KR20050024445A - Use of cetp inhibitors and antihypertensive agents as well as optionally hmg coa reductase inhibitors - Google Patents

Abstract

The present invention provides a pharmaceutical composition of a cholesteryl ester transfer protein (CETP) inhibitor or a pharmaceutically acceptable salt thereof, an antihypertensive agent or a pharmaceutically acceptable salt thereof, and optionally a HMG CoA reductase inhibitor or a pharmaceutically acceptable salt thereof. Red complexes, kits containing the complexes, and using the complexes in arteriosclerosis, peripheral vascular disease, dyslipidemia, hyperbetalipoproteinemia, hypoalphalipoproteinemia, hypercholesterol in mammals, including male and female humans. Hypertension, hypertriglyceridemia, familial-hypercholesterolemia, cardiovascular disorders, angina pectoris, ischemia, myocardial ischemia, seizures, myocardial infarction, reperfusion injury, restenosis after angioplasty, hypertension, vascular complications of diabetes, obesity or endotoxin A method of treating a patient suffering from hypertension.

Description

USE OF CETP INHIBITORS AND ANTIHYPERTENSIVE AGENTS AS WELL AS OPTIONALLY HMG COA REDUCTASE INHIBITORS} cholesteryl ester transfer protein inhibitors, antihypertensive agents and optionally HMCO COA reductase inhibitors

The present invention provides a cholesteryl ester transfer protein (CETP) inhibitor or a pharmaceutically acceptable salt thereof, and an antihypertensive agent or a pharmaceutically acceptable salt thereof, optionally an HMG CoA reductase inhibitor or a pharmaceutically acceptable salt thereof. Pharmaceutical complexes, kits containing the complexes, and atherosclerosis, peripheral vascular disease, dyslipidemia, hyperbetalipoproteinemia, hypoalphalipoproteinemia, high in mammals (including male or female humans) Hypercholesterolemia, hypertriglyceridemia, familial hypercholesterolemia, cardiovascular disorders, angina pectoris, ischemia, myocardial ischemia, seizures, myocardial infarction, reperfusion injury, restenosis after angioplasty, hypertension, vascular complications of diabetes, obesity or internalization A method of using this complex to treat a patient suffering from toxinemia.

Summary of the Invention

The present invention is arteriosclerosis, peripheral vascular disease, dyslipidemia, hyperbetalipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial-hypercholesterolemia, cardiovascular disorders, angina pectoris, ischemia, Cholesteryl esters to mammals, including humans with disorders or symptoms selected from the group consisting of myocardial ischemia, seizures, myocardial infarction, reperfusion injury, postvascular restenosis, hypertension, vascular complications of diabetes, obesity and endotoxins A delivery protein (CETP) inhibitor or a pharmaceutically acceptable salt thereof, and an antihypertensive agent or a pharmaceutically acceptable salt thereof, optionally together with an HMG CoA reductase inhibitor or a pharmaceutically acceptable salt thereof, Treating the disorder or symptom in a mammal comprising administering in an amount effective to treat the disorder or symptom. It is about a method.

In addition, the present invention is an arteriosclerosis, peripheral vascular disease, dyslipidemia, hyperbeta lipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial-hypercholesterolemia, cardiovascular disorders, angina pectoris, Ischemia, myocardial ischemia, seizures, myocardial infarction, reperfusion injury, postvascular restenosis, hypertension, vascular complications of diabetes mellitus, obesity and endotoxins to mammals, including humans with a disorder selected from the group consisting of A compound of I, a prodrug thereof, or a pharmaceutically acceptable salt of this compound or a prodrug; And administering an antihypertensive agent or a pharmaceutically acceptable salt thereof in an amount effective for the treatment of the disorder or condition, wherein these active drugs are optionally administered in combination with an HMG CoA reductase inhibitor or a pharmaceutically acceptable salt thereof. A method of treating said disorder or condition in a mammal is:

Where

R ¹ is Y, WX or WY;

W is carbonyl, thiocarbonyl, sulfinyl or sulfonyl;

