg R16 I NH s ZR10 Heteroaryl Secondary r J4 Amine (VLXX-H) It iK2. R13 J I R6 R12 R5 R7 2 equiv. NaH or n-BuLi 4 j 8 Aprotic Solvent 15 Br-78 °C, then heat to 150 °C Cyclohexane R5 R6 Heat, Cs2C03 Ri. R2 R3R15\Z R8 R9 R16-X R1 N, RlO *"' 114 114 /D3 : K2. R13 13 R I R12 VII-H : (Generic Substituted Polycyclic Aryl Heteroaryl Tertiary 2-hydroxyalkylamine)

R6 Scheme 13 Generic Substituted Polycyclic Phenyl Tertiary 2-Hydroxyalkylamine (VII) /riz R9\ J4_. R11 t 9 H < I Rg ll 12 R3 N i ; 212 ./y 13 14 \ R13 lez Ri R2 R12 X-Rl6 3-Heteroaryl Phenyl Rio Carbonyl (Xt-A) RgX _J4/Rl rt 4 "11 NaB (OAc) 3H 9) t < Acetic Acid 3R12 C1CH2CH2C1 /I 14 R13 Rl2/ R13 Rll/R6 R6 R12 R6 R5 R7 R6 I R5 7 R4 8 T {T/R15 z, R15-Z Nu2 60-90°C Phenyl Acetonitrile Amine (X-A) R1. 5- i Lewis Acid HN R3 HN R3 R2 1 X-R16 R2 R3 Phenyl Alkyl Amine (VLX) (XX) NOTE : Heteroaryl Analogs Can Be Prepared Using Heteroaryl Analogs of X-A, VLX, and XI-A. Scheme 14 R14 R9 Method A : H NY 10 R1AH t11 R12 R2 R3 t/Rl2 R2 Rs/ Phenyl Amines 60-90°C (XXII-A) Acetonitrile Lewis Acid j R14 R9 I/ iY/10 R, HN, ley 1 10 R2 R3 R12 "Rg 12 Phenyl Alkylamines (VLXX) R4 I zu J2 Du,, /D1 K1. R8 J1 R6 Pd (dba) 3/R- (+)-BINAP A7 Heteroaryl Halide 2. 5 eqiuv. Cs2C03 (LXXI-AH) Toluene M = Br or Cl 100 °C/1-20 Days P6 R6 I 11 R/2 11 I if R 4 I R8 R9 ex \ R/Y I R1 R R3 14 R13 I 11 R12 VII-H : (Generic Substituted Polycyclic Phenyl Heteroaryl Tertiary 2-Hydroxyalkyl- amine when R16-X equals HO) NOTE : Aryl Analogs (VII) of (VII-H) Can Be Prepared by Starting With Arvl Bromide Analoas of (LXXI-AH). Scheme 15 HO R9 10 sio Phenol (XXIP-A) R9 R13 NI 9 H2NO 10 NH 20S03-R12 HNOSio. 2 3 Aqueous KOH 60-90 OC Ri (xi) R12 R2 R3 Phenyl Hydroxylamine 60-90°C (XXIHA-A) Acetonitrile Lewis Acid R1 /io g R13 \ 11 2 R3 R12 Phenyl Oxy Alkyl R4 Amines (VLXX-O) 4 'TMS-C1 < 2sJ/X TEA Jazz 2 wdlt oKl l-Pd (dba) 3/R- (+)-BINAP R8 il 1-R6 2. 5 eqiuv. CS 2CO3 Toluene/100 °C/1-20 Days Heteroaryl Halide 2. Water (LXXI-AH) R6 6 M = Br or Cl ; « r | R R5\ iKl. w/7 12 1ll 1 11 R/D2 D1R R9 I R16-X 1/10 O R1 R R13 11 R12 VII-H : (Generic Substituted Polycyclic Phenyl Heteroaryl Tertiary 2-Hydroxyalkylamine when R16-X = HO and Y = 0) NOTE : Diaryl and Diheteroaryl Analogs Can Be Prepared by Using Aryl Bromide and Heteroaryl-OH, respectively.

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'H NMR and mass spectrometry. These compounds also may be formed in vivo.

The following examples contain detailed descriptions of the methods of preparation of compounds of Formula V-H. These detailed descriptions fall 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

3- [ (3-fluorophenyl)-[[3-(trifluoromethyl) phenyl] methyl] amino-1, 1, 1-trifluoro-2-propanol EX-1A) A solution of 3-fluoroaniline (1. 92 mL, 0. 02 mol) and trifluoro-m- tolualde-hyde (2. 68 mL, 0. 02 mol) in 30 mL of cyclohexane was refluxed using a Dean-Stark trap to remove water. After 4 hours, the cyclohexane was removed in vacuo to yield 5. 4 g (100%) of the desired imine product as an amber oil. MS m/z = 267 [M+]. 1H NMR (CDC13) â 8. 50 (s, 1H), 8. 22 (s, 1H), 8. 09 (d, 1H), 7. 78 (d, 1H), 7. 63 (t, 1H), 7. 39 (dq, 1H), 6. 99 (m, 3H). This imine (5. 34 g, 0. 02 mol) was then slurried in 30 mL of methanol at 0 °C. Solid NaBH4 (1. 32 g, 0. 0349 mol) was added in batches over 3 minutes at 0 °C. The reaction was stirred below 10 °Cfor 30 minutes and then warmed gradually to 15 °C. After 1 hour, the solution was cooled, and 3% aq. HCl solution was added until the aqueous layer was acidic. The aqueous solution was extracted twice with diethyl ether. The combined ether extracts were washed 3 times with brine, dried (MgSO4), and concentrated in vacuo to yield 4. 45 g (82%) of the desired N- (3-fluorophenyl)- [ [3- (trifluoromethyl) phenyllmethyl] amine product as a light amberoil. MS m/z = 269 [M]. H NMR (CDCL) 6 7. 57 (m, 4H), 7. 14 (dq, 1H), 6. 45 (m, 2H), 6. 33 (dt, lH), 4. 41 (s, 2H), 4. 27 (br, 1H).

The amine product EX-1A (2. 69 g, 0. 01 mol) was mixed with 3, 3, 3- trifluoro-1, 2-epoxypropane (1. 34 g, 0. 012 mol), and the mixture was heated to 90 °C for 40 hours in a tightly capped vessel. After cooling to room temperature, the reaction product was purified by eluting through silica gel with 10% ethyl acetate in hexanes to yield 2. 54 g (67%) of the desired aminopropanol as a light yellow oil, 100% pure product by GC and reverse phase HPLC. HRMS calcd.

for C17H14F7NO : 382. 1042 [M+H] +, found : 382. 1032. 1H NMR (CDC13) â 7. 47 (m, 4H), 7. 19 (q, 1H), 6. 50 (m, 3H), 4. 50 (ABq, 2H), 4. 39 (m. lH), 3. 93 (dd, 1 H), 3. 60 (dd, 1 H), 2. 51 (d, 1H).

Additional substituted 3-[(N-aryl)-[aryl]methyl]amino]-halo-2- propanols can be prepared by one skilled in the art using similar methods, as shown in Example Tables 1, 43, 46, and 47. Substituted 3- [ (N-aralkyl)- [laralkyl] amino]-halo-2-propanols can also be prepared by one skilled in the art using similar methods, as shown in Example Tables 2, 3, 44, and 45.

Substituted 3-[(N-aryl)-[[aralkyl] amino]-halo-2-propanols can be prepared by one skilled in the art using similar methods, as shown in Example Table 4.

Substituted 3- [ (N-aryl or N-aralkyl)-[[aryl]methyl]amino]-haloalkoxy-2- propanols can be prepared by one skilled in the art using similar methods, as shown in Example Tables 5 and 48.

Example Table 1. 3-[N-(aryl)-[(aryl)methyl]amino]-1,1,1-trifluoro-2-propanols Ex. Calc.* Obs.* RSUB1 RSUB2 No. mass mass LM+1 LM+1 2 H H 295. 1184 295. 1180 3 3-OCH3 3-CH3 339. 1446 339. 1449 4 3-OCH3 4-CH3 339. 1446 339. 1444 323.1497 323.1491 4-CH3 3-CH3 339.1446 339.1440 4-OCH3 4-CH3 7 4-Cl H 329. 0794 329. 0783 4-CH3 4-CH3 323.1497 323.1495 9 3-Cl 3-CH3 343.0951 343. 0950 10 3-F H 313. 1090 313. 1086 11 323.1497 323.1509 3-CH3 3-CH3 12 323.1497 323.1504 3-CH3 4-CH3 13 2-CH3 4-CH3 323. 1497 323. 1483 4 4-CH3 H 309.1340 309. 1331 15 2-CH3 H 309. 1340 309. 1337 16 3-Cl H 329. 0794 329. 0794 17 3-F, 4-F 3-CH3 345. 1152 345. 1143 18 3-F 3-F 331. 0996 331. 0984 19 3-F, 4-F 3-CF3 399.0869 399. 0827 20 377. 1214 377. 1180 21 2-CH3 3-CF3 377. 1214 377. 1176 22 3-F, 4-F 4-CF3 399. 0869 399. 0822 23 4-OCH3 4-CF3 393.1163 393.1159 Example Table 1 (continued). 3-[N-(aryl)-[(aryl)methyl]amino]-1,1,1-trifluoro 2-propanols. Ex. Calc.* Obs.* RSUB1 RSUB2 No. mass Mass LM"l LM-'i 24 3-F, 4-F 4-CH3 345. 1152 345. 1136 25 3-CH3 3-CF3 377.1214 377.1231 26 3-OCH3 4-CF3 393. 1163 393. 1179 27 2-CH3 3-CH3 323. 1497 323. 1486 28 4-OCH3 3-CH3 339. 1446 339. 1435 29 3-F, 5-F 4-CH3 345. 1152 345. 1159 30 3-Br 3-CF3 441.0163 441.0135 31 3-F 3-OCF3 397.0913 397.0894 32 4-CH3 3-F 327. 1246 327. 1291 33 3-F 4-CH3 328. 1324 328. 1333 34 3-Cl 4-CH3 344. 1029 345. 1045 35 H 3-CF3 3634.1136 364. 1122 36 3-Br 3-OCF3 458. 0190 458. 0145 37 4-CH3 4-CF3 378. 1292 378. 1259 38 3-cL 3-CF3 398.0746 398.0727 39 3-CH3 4-CF3 378.1292 378.1274 2-CH3 4-CF3 378. 1292 378. 1259 41 3-Cl 3-OCF3 414. 0695 414. 0699 42 3-CF3 3-OCF3 448.0959 448.0951 43 3-F 3-OCF2CF2H 430. 1053 430. 1042 44 3-1 3-OCF2CF2H 538.0114 538.0077 45 3-CF3 4-CH3 378.1292 378.1296 46 3-CF3 3-F 382.1042 382.1073 47 3-CF3 3-CF3 432.1010 432.1026 48 3-OCH3 3-CF3 394.1241 394.1227 49 3-F 3-CH3 328.1324 328.1300 Example Table 1 (continued). 3-lN-(aryl)-[(aryl) methyllaminol-l, 1, 1-trifluoro- 2-propanols. Ex. Calc.* Obs.* RSUB1 RSUB2 No. Mass Mass IM LM+1 50 3-Cl 4-CF3 398. 0746 398. 0731 51 4-OCH3 3-CF3 394. 1241 394. 1237 52 3-CF3, 4-F 3-CF3 450. 0915 450. 0913 53 3-CF3, 4-F 4-CH3 396. 1198 396. 1179 54 3-CF3 4-OCF3 448. 0959 448. 0967 55 3-Cl 4-OCF3 414. 0695 414. 0690 56 3-F, 4-F 4-OCF3 416. 0886 416. 0904 57 3-F 4-OCF3 398. 0991 398. 0975 58 3-CF3, 4-F 3-CH3 396.1197 396.1178 59 H 4-OCF3 380.1085 380.1077 60 3-OCF3 4-OCF3 464.0908 464.0877 61 3-CH3 4-OCF3 394.1241 394.1248 62 3-Br 4-OCF3 458. 0189 458. 0189 63 3-phenoxy 4-OCF3 472. 1347 472. 1344 64 3-F 3-phenoxy 406. 1430 406. 1418 65 3-F 4-phenyl 390. 1481 390. 1468 66 3-phenyl 3-OCF3 456. 1397 456. 1395 3-CF3, 4-Cl 3-CH3 412. 0903 412. 0892 68 3-F, 5-F 4-OCF3 416.0896 416 .0895 69 3-F, 3-F 3-CF3 400. 0941 416. 0956 70 2-F, 5-F 3-OCF2CF2H 448.0959 448. 0940 71 3-OCF3 3-OCF2CF2H 496.0971 496.0959 72 3-CH3 3-OCF3 394.1241 394.1244 73 H 3-OCF3 380.1085 380.1075 74 3-OCF3 3-OCF3 464. 0908 464. 0898 3-CF3, 4-F 4-CF3 450. 0915 450. 0906 Example Table 1 (continued). 3-[N-(aryl)-[(aryl)methyl]amino]-1,1,1-trifluoro- 2-propanols. Ex. Calc.* Obs.* RSUB1 RSUB2 No. Mass Mass LM"1 LM"1 3,4-(CH=CH)2- 3-OCF3 430.1241 430.1253 77 3-phenoxy 3-OCF3 472. 1347 472. 1342 78 3-F, 4-F 3-OCF3 416. 0896 416. 0884 79 4-phenyl 3-OCF3 456. 1398 456. 1368 80 2-F, 3-F 4-OCF3 416. 0897 416. 0885 81 3-F, 5-F 3-CH3 346.1230 346.1246 82 3-OCF3 3-phenoxy 472.1347 472.1342 3-OCF3 3-benzyloxy 486. 1504 486. 1503 84 3-phenoxy 3-phenoxy 480. 1786 480. 1772 85 2-phenyl 3-phenoxy 464. 1837 464. 1821 86 4-phenyl 3-phenoxy 464. 1837 464. 1836 87 4-phenyl 3-OCF2CF2H 488. 1460 488. 1443 88 4-n-octyl 3-OCF3 492. 2337 492. 2341 89 3,4-(OCF2CF2O) 3-OCF3 510.0763 510.0747 90 4-F 3-OCF3 398.0991 398.1023 91 3-phenoxy 3-ethoxy 432. 1787 432. 1770 92 3-phenoxy 3- (4-Cl-phenoxy) 514. 1397 514. 1426 93 3-OCF3 3- (4--CI-phenoxy) 506. 0958 506. 0971 94 3-phenoxy 3-(3,4-Cl2-C6H3O) 548. 1007 548. 1002 95 3-OCF3 3-(3,4-Cl2-C6H3O) 540.0568 540. 0555 96 3OCF3 3-(3,5-Cl2-C6H3O) 540.0568 540.0568 9 3-OCF3 4-OCH3 502. 1453 502. 1466 98 3-OCF3 3-CF3 540.1221 540.1248 99 3-OCF3 3-benzyloxy, 516.161 516.1626 4-OCH3 100 3-OCF3 3, 4-dibenzyloxy 592. 1922 592. 1915 101 3-OCF3 3-OCH2CH3 424.1347 424.1331 Example Table 1 (continued). 3- [N- (aryl)- I (aryl) methyl] amino]-1,, 1, 1-trifl uoro- 2-propanols. Ex. Calc.* Obs.* RSUB1 RSUB2 No. Mass Mass IM JLM-'l 102 3-OCF3 3-acetoxy 438. 114 438. 1142 103 3-OCF3 3- (2-OH-ethoxy) 440. 1297 440. 1302 104 3-1 (3-Cl, 2-OH)-488. 1063 488. 1050 3 n-propoxY} 105 3-OCF3 3,4-(OCH2CH2O) 438.114 438. 1142 3-OCF3 4-benzyloxy, 516. 1609 516. 1608 3-OCH 107 3-OCF3 3, 5-dibenzyloxy 592. 1922 592. 1903 108 3-CF3 3-(3-CF3-pheoxy) 524.1372 524.1281 109 3-CF3 3-phenoxy 456.1398 456.1421 110 4-CF3 3-(3-CF3-phenoxy) 524. 1272 524. 1259 111 4-CF3 3-phenoxy 456. 1398 456. 1415 112 4-CF3 3-OCF3 424.1347 424.1331 113 3-phenoxy 3-nitro 433.1375 433.1379 114 3-phenoxy 3-(3,5-Cl2-C6H3O) 548. 1007 548. 1016 115 3-phenoxy 3-(3-CF3-phenoxy) 548.166 548.1639 116 3-OCF3 3, 4-dimethoxy 440. 1296 420. 1294 117 3-OCF3 3-OCH2CH3, 454. 1453 454. 1458 4-OCH3 118 3-OCF3 3,4-diacetoxy 496.1194 496.1183 119 3-OCF3 4-acetoxy, 3-OCH3 468.1245 468. 1239 120 3-OCF3 4-n-butoxy 452. 1584 452. 1614 121 3-OCF3 3-OCH3 410. 1191 410. 1179 122 3-OCF3 4-OCH3 410. 1191 410. 1177 123 3-OCH3 3-OCH3 356.1473 356.1469 124 3-OCH3 3-OCF3 410. 1191 410. 1158 125 3-OCF3 4-n-propoxy 438. 1503 438. 1517 126 3-benzyloxy 3-OCF3 486. 1504 486. 1524 Example Table 1 (continued). 3-[N-(aryl)-[(aryl)methyl]amino]-1,1,1-trifluoro- 2-propanols. Ex. Calc.* Obs.* No. Mass Mass LM+1 LM+1 127 3-benzyloxy 3-phenoxy 494. 1947 494. 1956 128 3-ethoxy 3-OCF3 424.1347 424. 1363 129 3,4-(OCH2O) 3-OCF3 424.0983 424.0990 130 3,4-(OCH2O) 3-phenoxy 432.1424 432. 1432 131 3,4-(O(CH2)2O) 3-OCF3 438.1140 438.1165 132 3,4-dimethoxy 3-OCF3 440.1296 440. 1319 133 4-phenoxy 3-OCF3 472. 1347 472. 1334 134 4-OCF3 3-OCF3 464.0908 464. 0923 135 4-n-butoxy 3-OCF3 452. 1660 452. 1624 136 4-benzyl 3-OCF3 470.1554 470. 1148 137 3-phenoxy 3,4-(OCH2CH2O) 446.1579 446. 1583 138 3-OCF3 3,4-diethoxy 468.1609 468. 1638 139 3- (O (CH2) 30) 3-OCF3 452. 1297 452. 1307 140 3-OCF3 4-CF3 448.0959 448.0985 141 4-phenyl 4-CF3 440.1449 440.1451 142 3-cyano 4-CF@ 389.1089 389. 1097 143 3-CF 4-phenyl 440. 1449 440. 1444 144 4-CF3 4-phenyl 440.1449 440. 1457 145 3-phenoxy 3-CF, 5-CF3 524. 1272 524. 1285 14, 6 3-phenoxy 4-cyano 413. 1477 413. 147 3-phenoxy 3-cyano 413. 1477 413. 1493 148 3-phenoxy 4-nitro 433. 1375 433. 1398 149 3-phenoxy 3-CF3 456.1398 456. 1414 150 3-phenoxy 4-CF3 456.1398 456. 1394 151 4-phenoxy 3-phenoxy 480. 1786 480. 1794 152 3-OCF3 4-phenoxy 472. 1347 472. 1347 153 3-phenoxy 4-phenoxy 480. 1786 480. 1780 154 4-phenoxy 4-phenoxy 480. 1786 480. 1298 Example Table 1 (continued). 3-[N-(aryl)-[(aryl)methyl]amino]-1,1,1-trifluoro- 2-propanols. Ex. Calc.* Obs.* RSUB1 RSUB2 No. Mass Mass LM+1 Jim"1 155 4-phenoxy 40CF3 472. 1347 472. 1338 156 3-phenoxy 4-SOCHX 466. 1298 466. 1253 157 3-phenoxy 4-CO2CH3 446.1579 446.1569 158 3-OCF3 4-ethoxy 424.1347 424.1317 159 3-cyclopentoxy 3-OCF3 494. 1766 494. 1771 4methoxy 160 3, 4, 5-trimethoxy 3-OCF3 470. 1402 470. 1408 161 3-phenoxy 3-(OC6H4-4-OCH3) 510. 1892 510. 1881 162 3-cyano 3-OCF 405. 1038 405. 1021 163 4cyano 3-OCF 405. 1038 405. 104 164 4-CO2-n-C4H9 3-OCF3 480.161 480.1594 165 4-(4-Cl-phenoxy) 3-phenoxy 514.1397 514.1407 166 3- (4-F-phenoxy) 3-OCF 490. 1253 490. 1211 167 4-(4-CN-C6H4) 3-OCF3 481.135 481.1354 168 3-phenoxy 4-(OC6H4-4-OCH3) 510.1892 510.1919 *Note : Calculated (Calc.) and Observed (Obs.) masses measured tor Example Numbers 33 through 168 are [M+Hi+. Example Table 2. 3-[N-[(aryl)methyl]-[(aryl)methyl]amino]- 1, 1, 1-trifluoro-2-propanols. Ex. Calc. * Obs. * RSUB1 RSUB2 No. Mass [M+] Mass [M+] 169 3-F 4-CF3 395. 1120 395. 1107 170 4-F 4-CF3 395. 1120 395. 1113 171 2-F 4-CF3 395. 1120 395. 1102 172 3-Cl 4-CF3 411. 0825 411. 0779 173 4-Cl 4-CF3 411.0825 411. 0756 174 2-Cl 4-CF3 411.0825 411. 0779 175 3-Cl 2-CF3 411. 0825 411. 0753 176 4-Cl 2-CF3 411.0825 411. 0754 177 2-Cl 2-CF3 411.0825 411.0760 178 3-F 4-CH3 341.1403 341.1384 179 4-F 4-CH3 341. 1403 341. 1369 180 3-F 3-CH3 341. 1403 341. 1372 181 2-F 4-CH3 341. 1403 341. 1391 182 4-F 3-CH3 341. 1403 341. 1365 183 2-F 3-CH3 341. 1403 341. 1359 184 2-F 3-CF3 395. 1120 395. 1094 185 3-Cl 3-CF3 411. 0825 411. 0767 186 4-Cl 3-CF3 411.0825 411. 0770 187 2-CI 3-CF3 411. 0825 411. 0759 Example Table 2 (continued). 3-[N-[(aryl)methyl]-[(aryl)methyl]amino]- 1, 1, 1-trifluoro-2-propanols. Ex. Calc.* Obs.* RSUB1 RSUB2 No. Mass [M+] Mass [M+] 188 3-F 2-CF3 395.1120 395.1071 189 4-F 2-CF3 395.1120 395.1119 190 3-F 3-CF3 395.1120 395.1096 191 4-F 3-CF3 395.1120 395.1124 192 3-OCF3 3-OCF3 478.1064 478.0157 193 3-Cl 3-OCF3 428.0852 428.0878 194 3-Br 3-OCF3 472.0346 472.0366 195 3-phenoxy 3-OCF3 486.1503 486.1507 196 4-phenyl 3-OCF3 470.1554 470.1566 197 3-nitro 3-OCF3 439.1092 439.1051 *Note : Calculated (Calc.) and Observed (Obs.) masses measured for Example Numbers 192 through 197 are [M+H]+.

ExampleTable 3. 3- [N- (aralkyl)-N- (aralkyl) aminoJ-l, l, l-trifluoro-2- propanols. Ex. Calculated observed RSUB1 RSUB2 No. Mass Mass [M+H] [M+H] (2-(3-F-phenyl)- 3-(OCF2CF2H)- 458.1364 458.1384 198 ethyl benzyl Example Table 4. 3-[N-(aryl)-N-(aralkyl)amino]-1,1,1-trifluoro-2-propanols.

Ex. Calculated Observed No. Mass Mass [M+H] M+H 199 3-F-phenyl 2-402. 1481 402. 1501 fluorenylmethyl 200 3-F-phenyl 1-(4-OCH3- 390. 1430 390. 1415 naphthyl) methyl 201 2-fluorenyl 3-OCF3-benzyl 468.1398 468.1375 202 3-phenoxyphenyl 1- (4-CN- 427. 1633 427. 1627 phenyl)-ethyl 203 3-phenoxyphenyl 1- (3-F-phenyl)- 420. 1587 420. 1584 ethyl 204 2- (7-bromo- 3-OCF3-benzyl 546. 0503 546. 0531 fluorenyl) 205 3-phenoxyphenyl 1-(3-nitro- 447.1531 447.1554 phenyl) ethyl 206 3-phenoxyphenyl l-3-OCF3-486. 1503 486. 151 henyl)ethyl 207 3-dibenzofuryl 3-(OCF2CF2H) 502. 1253 502. 1241 benzyl Example Table 5. 3- [N- (aryl or aralkyl)-N- (aralkyl) amino]-1-haloalkoxy-2- propanols.

Ex. Calculate Observed RSUB1 RSUB2 No. d Mass Mass [M+H] [M+H] 208 3-OCF3-benzyl 3-OCF3 540.1232 540.1219 209 3-OCF3-phenyl 3-OCF3 526. 1076 526.1049 210 3-phenoxy-phenyl 3-OCF3 534. 1473 534. 1515 211 3-phenoxy-phenyl isopropoxy 508. 2111 508. 2112 212 3-phenoxy-phenyl 3-566. 1577 566. 1604 OCF2CF2H 213 3-phenoxy-phenyl 3-ethoxy 494.1954 494.1982 EXAMPLE 214

3- [ (3-phenoxyphenyl) [ [3- (1, 1, 2, 2-tetrafluoroethoxy) phenyl) methyl]amino]-1,1,1-trifluoro-2-propanol EX-214A) A solution of 3- (phenoxy) aniline (2. 78 g, 15 mmol) and 3- (1, 1, 2, 2-tetrafluoroethoxy) benzaldehyde (3. 33 g, 15 mmol) was prepared in 60

mL of dichloroethane. Acetic acid (0. 92 mL, 16. 05 mmol) and solid NaBH (OAc) 3 (4. 13 g, 19. 5 mmol) were added. The mixture was stirred at room temperature for 3 hours, then acidified with I N aqueous HCI. After neutralizing to pH 7. 5 with 2. 5 N sodium hydroxide, the mixture was extracted with methylene chloride. The organic layer was washed with brine and water, then dried over anhydrous MgSO4, and evaporated to give 5. 00 g (85%) of the desired N-(3-phenoxyphenyl)-[[3-(1,1, 2, 2-tetrafluoroethoxy)-phenyl lmethyl amine product as a brown oil, which was greater than 90% pure by reverse phase HPLC analysis. MS m/z = 391.

Amine product EX-214A (3. 13 g, 8 mmol) and 3, 3, 3-trifluoromethyl-1, 2- epoxypropane (1. 34 g, 12 mmol) were dissolved in 1. 5 mL of acetonitrile.

Ytterbium (III) trifluoromethanesulfonate (0. 25 g, 0. 4 mmol) was added, and the stirred solution was warmed to 50 °C for 1 hour under an atmosphere of nitrogen, at which time HPLC analysis indicated that no secondary 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 MgSO4. The crude product was purified by flash column chromatography on silica gel eluting with ethyl acetate : hexane (1 : 16) to give 2. 85 g (71%) of the desired aminopropanol product as a light amber oil, 99% pure by HPLC analysis. H NMR (CDC13) 8 7. 30 (m, 3H), 7. 27 (t, 1H), 7. 20 (m, 3H), 7. 02 (s, 1H), 6. 96 (m, 2H), 6. 48 (dd, 1H), 6. 41 (dd, 1H), 6. 37 (m, 1H), 5. 89 (tt, 1H), 4. 64 (ABq, 2H), 4. 34 (m, 1H), 3. 87 (dd, 1H), 3. 55 (dd, 1H), 2. 41 (bs, 1H). 19F NMR (CDC13) õ-79. 3 (d, 3F),-88. 6 (m, 2F),-137. 2 (dt, 2F).

HRMS calcd. for C24H2103NF7 : 504. 1410 [M+H] +, found : 504. 1425.

Additional examples of 3-1 N-(aryl)-l (aryl) methyl lamino]-1, 1, 1-trifl uoro- 2-propanols are prepared by one skilled in the art using similar methods, as shown in Example Tables 6 and 7.

Example Table 6. 3-[N-(aryl)-[(aryl)methyl]amino]-1,1,1-trifluoro-2-propanols .

Ex. Calculated Observed No. Mass Mass M+H] [M+H] 215 3-OCH3, 3-CF3 462. 1115 462. 1115 5-CF3 216 3-phenoxy 3-SCF3 488. 1119 488. 1116 217 3-phenoxy H 388. 1524 388. 1558 218 3-SO2-phenyl 3-OCF2CF2H 552.1080 552.1095 Example Table 7. 3-[N-(aryl)-[(aryl)methyl]amino]-1,1,1-trifluoro-2-propanols . Ex. Calculated Observed No. Mass Mass fM+HIfM+HI 219 322. 1419 322. 1426 N" EXAMPLE 220

N-(3-bromophenyl)-N-[2-[[(1,1-dimethylethyl)dimethylsilyl] oxy]-3, 3, 3-trifluoropropyl]- 3- (1, 1, 2, 2-tetrafluoroethoxy)- benzenemethanamine EX-220A) To a 1, 2-dichloroethane (30 mL) solution of 3- (1, 1, 2, 2- tetrafluoroethoxy)-benzaldehyde (2. 00 g, 9. 0 mmol) was added 3-bromoaniline (0. 98 mL, 9. 0 mmol), NaB (OAc) 3H (2. 48 g, 11. 7 mmol) and acetic acid (0. 57 mL, 10 mmol). The cloudy mixture was stirred at room temperature for 1 hour.

The reaction mixture was poured into water and extracted with dichloromethane.

The organic layer was washed with saturated NaHCO3 and brine, dried (MgSO4) and evaporated to yield 3. 27 g (96%) of the desired N- (3- bromophenyl)-[[3-(1,1, 2, 2-tetrafluoroethoxy) phenyll methyllamine product as a brown oil which was used without further purification. MS m/z = 377 [M].

EX-220B) To a dichloromethane (9 mL) solution of the EX-220A amine (3. 27 g, 8. 65 mmol) was added 1, 1, 1-trifluoro-2, 3-epoxypropane (0. 968 mL, 11. 3 mmol) and Yb (OTf) 3 (0. 536 g, 0. 86 mmol). The cloudy mixture was stirred at room temperature for 24 hours, then diluted with diethyl ether. The organic layer was washed with water and brine, dried (MgSO4) and evaporated to yield 4. 20 g (99%) of the desired 3- [ (3-bromophenyl)- [ [3- (1, 1, 2, 2- tetrafluoroethoxy) phenyl methyl amino]-1, 1, 1-trifluoro-2-propanol product as a pale brown oil which can be used without further purification. The formation of

the desired product was confirmed by the presence of the alcohol peak (8 1. 5, d) in the H NMR spectrum (C6D6). An analytical sample was purified by silica gel chromatography eluting with 20% ethyl acetate in hexane to give the desired pure product as a yellow oil. FABMS m/z = 491 [M+H] +. IH NMR (CDCl3) # 3. 55-3. 63 (m, 1H), 3. 88 (dd, 1H), 4. 36 (m, 1H), 4. 69 (s, 2H), 5. 914 (tt, 1H), 6. 66 (dd, 1H), 6. 92 (m, 2H), 7. 06 (s, 1H), 7. 09 (m, 3H), 7. 36 (t, 1H).

To a dichloromethane (10 mL) solution of EX-220B aminopropanol (4. 20 g, 8. 57 mmol) was added tert-butyldimethylsilyl trifluoromethanesulfonate (3. 0 mL, 13. 1 mmol) and triethylamine (2. 40 mL, 17. 3 mmol). The resulting solution was stirred at room temperature for 4 hours. The reaction mixture was diluted with dichloromethane, and washed with saturated NaHC03 and brine.

The organic layer was dried (MgSO4) and evaporated to an oil. Purification by flash chromatography on silica eluting with 2. 5% EtOAc in hexane gave 3. 0 g (58%) of the desired N-(3-bromophenyl)-N-l2-[[(l, l- dimethylethyl) dimethylsilyl] oxy]-3, 3, 3-trifluoropropyl]-3-(1, 1, 2, 2-tetrafluoro- ethoxy) benzenemethanamine product as a colorless oil. HRMS calcd for C24H29BrF7NO2Si : 606. 1098 [M+H] +, found 606. 1118. 1H NMR (C6D6) 8 -0. 19 (s, 3H),-0. 06 (s, 3H), 0. 88 (s, 9H), 3. 38 (m, 2H), 4. 11 (s, 2H), 4. 12 (q, 1H), 5. 10 (tt, 1H), 6. 33 (dd, 1H), 6. 61 (d, 1H), 6. 68 (t, 1H), 6. 81 (m, 2H), 6. 89 (m, 2H), 6. 97 (t, 1H).

EXAMPLE 221

3- [[3-(4-chloro-3-ethylphenoxy)phenyl]-[[3-(1,1 2, 2-tetrafluoro- ethoxy) phenyl] methyl] amino]-1, 1, 1-trifluoro-2-propanol A solution of N-(3-bromophenyl)-N-[2-[[(1,1-dimethylethyl)dimethylsilyl]ox y]- 3, 3, 3-trifluoropropyl]-3-(1,1,2,2-tetrafluoroethoxy) benzenemethanamine (75 mg, 0. 124 mmol), cesium carbonate (81 mg, 0. 248mmol), 4-chloro-3- ethylphenol (44 mg, 0. 358 mmol), copper triflate benzene complex (6. 24 mg, 10 mol%), 1-naphthoic acid (43 mg, 0. 248 mmol) in 2 : 1 toluene : dimethylacetamide (3. 0 mL) was heated at 105 9C for 96 hours. The reaction mixture was filtered through celite, and the solvent was evaporated. The residue was purified by reverse phase chromatography eluting with 50-90% acetonitrile in water to afford 16. 2 mg (23%) of the desired 3-113-(4-chloro-3-ethylphenoxy) phenyl]-[l3- (1, 1, 2, 2-tetrafluoroethoxy)phenyl] methyl]amino]-1,1,1-trifluoro-2-propanol product as an orange oil. HRMS calcd. for C26H23CIF7NO3 : 566. 1332 [M+H] +, found : 566. 1332. 1H NMR (CDCI3) 8 1. 18 (t, 3H), 2. 69 (q, 2H), 3. 50-3. 61 (m, 1H), 3. 87 (dd, 1H), 4. 28-4. 39 (m, 1H), 4. 63 (s, 2H), 5. 88 (tt, 1H), 6. 32-6. 40 (m, 2H), 6. 48 (dd, 1H), 6. 69 (dd, 1H), 6. 87 (d, 1H), 7. 0-7. 34 (m, 5H).

Additional examples of 3- [ (3-aryloxyphenyl and heteroaryloxy- phenyl) [ [3- (1, 1, 2, 2-tetrafluoroethoxy)phenyl]methyl]amino]-1, 1, 1-trifluoro-2- propanols are prepared by one skilled in the art using similar methods, as shown in Example Tables 8 and 9. Additional examples of 3- [ (3-arylthiophenyl)- [ [3- (1, 1, 2, 2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2- propanols are prepared by one skilled in the art using similar methods, as shown in Example Table 10.

Example Table 8. 3-[(3-Aryloxyphenyl)-[13-(l, 1, 2. 2-tetrafluoroethoxy) phenylSmethyl lamino]-1, 1, 1-trifluoro-2-propanols. Ex. Calculated Observed No. Mass Mass fM+HfM+H 222 2-chloro 538. 1019 538. 1021 223 2-fluoro 522. 1315 522. 1310 224 2-fluoro, 4-CF3 590.1189 590.1155 225 2, 3, 5-trifluoro 558. 1127 558. 1109 226 3-N, N-dimethylamino 547. 1831 547. 1844 227 2-fluoro, 3-CF3 590. 1189 590. 1184 228 3-NHCOCH3 561.1624 561.1590 229 2,3-dichloro 572.0630 572.0653 230 2-chloro, 4-fluoro 556. 0925 556. 0891 231 2-chloro, 4-chloro 572. 0630 572. 0667 232 3-methyl, 5-ethyl 546. 1879 546. 1899 233 3-ethyl 532. 1722 532. 1706 234 3, 5-dimethyl 532. 1722 532. 1705 235 2, 5-difluoro 540. 1221 540. 1255 236 4- (perfluorophenyl)- 741. 0796 741. 0799 2, 3, 5, 6-tetrafluoro-phenyl 237 2, 3, 4-trifluoro 558. 1127 558. 1161 238 2, 3-difluoro 540. 1221 540. 1182 239 3-acetyl 546. 1515 546. 1549 240 3-fluoro 522. 1315 522. 1337 241 3, 5-difluoro 540. 1221 540. 1217 242 4-fluoro, 3-methyl 536. 1471 536. 1480 243 4-propoxy 562. 1828 562. 1803 Example Table 8 (continued). 3-[(3-Aryloxyphenyl)-[[3-(1, 1, 2, 2- tetrafluoroethoxy) phenyl]-methylamino)-1, 1, 1-trifluoro-2-propanols. Ex. ( :Calculated Observed No. Mass Mass fM+HIfM+H 244 3-trifluoromethoxy 588. 1232 588. 1236 245 3-chloro, 4-fluoro 556. 0925 556. 0932 246 4-chloro, 3-fluoro 556. 0925 556. 0933 247 3, 4, 5-trimethyl 546. 1879 546. 1901 248 3-trifluoromethyl 572. 1283 572. 1265 249 3-isopropyl 546. 1879 546. 1878 250 4-isopropyl 546. 1879 546. 1899 251 4-butoxy 576. 1958 576. 1969 252 3-tert-butyl 560. 2035 560. 2055 253 4-isopropyl, 3-methyl 560. 2035 560. 2035 254 4-sec-butyl 560. 2035 560. 2051 255 4-(l, l-dimethyl-propyl) 574. 2192 574. 2208 256 3, 4-dichloro 572. 0630 572. 0630 257 4-cyclopentyl 572. 2035 572. 2029 258 3,4-(CH2)4 558.1879 558.1881 259 4-benzyl 594.1879 594.1906 260 4-phenyl 580. 1722 580. 1741 261 4-n-butyl 560. 2036 560. 2033 262 4-ethoxy 548. 1672 548. 1674 263 4-mercapto 536. 1130 536. 1163 264 3-phenyl 580. 1723 580. 1772 265 4-chloro, 2-fluoro 556. 0926 556. 0954 266 4-n-propyl 546. 1879 546. 1878 267 4-methylthio 550. 1209 550. 1251 268 3,5-dimethoxy 564.1623 564.1617 269 4-bromo 582. 0716 582. 0473 270 3-hydoxymethyl 564. 1621 564. 1617 271 3-methyl, 4-methylthio 564. 1443 564. 1476 272 4-chloro, 3, 5-dimethyl 552. 1176 552. 1185 273 4-methoxy 533. 1437 533. 1458 274 3-methoxy 533. 1437 533. 1450 275 4-chloro 537. 0942 537. 0944 276 4-(imidazo-1-yl) 569. 1549 569. 1552 277 3, 4-dimethyl 531. 1644 531. 1649 Example Table 8 (continued). 3-1 (3-Aryloxyphenyl)- [13- (1, 1. 2, 2- tetrafluoroethoxy) phenyl]-methyl] amino]-1, 1, 1-trifluoro-2-propanols. Calculated Observed No. Mass Mass M+H]+ [M+H]+ 278 3-methyl 517. 1488 517. 1493 279 4-chloro, 3-methyl 551. 1098 551.1101 280 4-ethoxy 547. 1594 547. 1594 281 4-methyl 517.1488 517. 1495

Example Table 9. 3- [ (3-Aryloxy and Heteroaryloxyphenyl)- [ [3- ( 1, 1, 2. 2- tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-pro panols. Ex. RSUB Calculated Observed No. Mass [M+H]+ Mass [M+H]+ 282 6-methyl-3-pyridyl 518. 1440 518. 1452 283 2-pyridyl 504. 1284 504. 1284 284 3-isoquinolyl 555. 1518 555. 1513 285 2-naphthyl 554. 1566 554. 1578 286 3-pyridyl 505. 1362 505. 1369 287 5-chloro-3-pyridyl 539. 0972 539. 1002 288 5-indolyl 543. 1519 543. 1630 289 2-methyl-3-pyridyl 519.1518 519.1517 Example Table 10. 3- [ (3-Arylthiophenyl)- [ [3- (1, 1, 2, 2-tetrafluoroethoxy) phenyl]-methyl] amino]-1, 1, 1-trifluoro-2-propanols.

Ex. Calculated Mass Observed Mass PSUB No. [M+H]+ 3-OCF3 290 H 519. 1518 519. 1119 291 4-methoxy 549.1209 549.1216

EXAMPLE 292

3- [ [3- [ (4-methoxyphenyl) amino] phenyl]- [ [3- (1, 1, 2, 2-tetrafluoro- ethoxy) phenyl] methyl] amino]-1, 1, 1-trifluoro-2-propanol A mixture containing N-(3-bromophenyl)-N-[2-[[(1,1-dimethylethyl) dimethylsilyl]oxy]-3, 3, 3-trifluoropropyl]-3-(1,1, 2, 2-tetrafluoroethoxy) benzenemethanamine (75 mg, 0. 124 mmol), cesium carbonate (57. 5 mg, 0. 176 mmol), 4-methoxyaniline (18. 6 mg, 0. 151 mmol) tris (dibenzylideneacetone) dipalladium (0) (4. 6 mg, 0. 005 mmol), R- (+)-2, 2'-bis (diphenylphosphino)-l, l'- binaphthyl (4. 7 mg, 0. 0075 mmol) and toluene (2. 5 mL) was heated to 95'C in a sealed vial for 48 h. Tetrabutylammonium fluoride (1 M, THF, 0. 372 mL,

0. 372 mmol) was added, and the reaction was stirred at 23 9C for 1. 5 h. The reaction mixture was filtered through celite, and the solvent was evaporated. The residue was purified by silica gel chromatography eluting with 20% ethyl acetate in hexane to give 49 mg (73%) of the desired 3- [ [3- ( (4- methoxyphenyl) amino] phenyl]-[[3-(1,1, 2, 2-tetrafluoroethoxy) phenyl Imethyl] amino]-l, l, 1-trifluoro-2-propanol product as an orange oil. HRMS calcd for C25H23F7N2O3: 532. 1597, found : 532. 1592 [M]. H NMR (CDC13) 8 3. 48-3. 57 (m, 1H), 3. 77 (s, 3H), 3. 83 (dd, 1H), 4. 33 (m, 1H), 4. 59 (s, 2H), 5. 87 (tt, 1H), 6. 27 (m, 1H), 6. 33 (bd, 1H), 6. 86 (dd, 4H), 7. 02-7. 12 (m, 4H).

7. 31 (t, 1H), 7. 41 (m, 1H), 7. 60 (m, 1H), 19F NMR (CDC13) 8-137. 201 (d, 2F),-88. 515 (s, 2F),-79. 120 (s, 3F).

Additional examples of 3-[[3-(N-arylamino and N-alkyl-N- arylamino)phenyl]-[[3-(1,1, 2, 2-tetrafl uoroethoxy) phenyl jmethyl] amino-1, 1, 1- trifluoro-2-propanols are prepared by one skilled in the art using similar methods, as shown in Example Tables 11 and 12. Additional examples of 3- [ [3- (piperidino)-phenyl]-[[3-(1,1, 2, 2-tetrafluoro-ethoxy) phenyl 1methyl1amino]- 1, 1, 1-trifluoro-2-propanols are prepared by one skilled in the art using similar methods, as shown in Example Table 13. Example Table 11. 3-[[3-(Arylamino)phenyl]-[[3-(1,1, 2, 2-tetrafluoroethoxy) phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanols.

Ex. Calculated Observed No. Mass Mass LE LE 293 4-fluoro 520.1397 520. 1389 294 H 502.1491 502. 1473 295 4-trifluoromethyl 570.1365 570. 1335 296 4-chloro 536. 1102 536. 1125 297 4-cyano 527. 1444 527. 1452 298 4-C02CH2CH3 574. 1703 574. 1703 299 4-n-propyl 544. 1961 544. 1959 300 4-[[3-(4-methyl-phenyl)- 660.1971 660. 1969 1, 2, 4-oxadiazol-5-yl] 301 4-lCOCH (CN)-641. 1761 641. 1755 C02CH2CH31 302 3-cyano 527. 1444 527. 1448 303 3-CO2CH2CH3 574.1703 574.1668 304 3-chloro 536.1102 536.1102 305 3-methoxy 532. 1597 532. 1593 306 3, 4, 5,-trimethoxy 592. 1703 592. 1703 307 3, 5-difluoro 538. 1303 538. 1329 308 4-trifluoromethoxy 586.1314 586. 1314 309 3, 4-dimethoxy 562. 1703 562. 1713 310 3-trifluoromethyl 570. 1365 570. 1332 Example Table 12. 3-[[3-(N-alkyl-N-Arylamino)phenyl]-[[3-(1, 1, 2, 2- tetrafluoroethoxy) phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanols.

Ex. Rsubl Rsub2 Calculated Observed No. Mass Mass LS+ [M]+ 311 H 3-trifluoromethyl-584. 1522 584. 1518 benzyl 312 _CH2CH3 3-methyl-phenyl 544. 1961 544. 1959 313 n-C4H9 4-C02CH2CH3-630. 2329 630. 2329 phenyl 314 -(CH2)2CN 4-methyl-phenyl 569.1913 569.1920 Example Table 13. 3- [ [3- (N-piperidino) phenylj- [ [3- (1, 1, 2, 2-tetrafluoroethoxy) phenyi]-methyl] amino]-l, 1 J-trifluoro-2-propanois.

Ex. Rsubl Rsub2 Calculated Observed Mas No. Mass [M]+ [M]+ 315 H H 494. 1804 494. 1804 316 H benzyl 584. 2274 584. 2280 317-OCH2CH20-552. 1859 552. 1863 EXAMPLE 318 3-[[3-[(4-methoxyphenyl) methylamino] phenyl] [ [3- (1, 1, 2, 2- tetrafluoroethoxy) phenyl] methyl] amino]-l, l, l-trifluoro-2- propanol To a solution of 3- [ [3- [ (4-methoxyphenyl) aminolphenyl]-113- (1, 1, 2, 2- tetrafluoro-ethoxy) phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol (44. 3 mg, 0. 083 mmol) in tetrahydrofuran (1. 0 mL), methyl iodide (6. 21 ßL, 0. 099 mmol) and cesium carbonate (36. 6 mg, 0. 112 mmol) were added. The dark solution was stirred at 23 9C for 2 h, then heated to 55'C for 12 h. The reaction mixture was filtered through celite, and the residue was purified by silica gel chromatography eluting with 20% ethyl acetate in hexane to give 25. 2 mg (55%)

of the desired 3-[[3-[(4-methoxyphenyl)methylamino]-phenyl][[3-(1,1, 2, 2- tetrafluoroethoxy) phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol product as an orange oil. HRMS calcd for C26H25F7N2O3:546. 1753, found : 546. 1750 +. 1-1 8 3. 54 (m, 1H), 3. 38 (s, 3H), 3. 65-3. 80 (m. 4H), 4. 59 (s, 2H), 5. 90 (tt, 1H), 6. 20 (d, 1H), 6. 37 (d, 1H), 6. 68 (s, 1H), 6. 76 (d, 2H), 6. 90-7. 15 (m, 6H), 7. 31 (t, 1H). 19F NMR (CDC13), 8-137. 21 (d, 2F),- 88. 52 (s, 2F),-78. 79 (s, 3F).

Additional examples of 3-[[3-[(4-methoxyphenyl) alkylamino and haloalkyl- amino) phenyl]- U [3- (1, 1, 2, 2-tetrafluoroethoxy)phenyl]methyl]amino-1,1,1- trifluoro-2-propanols are prepared by one skilled in the art using similar methods, as shown in Example Table 14.

Example Table 14. 3-[[3-[ (4-methoxyphenyl) alkylamino and haloalkylamino) phenyl]-[[3-(1,1, 2, 2-tetrafluoroethoxy) phenyl] methyl] amino)- 1, 1, 1-trifluoro-2-propanols. Ex. Calculated Observed Mass sub No. Mass [M]+ [M]+ 319 ethyl 560. 1910 560. 1910 320 -(CH2)3CF3 642.1940 642.1920 EXAMPLE 321

3- (5-chloro-2-thienyl) methyl] f (3-trifluoromethoxy) phenyl] amino]-1, 1, 1-trifluoro-2-propanol EX-321A) 3-Trifluoromethoxyaniline (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 to 80'C for 24 h. The excess aniline was removed by distillation (70 °C at 16. 2 Torr) to give 8. 6 g (88%) of the desired 3-1 (3- trifluoromethoxyphenyl) amino]-1, 1, 1-trifluoro-2-propanol product as a light yellow oil. 1 H NMR (CDC13) 8 3. 29-3. 37 (m, 1H), 3. 55 (dd, 1H), 4. 20 (m, 1H), 6. 48-6. 63 (m, 3H), 7. 12 (t, 1H). F NMR (CDCl3) 8-79. 36 (s, 3F),- 58. 44 (s, 3F).

EX-321B) The aminopropanol (18. 68 g, 64. 6 mmol) from EX-321A and imidazole (10. 99 g, 0. 162 mmol) were dissolved in dimethylformamide (40. 0 mL) and t-butyl-dimethylsilyl chloride (11. 69 g, 77. 6 mmol) was added in 3. 0 g portions over 15 min. The reaction was stirred at 23 9C for 18 h. The reaction solution was diluted with ethyl acetate and washed with water and brine. The organic layer was dried (MgSO4) and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 25% ethyl acetate in hexane to afford 17. 08 g (66%) of the desired silylated N- (3-trifluoromethoxyphenyl)-N- [2- [ [ (I, I-dimethylethyl) dimethylsilylloxyl-3, 3, 3-trifluoro- propylamine product as a light golden oil. FABMS m/z = 404 [M+H] +. NMR (CDC13) õ 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-321C) The silylated aminopropanol (0. 157 g, 0. 40 mmol) from EX-321B was dissolved in tetrahydrofuran (150 ßL) and cooled to 0'C. Potassium ten- butoxide (1. 0 M, THF, 0. 60 mL, 0. 60 mmol) was added in one portion via syringe. The dark solution was stirred at 0 for five minutes. 2-Chloro-5- bromomethyl-thiophene (73. 5 mg, 0. 44 mmol) was added in one portion to the cooled solution. The reaction mixture was stirred at 0 9C for 15 minutes then warmed to 23'C for 16 h. Tetrabutyl-ammonium fluoride (1. 0 M, THF, 1. 2 mL, 1. 2 mmol) was added to the dark reaction mixture and stirring followed for 2 h at 23 °C. The solution was diluted with ethyl acetate and washed with water and brine. The organic layer was dried (MgSO4) and concentrated in vacuo.

The residue was purified by silica gel chromatography eluting with 0-20% ethyl acetate in hexane to afford 63. 4 mg (39%) of the desired 3- [ [ (5-chloro-2- thienyl)methyl][(3-trifluoromethoxy)phenyl]amino-1,1,1-trifl uoro-2-propanol product as a light golden oil. HRMS calcd. for C15H12ClF6NO2S : 419. 1518, found : 419. 1527 [M] +. I H NMR (CDC13) 8 3. 50-3. 56 (m, 1H), 3. 77 (dd, 1H), 4. 28 (m, 1H), 4. 67 (s, 2H), 6. 62-6. 75 (m, 5H), 7. 24 (t, 1H). 9F NMR (CDC13) 8-79. 24 (s, 3F),-58. 04 (s, 3F).

Additional examples of 3-l [(aralkyl and heteroaralkyl)] l (3- trifluoromethoxy)-phenyl] amino]-l, l, l-trifluoro-2-propanols are prepared by one skilled in the art using similar methods, as shown in Example Table 15.

Example Table 15. 3-[[(aralkyl and heteroaralkyl)] [ (3-trifluoromethoxy)- phenyl]amino]-1,1,1-trifluoro-2-propanols. Ex. Calc. Obs. No. Mol. Mass Wt. [M]+ 322 3-iodo-benzyl 505 506 323 4-difluoromethoxy-benzyl 445 446 324 4-(2-cyanophenyl)-benzyl 480 481 325 3-CO2CH3-benzyl 437 438 326 2, 3, 5, 6-tetrafluoro-4-methoxy- 481 482 benzyl 327 3-cyano-benzyl 404 405 328 3, 5-difluoro-benzyl 415 416 329 2, 4difluoro-benzyl 415 416 330 2, 6-difluoro-benzyl 415 416 331 4nitro-benzyl 424 425 332 (1-napthyl) methyl 429 430 333 4phenyl-benzyl 455 456 334 2-chloro4, 5-(OCH2CH2O)-benzyl 457 458 335 3-nitro-benzyl 424 425 336 4-phenoxy-butyl 437 438 337 3-phenyl-propyl 407 408 338 3- (4-methoxy) phenyl-propyl 437 438 339 2-methoxyphenacetyl 437 438 340 2- (2, 5-dimethoxy-phenyl)- 467 468 2-oxoethyl 341 3-CO2CH3-benzyl 437 438 342 2-(anthraquinonyl)-methyl 509 510 343 perfluorobenzoyl 483 484 Example Table 15 (continued). 3- [I (aralkyl and heteroaralkyl) ll (3- trifluoromethoxy)-phenyl] amino]-1, 1, 1-trifluoro-2-propanols. Ex. Calc. Obs. No. Mol. Mass Wt. [M]+ 344 2- (3-indolyl) ethyl 432 433 345 3-pyridinylmethyl 380 381 346 (5-chloro-2-thienyl)-methyl 419 420 347 4-methoxy-benzyl 409 410 348 3-methoxy-benzyl 409 410 349 4-pyridinylmethyl 380 381 350 3, 5-dimethoxy-benzyl 439 440 351 3- (phenyl) propenoyl 419 420 352 3-phenyl-2, 3-propenyl 405 406 353 3, 5-dimethoxy-benzoyl 453 454 354 2, 4, 5-trimethoxy-benzyl 469 470 355 2, 5-dimethoxy-benzyl 439 440 356 3-CO2H-benzyl 423 424 357 3-OH-benzyl 395 396 358 2,5-dihydroxy-benzyl 411 412 359 3, 4, 5-trihydroxy-benzyl 427 428 360 3, 5,-dihydroxy-benzyl 411 412 361 2- (phenoxy) phenacetyl 499 500 362 2-quinolinylmethyl 430 431 363 2-pyridinylmethyl 380 381 364 2-benzimidazolyl-methyl 419 420 365 1-benzyl-2-imidazolyl-methyl 459 460 366 (2, 6-dichloro-4-449 450 pyridinyl) methyl EXAMPLE 367

N'- (4-butoxyphenyl)-N- (3, 3, 3-trifluoro- 2-hydroxypropyl)- N- [3- (trifluoromethoxy) phenyl] urea The silylated aminopropanol (0. 150 g, 0. 372 mmol) from EX-321B was dissolved in chloroform (0. 5 mL). Then 4-n-butoxyphenyl isocyanate (78. 25 mg, 0. 409 mmol) was added, and the resulting solution was stirred at 23'C in a sealed vial for 16 h followed by heating to 65"C for 24 h. The reaction was cooled to 23 °C, and a solution of tetrabutylammonium fluoride (1. 0 M, THF, 0. 5 mL, 0. 50 mmol) was added to the reaction, which was then stirred at 23 9C for 2 h. The solution was diluted with ethyl acetate and washed with water and brine. The residue was purified by silica gel chromatography eluting with 0-50% ethyl acetate in hexane to afford 73. 6 mg (38%) of the desired urea product as a pale yellow glass. FABMS m/z = 481 lM+H]. H NMR (CDC13), b 0. 99 (t, 3H), 1. 484 (m, 2H), 1. 740 (m, 2H), 3. 25-3. 35 (m, 1H), 3. 55 (dd, 1H), 3. 94 (m, 2H), 4. 207 (m, 1H), 6. 17 (s, 1H), 6. 48 (s, 1H), 6. 50-6. 65 (m, 2H), 6. 83 (d, 2H), 7. 15 (d, 2H), 7. 58 (t, 1H), 19F NMR (CDC13) 8-78. 87 (s, 3F),-58. 29 (s, 3F).

Additional examples of N'- (aryl and sulfonylaryl)-N- (3, 3, 3-trifluoro-2- hydroxy-propyl)-N- [3- (trifluoromethoxy) phenyl] ureas are prepared by one skilled in the art using similar methods, as shown in Example Table 16.

Example Table 16. N'- (aryl and sulfonylaryl)-N- (3, 3, 3-trifluoro-2- hydroxypropyl)-N- [3- (tnfluoromethoxy) phenyl] ureas.

Ex. Calculated Observed RSUB No. Mol. Wt. Mass [M]+ 368 2-CH3S-phenyl 454 455 369 4-biphenyl 484 485 370 4-CH3-phenyl-SO2-486 487 EXAMPLE 371 3-[[[3-(1,1, 2, 2-tetrafluoroethoxy) phenyl] methyl] (3, 3, 3- trifluoro-2-hydroxypropyl) amino] phenol EX-371A) To a solution of 3-aminophenol (4. 91 g, 45. 0 mmol) and 3- (1, 1, 2, 2-tetrafluoroethoxy) benzaldehyde (10. 0 g, 45. 0 mmol) dissolved in 100 mL of 1, 2-dichloroethane was added sodium triacetoxyborohydride (14. 28 g 67. 5 mmol) and glacial acetic acid (2. 7 mL, 47. 3 mmol). The reaction mixture was stirred for 6 h, water was added, and the mixture was extracted with

dichloromethane. The organics were washed with saturated aqueous sodium bicarbonate then dried over MgSO4. The dried organic layer was evaporated to give 11. 00 g (78%) of the desired 3-[[[3-(1,1,2, 2- tetrafluoroethoxy) phenyl] methyljamino] phenol product as a dark orange oil. H NMR (CD03) 6 4. 32 (s, 2H), 5. 88 (tt, 1H), 6. 08 (t, 1H), 6. 17-6. 22 (m, 2H), 7. 00 (t, 1H), 7. 11 (dd, 1H), 7. 24-7. 27 (m, 2H), 7. 33 (t, 1H).

A solution of 3-[[[3-(1,1, 2, 2-tetrafluoroethoxy) phenyllmethyl] aminolphenol (11. 0 g, 34. 9 mmol), 3, 3, 3-trifluoro-1, 2-epoxypropane (4. 5 mL, 52. 4 mmol) and ytterbium trifluoromethanesulfonate (2. 2 g, 10 mol%) in 20 mL of acetonitrile was heated at 50 °C in a sealed glass tube for 16 h. The reaction mixture was cooled, water was added, and the reaction mixture was extracted with ether. The ether layer was washed with saturated aqueous sodium bicarbonate and brine and dried over MgSO4 The dried organic layer was evaporated to give 8. 07 g (89%) of the desired 3- [ [13- (1, 1, 2, 2- tetrafluoroethoxy)phenyl]methyl] (3, 3, 3-trifluoro-2hydroxypropyl) amino] phenol product as a yellow oil. HRMS calcd. for C18H17F7NO3 : 428. 1097 [M+Hl found : 428. 1104. H NMR (CDC13) 6 3. 58 (dd, 1H), 3. 88 (dd, 1H), 4. 39 (m, 1H), 4. 68 (s, 2H), 5. 91 (tt, 1H), 6. 25-6. 37 (m, 3H), 7. 07-7. 14 (m, 4H), 7. 35 (t, 1H).

EXAMPLE 372

3- [[[3-(1,1, 2, 2-tetrafluoroethoxy) phenyllmethyl] [3- [ [3- (trifluoromethoxy) phenyl]-methoxylphenyl] amino]- 1, 1, 1-trifluoro-2-propanol To a solution of 3-[[[3-(1,1, 2, 2-tetrafluoroethoxy)phenyl]methyl] (3, 3, 3- trifluoro-2-hydroxypropyl) amino] phenol (100 mg, 0. 23 mmol), 3- trifluoromethoxybenzyl bromide (70. 0 mg, 0. 27 mmol) in 2. 5 mL of acetone and cesium carbonate (100 mg, 0. 31 mmol) were added. The reaction mixture was heated to 60 °C for 18 h then cooled. The reaction mixture was filtered through celite, and the solvent was evaporated. The residue was purified by reverse phase HPLC eluting with 50% to 90% acetonitrile in water to afford 63. 3 mg (45%) of the desired benzyl ether product as an orange oil. HRMS calcd. for C26H22F10NO4: 602. 1389 [M+H] +, found : 602. 1380. 1H NMR (CDCl3) 8 3. 61 (dd, 1H), 3. 83 (dd, 1H), 4. 32-4. 39 (m, 1H), 4. 62 (s, 2H), 4. 98 (s, 2H), 5. 84 (tt, 1H), 6. 43-6. 55 (m, 3H), 7. 04-7. 42 (m, 9H).

Additional examples of 3-ll [3-(1, 1, 2, 2-tetrafluoroethoxy)- phenylJmethyl] [3- [ (substituted) methoxy] phenyl) aminol-l, 1, 1-trifluoro-2- propanols are prepared by one skilled in the art using similar methods as shown in Example Tables 17 and 18.

Example Table 17. 3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3- [ (substituted-phenyl) methoxy] phenyl lamino]-1, 1, 1-trifluoro-2-propanols. E x. RSUB Calculated Observed N o. Mass Mass fM+HIfM+H 373 H 518.1566 518. 1578 374 4-trifluoromethoxy 602. 1389 602. 1383 375 ¢nitro 563. 1417 563. 1457 376 2, 3, 4, 5, 6-pentafluoro 608. 1095 608. 1092 377 3, 5-di (trifluoromethyl) 654. 1314 654. 1308 378 3, 5-difluoro 554. 1378 554. 1390 379 3-trifluoromethyl 586. 1440 586. 1419 380 2, 3, 5. 6-tetrafluoro-4-trifluoromethyl 658. 1063 658. 1003 381 4-fluoro-2-trifluoromethyl 604. 1346 604. 1321 382 3-nitro 563. 1417 563. 1416 383 3-cyano 543. 1519 543. 1523 384 4-cyano 543. 1519 543. 1517 385 4-methyl 532.1723 532. 1729 386 2, 3, 5, 6-tetrafluoro-4-methoxy 620. 1295 620. 1261 387 3-methoxycarbonyl 576. 1621 576. 1613 388 4-methoxycarbonyl 576. 1621 576. 1614 389 4-difluoromethoxy 584. 1483 584. 1480 390 2-fluoro 536. 1472 536. 1465 391 4-fluoro 536. 1472 536. 1454 392 2, 4, 6-trifluoro 572. 1284 572. 1267 393 3-chloro-2-fluoro 570. 1082 570. 1069 394 2-6-difluoro 554. 1378 554. 1385 395 2, 4-difluoro 554. 1378 554. 1346 Example Table 17 (continued). 3-[[[3-(1, 1, 2. 2- tetrafluoroethoxy) phenyl] methyl] [3- [ (substituted- phenyl)methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanols. Ex. Calculated Observed N o. Mass Mass M+H [M+Hl + 396 2, 4-di (trifluoromethyl) 654. 1314 654. 1321 397 2, 5-difluoro 554. 1378 554. 1350 398 3, 4-difluoro 554. 1378 554. 1381 399 2, 3-difluoro 554. 1378 554. 1364 400 2-fluoro-3-trifluoromethyl 604. 1346 604. 1329 401 3-bromo 596. 0671 596. 0641 402 3-methyl 532. 1723 532. 1692 403 2-bromo 596. 0671 596. 0666 404 2-chloro 552. 1176 552. 1175 405 3-iodo 644. 0533 644. 0517 406 3-fluoro 536. 1472 536. 1475 407 3-methoxy 548. 1672 548. 1676 408 2, 3, 5-trifluoro 572. 1284 572. 1276 409 4-trifluoromethylthio 618. 1161 618. 1165 410 3-trifluoromethylthio 618. 1161 618. 1151 411 3-fluoro-5-trifluoromethyl 604. 1346 604. 1309 412 4-fluoro-3-trifluoromethyl 604. 1346 604. 1336 413 ¢ (phenylmethoxy) 624. 1985 624. 1956 414 4-phenyl 594. 1879 594. 1845 415 4-ethyl 546. 1879 546. 1862 416 4-trifluoromethyl 586. 1440 586. 1400 417 2-methyl-3-nitro 577. 1573 577. 1576 418 4-tert-butyl 574. 2192 574. 2163 419 3, 4-dimethyl 546. 1879 546. 1881 420 3-chloro 552. 1176 552. 1157 421 4-bromo 596. 0671 596. 0669 422 3, 5-dichloro 586. 1787 586. 1378 423 3,5-dimethyl 546.1879 546. 1890 424 4-chloro 552. 1176 552. 1188 425 2-fluoro-3-methyl 550. 1628 550. 1625 426 3-phenoxy 610. 1828 610. 1819 427 4-isopropyl 560. 2036 560. 2020 Example Table 18. 3-[[[3-(1,1, 2, 2-tetrafluoroethoxy) phenyl] methylJ <BR> [3-[(substituted)-methoxy] phenyl] amino]-1, 1, 1-trifluoro-2-propanols.

Ex. Calculated Observed N o. Mass Mass [M+H]+ [M+H]+ 428 3-pyridylmethyl 519. 1519 519. 1483 429 1-phenylethyl 532. 1723 532. 1711 430 1-benzylimidazol-2-ylmethyl 598. 1941 598. 1946 431 5-chlorobenzo[b]thien-3-ylmethyl 608. 0897 608. 0884 432 2-pyridylmethyl 519. 1519 519. 1522 433 4-pyridylmethyl 519.1519 519. 1515 EXAMPLE 434

3- [ [3- [ (4-aminophenyl) methoxy] phenyl) [ [3- (1, 1, 2, 2-tetrafluoro- ethoxy) phenyl] methyl] amino]-1, 1, 1-trifluoro-2-propanol EX-434A) A solution of 3-[[[3-(1,1, 2, 2-tetrafluoroethoxy) phenyllmethyl] l3- [ (3-nitro-phenyl) methoxy] phenyl amino]-1, 1, 1-trifluoro-2-propanol (42. 0 mg, 0. 07 mmol) and zinc dust (37 mg, 0. 57 mmol) in acetic acid (0. 5 mL) was

stirred for 4 d. The reaction mixture was filtered, and the solvent was evaporated. The residue was purified by reverse phase HPLC eluting with 50% to 90% acetonitrile in water to afford 15. 4 mg (39%) of the desired reduced amine product as a brown oil. HRMS calcd. for C25H24F7N203 : 533. 1675 [M+H] +, found : 533. 1656. 1H NMR (acetone-d6) 8 3. 60 (dd, 1H), 3. 85 (m, 1H), 3. 90 (s, 2H), 4. 45 (m, 1H), 4. 73 (s, 2H), 6. 22-6. 64 (m, 4H), 6. 94 (dd, 1H), 7. 12-7. 45 (m, 9H).

EX-434B) 3-[[3-[(3-aminophenyl) methoxy] phenyl) [13- (1, 1, 2, 2-tetrafluoro- ethoxy)-phenyl] methyl] amino-1, 1, 1-trifluoro-2-propanol is prepared by one skilled in the art using similar methods. HRMS calcd. for C25H24F7N203 : 533. 1675 [M+H] +, found : 533. 1654.

EXAMPLE 435 3-[[3-[[[3-(1,1, 2, 2-tetrafluoroethoxy) phenyl] methyl] (3, 3, 3- trifluoro-2-hydroxypropyl) amino] phenoxy] methyl] benzoic acid EX-435A) A solution of ethyl 3-[[3-[[[3-(1,1, 2, 2-tetrafluoroethoxy) phenyl]methyl]-(3, 3, 3-trifluoro-2-hydroxypropyl) aminolphenoxylmethyl l benzoate (22. 1 mg, 0. 04 mmol) and lithium hydroxide (5 mg, 0. 12 mmol) in water (1 mL) and tetrahydrofuran (0. 5 mL) was heated at 80 °C for 16 h. The reaction mixture was added to 6 N hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and the solvent was evaporated. The residue was purified by reverse phase HPLC eluting with 10% to 90% acetonitrile in water to afford 5. 6 mg (19%) of the desired benzoic

acid product as a brown oil. HRMS calcd. for C26H23F7NO5 : 562. 1464 [M+H] +, found : 562. 1418. 1H NMR (acetone-d6) 8 3. 64 (dd, 1H), 3. 95 (m.

1H), 4. 45-4. 50 (m, 1H), 4. 80 (s, 2H), 5. 12 (s, 2H), 6. 27-6. 63 (m, 4H), 7. 06- 7. 27 (m, 4H), 7. 41 (t, 1H), 7. 50 (t, 1H), 7. 66 (d, 1H), 7. 99 (d. 1H), 8. 10 (s, 1H).

EX-435B) 4-[[3-[[[3-(1,1, 2, 2-tetrafluoroethoxy) phenyl methyll (3, 3, 3- trifluoro-2-hydroxypropyl) amino] phenoxy] methyl] benzoic acid is prepared by one skilled in the art using similar methods. HRMS calcd. for C26H23F7NO5 : 562. 1464 [M+H] +, found : 562. 1445.

EXAMPLE 436 3- [ [3-(2-nitrophenoxy)phenyl] [ [3- (1, 1, 2, 2-tetrafluoroethoxy) phenyl]-methyl] amino]-1, 1, 1-trifluoro-2-propanol A solution of 3- [ [ (3- (1, 1, 2, 2-tetrafluoroethoxy) phenylSmethyl] (3, 3,3-trifluoro-2- hydroxypropyl) amino] phenol (100 mg, 0. 23 mmol), 1-bromo-2-nitrobenzene (52. 4 mg, 0. 26 mmol), copper (I) trifluoromethanesulfonate benzene complex (3 mg, 2. 5 mol%) and cesium carbonate (100 mg, 0. 31 mmol) in toluene (1 mL) and ethyl acetate (I mL) was heated at 95 °C in a sealed vial for 4 d. The reaction mixture was filtered through celite, and the solvent was evaporated. The residue was purified by reverse phase HPLC eluting with 50% to 90% acetonitrile in water to afford 14. 1 mg (11%) of the desired 2-nitrophenyl ether product as an orange oil. HRMS calcd. for C24H20F7N2O5 : 549. 1260 [M+H], found :

549. 1235. H NMR (CDCl3) 6 3. 63 (dd, 1H), 3. 84 (dd, 1H), 4. 35-4. 42 (m.

1H), 4. 64 (s, 2H), 5. 90 (tt, 1H), 6. 47-6. 67 (m, 3H), 6. 98-7. 50 (m, 8H), 7. 97 (d, 1H).

Additional examples of 3-[[3-aryloxyphenyl][[3-(1, 1, 2, 2- tetrafluoroethoxy)-phenyl) methyl] amino]-1, 1, 1-trifluoro-2-propanols are prepared by one skilled in the art using similar methods, as shown in Example Table 19.

Example Table 19. 3-1 [3-aryloxyphenyl] [ [3- (1, 1, 2, 2-tetrafluoroethoxy)- phenyl] methyl] amino]-1, 1, 1-trifluoro-2-propanols.

Ex. Calculated Observed N o. Mass Mass [M+Hl t M+H]+ 437 4-tert-butylphenyl 560.2036 560. 2050 438 4-nitrophenyl 549.1260 549. 1306 439 4-bromo-2-nitrophenyl 627.0366 627. 0375 440 3-fluoro-2-nitrophenyl 567. 1166 567. 1135 441 2-cyano-3-pyridyl 530. 1315 530. 1300 442 5-carboxy-3-pyridyl 549. 1260 549. 1269 443 4-fluoro-2-pyridyl 523. 1268 523. 1243 444 3-trifl uoromethyl-2-pyridyl 573. 1236 573. 1205 445 5-trifluoromethyl-2-pyridyl 573. 1236 573. 1197 446 5-bromo-2-pyridyl 583. 0667 583. 0405 447 2-methyl-5-nitrophenyl 563. 1417 563. 1416 448 thiazol-2-yl 511.0926 511.0911 449 5-pyrimidinyl 506. 1315 506. 1315 EXAMPLE 450

3- [[3-(4-aminophenoxy)phenyl][[3-(1,1, 2, 2-tetrafluoroethoxy) phenyl]-methyl lamino]-1, 1, 1-trifluoro-2-propanol and 3-[[3-[4-(ethylamino) phenoxy] phenyl) [ [3- (1, 1, 2, 2- tetrafluoroethoxy) phenyl]-methyl] amino]-1, 1, 1-trifluoro-2- propanol A solution of 3-[[3-(4-nitrophenoxy)phenyl][[3-(1,1, 2, 2-tetrafluoroethoxy) phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol (33. 8 mg, 0. 06 mmol) in ethanol and 5% palladium on carbon (4 mL) was placed under 40 psi hydrogen gas for 7 h. The mixture was filtered through celite, the solvent was evaporated, and the residue was purified by silica gel chromatography eluting with 25% ethyl acetate in hexane to give 13. 4 mg (42%) of (EX-450A) as 3-[[3-(4- aminophenoxy) phenyl][[3-(1,1, 2. 2-tetrafluoroethoxy) phenyl]methyl]amino]- 1, 1, 1-trifluoro-2-propanol and 13. 9 mg (41%) of (EX-450B) as 3- [ [3-14- (ethylamino) phenoxy] phenyl][[3-(1,1, 2, 2-tetrafluoroethoxy) phenyl] methyl] amino]-1, 1, 1-trifluoro-2-propanol both as orange oils. 3- [ [3- (4- aminophenoxy) phenyl [[3-(1, 1, 2, 2-tetrafluoroethoxy) phenyl]methyl]-amino]- 1, 1, 1-trifluoro-2-propanol : HRMS calcd. for C24H22F7N2O3: 519. 1519 M+Hl, found : 519. 1529. 1H NMR (acetone-d6) # 3. 63 (dd, 1H), 3. 96 (dd, 1H), 4. 42-4. 58 (m, 1H), 4. 80 (s, 2H), 5. 88 (m, 1H), 6. 20 (m, 1H), 6. 32-6. 77 (m, 6H), 6. 92 (d, 1H), 7. 06-7. 26 (m, 3H), 7. 43 (m, 1H). 3- [ [3- [4- (ethylamino) phenoxy] phenyl] [ [3- (1, 1, 2, 2-tetrafluoroethoxy) phenyl 1-methyl I amino]-1, 1, 1-trifluoro-2-propanol : HRMS calcd. for C26H26F7N2O3:

547. 1832 [M+H] +, found : 547. 1819. 1H NMR (acetone-d6) 8 1. 23 (t, 3H), 3. 17 (q, 2H), 3. 63 (dd, 1H), 3. 96 (dd, 1H), 4. 42-4. 58 (m, 1H), 4. 79 (s, 2H), 5. 85 (d, 1H), 6. 20 (m, 1H), 6. 33 (m, 1H), 6. 47 (m, 1H), 6. 50 (tt, 1J), 6. 61 (d, 2H), 6. 78 (d, 2H), 7. 09 (t, 1H), 7. 20 (m, 1H), 7. 23 (d, 1H), 7. 42 (m, 1H).

EXAMPLE 451 3-[[3-(2-pyridinyl)phenyl][[3-(1,1, 2, 2-tetrafluoroethoxy) phenyl] methyl] amino]-1, 1, 1-trifluoro-2-propanol A solution of 3-[(3-bromophenyl)[[3-(1,1, 2, 2-tetrafluoroethoxy) phenyllmethyl] amino]-1, 1, 1-trifluoro-2-propanol (100 mg, 0. 22 mmol), 2-tributylstannyl pyridine (96 mg, 0. 26 mmol), dichlorobis (triphenylphospine) palladium (II) (6 mg, 6. 7 mol%) and lithium chloride (46 mg, 1. 09 mmol) in toluene (4 mL) was heated at 105 °C for 16 h. The reaction mixture was filtered through celite, and the solvent was evaporated. The residue was purified by silica gel column chromatography eluting with 25% ethyl acetate in hexane to afford 47. 7 mg (45%) of the desired pyridyl product as an orange oil. HRMS calcd. for C23H20F7N202 : 489. 1377 [M+H] +, found : 489. 1413. 1H NMR (acetone-d6) 8 3. 78 (dd, 1H), 4. 06 (dd, 1H), 4. 52-4. 61 (m, 1H), 4. 94 (s, 2H), 5. 89 (d, 1H), 6. 43 (tt, 1H), 6. 94 (m, 1H), 7. 18 (m, 1H), 7. 22-7. 42 (m, 5H), 7. 60 (s, 1H), 7. 80 (m, 2H), 8. 61 (m, 1H).

Additional examples of 3-[[3-(heteroaryl)phenyl][[3-(1,1, 2, 2-tetrafluoro- ethoxy) phenyl] methyl] amino]-I, 1, 1-trifluoro-2-propanols are prepared by one skilled in the art using similar methods, as shown in Example Table 20.

Example Table 20. 3-[[3-(heteroaryl)phenyl][[3-(1,1,2, 2-tetrafluoroethoxy)- phenyl] methyl] amino]-l, l, 1-trifluoro-2-propanols.

Ex. RSUB Calculated Observed Mass o. Mass IM+Hl IM+Hl 452 2-thienyl 494. 1024 494. 0987 453 2-furyl 478. 1025 478. 1025 454 3-pyridyl 489. 1413 489. 1391 455 3-methyl-2-pyridyl 503. 1570 503. 1531 EXAMPLE 456

1- [3- [ [ [3- (1, 1, 2, 2-tetrafluoroethoxy) phenyl] methyl] (3, 3, 3- trifluoro-2-hydroxypropyl) benzoyl] piperidine EX-456A) Ethyl 3-aminobenzoate (6. 75 mL, 0. 045 mol) and 3- (1, 1, 2, 2- tetrafluoro-ethoxy) benzaldehyde (10 g, 45 mmol) were dissolved in 100 mL of

dichloroethane and acetic acid (2. 7 mL, 47 mmol), then solid NaBH (OAc) 3 (14. 3 g, 67 mmol) was added. The mixture was stirred at room temperature for 3 hours, then quenched with aqueous sodium bicarbonate and extracted with dichloromethane. The organic layer was washed with brine, then dried over MgSO4, and evaporated to give 16. 7 g (98%) of the desired ethyl 3-[[[3- (1, 1, 2, 2-tetrafl uoroethoxy) phenyl] methyl1aminolbenzoate product as a yellow oil. H NMR (CDC13) 8 1. 3 (t, 3H), 4. 3 (q, 2H), 4. 5 (s, 2H), 6. 5 (tt, 1H), 6. 9 (d, 1H), 7. 1-7. 4 (m, 7H).

EX-456B) A solution of EX-456A (16. 7 g, 45 mmol) and 1, 1, 1-trifluoro- 2, 3-epoxypropane (4. 26 mL, 49. 5 mmol) were dissolved in 30 mL of acetonitrile. Ytterbium (III) trifluoromethanesulfonate (2. 79 g, 4. 5 mmol) was added, and the stirred solution was warmed to 50 °C for 18 hours. The reaction was quenched with water and extracted with ether. The ether layer was washed with brine, then dried over MgSO4. The crude product was purified by flash column chromatography on silica gel eluting with dichloromethane to give 12 g (55%) of the desired ethyl 3-[[[3-(1,1, 2, 2-tetra-fluoroethoxy) phenyll methyl l (3, 3, 3-trifluoro-2-hydroxypropyl) amino]-benzoate product as a colorless oil, which was greater than 98% pure by reverse phase HPLC analysis. HRMS calcd. for C21 H21 F7NO4 : 484. 1359 lM+H +, found : 484. 1342. I H NMR (CDC13) 8 1. 4 (t, 3H), 3. 6 (dd, 1H), 3. 9 (dd, 1H), 4. 3 (m, 3H), 4. 7 (dd, 2H), 5. 9 (tt, 1H), 6. 9 (d, 1H), 7. 1-7. 2 (m, 3H), 7. 2-7. 4 (m, 2H), 7. 5 (m, 1H).

To a solution of piperidine (102 ! 1L, 1. 03 mmol) in toluene (620 RL) was added 2 M trimethylaluminum in toluene (620 µL), and the solution was stirred for 2 h.

To the reaction mixture was added a solution of ethyl 3- [ (l, l, l-trifluoro-2- hydroxypropyl) [ [3- (1, 1, 2, 2-tetrafluoroethoxy) phenyl Imethyl1aminolbenzoate (100 mg, 0. 21 mmol) in toluene (1 mL). The reaction mixture was heated at 40 °C for 20 h and 60 °C for 5 h, then cooled. To the reaction mixture was added water dropwise followed by 2 M hydrochloric acid and ethyl acetate. The solution was placed on a celite plug for 5 min, then eluted with dichloromethane, and the solvent was evaporated. The residue was purified by reverse phase

HPLC eluting with 50% to 90% acetonitrile in water to afford 42. 6 mg (38%) of the desired 1- [3- ( [ [3- (1, 1, 2, 2-tetrafluoroethoxy) phenyll-methyll-(3, 3, 3- trifluoro-2-hydroxypropyl)benzoyl]piperidine product as an orange oil. HRMS calcd. for C24H26F7N2o3 : 523. 1832 [M+H] +, found : 523. 1815. 1H NMR (acetone-d6) 8 1. 22-1. 63 (m, 6H), 3. 16-3. 62 (m, 4H), 3. 74 (dd, 1H), 4. 00 (dd, 1H), 4. 44-4. 55 (m, 1H), 4. 83 (s, 2H), 6. 46 (tt, 1H), 6. 64-6. 69 (m, 2H), 6. 83 (dd, 1H), 7. 14-7. 28 (m, 4H), 7. 41 (t, 1H).

Additional examples of N, N-disubstituted-3-[ (3, 3, 3-trifluoro-2- hydroxypropyl)-[[3-(1,1, 2, 2-tetrafluoroethoxy) phenyllmethyl laminolbenzamide are prepared by one skilled in the art using similar methods, as shown in Example Table 21. Example Table 21. N, N-disubstituted-3-l (3, 3, 3-trifluoro-2-hydroxypropyl) lí3- (1, 1, 2, 2-tetrafluoroethoxy) phenyl] methyl laminolbenzamide

Calculated Observed N o. Mass Mass M+H]+ [M+H]+ 457 H isopropyl 497. 1675 497. 1697 458 H n-butyl 511.1832 511. 1809 459 H cyclohexyl 537. 1988 537. 1969 460 H tert-butyl 511.1832 511. 1845 461 H cyclopentyl 523. 1832 523. 1854 462 H neo-pentyl 525. 1988 525. 2028 463 H 2, 2, 2-trifluoroethyl 537. 1236 537. 1250 464 H 2, 2, 3, 3, 4, 4,4- 637.1172 637. 1177 heptafluorobutyl 465 H phenylmethyl 545. 1675 545. 1705 466 H (3-trifluoromethoxy)- 629.1498 629. 1510 phenylmethyl 467 H 4-(fluorophenyl)methyl 563.1581 563. 1611 468 methyl phenyl 545. 1675 545. 1631 469 methyl phenylmethyl 559. 1832 559. 1853 470-CH2CH2N (CH3) CH2CH2- 538.1941 538.1969 471 -CH2CH2OCH2CH2- 525.1624 525.1615 472 -CH2CH2CH2CH2- 509.1675 509.1675 EXAMPLE 473

3- [ [3- [ (l-methylethyl) thio] phenyl [ [3- (1, 1, 2, 2-tetrafluoroethoxy) phenyl]-methyl] amino]-1, 1, 1-trifluoro-2-propanol EX-473A) 3-Aminobenzenethiol (2. 4 mL, 22. 5 mmol) and 3- (1, 1, 2, 2- tetrafluoro-ethoxy) benzaldehyde (5 g, 22. 5 mmol) were dissolved in 40 mL of dichloroethane and acetic acid (1. 35 mL, 23. 7 mmol), then solid NaBH (OAc) 3 (6. 2 g, 29. 3 mmol) was added. The mixture was stirred at room temperature for 18 hours, then quenched with water and diluted with dichloromethane. The organic layer was washed with aqueous saturated sodium bicarbonate, then dried over MgS04, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel eluting with ethyl acetate : hexane 1 : 10 to give 5. 36 g (72%) of the desired 3-[[[3-(1, 1, 2, 2- tetrafluoroethoxy) phenyljmethyl) aminojbenzenethio ! product as a brown oil.

1H NMR (CDCl3) # 3. 4 (s, 1H), 4. 4 (s, 2H), 5. 9 (tt, 1H), 6. 4 (dd, 1H), 6. 55 (m, 1H), 6. 65 (d, 1H), 7. 05 (t, 1H), 7. 2-7. 4 (m, 4H).

EX-473B) The EX-473A benzenethiol amine (5. 36 g, 16. 2 mmol) and 1, 1, 1- trifluoro-2, 3-epoxypropane (1 g, 1. 6 mmol) were dissolved in 20 mL of acetonitrile. Ytterbium (III) trifluoromethanesulfonate (1 g, 1. 6 mmol) was added, and the stirred solution was warmed to 50 °C for 48 hours, at which time HPLC analysis indicated that no secondary amine starting material remained.

The reaction was quenched with water and extracted with ether. The ether layer was washed with brine, then dried over MgS04, and concentrated in vacuo. The

crude product was purified by flash column chromatography on silica gel eluting with ethyl acetate : hexane 1 : 10 to give 4. 5 g (63%) of the desired 3-[[[3-(1, 1. 2. 2- tetrafluoroethoxy) phenyl] methyl] (3, 3, 3-trifluoro-2-hydroxypropyl) amino] benzenethiol product as a yellow oil. H NMR (CDC13) 8 3. 0 (s, 1H), 3. 6 (dd, 1H), 3. 9 (dd, 1H), 4. 2 (m, 1H), 4. 7 (m, 2H), 5. 9 (tt, IH), 6. 5 (dd, 1H), 6. 7 (m, 2H), 7. 1 (m, 4H), 7. 4 (t, 1H). HRMS calcd. for C36H3, F, 4N204S2 : 885. 1502 [2 (M-1) +H] +, found : 885. 1471.

The EX-473B thiol product (150 mg, 0. 34 mmol) and 2-iodopropane (37 pL, 0. 37 mmol) were dissolved in 2 mL of acetonitrile. Cesium carbonate (144 mg, 0. 44 mmol) was added, and the stirred solution was warmed to 55 °C for 18 hours, at which time HPLC analysis indicated that no thiol/disulfide starting material remained. The reaction was quenched with water and filtered through pre-wetted celite eluting with ethyl acetate. The solvent was evaporated, and the residue was purified by reverse phase HPLC eluting with 10% to 90% acetonitrile in water to afford 69 mg (42%) of the desired 3-[[3-[(1- methylethyl) thio] phenyl] [ [3- (1, 1, 2, 2-tetrafluoroethoxy)phenyl]-methyl]amino]- 1, 1, 1-trifluoro-2-propanol product as a yellow oil, which was greater than 98% pure by reverse phase HPLC analysis. HRMS calcd. for C21H23F7NO2S : 486. 1338 [M+H] +, found : 486. 1351. H NMR (CDC13) b 1. 2 (t, 3H), 3. 3 (q, 1H), 3. 6 (dd, 1H), 3. 9 (dd, 1H), 4. 3 (m, 1H), 4. 7 (m, 3H), 5. 9 (tt, 1H), 6. 7 (dd, 1H), 6. 9 (m, 2H), 7. 0-7. 2 (m, 4H), 7. 3 (t, 1H).

Additional examples of 3-[[3-(alkanoyl-, aryl-, heteroaryl-, and aralkylthio) phenyl] [ [3- (1, 1, 2, 2-tetrafluoroethoxy) phenyl flmethylflamino]-1, 1, 1-trifl uoro-2- propanols are prepared by one skilled in the art using similar methods, as shown in Example Table 22.

Example Table 22. 3-[[3-(alkanoyl-, ary7l-, heteroaryl-, and aralkylthio)phenyl][[3-(1,1, 2, 2-tetrafluoro-ethoxy)phenyl]methyl]amino]-1,1, I- trifluoro-2-propanols. Ex. Calculated Observed N o. SUB Mass Mass M+H]+ [M+H]+ 474 4-pyridyl 521. 1134 521. 1115 475 4-nitrophenyl 565.1032 565. 1034 476 4-piperidyl 527.1603 527. 1597 477 2-pyridylmethyl 535.1290 535. 1291 478 4-acetylphenyl 562. 1287 562. 1261 479 4-(methvlsulfonyl) phenyl 598. 0957 598. 0946 480 (4-chloro-thien-2-yl) methyl 574. 0512 574. 0523 481 acetyl 486. 0974 486. 0936 EXAMPLE 482

3-[(3-[(1-methyl4ethyl)sulfonyl]phenyl][[3-(1, 1, 2, 2- tetrafluoroethoxy)-phenyl] methyl] amino]- 1, 1, 1-trifluoro-2-propanol To a solution of 3-[[3-[(1-methylethyl) thio] phenyl] li3-(1, 1, 2, 2- tetrafluoroethoxy)-phenyl] methyl] amino]-l, 1, 1-trifluoro-2-propanol (58 mg, 0. 12 mmol) in 2 mL of trifluoroacetic acid, was added 30% aqueous H202 (28 FL, 0. 25 mmol). The mixture was stirred at room temperature for 18 hours, then quenched with 5% aqueous sodium hydroxide and extracted with ether.

The organic layer was concentrated in vacuo. The crude product was purified by reverse phase HPLC eluting with 10% to 90% acetonitrile in water to give 29. 5 mg (48%) of the desired sulfone product as a brown oil, which was greater than 98% pure by reverse phase HPLC analysis. HRMS calcd. for C21H23F7NO4S : 518. 1236 [M+H] +, found : 518. 1226. 1H NMR (CDC13) 8 1. 1 (d, 6H), 3 (q, 1H), 3. 7 (dd, 1H), 3. 9 (dd, 1H), 4. 3 (m, 1H), 4. 7 (s, 1H), 5. 9 (tt, 1H), 7 (m, 2H), 7. 1-7. 2 (m, 4H), 7. 3 (m, 2H).

Additional examples of 3- [ (3- (aryl-, heteroaralkyl-, and heterocyclyl- sulfonyl) phenyl] [ [3- (1, 1, 2, 2-tetra-fluoroethoxy) phenyl] methyl] aminoJ-1, 1, 1- trifluoro-2-propanols are prepared by one skilled in the art using similar methods, as shown in Example Table 23.

Example Table 23. 3- [ (3- ( aryl-, heteroaralkyl-, and heterocyclyl- sulfonyl)phenyl][[3-(1,1, 2, 2-tetrafluoroethoxy) phenyl Imethyllamino l- 1, 1, 1-trifluoro-2-propanols.