X is -OY, -SY, -N (H) -Y or -N- (Y) ₂ ;

Each Y is independently Z or a fully saturated, partially unsaturated or fully unsaturated 1 to 10 membered linear or branched carbon chain, wherein carbon other than the linking carbon is independently selected from oxygen, sulfur and nitrogen. Or may be substituted with two heteroatoms, and the carbon may be mono-, di- or tri-substituted independently with halo, mono-substituted with hydroxy, mono-substituted with oxo, and Sulfur may be mono- or di-substituted with oxo, the nitrogen may be mono- or di-substituted with oxo, and the carbon chain may be mono-substituted with Z;

Z is a partially saturated, fully saturated or fully unsaturated 3-8 membered ring which may have 1 to 4 heteroatoms independently selected from oxygen, sulfur and nitrogen, or 1 independently selected from nitrogen, sulfur and oxygen A bicyclic ring formed by condensation of two independently selected rings of 3 to 6 members which are partially saturated, fully saturated or fully unsaturated, which may have from 4 to 4 heteroatoms;

The Z substituents are halo, (C ₂ -C ₆ ) alkenyl, (C ₁ -C ₆ ) alkyl, hydroxy, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) alkylthio, amino, nit Independently mono-, di- or as cyano, oxo, carboxy, (C ₁ -C ₆ ) alkyloxycarbonyl, mono-N- or di-N, N- (C ₁ -C ₆ ) alkylamino Tri-substituted, wherein the (C ₁ -C ₆ ) alkyl substituent is halo, hydroxy, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) alkylthio, amino, nitro, Independently mono-, di- or tri- as cyano, oxo, carboxy, (C ₁ -C ₆ ) alkyloxycarbonyl, mono-N- or di-N, N- (C ₁ -C ₆ ) alkylamino May be substituted, and may also be substituted with 1 to 9 fluorine;

R ² is a partially saturated, fully saturated, or fully unsaturated 1-6 membered linear or branched carbon chain, wherein carbon other than the linking carbon is selected from oxygen, sulfur and nitrogen as one or two heteroatoms independently selected from Can be substituted, the carbon atom may be independently mono-, di- or tri-substituted with halo, mono-substituted with oxo, mono-substituted with hydroxy, and sulfur is mono-substituted with oxo Or may be di-substituted, said nitrogen may be mono- or di-substituted with oxo, or R ² may be partially saturated which may have one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; Or a 3-7 membered ring which is fully saturated or fully unsaturated, wherein the R ² ring may be bonded via a (C ₁ -C ₄ ) alkyl;

The R ² ring is halo, (C ₂ -C ₆ ) alkenyl, (C ₁ -C ₆ ) alkyl, hydroxy, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) alkylthio, amino, Nitro, cyano, oxo, carboxy, (C ₁ -C ₆ ) alkyloxycarbonyl, mono-N- or di-N, N- (C ₁ -C ₆ ) alkylamino independently mono-, di- Or tri-substituted, wherein the (C ₁ -C ₆ ) alkyl substituent is halo, hydroxy, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) alkylthio, oxo or (C May be independently mono-, di- or tri-substituted with _1- C ₆ ) alkyloxycarbonyl;

R ³ is hydrogen or Q;

Q is a fully saturated, partially unsaturated or fully unsaturated 1-6 membered linear or branched carbon chain, wherein carbon other than the linking carbon may be substituted with one heteroatom selected from oxygen, sulfur and nitrogen, and Carbon may be independently mono-, di- or tri-substituted with halo, mono-substituted with hydroxy, mono-substituted with oxo, and the sulfur may be mono- or di-substituted with oxo. Wherein the nitrogen may be mono- or di-substituted with oxo and the carbon chain may be mono-substituted with V;

V is a partially saturated, fully saturated or fully unsaturated 3-8 membered ring which may have 1 to 4 heteroatoms independently selected from oxygen, sulfur and nitrogen, or 1 independently selected from nitrogen, sulfur and oxygen A bicyclic ring formed by condensation of two independently selected rings of 3 to 6 members which are partially saturated, fully saturated or fully unsaturated, which may have from 4 heteroatoms;

The V substituent is halo, (C ₁ -C ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl, hydroxy, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) alkylthio, amino, nit , Cyano, oxo, carboxamoyl, mono-N- or di-N, N- (C ₁ -C ₆ ) alkylcarboxamoyl, carboxy, (C ₁ -C ₆ ) alkyloxycarbonyl, mono- N- or di-N, N- (C ₁ -C ₆ ) alkylamino can be independently mono-, di-, tri- or tetra-substituted, wherein (C ₁ -C ₆ ) alkyl or (C ₂ -C ₆ ) alkenyl substituents are hydroxy, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) alkylthio, amino, nitro, cyano, oxo, carboxy, (C ₁ -C ₆₎ alkyloxycarbonyl, mono or di -N- _{-N, N- (C 1 -C 6} ) work independently alkyl amino-, a -, three-or four-can be optionally substituted, and 1 to 9 Can be substituted with fluorine;

R ⁴ is cyano, formyl, W ¹ Q ¹ , W ¹ V ¹ , (C ₁ -C ₄ ) alkylene V ¹ or V ² ;

W ¹ is carbonyl, thiocarbonyl, SO or SO ₂ ;

Q ¹ is a fully saturated, partially unsaturated or fully unsaturated 1-6 membered linear or branched carbon chain, wherein carbon may be substituted with one heteroatom selected from oxygen, sulfur and nitrogen, the carbon being halo Can be independently mono-, di- or tri-substituted, mono-substituted with hydroxy, mono-substituted with oxo, the sulfur can be mono- or di-substituted with oxo, and Nitrogen may be mono- or di-substituted with oxo and the carbon chain may be mono-substituted with V ¹ ;

V ¹ is a partially saturated, fully saturated or fully unsaturated 3-6 membered ring which may have 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, or independently selected from nitrogen, sulfur and oxygen A bicyclic ring formed by condensation of two independently selected rings of 3 to 6 members which are partially saturated, fully saturated or fully unsaturated, which may have 1 to 4 heteroatoms;

The V ¹ substituent is halo, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, hydroxy, oxo, amino, nitro, cyano, (C ₁ -C ₆ ) alkyloxycarbonyl, mono or di -N- _{-N, N- (C 1 -C 6} ) work independently alkyl amino-, a -, three-or four-can be optionally substituted, this time, (C ₁ -C ₆₎ Alkyl substituents may be mono-substituted with oxo and may also be substituted with 1 to 9 fluorine;

V ² is a partially saturated, fully saturated or fully unsaturated 5 to 7 membered ring containing 1 to 4 heteroatoms independently selected from oxygen, sulfur and nitrogen;

The V ² substituents may be independently mono-, di- or tri-substituted with halo, (C ₁ -C ₂ ) alkyl, (C ₁ -C ₂ ) alkoxy, hydroxy or oxo, wherein the ( C ₁ -C ₂ ) alkyl may have 1 to 5 fluorine;

R ³ should include V or R ⁴ should include V ¹ ;

R ⁵ , R ⁶ , R ⁷ and R ⁸ are each independently hydrogen, a bond, nitro or halo, wherein the bond is substituted with T, or partially saturated or fully saturated or fully unsaturated (C _1- C ₁₂ ) a linear or branched carbon chain, which carbon may be substituted with one or two heteroatoms independently selected from oxygen, sulfur and nitrogen, wherein the carbon atoms are independently mono-, di- or tri- Can be substituted, mono-substituted with hydroxy, mono-substituted with oxo, the sulfur can be mono- or di-substituted with oxo, and the nitrogen is mono- or di-substituted with oxo The carbon chain may be mono-substituted with T;