Ex. Calculated Observed Mass No. RSUB Mass [M+H]+ [M+H]+ 483 4nitrophenyl 597. 0930 597. 0925 484 4-piperidyl 559. 1502 559. 1526 485 3-(pyridyl-N-oxide)methyl 583.1138 583. 1137 486 ¢acetylphenyl 594. 1185 594. 1181 487 4- (methylsulfonyl) phenyl 630. 0855 630. 0826 EXAMPLE 488

3-[[3-(cyclohexylmethoxy)phenyl][[3-(1,1, 2, 2-tetrafluoroethoxy) phenyl]-methyl] amino]-1, 1, 1-trifluoro-2-propanol 3-[[[3-(1, 1, 2, 2-tetrafluoroethoxy) phenyl]methyl](1,1,1-trifluoro-2-hydroxy- propyl)-amino]phenol (100 mg, 0. 23 mmol) and bromomethylcyclohexane (42

ßL, 0. 30 mmol) were dissolved in 2 mL of acetonitrile. Cesium carbonate (144 mg, 0. 44 mmol) was added, and the stirred solution was warmed to 50 °C for 48 hours, at which time HPLC analysis indicated that no phenolic starting material remained. The reaction was quenched with water and filtered through pre-wetted celite eluting with ethyl acetate. The solvent was evaporated and the residue was purified by reverse phase HPLC eluting with 10% to 90% acetonitrile in water to afford 55 mg (35%) of the desired ether product as a brown oil, which was greater than 99% pure by reverse phase HPLC analysis.

HRMS calcd. for C25H29F7NO3 : 524. 2036 fM+H) , found : 524. 2028. 1 H NMR (CDC13) 8 0. 9-1. 4 (m, 5H), 1. 7-1. 9 (m, 6H), 3. 6 (m, 3H), 3. 9 (dd, 1H), 4. 3 (m, 1H), 4. 7 (m, 2H), 5. 1 (s, 1H), 5. 9 (tt, 1H), 6. 5 (m, 3H), 7. 0-7. 4 (m, 5H).

Additional examples of 3- [ (3-alkoxy- and cycloalkoxy-phenyl) [[3- (1, 1, 2, 2-tetrafluoroethoxy) phenyl] methyl] amino]-1, 1, 1-trifluoro-2-propanols are prepared by one skilled in the art using similar methods, as shown in Example Table 24. Example Table 24. 3-[(3-alkoxy- and cycloalkoxy-phenyl)[[3-(1,1,2, 2- tetrafluoroethoxy) phenyl] methyll amino]-1, 1, 1-trifluoro-2-propanols.

Ex. Calculated Observed No. RSUB Mass Mass LM+H + [M+H + 489 isopropyl 470.1488 470. 1565 490 (methoxycarbonyl)methyl 500.1308 500. 1297 491 cyanomethyl 467. 1206 467. 1228 492 2-methylpropyl 484.1723 484.1718 493 2-oxobutyl 498.1515 498.1529 494 cyclohexyi 510. 1880 510. 1910 495 5-oxohexyl 526. 1828 526. 1827 496 4-(methoxycarbonyl)butyl 542.1777 542. 1827 497 2-(phenylsulphonyl) ethyl 596. 1342 596. 1349 498 2-pyrrolidinylethyl 525. 1988 525. 2008 499 3- (methoxycarbonyl)-2-propenyl 526. 1464 526. 1482 500 carbamoylmethyl 485. 1311 485.1304 501 3-cyanopropyl 495. 1519 495. 1541 502 l-(N-phenylcarbamoyl) ethyl 575. 1780 575. 1778 503 2-oxo-2-phenylethyl 546. 1515 546. 1543 504 3-hydroxypropyl 486. 1515 484. 1481 505 2-methoxyethyl 486. 1515 486. 1537 506 neo-pentyl 498.1879 498. 1845 507 4-tetrahydropyranyl 512. 1672 512. 1631 508 1-ethoxycarbonylbutyl 556.1934 556.1948 509 cyclopentyl 496.1723 496. 1719 510 3-methyl-2-butenyl 496. 1722 496. 1675 511 2-(N,N-dimethylamino)ethyl 499.1831 499.1826 512 3-hvdroxy-2, 2-dimethylpropyl 514. 1828 514. 1814 513 3. 3-dimethyl-2-oxobutyl 526. 1828 526. 1806 EXAMPLE 514

3-[[[3-(1,1, 2, 2-tetrafluoroethoxy) phenyl] methyl][3-[[(3- trifluoromethyl)-phenyl] methyl] phenyl] amino]- 1, 1, 1-trifluoro-2-propanol EX-514A) To a solution of (3-nitrobenzene) methanol (10 g, 65. 3 mmol) in 50 mL of 5% aqueous sodium hydroxide, was added dimethylsulfate (20 g, 156 mmol). The mixture was stirred at 70 °C for 18 hours, then diluted with water and ethyl acetate. The organic layer was washed with water, then dried over MgSO4, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel eluting with ethyl acetate : hexane 1 : 5 to give 4. 73 g (43%) of the desired 3-(methoxy-methyl) nitrobenzene product as a yellowoil. lHNMR (CDC13) o3. 5 (s, 3H), 4. 5 (s, 2H), 6. 5 (t, 1H), 7. 7 (d, 1H), 8. 1 (d, 1H), 8. 2 (s, 1H).

EX-514B) The 3- (methoxymethyl) nitrobenzene (4. 18 g, 25 mmol) from EX- 514A was dissolved in 160 mL of acetic acid. Zinc dust (5 g, 76. 5 mmol) was added, and the solution was stirred at room temperature for 18 hours, at which time HPLC analysis indicated that no 3- (methoxymethyl) nitrobenzene starting material remained. The reaction mixture was filtered through celite and concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with aqueous saturated sodium bicarbonate. The organic layer was washed with water, then dried over MgSO4, and concentrated in vacuo to give 3. 4 g (99%) of

the desired 3- (methoxymethyl) aniline as a brown oil. The crude product was used without further purification. HRMS calcd. for C8H12NO : 138. 0919 [M+H] +, found : 138. 0929. 1H NMR (CDC13) 8 3. 4 (s, 3H), 3. 7 (s, 2H), 4. 4 (s, 2H), 6. 6 (d, 1H), 6. 7 (m, 2H), 7. 2 (t, 1H).

EX-514C) The 3- (methoxymethyl) aniline (1. 85 g, 13. 51 mmol) product from EX-514B and 3- (1, 1, 2, 2-tetrafluoroethoxy) benzaldehyde (3 g, 13. 5 mmol) were dissolved in 25 mL of dichloroethane and acetic acid (0. 85 mL, 14. 8 mmol), then solid NaBH (OAc) 3 (3. 73 g, 17. 6 mmol) was added. The mixture was stirred at room temperature for 48 hours, then quenched with aqueous saturated sodium bicarbonate and diluted with ethyl acetate. The organic layer was washed with brine, then dried over MgSO4, and concentrated in vacuo to give 4. 27 g (12. 4 mmol) of crude product. The crude product and 1, 1, 1- trifluoro-2, 3-epoxypropane (1. 2 mL, 13. 7 mmol) were dissolved in 20 mL of acetonitrile. Ytterbium (III) trifluoromethanesulfonate (0. 77 g, 1. 24 mmol) was added, and the stirred solution was warmed to 50 °C for 18 hours. The reaction was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, then dried over MgSO4, and concentrated in vacuo to give 5. 96 g (97%) of the desired 3-[[3-(methoxymethyl)phenyl][[3-(1,1,2, 2- tetrafluoroethoxy)-phenylmethyl] amino]-l, l, l-trifluoro-2-propanol product as a brown oil. The crude product was greater than 95% pure by reverse phase HPLC analysis and was used without further purification. HRMS calcd. for C20H21F7NO3 : 456. 1410 [M+H] +, found : 456. 1409. 1H NMR (CDC13) 8 3. 3 (s, 3H), 3. 6 (dd, 1H), 3. 9 (dd, 1H), 4. 3 (m, 1H), 4. 4 (s, 2H), 4. 7 (m, 2H), 5. 9 (tt, 1H), 6. 6-6. 8 (m, 3H), 7. 1-7. 2 (m, 4H), 7. 3 (t, 1H).

EX-514D) The 3-[[3-(methoxymethyl) phenylal 13-(1, 1, 2, 2-tetrafluoroethoxy) phenyl]-methyl] amino]-1, 1, 1-trifluoro-2-propanol from EX-514C (I g, 2. 2 mmol) was dissolved in 10 mL of dichloromethane. The solution was cooled to -50 °C and a 1 M solution of BBr3 in dichloromethane (2. 3 mL, 2. 3 mmol) was added. The solution was stirred at-50 °C for 1 hour and warmed to room temperature over 1 hour, at which time HPLC analysis indicated that no methyl

ether starting material remained. The reaction mixture was quenched with aqueous saturated sodium bicarbonate and diluted in dichloromethane. The organic layer was washed with brine, then dried over MgSO4, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel eluting with ethyl acetate : hexane 1 : 7 to give 0. 65 g (59%) of the desired 3- [ [3- (bromomethyl) phenyll [ [3- (1, 1, 2, 2-tetrafluoroethoxy)-phenyl]methyl] amino]-1, 1, 1-trifluoro-2-propanol product as a brown oil. HRMS calcd. for C19Hl8BrF7NO2 : 504. 0409 [M+H], found : 504. 0361. 1H NMR (CDC13) â 3. 3 (s, 1H), 3. 6 (dd, 1H), 3. 9 (dd, 1H), 4. 3 (m, 1H), 4. 4 (s, 2H), 4. 8 (m, 2H), 5. 9 (tt, 1H), 6. 7 (d, 1H), 6. 8-6. 9 (m, 2H), 7. 1-7. 3 (m, 4H), 7. 4 (t, 1H).

The 3-[[3-(bromomethyl)phenyl][[3-(1,1, 2, 2-tetrafluoroethoxy) phenyl] methyl amino]-1, 1, 1-trifluoro-2-propanol from EX-514D (0. 1 g, 0. 19 mmol) and 3- trifluoromethyl-benzeneboronic acid (47. 5 mg, 0. 25 mmol) were dissolved in 2 mL of toluene and 0. 2 mL of 2 M aqueous sodium carbonate. Pd (PPh3) 4 was added, and the solution was stirred at 105 °C for 2. 5 hours, at which time HPLC analysis indicated that no bromomethyl starting material remained. The reaction mixture was filtered through celite and concentrated in vacuo. The residue was quenched with water and filtered through pre-wetted celite eluting with ethyl acetate. The solvent was evaporated, and the residue was purified by reverse phase HPLC eluting with 10% to 90% acetonitrile in water to afford 16. 7 mg (15%) of the desired 3-[[[3-(1,1, 2, 2-tetrafluoroethoxy) phenyllmethyll- [3- [ (3- trifluoromethyl) phenyl] methyl] phenyl]-amino]-1, 1, 1-trifluoro-2-propanol product as a brown oil. HRMS calcd. for C26H22FI oNO2 : 570. 1413 lM+H] found : 570. 1480. 1H NMR (CDC13) â 3. 8 (m, 2H), 4. 0 (s, 2H), 4. 3 (m, 1H), 4. 5 (d, 1H), 4. 8 (d, 1H), 5. 9 (tt, 1H), 6. 6-6. 8 (m, 4H), 6. 9-7. 1 (m, 3H), 7. 2- 7. 5 (m, 5H).

Additional examples of 3-[[[3-(1,1, 2, 2-tetrafluoroethoxy)phenyl]methyl] [3- (aryl) methyl] phenylamino]-1, 1, 1-trifluoro-2-propanols are prepared by one skilled in the art using similar methods, as shown in Example Table 25. Example Table 25. 3-[[[3-(1,1, 2, 2-tetrafluoroethoxy) phenyllmethyl]- [3- (aryl) methyl] phenylamino]-1, 1, 1-trifluoro-2-propanols.

Example Calculated Observed Mass Number Mass [M+H]+ [M+H]+ 515 502. 1617 502. 1609 516 3-nitro 547. 1468 547. 1449 517 4-methyl 516. 1774 516. 1769 518 3. 5-dichloro 570. 0838 570. 0801 519 4-fluoro 520. 1523 520. 1505 520 4-tert-butyl 558. 2243 558. 2236 521 3-methyl-4-fluoro 534.1679 534. 1688 522 3-methylXchloro 550. 1384 550. 1380 523 3,4-dimethyl 530.1930 530. 1887 524 3-chloro, 4-fluoro 554. 1133 554. 1108 525 3-chloro 536. 1227 536. 1218 526 4-methylthio 548. 1494 548. 1503 527 3-methoxy 532. 1723 532. 1705

EXAMPLE 528

4-fluoro-N-[3-[[[3-(1,1, 2, 2-tetrafluoroethoxy) phenyl] methyl] (3, 3, 3-trifluoro-2-hydroxypropyl) amino] phenyl] benzenesulfonamide EX-528A) 3-nitroaniline (1. 87 g, 13. 51 mmol) and 3- (1, 1, 2, 2- tetrafluoroethoxy)-benzaidehyde (3 g, 13. 5 mmol) were dissolved in 25 mL of dichloroethane and acetic acid (0. 85 mL, 14. 9 mmol), then solid NaBH (OAc) 3 (3. 73 g, 17. 6 mmol) was added. The mixture was stirred at room temperature for 48 hours, then quenched with aqueous saturated sodium bicarbonate and diluted with ethyl acetate. The organic layer was dried over MgSO4, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel eluting with ethyl acetate : hexane 1 : 7 to give 3. 25 g (70%) of the desired N- (3-nitrophenyl)-3- (1, 1, 2, 2-tetrafluoroethoxy) benzenemethan-amine product as a brown oil. HRMS calcd. for Cl5Hl3F4N203 : 345. 0862 [M+H] +, found : 345. 0864. 1H NMR (CDC13) b 4. 4 (s, 2H), 4. 5 (s, 1H), 5. 9 (tt, 1H), 6. 9 (d, 1H), 7. 1 (d, 1H), 7. 2-7. 3 (m, 3H), 7. 4 (m, 2H), 7. 5 (d, 1H).

EX-528B) N- (3-nitrophenyl)-3- (1, 1, 2, 2-tetrafluoroethoxy) benzene- methanamine (3. 25 g, 9. 44 mmol) from EX-528A and 1, 1, 1-trifluoro-2, 3- epoxypropane (0. 895 mL, 10. 4 mmol) were dissolved in 15 mL of acetonitrile.

Ytterbium (III) trifluoromethane-sulfonate (0. 77 g, 1. 24 mmol) was added, and

the stirred solution was warmed to 55 °C for 48 hours. The reaction was quenched with water and extracted with ethyl acetate. The organic layer was dried over MgSO4, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel eluting with ethyl acetate : hexane 1 : 10 to give 1. 93 g (45%) of the desired 3- [ (3-nitrophenyl) [ (3- (1, 1, 2, 2- tetrafluoroethoxy) phenyllmethyl lamino]-1, 1, I-trifluoro-2-propanol product as a brown oil. HRMS calcd. for C18Hl6F7N204 : 457. 0998 lM+Hl, found : 457. 1008. 1H NMR (CDCl3) # 3. 7 (dd, 1H), 3. 9 (dd, 1H), 4. 4 (m, 1H), 4. 8 (m, 2H), 5. 9 (tt, 1H), 7. 0-7. 2 (m, 4H), 7. 3-7. 4 (m, 2H), 7. 6 (m, 2H).

EX-528C) The 3- [ (3-nitrophenyl) [ [3- (1, 1, 2, 2-tetrafluoroethoxy) phenyl methyl] amino]-l, l, l-trifluoro-2-propanol (1. 93 g, 4. 2 mmol) from EX-528B) was dissolved in 60 mL of acetic acid. Zinc dust (2. 1 g, 31. 5 mmol) was added, and the solution was stirred at room temperature for 18 hours, at which time HPLC analysis indicated that no nitro starting material remained. The reaction mixture was filtered through celite and concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with aqueous saturated sodium bicarbonate. The organic layer was washed with brine, then dried over MgSO4, and concentrated in vacuo to give 1. 4 g (78%) of the desired 3- [ (3- aminophenyl) [ [3- (1, 1, 2, 2-tetrafluoroethoxy) phenyl methylamino]-1, 1, 1- trifluoro-2-propanol product as a red oil. The crude product was used without further purification. HRMS calcd. for C18Hl8F7N202 : 427.1256 [M+H]+, found : 427. 1251. H NMR (CDCl3) õ 3. 4-3. 7 (m, 4H), 3. 8 (dd, 1H), 4. 3 (m, 1H), 4. 8 (m, 2H), 5. 9 (tt, 1H), 6. 1 (s, 1H), 6. 2 (m, 2H), 7. 0-7. 2 (m, 4H), 7. 3 (t, 1H).

The 3-[(3-aminophenyl)[[3-(1,1, 2, 2-tetrafluoroethoxy) phenyl lmethYlflamino]- 1, 1, 1-trifluoro-2-propanol from EX-528C (50 mg, 0. 12 mmol) was dissolved in 1 mL of dichloromethane. Triethylamine (25 µL, 0. 18 mmol) followed by 4- fluorobenzene-sulfonyl chloride were added. The solution was stirred at room temperature for 5 hours, at which time HPLC analysis indicated that no free amine starting material remained. The reaction was quenched with water and

filtered through pre-wetted celite eluting with ethyl acetate. The solvent was evaporated, and the residue was purified by reverse phase HPLC eluting with 10% to 90% acetonitrile in water to afford 20. 1 mg (29%) of the desired 4- fluoro-N-[3-[[[3-(1,1, 2, 2-tetrafluoroethoxy) phenyllmethyl]- (3, 3, 3-trifluoro-2- hydroxypropyl) amino] phenyl]benzenesulfonamide product as a yellow oil, which was greater than 98% pure by reverse phase HPLC analysis. HRMS calcd. for C24H21F8N204S : 585. 1094 [M+H], found : 585. 1083. 1H NMR (CDC13) 8 3. 6 (m, 2H), 3. 8 (dd, 1 H), 4. 3 (m, 1 H), 4. 6 (s, 2H), 5. 9 (tt, 1 H), 6. 4 (d, 1H), 6. 5-6. 6 (m, 3H), 6. 9-7. 4 (m, 7H), 7. 6 (m, 1H).

Additional examples of N-[3-[[[3-(1, 1, 2, 2-tetrafluoroethoxy) phenyl] methyl- (3, 3,-trifluoro-2-hydroxypropyl) aminolphenyllaryl or alkylsulfonamide are prepared by one skilled in the art using similar methods, as shown in Example Table 26.

Example Table 26. N-[3-[[[3-(1, 1, 2, 2-tetrafluoroethoxy)phenyl]methyl]-(3, 3, 3- trifluoro-2-hydroxypropyl) aminolphenyl] aryl or alkylsulfonamides.

Example Calculated Observed Number Mass Mass M+H]+ [M+H]+ 529 phenyl 567. 1189 567. 1198 530 3-methylphenyl 581. 1345 581. 1327 531 3-trifluoromethylphenyl 635. 1062 635. 1066 532 3-nitrophenyl 612. 1039 612. 1011 533 3-chloro-4-fluorophenyl 619. 0705 619. 0711 534 isopropyl 533. 1345 533.1359 EXAMPLE 535

4-fluoro-N-[3-[[[3-(1,1, 2, 2-tetrafluoroethoxy)phenyl]methyl] (3, 3, 3-trifluoro-2-hydroxypropyl) amino] phenyl] benzamide 3- [ (3-aminophenyl) [ [3- (1, 1, 2, 2-tetrafluoroethoxy) phenyl lmethyl ìaminoJ-1, 1, 1- trifluoro-2-propanol (50 mg, 0. 12 mmol) was dissolved in 1 mL of dichloromethane. Triethylamine (25 µL, 0. 18 mmol) followed by 4- fluorobenzoyl chloride were added. The solution was stirred at room temperature for 5 hours, at which time HPLC analysis indicated that no starting material remained. The reaction was quenched with water and filtered through pre-wetted celite eluting with ethyl acetate. The solvent was evaporated, and the residue was purified by reverse phase HPLC eluting with 10% to 90% acetonitrile in water to afford 15 mg (23%) of the desired 4-fluoro-N-l3-lll3-(1, 1, 2, 2- tetrafluoroethoxy) phenyl) methyl) (3, 3, 3-trifluoro-2-hydroxypropyl) amino)- phenyl lbenzamide product as a yellow oil, which was greater than 98% pure by reverse phase HPLC analysis. HRMS calcd. for C25H21F8N203 : 549. 1424 [M+H] +, found : 549. 1436. 1H NMR (CD.'13) 8 3. 6 (dd, 1H), 3. 8 (dd, 1H), 4. 4 (m, 1H), 4. 6 (s, 2H), 5. 9 (tt, 1H), 6. 6 (d, 1H), 6. 8 (d, 1H), 7. 0-7. 4 (m, 7H), 7. 8 (m, 3H).

Additional examples of N-[3-[[[3-(1,1, 2, 2-tetrafluoroethoxy) phenyll methyl)- (3, 3, 3-trifluoro-2-hydroxypropyl) amino] phenyl Jcarboxamides are prepared by one skilled in the art using similar methods, as shown in Example Table 27.

Example Table 27. N-[3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]- (3, 3,3-trifluoro-2-hydroxypropyl)amino]phenyl]carboxamides.

Example Calculated Observed Mass Number Mass [M+H]+ [M+H]+ 536 phenyl 531. 1589 531. 1538 537 3-methoxylphenyl 561.1624 561. 1625 538 isobutoxy 527.1781 527. 1768 539 3-pyridyl 532. 1471 532. 1458 540 isopropyl 497. 1675 497. 1701 EXAMPLE 541

3-[[3-[(2-methylpropyl)amino]phenyl][[3-(1, 1, 2, 2-tetrafluoro- ethoxy)-phenyl]-methyl] amino]-1, 1, 1-trifluoro-2-propanol The 3-[(3-aminophenyl)[[3-(1,1, 2, 2-tetrafluoroethoxy) phenyl methyl] aminol- 1, 1, 1-trifluoro-2-propanol (50 mg, 0. 12 mmol) was dissolved in 1 mL of dichloroethane. Acetic acid (8 pL, 0. 14 mmol) followed by isobutyraldehyde (11. 7 FL, 0. 13 mmol) and solid NaBH (OAc) 3 (37. 3 mg, 0. 18 mmol) were

added. The solution was stirred at room temperature for 18 hours. The reaction was filtered through pre-wetted celite eluting with ethyl acetate. The solvent was evaporated, and the residue was purified by reverse phase HPLC eluting with 10% to 90% acetonitrile in water to afford 16. 1 mg (29%) of the desired 3-[[3- [ (2-methylpropyl) aminolphenylj [ [3- (1, 1, 2, 2-tetrafluoroethoxy) phenyl]methyl] amino]-l, 1, l-trifluoro-2-propanol product as a yellow oil, which was greater than 98% pure by reverse phase HPLC analysis. HRMS calcd. for C22H26F7N202 483. 1883 IM+H], found : 483. 1932. 1H NMR (CDC13) b 1. 0 (m, 6H), 2. 0 (m, 1H), 3. 0 (m, 2H), 3. 6 (dd, 1H), 3. 8 (dd, 1H), 4. 3 (m, 1H), 4. 6 (m, 2H), 5. 9 (tt, 1H), 6. 6 (d, 1H), 6. 7 (d, 1H), 6. 9-7. 4 (m, 6H).

Additional examples of 3-[[3-(aralkylamino)phenyl][[[3-(1, 1, 2, 2- tetrafluoro-ethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-pr opanols are prepared by one skilled in the art using similar methods, as shown in Example Table 28.

Example Table 28. 1,1,1-trifluoro-3-[[3-(aralkylamino)phenyl]-[[3-(1, 1, 2, 2- tetrafluoroethoxy) phenyl ImethylSamino1-2-propanols. Example Calculated Observed Number Mass Mass [M+H]+ [M+H]+ 542 phenyl 517.1726 517.1750 543 4fluorophenyl 535. 1632 535. 1627 3-(OCF2CF2H)-phenyl 633.1611 633.1653 EXAMPLE 545

N-(4-fluorophenyl)-N'-[3-[[[3-(1,1, 2, 2-tetrafluoroethoxy) phenyl] methyl]- (3, 3, 3-trifluoro-2-hydroxypropyl) amino] phenyl] urea The 3- [ (3-aminophenyl) [ [3- (1, 1, 2, 2-tetrafluoroethoxy) phenyl lmethyl lamino 1- 1, 1, 1-trifluoro-2-propanol (50 mg, 0. 12 mmol) was dissolved in 1 mL of dichloromethane. Triethylamine (20 µL, 0. 14 mmol) followed by 4-fluorophenyl isocyanate (14. 6 FL, 0. 13 mmol) were added. The solution was stirred at room temperature for 18 hours. The reaction was filtered through pre-wetted celite eluting with ethyl acetate. The solvent was evaporated, and the residue was purified by reverse phase HPLC eluting with 10% to 90% acetonitrile in water to afford 26 mg (40%) of the desired N-(4-fluorophenyl)-N'-[3-[[[3-(1,1, 2, 2- tetrafluoroethoxy) phenyl] methyls (3, 3, 3-trifl uoro-2-hydroxypropyl) amino] phenyllurea product as a yellow oil, which was greater than 95% pure by reverse phase HPLC analysis. HRMS calcd. for C25H22F8N303 : 564. 1533 lM+Hl, found : 564. 1566. 1H NMR (CDC13) 6 3. 7 (m, 2H), 4. 1 (m, 1H), 4. 7 (m, 2H), 5. 9 (tt, 1H), 6. 6 (d, 1H), 6. 9-7. 4 (m, 11H), 7. 5 (s, 1H), 7. 8 (s, 1H).

Additional examples of N-substituted-N'-[3-[[[3-(1,1, 2, 2- tetrafluoroethoxy)-phenyl lmethyl] (3, 3, 3-trifluoro-2-hydroxypropyl) amino] phenyl] ureas are prepared by one skilled in the art using similar methods, as shown in Example Table 29.

Example Table 29. N-substituted-N'-[3-[[[3-(1,1, 2, 2-tetrafluoroethoxy)phenyl]- methyl] (3, 3, 3-trifluoro-2-hydroxypropyl) amino] phenyl) ureas.

Example Calculated Observed Number Mass Mass [M+H]+ [M+H]+ 546 phenyl 546.1628 546. 1655 547 3-methoxyphenyl 576. 1733 576.1773 548 3-trifluoromethylphenyl 614. 1501 614. 1518 549 isopropyl 512. 1784 512. 1801 EXAMPLE 550

1, 1, 1-trifluoro-3- [ [ [3- (1, 1, 2, 2-tetrafluoroethoxy)phenyl]methyl] [[3'-(trifluoromethyl)1,1'-biphenyl]-3-yl]amino]-2-propanol 3-Trifluoromethylbenzene boronic acid (35. 4 mg, 0. 233 mmol) was dissolved in 640 mL of 2 M Na2C03, and 630 mL of ethanol then 1. 5 mL of a stock solution of 3-[(3-bromophenyl)[[3-(1,1, 2, 2-tetrafluoroethoxy) phenyljmethyl jamino]-

1, 1, 1-trifluoro-2-propanol (0. 105 M) and 10. 9 mg/mL of Pd (PPh3) 4 in toluene was added. After stirring at 105 °C for 5 hours, HPLC analysis indicated that the reaction had gone to completion. The reaction mixture was filtered through celite, evaporated, and the crude material purified by reverse phase HPLC eluting with 40% to 90% acetonitrile in water to afford 40. 5 mg (44. 7%) of the desired biphenyl aminopropanol product as an orange oil. HRMS calcd. for C25H19F10NO2: 556. 1334 [M+H] +, found : 556. 1339. 1H NMR (CDC13) 8 3. 60-3. 73 (m, 1H), 3. 95 (dd, 1H), 4. 36-4. 44 (m, 1H), 4. 76 (s, 2H), 5. 87 (tt, 1H), 6. 81 (dd, 1H), 6. 95 (s, 1H), 7. 03 (d, 1H), 7. 05-7. 20 (m, 3H), 7. 26-7. 40 (m, 2H), 7. 46-7. 73 (m, 4H).

Additional examples of 3- [ [13- (1, 1, 2, 2-tetrafluoroethoxy) phenyl methyl] [ [3-aryl] phenyl] amino]-l, l, l-trifluoro-2-propanols are prepared by one skilled in the art using similar methods, as shown in Example Table 30.

Example Table 30. 3-[[[3-(1,1, 2, 2-tetrafluoroethoxy) phenyllmethyl] [ [3- aryl] phenyl] amino]-1, 1, 1-trifluoro-2-propanols. Example Calculated Observed Number SUB Mass Mass [M+H]+ [M+H]+ 551 3, 5-di (trifluoromethyl) 624. 1208 624. 1216 552 4-trifluoromethyl 556. 1334 556. 1355 553 4-methylthio 534. 1337 534. 1366 554 3-chloro-4-fluoro 540. 0976 540. 0957 555 3, 5-dichloro-4-methoxy 586. 0786 586. 0818 Example Calculated Observed Number Mass Mass M+H [M+Hl + 556 3-nitro 533. 1311 533. 1262 557 3, 5-dichloro 556. 0681 556. 0612 558 4-methoxy 518.1566 518. 1533 559 3, 4-difluoro 524. 1272 524. 1249 560 2, 3, 4-trifluoro 542. 1177 542. 1152 561 3, 4-dichloro 556. 0681 556. 0698 562 3-methyl-4-methoxy 532.1722 532. 1676 563 3, 5-dimethyl-4- (N, N-559. 2195 5592182 dimethylamino) 564 H 488. 1460 488. 1457 565 4-chloro 522.1071 522. 1049 566 4-methyl 502. 1617 502. 1613 567 2, 4-dichloro 556. 0681 556. 0651 568 4-fluoro 506. 1366 506. 1336 569 4-fluoro-3-methyl520. 1523520. 1494 570 2-trifluoromethyl 556. 1334 556. 1286 571 3-methoxy 518. 1566 518. 1544 572 3-amino 503. 1569 503. 1593 573 4-carboxy 532.1358 532. 1329 574 4-tert-butyl 544. 2087 544. 2090 EXAMPLE 575

3-[[[4'-(methylsulfonyl)1,1'-biphenyl]-3-yl][[3-(1, 1, 2, 2- tetrafluoroethoxy) phenyl]-methyl] amino]- 1, 1, 1-trifluoro-2-propanol To a solution of 3- [ [ [3- (1, 1, 2, 2-tetrafluoroethoxy)phenyl]methyl][[4- (methylthio)-phenyl] phenyl] amino]-l, l, l-trifluoro-2-propanol in 2 mL of

trifluoroacetic acid was added 11 mL of 30% H202 (0. 097 mmol). After stirring at room temperature overnight, an additional 11 mL of 30% H202 (0. 097 mmol) was added. After 5 hours, TLC analysis indicated that the reaction had gone to completion. The solvent was removed, and the residue was filtered through silica gel eluting with 30% ethyl acetate in hexane. The material was evaporated to give 36. 6 mg (100%) of the desired sulfone product as an oil which was 100% pure by reverse phase HPLC analysis. HRMS calcd. for C25H22F7NO4S : 566. 1236 [M+H] +, found : 566. 1193. H NMR (CDC13) 8 3. 04 (s, 3H), 3. 66-3. 79 (m, 1H), 3. 97 (d, 1H), 4. 35-4. 43 (m, 1H), 4. 69-4. 81 (m, 2H), 5. 86 (dt, 1H), 6. 90 (d, 1H), 7. 01 (s, 1H), 7. 05-7. 18 (m, 4H), 7. 31- 7. 40 (m, 2H), 7. 60 (d, 2H), 7. 93 (d, 2H).

EXAMPLE 576 3-[[[3-(1,1, 2, 2-tetrafluoroethoxy) phenyl] methyl] (3, 3, 3-trifluoro-2-hydroxypropyl) amino] benzonitrile EX-576A) A solution of 3-aminobenzonitrile (1. 06 g, 9. 1 mmol) and 3- (1, 1, 2, 2-tetrafluoroethoxy) benzaldehyde (2. 00g, 9. 01 mmol) was dissolved in 25 mL of dichloroethane and acetic acid (536 mL, 9. 37 mmol), then solid NaBH (OAc) 3 (2. 48 g, 11. 7 mmol) was added. The mixture was stirred at room temperature for 3 hours, then quenched with water and extracted with dichloromethane. The organic layer was washed with saturated NaHC03, then dried over MgSO4, and evaporated. The crude product was purified by MPLC on silica gel eluting with 20% to 30% ethyl acetate in hexane to give 1. 58 g

(54%) of the desired 3- [[[3-(1,1, 2, 2-tetrafluoroethoxy)-phenyllmethyllamino benzonitrile product as a clear oil. H NMR (CDC13) b 4. 38 (s, 3H), 5. 89 (dt, 1H), 6. 79 (t, 1H), 6. 98 (d, 2H), 7. 12-7. 28 (m, 4H), 7. 40 (t, 1H).

The benzonitrile (1. 58 g, 4. 88 mmol) from EX-576A and l, l, l-trifluoro-2, 3- epoxy-propane (546 mL, 6. 34 mmol) were dissolved in 4 mL of acetonitrile.

Ytterbium (III) trifluoromethanesulfonate (304 mg, 0. 49 mmol) was added, and the stirred solution was warmed to 50 °C overnight. The reaction was quenched with water and extracted with ether. The ether layer was washed with brine, dried over MgSO4 and evaporated. The crude product was purified by MPLC on silica gel eluting with dichloromethane to give 1. 61 g (76%) of the desired 3- [[[3-(1,1, 2, 2-tetrafluoroethoxy) phenyl] methyl]- (3, 3, 3-trifluoro-2- hydroxypropyl) amino] benzonitrile product as a clear oil, greater than 98% by reverse phase HPLC. HRMS calcd. for C19H15F7N2O2: 437. 1100 [M+H] +, found : 437. 1097. 1H NMR (CDC13) 8 3. 60-3. 69 (m, 1H), 3. 86 (d, 1H), 4. 32 (bs, 1H), 4. 69 (q, 2H), 5. 86 (dt, 1H), 6. 85-6. 95 (m, 2H), 6. 97-7. 01 (m, 2H), 7. 04-7. 12 (m, 2H), 7. 23-7. 37 (m, 2H).

EXAMPLE 577 3-[[[3-(1,1, 2, 2-tetrafluoroethoxy) phenylmethyl] [3- (1H-tetrazol-5-yl) phenyl] amino]-1, 1, 1-trifluoro-2-propanol To a solution of 3-[[[3-(1,1, 2, 2-tetrafluoroethoxy) phenyl) methyl_ (3, 3, 3- trifluoro-2-hydroxypropyl) aminolbenzonitrile (76 mg, 0. 17 mmol) in 2 mL of

toluene was added trimethyltin azide (41 mg, 0. 20 mmol). The reaction mixture was heated to 105 °C and stirred overnight. TLC showed starting material to still be present so additional trimethyltin azide (41 mg. 0. 20 mmol) was added.

The reaction mixture was stirred overnight at 105 °Cs cooled to room temperature, then THF (800 µL) and concentrated HCl (500 µL) were added.

HPLC analysis showed 2 peaks after 5 hours, so additional concentrated HCI (200 ßL) was added. After stirring overnight, HPLC analysis showed the reaction to be complete. The mixture was filtered through a celite plug and evaporated in vacuo. The residue was purified by reverse phase HPLC eluting with 10% to 90% acetonitrile in water to give 27. 2 mg (33%) of the desired tetrazole product as an oil. HRMS calcd. for C19H16F7N5O2 : 480. 1270 lM+Hl +, found : 480. 1252. H NMR (CDC13) 8 3. 66-3. 99 (m, 2H), 4. 45- 4. 75 (m, 3H), 5. 80 (dt, 1H), 6. 49-6. 70 (m, IH), 6. 95 (s, 1H), 6. 97-7. 06 (m, 3H), 7. 18-7. 28 (m, 3H), 7. 34 (s, 1H).

EXAMPLE 578

(4-Fluoro-3-methylphenyl)[3-[[[(1,1, 2, 2-tetrafluoroethoxy) phenyl]methyl] (3, 3, 3-trifluoro-2-hydroxypropyl) amino] phenyl] methanone To a solution of 3-[[[3-(1,1, 2, 2-tetrafluoroethoxy) phenyl]methyl](3, 3, 3- trifluoro-2-hydroxypropyl) amino] benzonitrile (100 mg, 0. 23 mmol) in 1 mL of anhydrous THF under nitrogen was added 4-fluoro-3-methylphenylmagnesium bromide (0. 81 mL of 1. 0 M solution, 0. 81 mmol), and the mixture was stirred at room temperature overnight. HPLC analysis of the reaction mixture showed the

presence of starting material so additional 4-fluoro-3-methylphenylmagnesium bromide (0. 46 mL, 0. 41 mmol) was added. HPLC analysis 24 hours later showed the reaction to be complete. The reaction was quenched and acidified with 1 N HCI. After hydrolysis of imine was complete by HPLC analysis, the mixture was filtered through celite and evaporated. The crude product was purified by reverse phase HPLC eluting with 10% to 90% acetonitrile in water to give 28. 0 mg (22%) of the desired ketone product as an oil. HRMS calcd. for C26H21F8NO3 : 548. 1410 [M+H], found : 548. 1441. H NMR (CDC13) 8 2. 26 (s, 3H), 3. 60-3. 70 (m, 1H), 3. 92 (d, 1H), 4. 26-4. 40 (m, 1H), 4. 68 (t, 2H), 5. 87 (dt, 1H), 6. 91-7. 03 (m, 3H), 7. 05-7. 12 (m, 4H), 7. 26-7. 35 (m, 2H), 7. 43-7. 52 (m, 1H), 7. 63 (d, 1H).

Additional examples of (aryl-, alkyl- or cycloalkyl-)[3-[[[(1,1, 2, 2-tetrafluoro- ethoxy) phenyl] methyl] (3, 3, 3-trifluoro-2-hydroxypropyl) aminojphenyl] methanones are prepared by one skilled in the are using similar methods, as shown in Example Table 31.

Example Table 31. (Aryl-, alkyl-or cycloalkyl-) [3-1ll (1, 1, 2, 2- tetrafluoroethoxy)-phenyl methy ! j (3, 3, 3-trifluoro-2- hydroxypropyl) aminolphenyl lmethanones. Example Calculated Observed Mass Number Mass [M+H]+ [M+H]+ 579 phenyl 516. 1410 516 1383 580 4-fluorophenyl 534. 1315 534 1273 581 cyclopentyl 508. 1723 508. 1675 582 isopropyl 482.1566 482. 1576 EXAMPLE 583

a-Phenyl-3- [ [ [3- (1, 1, 2, 2-tetrafluoroethoxy) phenyl] methyl]] (3, 3, 3-trifluoro-2-hydroxypropyl) benzenemethanol To a solution of phenyl [3-[[[(1,1, 2, 2-tetrafluoroethoxy) phenyl] methyl] (3, 3, 3- trifluoro-2-hydroxypropyl) aminolphenyl] methanone (155. 8 mg, 0. 302 mmol) in 2. 3 mL of methanol cooled to 5 °C was added solid NaBH4 (34.5 mg, 0.912 mmol). HPLC analysis after 1 hour showed no ketone starting material. The reaction was evaporated to dryness and purified by reverse phase HPLC eluting with 50% to 90% acetonitrile in water to give 35. 6 mg (24%) of the desired alcohol product as an oil. HRMS calcd. for C25H22F7NO3 : 518. 1566 [M+H] +, found : 518. 1563. H NMR (acetone-d6) õ 3. 56-3. 73 (m, 1H), 3. 92- 4. 06 (m, 1H), 4. 40-4. 55 (m, 1H), 4. 82 (s, 2H), 5. 71 (s, 1H), 6. 28-6. 69 (m, 2H), 6. 71-6. 82 (m, 1H), 6. 93 (s, 1H), 7. 07-7. 51 (m, 10H).

Additional examples of a-alkyl-3- [ [ [3- (1, 1, 2, 2-tetrafluoroethoxy) phenyl methyl] [ (3, 3, 3-trifluoro-2-hydroxypropyl) benzenemethanols are prepared by one skilled in the art using similar methods, as shown in Example Table 32. Example Table 32. a-alkyl-3-[ll3-(1, 1, 2, 2-tetrafluoroethoxy) phenyljmethy ! j- [ (3, 3, 3-trifl uoro-2-hydroxypropyl) benzenemethanol s

Example Calculated Mass Observed Mass Number [M+H]+ [M+H]+ 584 isopropyl 484. 1723 484. 1725 EXAMPLE 585

Ethyl 3-[ (3, 3, 3-trifluoro-2-hydroxypropyl) [ [ (3-trifluoromethoxy) phenyllmethyl] amino] benzoate EX-585A) Ethyl 3-aminobenzoate (3. 9 mL, 26 mmol) and 3-trifluoromethoxy- benzaldehyde (4. 91 g, 25. 8 mmol) were dissolved in 65 mL of dichloroethane and acetic acid (1. 6 mL, 28 mmol), then solid NaBH (OAc) 3 (7. 5 g, 34. 2 mmol) was added. The mixture was stirred at room temperature overnight, then quenched with water and extracted with dichloromethane. The organic layer was washed with brine, then dried over MgSO4, and evaporated to give 9. 76 g (>100%) of the desired ethyl 3-[[[(3-trifluoromethyl)phenyl]methyl] amino]benzoate product as a yellow oil, which was greater than 95% pure by

reverse phase HPLC analysis. IN NMR (CDC ! g) 5 1. 35 (t, 3H), 4. 26-4. 41 (m, 5H), 6. 73 (d, 1H), 7. 12 (d, 1H), 7. 15-7. 25 (m, 2H), 7. 25-7. 43 (m, 4H).

The ethyl 3-[[[(3-trifluoromethyl)phenyl]methyl]amino]benzoate (9. 76 g, 25. 8 mmol) product from EX-585A and 1, 1, 1-trifluoro-2, 3-epoxypropane (2. 9 mL, 33. 5 mmol) were dissolved in 25 mL of acetonitrile. Ytterbium (III) trifluoromethanesulfonate (1. 6 g, 2. 6 mmol) was added, and the stirred solution was warmed to 50 °C for 20 hours. The reaction was quenched with water and extracted with dichloromethane. The organic layer was washed with water and brine, then dried over MgSO4. The crude product was purified by column chromatography on silica gel eluting with dichloromethane to give 10. 7 g (92%) of the desired ethyl 3- [ (3, 3, 3-trifluoro-2-hydroxypropyl) [L (3-trifluoromethyl) phenyl] methyl] amino] benzoate product as a yellow oil. HRMS calcd. for C20H1gNO4F6. 452. 1297 [M+H] +, found : 452. 1256. 1H NMR (CDC13) 8 1. 32 (t, 3H), 2. 94-3. 02 (m, 1H), 3. 54-3. 64 (m, 1H), 3. 91 (d, IH), 4. 24-4. 40 (m, 3H), 4. 69 (t, 2H), 6. 86 (d, 1H), 7. 05 (s, 1H), 7. 07-7. 14 (m, 2H), 7. 20- 7. 34 (m, 2H), 7. 39-7. 47 (m, 2H).

EXAMPLE 586 3- [ (3, 3, 3-trifluoro-2-hydroxypropyl) [ [ (3-trifluoromethyl) phenyl] methyl] amino] benzoic Acid Ethyl 3- [ (3, 3, 3-trifluoro-2-hydroxypropyl) l l (3-trifluoromethyl) phenyl lmethyl] amino]-benzoate was dissolved in 70 mL of THF and 35 mL of water. Lithium hydroxide monohydrate (2. 93 g, 69. 8 mmol) was added, and the mixture was heated to 45 °C under nitrogen overnight, at which time HPLC analysis indicated

that the reaction had gone to completion. The mixture was acidified with 1 N HCI to a pH of 3-4, then extracted with ethyl acetate several times, and the combined organic layers were dried over MgSO4. The dried organic layer was evaporated to give 11. 2 g (100%) of the desired benzoic acid product as a pale orange oil, which was greater than 98% pure by reverse phase HPLC analysis.

HRMS calcd. for C 18H 15NO4F6. 424. 0984 [M+H] +, found : 424. 0991. 1 H NMR (acetone-d6) 8 3. 68-3. 81 (m, 1H), 3. 99-4. 09 (m, 1H), 4. 43-4. 58 (m, 1H), 4. 87 (s, 2H), 7. 02 (d, 1H), 7. 19 (d, 1H), 7. 22-7. 40 (m, 4H), 7. 40-7. 49 (m, 2H).

EXAMPLE 587

3- [ (3-phenoxyphenyl) [ [3- (2-pyridinyl) phenyl] methyl] amino]- 1, 1, 1-trifluoro-2-propanol EX-587A) To a THF solution (8 mL) of 2-bromopyridine (1. 30 g, 8. 23 mmol) at-78 °C was added 1. 6 M n-BuLi in hexanes (5. 3 mL, 8. 48 mmol). The resulting dark red solution was stirred at-78 °Cfor 10 min, and a solution of 0. 5 M ZnC12 in THF (18 mL, 9. 0 mmol) was added giving a light brown slurry.

After warming to room temperature, 3-bromobenzaldehyde (0. 816 mL, 7. 0 mmol) and Pd (PPh3) 4 (0. 242 g, 0. 21 mmol) were added, and the mixture was stirred for 18 h at room temperature under argon. The reaction mixture was poured into 1 N HCI (30 mL) and washed with diethyl ether. The aqueous layer was neutralized with NaHC03 and extracted with diethyl ether. The solvent was

removed in vacuo to give the crude product as an oil. Purification by flash chromatography on silica gel eluting with 20% ethyl acetate in hexane gave 0. 49 g (38%) of the desired 3- (2-pyridinyl) benzaidehyde product as a colorless oil.

GCMS : m/z = 183 [M+].

EX-587B) To a 1, 2-dichloroethane (5 mL) solution of aldehyde (0. 37 g, 2. 0 mmol) from EX-587A was added 3-phenoxyaniline (0. 37 g, 2. 0 mmol), NaB (OAc) 3H (0. 55 g, 2. 6 mmol) and acetic acid (0. 12 mL, 2. 0 mmol). The cloudy solution was stirred at room temperature for 2 h. The reaction mixture was poured into water and extracted with dichloromethane. The organic layer was washed with saturated NaHCO3 and brine, dried (MgSO4) and evaporated to yield 0. 70 g (100%) of the desired N-3- (phenoxyphenyl)-1 [3- (2- pyridinyl) phenyl] methyl] amine product as a yellow oil. HRMS : calcd. for C24H21N2O : 353. 1654 [M+H] +, found : 353. 1660.

A THF (1 mL) solution of amine (0. 47 g, 1. 3 mmol) from EX-587B and 1, 1, 1-trifluoro-2, 3-epoxypropane (0. 35 mL, 4. 1 mmol) was placed in a sealed vial and heated to 90 °C for 18 h with stirring. The solvent was removed in vacuo to give the crude product as an oil. Purification by flash chromatography on silica gel eluting with 20% ethyl acetate in hexane gave 0. 026 g (4. 2%) of the desired 3- [ (3-phenoxyphenyl) [ [3- (2-pyridinyl) phenyl] methyl] amino]-1, 1, 1- trifluoro-2-propanol product as a yellow oil. HRMS calcd. for C27H24N2O2F3: 465. 1790 [M+H] +, found : 465. 1798. 1H NMR (CDC13) b 3. 63 (dd, 1H), 3. 73 (br s, 1H), 3. 82 (dd, 1H), 4. 30 (m, 1H), 4. 67 (d, 2H), 6. 34 (dd, 1H), 6. 44 (t, 1H), 6. 52 (dd, 1H), 6. 92 (d, 2H), 7. 02 (t, 1H), 7. 12 (t, 1H), 7. 2 (m, 4H), 7. 38 (t, 1H), 7. 65 (d, 1H), 7. 72 (d, 1H), 7. 74 (d 1H), 7. 84 (s, 1H), 8. 62 (d, 1H).

EXAMPLE 588

3- [ (3-phenoxyphenyl) [ [3- [ (3-trifluoromethyl)-2-pyridinyl]<BR> <BR> <BR> <BR> <BR> phenyl] methyl] amino]-1, 1, 1-trifluoro-2-propanol EX-588A) To a toluene (10 mL) solution of 2-bromo-3- trifluoromethylpyridine (1. 10 g, 4. 87 mmol) was added 3-formylphenylboronic acid (0. 90 g, 6. 0 mmol) and DMF (4 mL). To the resulting solution was added K2CO3 (1. 67 g, 12. 1 mmol) and Pd (PPh3) 4 (0. 35 g, 0. 30 mmol). The slurry was heated to reflux under argon for 18 h. The cooled mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried (MgS04) and evaporated to an oil. Purification by flash chromatography on silica gel eluting with 20% ethyl acetate in hexane gave 0. 55 g (45 %) of the desired 3-[(3-trifluoromethyl)-2-pyridinyllbenzaldehyde product as a color-less oil which solidified upon standing. HRMS : calcd. for C13H9NOF3 : 252. 0636 [M+H] +, found : 252. 0639.

EX-588B) A mixture of solid 3-phenoxyaniline (2. 96 g, 16 mmol) and 1, 1, 1- trifluoro-2, 3-epoxypropane (1. 30 mL, 15. 0 mmol) was placed in a sealed tube and heated to 100 °C giving a dark solution. The stirred solution was heated 18 h and cooled to give a dark oil. Purification by flash chromatography on silica gel eluting with dichloromethane gave 3. 15 g (71%) of the desired 3- [ (N-3- phenoxy-phenyl) amino1-1, 1, 1-trifluoro-2-propanol product as a colorless oil.

Anal. calcd. for C15Hl4NO2F3-0. 05 CH2C12 : C, 59. 92 ; H, 4. 71 ; N, 4. 64.

Found : C, 59. 92 ; H, 4. 53 ; N, 4. 73. HRMS calcd. 298. 1055 lM+H], found : 298. 1056.

To a 1, 2-dichloroethane (8 mL) solution of aldehyde (0. 55 g, 2. 2 mmol) from EX-588A was added the amine (0. 66 g, 2. 2 mmol) from EX-588B, NaB (OAc) 3H (0. 61 g, 2. 9 mmol) and acetic acid (0. 15 mL, 2. 6 mmol). The cloudy solution was stirred at room temperature for 4 h. The reaction mixture was poured into water and extracted with dichloromethane. The organic layer was washed with saturated NaHCO3 and brine, dried (MgSO4) and evaporated to give an oil. Purification by flash chromatography on silica gel eluting with 20% ethyl acetate in hexane gave 0. 33 g (29%) of the desired 3- [ (3- <BR> <BR> <BR> phenoxyphenyl) [ [3- [ (3-trifluoromethyl)-2-pyridinyl] phenyl] methyl] amino]- 1, 1, 1-trifluoro-2-propanol product as a white foam, >97% pure by HPLC analysis. Anal. calcd. for C28H22N202F6 : C, 63. 16 ; H, 4. 16 ; N, 5. 26.

Found : C, 62. 87 ; H, 4. 02 ; N, 5. 33. HRMS : calcd. 533. 1664 lM+Hl, found : 533. 1658. 1H NMR (C6D6) 6 2. 97 (d, 1H), 3. 26 (dd, 1H), 3. 46 (dd, 1H), 3. 77 (m, 1H) 4. 22 (dd, 2H), 6. 31 (dd, 1H), 6. 35 (dd, 1H), 6. 40 (dd, 1H), 6. 54 (t, 1H), 6. 80 (t, 1H), 6. 9-7. 0 (m, 7H), 7. 26 (d, 1H), 7. 33 (d, 1H), 7. 40 (s, 1H), 8. 17 (d, 1H).

Additional examples of 3- [ (3-phenoxyphenyl) [ [3- (heteroaryl) phenyll methyl]-amino]-1,1,1-trifluoro-2-propanols are prepared by one skilled in the art using similar methods, as shown in Example Table 33. Example Table 33. 3-[(3-phenoxyphenyl)[[3-(heteroaryl)phenyl]methyl]amino]- 1, 1, 1-trifl uoro-2-propanol s.

Ex. Calculated Observed SUB No. Mass [M+H]+ Mass [M+H]+ 589 3-methyl-pyridin-2-yl 479. 1949 479. 1946 590 pyridin-3-yl 465.1790 465.1778 591 pyridin-4-yl 465.1790 465.1821 EXAMPLE 592

3- [ (3-phenoxyphenyl) [ [3- (2-furanyl) phenyl] methyllamino]- 1, 1, 1-trifluoro-2-propanol EX-592A) To a dioxane (20 mL) solution of 3-bromobenzaldehyde (0. 63 mL, 5. 4 mmol) was added 2- (tributylstannyl) furan (1. 89 mL, 6. 00 mL) and Pd (PPh3) 2C12 (0. 21 g, 0. 30 mmol). The mixture was heated to reflux under argon for 1. 5 h. The cooled mixture was poured into a mixture of saturated KF

and ethyl acetate and stirred 18 h. The slurry was filtered through celite. The organic layer was separated, washed with brine, dried (MgSO4) and evaporated to an oil. Purification by flash chromatography on silica gel eluting with 5% ethyl acetate in hexane gave 0. 80 g (86%) of the desired 3- (2- furanyl) benzaldehyde product as an yellow oil which solidified upon standing.

MS : m/z = 173. 1 [M+H] +.

EX-592B) To a 1, 2-dichloroethane (7 mL) solution of aldehyde (0. 40 g, 2. 3 mmol) from EX-592A was added 3-phenoxyaniline (0. 43 g, 2. 3 mmol), NaB (OAc) 3H (0. 64 g, 3. 0 mmol) and acetic acid (0. 15 mL, 2. 6 mmol). The cloudy solution was stirred at room temperature for 2 h. The reaction mixture was poured into water and extracted with dichloromethane. The organic layer was washed with saturated NaHC03 and brine, dried (MgSO4) and evaporated to yield 0. 74 g (94%) of the desired N- (3-phenoxyphenyl) [ [3- (2- furanyl) phenyl] methyl] amine product as an yellow oil which was used without further purification. MS : m/z = 342. 3 [M+H] +.

To a dichloromethane (3 mL) solution of amine (0. 74 g, 2. 2 mmol) from EX- 592B was added 1, 1, 1-trifluoro-2, 3-epoxypropane (0. 28 mL, 3. 3 mmol) and Yb (OTf) 3 (0. 136 g, 0. 20 mmol). The cloudy solution was stirred at room temperature for 4 days, then diluted with diethyl ether, and washed with water and brine. The organic layer was dried (MgSO4) and evaporated to an oil.

Purification by flash chromatography on silica gel eluting with 10% ethyl acetate in hexane gave an oil which was dissolved in EtOH, stripped and dried in vacuo to give 0. 49 g (49%) of the desired 3- [ (3-phenoxyphenyl) [ [3- (2- furanyl) phenyl] methyl] amino)-1, 1, 1-trifluoro-2-propanol product as a colorless oil, > 98% pure by HPLC analysis. Anal. calcd. for C26H22N03F3-0. 5 EtOH-0. 3 H20 : C, 67. 30 ; H, 5. 35 ; N, 2. 91. Found : C, 67. 12 ; H, 5. 12 ; N, 2. 89. HRMS calcd. 454. 1630 [M+H] +, found : 454. 1635. 1H NMR (C6D6) b 2. 15 (d, 1H), 3. 21 (dd, 1H), 3. 50 (dd, 1H), 3. 81 (m, 1H), 4. 24 (s, 2H), 6. 09

(dd, 1H), 6. 33 (d, 1H), 6. 35 (d, 1H), 6. 44 (dd, 1H), 6. 52 (t, 1H), 6. 79 (m, 1H), 6. 81 (s, 1H), 6. 9-7. 0 (m, 7H), 7. 44 (d, 1H), 7. 47 (s, 1H).

Additional examples of 3- [ (3-phenoxyphenyl) [ [4-substituted-3- (2- furanyl)-phenylSmethyllamino]-l, l, l-trifluoro-2-propanols are prepared by one skilled in the art using similar methods, as shown in Example Table 34.

Example Table 34. 3- [ (3-phenoxyphenyl) [ [4-substituted-3- (2-furanyl)- phenyl] methyl amino]-1, 1, 1-trifluoro-2-propanols. Ex. Calculated Mass Observed Mass RSUB No. [M+H]+ [M+H]+ 593 F 472. 1536 472. 1530 594 Me 468.1787 468. 1783 EXAMPLE 595

3- [ (3-phenoxyphenyl) [ [3- (2-thienyl) phenyl] methyl] amino]- 1, 1, 1-trifluoro-2-propanol EX-595A) To a 1, 2-dichloroethane (90 mL) solution of (5. 60 g, 30. 3 mmol) was added 3-phenoxyaniline (5. 60 g, 30. 2 mmol), NaB (OAc) 3H (8. 26 g, 39. 0 mmol) and acetic acid (1. 8 mL, 31. mmol). The cloudy solution was stirred at room temperature for 1. 5 h. The reaction mixture was poured into water and extracted with dichloromethane. The organic layer was washed with saturated NaHC03 and brine, dried (MgSO4) and evaporated to yield 10. 49 g (98%) of the desired N- (3-phenoxyphenyl) ( (3- bromophenyl) methyl] amine product as a light brown oil. H NMR (CDC13) 6 4. 26 (s, 2H), 6. 27 (s, 1H), 6. 38 (d, 2H), 7. 00 (d, 2H), 7. 13 (m, 2H), 7. 19 (t, 1H), 7. 26 (d, 1H), 7. 30 (m, 2H), 7. 38 (d, 1H), 7. 96 (s, 1H). The formation of the desired product was monitored by the disappearance of the aldehyde peak (8 #10) and the formation of the benzyl peak (b 4. 26) in the H NMR spectrum.

EX-595B) To a dichloromethane (15 mL) solution of amine from EX-595A (6. 01 g, 17. 0 mmol) was added 1, 1, 1-trifluoro-2, 3-epoxypropane (1. 75 mL, 20. 3 mmol) and Yb (OTf) 3 (1. 05 g, 1. 69 mmol). The cloudy solution was stirred at room temperature for 24 h, diluted with diethyl ether, and washed with water and brine. The organic layer was dried (MgSO4) and evaporated to an oil.

Purification by flash chromatography on silica gel eluting with 3-8% ethyl acetate

in hexane gave an oil which was dissolved in EtOH, stripped and dried in vacuo to give 4. 71 g (60%) of the desired 3-1 (3-PhenoxyPhenyl) ll3- bromophenyl] methyl] amino]-1, 1, 1-trifluoro-2-propanol product as a colorless oil. Anal. calcd. for C22H19NO2F3Br#0, 41 EtOH : C, 56. 49 ; H, 4. 46 ; N, 2. 89.

Found : C, 56. 15 ; H, 4. 22 ; N, 2. 92. HRMS calcd. 466. 0629 [M+H] +, found : 466. 0598.

To a dioxane (5 mL) solution of aminopropanol from EX-595B (0. 38 g, 0. 82 mmol) was added 2-(tributylstannyl) thiophene (0. 29 mL, 0. 90 mmol) and Pd (PPh3) 2C12 (0. 040 g, 0. 057 mmol). The mixture was heated to reflux under argon for 18 h. The cooled mixture was poured into a mixture of 10 % aq. KF and ethyl acetate and stirred 1 h. The slurry was filtered through celite. The organic layer was separated, washed with brine, dried (MgSO4) and evaporated to an oil. Purification by flash chromatography on silica gel eluting with 5-15% ethyl acetate in hexane gave an oil which was dissolved in EtOH, stripped and dried in vacuo to give 0. 17 g (45%) of the desired 3- [ (3-phenoxy-phenyl) [ 3- (2- thienyl) phenyl] methyl] amino]-l, l, l-trifluoro-2-propanol product as a colorless oil. Anal. calcd. for C26H22NO2F3S-0. 62 EtOH : C, 65. 69 ; H, 5. 20 ; N, 2. 81.

Found : C, 65. 36 ; H, 4. 84 ; N, 2. 81. HRMS calcd. 470. 1402 lM+Hl, found : 470. 1392. 1H NMR (CDCl3) # 2. 60 (br s, 1H). 3. 64 (dd, 1H), 3. 89 (dd, 1H), 4. 37 (m, 1H), 4. 68 (s, 2H), 6. 42 (dd, 1H), 6. 45 (t, IH), 6. 55 (dd, 1H), 6. 98 (dd, 2H), 7. 1 (m, 3H), 7. 20 (t, 1H), 7. 2-7. 3 (m, 5H), 7. 43 (s, 1H), 7. 52 (d, 1H).

EXAMPLE 596

3- [ (3-phenoxyphenyl) [ [3- (phenvlmethyl) phenyl] amino1- 1, 1, 1-trifluoro-2-propanol To a THF (4 mL) solution of 3-[(3-phenoxyphenyl) [l3-bromophenyl] methylfl amino]-1, 1, 1-trifluoro-2-propanol (0. 60 g, 1. 3 mmol) from EX-595B was added benzyl-magnesium bromide in THF (2. 0 mL, 2. 0 M, 4. 0 mmol) and Pd (PPh3) 4. The resulting yellow solution was refluxed under N2 for 18 h. The cooled solution was poured into saturated aq. NH4CI, extracted with ethyl acetate, dried (MgSO4) and evaporated to an oil. Purification by flash chromatography on silica gel eluting with 15% ethyl acetate in hexane gave an oil which was dissolved in EtOH, stripped and dried in vacuo to give 0. 39 g (62%) of the desired 3-[(3-phenoxyphenyl) [[3-(phenylmethyl)phenyl] methyl]amino]- 1, 1, 1-trifluoro-2-propanol product as a colorless oil. Anal. calcd. for C29H26NO2F3-0. 4 EtOH : C, 72. 17 ; H, 5. 77 ; N, 2. 82. Found : C, 72. 17 ; H, 5. 42 ; N, 2. 83. HRMS calcd. 478. 1994 ( [M+H] +, found : 478. 1984. H NMR (C6D6) b 1. 58 (d, 1H), 3. 22 (dd, 1H), 3. 46 (dd, 1H), 3. 69 (s, 2H), 3. 73 (m, IH), 4. 18 (s, 2H), 6. 34 (dd, 1H), 6. 47 (dd, 1H), 6. 53 (t, 1H), 6. 8-7. 1 (m 15H).

Additional examples of 3- [ (3-phenoxyphenyl) [ [3- (alkyl- or cycloalkyl- ) phenyl] methyl] amino]-1, 1, 1-trifluoro-2-propanols are prepared by one skilled in the art using similar methods, as shown in Example Table 35.

Example Table 35. 3- [ (3-phenoxyphenyl) [ [3- (alkyl- or cycloalkyl-) phenyl I methyl] amino]-l, 1, 1-trifluoro-2-propanols.

Ex. RSUB Calculated Observed Mass PSUB No. Mass [M+H]+ [M+H]+ 597 3-methylbutyl 458. 2307 458. 2295 , 598 2-methylpropyl 444. 2150 444. 2157 599 cyclopropyl 428.1837 428. 1806 EXAMPLE 600

3-[(3-phenoxyphenyl) [[2'-(trifluoromethyl) [1, I'-biphenyl]-3-<BR> <BR> <BR> <BR> yl] methyl] aminol-l, l, l-trifluoro-2-propanol To a toluene (8 mL) solution of 3-[(3-phenoxyphenyl)[[3-bromophenyl] methyll-amino]-1, 1, 1-trifluoro-2-propanol (0. 51 g, 1. 1 mmol) from EX-595B <BR> <BR> <BR> was added 2- (tri-fluoromethyl) phenylboronic acid (0. 33 g, 1. 7 mmol) and DMF ; (3 mL). To the resulting solution was added K2CO3 (0. 31 g, 2. 2 mmol) and Pd (PPh3) 4 (0. 060 g, 0. 05 mmol). The slurry was heated to reflux under argon

for 18 h. The cooled mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4) and evaporated to an oil. Purification by flash chromatography on silica gel eluting with 20% ethyl acetate in hexane gave an oil which was dissolved in EtOH, stripped and dried in vacuo to give 0. 32 g (55%) of the desired 3-[ (3- phenoxyphenyl) [ [(2'-(trifluoromethyl) [1, l'-biphenyl]-3-yl jmethyllamino1- 1, 1, 1-tri-fluoro-2-propanol product as a colorless oil. Anal. calcd. for C29H23NO2F6-0. 8 EtOH : C, 64. 67 ; H, 4. 93 ; N, 2. 46. Found : C, 64. 53 ; H, 4. 69 ; N, 2. 49. HRMS calcd. 532. 1711 [M+H] +, found : 532. 1708. IH NMR (C6D6) 8 1. 72 (d, 1H), 3. 17 (dd, 1H), 3. 46 (dd, 1H), 3. 72 (m, 1H), 4. 23 (s, 2H), 6. 33 (dd, 1H), 6. 43 (dd, 1H), 6. 52 (t, 1H), 6. 82 (m, 2H), 6. 9-7. 1 (m, 11H), 7. 43 (d, 1H).

EXAMPLE 601

3- [ (3-phenoxyphenyl) [ [3- (3-furanyl) phenyl] methyl] amino]- 1, 1, 1-trifluoro-2-propanol EX-601A) To a toluene (10 mL) solution of 3-bromofuran (0. 54 mL, 6. 0 mmol) was added 3-formylphenylboronic acid (1. 00 g, 6. 7 mmol) and DMF (4 mL). To the resulting solution was added K2CO3 (1. 85 g, 13. 4 mmol) and Pd (PPh3) 4 (0. 40 g, 0. 35 mmol). The slurry was heated to reflux under argon for 2 h. The cooled mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4) and

evaporated to an oil. Purification by flash chromatography on silica gel eluting with 5 % ethyl acetate in hexane gave 0. 10 g (10%) of the desired 3- (3- furanyl) benzaldehyde product as a yellow oil. MS : m/z = 173. 0 [M+H EX-601B) To a 1, 2-dichloroethane (3 mL) solution of the aldehyde (0. 10 g, 0. 58 mmol) from EX-601A was added 3-phenoxyaniline (0. 11 g, 0. 59 mmol), NaB (OAc) 3H (0. 16 g, 0. 75 mmol) and acetic acid (0. 040 mL, 0. 70 mmol). The cloudy solution was stirred at room temperature for 2 h. The reaction mixture was poured into water and extracted with dichloromethane. The organic layer was washed with saturated NaHCO3 and brine, dried (MgSO4) and evaporated to yield 0. 20 g (100%) of the desired N-3-phenoxyphenyl)- [ [3- (3- furanyl) phenyl] methyl] amine product as a yellow oil which was used without further purification. IH NMR (CDC713) 6 4. 1 (br s, 1H), 4. 30 (s, 2H), 6. 29 (d, 1H), 6. 32 (dd, 1H), 6. 39 (dd, 1H), 6. 66 (s, 1H), 6. 95-7. 05 (m, 4H), 7. 2-7. 5 (m, 7H), 7. 70 (s, 1H). The formation of the desired product was monitored by the disappearance of the aldehyde peak (6-10) and the formation of the benzyl peak (# 4. 30) in the 1 H NMR spectrum.

To a CH3CN (2 mL) solution of amine (0. 20 g, 0. 58 mmol) from EX-601B was added 1, 1, 1-trifluoro-2, 3-epoxypropane (0. 10 mL, 1. 2 mmol) and Yb (OTf) 3 (0. 035 g, 0. 056 mmol). The cloudy solution was stirred in a sealed flask at 40 °C. After 18 h, additional 1, 1, 1-trifluoro-2, 3-epoxypropane (0. 20 mL, 2. 4 mmol) and Yb (OTf) (0. 035 g, 0. 056 mmol) were added, and the mixture was heated an additional 4 h, diluted with diethyl ether and washed with water and brine. The organic layer was dried (MgSO4) and evaporated to an oil.

Purification by flash chromatography on silica gel eluting with 10% ethyl acetate in hexane gave an oil which was dissolved in EtOH, stripped and dried in vacuo to give 0. 14 g (53%) of the desired 3-[(3-phenoxyphenyl) [[3-(3- furanyl) phenyl methyl] amino]-1, 1, 1-trifluoro-2-propanol product as a colorless oil, > 99% pure by HPLC analysis. Anal. calcd. for C26H22NO3F3-0. 3 EtOH :

C, 68. 37 ; H, 5. 13 ; N, 3. 00. Found : C, 68. 29 ; H, 5. 09 ; N. 2. 99. HRMS calcd.

454. 1630 [M+H], found : 454. 1635. 1H NMR (C6D6) 8 1. 62 (d. 1H), 3. 18 (dd, 1H), 3. 48 (dd, 1H), 3. 74 (m, 1H), 4. 22 (s. 2H), 6. 32 (dd, lH), 6. 35 (m, 1H), 6. 44 (dd, 1H), 6. 52 (t, 1H), 6. 78 (m, 1H), 6. 82 (d, 1H), 6. 9-7. 1 (m, 9H), 7. 37 (s, 1H).

EXAMPLE 602 3- [ (3-phenoxyphenyl) [ [3-(1-methyl-1H-pyrrol-2-yl) phenyl methyls amino]-1, 1, 1-trifluoro-2-propanol EX-602A) To solution of N-methylpyrrole (0. 97 mL, 11 mmol) in Et20 (20 mL) was added neatTMEDA (1. 5 mL, 10 mmol) and 1. 6 M n-BuLi in hexanes (6. 3 mL, 10 mmol). The solution was heated to reflux under N2 for 1 h and then cooled to-78 °C. A 1. 0 M solution of Me3SnCI in THF was added over 15 min, and the resulting solution stirred for 30 min at-78 °C. After warming to room temperature, 3-bromo-benzaldehyde (0. 70 mL, 6. 0 mmol), Pd (PPh3) 2CI2 (0. 25 g, 0. 35 mmol) and dioxane (10 mL) were added. The slurry was heated to reflux for 18 h. The cooled mixture was poured into a mixture of saturated KF and ethyl acetate and stirred 15 min. The slurry was filtered through celite. The organic layer was separated, washed with brine, dried (MgSO4) and evaporated to an oil. Purification by flash chromatography on silica gel eluting with 5% ethyl acetate in hexane gave 0. 45 g (24%) of the desired 3- (1-methyl-1H-pyrrol- 2-yl) benzaldehyde product as a yellow oil. MS : m/z =186. 2 [M+H]'.

EX-602B) To a 1, 2-dichloroethane (10 mL) solution of aldehyde (0. 45 g. 2. 4 mmol) from EX-602A was added 3-phenoxyaniline (0. 45 g, 2. 4 mmol), NaB (OAc) 3H (0. 67 g, 3. 2 mmol) and acetic acid (0. 15 mL, 2. 4 mmol). The cloudy solution was stirred at room temperature for 2 h. The reaction mixture was poured into water and extracted with dichloromethane. The organic layer was washed with saturated NaHCO3 and brine, dried (MgSO4) and evaporated to yield 0. 67 g (79%) of the desired N- (3-phenoxyphenyl) [ [3- (1-methyl-IH- pyrrol-2-yl) phenyllmethyl] amine product as a yellow oil which was used without further purification. H NMR (CDC13) õ 3. 60 (s, 3H), 4. 15 (br s, 1 H), 4. 35 (s, 2H), 6. 2- 6. 4 (m, 5H), 6. 67 (s, 1H), 7. 00-7. 05 (m, 4H), 7. 1-7. 2 (m, 6H). The formation of the desired product was monitored by the disappearance of the aldehyde peak (6 ~ 10) and the formation of the benzyl peak (8 4. 35) in the H NMR spectrum.

To a CH3CN (2 mL) solution of amine (0. 67 g, 1. 9 mmol) from EX-602B was added 1, 1, 1-trifluoro-2, 3-epoxypropane (0. 33 mL, 3. 8 mmol) and Yb (OTf) 3 (0. 120 g, 0. 19 mmol). The cloudy solution as stirred in a sealed flask at 40 °C for 18 h. The cooled reaction mixture was diluted with diethyl ether and washed with water and brine. The organic layer was dried (MgSO4) and evaporated to an oil. Purification by flash chromatography on silica gel eluting with 10% ethyl acetate in hexane gave an oil which was dissolved in EtOH, stripped and dried in vacuo to give 0. 57 g (66 %) of the desired 3-[ (3- phenoxyphenyl) l [3-(1-methyl-1 H-pyrrol-2-yl) phenylSmethyl] amino]-1, 1, 1- trifluoro-2-propanol product as a colorless oil, > 99% pure by HPLC analysis.

Anal. calcd. for C27H25N2°2F3 0-9 EtOH : C, 68. 10 ; H, 6. 03 ; N, 5. 51.

Found : C, 68. 36 ; H, 5. 94 ; N, 5. 65. HRMS calcd. 467. 1946 [M+H]+, found : 467. 1950. 1 H NMR (C6D6) b 2. 01 (d, 1 H), 2. 97 (s, 3H), 3. 21 (dd, I H), 3. 49 (dd, 1H), 3. 78 (m, 1H), 4. 28 (s, 2H), 6. 3-6. 4 (m, 4H), 6. 45 (dd, 1H), 6. 53 (t, 1 H), 6. 8-7. 1 (m, 1 OH).

EXAMPLE 603

3- [ (3-phenoxyphenyl) [ [3- (2-pyrimidinyl) phenyl] methyl] amino] 1, 1, 1-trifluoro-2-propanol EX-603A) To a toluene (15 mL) solution of 2-chloropyrimidine (1. 00 g, 8. 7 mmol) was added 3-formylphenylboronic acid (1. 42 g, 9. 5 mmol) and DMF (8 mL). To the resulting solution was added K2CO3 (2. 63 g, 19. 0 mmol) and Pd (PPh3) 4 (0. 52 g, 0. 45 mmol). The slurry was heated to reflux under argon for 18 h. The cooled mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried (MgS04) and evaporated to an oil. Purification by flash chromatography on silica gel eluting with 20% ethyl acetate in hexane gave 0. 63 g (39%) of the desired 3- (2- pyrimidinyl) benzaldehyde product as a brown oil which solidified upon standing. MS : m/z = 185. 1 [M+H] .

EX-603B) To a 1, 2-dichloroethane (10 mL) solution of aldehyde (0. 62 g, 3. 4 mmol) from EX-603A was added 3-phenoxyaniline (0. 62 g, 3. 4 mmol), NaB (OAc) 3H (0. 93 g, 4. 4 mmol) and acetic acid (0. 20 mL, 3. 4 mmol). The cloudy solution was stirred at room temperature for 2 h. The reaction mixture was poured into water and extracted with dichloromethane. The organic layer was washed with saturated NaHC03 and brine, dried (MgSO4) and evaporated to yield 1. 19 g (99%) of the desired N- (3-phenoxyphenyl)- [ [3- (2-

pyrimidinyl) phenylSmethyl] amine product as a brown oil which was used without further purification. MS : m/z = 354. 2 [M+H] +.

To a CH#CN (4 mL) solution of amine (1. 19 g, 3. 4 mmol) from EX-603B was added 1, 1, 1-trifluoro-2, 3-epoxypropane (0. 585 mL, 6. 8 mmol) and Yb (OTf) 3 (0. 112 g, 0. 18 mmol). The cloudy solution was stirred in a sealed flask at 40 °C. After 18 h, more 1, 1, l-trifluoro-2, 3-epoxypropane (0. 585 mL, 6. 8 mmol) and Yb (OTf) 3 (0. 112 g, 0. 18 mmol) were added, and the slurry was heated an additional 4 h. The cooled reaction mixture was diluted with diethyl ether and washed with water and brine. The organic layer was dried (MgSO4) and evaporated to an oil. Purification by silica gel flash chromatography eluting with 25% ethyl acetate in hexane gave an oil which was dissolved in EtOH, concentrated and dried in vacuo to give 0. 33 g (21%) of the desired 3-1 (3- phenoxyphenyl) [ [3- (2-pyrimidinyl) phenyl] methyl] amino)-1, 1, 1-trifluoro-2- propanol product as a pale yellow oil, > 99% pure by HPLC analysis. Anal. calcd. for C26H22N302F3 0. 5 EtOH : C, 66. 39 ; H, 5. 16 ; N, 8. 60. Found : C, 66. 26 ; H, 4. 85 ; N, 8. 60. HRMS calcd. 466. 1742 [M+H] +, found : 466. 1724.

1H NMR (C6D6) 8 2. 28 (br s, 1H), 3. 27 (dd. 1H), 3. 50 (dd, 1H), 3. 78 (m, 1H), 4. 26 (m, 2H), 6. 08 (t, 1H), 6. 39 (dd, 1H), 6. 52 (t, 1H), 6. 75 (m, 1H), 6. 9-7. 0 (m, 6H), 7. 18 (t, 1H), 8. 12 (d, 2H), 8. 58 (s, 1H), 8. 66 (d, 1H).

EXAMPLE 604

3- [ (3-phenoxyphenyl) [ [3- (2-furanyl)-4- (4-morpholinyl) phenyl] methyl] amino]-1, 1, 1-trifluoro-2-propanol EX-604A) To a pyridine (15 mL) solution of 3-bromo4fluorobenzaldehyde (1. 0 g, 4. 9 mmol) was added morpholine (0. 5 mL, 5. 7 mmol) and K2CO3 (0. 69 g, 5. 0 mmol), and the slurry was refluxed for 18 h. The solvent was removed, and the residue was partitioned between ethyl acetate and water. The organic layer was separated, dried (MgSO4) and evaporated to a yellow oil.

Purification by flash chromatography on silica gel eluting with 15 % ethyl acetate in hexane gave 0. 77 g (58 %) of the desired 3-bromo-4- (4- morpholinyl) benzaldehyde product as an white solid. 1H NMR (CDC13) 8 3. 18 (m, 4H), 3. 90 (m, 4H), 7. 10 (d, 1H), 7. 78 (d, 1H), 8. 07 (s, 1H), 9. 83 (s, 1H).

EX-604B) To a dioxane (8 mL) solution of the aldehyde from EX-604A (0. 77 g, 2. 8 mmol) was added 2- (tributylstannyl) furan (1. 07 mL, 3. 42 mmol) and Pd (PPh3) 2C12 (0. 12 g, 0. 17 mmol). The mixture was heated to reflux under argon for 18 h. The cooled mixture was poured into a mixture of saturated aq. KF and ethyl acetate and stirred 3 h. The slurry was filtered through celite.

The organic layer was separated, washed with brine, dried (MgSO4) and evaporated to a yellow oil. Purification by silica gel flash chromatography eluting with 20 % ethyl acetate in hexane gave 0. 61 g (84%) of the desired 3- (2-

furanyl)- (-morpholinyl) benzaldehyde product as a yellow oil. MS : m/z = 258. 1 [M+H] +.

To a 1, 2-dichloroethane (6 mL) solution of aldehyde (0. 59 g, 2. 0 mmol) from EX-604B was added N- (3-phenoxyphenyl)-3-amino-l, l, l-trifluoro-2- propanol (0. 50 g, 1. 9 mmol), NaB (OAc) 3H (0. 52 g, 2. 5 mmol) and acetic acid (0. 12 mL, 2. 1 mmol). The cloudy solution was stirred at room temperature for 18 h. The reaction mixture was poured into water and extracted with dichloromethane. The organic layer was washed with saturated NaHCO3 and brine, dried (MgSO4) and evaporated to give an oil. Purification by flash chromatography on silica gel eluting with 15 % ethyl acetate in hexane gave 0. 25 g (25 %) of the desired 3-[(3-phenoxyphenyl)[[3-(2-fluranyl)-4- (4- morpholinyl) phenyl jmethyl] amino]-1, 1, 1-trifluoro-2-propanol product as a white foam, > 99% pure by HPLC analysis. Anal. calcd. for C30H29N204F3 : C, 66. 91 ; H, 5. 43 ; N, 5. 20. Found : C, 66. 54 ; H, 5. 67 ; N, 5. 02. HRMS : calcd. 539. 2187 lM+H], found : 539. 2158. H NMR (C6D6) 8 1. 73 (d, 1H), 2. 55 (m, 4H), 3. 23 (dd, 1H), 3. 50 (dd, 1H), 3. 52 (m, 4H), 3. 75 (m, 1H), 4. 25 (s, 2H), 6. 21 (dd, 1H), 6. 36 (dd, 1H), 6. 34 (dd, 1H), 6. 56 (t, 1H), 6. 69 (d, 1H), 6. 8 (m, 2H), 6. 9-7. 0 (m, 5H), 7. 09 (t, 1H), 7. 22 (d, 1H), 7. 34 (d, 1H).

EXAMPLE 605 3- [ (3-phenoxyphenyl) [ [3- (2-pyrimidinyloxy) phenyl] methyll amino]-1, 1, 1-trifluoro-2-propanol EX-605A) A slurry of 3-hydroxybenzaldehyde (1. 22 g, 10 mmol), 2- chloropyrimidine (1. 14 g, 10 mmol) and K2CO3 (1. 65 g, 12 mmol) in DMSO

(20 mL) was heated to 100 °C for 1 h. The cooled mixture was poured into water and extracted with Et2O. The organic layer was washed with 2. 5 N NaOH, 1 N HCI, saturated NaHCO3 and brine, dried (MgSO4) and evaporated to yield 1. 42 g (71 %) of the desired 3-(2-pyrimidinyl-oxy)benzaldehyde product as a white solid which was used without further purification. 1H NMR (C6D6) 8 7. 12 (t, 1H), 7. 54 (m, 1H), 7. 66 (t, 1H), 7. 78 (m, 1H), 7. 83 (m, 1H), 8. 64 (d, 2H), 10. 05 (s, 1H).

To a 1, 2-dichloroethane (10 mL) solution of aldehyde (0. 56 g, 2. 8 mmol) from EX-605A was added N- (3-phenoxyphenyl)-3-amino-1, 1, 1-trifluoro-2- propanol (0. 83 g, 2. 8 mmol), NaB (OAc) 3H (0. 77 g, 3. 6 mmol) and acetic acid (0. 84 mL, 15 mmol). The cloudy solution was stirred at room temperature for 18 h. The reaction mixture was poured into water and extracted with dichloromethane. The organic layer was washed with saturated NaHCO3 and brine, dried (MgSO4) and evaporated to give an oil. Purification by flash chromatography on silica gel eluting with 2 % methanol in CH2C12 gave an oil which was dissolved in EtOH, stripped and dried in vacuo to give 0. 28 g (21 %) of the desired 3- [ (3-phenoxyphenyl) [ [3- (2-pyrimidinyloxy) phenyl]- methyl]amino]-1,1,1-trifluoro-2-propanol product as a colorless oil, > 99% pure by HPLC analysis. Anal. calcd. for C26H22N3O3F3#0.4 EtOH : C, 64. 39 ; H, 4. 92 ; N, 8. 41. Found : C, 64. 22 ; H, 4. 87 ; N, 8. 53. HRMS calcd. 482. 1692 [M+H] +, found : 482. 1698. 1H NMR (C6D6) 8 3. 12 (d, 1H), 3. 16 (dd, 1H), 3. 49 (d, 1H), 3. 79 (m, 1H), 4. 12 (dd, 1H), 5. 88 (t, 1H), 6. 31 (dd, 1H), 6. 41 (dd, 1H), 6. 51 (t, 1H), 6. 65 (t, 1H), 6. 80 (t, 1H), 6. 85-7. 05 (m, 8H), 7. 82 (d, 2H).

EXAMPLE 606

3- [ (3-phenoxyphenyl) [ ( [1, 1'-biphenyl]-3-ylmethyl) amino]- 1, 1, 1-trifluoro-2-propanol EX-606A) To an ethylene glycol dimethyl ether (10 mL) solution of 3-bromo- benzaldehyde (0. 63 mL, 5. 4 mmol) was added phenylboronic acid (0. 73 g, 6. 0 mmol), 2 M Na2C03 (10 mL) and Pd (PPh3) 4 (0. 35 g, 0. 30 mmol). The slurry was heated to reflux under argon for 18 h. The cooled mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4) and evaporated to an oil. Purification by flash chromatography on silica gel eluting with 15 % ethyl acetate in hexane gave 0. 77 g (98%) of the desired 1 (1, 1'-biphenyl)-3-yl]-carboxaldehyde product as a colorless oil which solidified upon standing. 1H NMR (C6D6) 8 7. 45 (m, 3H), 7. 65 (m, 3H), 7. 70 (dd, 2H), 8. 15 (m, I H), 10. 13 (s, I H).

EX-606B) To a 1, 2-dichloroethane (12 mL) solution of aldehyde (0. 77 g, 4. 2 mmol) from EX-606A was added 3-phenoxyaniline (0. 78 g, 4. 2 mmol), NaB (OAc) 3H (1. 16 g, 5. 5 mmol) and acetic acid (0. 25 mL, 4. 2 mmol). The cloudy solution was stirred at room temperature for 2 h. The reaction mixture was poured into water and extracted with dichloromethane. The organic layer was washed with saturated NaHCO3 and brine, dried (MgSO4) and evaporated to yield 1. 49 g (100%) of the desired N- (3-phenoxyphenyl) ( [1, 1'-biphenyl]-3- methyl) amine product as a colorless oil which was used without further purification. OH NMR (CDC13) 8 4. 35 (s, 2H), 6. 35 (m, 2H), 6. 44 (d, 1H),

6. 97 (d, 2H), 7. 05 (t, 1H), 7. 12 (t, 1H), 7. 3-7. 4 (m, 7H), 7. 49 (d, 1H), 7. 56 (m, 3H). The formation of the desired product was monitored by the disappearance of the aldehyde peak (d ~ 10) and the formation of the benzyl peak (8 4. 35) in the 1H NMR spectrum.

To a CH3CN (4 mL) solution of amine (1. 48 g, 4. 2 mmol) from EX-606B was added 1, 1, 1-trifluoro-2, 3-epoxypropane (0. 475 mL, 5. 5 mmol) and Yb (OTf) 3 (0. 26 g, 0. 42 mmol). The cloudy solution was stirred in a sealed flask at 40 °C for 18 h. The cooled reaction mixture was diluted with diethyl ether and washed with water and brine. The organic layer was dried (MgSO4) and evaporated to an oil. Purification by flash chromatography on silica gel eluting with 10% ethyl acetate in hexane gave an oil which was dissolved in EtOH, stripped and dried in vacuo to give 0. 65 g (34%) of the desired 3- [ (3- phenoxyphenyl)[([1,1'-biphenyl]-3-ylmethyl) amino]-1, 1, 1-trifluoro-2-propanol product as a colorless oil which solidified upon standing, > 99% pure by HPLC analysis. Anal. calcd. for C28H24NO2F3 û. 05 CH2C12 : C, 72. 03 ; H, 5. 19 ; N, 2. 99. Found : C, 71. 67 ; H, 5. 10 ; N, 2. 94. HRMS calcd. 464. 1837 lM+Hl, found : 464. 1834. 1H NMR (C6D6) 8 1. 43 (d, 1H), 3. 17 (dd, 1H), 3. 46 (dd, 1H) 3. 70 (m, 1H), 4. 26 (s, 2H), 6. 32 (dd, 1H), 6. 44 (dd, 1H), 6. 52 (t, 1H), 6. 77 (m, 1H), 6. 85-6. 95 (m, 5H), 7. 1 (m, 3H), 7. 16 (t, 2H), 7. 26 (s, 1H), 7. 27 (d, 1H), 7. 40 (dd, 2H).

EXAMPLE 607

3- [ (3-phenoxyphenyl) [ [3-cyclopentylphenyl] methyl] amino]- 1, 1, 1-trifluoro-2-propanol EX-607A) To a 1, 2-dichloroethane (12 mL) solution of 3- cyclopentylbenzaldehyde (0. 69 g, 4. 0 mmol ; P. L. Ornstein et al., J. Med.

Chem. 1998, 41, 358-378) was added 3-phenoxyaniline (0. 73 g, 4. û mmol), NaB (OAc) 3H (1. 08 g, 5. 1 mmol) and acetic acid (0. 24 mL, 4. 2 mmol). The cloudy solution was stirred at room temperature for 2 h. The reaction mixture was poured into water and extracted with dichloromethane. The organic layer was washed with saturated NaHCO3 and brine, dried (MgSO4) and evaporated to an oil. Purification by flash chromatography on silica gel eluting with 10% ethyl acetate in hexane gave 0. 30 g (22 %) of the desired N- (3-phenoxyphenyl)- [ [3-cyclopentylphenyl] methyl] amine product as a colorless oil. IH NMR (CDCI3) 8 1. 55 (m, 2H), 1. 63 (m, 2H), 1. 78 (m, 2H), 2. 02 (m, 2H), 2. 94 (m, 1H), 4. 10 (m, 1H), 4. 22 (m, 2H), 6. 35 (m, 3H), 7. 0-7. 2 (m, 10H). The formation of the desired product was monitored by the disappearance of the aldehyde peak (o ~ 10) and the formation of the benzyl peak (6 4. 22) in the H NMR spectrum.

To a CH3CN (0. 9 mL) solution of amine (0. 30 g, 0. 87 mmol) from EX-607A was added 1, 1, l-trifluoro-2, 3-epoxypropane (0. 15 mL, 1. 7 mmol) and Yb (OTf) (0. 080 g, 0. 13 mmol). The cloudy solution was stirred in a sealed

flask at 50 °C for 18 h. The cooled reaction mixture was diluted with diethyl ether and washed with water and brine. The organic layer was dried (MgSO4) and evaporated to an oil. Purification by flash chromatography on silica gel eluting with 10% ethyl acetate in hexane gave an oil which was dissolved in EtOH, stripped and dried in vacuo to give 0. 19 g (48 %) of the desired 3- [ (3- phenoxyphenyl) [ [3-cyclopentylphenyl] methyl] amino]-1, 1, 1-trifluoro-2-propanol product as a colorless oil which solidified upon standing, > 99% pure by HPLC analysis. Anal. calcd. for C27H28NO2F3-0. 4 EtOH : C, 70. 45 ; H, 6. 47 ; N, 2. 96. Found : C, 70. 21 ; H, 6. 39 ; N, 2. 94. HRMS calcd. 456. 2150 lM+H] +, found : 456. 2143. 1H NMR (C6D6) 8 1. 43 (m, 4H), 1. 58 (m, 2H), 1. 62 (d, 2H), 1. 85 (m, 2H), 2. 71 (m, 1H), 3. 22 (dd, 1H), 3. 49 (dd, 1H), 3. 73 (m, 1H), 4. 26 (s, 2H), 6. 35 (dd, 1H), 6. 43 (dd, 1H), 6. 55 (t, 1H), 6. 8 (m, 2H), 6. 95-7. 05 (m, 8H).

EXAMPLE 608

3- [ (3-phenoxyphenyl) [ [3- (tetrahydro-2-furanyl) phenyl] methyl] amino]-1, 1, 1-trifluoro-2-propanol EX-608A) Trifluoromethanesulfonic anhydride (2. 0 mL, 11. 9 mmol) was added dropwise over 5 minutes to a slurry of 3-hydroxybenzaldehyde (1. 11 g, 9. 09 mmol) in dichloromethane (40 mL) at-78 °C. To this slurry was added neat N, N-di-isopropyl-ethylamine (2. 4 mL, 13. 8 mmol) dropwise over 5 min, and the resulting yellow solution was allowed to warm to room temperature.

After 30 min at room temperature, the dark solution was diluted with dichloromethane and washed with 2. 5 N NaOH. 1 N HCI, saturated NaHCO3

and brine. The organic layer was dried (MgSO4) and evaporated to give a red oil. Purification by flash chromatography on silica gel eluting with 10 % ethyl acetate in hexane gave 1. 70 g (74%) of the desired triflate ester product as a pale yellow oil. MS : m/z = 254 [M+H) +.

EX-608B) To a mixture of Pd2 (dba) 3 (120 mg, 0. 13 mmol) and P (o-tolyl) 3 (150 mg, 0. 50 mmol) in toluene (15 mL) was added the triflate ester from EX- 608A (1. 70 g, 6. 7 mmol), N, N-di-isopropylethylamine (3. 50 mL, 20. 1 mmol) and 2, 3-dihydrofuran (2. 53 mL, 33. 5 mmol). The solution was heated to 70 °C in a sealed flask under argon for 18 h. The cooled solution was then diluted with ethyl acetate and washed with water, 1 N HCI, saturated NaHCO3 and brine.