T is a partially saturated, fully saturated or fully unsaturated 3 to 12 membered ring which may have 1 to 4 heteroatoms independently selected from oxygen, sulfur and nitrogen, or 1 independently selected from nitrogen, sulfur and oxygen A bicyclic ring formed by condensation of two independently selected rings of 3 to 6 members which are partially saturated, fully saturated or fully unsaturated, which may have from 4 heteroatoms;

The T substituent is halo, (C ₁ -C ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl, hydroxy, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) alkylthio, amino, nit Independently mono-, di- or as cyano, oxo, carboxy, (C ₁ -C ₆ ) alkyloxycarbonyl, mono-N- or di-N, N- (C ₁ -C ₆ ) alkylamino Tri-substituted, wherein the (C ₁ -C ₆ ) alkyl substituent is hydroxy, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) alkylthio, amino, nitro, cyano Independently mono-, di- or tri-substituted with oxo, carboxy, (C ₁ -C ₆ ) alkyloxycarbonyl, mono-N- or di-N, N- (C ₁ -C ₆ ) alkylamino May also have 1 to 9 fluorine;

R ⁵ and R ⁶ , or R ⁶ and R ⁷ , and / or R ⁷ and R ⁸ together may also be partially saturated or fully unsaturated, which may have 1 to 3 heteroatoms independently selected from nitrogen, sulfur and oxygen. May form one or more four to eight membered rings;

The ring formed by R ⁵ and R ⁶ , or R ⁶ and R ⁷ , and / or R ⁷ and R ⁸ may be halo, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₄ ) alkylsulfonyl, (C ₂ -C ₆ ) alkenyl, hydroxy, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) alkylthio, amino, nitro, cyano, oxo, carboxy, (C ₁ -C ₆ ) alkyl Independently mono-, di- or tri-substituted with oxycarbonyl, mono-N- or di-N, N- (C ₁ -C ₆ ) alkylamino, wherein (C ₁ -C ₆ ) Alkyl substituents are hydroxy, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) alkylthio, amino, nitro, cyano, oxo, carboxy, (C ₁ -C ₆ ) alkyloxycarbonyl, mono -N- or di _{-N, N- (C 1 -C 6} ) work independently alkylamino -, phenyl or phenoxy may be optionally substituted, can also have from one to nine fluorines.

The present invention also relates to the above process, wherein said compound of formula (I) is a compound of formula (I '), a prodrug thereof, or a pharmaceutically acceptable salt of this compound or prodrug:

Where

R ¹ is Y, WX or WY;

W is carbonyl;

X is -O-Y;

Each Y is independently Z or a fully saturated, partially unsaturated or fully unsaturated 1 to 10 membered linear or branched carbon chain, wherein carbon other than the linking carbon is independently selected from oxygen, sulfur and nitrogen. Or may be substituted with two heteroatoms, and the carbon may be mono-, di- or tri-substituted independently with halo, mono-substituted with hydroxy, mono-substituted with oxo, and Sulfur may be mono- or di-substituted with oxo and the nitrogen may be mono- or di-substituted with oxo;

R ² is a partially saturated, fully saturated, or fully unsaturated 1-6 membered linear or branched carbon chain, wherein carbon other than the linking carbon may be substituted with one heteroatom independently selected from oxygen, sulfur and nitrogen. Wherein the carbon atom may be independently mono-, di- or tri-substituted with halo, the carbon may be mono-substituted with oxo, mono-substituted with hydroxy, and the sulfur is mono-substituted with oxo Or can be di-substituted) or a partially saturated, fully saturated or fully unsaturated 3-6 membered ring which may have one or two heteroatoms independently selected from oxygen, sulfur and nitrogen;

R ³ is a fully saturated 1 or 2 membered carbon chain, where carbon may be mono-substituted with oxo, and the carbon chain is mono-substituted with V; At this time,

V is a partially saturated, fully saturated or fully unsaturated 5 or 6 membered ring which may have from 1 to 3 heteroatoms independently selected from oxygen, sulfur and nitrogen;

The V substituent may be independently mono-, di- or tri-substituted with halo or (C ₁ -C ₂ ) alkyl, wherein the (C ₁ -C ₂ ) alkyl substituent is substituted with 1 to 5 fluorine Can;

R ⁴ is acetyl, formyl or (C ₁ -C ₆ ) alkoxy;

R ⁵ and R ⁸ are hydrogen;

R ⁶ and R ⁷ are each independently hydrogen, halo, (C ₁ -C ₂ ) alkoxy or saturated (C ₁ -C ₂ ) alkyl chains, wherein the (C ₁ -C ₂ ) alkyl chains are independent of fluorine And may be mono-, di- or tri-substituted.