The organic layer was dried (MgSO4) and evaporated to give a red oil. The major product was isolated by flash chromatography on silica gel eluting with 10% ethyl acetate in hexane and gave 0. 72 g (62 %) of the desired 3- (dihydro-2- furanyl) benzaldehyde product as a cloudy yellow oil. MS : m/z = 175. 1 [M+H] .

EX-608C) A THF (15 mL) solution of the aldehyde from EX-608B (0. 70 g, 4. 0 mmol) and 2, 6-lutidine (0. 46 mL, 4. 0 mmol) was stirred in a hydrogen atmosphere (50 psi) in the presence of 10% Pd/C (0. 29 g) for 18 h at room temperature. The slurry was filtered through celite, and the solvent was removed. The residue was taken up in ethyl acetate and washed with 1 N HCI and brine. The organic layer was dried (MgSO4) and evaporated to give 0. 50 g (70 %) of the desired 3- (tetrahydro-2-furanyl) phenylmethanol product as a yellow oil. The formation of the desired product was monitored by the disappearance of the aldehyde (o ~ 10) and olefin peaks in the H NMR spectrum.

EX-608D) A slurry of the phenylmethanol product from EX-608C (0. 50 g, 2. 8 mmol) and MnO2 (2. 10 g, 24. 3 mmol) in dichloromethane (15 mL) was refluxed for 3 h. The slurry was filtered through celite, and the filtrate was evaporated to a yellow oil. Purification by flash chromatography on silica gel

eluting with 10% ethyl acetate in hexane gave 0. 19 g (45%) of the desired aldehyde product as a pale yellow oil. GCMS : m/z = 177 gM+H].

EX-608E) To a 1, 2-dichloroethane (4 mL) solution of the aldehyde (0. 19 g, 1. 1 mmol) from EX-608D was added 3-phenoxyaniline (0. 20 g, 1. 1 mmol), NaB (OAc) 3H (0. 30 g, 1. 4 mmol) and acetic acid (0. 065 mL, 1. 1 mmol). The cloudy solution was stirred at room temperature for 3 h. The reaction mixture was poured into water and extracted with dichloromethane. The organic layer was washed with saturated NaHC03 and brine, dried (MgSO4) and evaporated to yield 0. 32 g (84%) of the desired N- (3-phenoxyphenyl)- [ [3- (tetrahydro-2- furanyl) phenyl] methyl] amine product as a yellow oil which was used without further purification. The formation of the desired product was monitored by TLC.

To a CH3CN (1 mL) solution of the amine (0. 32 g, 0. 93 mmol) from EX- 608E was added 1, 1, 1-trifluoro-2, 3-epoxypropane (0. 24 mL, 2. 8 mmol) and Yb (OTf) 3 (0. 115 g, 0. 18 mmol). The cloudy solution was stirred in a sealed flask at 40 °C for 18 h. The cooled reaction mixture was diluted with diethyl ether and washed with water and brine. The organic layer was dried (MgSO4) and evaporated to an oil. Purification by flash chromatography on silica gel eluting with 15% ethyl acetate in hexane gave an oil which was dissolved in EtOH, stripped and dried in vacuo to give 0. 13 g (30%) of the desired 3- [ (3- phenoxyphenyl) [ [3- (tetrahydro-2-furanyl) phenyl] methyl) amino]-1, 1, 1-trifluoro- 2-propanol product as a colorless oil. Anal. calcd. for C26H26NO3F3-0. 5 EtOH : C, 67. 33 ; H, 6. 04 ; N, 2. 94. Found : C, 67. 49 ; H, 6. 08 ; N, 2. 91. HRMS calcd. 458. 1943 [M+H] +, found : 458. 1937. 1H NMR (C6D6) 8 0. 45 (d, 1H), 1. 43 (m, 3H), 1. 79 (m, 1H), 1. 99 (m, 1H), 3. 24 (m, 1H), 3. 43 (m, IH), 3. 76 (m, 2H), 4. 24 (s, 2H), 4. 60 (t, 1H), 6. 35 (m, 1H), 6. 43 (dd, 1H), 6. 54 (dd, 1H), 6. 8 (m, 2H), 6. 9-7. 0 (m, 7H), 7. 15 (d, 1H).

EXAMPLE 609

4- [3- [ ( [3- (1, 1, 2, 2-tetrafluoroethoxy) phenyl]methyl] (3, 3, 3- trifluoro-2-hydroxypropyl) amino] phenoxy] phenol A 1, 2-dichloroethane (4 mL) solution of N- [ (4-methoxyphenoxy) phenyl]-3- [ [3- (1, 1, 2, 2-tetrafluoroethoxy) phenylSmethyl jamino]-1, 1, 1-trifluoro-2-propanol (0. 33g, 0. 62 mmol) and boron tribromide-methyl sulfide complex (2. 5 mL, 1. 0 M in CH2Cl2, 2. 5 mmol) was refluxed for 8 h under argon. The reaction was diluted with Et20 and washed with water, 1 N NaOH and saturated aq. NH4Cl.

The organic layer was dried (MgSO4) and evaporated to give a red oil.

Purification by flash chromatography on silica gel eluting with 30% ethyl acetate in hexane gave an oil which was dissolved in EtOH, stripped and dried in vacuo to give 0. 082 g (25%) of the desired 4-13- [1 [3- (1, 1, 2, 2- tetrafluoroethoxy) phenyllmethyl] (3, 3, 3-trifluoro-2-hydroxypropyl) amino] phenoxy] phenol product as a light red oil. Anal. calcd. for C24H2oNO4F7-0. 35 EtOH-0. 65 H2O : C, 54. 21 ; H, 4. 31 ; N, 2. 56. Found : C, 54. 20 ; H, 4. 30 ; N, 2. 55. HRMS calcd. 520. 1359 [M+H] +, found : 520. 1325. 1H NMR (C6D6) 6 1. 96 (d, 1H), 3. 09 (dd, 1H), 3. 43 (dd, 1H), 3. 74 (m, 1H), 4. 10 (s, 2H), 4. 52 (s, 1H), 5. 09 (tt, 1H), 6. 17 (dd, 1H), 6. 4 (m, 4H), 6. 66 (d, 1H), 6. 8-6. 9 (m, 6H).

EXAMPLE 610

3- (3-phenoxyphenyl)-2- (3- ( 1, 1, 2, 2-tetrafluoroethoxy) phenyl- 5- (trifluoromethyl) oxazolidine A toluene solution (5 mL) of 3- (1, 1, 2, 2-tetrafluoroethoxy) benzaldehyde (0. 45 g, 2. 0 mol) and N- (3-phenoxyphenyl)-3-amino-1, 1, 1-trifluoro-2-propanol (0. 60 g, 2. 0 mmol) was refluxed in the presence of molecular sieves and ZnI2 (-5 mg) for 18 h under N2. The reaction mixture was filtered to remove the sieves, and the filtrate was diluted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4) and evaporated to give 0. 92 g (92%) of the desired 3- (3- phenoxyphenyl)-2-[3-(1,1, 2, 2-tetrafluoro-ethoxy) phenyl]-5- (trifluoromethyl) oxazolidine product as a colorless oil. The formation of the desired product was monitored by the disappearance of the aldehyde peak (# # 10) in the IH NMR spectrum. HRMS calcd. 502. 1253 lM+H], found : 502. 1220.

EXAMPLE 611

4- [bis- [ [3- (trifluoromethoxy) phenyl) methyl] amino]- 1, 1, 1-trifluoro-2-butanol EX-611A) The 2-hydroxy-1, 1, 1-trifluorobutyronitrile (5. 0 g, 36 mmol ; H. C.

Brown et al. J. Org. Chem. 60, 41-46, 1995) was added slowly to a stirred suspension of LiAIH4 (1. 7 g, 43. 7 mmol) in 8 mL of dry diethyl ether at 0-5 °C.

The mixture was stirred at this temperature for 30 min, heated for 45 min, then stirred at room temperature for 2 h. The reaction mixture was quenched with 5. 5 mL of aq. sat. Na2SO4 and stirred for 1 h. The mixture was filtered through a celite pad, and the pad was washed with ether. The filtrate and ether washings were collected and evaporated to give 4. 2 g (82%) of crude 4-amino-2-hydroxy- 1, 1, 1-trifluorobutane product as a brownish solid. HRMS calcd. for C4H8NOF3 : 144. 0636 [M+H] +, found 144. 0622.

The 4-amino-2-hydroxy-1, 1, 1-trifluorobutane (0. 57 g, 4 mmol) from EX- 611 A and 3-(trifluoromethoxy) benzyl bromide (2. 04 g, 8. 0 mmol) were dissolved in 10 mL of anhydrous ethanol. Potassium carbonate (1. 10 g, 8 mmol) was added, and the mixture was heated to reflux for 3 days, at which time HPLC analysis indicated the formation of product, as confirmed by MS.

The reaction mixture was quenched with water and extracted with ether. The ether layer was washed with water and brine, then dried over MgS04, and evaporated to give crude product, which was purified by flash column chromatography on silica gel eluting with 1 : 10 : 0. 01 to 1 : 7 : 0. 01 of ethyl

acetate : hexane : ammonium hydroxide to give 0. 53 (27%) of the desired 4-lbis- [ [3- (tri-fluoromethoxy) phenyllmethyljarnino]-1, 1, 1-trifluoro-2-butanol product as a yellow oil. H NMR (CDC13) b 7. 37 (t, 2H), 7. 23 (d, 2H), 7. 14 (d, 4H), 5. 68 (bs, 1H), 3. 98 (m, 1H), 3. 76 (d, 2H), 3. 45 (d, 2H), 2. 78 (dd, 2H), 1. 90 (m, 1H), 1. 83 (m, 1H). 19F NMR (CDCl3) 8-58. 27 (s, 6F),-80. 54 (d, 3F).

HRMS calcd. for C20H 18NO3F9 : 492. 1221 [M+H] +, found : 492. 1184.

EXAMPLE 612 N,N-dimethyl-3-[[3-phenoxyphenyl) (3, 3, 3-trifluoro- 2-hydroxypropyl) amino] methyl] benzamide EX-612A) Methyl 3-(bromomethyl) benzoate (7. 2 g, 0. 031 mol) was added dropwise to a solution of 3-phenoxyaniline (20. 5 g, 0. 11 mol) in 160 mL of cyclohexane. The reaction mixture was refluxed overnight then cooled to room temperature and diluted with water and methylene chloride. The layers were separated, and the aqueous layer was extracted with methylene chloride. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo to give a dark oil. The crude product was purified by reverse phase HPLC eluting with 20% to 90% acetonitrile in water to afford 6. 2 g (59%) of the desired methyl 3-[[(3-phenoxyphenyl)amino]methyl] benzoate product as a yellow oil. ESMS m/z = 334 [M+H].

EX-612B) To a mixture of methyl 3- [ [ (3-

phenoxyphenyl) amino] methyl] benzoate (6. 2 g, 0. 019 mol) from EX-612A and 1, 1, 1-trifluoro-2, 3-epoxypropane (8. 58 g, 0. 077 mol) in 12 mL of acetonitrile was added ytterbium (III) trifluoromethanesulfonate (1. 2 g, 0. 0019 mol). The resulting mixture was heated at 50 °C in a sealed glass tube for 18 h. The reaction mixture was cooled to room temperature, then diluted with water and methylene chloride. The aqueous layer was extracted with methylene chloride.

The organic layers were combined, dried over MgSO4, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with 1 : 9 ethyl acetate in hexane to afford 8. 0 g (96%) of the desired methyl 3- [ [ (3-phenoxy-phenyl) (3, 3, 3-trifluoro-2-hydroxypropyl) amino] methyl l benzoate product as a yellow oil. Anal. calcd. for C24H22F3NO4-1. 4 H2O C, 61. 25 ; H, 5. 31 ; N, 2. 98. found : C, 61. 52 ; H, 5. 06 ; N, 2. 89. HRMS calcd. : 446. 1579 [M+H] +, found : 446. 1596. 1H NMR (CDC ! g) 8 7. 28 (m, 4H), 7. 14 (t, 1H), 7. 07, (m, 3H), 7. 00 (s, 1H), 6. 94 (d, 2H), 6. 46 (dd, 1H), 6. 38 (dd, 1H), 6. 35 (t, 1H), 5. 84 (t, 1H), 4. 60 (t, 2H), 4. 36 (m, 1H), 3. 82 (d, 1H), 3. 48 (m, 1H), 2. 51 (s, 1H). 19F NMR (CDC13) b-79. 0 (d, 3F).

To a solution of N, N-dimethylamine hydrochloride (525 mg, 0. 0064 mol) in 3. 0 mL of toluene at-40 °C was added dropwise a 2. 0 M solution of trimethylaluminum in toluene (3. 2 mL, 0. 0064 mol) over 15 min. The reaction mixture was warmed to room temperature and stirred for 2 h. To a solution of methyl 3-[[(3-phenoxyphenyl) (3, 3, 3-trifluoro-2-hydroxypropyl) aminol methyl] benzoate (209 mg, 0. 00047 mol) from EX-612B in 2. 5 mL of toluene at-10 °C was slowly added the (N, N-dimethylamino)-chloromethylaluminum reagent (850 µL, 0. 00085 mol). The reaction mixture was warmed to room temperature then heated at 40 °C overnight. The reaction mixture was cooled to room temperature, then diluted with ethyl acetate and quenched with 10% aqueous potassium hydrogen phosphate. The organic layer was dried over MgSO4 and concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with 2 : 3 ethyl acetate in hexane to afford 195 mg (91%) of the desired N,N-dimethyl-3-[[3-(phenoxyphenyl) (3, 3, 3- trifluoro-2-hydroxypropyl) amino] methyl]-benzamide product as a pale yellow

solid. Anal. calcd. for C25H25F3N203-0. 5 H2O : C, 64. 23 ; H, 5. 61 ; N, 5. 99.

Found : C, 64. 49 ; H, 5. 77 ; N, 5. 85. HRMS calcd. 459. 1896 lM+Hl * found : 458. 1887. 1H NMR (C6D6) õ 7. 01-6. 95 (m, 3H), 6. 92-6. 87 (m, 5H), 6. 79 (t, 1H), 6. 46 (s, 1H), 6. 37 (t, 2H), 4. 91 (bs, 1H), 4. 26 (s, 2H), 4. 10 (bq, 1H), 3. 84 (dd, 1H), 3. 38 (dd, 1H), 2. 53 (bs, 3H), 2. 14 (bs, 3H). 19F NMR (C6D6) 8-78. 69 (d, 3F).

Additional examples of N,N-dialkyl- and N,N-cycloalkyl-3-[[(3- phenoxy-phenyl)- (3, 3, 3-trifluoro-2-hydroxypropyl) amino] methyl] benzamides can be prepared by one skilled in the art using similar methods, as shown in Example Table 36.

Example Table 36. N, N-dialkyl-and N, N-cycloalkyl-3-[[(3-phenoxyphenyl)- (3, 3, 3-trifluoro-2-hydroxypropyl) amino] methyl] benzamides. Ex. Calculated Observed Mass RSUBI RSUB2 No. Mass [M+H]+ [M+H]+ 613 methyl ethyl 473. 2052 473. 2055 614 methyl propyl 487.2209 487. 2193 615 methyl butyl 501. 2365 501. 2357 616 -(CH2CH2CH2CH20- 485.2052 485.2057 EXAMPLE 617

a, α-dimethyl-3-[[(3-phenoxyphenyl) (3, 3, 3-trifluoro- 2-hydroxypropyl) amino] methyl] benzenemethanol To a solution of methyl 3- [ ( (3-phenoxyphenyl) (3, 3. 3-trifluoro-2-hydroxy- propyl) amino] methyl] benzoate (218 mg, 0. 00049 mol) in 0. 7 mL of tetrahydrofuran at 0 °C was slowly added a 3. 0 M solution of methylmagnesium chloride in THF (650 FL, 0. 0020 mol). The reaction mixture was warmed to room temperature, stirred for 2 h, then diluted with diethyl ether and quenched with saturated aqueous ammonium chloride. The aqueous layer was extracted with dichloromethane, and the combined organic layers were dried over MgSO4 and concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with 1 : 4 ethyl acetate : hexane to afford 174 mg (80%) of the desired α,α-dimethyl-3-[[(3-phenoxy-phenyl) (3, 3, 3-trifluoro- 2-hydroxypropyl) aminolmethyllbenzenemethanol product as a slightly yellow oil. Anal. calcd. for C25H26F3NO3'0. 5 H2O : C, 66. 07 ; H, 5. 99 ; N, 3. 08. found : C, 66. 12 ; H, 6. 34 ; N, 2. 92. HRMS calcd. 466. 1943 [M+H] +, found : 446. 1938. 1HNMR (CDC13) o7. 34 (s, 1 H), 7. 32-7. 21 (m, 4H), 7. 13 (t, 1H), 7. 09-7. 01 (m, 2H), 6. 94 (d, 2H), 6. 50 (d, 1H), 6. 41 (s, 1H), 6. 37 (d, 1H), 4. 61 (s, 2H), 4. 27 (bt, 1H), 3. 81 (appd, 1H), 3. 53 (dd, 1H), 3. 33 (bs, 1H), 1. 96 (bs, 1H), 1. 51 (s, 6H). 19F NMR (CDCl3) 8-78. 88 (d, 3F).

EXAMPLE 618

3-[[(3-phenoxyphenyl) (3, 3, 3-trifluoro-2-hydroxypropyl) amino] methyllbenzenemethanol To a solution of methyl 3- [ [ (3-phenoxyphenyl) (3, 3, 3-trifluoro-2-hydroxy- propyl) amino] methylSbenzoate (197 mg, 0. 00044 mol) in 2. 0 mL of dichloromethane at-40 °C was slowly added a 1. 0 M solution of lithium aluminum hydride in THF (1. 1 mL, 0. 0011 mol). The reaction mixture was stirred at-40 °C for 1 h, then diluted with ethyl acetate and quenched with water.

The organic layer was dried over MgSO4 and concentrated in vacuo. The crude material was determined to contain a significant amount of unreacted starting material by HPLC at this stage. The crude material was resubjected to the reaction conditions using 2 mL of anhydrous tetrahydrofuran and 1. 0 M lithium aluminum hydride (1. 3 mL, 0. 0013 mol) at-40 °C for I h, then diluted with ethyl acetate and quenched with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried over MgSO4 and concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with 2 : 3 ethyl acetate : hexane to afford 99 mg (54%) of the desired 3- [ [ (3-phenoxyphenyl)- (3, 3, 3-trifluoro-2- hydroxypropyl) amino] methyl] benzenemethanol product as a white solid. Anal. calcd. for C23H22F3NO3 : C, 66. 18 ; H, 5. 31 ; N, 3. 36. Found : C, 65. 98 ; H, 5. 39 ; N, 3. 22. HRMS calcd. 418. 1630 lM+H] +, found : 418. 1636. 1H NMR (C6D6) 6 7. 08-6. 92 (m, 8H), 6. 89-6. 80 (m, 2H), 6. 56 (s, 1H), 6. 46 (d, 1H),

6. 38 (d, 1H). 4. 26 (s, 2H), 4. 21 (d, 2H), 3. 77 (appq, 1H), 3. 52 (d, 1H), 1. 92 (bs, 1H), 0. 96 (bs, 1H). 19F NMR (C6D6) 8-78. 91 (d, 3F).

EXAMPLE 619

a, a-bis (trifluoromethyl)-3-[[(3-phenoxyphenyl) (3, 3, 3-trifluoro- 2-hydroxypropyl) amino] methyl] benzenemethanol To a solution of methyl 3- [ [ (3-phenoxyphenyl) (3, 3, 3-trifluoro-2- hydroxypropyl)-amino] methyl] benzoate (331 mg, 0. 00074 mol) and trimethyl (trifluoromethyl) silane (423 mg, 0. 0030 mol) in 3. 0 mL of toluene at room temperature was added a 1. 0 M solution of tetrabutylammonium fluoride in THF (150 FL, 0. 00015 mol) which had been dried over molecular sieves. The reaction mixture was heated at 40 °C for 18 h. HPLC analysis indicated incomplete reaction therefore additional trimethyl (trifluoro-methyl) silane (440 uL, 0. 0030 mol) and tetrabutylammonium fluoride (150 L, 0. 00015 mol) were added, and the reaction mixture was heated to 50 °C in a sealed glass vial. After 2 h, HPLC analysis indicated no ester starting material remained. The reaction mixture was quenched with water and extracted with dichloromethane. The organic layer was dried over MgSO4 and concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with 1 : 9 ethyl acetate : hexane to afford 26 mg (6%) of the desired a, a- bis (trifluoromethyl)-3- [ [ (3-phenoxyphenyl) (3, 3, 3-trifluoro-2-hydroxypropyl) amino] methyl] benzenemethanol product as a yellow-brown oil. HRMS calcd. forC25H20FgN03 : 554. 1378 [M+H] +, found : 554. 1385. 1H NMR (CDC13)

57. 69 (dd. 1H), 7. 57 (apps, 1H), 7. 52 (dd, 1H), 7. 37 (t, 1H), 7. 29-7. 23 (m, 2H), 7. 14 (t. 1H), 7. 05 (t, 1H), 6. 92 (d, 2H), 6. 47 (d, 1H), 6. 38 (d, 1H). 6. 37 (s, 1H), 4. 66 (s, 2H), 4. 29 (m, 1H), 3. 82 (d, 1H), 3. 54 (dd, 1H). F NMR (CDC13) o-75. 81 (dq, 6F),-79. 18 (d, 3F).

EXAMPLE 620

1-[3-[[(3-phenoxyphenyl) (3, 3, 3-trifluoro-2-hvdroxypropyl)- amino] methyl] phenyl]-1-propanone EX-620A) To a slurry of methyl 3- [ [ (3-phenoxyphenyl) (3, 3, 3-trifluoro-2- hydroxypropyl) amino] methyl] benzoate (1. 03 g, 0. 0023 mol) and N, O-dimethyl- hydroxylamine hydrochloride (386 mg, 0. 0040 mol) in 4. 6 mL of tetrahydrofuran at-15 °C was added a 2. 0 M solution of isopropylmagnesium chloride in THF (4. 6 mL, 0. 0092 mol) over 15 min. The reaction was stirred for 1 h at-15 °C, then quenched with 20% aqueous ammonium chloride and extracted with ethyl acetate. The organic layers were dried over Na2SO4 and concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with 1 : 1 ethyl acetate : hexane to afford 0. 72 g (66%) of the desired N-methoxy-N-methyl-3- [ [ (3-phenoxyphenyl)- (3, 3, 3- trifluoro-2-hydroxypropyl) amino]methyl]benzamide product as an off-white solid. HRMS calcd. for C25H25N2O4F3: 475. 1845 [M+H] +, found : 475. 1840.

To a solution of N-methoxy-N-methylbenzamide (208 mg, 0. 00044 mol) from EX-620A in 2. 2 mL of tetrahydrofuran at-15 °C was added a 1. 0 M solution of ethyl-magnesium bromide in THF (950 FL, 0. 0095 mol). The reaction mixture was slowly warmed to room temperature then left stirring overnight.

HPLC analysis indicated unreacted starting material was still present so additional ethylmagnesium bromide (440 FL, 0. 0044 mol) was added. After 3 h at room temperature, the reaction mixture was diluted with diethyl ether and quenched with 1 N HCI. The aqueous layer was extracted with diethyl ether and the combined organic layers were dried over MgSO4 and concentrated in vacuo.

The crude product was purified by column chromatography on silica gel eluting with 1 : 4 ethyl acetate in hexane to afford 121 mg (62%) of the desired 1-[3-[[(3- phenoxyphenyl) (3, 3, 3-trifluoro-2-hydroxypropyl)-aminojmethyljphenyl]-1- propanone product as a pale yellow oil. HRMS calcd. for C25H24F3NO3 : 444. 1787 [M+H], found : 444. 1786. 1H NMR (CDC13) 8 7. 83 (d, 1H), 7. 78 (s, 1H), 7. 38 (appq, 2H), 7. 27 (appq, 2H), 7. 15 (t, 1H) 7. 06 (t, IH). 6. 94 (d, 2H), 6. 48 (d, 1H), 6. 39 (d, 1H), 6. 37 (s, 1H), 4. 68 (s, 2H), 4. 35 (m, 1H), 3. 88 (dd, 1H), 3. 56 (dd, 1H), 2. 95 (q, 2H), 1. 20 (t, 3H). 19F NMR (CDC13) 8-79. 17 (d, 3F).

Additional examples of 1- [3- [ [ (3-phenoxyphenyl) (3, 3, 3-trifluoro-2-hydroxy- propyl) amino] methyl]-phenyl]-1-alkanones can be prepared by one skilled in the art using similar methods, as shown in Example Table 37. Example Table 37. 1-[3-[[(3-phenoxyphenyl) (3, 3, 3-trifluoro-2-hydroxy- propyl) amino] methyl]-phenyl]-1-al kanones.

Ex. Calculated Mass Observed Mass RSUB No. [M+H]+ [M+H]+ 621 isobutyl 472. 2130 472. 2100 EXAMPLE 622

3- [ [4- (phenylethynyl)- (3- (trifluoromethyl) phenyl] [ [3- (trifluoro- methyl) phenyl] methyl] amino]-1, 1, 1-trifluoro-2-propanol The 3- [ (3- (trifluoromethyl)-4-bromophenyl) [ [3- (l, 1, 1-trifluoromethyl) phenyll methyl]-amino]-l, l, 1-trifluoro-2-propanol (0. 33 g, 0. 648 mmol) and tributylstannylphenyl-acetylene (0. 278 g, 0. 712 mmol) were added to degassed 1, 2-dichloroethane. The resulting mixture was stirred at room temperature for 10

min, then Pd (PPh3) 2C12 (0. 032 g. 0. 045 mmol) was added. The mixture was stirred 18 h at room temperature. More tributyl-stannylphenylacetylene (0. 278 g.

0. 712 mmol) and Pd (PPh3) 2Cl2 (0. 032 g, 0. 045 mmol) were added. The solution was refluxed for 72 h. The reaction mixture was diluted with diethyl ether and stirred in 10% aq. KF for 18 h. The organic layer was collected, dried over MgSO4 and concentrated. The crude product was purified by flash column chromatography on silica gel eluting with 1 : 4 ethyl acetate in hexane to give 0. 102 g (30%) of the desired 3-[[4-(phenylethynyl)-(3-(trifluoromethyl)phenyl]- [[3-(trifluoromethyl)phenyl]methyl]amino]-1, 1, 1-trifluoro-2-propanol product as a pure yellow oil. Anal calcd. For C26H I 8NOF9 : C, 58. 76 ; H, 3. 41 ; N, 2. 64.

Found : C. 58. 72 ; H, 3. 67 ; N, 2. 47. HRMS calcd. 532. 1322 [M+H] +, found : 532. 1304. 1H NMR (CDC13) 8 7. 52 (m, 4H), 7. 38 (dd, 2H), 7. 32 (dd, 2H), 7. 24 (dd, IH), 7. 00 (s, 1H), 6. 78 (dd, 1H), 4. 80 (s, 2H), 4. 36 (m, 1H), 3. 92 (d, 1H), 3. 65 (m, 1H), 2. 60 (d, 1H). F NMR (CDC13) 8-63. 5 (s, 6F),- 79. 38 (d, 3F).

Additional examples of 3- [ [4- (heteroaryl)- (3- (trifluoromethyl) phenyl] [ [3- (tri-fluoromethyl) phenyllmethyljamino-trifluoro-2-propanols can be prepared by one skilled in the art using similar methods, as shown in Example Table 38. Example Table 38. 3-[[4-(heteroaryl)-(3-(trifluoromethyl)phenyl]-[[3- <BR> (trifluoromethyl) phenyl Imethyl lamino]-1, 1, 1-trifluoro-2-propanols.

Ex. Calculated Mass Observed Mass PSUB No. [M+Hl IM+Hl 623 2-thienyl 514. 0887 514. 0912 624 2-furanyl 498.1037 498.1116 EXAMPLE 625

3- [4-bromo-3-(trifluoromethyl) phenyl [ [3- (trifluoromethyl)- phenyl] methyl] amino]-l, 1, 1-trifluoro-2-propanol EX-625A) The a, a, a-trifluoro-m-tolualdehyde (3. 63 g, 0. 021 mol) was added neat to 4-bromo-3-trifluoromethylaniline (5. 0 g, 0. 021 mol).

Dichloroethane (50 mL) was added followed by sodium triacetoxyborohydride (4. 85 g, 0. 023 mol) and acetic acid (1. 42 g, 0. 024 mol). The resulting mixture was stirred at room temperature for 18 h, then diluted with methylene chloride, quenched with sodium bicarbonate and extracted with methylene chloride. The

organic layers were combined and dried over MgSO4 and concentrated to give 6. 97 g of the desired 3- [4-bromo-3- (trifluoromethyl)-phenyl [ [3- (trifluoromethyl) phenyl]methyl]amine product as a yellow oil, which was carried forward without purification. ESMS m/z = 397 [M+H] +.

The amine product (6. 97 g, 0. 018 mol) from EX-625A was mixed with 1, 1, 1- trifluoro-2, 3-epoxypropane (3. 92 g, 0. 035 mol) in a pressurized vial. A suspension of ytterbium triflate (1. 08 g, 0. 002 mol) in 2. 0 mL of acetonitrile was added. The resulting mixture was stirred at room temperature for 18 h, then quenched with water and extracted with ethyl acetate. The crude product was purified by flash column chromatography on silica gel eluting with 1 : 4 ethyl acetate in hexane to give 1. 04 g (11%) of the desired 3- [4-bromo-3- (trifluoromethyl)phenyl[[3-(trifluoromethyl)-phenyl]methyl]a mino]-1, 1, 1- trifluoro-2-propanol product as a pure yellow oil. Anal calcd. for C18Hl3NOFgBr : C, 42. 38 ; H, 2. 57 ; N, 2. 75. Found : C, 42. 16; H, 2. 71 ; N, 2. 71. HRMS calcd. 510. 0115 [M+H] +, found : 510. 0139. 1H NMR (C6D6) 8 7. 40 (d, 2H), 7. 20 (d, 1H), 7. 10 (m, 2H), 6. 98 (d, 1H), 6. 18 (dd, 1H), 4. 00 (s, 2H), 3. 63 (m, 1H), 3. 40 (d, 1H), 3. 02 (m, 1H), 1. 80 (d, lH). F NMR (C6D6) 6-62. 35 (s, 3F),-65. 00 (s, 3F),-78. 58 (d, 3F).

EXAMPLE 626

3- [ (1-methyl-3- [3- (trifluoromethoxy) phenyl] propyl] (3- phenoxyphenyl) aminol-1, 1, 1-trifluoro-2-propanol EX-626A) Tetrabutylammonium iodide (0. 4 g, 0. 05 mol) was added to a well- stirred biphasic mixture of 12 mL of 50% NaOH and 20 mL of methylene chloride under a nitrogen atmosphere. A solution of 3- trifluoromethoxybenzaldehyde (4. 0 g, 0. 021 mol) and diethyl (2- oxopropyl) phosphonate (4. 08 g, 0. 021 mol) in 4. 0 mL of methylene chloride was added dropwise to the stirred solution. The resulting mixture was stirred at room temperature for 15 min, then quenched with water and extracted with hexane. The hexane layer was dried over MgSO4. The crude product was purified by flash column chromatography on silica gel eluting with 1 : 10 ethyl acetate in hexane to give 2. 6 g (54%) of the desired 4- [3- (trifluoromethoxy) phenyl]-3-buten-2-one product as a yellow oil. IH NMR (CDC13) b 7. 43 (m, 4H), 7. 20 (d, 1H), 6. 65 (d, 2H), 2. 29 (s, 3H). 19F NMR (CDC13) 8-62. 05 (s, 3F).

EX-626B) The product (1. 0 g, 0. 0004 mol) from EX-626A was dissolved in 25 mL of ethanol and the reaction vessel was charged with nitrogen. Palladium (10% on carbon) (0. 30 g, 30%) was added to the solution. The mixture was hydrogenated for 3 h at room temperature. The palladium was filtered off through a celite pad. The filtrate was concentrated to give 0. 79 g (85%) of the desired 4- [3- (trifluoromethoxy) phenyl]- butan-2-one as a yellow oil. ESMS m/z = 232 lM+H].

EX-626C) In a flask equipped with a stir bar and molecular sieves, a solution of 3-phenoxyaniline (1. 1 g, 0. 0059 mol) in 15 mL of cyclohexane was prepared under nitrogen. A solution of the ketone (1. 3 g, 0. 006 mol) product from EX- 626B dissolved in 5 mL of cyclohexane was added. The mixture was refluxed for 18 h, filtered and concentrated to give the desired imine product as a dark yellow oil. ESMS m/z = 400 lM+H].

EX-626D) The imine product (1. 3 g, 0. 003 mol) from EX-626C was stirred with 5 mL of methanol at 0 °C. Sodium borohydride (0. 23 g, 0. 005 mol) was added to the mixture, and the mixture was stirred at room temperature for 18 h.

The mixture was acidified with 4 mL of 3% HCI and extracted with diethyl ether.

The ether layers were combined, dried over MgSO4 and concentrated to give 1. 07 g (81%) of the desired 3-fl-methyl-3- [3- (trifluoromethoxy) phenyl] propyl] (3-phenoxyphenyl) amine product as an orange oil. ESMS m/z = 402 IM+H] The 3- [1-methyl-3- [3- (trifluoromethoxy) phenyl] propyl] (3-phenoxyphenyl) amine (1. 0 g, 0. 002 mol) product from EX-626D and 1, 1, 1-trifluoro-2, 3- epoxypropane (0. 56 g, 0. 005 mol) were heated at 90 °C for 18 h. Excess epoxide was evaporated. The crude product was purified by flash column chromatography on silica gel eluting with 1 : 13 ethyl acetate in hexane to give 0. 16 g (13%) of the desired 3-[1l-methyl-3-l3-(trifluoro-methoxy) phenyll propyl] (3-phenoxyphenyl) amino]-1, 1, 1-trifluoro-2-propanol product as a yellow oil. Anal calcd. for C26H25NO3F6 : C, 60. 82 ; H, 4. 91 ; N, 2. 72.

Found : C, 60. 63 ; H, 4. 89 ; N, 2. 70. HRMS calcd. 514. 1816 [M+H] +, found : 514. 1789. 1H NMR (C6D6) 8 7. 28 (m, 4H), 7. 14 (t, 1H), 7. 07, (m, 3H), 7. 00 (s, 1H), 6. 94 (d, 2H), 6. 46 (dd, 1H), 6. 38 (dd, 1H), 6. 35 (t, H), 4. 18 (m, 1H), 3. 78 (m, 1H), 3. 52 (dd, 1H), 3. 28 (m, 1H), 2. 76 (s, 1H), 2. 53 (m, 2H), 1. 92 (m, 1H), 1. 63 (m, 1H), 1. 24 (m, 3H). 19F NMR (CDC13) 8-56. 84 (s, 3F),-79. 0 (s, 3F).

EXAMPLE 627

3- [ [ (3-phenoxyphenyl) (3, 3, 3-trifluoro-2-hydroxypropyl) amino] methyl] methoxymethylbenzene EX-627A) A suspension of N-bromosuccinimide (17. 6 g, 0. 099 mol) in carbon tetra-chloride was added to a stirring solution of m-xylene in carbon tetrachloride.

Then 2, 2-azobisisobutyronitrile catalyst (0. 71 g, 0. 004 mol) was added. The resulting mixture was refluxed for 2 h, then quenched with 50 mL of water. The organic layer was collected, washed with water followed by brine, dried over MgSO4 and concentrated to give 2. 0 g (16%) of the desired crude 1, 3- dibromoxylene product. ESMS m/z = 264 [M+H] +.

EX-627B) The 1, 3-dibromoxylene (2. 0 g, 0. 0076 mol) from EX-627A and sodium methoxide (2. 45 g, 0. 045 mol) were mixed in 25 mL of MeOH. The resulting mixture was stirred at room temperature for 18 h, concentrated, dissolved in methylene chloride and washed with water. The organic layer was further washed with brine and dried over MgSO4 and concentrated to give 0. 912 g (72%) of the desired 1, 3-di- (methoxy-methyl) benzene product as a yellow oil.

ESMS m/z = 166 [M+H] +.

EX-627C) The diether product (0. 90 g, 0. 0054 mol) from EX-627B was stirred in a mixture of 10 : 1 methylene chloride : water. To this was added 2, 3- dichloro-5, 6-dicyano-benzoquinone (1. 84 g, 0. 0081 mol). The resulting biphasic mixture was stirred at room temperature for 72 h. The mixture was then washed with saturated sodium bicarbonate followed by brine, dried over MgSO4

and concentrated. The crude product was purified by flash column chromatography on silica eluting with 1 : 4 ethyl acetate : hexane to give 0. 430 g (53%) of the desired 3- (methoxymethyl) benzaldehyde product as a pink oil. H NMR (CDCI3) 610. 00 (s, 1H), 7. 89 (s, 1H), 7. 83 (d, 1H), 7. 63 (d, 1H), 7. 51 (t, 1H), 4. 58 (s, 2H), 3. 40 (s, 3H).

EX-627D) The 3- (methoxymethyl) benzaldehyde (0. 430 g, 2. 87 mmol) from EX 627C was added to a stirring solution of 3-phenoxyaniline (0. 530 g, 2. 87 mmol) in 5 mL of dichloromethane. Then sodium triacetoxyborohydride (0. 670 g, 3. 16 mmol) was added followed by acetic acid (0. 196 g, 3. 27 mmol). The resulting mixture was stirred at room temperature 18 h, then diluted in methylene chloride and quenched with sodium bicarbonate. The organic layer was washed with brine, dried over MgSO4 and concentrated to give 0. 870 g (95%) of the desired N-3-(phenoxyphenyl)-[[3-(methoxy-methyl)phenyl]methyl]amine product as a pink oil. ESMS m/z = 320 [M+H] +.

The N-3-(phenoxyphenyl)-[l3-(methoxymethyl) phenyllmethyllamine product (0. 87 g, 0. 003 mol) from EX-627D was mixed with 1, 1, 1-trifluoro-2, 3- epoxypropane (0. 61 g, 0. 005 mol) in a pressurized vial. A suspension of ytterbium triflate (0. 16 g, 0. 272 mmol) in 0. 5 mL of acetonitrile was added. The resulting mixture was stirred at room temperature for 18 h, then quenched with water and extracted with ethyl acetate. The crude product was purified by flash column chromatography on silica gel eluting with 1 : 4 ethyl acetate : hexane to give 0. 35 g (30%) of the desired 3-[[(3-phenoxyphenyl)-(3, 3, 3-trifluoro-2- hydroxypropyl) aminojmethyljmethoxymethylbenzene product as a pure yellow oil. Anal calcd. for C24H24NO3F3-0. 5 H20 : C, 65. 18 ; H, 5. 61 ; N, 3. 17.

Found : C, 65. 19 ; H, 5. 36 ; N, 3. 13. HRMS calcd. 432. 1786 lM+H] +, found : 432. 1803. 1 H NMR (C6D6) 8 6. 82 (m, 7H), 6. 60 (dd, 1H), 6. 42 (dd, 1H), 6. 38 (s, 1H), 6. 18 (dd, 1H), 4. 00 (s, 2H), 3. 63 (m, 1H), 3. 40 (d, 1H), 3. 02 (m, 1H), 1. 80 (d, 1 H). 19F NMR (C6D6) b-78. 55 (s, 3F).

EXAMPLE 628

3- [ (3-phenoxyphenyl) [ [3- (1, 1, 2, 2-tetrafluoroethoxy) phenyl] methyl] amino]-1, 1, 1-trifluoro-2-propanol EX-628A) To a solution of 3- (1, 1, 2, 2-tetrafluoroethoxy) toluene (50 g, 0. 24 mol) and N-bromosuccinimide (42. 75 g, 0. 24 mol) in 100 mL of carbon tetrachloride under nitrogen was added 2, 2'-azobisisobutyronitrile (0. 71 g, 0. 004 mol). The resultant mixture was refluxed for 2 h then cooled to room temperature and quenched with 300 mL of water. The organic layer was collected, washed with water and brine, dried over MgSO4, and concentrated in vacuo to give 66. 0 g (96%) of the desired crude 3- (1, 1, 2, 2- tetrafluoroethoxy) bromomethylbenzene product as a yellow oil. H NMR indicates that this oil is a mixture of products : 7% dibrominated, 67% monobrominated, and 20% starting material. The crude product was used without further purification. ESMS m/z = 287 lM+H].

EX-628B) The crude product (56 g, 0. 14 mol) from EX-628A in 200 mL of cyclohexane was added dropwise under nitrogen to a solution of 3- phenoxyaniline (89 g, 0. 480 mol) in 500 mL of cyclohexane. The reaction mixture was refluxed overnight, then cooled to room temperature and diluted with water and diethyl ether. The layers were separated, and the aqueous layer was extracted with diethyl ether. The combined organic layers were dried over MgSO4 and concentrated in vacuo to give a dark oil. The crude product was purified by column chromatography on silica gel eluting with 1 : 4 ethyl acetate in hexane to afford 44. 96 g (83%) of the desired N-3- (phenoxyphenyl)- [ [3-

(1, 1. 2, 2-tetrafl uoroethoxy) phenyl lmethyl lamine product as a yellow oil. ESMS m/z = 392 [M+H] .

To a mixture of the amine product (15. 0 g, 0. 038 mol) from EX-628B and 1, 1, 1-tri-fluoro-2, 3-epoxypropane (8. 58 g, 0. 077 mol) was added a suspension of ytterbium (III) trifluoromethanesulfonate (2. 37 g, 0. 0031 mol) in 15 mL of acetonitrile. The resulting mixture was heated at 50 °C in a sealed glass vial for 1. 5 h. The reaction mixture was cooled to room temperature then diluted with water and ethyl acetate and extracted. The organic layers were combined, dried over MgSO4, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with 1 : 4 ethyl acetate in hexane to afford 12. 03 g (62%) of the desired 3-[(3-phenoxyphenyl)-[[3-(1,1, 2, 2- tetrafluoroethoxy) phenyl] methyl] amino]-l, l, l-trifluoro-2-propanol product as a yellow oil. Anal. calcd. for C24H20F7NO3 : C, 57. 26 ; H, 4. 00 ; N, 2. 78.

Found : C, 56. 96 ; H, 4. 35 ; N, 2. 69. HRMS calcd. 504. 1410 [M+Hl found : 504. 1431. 1H NMR (CDCl3) 8 7. 28 (m, 4H), 7. 14 (t, 1H), 7. 07, (m, 3H), 7. 00 (s, 1H), 6. 94 (d, 2H), 6. 46 (dd, 1H), 6. 38 (dd, IH), 6. 35 (t, 1H), 5. 84 (t, 1H), 4. 60 (t, 2H), 4. 36 (m, 1H), 3. 82 (d, 1H), 3. 48 (m, 1H), 2. 51 (s, 1H).

9F NMR (CDC13) 6-79. 0 (s, 3F),-88. 21 (d, 2F),-137. 05 (dd, 2F).

EXAMPLE 629

3- [ [3- (2-bromo-5-fluorophenoxy) phenyl] [ [3- (1, 1, 2, 2-tetrafluoro- ethoxy) phenyl methyl] amino]-1, 1, 1-trifluoro-2-propanol EX-629A) 3-Aminophenol (5 g, 46 mmol), 1-bromo-2, 4-difluorobenzene (10 g, 50 mmol) and Cs2CO3 (16 g, 50 mmol) were mixed in 25 mL of dimethyiformamide. Solid (CuOTf) 2C6H6 (100 mg) was added, and the mixture was stirred under nitrogen at 85 °C for 22 h, at which time HPLC analysis indicated that the reaction had gone to completion and formed two products. The DMF was removed under reduced pressure. The residue was diluted with ether and filtered through a celite pad. The pad was washed with ether and a small amount of water. The mixture was extracted with ether several times. The combined ether layers were washed with water and brine, then dried over MgSO4. The dried organic layer was evaporated to give 10. 2 g (80%) of the desired product, which consisted of a 11 : 1 ratio of 3- (2-bromo-5- fluorophenoxy)-aniline and 3- (4-bromo-3-fluorophenoxy) aniline. The crude product was purified by flash column chromatography on silica gel eluting with 1 : 7 : 0. 01 of ethyl acetate : hexane : ammonium hydroxide to give 8. 8 g (68%) of the desired product as a yellow oil, which was a 25 : 1 ratio of 3- (2-bromo-5- fluorophenoxy) aniline and 3- (4-bromo-3-fluorophenoxy) aniline. HRMS calcd. for C 12H9NOFBr : 281. 9930 [M+H] +, found : 281. 9950.

EX-629B) The crude 3- (2-bromo-5-fluorophenoxy) aniline (1. 39 g, 4. 95 mmol) product from EX-629A and 3- (1, 1, 2, 2-tetrafluoroethoxy) benzaldehyde (1. 0 g, 4. 5 mmol) were dissolved in 15 mL of dichloroethane and acetic acid

(0. 30 mL, 5. 4 mmol), then solid NaBH (OAc) 3 (1. 26 g, 5. 9 mmol) was added.

The mixture was stirred at room temperature for 1 h, then quenched with water and extracted with ether. The ether layer was washed with water and brine, then dried over MgSO4, and evaporated to give 2. 1 g (97%) of crude product, which was purified by flash column chromatography on silica gel eluting with 1 : 7 : 0. 01 of ethyl acetate : hexane : ammonium hydroxide to give 2. 0 g (91%) of the desired 3- [3- (2-bromo-5-fluorophenoxy) phenyl] [ [3- (1, 1, 2, 2-tetrafluoro-ethoxy) phenyl 1 methyl] amine product, as a light yellow oil, > 90% pure by HPLC analysis.

HRMS calcd. for C21H15NO2BrF5 : 488. 0285 [M+H] +, found : 488. 0269.

The 3- [3- (2-bromo-5-fluorophenoxy) phenyl] [f3- (l, 1. 2. 2-tetrafluoroethoxy) phenyl]-methyl] amine (0. 97 g, 2. 0 mmol) product from EX-629B and 1, 1, 1- trifluoro-2, 3-epoxypropane (0. 45 g, 4. 0 mmol) were dissolved in 1. 0 mL of acetonitrile. Ytterbium (III) trifluoromethanesulfonate (0. 12 g, 0. 2 mmol) was added, and the stirred solution was warmed to 40 °C for 1 h, at which time HPLC analysis indicated that no secondary 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 MgSO4. The crude product was purified by flash column chromatography on silica gel eluting with 1 : 7 : 0. 01 of ethyl acetate : hexane : ammonium hydroxide to give 0. 83 g (69%) of the desired 3- [ [3-(2-bromo-5-fluorophenoxy)phenyl][[3-(1,1,2, 2-tetrafluoroethoxy) phenyl | -methyl] amino]-1,1,1-trifluoro-2-propanol product as a clear colorless oil, > 95% pure by HPLC analysis. H NMR (CDC13) b 7. 50 (dd, 1H), 7. 30 (t, 1H), 7. 18 (t, 1H), 7. 07 (t, 2H), 6. 99 (s, 1H), 6. 70 (dt, 1H), 6. 56 (dd, 1H), 6. 52 (dd, 1H), 6. 38 (dd, 1H), 6. 32 (m, 1H), 5. 87 (tt, 1H), 4. 65 (d, 2H), 4. 33 (m, 1H), 3. 85 (dd, 1H), 3. 56 (dd, 1H), 2. 48 (bs. 1H). NOE difference spectra confirmed that the isolated material was the indicated N-[3-(2-bromo-5- fluorophenoxy)phenyl]-3-aminopropanol product. 19F NMR (CDCl3) # -79.24 (d, 3F),-88. 57 (m, 2F),-112. 04 (q, 1H),-137. 16 (dt, 2F). Anal. calcd. for C24H18NO3BrF8 : C, 48. 02 ; H, 3. 02 ; N, 2. 33. Found : C, 48. 48 ; H, 3. 18 ; N, 2. 33. HRMS calcd. 600. 0420 [M+H]+, found: 600. 0415.

EXAMPLE 630

3- [ [3- (-5-bromo-2-fluorophenoxy) phenyl] [ [3- (1, 1, 2, 2-tetrafluoro- ethoxy) phenyl] methyl] amino]-1, 1, 1-trifluoro-2-propanol EX-630A) 3-Aminophenol (5 g, 46 mmol), 1-bromo-3, 4-difluorobenzene (10 g, 50 mmol) and Cs2CO3 (16 g, 50 mmol were mixed in 25 mL of DMF. Solid (CuOTf) 2C6H6 (100 mg) was added, and the mixture was stirred under nitrogen at 85 °C for 22 h, at which time HPLC analysis indicated that the reaction had gone to completion and formed two products. The DMF was removed under reduced pressure. The residue was diluted with ether and filtered through a celite pad. The pad was washed with ether and a small amount of water. The mixture was extracted with ether several times. The combined ether layers were washed with water and brine, then dried over MgSO4. The dried organic layer was evaporated to give 7. 5 g (58%) of the desired products, which comprised a 10 : 1 ratio of 3- (5-bromo-2-fluorophenoxy) aniline and 3- (4-bromo-2-fluorophenoxy) aniline. The crude product was purified by flash column chromatography on silica gel eluting with 1 : 7 : 0. 01 of ethyl acetate : hexane : ammonium hydroxide to give 4. 5 g (35%) of the desired products as a yellow oil, which were a 20 : 1 ratio of 3- (5-bromo-2-fluorophenoxy) aniline and 3- (4-bromo-2-fluorophenoxy)- aniline. HRMS calcd. for C12HgNOFBr : 281. 9930 [M+H] +, found 281. 9951.

EX-630B) The crude 3- (5-bromo-2-fluorophenoxy) aniline (1. 39 g, 4. 95 mmol) product from EX-630A and 3- (1, 1, 2, 2-tetrafluoroethoxy) benzaldehyde

(1. 0 g, 4. 5 mmol) were dissolved in 15 mL of dichloroethane and acetic acid (0. 30 mL, 5. 4 mmol), then solid NaBH (OAc) 3 (1. 26 g, 5. 9 mmol) was added.

The mixture was stirred at room temperature for 1 h, then quenched with water and extracted with ether. The ether layer was washed with water and brine, then dried over MgSO4, and evaporated to give 2. 1 g (97%) of crude product, which was purified by flash column chromatography on silica gel eluting with 1 : 7 ethyl acetate : hexane to give 2. 0 g (91 %) of the desired 3- [3- (5-bromo-2- fluorophenoxy) phenyl] [ [3- (1, 1, 2, 2-tetrafluoroethoxy) phenyl] methyl] amine product, as a yellow oil, > 95% pure by HPLC analysis. Anal. calcd. for C21Hl5NO2BrF2 : C, 51. 66 ; H, 3. 10 ; N, 2. 87. Found : C, 51. 90 ; H, 3. 08 ; N, 2. 86. HRMS calcd. 488. 0284 [M+H] +, found 488. 0281.

The amine (1. 1 g, 2. 26 mmol) product from EX-630B and 1, 1, 1-trifluoro-2, 3- epoxypropane (0. 38 g, 3. 39 mmol) were dissolved in 1 mL of acetonitrile.

Ytterbium (III) trifluoromethanesulfonate (0. 14 g, 0. 23 mmol) was added, and the stirred solution was warmed to 40 °C for 1 h, at which time HPLC analysis indicated that no secondary 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 MgSO4. The crude product was purified by flash column chromatography on silica gel eluting with 1 : 7 ethyl acetate : hexane to give 0. 5 g (37%) of the desired 3- [ [3- (5-bromo-2-fluorophenoxy) phenyl] [13- (1, 1, 2, 2-tetrafluoroethoxy) phenyl Imethyllamino]-1, 1, 1-tri-fluoro-2-propanol product as a yellow oil, > 95% pure by HPLC analysis. H NMR (CDC13) 8 7. 50 (t, 1H), 7. 20 (dd, 1H), 7. 17 (dd, 1H), 7. 17 (dd, 1H), 7. 09 (t, 2H), 7. 00 (dd, 2H), 6. 52 (dd, 1H), 6. 38 (dd, 1H), 6. 37 (s, 1H), 5. 87 (tt, 1H), 4. 64 (s, 2H), 4. 33 (m, 1H), 3. 85 (dd, 1H), 3. 56 (dd, 1H). 19F NMR (CDC13) õ- 79. 20 (d, 3F),-88. 55 (m, 2F),-113. 04 (m, 1H),-137. 05 (dt, 2F). NOE difference and pcosy spectra confirmed that the isolated material was the indicated N- [3- (5-bromo-2-fluorophenoxy) phenyll-3-aminopropanol product.

Anal. calcd. for C24H18NO3BrF8 : C, 48. 02 ; H, 3. 02 ; N, 2. 33. Found : C, 48. 07 ; H, 3. 14 ; N, 2. 31. HRMS calcd. 600. 0420 lM+Hl, found : 600. 0404.

EXAMPLE 631

3- [ (3-phenoxyphenyl) [ [4- (N, N-diethylamino) phenyllmethyl] amino]-1, 1, 1-trifluoro-2-propanol EX-631A) The 3-phenoxyaniline aniline (0. 74 g, 4. 0 mmol) and 4- (N, N- diethylamino) benzaldehyde (0. 59 g, 3. 3 mmol) were dissolved in 10 mL of dichloroethane and acetic acid (0. 22 mL, 4. 0 mmol). Then solid NaBH (OAc) 3 (0. 94 g, 4. 4 mmol) was added. The mixture was stirred at room temperature for 1 h, then quenched with water and extracted with ether. The ether layer was washed with water and brine, then dried over MgSO4, and evaporated to give 1. 3 g of crude product, which was purified by flash column chromatography on silica gel eluting with 1 : 7 ethyl acetate : hexane to give 1. 0 g (87%) of the desired 3- [ (3-phenoxyphenyl) (4- (N N-diethylamino) phenylmethyl]-amine product.

HRMS calcd. for C23H26 N20 : 347. 2123 lM+Hl, found 347. 2124.

The 3-[(3-phenoxyphenyl) [4-(N, N-diethylamino) phenyl1methyl] amine (0. 69 g, 2. 0 mmol) product from EX-631A and 1, 1, 1-trifluoro-2, 3-epoxypropane (0. 45 g, 4 mmol) were dissolved in 1 mL of acetonitrile. Ytterbium (III) trifluoromethanesulfonate (0. 12 g, 0. 1 mmol) was added, and the stirred solution was warmed to 40 °C for 4 h, at which time HPLC analysis indicated that no secondary 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 MgSO4. The crude product was purified by flash column chromatography on silica gel eluting with 1 : 7 : 0. 01 ethyl acetate :

hexane : ammonium hydroxide followed by reverse phase preparative HPLC eluting with 10% to 90% acetonitrile in water to give 160 mg (17%) of the desired 3- [ (3-phenoxyphenyl)- [ [¢ (N, N-diethylamino) phenyl Imethyl laminol- 1, 1, 1-trifluoro-2-propanol product as a yellow oil, > 95% pure by HPLC analysis. H NMR (CD30D) 8 7. 39 (d. 2H), 7. 31 (d, 2H), 7. 22 (m, 3H), 7. 13 (d, 1H), 6. 98 (t, 1H), 6. 75 (dd, 2H), 6. 47 (dd, 1H), 6. 20 (d, 1H), 4. 03 (m, 1H), 3. 90 (s, 2H), 3. 58 (m, 4H), 3. 36 (dd, 1H), 3. 12 (dd, 1H), 1. 05 (t, 6H).

F NMR (CD30D) 8-80. 51 (d, 3F). HRMS calcd. 459. 2259 [M+HI+, found : 459. 2250.

EXAMPLE 632

N-[2-chloro-6-(p-fluorophenoxy)-1, 3, 5-triazin-4-yl]-3-[[[3- (trifluoromethoxy) phenyl] methyl] amino]-1, 1, 1-trifluoro-2- propanol EX-632A) 3-Trifluoromethoxybenzenemethanamine (1. 15g, 6 mmol) and 1, 1, 1-trifluoro-2, 3-epoxypropane (0. 67 g, 6 mmol) were combined and stirred at 80 °C for 1. 5 h. The mixture was cooled to room temperature, and the resulting solid was recrystallized from hot hexanes. The white solid was isolated by vacuum filtration and washed with cold hexanes to give 0. 67 g (37%) of pure 3-[[[3-(trifluoromethoxy)-phenhl]methyl]amino]-1,1,1-trifluo ro-2-propanol. 1H NMR (CDC13) b 7. 37 (t, 1H), 7. 24 (d, 1H), 7. 15 (m, 2H), 3. 99 (m, 1H), 3. 85 (d, 2H), 2. 98 (dd, 1H), 2. 88 (dd, 1H), 2. 79 (s, 1H). F NMR (CDC13) 6

-58. 19 (s, 3F),-78. 88 (s, 3F). HRMS calcd. for C11H11F6NO2: 304. 0772 [M+H] +, found : 304. 0794.

EX-632B) To a solution of 4-fluorophenol 1. 00 g (8. 92 mmol) in 30 mL of tetrahydrofuran at 0 °C was added a 60% dispersion of sodium hydride in mineral oil (0. 36 g, 8. 92 mmol). After 30 min, cyanuric chloride (1. 64 g, 8. 92 mmol) was added as a heterogeneous mixture in tetrahydrofuran at 0 °C. The reaction mixture was allowed to slowly warm to room temperature. After 14 h, the mixture was cooled to 0 °C, and a saturated aq. NH4CI solution was added.

The aqueous solution was extracted with diethyl ether (3 x 50 mL). The combined ether extracts were washed with brine, dried (MgS04), and concentrated in vacuo to afford 1. 34 g (58%) of the desired 2, 4-dichloro-6- (4- fluorophenoxy)-1, 3, 5-triazine product as an off white solid which was taken on to the next step without purification. MS m/z = 260 lM+H1+.

To a stirred solution of aminopropanol from EX-632A (0. 100 g, 0. 330 mmol) in N, N-dimethylformamide at 0 °C was added the 2, 4-dichloro- (4- fluorophenoxy)-1, 3, 5-triazine ether product from EX-632B (0. 086 g, 0. 330 mmol) as a solution in N, N-di-methylfonnamide. reaction reaction mixture allowed to slowly warm to room temperature. After 14 h, the reaction mixture was cooled to 0 °C, and a saturated aq. NaHCO3 solution was added. After stirring the reaction mixture for 30 min at room temperature, the aqueous layer was extracted with ether (3 x 30 mL). The combined ether extracts were washed with brine, dried (MgSO4), and concentrated in vacuo to give a yellow oil. The crude residue was purified by column chromatography on silica gel eluting with 20 % ethyl acetate in hexanes to give 0. 075 g (43%) of the desired N- (2-chloro- 6- (p-fluorophenoxy)-1, 3, 5-triazin-4-y 1-3-1 [l3-(trifluoromethoxy) phenyl1- methyljamino]-l, l, l-trifluoro-2-propanol product as a pale yellow oil. HRMS calcd. forC20H14CIF7N403 : 526. 0643 [M], found : 526. 0632. 1H NMR

(C6D6) 8 6. 95 (s, 1H), 6. 63 (m, 14H), 4. 74 (d, 1H), 4. 37 (d, 1H), 4. 16 (d, 1H), 4. 00 (d, 2H), 3. 73 (m, 1H), 3. 48 (m, 2H), 3. 26 (m, 2H), 3. 12 (m, 2H).

EXAMPLE 633 3-[[3-(2-methyl-5-pyridyloxy)phenyl][[3-(trifluoromethoxy) phenyl] methyl]-amino]-1, 1, 1-trifluoro-2-propanol EX-633A) 3-Bromoaniline (2. 15 g, 12. 5 mmol) and 1, 1, 1-trifluoro-2, 3- epoxypropane (1. 0 g, 8. 9 mmol) were placed in a sealed vial, heated to 70 °C and stirred for 1 h under an atmosphere of nitrogen. The crude product was purified by flash column chromatography on silica gel eluting with CH2CH2 : hexane (2 : 1) to give 2. 11 g (84%) of the desired 3-1 (3- bromophenyl) amino]-1, 1, 1-trifluoro-2-propanol product as a light amber oil, 98% pure by HPLC analysis. MS m/z = 284/286 lM+H].

EX-633B) The 3- [ (3-bromophenyl) amino]-1, 1, 1-trifluoro-2-propanol (1. 14 g, 4 mmol) from EX-633A and 3- (trifluoromethoxy) benzaldehyde (0. 78 g, 4. 1 mmol) were dissolved in dichloroethane (18 mL). Acetic acid (0. 253 mL, 4. 2 mmol) and solid NaBH (OAc) 3 (1. 07 g, 5. 05 mmol) were added. The mixture was stirred at room temperature for 3 h, then acidified with 1 N HCI solution.

After neutralizing to pH 7. 5 with 2. 5 N sodium hydroxide, the mixture was extracted with methylene chloride. The organic layer was washed with brine and water, then dried over anhydrous MgSO4, and evaporated to give 1. 12 g (62%) of the desired N-3-bromophenyl-[[3-(trifluoromethoxy)phenyl]methyl]amino]-

1, 1, 1-trifluoro-2-propanol product as a brown oil, which was greater than 80% pure by reverse phase HPLC analysis. HRMS calcd. for C17Hl4NO2F6Br : 458. 0190 [M+H] +, found : 458. 0199.

The 3-[(3-bromophenyl)[[3-(trifluoromethoxy)phenyl]methyl]amino] -1,1,1- trifluoro-2-propanol (500 mg, 1. 1 mmol) product from EX-633B and 5- hydroxy-2-methylpyridine (262 mg, 2. 4 mmol) were dissolved in dimethylacetamide (6 mL). Cs2CO3 (1. 0 g, 3. 1 mmol) and (CuCF3SO3) 2C6H6 (150 mg) were added, and the mixture was heated to 105 °C for 96 h under an atmosphere of nitrogen, at which time HPLC analysis indicated that most of the starting materials had been consumed. After adding water, the reaction mixture was extracted with ether, and the ether extracts were washed with brine and dried over anhydrous MgSO4. The crude product was purified by flash column chromatography on silica gel eluting with ethyl acetate : hexane (1 : 12) to give 326 mg (61%) of the desired 3- [13- (2-methyl-5- pyridyloxy) phenyl] [[3-(trifluoro-methoxy)phenyl]methyl]amino]-1,1,1- trifluoro-2-propanol product as a light amber oil, 99% pure by HPLC analysis.

H NMR (CDCl3) # 8. 00 (s, 1H), 7. 29 (t 1H), 6. 99 (s, 1H), 7. 02-7. 15 (m, 5H), 6. 46 (dd, 1H), 6. 29 (t, 1H), 6. 25 (dd, 1H), 4. 88 (br s, 1H), 4. 67 (ABq, 2H), 4. 36 (m, 1H), 3. 88 (dd, 1H), 3. 56 (dd, 1H), 2. 49 (s, 3H). 19F NMR (CDC13) 8-58. 2, (s, 3F),-79. 1 (d, 3F). HRMS calcd. for C23H20N203F6 : 487. 1456 [M+H] +, found : 487. 1425.

EXAMPLE 634

3- [ [3-(4-fluorophenoxy) phenyl] [ [3- (1, 1, 2, 2-tetrafluoroethoxy)- phenyl] methyl] amino]-1, 1, 1-trifluoro-2-propanol EX-634A) Dinitrobenzene (1. 68 g, 10 mmol) and 4-fluorophenol (1. 13 g, 10 mmol) were dissolved in anhydrous dimethylsulfoxide (25 mL), and powdered cesium carbonate (8 g, 24. 8 mmol) was added. The mixture was stirred and heated to 100 °C using a reflux condenser under a nitrogen atmosphere. After 16 h, the mixture was diluted with water (120 mL), and the aqueous layer was extracted with diethyl ether (4 x 60 mL). The combined ether layers were washed with 3 % HCI, 5% sodium hydroxide, and water, then dried over anhydrous MgS04. The ether was removed in vacuo, and the recovered oil was purified by flash column chromatography on silica gel eluting with ethyl acetate in hexane (1 : 25) to give 1. 68 g (69%) of the desired 3- (4- fluorophenoxy) nitrobenzene product as orange crystals, 97% pure by HPLC analysis. MS m/z = 234 lM+Hl- EX-634B) 3- (4-Fluorophenoxy) nitrobenzene (1. 15 g, 4. 93 mmol) from EX- 634A was dissolved in ethanol (45 mL), and the solution was hydrogenated for 4 h in the presence of 5% palladium on charcoal. After the mixture was filtered through celite. the ethanol was removed in vacuo. The product was purified by flash column chromatography on silica gel eluting with ethyl acetate in hexane (1 : 10) to give 0. 92 g (90%) of 3- (4-fluorophenoxy) aniline as a yellow oil, 99% pure by HPLC analysis. HRMS calcd. for C12Hl 1FN° : 204. 0824 [M+H] +, found : 204. 0837.

EX-634C) The 3- (4-fluorophenoxy) aniline (812 mg, 4 mmol) from EX-634B and 3- (1, 1, 2, 2-tetrafluoroethoxy) benzaldehyde (888 mg, 2 mmol) were dissolved in dichloroethane (15 mL) and acetic acid (0. 25 mL. 4. 2 mmol), then solid NaBH (OAc) 3 (1. 01 g, 5 mmol) was added. The mixture was stirred at room temperature for 3 h, then acidified with 1 N HCI. After neutralizing to pH 7. 5 with 2. 5 N sodium hydroxide, the mixture was extracted with methylene chloride. The organic layer was washed with brine and water, then dried over anhydrous MgSO4, and evaporated to give 1. 32 g (78%) of the desired of N-13- (4-fluorophenoxy) phenyl] [ [3- (1, 1, 2, 2-tetrafluoroethoxy) phenyl Imethyl] amine product as a brown oil, which was greater than 90% pure by reverse phase HPLC analysis. MS m/z = 410 [M+H] The N- [3- (4-fluorophenoxy) phenyl] [ [3- (1, 1, 2, 2-tetrafluoroethoxy) phenyl] methyl] amine (612 mg, 1. 5 mmol) product from EX-634C and 1, 1, 1-trifluoro- 2, 3-epoxypropane (268 mg, 2. 4 mmol) were dissolved in 1. 0 mL of acetonitrile.

Ytterbium (III) trifluoromethanesulfonate (43 mg, 0. 07 mmol) was added, and the stirred solution was warmed to 40 °C for 2. 5 h under an atmosphere of nitrogen, at which time HPLC analysis indicated that no secondary amine starting material remained. The reaction was quenched with water and extracted with ether. The ether layer was washed with brine and water, then dried over anhydrous MgSO4. The ether was removed in vacuo, and the crude product was purified by flash column chromatography on silica gel eluting with ethyl acetate in hexane (1 : 11) to give 633 mg (81%) of the desired 3-[[3-(4- fluorophenoxy) phenyl] [ [3- (1, 1, 2, 2-tetrafluoro-ethoxy) phenyl] methyl] amino]- 1, 1, l-trifluoro-2-propanol product as a yellow oil, 99% pure by HPLC analysis.

1H NMR (CDC13) õ 7. 35 (t, 1H), 7. 15 (m, 3H), 6. 98 (m, 5H), 6. 49 (dd, 1H), 6. 38 (dd, 1H), 6. 33 (m, 1H), 5. 92 (tt, 1H), 4. 67 (ABq, 2H), 4. 37 (m, 1H), 3. 91 (dd, 1H), 3. 59 (dd, 1H), 2. 48 (d, 1H). F NMR (CDC13) 8-79. 2 (d, 3F),-88. 5 (m, 2F),-120. 33 (m, 1F), -137. 2 (dt, 2F). HRMS calcd. for C24H1gF8NO3 : 522. 1315 [M+H] +, found : 522. 1297.

Additional examples 3-[(aryloxyphenyl) [[phenyljmethyllaminol- 1, 1, 1-trifluoro-2-propanols are prepared by one skilled in the art using similar methods, as shown in Example Tables 39 and 40.

Example Table 39. 3-[(aryloxyphenyl)[[phenyl]methyl]amino]- 1, 1, 1-trifluoro-2-propanols.

Ex. Calculated Observed RSUB RSUB2 No. Mass [M+H]+ Mass [M+H] 1 635 4-F 3-OH 422. 1379 422. 1396 636 4-F 3-SCF3 505.0946 505.0927 637 ug 3-SCF3 502. 1275 502. 1261 638 3,4-F2 3-OCF2CF2H 540.1221 540.1248 639 2,4-F2 3-OCF2CF2H 540.1221 540.1194 640 4-F 4-CF3 474.1304 474.1300

Example Table 40. 3-[[(3-aryloxy)-5-(trifluoromethyl)phenyl][[phenyl] methyl] amino]-1, 1, 1-trifluoro-2-propanols.

Ex. Calculated Observed Mass No. RSUB1 RSUB2 Mass fM+Hl + [M+H]+ 641 4-F 3-CF3 542.1178 542.1205 642 4-F 3-SCF3 574.0898 574.0899 643 4-F 3-OCF3 558.1127 558.1137 644 4-F 3-OCF2CF2H 590.1189 590. 1212 EXAMPLE 645

3- [ (3-phenoxyphenyl) [ [3- (isopropoxy) phenyl] methyl] amino]- 1, 1, 1-trifluoro-2-propanol EX-645A) 3-Hydroxybenzaldehyde (5. 60 g, 45. 9 mmol) and 2-iodopropane (7. 86 g, 46. 2 mmol) were dissolved in 50 mL of isopropanol. Potassium carbonate (20 g, 145 mmol) was added, and the mixture was heated to reflux for

8 h, at which time TLC analysis indicated that the reaction had gone to completion. Water was added to dissolve all solids, and the mixture was extracted with ether (3x). The combined ether layer was washed with water, 2 M NaOH, again with water until clear (4x), and finally with brine. The solution was dried over MgS04, filtered, and evaporated to give 5. 03 g (67%) of the desired 3-isopropoxybenzaldehyde product as a pale oil. 1H NMR (C6D6) 8 9. 62 (s, 1H), 7. 29 (s, 1H), 7. 03 (m, 1H), 6. 91 (t, 1H), 6. 84 (m, 1H), 4. 03 (septet, 1H), 0. 96 (d, 6H).

EX-645B) The 3-isoproxybenzaldehyde (0. 780 g, 4. 75 mmol) product from EX-645A and 3-phenoxyaniline (0. 881 g, 4. 76 mmol) were combined in 20 mL of methanol, then solid NaCNBH3 (0. 238 g, 3. 79 mmol) was added, and the mixture was stirred until uniform. Acetic acid (2 ml) was added, and the mixture was stirred at room temperature overnight, then quenched with water, made basic with potassium carbonate, and extracted with ether (3x). The combined ether layers were washed with water and brine, dried over MgSO4, filtered, and evaporated to give 1. 32 g (84%) of the desired N- (3- phenoxyphenyl)-[[3-isopropoxyphenyl]methyl]amine product as an amber oil.

IH NMR (C6D6) 6 6. 6-7. 1 (m, 10H), 6. 44 (m, 1 H), 6. 25-6. 00 (dd, 1 H), 6. 15 (m, 1H), 4. 25 (s, 1H), 4. 19 (m, 1H), 3. 80 (s, 1H), 2. 65 (s, 1H), 1. 07 (m, 6H). MS m/z= 333 [M].

The N-(3-phenoxyphenyl)-[[3-isopropoxyphenyl]methyl]amine (0. 528 g, 1. 59 mmol) product from EX-645B and 1, 1, 1-trifluoro-2, 3-epoxypropane (0. 506 g, 4. 51 mmol) were heated to 90 °C in a sealed container for 2 d under an argon atmosphere. The resulting mixture was eluted from silica gel with an ethyl acetate in hexane gradient (0-10% ethyl acetate) and fractions were pooled after TLC analysis to give 197 mg (28%) of the desired 3-l (3-phenoxyphenyl) ll3- (isopro-poxy) phenyl] methyl] amino]-1, 1, 1-trifluoro-2-propanol product as clear, colorless oil. HRMS calcd. for C25H26F3NO3: 446.1943 [M+H]+, found : 446. 1936. 1H NMR (C6D6) 8 6. 9-7. 1 (m, 6H), 6. 84 (tt, 1H), 6. 74 (s, 1H), 6. 66 (dd, 1H), 6. 61 (d, 1H), 6. 56 (t, 1H), 6. 41 (td, 2H), 4. 33 (s, 2H), 4. 17

(septet. 1H), 3. 91 (br s, 1H), 3. 56 (dd, 1H), 3. 31 (m, 1H,), 2. 8 (br s, 1H).

1. 06 (s, 6H). F NMR (C6D6) 8-78. 85 (d, 3F).

Additional examples of 3-[aryloxyphenyl[[3-aryl]methyl]amino]-1,1,1- trifluoro-2-propanols are prepared by one skilled in the art using similar methods, as shown in Example Table 41. <BR> <BR> <BR> <BR> <P> Example Table 41. 3- [aryloxyphenyl [ [3-aryl] methyl] amino]-1, 1, 1-trifluoro-2- propanols. Ex. RSUB1 RSUB2 Calculated Observed Mass [M+H]+ [M+H]+ 646 F ethyl 450. 1692 450. 1682 647 F isopropyl 464. 1849 464. 1867 648 F n-propyl 464. 1849 464 1820 649 F n-butyl 478.2005 478. 2015 650 F sec-butyl 478. 2005 478. 1880 651 F -CH2-cyclopropyl 476.1849 476.1857 652 F isobutyl 478. 2005 478. 1970 653 F cyclopentyl 490.2005 490. 1998

EXAMPLE 654

3- [ (3-phenoxyphenyl) [ [3- (1, 1-dimethylethoxy) phenyl] methyl] amino]-1, 1, 1-trifluoro-2-propanol EX-654A) 3-Hydroxybenzaldehyde (4. 08 g. 33. 4 mmol) was slurred in 50 mL of anhydrous CH2C12 and added to t-butyl-2, 2, 2-trichloroacetimidate (25. 0 g, 114 mmol) in 200 mL of anhydrous cyclohexane with an additional 50 mL of CH2CI2 used in transfer. The mixture was stirred under nitrogen until uniform, then boron trifluoride diethyl etherate (0. 50 mL, 4 mmol) was added via syringe and stirring was continued for 1 h. Powdered sodium bicarbonate (50 g, 0. 6 mol) was added, and the solution was filtered through a silica gel plug, washing the plug with hexane. The solvent was evaporated to give crude product 3. 54 g (59%) as an amber oil (85% pure by GC analysis). Chromatography on silica gel eluting with 0-10% ethyl acetate in hexane gave 1. 88 g (32%) of pure 3-t- butoxybenzaldehyde product as a colorless oil. H NMR (C6D6) 8 9. 59 (s, 1H), 7. 44 (br s, 1H), 7. 20 (d t, 1H), 6. 92 (m, 2H), 1. 07 (s, 9H).

EX-654B) The 3-t-butoxybenzaldehyde (0. 585 g, 3. 27 mmol) product from EX-654A and 3-phenoxyaniline (0. 595 g, 3. 21 mmol) were combined in 50 mL of THF, then solid NaBH (OAc) 3 (0. 860 g, 4. 06 mmol) was added, and the mixture was stirred until uniform. Acetic acid (0. 2 g, 3. 33 mmol) was added, and the mixture was stirred at room temperature for 4 h, then quenched with 5% aq. NaHCO3. The aqueous layer was separated and extracted twice with ether.

The combined ether layers were washed with water and brine, dried over

MgSO4, filtered, and evaporated to give 1. 29 g (115%) of crude product as a brown oil. Chromatography on silica gel eluting with 0-10% ethyl acetate in hexane gave 464 mg (40%) of the desired N-(3-phenoxyphenyl)[[3-(1,1,- dimethyl-ethoxy) phenyllmethyllamine product as a colorless oil, pure by TLC.

MS m/z = 347 [M].

The N- (3-phenoxyphenyl) [ [3- (I, I-dimethylethoxy) phenyljmethyllamine (0. 270 g, 0. 78 mmol) product from EX-654B was dissolved in 2 mL of acetonitrile.

Ytterbium triflate (16 mg, 0. 026 mmol) was added in 0. 5 mL of acetonitrile, and the mixture was stirred under nitrogen. 1, l, l-Trifluoro-2, 3-epoxypropane (0. 105 g, 0. 94 mmol) was added, the vial was sealed and heated to 45 °C. After 24 h, TLC analysis showed 50% conversion, so additional 1, 1, 1-trifluoro-2,3- epoxypropane (88. 6 mg, 0. 79 mmol) was added and heating continued for an additional 24 h. The resulting mixture was eluted from silica gel with an ethyl acetate in hexane gradient (1. 5-7% ethyl acetate). Fractions were pooled based on TLC analysis to give 150 mg (42%) of the desired 3-[ (3-phenoxy-phenyl) [ [3- (1, 1-dimethylethoxy) phenyllmethyl] aminol-1, 1, 1-trifluoro-2-propanol product as a clear, colorless oil, and an additional 60 mg (17%) was obtained as an amber oil. HRMS calcd. for C26H28F3NO3 : 460. 2100 lM+Hl, found : 460. 2103.

H NMR (C6D6) õ 6. 78-7. 08 (m, 9H), 6. 68 (d, 1 H), 6. 55 (t, 1 H), 6. 43 (dd, 1H), 6. 34 (dd, 1H), 4. 23 (s, 2H), 3. 81 (m, 1H), 3. 48 (dd, 1H), 3. 24 (m, 1H), 2. 25 (br s, 1H), 1. 07 (s, 9H). 19F NMR (C6D6) 8-78. 92 (d, 3F).

EXAMPLE 655

3- [ (3-phenoxyphenyl) [ [3- (2-hydroxy-3, 3, 3-trifluoro-n- propoxy) phenyllmethyl] amino]-1, 1, I-trifluoro-2-propanol EX-655A) The 3- (phenoxy) aniline (555 mg, 3 mmol) and 3- hydroxybenzaldehyde (366 mg, 3 mmol) were dissolved in 7 mL of 1, 2- dichloroethane. Acetic acid (0. 189 mL, 3. 15 mmol) and solid NaBH (OAc) 3 (1. 01 g, 5 mmol) were added. The mixture was stirred at room temperature for 3 h, then acidified with 1 N HCI solution. After neutralizing to pH 7. 5 with 2. 5 N sodium hydroxide, the mixture was extracted with methylene chloride. The organic layer was washed with brine and water, then dried over anhydrous MgSO4, and evaporated to give 609 mg (69%) of the desired N- (3- phenoxyphenyl) [l3-hydroxyphenyl lmethyl lamine product as a brown oil, which was greater than 90% pure by reverse phase HPLC analysis. MS m/z = 291.

The N-(3-phenoxyphenyl)[[3-hydroxyphenyl]methyl]amine (400 mg, 1. 35 mmol) product from EX-655A and 1, 1, 1-trifluoro-2, 3-epoxypropane (348 mg, 3 mmol) were placed in a sealed vial, then stirred and heated to 95 °C for 15 h under an atmosphere of nitrogen. The vial was cooled, and more 1, 1, 1-trifluoro- 2, 3-epoxypropane (112 mg, 1 mmol) was added. The vial was sealed, then stirred and heated to 95 °C for a further 20 h under an atmosphere of nitrogen.

The crude product was purified by flash column chromatography on silica gel eluting with ethyl acetate in hexane (1 : 6) to give 518 mg (77%) of the desired 3- [ (3-phenoxyphenyl) [ [3- (2-hydroxy-3, 3, 3-trifluoro-n-propoxy)-phenyl methyl]

amino-1, 1, 1-trifluoro-2-propanol product as a light amber oil, 98% pure by HPLC analysis. H NMR (CDC13) # 7, 20-7. 32 (m, 3H), 7. 14 (t, 1H), 7. 07 (t, 1H), 6. 95 (d, 2H), 6. 80 (m, 2H), 6. 74 (s, 1H), 6. 48 (dd, 1H), 6. 38 (m, 2H), 4. 59 (ABq, 2H), 4. 31 (m, 1H), 4. 18 (dd, 1H), 4. 10 (dd, 1H), 3. 83 (dd, 1H), 3. 54 (dd, 1H), 2. 92 (d, 1H), 2. 61 (d, 1H). F NMR (CDCl3) 8-78. 0 (d, 3F), -79. 2 (d, 3F). HRMS calcd. for C25H23F6 NO4: 516. 1611 [M+H] +, found : 516. 1618.

EX-655B) Another example, 3-[3-(4-fluorophenoxy)phenyl[[3-(2-hydroxy- 3, 3, 3-trifl uoro-n-propoxy) phenyl] methyl] amino]-1, 1, 1-trifluoro-2-propanol, was prepared by a similar method using 3- (4-fluorophenoxy) aniline as the staring material. HRMS calcd. for C25H22F7NO4 : 534. 1515 [M+H] +, found : 534. 1505.

EXAMPLE 656 3- [ [3- (4-trifluoromethylphenoxy) phenyl] [ [3- (1, 1, 2, 2- tetrafluoroethoxy)-phenyl] methyl] amino]-1, 1, 1-trifluoro-2- propanol EX-656A) 3-Aminophenol (5. 0 g, 45. 8 mmol) and 4-bromo-a, a, a- trifluorotoluene (14. 0 g, 62. 2 mmol) were dissolved in anhydrous dimethylacetamide (20 mL), then anhydrous cesium carbonate (30 g, 92. 3 mmol) and copper triflate benzene complex (200 mg) were added. The mixture was stirred and heated to 85 °C using a reflux condenser under an argon

atmosphere. After 16 h, the mixture was diluted with water (120 mL). and the aqueous layer was extracted with diethyl ether (4 x 60 mL). The combined ether layers were washed with 3 % HCI, 5% NaOH and water, then dried over anhydrous MgSO4. The ether was removed in vacuo, and the recovered oil purified by flash column chromatography on silica gel eluting with ethyl acetate in hexane (1 : 8) to give 6. 8 g (59 %) of the desired 3- (4- trifluoromethylphenoxy) aniline product as a yellow oil, which solidified to a yellow powder, 98% pure by HPLC analysis. HRMS calcd. for C13HloF3NO : 254. 0792 lM+H], found : 254. 0798.

EX-656B) The 3- (4-trifluoromethylphenoxy) aniline (632 mg, 2. 5 mmol) from EX-656A and 3- (1, 1, 2, 2-tetrafluoroethoxy) benzaldehyde (555 mg, 2. 5 mmol) were dissolved in 6 mL of dichloroethane and glacial acetic acid (0. 15 mL, 2. 8 mmol), and solid NaBH (OAc) 3 (1. 01 g, 5 mmol) was added. The mixture was stirred at room temperature for 3 h, then acidified with 1 N HCI. After neutralizing to pH 7. 5 with 2. 5 N sodium hydroxide, the mixture was extracted with CH2C12 (3 x 20 mL). The organic layer was washed with brine and water, then dried over anhydrous MgSO4, and evaporated to give 861 mg (75%) of the desired N-3- (4-trifluoromethylphenoxy)-phenyl [13- (1, 1, 2, 2-tetrafluoroethoxy) phenyllmethyl] amine product as a brown oil, which was greater than 90% pure by reverse phase HPLC analysis. MS m/z = 460 [M+H] +.

The N-3-($trifluoromethyl phenoxy)-phenyl [13-(1, 1, 2, 2-tetrafluoroethoxy) phenyl]-methyl] amine (689 mg, 1. 5 mmol) product from EX-656B and 1, 1, 1- trifluoro-2, 3-epoxypropane (252 mg, 2. 25 mmol) were dissolved in 1. 0 mL of acetonitrile. Ytterbium (III) trifluoromethanesulfonate (43 mg, 0. 07 mmol) was added, and the stirred solution was warmed to 50 °C for 2. 5 h under an atmosphere of nitrogen, at which time HPLC analysis indicated that no secondary amine starting material remained. The reaction was quenched with water and extracted with ether. The ether layer was washed with brine and water, then dried over anhydrous MgSO4. The crude product was purified by flash column chromatography on silica gel eluting with ethyl acetate in hexane (1 : 12) to give

520 mg (61%) of the desired 3- [13- (4-trifluoromethylphenoxy) phenyl] [13- (1, 1, 2, 2-tetrafl uoroethoxy) phenyl methyl] amino]-1, 1, 1-trifluoro-2-propanol product as a yellow oil. 99% pure by HPLC analysis. H NMR (CDC13) 8 7. 49 (d, 2H), 7. 30 (t, 1H), 7. 20 (t, 1H), 7. 07 (m, 2H), 7. 00 (s, 1H), 6. 95 (d, 2H).

6. 55 (dd, 1H), 6. 43 (dd, 1H), 6. 34 (t, 1H), 5. 87 (tt, 1H), 4. 64 (ABq, 2H), 4. 33 (m, 1H), 3. 88 (dd, 1H), 3. 58 (dd, 1H), 2. 43 (bs, 1H). F NMR (CDC13) 6-62. 2 (s, 3F),-79. 2 (d, 3F),-88. 6 (m, 2F),-137. 2 (dt, 2F). HRMS calcd. for C25H I 9F I ON03 : 572. 1282 [M+H] +, found : 572. 1268.

Additional examples of 3-[aryloxyphenyl[[phenyl]methyl]amino]-1,1,1- tri-fluoro-2-propanols are prepared by one skilled in the art using similar methods, as shown in Example Table 42.

Example Table 42. 3-[Aryloxyphenyl[[phenyl]methyl]amino]- 1, 1, 1-trifluoro-2-propanols

Ex. Calculated Mass Observed Mass RSUB No. [M+H]+ [M+H]+ 657 CN 529. 1362 529. 1364 658 OCF3 588. 1233 588. 1241 EXAMPLE 659

3- [ (3-phenoxyphenyl) [ [3- (2, 2, 2-trifluoroethoxy) phenyl] methyls amino-1, 1, 1-trifluoro-2-propanol EX-659A) 3-Hydroxybenzaldehyde (12. 22 g, 0. 10 mol) and 100 mL of anhydrous methanol were combined in a 250 mL round-bottom flask. Sodium methoxide was slowly added as a 25 wt. % solution in methanol (21. 61 g, 0. 10 mol), and the methanol was removed under vacuum. Then 2, 2, 2-trifluoroethyl- p-toluenesulfonate (25. 42 g, 0. 10 mol) was added, the flask was purged with nitrogen, and 100 mL of N-methyl pyrrolidine was added. The solution was stirred for 24 h at 90 °C, quenched with water, and extracted with ether (3x).

The combined ether layers were washed with 1 M NaOH (2x), water, and brine, dried over MgSO4, filtered, and evaporated to give 11. 72 g of crude product.

Chromatography over silica gel eluting with 0-10% ethyl acetate in hexane followed by a second chromatography with toluene gave 5. 24 g (26%) of the desired 3- (2, 2, 2-trifluorcethoxy) benzaldehyde product as a pale oil. 1H NMR (C6D6) 8 9. 61 (s, 1H), 7. 14 (d, 1H), 7. 06 (s, 1H), 6. 97 (t, 1H), 6. 75 (m, 1H), 3. 75 (m, 2H). 19F NMR (C6D6) 8-74. 45 (t, 3F).

EX-659B) The 3- (2, 2, 2-trifluoroethoxy) benzaldehyde (0. 360 g, 1. 76 mmol) product from EX-659A and 3-phenoxyaniline (0. 326 g, 1. 76 mmol) were combined in 50 mL of cyclohexane with 3A molecular sieves (1 g) and stirred overnight at 80 °C. The mixture was cooled, filtered, and evaporated, then dissolved in 50 mL of methanol and cooled to 0 °C. Solid sodium borohydride

(0. 030 g, 0. 79 mmol) was added in portions, and the mixture was stirred overnight. The reaction was quenched with 5% aq. NaHCO3 and extracted with ether (3x). The combined ether layers were washed with water and brine, dried over MgSO4, filtered, and evaporated to give 0. 50 g (76%) of the desired N- (3- phenoxyphenyl) l l3-(2, 2, 2-trifluoroethoxy) phenyl] methyl] amine product as an amber oil, >95% pure by normal phase HPLC analysis. MS m/z = 373 [M l- The N- (3-phenoxyphenyl) [ [3- (2, 2, 2-trifluoroethoxy) phenyl]methyl]amine (0. 50 g, 1. 35 mmol) product from EX-659B and 1, 1, 1-trifluoro-2, 3-epoxy- propane (1. 0 ml, 11 mmol) were heated to 90 °C in a sealed container under argon for 2 d. The resulting mixture was eluted from silica gel with 4% ethyl acetate in hexane, and fractions were pooled based on TLC analysis to give 134 mg (21%) of the desired 3- [ (3-phenoxyphenyl) l [3- (2, 2, 2- trifluoroethoxy) phenyl] methyl] amino]-l, l, l-trifluoro-2-propanol product as a clear, colorless oil. H NMR (C6D6) 8 6. 80-7. 08 (m, 7H), 6. 64 (d, 1H), 6. 53 (bt, 1H), 6. 49 (t, 1H), 6. 44 (dd, 1H), 6. 34 (dt, 2H), 4. 23 (s, 2H), 3. 84 (m, 1H), 3. 61 (m, 2H), 3. 53 (dd, 1H), 3. 20 (m, 1H), 2. 03 (d, 1H). 19F NMR (C6D6) 6-74. 20 (t, 3F),-78. 95 (d, 3F). HRMS calcd. for C24H21F6NO3 : 486. 1504 [M+H] +, found : 486. 1498.

EXAMPLE 660

3- [ (4-chloro-3-ethylphenoxy) phenyl [ [3- (pentafluoroethyl) phenyl] methyl]-amino]-1, 1, 1-trifluoro-2-propanol.

EX-660A) Sodium pentafluoroethyl propionate (8. 4 g, 50 mmol) and 3- iodotoluene (5. 5 g, 25 mmol) were dissolved in anhydrous DMF (300 mL). Cul (9. 5 g, 50 mmol) was added, and the mixture was heated to 160 °C under nitrogen for 4 h, at which time a 15 mL fraction of a mixture of DMF and 3- pentafluoroethyl toluene was collected. The distillat was diluted with Et20 and was washed with brine. The ether layer was dried over MgSO4, filtered and concentrated in vacuo to give 5. 25 g (55%) of the desired 3-pentafluoroethyl- toluene product as a colorless oil. H NMR (CDC13) 6 7. 36 (m, 4H), 2. 40 (s, 3H). 19F (CDCl3) 8-85. 2 (s, 3F),-115. 2 (s, 2F).

EX-660B) The 3-pentafluoroethyl-toluene (2. 9 g, 13. 8 mmol) product from EX-660A and N-bromosuccinimide (2. 5 g, 13. 8 mmol) were dissolved in CC14 (25 mL). AIBN (50 mg) was added, and the mixture was refluxed for 3. 5 h under N2. The reaction mixture was cooled to room temperature and diluted with water. The layers were separated, and the organic layer was washed with brine, dried with anhydrous MgSO4, filtered, and concentrated in vacuo to give 3. 4 g (87%) of a colorless oil. The H NMR spectrum indicated that the crude product contained 3-pentafluoroethyl-benzylbromide (70%), the benzyl

dibromide (10%) and 3-pentafluoroethyl toluene (20%). 1H NMR (CDC13) 8 7. 60 (m, 2H), 7. 50 (m, 2H), 4. 50 (s, 2H). IF NMR (CD03) 8-85. 1 (s, 3F), -115. 4 (s, 2F).