Particularly preferred compounds of the present invention include the following compounds and pharmaceutically acceptable salts of these compounds:

[2S, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-isopropyl-6-trifluoromethyl-3,4-dihydro- 2H-quinoline-1-carboxylic acid isopropyl ester;

[2S, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -6-chloro-2-cyclopropyl-3,4-dihydro-2H-quinoline -1-carboxylic acid isopropyl ester;

[2S, 4S] 2-Cyclopropyl-4-[(3,5-dichloro-benzyl) -methoxycarbonyl-amino] -6-trifluoromethyl-3,4-dihydro-2H-quinoline- 1-carboxylic acid isopropyl ester;

[2S, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro- 2H-quinoline-1-carboxylic acid t-butyl ester;

[2S, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro- 2H-quinoline-1-carboxylic acid isopropyl ester;

[2S, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-cyclobutyl-6-trifluoromethyl-3,4-dihydro- 2H-quinoline-1-carboxylic acid isopropyl ester;

[2R, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H -Quinoline-1-carboxylic acid isopropyl ester;

[2S, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-methoxymethyl-6-trifluoromethyl-3,4-dihydro -2H-quinoline-1-carboxylic acid isopropyl ester;

[2R, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H -Quinoline-1-carboxylic acid 2-hydroxy-ethyl ester;

[2S, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro- 2H-quinoline-1-carboxylic acid ethyl ester;

[2R, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H -Quinoline-1-carboxylic acid ethyl ester;

[2S, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro- 2H-quinoline-1-carboxylic acid propyl ester;

[2R, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H -Quinoline-1-carboxylic acid propyl ester;

[2S, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -formyl-amino] -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline -1-carboxylic acid isopropyl ester;

[2S, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -formyl-amino] -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline -1-carboxylic acid propyl ester;

[2S, 4S] 4- [acetyl- (3,5-bis-trifluoromethyl-benzyl) -amino] -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline -1-carboxylic acid t-butyl ester;

[2R, 4S] 4- [acetyl- (3,5-bis-trifluoromethyl-benzyl) -amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline- 1-carboxylic acid isopropyl ester; or

[2R, 4S] 4- [acetyl- (3,5-bis-trifluoromethyl-benzyl) -amino] -2-methyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline- 1-carboxylic acid ethyl ester;

[2S, 4S] 4- [1- (3,5-Bis-trifluoromethyl-benzyl) -ureido] -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H- Quinoline-1-carboxylic acid isopropyl ester;

[2R, 4S] 4- [acetyl- (3,5-bis-trifluoromethyl-benzyl) -amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline- 1-carboxylic acid ethyl ester;

[2S, 4S] 4- [acetyl- (3,5-bis-trifluoromethyl-benzyl) -amino] -2-methoxymethyl-6-trifluoromethyl-3,4-dihydro-2H- Quinoline-1-carboxylic acid isopropyl ester;

[2S, 4S] 4- [acetyl- (3,5-bis-trifluoromethyl-benzyl) -amino] -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline -1-carboxylic acid propyl ester;

[2S, 4S] 4- [acetyl- (3,5-bis-trifluoromethyl-benzyl) -amino] -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline -1-carboxylic acid ethyl ester; or

[2R, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -formyl-amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline- 1-carboxylic acid isopropyl ester;

[2R, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -formyl-amino] -2-methyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline- 1-carboxylic acid ethyl ester;

[2S, 4S] 4- [acetyl- (3,5-bis-trifluoromethyl-benzyl) -amino] -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline -1-carboxylic acid isopropyl ester;

[2R, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -formyl-amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline- 1-carboxylic acid ethyl ester;

[2S, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -formyl-amino] -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline -1-carboxylic acid ethyl ester;

[2R, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -formyl-amino] -2-methyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline- 1-carboxylic acid isopropyl ester; And

[2R, 4S] 4- [acetyl- (3,5-bis-trifluoromethyl-benzyl) -amino] -2-methyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline- 1-carboxylic acid isopropyl ester.