EX-660C) A solution of 3- (4-chloro-3-ethylphenoxy) aniline (1. 7g, 6. 9 mmol) was prepared in cyclohexane (13 mL). A solution of crude 3-pentafluoroethyl benzylbromide (1 g, 3. 5 mmol) product from EX-660B in cyclohexane (10 mL) was added dropwise over 3 min. The reaction mixture was refluxed under N2 for 24 h and then was cooled to room temperature. The mixture was diluted with Et20 and saturated aqueous NaHCO3. The layers were separated, and the aqueous layer was extracted with Et20. The organic layer was washed with brine, dried with anhydrous MgSO4, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel eluting with hexanes in ethyl acetate (95 : 5) which gave 0. 56 g (35%) of the desired N- [3- (4-chloro-3- ethylphenoxy) phenyl] [ [3- (pentafluoro-ethyl) phenyl] methyl] amine product as an amber oil. H NMR (CDC13) b 7. 53 (m, 4H), 7. 27 (d, 1H), 7. 15 (t, 1H), 6. 93 (d, 1H), 6. 77 (dd, 1H), 6. 41 (tt, 2H), 6. 30 (t, 1H), 4. 41 (s, 2H), 2. 73 (q, 2H), 1. 23 (t, 3H). CNMR (CDCl3) 6158. 6, 156. 1, 143. 4, 141. 3, 140. 2, 131. 3, 130. 7, 130. 4, 129. 4, 128. 1, 120. 4, 117. 8, 108. 8. 103. 9, 48. 5, 27. 5, 14. 1. 19F NMR (CDC13) 8-85. 1 (s, 3F),-115. 2 (s, 2F). HRMS calcd. for C23HlgCIF5NO : 456. 1154 [M+H] +, found : 456. 1164.

The N- [3- (4-chloro-3-ethylphenoxy) phenyl] [ [3- (pentafluoroethyl) phenyl] methyl]-amine (0. 05 g, O. llmmol) product of EX-660C was dissolved in anhydrous acetonitrile (0. 2 mL). 1, 1, 1-trifluoro-2, 3-epoxypropane (0. 1 g, 0. 89 mmol) and Yb (OTf) 3 (7 mg, 0. 001 mmol) were added, and the reaction mixture was stirred under N2 at 45 °C. After 3 h, the reaction mixture was cooled to room temperature and diluted with Et20 and saturated aqueous NaHCO3. The layers were separated and the aqueous layer was extracted with Et20. The ether

layers were combined, washed with brine, dried with anhydrous Na2SO4, filtered, and concentrated in vacuo. The viscous oil was adsorbed onto silica gel and eluted with hexanes in ethyl acetate (95 : 5) which gave 20 mg (32%) of the desired 3- [ (4-chloro-3-ethylphenoxy) phenyl [ [3- (pentafluoroethyi) phenyl I- methyl lamino]-1, 1, 1-trifluoro-2-propanol product as a viscous, colorless oil. H NMR (CDC13) a 7. 47 (m, 4H), 7. 23 (m, 3H), 6. 90 (d, IH), 6. 72 (dd, 1H), 6.52 (d, 1H), 6.42 (m, 2H), 4.73 (s, 2H), 4.39 (m, 1H), 3.91 (dd, 1H), 3.58 (m, 2H), 2.73 (q, 2H), 2.57 (s, 1H), 1.22 (t, 3H). 19F NMR (CDCl3) # -79.2 (s, 3F),-84. 9 (s, 3F),-115. 2 (s, 2F). HRMS calcd. for C26H22C1FgNO2 : 568. 1290 [M+H] +, found : 568. 1314.

EXAMPLE 661

6-fluoro-3, 4-dihydro-4- [ [3- (1, 1, 2, 2-tetrafluoroethoxy) phenyl] methyl]-2-(trifluoromethyl)-2H-1, 4-benzoxazine EX-661A) A mixture of 2, 5-difluoroaniline (2. 58 g, 20 mmol) and 3- (1, 1, 2, 2- tetrafluoroethoxy) benzaldehyde (4. 44 g, 20 mmol) in cyclohexane (50 mL) was heated under reflux for 5 h using a Dean-Stark trap to remove water. The solvent was removed in vacuo, and the residue was dissolved in methanol (30 mL). The solution was stirred and cooled to 0 °C, then sodium borohydride was added (1. 32 g, 35 mmol). The mixture was allowed to warm to room temperature and stirred for 2 h, then acidified with I N HCI. After neutralizing to pH 7. 5 with 2. 5 N sodium hydroxide, the mixture was extracted with diethyl ether (3 x 20 mL). The organic layer was washed with brine and water, then

dried over anhydrous MgSO4, and evaporated to give 5. 7 g (86%) of the desired N-(2, 5-difluorophenyl) [ [3- (1, 1, 2, 2-tetrafluoroethoxy) phenyl l-methyl lamine product as a brown oil, which was greater than 90% pure by reverse phase HPLC analysis. MS m/z = 336 [M].

EX-661B) The N-(2, 5-difluorophenyl) [l 3-(1, 1 *2, 2-tetrafluoroethoxy) phenyl 1 methyl]-amine (2. 22 g, 6. 67 mmol) product from EX-661A and 1, 1,1- trifluoro-2, 3-epoxypropane (1. 12 g, 10 mmol) were dissolved in 1. 5 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 secondary 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 MgSO4. The crude product was purified by flash column chromatography on silica gel eluting with ethyl acetate in hexane (1 : 10) to give 2. 49 g (84%) of the desired 3- [ (2, 5-difluorophenyl) [ [3- (1, 1, 2, 2- tetrafluoro-ethoxy) phenyl) methyl] amino]-l, l, l-trifluoro-2-propanol product as a yellow oil, 99% pure by HPLC analysis. HRMS calcd. for C18Hl4F9NO2 : 448. 0959 [M+H] +, found : 448. 0940.

The 3-1 (2, 5-difluorophenyl) [ [3- (1, 1, 2, 2-tetrafluoroethoxy) phenyl lmethYIl aminol-l, 1, 1- trifluoro-2-propanol (200 mg, 0. 45 mmol) product from EX- 661B was dissolved in anhydrous dimethylformamide (20 mL), and powdered K2CO3 (180 mg) was added. The mixture was stirred and heated to 145 °C for 15 h. The mixture was diluted with water (60 mL) and extracted into ether (2 x 40 mL), which was washed with brine and water. The ether solution was dried over anhydrous MgSO4, and the ether was removed in vacuo. The crude product was purified by flash column chromatography on silica gel eluting with ethyl acetate in hexane (1 : 15) to give 86. 9 mg (48%) of the desired 6-fluoro-3, 4- dihydro-4- [ {3- ( 1, 1, 2, 2-tetrafluoroethoxy) phenyl 1-2- (tri-fluoromethyl)- 2H-1, 4-benzoxazine product as a yellow oil, 98% pure by HPLC analysis. H

NMR (CDC13) 8 7. 39 (t, 1H), 7. 17 (m, 3H), 6. 88 (m, 1H), 6. 41 (m, 2H), 5. 92 (tt, 1H), 4. 54 (m, 1H), 4. 45 (s, 2H), 3. 44 (m, 2H). 19F NMR (CDC13) b- 77. 7 (d, 3F),-88. 6 (m, 2F),-120. 28 (m, 1F), -137. 2 (dt, 2F). HRMS calcd. for C18Hl3F8NO2 : 428. 0899 lM+H I * found : 428. 0910.

EXAMPLE 662

2, 2, 2-trifluoro-1- [[(3-fluorophenyl) [3- (trifluoromethyl) benzoyl]amino]-methyl]ethyl 3-trifluoromethylbenzoate EX-662A) 3-[(3-fluorophenyl)[phenylmethyl]amino]-1,1,1-trifluoro-2- propanol (2. 56 g, 8. 2 mmol) was dissolved in methanol (30 mL) and hydrogenated over 5% palladium on charcoal for 3 h. The mixture was filtered through celite, and the solvent was removed in vacuo to give 1. 8 g (98%) of the desired 3- [ (3-fluorophenyl) amino]-1, 1, 1-trifluoro-2-propanol product as an oil, 99% pure by HPLC analysis. MS m/z = 224 [M+H] +.

The 3-1 (3-fluorophenyl) amino-1, 1, 1-trifluoro-2-propanol (446 mg, 2. 0 mmol) from EX-662A and triethylamine (544 mg) were dissolved in anhydrous CHC13 (30 mL) and cooled to 0 °C. Then a solution of 3-trifluoromethylbenzoyl chloride (1. 04 g, 5. 0 mmol) in anhydrous CHCl3 (6 mL) was added over a period of 15 min. The solution was stirred at room temperature. After 14 h, the solution was washed with 5% NaHCO3 (2 x 20 mL) and brine (2 x 10 mL), and

then dried over anhydrous MgSO4. Removal of the solvent in vacuo gave 832 mg (73%) of the desired 2, 2, 2-trifluoro-1-[[(3-fluoro-phenyl)[3- (trifluoromethyl)benzoyl]amino]methyl]ethyl 3-trifluoromethyl-benzoate product as an amber oil, which was greater than 95% pure by reverse phase HPLC analysis. 1H NMR (CDC13) 8 7. 25-8. 39 (m, 9H), 7. 02 (q, 1H), 6. 71 (m, 2H), 6. 11 (m, 1H), 4. 58 (dd, 1H), 4. 35 (dd, 1H). 19F NMR (CDCl3) 8-64. 4 (m, 6F),-77. 4 (s, 3F),-111. 3 (m, 1F). HRMS calcd. for C25H15F10NO3: 568. 0970 [M+H] +, found : 568. 0968.

EXAMPLE 663

N- (3-fluorophenyl)-N- (3, 3, 3-trifluoro-2-hydroxypropyl)- 3-(trifluoromethyl) benzamide A solution of 2, 2, 2-trifluoro-1- [ [ (3-fluorophenyl) (3- (trifluoromethyl) benzoyl] amino]-methyl] ethyl 3-trifluoromethyl-benzoate (600 mg, 1. 06 mmol) from EX-662 in methanol was treated with 28% ammonia solution (122 µL). The solution was stirred at room temperature for 10 h. The reaction was quenched with water and extracted with ether. The ether layer was washed with brine and water, then dried over anhydrous MgSO4. The crude product was purified by flash column chromatography on silica gel eluting with ethyl acetate in hexane (1 : 8) to give 255 mg (61%) of the desired N- (3-fluorophenyl)-N- (3, 3, 3- trifluoro-2-hydroxypropyl)-3- (trifluoromethyl) benzamide product as a white powder, 97% pure by HPLC analysis. H NMR (CDC13) 8 7. 56 (m, 3H), 7. 32

(m 2H), 6. 98 (m, 1H), 6. 90 (m, 2H), 4. 49 (dd, 1H), 4. 34 (d, 1H), 4. 26 (m.

1H), 4. 01 (dd, 1H). 9F NMR (CDC13) 6-64. 7 (s, 3F),-80. 3 (s, 3F),-111. 0 (m, IF). HRMS calcd. for C17Hl2F7NO2 : 396. 0854 [M+H] +, found : 396. 0821.

EXAMPLE 664

2, 2, 2-trifluoro-1-[[[(3-fluorophenyl)[3-(trifluoromethyl) phenyl]-methyl] amino] methyl] ethyl acetate A solution of 3- [ (3-fluorophenyl) [ [3- (3-trifl uoromethyl) phenyl imethyl] aminol- 1, l, l-tri-fluoro-2-propanol (200 mg, 0. 52 mmol) from EX-1 in triethylamine (0. 6 mL) and acetic anhydride (0. 5 mL) was stirred and heated to 80 °C for 1 h.

The mixture was cooled and diluted with water (20 mL) and extracted into ether (2 x 40 mL), which was washed with 0. 1 N NaOH and water. The ether solution was dried over anhydrous MgSO4. The ether was removed in vacuo giving the desired 2, 2, 2-trifluoro-1-[[[ (3-fluorophenyl) l3-(trifluoromethyl) phenyl]methyl]amino] methyl]ethyl acetate product as an amber oil, 98% pure by HPLC analysis. 1H NMR (CDCl3) # 7. 42-7. 59 (m, 3H), 7. 38 (d 1H), 7. 18 (q, 1H), 6. 42-6. 56 (m, 3H), 5. 69 (m, 1H), 4. 64 (ABq, 2H), 3. 89 (d, 1H), 3. 87 (s, 1H), 1. 98 (s, 3H). 19F NMR (CDCl3) # 64. 0 (s, 3F),-77. 2 (s, 3F),-112. 9 (s, 1F). HRMS calcd. for C19H16F7NO2 : 424. 1148 fM+Hj found : 424. 1159.

EXAMPLE 665

1, 1'- [methylenebis [3, 1-phenylene [[[3- (trifluoromethoxy) phenyl] methyl] imino]]] bis [3, 3, 3-trifluoro-2-propanol] EX-665A) A solution of 3, 3'-diaminophenylmethane (1. 48 g, 7. 5 mmol) and 3-trifluoromethoxy-benzaldehyde (2. 85 g, 15 mmol) in cyclohexane (50 mL) was heated under reflux for 5 h using a Dean-Stark trap to remove water. The solvent was removed in vacuo, and the residue was dissolved in methanol (30 mL). The solution was stirred and cooled to 0 °C, and solid sodium borohydride was added (0. 87 g, 23 mmol). The mixture was allowed to warm to room temperature and stirred for 2 h, then acidified with 1 N HCI. After neutralizing to pH 7. 5 with 2. 5 N sodium hydroxide, the mixture was extracted with diethyl ether (3 x 30 mL). The organic layer was washed with brine and water, then dried over anhydrous MgSO4, and evaporated to give 3. 19 g (78%) of the desired 3, 3'-N, N'-bis (trifluoromethoxyphenyl) diamino-phenylmethane product as a brown oil, which was greater than 90% pure by reverse phase HPLC analysis. MS m/z = 546 [M +I- The amine (2. 18 g, 4 mmol) product from EX-665A and 1, 1, 1-trifluoro-2, 3- epoxy-propane (0. 67 g, 6 mmol) were combined in a sealed vial and heated to 95 °C for 2 days, at which time HPLC analysis indicated that little secondary amine starting material remained. The excess oxirane was removed under nitrogen, and

the crude product was purified by flash column chromatography on silica gel eluting with ethyl acetate in hexane (1 : 12) to give 2. 0 g (67%) of the desired 1,1'-[methylenebis[3,1-phenylene[[[3-(trifluoromethoxy)pheny l]methyl]imino]]] bis- [3, 3, 3-trifluoro-2-propanol] product as a light amber oil, 99% pure by HPLC analysis. H NMR (CDCl3) # 7. 30 (t, 2H), 7. 10 (m, 6H), 7. 02 (s, 2H), 6. 58 (m, 4H), 6. 52 (s, 2H), 4. 60 (s, 4H), 4. 22 (m, 2H), 3. 80 (s, 2H), 3. 79 (dd, 2H), 3. 48 (dd, 2H), 2. 60 (br s, 2H). 19F NMR (CDC13) 8-66. 2 (s, 6F),-79. 2 (d, 6F). HRMS calcd. for C35H30 F12N2O4; : 771. 2092 [M+Hl+, found : 771. 2072.

EXAMPLE EX-666

4- [ [ (4-fluorophenoxy) phenyl] [ [3- (1, 1, 2, 2-tetrafluoroethoxy) phenyl]-methyl] amino]-1, 1, 1-trifluoro-2-butanol EX-666A) The 4-amino-2-hydroxy-1, 1, 1-trifluorobutane (1. 0 g, 7. 0 mmol) from EX-611A and 3- (1, 1, 2, 2-tetrafluoroethoxy) benzaldehyde (1. 5 g, 7. 0 mmol) were dissolved in 20 mL of dichloroethane and acetic acid (0. 40 mL, 7. 7 mmol), then solid NaBH (OAc) 3 (1. 8 g, 8. 4 mmol) was added. The mixture was stirred at room temperature for 3 d, then quenched with water and extracted with ether. The ether layer was washed with water and brine, then dried over MgSO4, and evaporated to give 1. 6 g of crude product, which was purified by reverse phase HPLC to give 0. 90 g (37 %) of the desired 4-[1l3-(1, 1, 2, 2- tetrafluoroethoxy) phenyl1methyllaminol-l, l, l-trifluoro-2-butanol product as a

yellow oil. HRMS calcd. for C13Hl4F7NO2 : 350. 0991 [M+Hl+, found : 350. 0971.

The 1, 1, 1-trifluoro[[3-(1, 1, 2, 2-tetrafluoroethoxy) phenyl] methyl] amino]-2- butanol (0. 35 g, 1 mmol) from EX-666A, 3- (4-fluorophenoxy) bromobenzene (0. 32 g, 1. 2 mmol), Pd2 (dba) 2 (18 mg, 0. 02 mmol), (R, +) BINAP (49 mg.

0. 08 mmol), and Cs2C03 (0. 46 g, 1. 4 mmol) were mixed in 9 mL of toluene and heated to 100 °C for over 2 weeks, at which time FABMS (m/z = 536. 3 lM+H]) indicated that the desired 4- [ [ (4-fluorophenoxy) phenyl]-113- (1, 1, 2, 2- tetrafluoroethoxy) phenyl] methyl] amino]-1, 1, 1-tri-fluoro-2-butanol product had formed.

Based on the preceding procedures, other substituted 3- [ (N-aryl)- [[aryl] methyl1amino]-halo-2-propanols can be prepared by one skilled in the art using similar methods, as shown in Example Tables 43, 46, and 47.

Substituted 3-[(N-aralkyl)-[[aralkyl] amino]-halo-2-propanols can also be prepared by one skilled in the art using similar methods, as shown in Example Tables 44 and 45. Substituted 3-[(N-aryl)-[[aryllmethylJamino]-haloalkoxy-2- propanols can be prepared by one skilled in the art using similar methods, as shown in Example Table 48. Example Table 43. 3-[(N-aryl)-[(aryl)methyl]amino]- 1, 1, 1-trifluoro-2-propaols. Ex. Calculated Observed No. Mass Mass [M+H]+ [M+H]+ 2-OCH3 4-CH3 340.1524 340.1492 668 2-OCH3 3-CH3 340 1524 340. 1527 2-OCH3 3-CF3 394.1242 394.1239 670 3-F 2-CF3 382. 1042 382. 1029 671 3-F 2-CH3 328. 1325 328. 1319 672 4-CF3 4-CH3 378. 1293 378. 1273 673 2-CF3 4-CH3 378.1293 378.1284 674 3-F 3-(3-CF3-phenoxy) 474.1304 474.1276 675 3-F 3-(4-OCH3-436. 1536 436. 1532 phenoxy) 676 3-F 3- (4-Cl-phenoxy) 440. 1040 440. 1048 677 3-F 3,5-(CF3)2 450.0916 450. 0923 678 2, 3-difluoro 3-CH3 346. 1230 346. 1209 679 2-F, 3-CF3 4-CH3 396.1198 396.1200 680 2-F, 3-CF3 3-CH3 396.1198 396.1180 681 2, 3-difluor 4-CH3 346. 1230 346. 1228 682 2-OCH3 4-CF3 394.1242 394. 1246 683 3-OCF3 4-benzyloxy 486. 1504 486. 1538 684 3-phenoxy 2-NO2, 4-Cl 467.9 467.9 685 3-phenoxy 4-(3,4-Cl2- 548 548 Ex. Calculated Observed No. Mass Mass M+H]+ [M+H]+ phenoxy) 686 3-phenoxy 4-OCH3 418 418 687 3-phenoxy 3,4-(OCF2CF2O) 518.1202 518.1286 688 3-OCF3 3-CF3 448 448 689 4-phenyl 3-CF3 440. 1449 440. 1430 690 3,5-(CF3)2 3-phenoxy 524 524 691 2,5-(CF3)2 3-CF3 500 500 692 3-OH 3-OCF3 396. 1034 396. 1053 693 3-t4- (propan-560. 1672560. 1694 oyl) phenoxyl Example Table 44. 3-[N-[(aryl)methyl]-[(aryl)methyl]amino]- 1, 1, 1-trifluoro-2-propanols.

Ex. Calculated Observed Mass RSUB1 RSUB2 No. Mass [M+H] [M+H] 694 3-Cl 3-OCF3 428.0852 428. 0817 695 3-Br 3-OCH3 472.0347 472.0312 696 2-F 2-CF3 496.1198 396.1193 Example Table 45. 3-[N-[(aryl)methyl]-[(aryl)methyl]amino]-1,1,1-trifluoro-2- propanols.

Ex. Calculated Observed Mass RSUB1 RSUB2 No. Mass [M+H] [M+H] 697 3-OCF3 3-OCF3 442.1253 442.1232 Example Table 46. 3-[N-(aryl)-N-(aralkyl)amino]-1, 1, 1-trifluoro-2-propanols.

Ex. Calculated Observed No. Mass Mass [M+Hl M+H 698 3-OCF3-2-methoxy-500. 1297 500. 1295 benzyl dibenzofuran-3-yl 699 3-OCF3-2-fluorenyl 468. 1398 468. 1374 benzyl

Example Table 47. 3-[N-(aryl)-[(aryl)methyl]amino]-1,1,1-trifluoro-2- propanols.

Ex. Calculated Observed Mass No.. Mass [M+Hl IM+Hl 700 280. 280. 0949 280. 0938 ZU ZOZO Example Table 48. 3-lN-(aryl)-N-(aralkyl) aminol-l-haloalkoxy-2-propanols.

Ex. Calculated Observed Mass No. RSUB1 Mass [M+H] [M+H 701 F 584. 1483 584. 1473 702 CF3 634. 1451 634. 1432

Based on the preceding procedures, additional substituted 3-l (N-aryl)- [laryllmethyljamino]-halo-2-propanols are prepared by one skilled in the art using similar methods, as shown in the multiple sections of Example Table 49.

Substituted 4-1N-(aryl)-[(aryl) methyl] amino]-l, l, 1, 2, 2-pentafluoro-3-butanols are prepared by one skilled in the art using similar methods, as shown in

Example Table 50. Substituted 3-lN-(aryl)-[(aryl) oxyJaminoJ-l, l, l-trifluoro-2- propanols are prepared by one skilled in the art using similar methods, as shown in Example Table 51. Substituted 3-lN-(aryl)-l (aryl) methyllaminol-l, l, l- trifluoro-2-butanols are prepared by one skilled in the art using similar methods. as shown in Example Table 52.

Substituted 3- [N, N'- (diaryl) amino]-1, 1, 1-trifluoro-2-propanols are prepared by one skilled in the art using similar methods, as shown in Example Table 53.

Substituted 2- [N- (aryl)- [ (aryl) methyl] amino]-I-trifluoromethylcyclopentanols are prepared by one skilled in the art using similar methods, as shown in Example Table 54.

Example Table 49. Substituted 3-[N-(aryl)-[(aryl)methyl]amino]-1,1,1- trifluoro-2-propanols. Ex. Ex. RSUB1 RSUB2 No. No. 703 3-isopropyl 1048 3-CF3O-benzyloxy 704 2-CL, 3-Cl 1049 3-CF3-benzyloxy 705 3-CF3O 1050 3-F, 5-F-benzyloxy 706 4-F 1051 cyclohexylmethyleneoxy 707 4-CH3 1052 benzyloxy 708 2-F, 5-Br 1053 3-CF3, 5-CF3-benzyloxy 709 3-CHF2O 1054 4-CF3O-benzyloxy 710 3-CH3CH2 1055 4-CH3CH2-benzyloxy 711 3-CH3. 5-CH3 1056 isopropoxy 712 3-(CH3)3C 1057 3-CF3-benzyl 713 4-F, 3-CH3 1058 isopropylthio 714 3-Cl, 4-Cl 1059 cyclopentoxy 715 3, 4-(CH2)4 1060 3-Cl-5-pyridinyloxy 716 3-HCF2CF2O 1061 3-CF3S-benzyloxy 717 H 1062 3-CH3, 4-CH3-benzyloxy 3- (CH3) 2N 1063 2-F, 3-CF3-benzyloxy 719 3-cyclopropyl 1064 c#r-#. 3-F, 5-CF3-benzyloxy 720 3-(2-furyl) 1065 4- (CH3)2CH-benzyloxy 721 3-CF3CF2 1066 1-phenylethoxy 722 4-NH2 1067 4-F, 3-CH3-benzoyl Example Table 49 (Continued). Substituted 3-[N-(aryl)-[(aryl)methyl]amino]- 1, 1, 1-trifl uoro-2-propanol s. RSUB1 RSUB2 No. No. 723 1068 3-CH3, 4-CH3, 3-CF3-phenyl- 5-CH3 724 1069 4-CH3CH2CH2O 4-CH3O-phenylamino- 2-NO2 4-NO2-phenylthio- Ex. Ex. RSUB1 RSUB2 No. No. 726 3-isopropyl 1071 3-CF3O-benzyloxy 727 2-Cl, 3-Cl 1072 3-CF3-benzyloxy 728 1073 3-F, 5-F-benzyloxy 3-CF3O 729 4-F 1074 cyclohexylmethyleneoxy 730 1075 benzyloxy 4-CH3 731 2-F, 5-Br 1076 3-CF3, 5-CF3-benzyloxy 732 2-Br, 5-F 1077 4-CF3O-benzyloxy 733 1078 3-CH3CH2 4-CH3CH2-benzyloxy 734 1079 isopropoxy 3-CH3, 5-CH3 735 1080 3-(CH3)3C 3-CF3-benzyl 736 1081 isopropylthio 4-F, 3-CH3 737 3-Cl, 4-Cl 1082 cyclopentoxy 738 1083 3-Cl-5-pyridinyloxy 3,4-(CH2)4 739 1084 3-HCF2CF2O 3-CF3S-benzyloxy 740 1085 3-CHF2O 3-CH3, 4-CH3-benzyloxy Example Table 49 (Continued). Substituted 3- [N- (aryl)- [ (aryl) methyl] amino]- 1, 1, 1-trifluoro-2-propanols. Ex. Ex. RSUB1 RSUB2 No. no. 741 1086 3-(CH3)2N 2-F, 3-CF3-benzyloxy 742 3-cyclopropyl 1087 3-F, 5-CF3-benzyloxy 743 3-(2-furyl) 1088 4-(CH3)2-CH-benzyloxy 744 1089 1-phenylethoxy 3-CF3CF2 745 1090 4-NH2 4-F, 3-CH3-benzoyl 746 1091 3-CH3, 4-CH3, 3-CF3-phenyl- 5-CH3 747 1092 4-CH3CH2CH2O 4-CH3O-phenylamino- 2-NO2 4-NO2-phenylthio- Ex. RSUB1 Ex. RSUB2 749 3-isopropyl 1094 3-CF30-benzyloxy 750 2-Cl, 3-Cl 1095 3-CF3-benzyloxy 751 1096 3-F, 5-F-benzyloxy 3-CF3O 752 4-F 1097 cyclohexylmethyleneoxy 753 4-CH3 1098 benzyloxy 754 2-F, 5-Br 1099 3-CF3, 5-CF3-benzyloxy 755 1100 4-Cl, 3-CH3CH2 4-CF3O-benzyloxy 756 1101 3-CH3CH2 4-CH3CH2-benzyloxy 3-CH3, 5-CH3 1102 isopropoxy Example Table 49 (Continued). Substituted 3-[N-(aryl)-[(aryl)methyl]amino]- 1, 1, 1-trifluoro-2-propanol s. Ex. Ex. RSUB1 RSUB2 No. No. 3- (CH3)3C 1103 3-CF3-benzyl 759 4-F, 3-CH3 1104 isopropylthio 760 3-Cl, 4-CI 1105 cyclopentoxy 761 3,4-(CH2)4 1106 3-Cl-5-pyridinyloxy 762 3-HCF2CF2O 1107 3-CF3S-benzyloxy 763 3-CHF20 1108 3-CH3, 4-CH3-benzyloxy 764 (CH3) 2N 1109 2-F, 3-CF3-benzyloxy 765 3-cyclopropyl 1110 3-F, 5-CF3-benzyloxy 766 3-(2-furyl) 111 4-(CH3)2CH-benzyloxy 3-CF3CF2 1112 1-phenylethoxy 768 4-NH2 1113 4-F, 3-CH3-benzoyl 769 3-CH3, 4-CH3, 1114 3-CF3-phenyl- 5-CH3 770 1115 4-CH3CH2CH2O 4-CH3O-phenylamino- 2-NO2 4-NO2-phenylthio- Ex. Ex. RSUB1 RSUB2 No. No. 772 3-isopropyl 1117 3-CF30-benzyloxy 773 2-Cl, 3-Cl 1118 3-CF3-benzyloxy 774 3-CF30 1119 3-F, 5-F-benzyloxy 775 4-F 1120 cyclohexylmethyleneoxy Example Table 49 (Continued). Substituted 3-[N-(aryl)-[(aryl)methyl]amino]- 1, 1, 1-trifluoro-2-propanols. Ex. Ex. RSUB1 RSUB2 No. No. 776 1121 benzyloxy 4-CH3 777 2-F, 5-Br 1122 3-CF3, 5-CF3-benzyloxy 778 1123 4-Cl, 3-CH3CH2 4-CF3O-benzyloxy 779 1124 3-CH3CH2 4-CH3CH2-benzyloxy 780 1125 isopropoxy 3-CH3, 5-CH3 781 1126 3-(CH3)3C 3-CF3-benzyl 782 1127 isopropylthio 4-F, 3-CH3 783 3-Cl, 4-Cl 1128 cyclopentoxy 784 1129 3-Cl-5-pyridinyloxy 3,4-(CH2)4 785 1130 3-HCF2CF2O 3-CF3S-benzyloxy 786 1131 3-CHF2O 3-CH3, 4-CH3-benzyloxy 787 1132 3-(CH3)2N 2-F, 3-CF3-benzyloxy 788 3-cyclopropyl 1133 3-F, 5-CF3-benzyloxy 789 3-(2-furyl) 1134 4-(CH302CH-benzyloxy 790 1135 1-phenylethoxy 3-CF3CF2 791 1136 4-NH2 4-F, 3-CH3-benzoyl 792 1137 3-CH3, 4-CH3, 3-CF3-phenyl- 5-CH3 793 1138 4-CH3CH2CH2O 4-CH3O-phenylamino- 794 1139 2-NO2 4-NO2-phenylthio- Example Table 49 (Continued). Substituted 3-[N-(aryl)-[(aryl)methyl]amino]- 1, 1, 1-trifl uoro-2-propanol s. Ex. Ex. RSUB1 RSUB2 No. No. 795 3-isopropyl 1140 3-CF30-benzyloxy 796 2-Cl, 3-Cl 1141 3-CF3-benzyloxy 797 3-CF30 1142 3-F, 5-F-benzyloxy 798 4-F 1143 cyclohexylmethyleneoxy 799 4-CH3 1144 benzyloxy 800 2-F, 5-Br 1145 3-CF3, 5-CF3-benzyloxy 801 4-Cl, 3-CH3CH2 1146 4-CF3O-benzyloxy 802 3-CH3CH2 1147 4-CH3CH2-benzyloxy 803 3-CH3, 5-CH3 1148 isopropoxy 3- (CH3) 3C 1149 3-CF3-benzyl 805 4-F, 3-CH3 1150 isopropylthio 806 3-Cl, 4-CI 1151 cyclopentoxy 807 1152 3-Cl-5-pyridinyloxy 3,4-(CH2)4 808 1153 3-HCF2CF2O 3-CF3S-benzyloxy 809 1154 3-CHF2O 3-CH3, 4-CH3-benzyloxy 810 3- (CH3) 2N 1155 2-F, 3-CF3-benzyloxy 811 3-cyclopropyl 1156 3-F, 5-CF3-benzyloxy 812 3-(2-furyl) 1157 4-(CH3)2CH-benzyloxy 813 1158 1-phenylethoxy 3-CF3CF2 814 4-NH2 1159 4-F, 3-CH3-benzoyl 815 3-CH3, 4-CH3, 1160 3-CF3-phenyl- 5-CH3 Example Table 49 (Continued). Substituted 3-[N-(aryl)-[(aryl)methyl]amino]- 1, 1, 1-trifluoro-2-propanols. Ex. Ex. No. RSUB1 No. RSUB2 816 4-CH3CH2CH20 1161 4-CH30-phenylamino- 2-NO2 1162 4-NO2-phenylthio- Ex. Ex. No. No. 818 3-isopropyl 1163 3-CF30-benzyloxy 819 2-Cl, 3-Cl 1164 3-CF3-benzyloxy 820 3-CF3O 1165 3-F, 5-F-benzyloxy 821 4-F 1166 cyclohexylmethyleneoxy 822 4-CH3 1167 benzyloxy 823 2-F, 5-Br 1168 3-CF3, 5-CF3-benzyloxy 824 1169 4-Cl, 3-CH3CH2 4-CF3O-benzyloxy 825 1170 3-CH3CH2 4-CH3CH2-benzyloxy 826 1171 isopropoxy 3-CH3, 5-CH3 827 1172 3-(CH3)3C 3-CF3-benzyl 828 4-F, 3-CH3 1173 isopropylthio 829 3-Cl, 4-Cl 1174 cyclopentoxy 830 1175 3-Cl-5-pyridinyloxy 3,4-(CH2)4 831 1176 3-HCF2CF2O 3-CF3S-benzyloxy 832 3-CHF20 1177 3-CH3, 4-CH3-benzyloxy 833 3-(CH3) 2N 1178 2-F, 3-CF3-benzyloxy 834 3-cyclopropyl 1179 3-F, 5-CF3-benzyloxy Example Table 49 (Continued). Substituted 3-[N-(aryl)-[(aryl)methyl]amino]- 1, 1, 1-trifl uoro-2-propanol s. Ex. Ex. RSUB1 RSUB2 No. No. 835 3-(2-furyl) 1180 4-(CH3)2CH-benzyloxy 836 3-CF3CF2 1181 I-phenylethoxy 837 4-NH2 1182 4-F, 3-CH3-benzoyl 3-CH3, 4-CH3, 1183 3-CF3-phenyl- 5-CH3 839 4-CH3CH2CH20 1184 4-CH30-phenylamino- 2-NO2 1185 4-NO2-phenylthio- Ex. Ex. No. RSUB1 No. RSUB2 3-CF30-benzyloxy 842 2-Cl, 3-Cl 1187 3-CF3-benzyloxy 843 3-CF30 1188 3-F, 5-F-benzyloxy 844 4-F 1189 cyclohexylmethyleneoxy 845 1190 benzyloxy 4-CH3 846 2-F, 5-Br 1191 3-CF3, 5-CF3-benzyloxy 847 192 4-Cl, 3-CH3CH2 4-CF3O-benzyloxy 848 1193 3-CH3CH2 4-CH3CH2-benzyloxy 849 1194 isopropoxy 3-CH3, 5-CH3 850 1195 3-(CH3)3C 3-CF3-benzyl 851 4-F, 3-CH3 1196 isopropylthio 852 3-Cl, 4-Cl 1197 cyclopentoxy Example Table 49 (Continued). Substituted 3- [N- (aryl)- [ (aryl) methy !) amino]- 1, 1, 1-trifluoro-2-propanols. Ex. Ex. RSUB1 RSUB2 No. No. 853 1198 3-Cl-5-pyridinyloxy 3,4-(CH2)4 854 1199 3-HCF2CF2O 3-CF3S-benzyloxy 855 3-CHF2O 1200 3-CH3, 4-CH3-benzyloxy 856 3- (CH3) 2N 1201 2-F, 3-CF3-benzyloxy 857 3-cyclopropyl 1202 3-F, 5-CF3-benzyloxy 858 3-(2-furyl) 1203 4- (CH3)2CH-benzyloxy 859 3-CF3CF2 1204 1-phenylethoxy 860 4-NH2 1205 4-F, 3-CH3-benzoyl 861 3-CH3, 4-CH3, 1206 3-CF3-phenyl- 5-CH3 862 4-CH3CH2CH2O 1207 4-CH3O-phenylamino- 863 2-NO2 1208 4-NO2-phenylthio- Ex. Ex. RSUB1 RSUB2 No. No. 864 3-isopropyl 1209 3-CF3O-benzyloxy 865 2-Cl, 3-Cl 1210 3-CF3-benzyloxy 866 1211 3-F, 5-F-benzyloxy 3-CF3O 867 4-F 1212 cyclohexylmthyleneoxy 868 1213 benzyloxy 4-CH3 869 2-F, 5-Br 1214 3-CF3, 5-CF3-benzyloxy 870 1215 4-Cl, 3-CH3CH2 4-CF3O-benzyloxy Example Table 49 (Continued). Substituted 3-[N-(aryl)-[(aryl)methyl]amino]- 1, 1, 1-trifluoro-2-propanols. Ex. Ex. RSUB1 RSUB2 No. No. 871 3-CH3 CH2 1216 4-CH3 CH2-benzyloxy 872 3-CH3, 5-CH3 1217 isopropoxy 873 (CH3) 3C 1218 3-CF3-benzyl 874 4-F, 3-CH3 1219 isopropylthio 875 3-Cl, 4-Cl 1220 cyclopentoxy 1221 3-Cl-5-pyridinyloxy 3,4-(CH2)4 1222 3-HCF2CF2O 3-CF3S-benzyloxy 878 3-CHF2O 1223 3-CH3, 4-CH3-benzyloxy 3- (CH3) 2N 1224 2-F, 3-CF3-benzyloxy 880 3-cyclopropyl 1225 3-F, 5-CF3-benzyloxy 881 3-(2-furyl) 1226 4-(CH3)2CH-benzyloxy 882 3-CF3CF2 1227 I-phenylethoxy 883 4-NH2 1228 4-F, 3-CH3-benzoyl 884 3-CH3, 4-CH3, 1229 3-CF3-phenyl- 5-CH3 885 4-CH3CH2CH2O 1230 4-CH3O-phenylamino- 886 2-NO2 1231 4-NO2-phenylthio- Ex. Ex. RSUB1 RSUB2 No. No. 887 3-isopropyl 1232 3-CF3O-benzyloxy Example Table 49 (Continued). Substituted 3-[N-(aryl)-[(aryl)methyl]amino]- 1, 1, 1-trifluoro-2-propanols. RSUB1 RSUB2 No. No. 888 2-Cl, 3-Cl 1233 3-CF3-benzyloxy 889 1234 3-F, 5-F-benzyloxy 3-CF3O 890 4-F 1235 cyclohexylmethyleneoxy 891 1236 benzyloxy 4-CH3 892 2-F, 5-Br 1237 3-CF3, 5-CF3-benzyloxy 893 4-Cl, 3-CH3CH2 1238 4-CF30-benzyloxy 894 3-CH3CH2 1239 4-CH3CH2-benzyloxy 895 3-CH3, 5-CH3 1240 isopropoxy 896 3-(CH3)3C 1241 3-CF3-benzyl 897 4-F, 3-CH3 1242 isopropylthio 898 3-Cl, 4-Cl 1243 cyclopentoxy 3,4-(CH2)4 1244 3-Cl-5-pyridinyloxy 3-HCF2CF20 1245 3-CF3S-benzyloxy 901 3-CHF2O 1246 3-CH3, 4-CH3-benzyloxy 902 3-(CH3)2N 1247 2-F, 3-CF3-benzyloxy 903 3-cyclopropyl 1248 3-F, 5-CF3-benzyloxy 904 3-(2-furyl) 1249 4-(CH3)2CH-benzyloxy 3-CF3CF2 1250 1-phenylethoxy 906 4-NH2 1251 4-F, 3-CH3-benzoyl 3-CH3, 4-CH3, 1252 3-CF3-phenyl- 5-CH3 8 1253 4-CH3CH2CH2O 4-CH3O-phenylamino- 2-NO2 4-NO2-phenylthio- Example Table 49 (Continued). Substituted 3-[N-(aryl)-[(aryl)methyl]amino]- 1, 1, 1-trifluoro-2-propanols. Ex. Ex. RSUB1 RSUB2 No. No. 910 3-isopropy 1255 3-CF3O-benzyloxy 911 2-Cl, 3-Cl 1256 3-CF30-benzyloxy 912 3-CF30 1257 3-F, 5-F-benzyloxy 913 4-F 1258 cyclohexylmethyleneoxy 914 1259 benzyloxy 4-CH3 915 2-F, 5-Br 1260 3-CF3, 5-CF3-benzyloxy 916 4-Cl, 3-CH3CH2 1261 4-CF3O-benzyloxy 917 3-CH3CH2 1262 oxy 918 3-CH3, 5-CH3 1263 isopropoxy 919 3_ (CH3) 3C 1264 3-CF3-benzyl 920 4-F, 3-CH3 1265 isopropylthio 921 3-Cl, 4-Cl 1266 cyclopentoxy 922 1267 3-Cl-5-pyridinyloxy 3,4-(CH2)4 923 1268 3-HCF2CF2O 3-CF3S-benzyloxy 924 1269 3-CHF2O 3-CH3, 4-CH3-benzyloxy 925 3- (CH3) 2N 1270 2-F, 3-CF3-benzyloxy 926 3-cyclopropyl 1271 3-F, 5-CF3-benzyloxy 3-F, 5-CF3-benzyloxy 927 3-(2-furyl) 1272 4-(CH3)2CH-benzyloxy 928 1273 1-phenylethoxy 3-CF3CF2 929 1274 4-NH2 4-F, 3-CH3-benzoyl 930 3-CH3, 4-CH3, 1275 3-CF3-phenyl- 5-CH3 L- Example Table 49 (Continued). Substituted 3-[N-(aryl)-[(aryl)methyl]amino]- 1, 1, 1-trifluoro-2-propanols. Ex. Ex. RSUB2 931 4-CH3CH2CH2O 1276 4-CH3O-phenylamino- 932 2-N02 1277 4-N02-phenylthio- Ex. Ex. RSUB1 RSUB2 No. No. 3-CF30-benzyloxy 934 2-Cl, 3-Cl 1279 3-CF3-benzyloxy 3-CF3-benzyloxy 935 3-CF30 1280 3-F, 5-F-benzyloxy 936 4-F 1281 cyclohexylmethyleneoxy 937 4-CH3 1282 benzyloxy 938 2-F, 5-Br 1283 3-CF3, 5-CF-benzyloxy 939 ¢Cl, 3-CH3CH2 1284 4-CF30-benzyloxy 940 3-CH3CH2 1285 4-CH3CH2-benzyloxy 941 3-CH3, 5-CH3 1286 isopropoxy 942 3-(CH3)3C 1287 3-CF3-benzyl 943 4-F, 3-CH3 1288 isopropylthio 944 3-Cl, 4-Cl 1289 cyclopentoxy 945 3,4-(CH2)4 1290 3-Cl-5-pyridinyloxy 946 1291 3-HCF2CF2O 3-CF3S-benzyloxy 947 1292 3-CHF2O 3-CH3, 40-CH3-benzyloxy 948 3-(CH3)2N 1293 2-F, 3-CF3-benzyloxy Example Table 49 (Continued). Substituted 3-[N-(aryl)-[(aryl)methyl]amino]- 1, 1, 1-trifluoro-2-propanols. Ex-| RSUB1 Ex. RStlB2 949 3-cyclopropyl 1294 3-F, 5-CF3-benzyloxy 950 3-(2-furyl) 1295 4-(CH3)2CH-benzyloxy 951 1296 1-phenylethoxy 3-CF3CF2 952 4-NH2 1297 4-F, 3-CH3-benzoyl 953 3-CH3, 4-CH3, 1298 3-CF3-phenyl- 5-CH3 954 1299 4-CH3CH2CH2O 4-CH3O-phenylamino- 2-NO2 4-NO2-phenylthio RSUB1 RSUB2 No. No. 956 3-isopropyl 1301 3-CF3O-benzyloxy 957 2-Cl, 3-Cl 1302 3-CF3-benzyloxy 958 1302 3-F, 5-F-benzyloxy 3-CF3O 959 4-F 1304 cyclohexylmethyleneoxy 960 1305 benzyloxy 4-CH3 961 2-F, 5-Br 1306 3-CF3, 5-CF3-benzyloxy 962 2-Br, 5-F 1307 4-CF3O-benzyloxy 963 1308 3-CH3CH2 4-CH3CH2-benzyloxy 964 1309 isopropoxy 3-CH3, 5-CH3 Example Table 49 (Continued). Substituted 3-[N-(aryl)-[(aryl)methyl]amino]- 1, 1, 1-trifluoro-2-propanols. Ex. Ex. RSUB1 RSUB2 No. No. 965 1320 3-(CH3)3C 3-CF3-benzyl 966 1311 isopropylthio 4-F, 3-CH3 967 3-Cl, 4-Cl 1312 cyclopentoxy 968 1313 3-Cl-5-pyridinyloxy 3,4-(CH2)4 969 1314 3-HCF2CF2O 3-CF3S-benzyloxy 970 1315 3-CHF2O 3-CH3, 4-CH3-benzyloxy 971 1316 3-(CH3)2N 2-F, 3-CF3-benzyloxy 972 3-cyclopropyl 1317 3-F, J5-CF3-benzyloxy 973 3-(2-furyl) 1318 4-(CH3)2CH-benzyloxy 974 1319 1-phenylethoxy 3-CF3CF2 975 1320 4-NYH2 4-F, 3-CH3-benzoyl 976 1321 3-CH3, 4-CH3, 3-CF3-phenyl- 5-CH3 977 1322 4-CH3CH2CH2O 4-CH3O-phenylamino- 978 1323 2-NO2 4-NO2-phenylthio- Ex. Ex. RSUB1 RSUB2 No. No. 979 3-isopropyl 1324 3-CF3O-benzyloxy 980 2-Cl, 3-Cl 1325 3-CF3-benzyloxy 981 1326 3-F, 5-F-benzyloxy 3-CF3O Example Table 49 (Continued). Substituted 3-[N-(aryl)-[(aryl)methyl]amino]- 1, 1, 1-trifluoro-2-propanols. Ex. Ex. RSUB1 RSUB2 No. No. 982 4-F 1327 cyclohexylmethylencoxy 983 1328 benzyloxy 4-CH3 984 2-F, 5-Br 1329 3-CF3, 5-CF3-benzyloxy 985 1330 4-Cl, 3-CH3CH2 4-CF3O-benzyloxy 986 1331 3-CH3CH2 4-CH3CH2-benzyloxy 987 1332 isopropoxy 3-CH3, 5-CH3 988 1333 3-(CH3)3C 3-CF3-benzyl 989 1334 isopropylthio 4-F, 3-CH3 990 3-Cl, 4-Cl 1335 cyclopentoxy 991 1336 3-Cl-5-pyridinyloxy 3,4-(CH2)4 992 1337 3-HCF2CF2O 3-CF3S-benzyloxy 993 1338 3-CHF2O 3-CH3, 4-CH3-benzyloxy 994 1339 3-(CH3)2N 2-F,3-CF3-benzyloxy 995 3-cyclopropyl 1340 3-F, 5-CF3-benzyloxy 996 3-(2-furyl) 1351 4-(CH3)2CH-benzyloxy 997 1342 1-phenylethoxy 3-CF3CF2 998 1343 4-NH2 4-F, 3-CH3-benzoyl 999 1344 3-CH3, 4-CH3, 3-CF3-phenyl- 5-CH3 1000 1345 4-CH3CH2CH2O 4-CH3O-phenylamino- 2-NO2 4-NO2-phenylthio- Example Table 49 (Continued). Substituted 3-[N-(aryl)-[(aryl)methyl]amino]- 1, 1, 1-trifluoro-2-propanol s. Ex. Ex. RSUB1 RSUB2 No. No. 1002 3-isopropyl 1347 3-CF3O-benzyloxy 1003 2-Cl, 3-Cl 1348 3-CF3-benzyloxy 1004 1349 3-F, 5-F-benzyloxy 3-CF3O 1005 4-F 1350 cyclohexylmethyleneoxy 1006 1351 benzyloxy 4-CH3 1007 2-F, 5-Br 1352 3-CF3, 5-CF3-benzyloxy 1008 1353 4-Cl, 3-CH3CH2 4-CF3O-benzyloxy 1009 3-CH3CH2 1354 4-CH3CH2-benzyloxy 1010 3-CH3, 5-CH3 1355 isopropoxy 1011 3-(CH3) 3C 1356 3-CF3-benzyl 1012 4-F, 3-CH3 1357 isopropylthio 1013 3-Cl, 4-CI 1358 cyclopentoxy 1014 1359 3-Cl-5-pyridinyloxy 3,4-(CH2)4 1015 1360 3-HCF2CF2O 3-CF3S-benzyloxy 1016 3-CHF20 1361 3-CH3, 4-CH3-benzyloxy 1017 3-(CH3) 2N 1362 2-F, 3-CF3-benzyloxy 1018 3-cyclopropyl 1363 3-F, 5-CF3-benzyloxy 1019 3-(2-furyl) 1364 4-(CH3)2CH-benzyloxy 1020 3-CF3CF2 1365 1-phenylethoxy 1021 4-NH2 1366 4-F, 3-CH3-benzoyl 1022 3-CH3, 4-CH3, 1367 3-CF3-phenyl- Example Table 49 (Continued). Substituted 3-[N-(aryl)-[(aryl)methyl] amino]- 1, 1, 1-trifl uoro-2-propanol s. RSUB1 RSUB2 No. No. 5-CH3 1023 1368 4-CH3CH2CH2O 4-CH3O-phenylamino- 1024 2-NO2 1369 4-N02-phenylthio- Ex. Ex. No. No. 1025 3-isopropyl 1370 3-CF30-benzyloxy 1026 2-Cl, 3-CI 1371 3-CF3-benzyloxy 1027 3-CF30 1372 3-F, 5-F-benzyloxy 1028 4-F 1373 cyclohexylmethyleneoxy 1029 4-CH3 1374 benzyloxy 1030 2-F, 5-Br 1375 3-CF3, 5-CF3-benzyloxy 1031 4-Cl, 3-CH3CH2 1376 4-CF3O-benzyloxy 1032 3-CH3CH2 1377 4-CH3CH2-benzyloxy 1033 3-CH3, 5-CH3 1378 isopropoxy 1034 3-(CH3)3C 1379 3-CF3-benzyl 1035 4-F, 3-CH3 1380 isopropylthio 1036 3-Cl, 4-Cl 1381cyclopentoxy 1037 1382 3-Cl-5-pyridinyloxy 3,4-(CH2)4 1038 3-HCF2CF2O 1383 3-CF3S-benzyloxy 1039 3-CHF2O 1384 3-CH3, 4-CH3-benzyloxy 1040 (CH3) 2N 1385 2-F, 3-CF3-benzyloxy Example Table 49 (Continued). Substituted 3-[N-(aryl)-[(aryl)methyl]amino]- 1, 1, 1-trifluoro-2-propanols. RSUB1 RSUB2 1041 3-cyclopropyl 1386 3-F, 5-CF3-benzyloxy 1042 3- (2-furyl) 1387 4- (CH3) 2CH-benzyloxy 1043 3-CF3CF2 1388 1-phenylethoxy 1044 4-NH2 1389 4-F, 3-CH3-benzoyl 1045 1390 3-CH3, 4-CYH3, 3-CF3-phenyl- 5-CH3 046 4-CH3CH2CH20 1391 4-CH30-phenylamino- 2-NO2 1392 4-NO2-phenylthio- Example Table 50. Substituted 4-[N-(aryl)-[(aryl)methyl]amino]-1,1,1, 2, 2- pentafluoro-3-butanols. Ex. Ex. No. No. 1393 3-isopropyl 1416 3-CF3O-benzyloxy 1394 2-Cl, 3-Cl 1417 3-CF3-benzyloxy 1395 1418 3-F, 5-F-benzyloxy 3-CF3O 1396 4-F 1419 cyclohexylmethyleneoxy 1397 4-CH3 1420 benzyloxy 1398 2-F, 5-Br 1421 3-CF3, 5-CF3-benzyloxy 1399 1422 4-Cl, 3-CH3CH2 4-CF3O-benzyloxy 1400 3-CH3CH2 1423 4-CH3CH2-benzyloxy 1401 3-CH3, 5-CH3 1424 isopropoxy 1402 3-(CH3) 3C 1425 3-CF3-benzyl 1403 4-f, 3-CH3 1426 isopropylthio 1404 3-Cl, 4-Cl 1427 cyclopentoxy 1405 1428 3-Cl-5-pyridinyloxy 3,4-(CH2)4 1406 1429 3-HCF2CF2O 3-CF3S-benzyloxy 1407 1430 3-CHF2O 3-CH3, 4-CH3-benzyloxy 1408 3-(CH3) 2N 1431 2-F, 3-CF3-benzyloxy 1409 3-cyclopropyl 1432 3-F, 5-CF3-benzyloxy 1410 3-(2-furyl) 1433 1410 (CH3)2CH-benzyloxy 1411 3-CF3 CF2 1434 1-phenylethoxy 1412 4-NH2 1435 4-F, 3-CH3-benzoyl 1413 3-CH3, 4-CH3, 1436 3-CF3-phenyl- Example Table 50 (continued). Substituted 4-[N-(aryl)-[(aryl(methyl]amino]- 1, 1, 1, 2, 2-pentafluoro-3-butanols. Ex. Ex. RSUB1 RSUB1 No. No. 5-CH3 1414 4-CH3CH2CH20 ! am) no- 1415 2-N02 1438 4-N02-phenylthio- Example Table 51. Substituted 3-[N-(aryl)-[(aryl)oxy]amino]-1,1,1-trifluoro-2- propanols. Ex. RSUB1 RSUB1 Ex. No. 3-isopropyl 1462 3-CF3O-benzyloxy 1439 2-Cl, 3-Cl 1463 3-CF3-benzyloxy 1440 1464 3-F, 5-F-benzyloxy 1441 4-F 1465 cyclohexylmethyleneoxy 1442 1466 benzyloxy 1443 2-F, 5-Br 1467 3-CF3, 5-CF3-benzyloxy 1444 1468 4-Cl, 3-CH3CH2 4-CF3O-benzyloxy 3-CH3CH2 4-CH3CH2-benzyloxy 1446 1470 isopropoxy 3-CH3, 5-CH3 3-(CH3)3C 3-CF3-benzyl 1448 1472 isopropylthio 4-F, 3-CH3 1449 3-Cl, 4-Cl 1473 cyclopentoxy 1450 1474 3-Cl-5-pyridinyloxy 3,4-(CH2)4 3-HCF2CF2O 3-CF3S-benzyloxy 1452 1476 3-CHF2O 3-CH3, 4-CH3-benzyloxy 1453 1477 3-(CH3)2N 2-F, 3-CF3-benzyloxy 1454 3-cyclopropyl 1478 3-F, 5-CF3-benzyloxy 1455 Example Table 51 (continued). Substituted 3-[N-(aryl)-[(aryl)oxy]amino]- 1, 1,1-trifluoro-2-propanols. Ex. RSUB1 RSUB2 Ex. No. 3-(2-furyl) 1479 4-(CH3)2CH-benzyloxy 1456 1480 1-phenylethoxy 1457 4-NH2 4-F, 3-CH3-benzoyl 1458 1482 3-CH3, 4-CH3, 3-CF3-phenyl- 5-CH3 1483 4-CH3CH2CH2O 4-CH3O-phenylamino- 1460 1484 2-NO2 4-NO2-phenylthio- 1461 Example Table 52. Substituted 3-[N-(aryl)-[(aryl)methyl]amino]-1,1,1- trifluoro-2-butanols. Ex. Ex. RSUB1 RSUB2 No. No. 1485 3-isopropyl 1531 3-CF30-benzyloxy 1486 2-Cl, 3-CI 1532 3-CF3-benzyloxy 1487 3-CF30 1533 3-F, 5-F-benzyloxy 1488 4-F 1534 cyclohexylmethyleneoxy 1489 4-CH3 1535 benzyloxy 1490 2-F, 5-Br 1536 1490 2-F, 5-Br 1536 3-CF3, 5-CF3-benzyloxy 1491 4-Cl, 3-CH3CH2 1537 oxy 1492 3-CH3CH2 1538 4-CH3CH2-benzyloxy 1493 3-CH3, 5-CH3 1539 isopropoxy 1494 3-(CH3)3C 1540 3-CF3-benzyl 1495 4-F, 3-CH3 1541 isopropylthio 1496 3-Cl, 4-Cl 1542 cyclopentoxy 1497 1543 3-Cl-5-pyridinyloxy 3,4-(CH2)4 1498 1544 3-HCF2CF2O 3-CF3S-benzyloxy 1499 1545 3-CHF2O 3-CH3, 4-CH3-benzyloxy 1500 3-(CH3) 2N 1546 2-F, 3-CF3-benzyloxy 1501 3-cyclopropyl 1547 3-F, 5-CF3-benzyloxy 3-F, 5-CF3-benzyloxy 1502 3-(2-furyl) 1548 1502 3-(2-furyl) 1548 4-(CH3) 2CH-benzyloxy 1503 3-CF3CF2 1549 1-phenylethoxy 1504 4-NH2 1550 4-F, 3-CH3-benzoyl 1505 3-CH3, 4-CH3, 1551 3-CF3-phenyl- 5-CH3 Example Table 52 (continued). Substituted 3-[N-(aryl)-[(aryl)methyl]amino]- 1, 1, 1-trifluoro-2-butanols. RSUB1 RSUB2 1506 4-CH3 CH2CH2° 1552 4-CH30-phenylamino- 2-NO2 4-NO2-phenylthio- 1508 3-isopropyl 1554 3-CF3O-benzyloxy 1509 2-Cl, 3-Cl 1555 3-CF3-benzyloxy 1510 1556 3-F, 5-F-benzyloxy 3-CF3O 1511 4-F 1557 cyclohexylmethyleneoxy 1512 4-CH3 1558 benzyloxy 1513 2-F, 5-Br 1559 3-CF3, 5-CF3-benzyloxy 1514 1560 4-Cl, 3-CH3CH2 4-CF3O-benzyloxy 1515 1561 3-CH3CH2 4-CH3CH2-benzyloxy 1516 3-CH3, 5-CH3 1562 isopropoxy 1517 3-(CH3)3C 1563 3-CF3-benzyl 1518 4-F, 3-CH3 1564 isopropylthio 1519 3-Cl, 4-Cl 1565 cyclopentoxy 1520 3, 4- (CH2) 4 1566 3-Cl-5-pyridinyloxy 1521 3-HCF2CF20 1567 3-CF3S-benzyloxy 1522 3-CHF20 1568 3-CH3, 4-CH3-benzyloxy 1523 3-(CH3)2N 1569 2-F, 3-CF3-benzyloxy 1524 3-cyclopropyl 1570 3-F, 5-CF3-benzyloxy 1525 3-(2-furyl) 1571 4-(CH3)2CH-benzyloxy 1526 1572 1-phenylethoxy 3-CF3CF2 1527 1573 4-NH2 4-F, 3-CH3-benzoyl 1528 1574 3-CH3, 4-CH3, 3-CF3-phenyl- 5-CH3 1529 1575 4-CH3CH2CH2O 4-CH3O-phenylamino- 1530 2-NO2 1576 4-N02-phenylthio- Example Table 53. Substituted 3-[N,N'-(diaryl)amino]-1,1,1, 2, 2-pentafluoro- 2-propanols. Ex. Ex. RSUB1 RSUB2 No. No. 1577 3-isopropyl 1600 3-CF3O-benzyloxy 1578 2-Cl, 3-Cl 1601 3-CF3-benzyloxy 1579 1602 3-F, 5-F-benzyloxy 3-CF3O 1580 4-F 1603 cyclohexylmethyleneoxy 1581 4-CH3 1604 benzyloxy 1582 2-F, 5-Br 1605 3-CF3, 5-CF3-benzyloxy 1583 1606 4-Cl, 3-CH3CH2 4-CF3O-benzyloxy 1584 3-CH3CH2 1607 4-CH3CH2-benzyloxy 1585 3-CH3, 5-CH3 1608 isopropoxy 1586 3-(CH3)3C 1609 3-CF3-benzyl 1587 4-F, 3-CH3 1610 isopropylthio 1588 3-CI, 4-CI 1611 cyclopentoxy 1589 3, 4- (CH2) 4 1612 3-CI-5-pyridinyloxy 1590 3-HCF2CF20 1613 3-CF3S-benzyloxy 1591 3-CHF20 1614 3-CH3, 4-CH3-benzyloxy 1592 3-(CH3)2N 1615 2-F, 3-CF3-benzyloxy 1593 3-cyclopropyl 1616 3-F, 5-CF3-benzyloxy 1594 3-(2-furyl) 1617 1594 (CH3) 2CH-benzyloxy 1595 3-CF3CF2 1618 1-phenylethoxy 1596 4-NH2 1619 4-F, 3-CH3-benzoyl 1597 3-CH3, 4-CH3, 1620 3-CF3-phenyl 5-CH3I I Example Table 53 (continued). Substituted 3-[N,N'-(diaryl)amino]-1, 1, 1, 2, 2- pentafluoro-2-propanols. Ex. Ex. RSUB1 RSUB2 No. No. 1598 1621 4-CH3CH2CH2O 4-CH3O-phenylamino 2-NO2 4-NO2-phenylthio Example Table 54. Substituted 2-[N-(aryl)-[(aryl)methyl]amino]-1- trinuoromethyicydopentanois. Ex. Ex. No. No. 1623 3-isopropyl 1646 3-CF3O-benzyloxy 1624 2-Cl, 3-Cl 1647 3-CF3-benzyloxy 1625 1648 3-F, 5-F-benzyloxy 3-CF3O 1626 4F 1649 cyclohexylmethyleneoxy 1627 1650 benzyloxy 4-CH3 1628 2-F, 5-Br 1651 3-CF3, 5-CF3-benzyloxy 1629 4-Cl, 3-CH3CH2 1652 4-CF3O-benzyloxy 1630 3-CH3CH2 1653 4-CH3CH2-benzyloxy 1631 3-CH3, 5-CH3 1654 isopropoxy 1632 3-(CH3)3C 1655 3-CF3-benzyl 1633 4-F, 3-CH3 1656 isopropylthio 1634 3-Cl, 4-Cl 1657 cyclopentoxy 1635 1658 3-Cl-5-pyridinyloxy 3,4-(CH2)4 1636 3-HCF2CF2O 1659 3-CF3S-benzyloxy 1637 3-CHF2O 1660 3-CH3, 4-CH3-benzyloxy 1638 3-(CH3)2N 1661 2-F, 3-CF3-benzyloxy 1639 3-cyclopropyl 1662 3-F, 5-CF3-benzyloxy 1640 3-(2-furyl) 1663 4-(CH3)2CH-benzyloxy 1641 3-CF3CF2 1664 1-phenylethoxy 1642 4-NH2 1665 4-F, 3-CH3-benzoyl 1643 3-CH3, 4CH3, 1666 3-CF3-phenyl- 5-CH3 Example Table 54. (Continued) Substituted 2-[N-(aryl)-[(aryl)methyl]amino]-1- trifluoromethylcyclopentanols. Ex. Ex. RSUB1 RSUB2 No. No. 1644 4- 1667 4-CH3O-phenylamino- CH3CH2CH2O 2-NO2 4-NO2-phenylthio- EXAMPLE 1669