The term "HMG CoA reductase inhibitor" refers to lovastatin, simvastatin, pravastatin, fluindostatin, velostatin, dihydrocomptin, compactin, fluvastatin, atorvastatin, glenvastatin, dalvastatin, carbastatin, krillba It is selected from, but is not limited to, statins, burvastatin, cerivastatin, rosuvastatin, pitavastatin, mevastatin, and rivastatin.

The term “antihypertensive agent” is selected from, but is not limited to, calcium channel blockers, ACE inhibitors, A-ll antagonists, diuretics, beta-adrenergic receptor blockers and alpha-adrenergic receptor blockers.

The invention also relates to the hemicalcium salt of atorvastatin.

The term "antihypertensive agent" also refers to verapamil, diltiazem, mibepradil, isradipine, lassidipine, nicadipine, nifedipine, nimodipine, nisoldipine, nirenedipine, avanidine, amlodipine, amlodipine besylate And calcium channel blockers consisting of manidipine, silinidipine, lucanidipine, felodipine and pharmaceutically acceptable salts thereof.

The present invention also relates to calcium channel blockers selected from the group consisting of felodipine, nifedipine, amlodipine and their pharmaceutically acceptable salts.

The present invention also relates to an antihypertensive agent selected from A-II antagonists consisting of losartan, avesatan, telmisartan, balsa charcoal and pharmaceutically acceptable salts thereof.

The present invention also relates to an antihypertensive agent selected from diuretics consisting of amylolide, bendroflumetiazide and their pharmaceutically acceptable salts.

The invention also relates to an antihypertensive agent selected from beta-adrenergic receptor blockers, which are carvedilol or a pharmaceutically acceptable salt thereof.

In addition, the present invention is benazepril, captopril, enalapril, posinopril, ricinopril, perindopril, quinapril, trandolapril, ramipril, estril, jofenofril, silapril, temocapril , An ACE inhibitor selected from spirapril, moexipril, delapril, imidapril, ramipril, terrazosin, urapidine, indoramine, amolsuladol, alfuzosin, and pharmaceutically acceptable salts thereof It is associated with hypertension.

The present invention also relates to an antihypertensive agent selected from alpha-adrenergic receptor blockers consisting of doxazosin, prazosin, trimazocin and their pharmaceutically acceptable salts.

The invention is not limited to any particular structure or group of CETP inhibitors. Rather, the invention has general applicability to CETP inhibitors as a class. Compounds that may be the subject of the present invention include DE 19741400 A1; DE 19741399 A1; WO 9914215 A1; WO 9914®; DE 19709125 A1; DE 19704244 A1; DE 19704243 A1; EP 818448 A1; WO 9804528 A2; DE 19627431 A1; DE 19627430 A1; DE 19627419 A1; EP 796846 A1; DE 19832159; DE 818197; DE 19741051; WO 9941237 A1; WO 9914204 A1; WO 9835937 A1; JP 11049743; WO 200018721; WO 200018723; WO 200018724; WO 200017164; WO 200017165; WO 200017166; It can be found in a number of patents and published applications, including EP 992496 and EP 987251, all of which are incorporated herein by reference in their entirety for all purposes.