N- (3-phenoxyphenyl)-N- (3, 3, 3, 2-tetrafluoropropyl)-3- (1, 1, 2, 2- tetrafluoroethoxy) benzenemethanamine To a solution of 3- [ (3-phenoxyphenyl) [ [3- (1, 1, 2, 2-tetrafluoroethoxy) phenyl]- methyl] amino]-l, l, l-trifluoro-2-propanol (474 mg, 0. 00094 mol) in 4. 5 mL of dichloromethane at 0 °C was added (diethylamino) sulfur trifluoride (378 mg, 0. 0023 mol). The reaction mixture was warmed to room temperature and stirred for 2 h, then quenched with water and extracted with dichloromethane.

The organic layers were combined, dried over MgSO4, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with 1 : 9 ethyl acetate in hexane to afford 240 mg (50%) of the desired N- (3-phenoxyphenyl)-N- (3, 3, 3, 2-tetra-fluoropropyl)-3- (1, 1, 2, 2- tetrafluoroethoxy) benzenemethanamine product as a yellow oil. HRMS calcd. for C24H19F8N02 : 506. 1366 [M+H], found : 506. 1368. 1H NMR (CDC13) 6 7. 26 (m, 3H), 7. 20 (m, 5H), 6. 87 (d, 2H), 6. 62 (d, 1H), 6. 50 (s, 1H), 6. 49 (d, 1H), 5. 87 (t, 1H), 4. 89 (d, 1H), 4. 77-4. 52 (m, 1H), 4. 73 (d, 1H), 4. 60 (s, 2H).

F NMR (CDC13) 6-69. 83 (t, 3F),-88. 63 (s, 2F),-137. 19 (dt, 2F),-228. 82 (1F).

EXAMPLE 1670

2-ll3-(4-chloro-3-ethylphenoxy) phenyl] l [3-(1, I, 2, 2- tetrafluoroethoxy) phenyl] methyl] amino]-3, 3, 3-trifluoropropanol To a dichloromethane (2 mL) solution of N [ (4-chloro-3-ethyl- phenoxy) phenyl] [ [3- (1, 1, 2, 2-tetrafluoroethoxy) phenyl) methyl] amine (0. 25g, 0. 55 mmol) and 2-diazo-3, 3, 3-trifluoropropionic acid p-nitrophenyl ester (0. 14 g, 0. 51 mmol) was added solid Rh2 (OAc) 4 (0. 015 g, 0. 034 mmol). The resulting green slurry was stirred at room temperature under nitrogen for 24 h.

The solvent was removed to give a green oil, and the crude intermediate was dissolved in THE (4 mL). This green solution was cooled to 0 °C, and a 1. 0 M solution of LiAIH4 in THF (0. 6 mL, 0. 6 mmol) was added dropwise. The resulting dark solution was stirred for 30 min at 0 °C and quenched by the slow addition of water. The reaction mixture was extracted with Et20, dried (MgSO4) and evaporated to give a brown oil. Purification by flash column chromatography on silica gel eluting with 20% ethyl acetate in hexane gave 0. 032 g (11%) of the desired 2- [ [3- (4-chloro-3-ethylphenoxy) phenyl] [ [3- (1, 1, 2, 2-tetrafluoro-ethoxy) phenyl] methyl] amino]-3, 3, 3-trifluoropropanol

product as a light brown oil. HRMS calcd. for C26H23NO3CIF7 : 566. 1333 [M+H] +, found : 566. 1335. H NMR (C6D6) 6 0. 53 (t, 1H, exchangeable with D20), 0. 93 (t, 3H), 2. 43 (t, 2H), 3. 33 (m, 2H), 4. 11 (s, 2H), 4. 13 (m, 1H), 5. 04 (tt, 1H), 6. 4 (m, 3H), 6. 55 (t, 1H), 6. 7-6. 8 (m, 5H), 6. 97 (d, 1H), 7. 04 (s, 1H).

EXAMPLE 1671 N- (3-phenoxyphenyl)-N- (4, 4, 4-trifluorobutyl)-3- (tritluoromethoxy) benzenemethanamine EX-1671A) To a solution of 3-phenoxyaniline (10. 9 g, 58. 8 mmol) in 100 mL of cyclohexane was added solid NaH (60% in mineral oil, 1. 96 g, 49 mmol). Then 3-trifluoromethoxybenzyl bromide (10. 0 g, 39. 2 mmol) was added dropwise under a nitrogen atmosphere, and the mixture was heated to reflux for 18 h, at which time TLC analysis indicated that no 3-trifluoromethoxybenzyl bromide remained. The reaction mixture was cooled to room temperature and quenched with water, then extracted with ether. The ether layer was washed with water and brine, then dried over MgSO4, and evaporated to give crude product. The crude product was purified by flash column chromatography on silica gel eluting with 1 : 7 : 0. 01 of ethyl acetate : hexane : ammonium hydroxide to give the desired N-benzylaniline product, which contained a small portion of

dibenzylated amine. This product was further purified by conversion to the corresponding HCI salt to give 11. 0 g (73%) of the desired N- (3- phenoxyphenyl)-N [ (3-trifluoromethoxy) phenyl] methyl] amine hydrochloride product. HRMS calcd. for C20Hl6No2F3 : 360. 1211 [M+H] +, found 360. 1208.

The N-(3-phenoxyphenyl)-N [ (3-trifluoromethoxy) phenyl] methyl) amine hydrochloride (1. 0 g, 2. 5 mmol) product from EX-1671A was dissolved in 20 mL of under nitrogen. Solid NaNH2 (50% in xylene, 0. 2 g, 2. 6 mmol) was added, and the mixture was stirred at room temperature. Then 1-iodo-4, 4, 4- trifluorobutone (1. 0 g, 4. 2 mmol) and additional NaNH2 (50% in xylene, 0. 2 g, 2. 6 mmol) was added. The mixture was heated at reflux for 24 h, at which time HPLC analysis indicated that no secondary 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 MgSO4. The crude product was purified by flash column chromatography on silica gel eluting with 1 : 4 : 0. 01 of ethyl acetate : hexane : ammonium hydroxide to give 1. 0 g (85%) of the desired N- (3-phenoxyphenyl)-N- (4, 4, 4-trifluorobutyl)-3- (trifluoromethoxy) benzene-methanamine product as an off-white oil. H NMR (CDC13) b 7. 29 (m, 3H), 7. 09 (m, 4H), 7. 01 (s, 1H), 6. 95 (d, 2H), 6. 43 (d, 1H), 6. 36 (d, 1H), 6. 31 (s, 1H), 4. 49 (s, 2H), 3. 41 (t, 2H), 2. 08 (m, 2H), 1. 89 (q, 2H). 19F NMR (CDC13) 6-58. 18 (s, 3F),-66. 44 (t, 3F). Anal. calcd. for C24H21NO2F6 : C, 61. 41 ; H, 4. 51 ; N, 2. 98. Found : C, 61. 16 ; H, 4. 53 ; N, 2. 92. HRMS calcd.

470. 1555 [M+H], found : 470. 1565.

EXAMPLE 1672

3-[[3-(4-chloro-3-ethylphenoxy)phenyl]-[[3-(1,1, 2, 2-tetrafluoro- ethoxy) phenyl] methyl) amino]-1, 1, 1-trifl uoro-2-propanthiol EX-1672A) A solution of 3- (4-chloro-3-ethylphenoxy) aniline (3. 72 g, 15 mmol) and 3-(1, I, 2, 2-tetrafluoroethoxy) benzaldehyde (3. 33 g, 15 mmol) is prepared in 60 mL of dichloroethane. Acetic acid (0. 92 mL, 16. 05 mmol) and solid NaBH (OAc) 3 (4. 13 g, 19. 5 mmol) are added. The mixture is stirred at room temperature for 3 hours, then is acidified with 1 N aqueous HCI. After neutralizing to pH 7. 5 with 2. 5 N sodium hydroxide, the mixture is extracted with methylene chloride. The organic layer is washed with brine and water, then dried over anhydrous MgSO4, and evaporated to give 5. 00 g (85%) of the desired N-(3-(4-chloro-3-ethylphenoxy)phenyl)-[[3-(1,1,2,2-tetrafluo roethoxy)- phenyllmethyllamine product.

Amine product EX-1672A (8 mmol) and 3, 3, 3-trifluoromethylthiirane (1. 54 g, 12 mmol) are dissolved in 1. 5 mL of acetonitrile. Ytterbium (III) trifluoromethanesulfonate (0. 25 g, 0. 4 mmol) is added, and the stirred solution is warmed to 50 °C under an atmosphere of nitrogen until completion of reaction as is indicated by HPLC analysis showing that no secondary amine starting material remains. The reaction is quenched with water and extracted with ether.

The ether layer is washed with water and brine, then is dried over MgSO. The crude product is purified by flash column chromatography on silica gel with a solvent mixture to give the desired aminopropanethiol product.

EXAMPLE 1673 3-[[3-(4-chloro-3-ethylphenoxy)phenyl]-[[3-(1, 1, 2, 2-tetrafluoro- ethoxy) phenyl] methyl] amino]-1, 1, 1-trifluoro-2-propanamine Amine product EX-1672A (8 mmol) and 3, 3, 3-trifluoromethylaziridine (1. 33 g, 12 mmol) are dissolved in 1. 5 mL of acetonitrile. Ytterbium (III) trifluoromethanesulfonate (0. 25 g, 0. 4 mmol) is added, and the stirred solution is warmed to 50 °C under an atmosphere of nitrogen until completion of reaction as is indicated by HPLC analysis showing that no secondary amine starting material remains. The reaction is quenched with water, the pH is adjusted to 9. 5 with 2. 5 N sodium hydroxide, and it is extracted with ether. The ether layer is washed with water and brine, then is dried over Na^, CO3. The crude product is purified by flash column chromatography on silica gel with a solvent mixture to give the desired propanediamine product.

BIOASSAYS CETP Activity In Vitro ASSAY OF CETP INHIBITION USING PURIFIED COMPONENTS (RECONSTITUTED BUFFER ASSAY) The ability of compounds to inhibit CETP activity was assessed using an in vitro assay that measured the rate of transfer of radiolabeled cholesteryl ester ([3H] CE) from HDL donor particles to LDL acceptor particles. Details of the assay are provided by Glenn, K. C. et al. (Glenn and Melton,"Quantification of 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, l3HlCE-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 iL, 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 ß M. The inhibitors were then diluted 1 : 1 with CETP in assay buffer, and then 25 ßL of that solution was mixed with 175 PL of lipoprotein pool for assay. Following incubation, LDL was differentially precipitated by the addition of 50 ßL of 1% (w/v) dextran sulfate/0. 5 M magnesium chloride, mixed by vortex, and incubated at room temperature for 10 minutes. A potion of the solution (200 yL) was transferred to a filter plate (Millipore). After filtration, the radioactivity present in the precipitated LDL was measured by liquid scintillation counting. Correction for non-specific transfer or precipitation was made by including samples that do not contain CETP. The rate of [3H] CE transfer using this assay was linear with respect to time and CETP concentration, up to 25-30% of [3H] CE transferred.

The potency of test compounds was determined by performing the above described assay in the presence of varying concentrations of

the test compounds and determining the concentration required for 50% inhibition of transfer of [3H] CE from HDL to LDL. This value was defined as the IC0. The ICso values determined from this assay are accurate when the ICso is greater than 10 nM. In the case where compounds have greater inhibitory potency, accurate measurements of ICso may be determined using longer incubation times (up to 18 hours) and lower final concentrations of CETP (< 50 nM).

Examples of ICo values determined by these methods are specified in Table 6.

ASSAY OF CETP INHIBITION IN HUMAN PLASMA Blood was obtained from healthy volunteers, recruited from the personnel of Monsanto Company, Saint Louis, MO. Blood was collected in tubes containing EDTA (EDTA plasma pool). The EDTA human plasma pool, previously stored at-20 °C, was thawed at room temperature and centrifuged for 5 minutes to remove any particulate matter. Tritiated HDL, radiolabeled in the cholesteryl ester moiety ([3H] CE-HDL) as described by Morton and Zilversmit (J. Biol. Chem., 256, 11992-95 (1981)), was added to the plasma to a final concentration of 25 ßg/mL cholesterol. Equal volumes (396 ßL) of the plasma containing the [3H] CE-HDL were added by pipette into micro tubes (Titertube, Bio-Rad laboratories, Hercules, CA). Inhibitor compounds, dissolved as 20-50 mM stock solutions in DMSO, were serially diluted in DMSO (or an alternative solvent in some cases, such as dimethylformamide or ethanol). Four yL of each of the serial dilutions of inhibitor compounds or DMSO alone were then added to each of the tubes containing plasma (396 L). After mixing, triplicate aliquots (100 ßL) from each plasma tube were then transferred to wells of 96-well round- bottomed polystyrene microtiter plates (Corning, Coming, NY). Plates were sealed with plastic film and incubated at 37 °C for 4 hours."Test"samples contained plasma with dilutions of inhibitor compounds."Control"samples contained plasma with DMSO diluted to the same concentration as the test samples, but without inhibitor."Blank"samples were prepared as"control" samples, but were left in the micro tubes at 4 °C for the 4 hour incubation and were then added to the microtiter wells at the end of the incubation period. VLDL

and LDL were precipitated by the addition of 10 yL of precipitating reagent (1 % (w/v) dextran sulfate (Dextralip50)/0. 5 M magnesium chloride, pH 7. 4) to all wells. The wells were mixed on a plate mixer and then incubated at ambient temperature for 10 min. The plates were then centrifuged at 1000 x g for 30 min at 10 °C. The supernatants (50 HL) from each well were then transferred to PicoplateTM 96 plate wells (Packard, Meriden, CT) containing MicroscintTM40 (Packard, Meriden, CT). The plates were heat-sealed (TopSealTM-P, Packard, Meriden, CT) according to the manufacturer's directions and mixed for 30 min.

Radioactivity was measured on a microplate scintillation counter (TopCount, Packard, Meriden, CT). The maximum percentage transfer in the control wells (% transfer) was determined using the following equation : [dpmbiank-dpmntroi] x 100 % Transfer = dpm blank The percentage of transfer relative to the control (% control) was determined in the wells containing inhibitor compounds was determined as follows : [dpmbik-Ptest x 100 % Control = dPmblankdPm control ICso values were then calculated from plots of % control versus concentration of inhibitor compound. ICso values were determined as the concentration of inhibitor compound inhibiting transfer of [3H] CE from the supernatant [3H] CE- HDL to the precipitated VLDL and LDL by 50% compared to the transfer obtained in the control wells.

Examples of ICI values determined by this method are specified in Table 7. Table 6. Inhibition of CETP Activity by Examples in Reconstituted Buffer Assay. Ex. IC50 Ex. IC50 Ex. IC50 No. (AM) No. (AM) No. (ttm) 249 0. 020 419 0. 19 425 0. 34 244 0. 029 230 0. 20 514 0. 34 634 0. 032 248 0. 20 237 0. 35 221 0. 034 266 0. 20 399 0. 35 229 0. 034 378 0. 20 645 0. 35 660 0. 040 488 0. 20 225 0. 37 630 0. 050 241 0. 21 247 0. 37 629 0. 054 245 0. 21 473 0. 37 372 0. 062 400 0. 21 216 0. 39 233 0.063 639 0.21 243 0.39 234 0. 069 226 0. 22 636 0. 39 252 0. 075 373 0. 22 650 0. 41 242 0. 076 377 0. 23 385 0. 42 277 0. 076 253 0. 24 427 0. 42 256 0. 079 411 0. 25 436 0. 42 232 0. 080 638 0. 26 509 0. 42 278 0. 098 222 0. 27 619 0. 42 379 0. 098 240 0. 27 521 0. 43 258 0. 099 374 0. 27 250 0. 44 238 0. 12 420 0. 27 429 0. 44 227 0. 13 223 0. 29 658 0. 44 423 0. 13 415 0. 29 637 0. 47 656 0. 13 235 0. 31 592 0. 48 214 0. 14 607 0. 31 251 0. 49 628 0. 14 265 0. 33 421 0. 49 281 0. 14 402 0. 33 271 0. 50 224 0. 16 489 0. 33 287 0. 50 279 0. 16 231 0. 34 550 0. 50 401 0. 18 275 0. 34 416 0. 51 410 0.19 390 0.34 438 0.52 Table 6 (cont.). Inhibition of CETP Activity by Examples in Reconstituted Buffer Assay. Ex. IC50 Ex. IC50 Ex. IC50 No. (µM) No. (µM) No. (AM) 647 0. 52 518 0. 79 442 1. 1 598 0. 54 397 0. 81 595 1. 1 567 0. 55 393 0. 82 642 1. 1 391 0. 56 499 0. 83 450B 1. 1 559 0. 56 648 0. 83 71 1. 2 246 0. 57 282 0. 84 305 1. 2 268 0. 58 396 0. 86 381 1. 2 527 0. 58 581 0. 87 441 1. 2 269 0. 59 294 0. 88 446 1. 2 292 0. 59 557 0. 88 492 1. 2 405 0. 60 218 0. 91 496 1. 2 409 0. 61 601 0. 91 524 1. 2 475 0. 64 653 0. 91 569 1. 2 254 0. 65 422 0. 92 693 1. 2 450A 0. 66 556 0. 92 286 1. 3 654 0. 67 506 0. 97 296 1. 3 558 0. 69 541 0. 97 655B 1. 3 389 0.70 274 0.99 264 1.4 412 0.71 651 0.99 392 1.4 408 0. 75 77 1. 0 406 1. 4 554 0. 75 267 1. 0 522 1. 4 280 0. 76 293 1. 0 526 1. 4 525 0. 76 439 1. 0 568 1. 4 578 0.76 560 1.0 582 1.4 440 0. 77 657 1. 0 74 1. 5 523 0. 77 659 1. 0 79 1. 5 646 0. 77 599 1. 0 403 1. 5 166 0.78 285 1.1 407 1.5 424 0. 78 395 1. 1 444 1. 5 593 0. 78 398 1. 1 495 1. 5 Table 6 (cont.). Inhibition of CETP Activity by Examples in Reconstituted Buffer Assay. Ex. IC50 Ex. IC50 Ex. IC50 No. (µM) No. (µM) No. (tam) 456B 1. 5 167 2. 0 302 2. 5 565 1. 5 307 2. 0 426 2. 5 652 1. 5 597 2. 0 519 2. 5 699 1. 5 315 2. 1 555 2. 5 91 1. 6 404 2. 1 564 2. 5 140 1. 6 418 2. 1 688 2. 5 149 1. 6 503 2. 1 690 2. 5 255 1. 6 508 2. 1 309 2. 6 384 1. 6 513 2. 1 311 2. 6 517 1. 6 562 2. 1 494 2. 6 571 1.6 643 2.1 44 2. 7 644 1. 6 257 2. 2 452 2. 7 150 1. 7 387 2. 2 543 2. 7 261 1. 7 437 2. 2 566 2. 7 432 1. 7 483 2. 2 445 2. 8 505 1. 7 490 2. 2 73 3. 0 584 1. 7 89 2. 3 104 3. 0 1670 1. 8 299 2. 3 115 3. 0 212 1. 8 318 2. 3 220B 3. 0 289 1. 8 382 2. 3 322 3. 0 312 1. 8 383 2. 3 388 3. 0 478 1. 8 507 2. 3 460 3. 0 493 1. 8 544 2. 3 464 3. 0 515 1.8 580 2.3 516 3.0 561 1. 8 608 2. 3 691 3. 0 570 1. 8 128 2. 4 316 3. 1 579 1. 8 542 2. 4 394 3. 1 304 1. 9 168 2. 5 633 3. 1 480 1. 9 259 2. 5 386 3. 2 70 2. 0 2. 5 376 3. 3 Table 6 (cont.). Inhibition of CETP Activity by Examples in Reconstituted Buffer Assay. : IC50 Ex. IC50 Ex. IC50 No. (µM) No. (µM) No. (ftm) 459 3. 3 595B 4. 5 310 6. 6 317 3. 4 701 4. 5 514C 6. 6 63 3. 5 414 4. 6 603 6. 7 159 3. 5 454 4. 6 428 6. 8 204 3. 5 319 4. 7 602 6. 8 609 3.5 482 4.8 632 6.8 622 3. 5 553 4. 8 42 7. 0 210 3. 6 273 4. 9 52 7. 0 501 3.6 649 4.9 59 7.0 655 3. 6 84 5. 0 75 7. 0 262 3. 7 141 5. 0 127 7. 0 371 3. 9 321 5. 0 162 7. 0 449 3. 9 620 5. 0 172 7. 0 36 4. 0 689 5. 0 194 7. 0 43 4. 0 60 5. 5 346 7. 7 66 4. 0 433 5. 6 617 7. 9 87 4. 0 502 5. 7 26 8. 0 126 4. 0 585 5. 8 82 8. 0 153 4. 0 76 6. 0 122 8. 0 201 4. 0 101 6. 0 124 8. 0 588 4. 1 134 6. 0 139 8. 0 627 4.1 208 6.0 147 8.0 594 4. 2 474 6. 0 152 8. 0 606 4. 2 239 6. 1 453 8. 0 448 4. 3 512 6. 1 290 8. 1 640 4. 3 591 6. 2 625 8. 3 297 4. 4 576 6. 4 291 8. 4 491 4. 4 583 6. 4 90 9. 0 209 4. 5 434B 6. 4 112 9. 0 375 4. 5 270 6. 5 129 9. 0 Table 6 (cont.). Inhibition of CETP Activity by Examples in Reconstituted Buffer Assay. Ex. ICso Ex. ICSO Ex. ICso No. (µM) No. (» M) No. (RM) 323 9. 0 136 12 67 15 215 9. 2 158 12 68 15 456 9. 2 288 12 98 15 621 9. 3 431 12 145 15 447 9. 8 462 12 148 15 25 10 466 12 185 15 47 10 605 12 186 15 72 10 611 12 198 15 78 10 687 12 200 15 131 10 38 13 308 15 146 10 451 13 347 15 163 10 457 13 589 15 193 10 458 13 661 15 199 10 461 13 686 15 236 10 463 13 694 15 486 10 596 13 695 15 551 10 211 14 514D 15 572 10 314 14 35 16 613 10 504 14 692 16 213 11 590 14 612A 16 301 11 19 15 276 17 380 11 23 15 295 17 472 11 39 15 413 17 477 11 50 15 417 17 641 11 53 15 1669 17 528B 11 54 15 62 18 1671 11 57 15 197 18 31 12 58 15 220 18 41 12 64 15 574 18 92 12 18 Table 6 (cont.). Inhibition of CETP Activity by Examples in Reconstituted Buffer Assay. Ex. IC50 Ex. IC50 Ex. IC50 No. (µM) No. (jus) No. (M) 51 20 106 30 17 45 55 20 138 30 118 45 56 20 195 30 345 45 65 20 520 30 362 45 69 20 626 30 604 46 80 20 300 31 529 49 83 20 217 32 22 50 86 20 320 32 34 50 113 20 303 33 93 50 135 20 103 35 96 50 137 20 105 35 120 50 160 20 348 35 350 50 173 20 352 35 351 50 313 20 468 35 471 50 324 20 612 35 662 50 610 20 702 35 697 55 683 20 1 38 3 60 30 22 94 40 4 60 455 22 114 40 14 60 61 23 116 40 16 60 192 23 142 40 18 60 587 23 156 40 95 60 298 24 196 40 102 60 620A 24. 6 335 40 108 60 109 25 357 40 110 60 117 25 363 40 203 60 125 25 497 42 685 60 132 25 473B 42 111 65 133 25 528C 42 119 70 306 25 528 43 342 70 Table 6 (cont.). Inhibition of CETP Activity by Examples in Reconstituted Buffer Assay. Ex. IC50 Ex. IC50 Ex. IC50 No. (µM) No. (µM) No. (fi) 353 70 435 >50 263 >50 664 70 435B >50 284 >50 28 75 443 >50 430 >50 88 75 465 >50 434 >50 107 75 467 >50 563 >50 355 75 469 >50 573 >50 85 80 470 >50 575 >50 130 80 476 >50 577 >50 143 80 479 >50 586 >50 332 80 484 >50 632A >50 366 80 487 >50 5 >100 635 80 498 >50 6 >100 665 80 500 >50 7 >100 97 90 511 >50 8 >100 100 90 530 >50 9 >100 123 90 531 >50 100 >100 165 90 532 >50 11 >100 207 90 533 >50 12 >100 2 100 534 >50 13 >100 45 100 535 >50 15 >100 144 100 536 >50 20 >100 333 100 537 >50 21 >100 334 100 538 >50 24 >100 340 100 539 >50 27 >100 343 100 540 >50 29 >100 618 100 545 >50 32 >100 663 100 546 >50 37 >100 672 100 547 >50 40 >100 696 100 548 >50 46 >100 698 100 549 >50 48 >100 Table 6 (cont.). Inhibition of CETP Activity by Examples in Reconstituted Buffer Assay. Ex. IC50 Ex. IC50 Ex. IC50 No. (µM) No. (µM) No. (AM) 49>100325>100 588B >100 81 >100 326 >100 614 >100 99 >100 327 >100 615 >100 121 >100 328 >100 631 >100 161>100329>100 634C >100 164 >100 330 >100 667 >100 169 >100 331 >100 668 >100 170 >100 336 >100 669 >100 171 >100 337 >100 670 >100 174 >100 338 >100 671 >100 175 >100 339 >100 673 >100 176 >100 341 >100 674 >100 177 >100 344 >100 675 >100 178 >100 349 >100 676 >100 179 >100 354 >100 677 >100 180 >100 356 >100 678 >100 181 >100 358 >100 679 >100 182 >100 359 >100 680 >100 183 >100 360 >100 681 >100 184 >100 361 >100 682 >100 187 >100 364 >100 684 >100 188 >100 365 >100 189 >100 367 >100 190 >100 368 >100 191 >100 369 >100 202 >100 370 >100 205 >100 151 >100 206 >100 154 >100 219 >100 155 >100 283 >100 157 >100 Table 7. Inhibition of CETP Activity by Examples in Human Plasma Assay. Ex. IC50 Ex. IC50 Ex. IC50 No. (µM) No. (µM) No. (µM) 229 0. 56 256 7. 8 554 18 221 0. 88 559 8. 0 266 21 233 1. 0 637 8. 0 645 21 234 1. 0 245 8. 4 269 22 660 1. 1 489 8. 8 287 22 630 1. 8 450A 9. 0 280 23 249 2. 3 265 9. 6 216 24 402 2. 9 240 9. 7 377 24 242 3. 1 248 10 390 24 399 3. 4 275 10 440 24 232 3. 4 395 10 657 24 629 3.4 396 10 391 25 244 3. 8 397 10 251 26 252 3. 9 281 11 253 27 634 4.1 560 11 267 27 401 4.2 638 11 385 29 488 4. 3 241 12 438 29 429 4. 4 282 12 166 30 619 4. 9 373 12 294 30 393 5. 0 378 12 550 30 639 5. 0 654 12 650 30 258 5. 2 246 13 658 30 214 5. 7 278 13 218 31 628 5. 7 439 13 250 31 372 5. 7 647 13 243 34 405 6.2 436 14 271 34 400 6. 3 279 15 499 34 277 6. 5 274 16 557 34 656 6. 9 473 16 128 35 379 7. 7 71 36 Table 7 (cont.). Inhibition of CETP Activity by Examples in Human Plasma Assay. Ex, IC50 Ex. IC50 Ex. IC50 No. (µM) No. (µM) No. (µM) 268 37 42 80 299 >100 475 37 140 80 302 >100 292 38 150 80 309 >100 558 38 307 81 311 >100 653 38 601 83 315 >100 374 39 296 86 316 >100 77 40 59 100 317 >100 293 42 73 100 321 >100 595 42 43 110 322 >100 126 45 201 110 346 >100 74 48 60 120 600 >100 655 48 63 120 649 >100 556 49 66 120 686 >100 593 49 75 200 688 >100 642 50 389 >50 691 >100 592 52 447 >50 220B >100 699 55 104 >100 595B >100 79 60 115 >100 35 >200 87 60 127 >100 36 >200 89 60 131 >100 76 >200 655B 63 141 >100 661 >200 70 65 149 >100 664 >200 312 65 168 >100 33 500 659 65 204 >100 84 70 208 >100 91 70 209 >100 690 75 210 >100 304 76 219 >100 305 76 273 >100 254 77 297 >100