One class of CETP inhibitors that can be used in the present invention is oxy substituted 4-carboxyamino-2-methyl-1,2,3,4-tetrahydroquinoline having the formula It consists of acceptable salts, enantiomers or stereoisomers:

Where

R _I-1 is hydrogen, Y _I , W _I -X _I or W _I -Y _I ; At this time

W _I is carbonyl, thiocarbonyl, sulfinyl or sulfonyl;

X _I is -OY _I , -SY _I , -N (H) -Y _I or -N (Y _I ) ₂ ; At this time

Y _I is each independently Z _I , or a 1 to 10 membered fully saturated, partially unsaturated or fully unsaturated linear or branched carbon chain, wherein carbon other than the linking carbon is independently selected from oxygen, sulfur and nitrogen May be substituted with one or two heteroatoms, the carbon may be independently mono-, di- or tri-substituted with halo, mono-substituted with hydroxy, mono-substituted with oxo, The sulfur may be mono- or di-substituted with oxo, the nitrogen may be mono- or di-substituted with oxo and the carbon chain may be mono-substituted with Z _I ; At this time

Z _I is a 3-8 membered partially saturated or fully saturated or fully unsaturated ring which may have 1 to 4 heteroatoms independently selected from oxygen, sulfur and nitrogen, or independently selected from nitrogen, sulfur and oxygen A bicyclic ring formed by condensation of two independently selected rings of 3 to 6 members which are partially saturated, fully saturated or fully unsaturated, which may have 1 to 4 heteroatoms;

The Z _I substituent is independently halo, (C ₂ -C ₆ ) alkenyl, (C ₁ -C ₆ ) alkyl, hydroxy, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) alkylthio, Amino, nitro, cyano, oxo, carboxyl, (C ₁ -C ₆ ) alkyloxycarbonyl, mono-N- or di-N, N- (C ₁ -C ₆ ) alkylaminoroyl-, di- Or tri-substituted, wherein the (C ₁ -C ₆ ) alkyl substituent is independently halo, hydroxy, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) alkylthio, amino, nit Rho, cyano, oxo, carboxyl, (C ₁ -C ₆ ) alkyloxycarbonyl, mono-N- or di-N, N- (C ₁ -C ₆ ) alkylamino as mono-, di- or tri- May be substituted, and may also be substituted with 1 to 9 fluorine;

R _I-3 is hydrogen or Q _I ; At this time

Q _I is a 1-6 membered fully saturated, partially unsaturated or fully unsaturated linear or branched carbon chain, wherein carbon other than the linking carbon may be substituted with one heteroatom selected from oxygen, sulfur and nitrogen, The carbon may be independently mono-, di- or tri-substituted with halo, mono-substituted with hydroxy, mono-substituted with oxo, and the sulfur is mono- or di-substituted with oxo. The nitrogen may be mono- or di-substituted with oxo and the carbon chain may be mono-substituted with V _I ; At this time

V _I is a 3-8 membered partially saturated, fully saturated or fully unsaturated ring which may have 1 to 4 heteroatoms independently selected from oxygen, sulfur and nitrogen, or independently selected from nitrogen, sulfur and oxygen A bicyclic ring formed by condensation of two independently selected rings of 3 to 6 members which are partially saturated, fully saturated or fully unsaturated, which may have 1 to 4 heteroatoms;

The V _I substituent is independently halo, (C ₁ -C ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl, hydroxy, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) alkylthio, Amino, nitro, cyano, oxo, carbamoyl, mono-N- or di-N, N- (C ₁ -C ₆ ) alkylcarbamoyl, carboxyl, (C ₁ -C ₆ ) alkyloxycarbonyl, mono May be mono-, di-, or tri-substituted with -N- or di-N, N- (C ₁ -C ₆ ) alkylamino, wherein said (C ₁ -C ₆ ) alkyl or (C ₂ -C ₆ ) Alkenyl substituents are independently hydroxy, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) alkylthio, amino, nitro, cyano, oxo, carboxyl, (C ₁ -C ₆ ) alkyl May be mono-, di-, or tri-substituted with oxycarbonyl, mono-N- or di-N, N- (C ₁ -C ₆ ) alkylamino, and also substituted with 1 to 9 fluorine;

R _I-4 is Q _I-1 or V _I-1 ; At this time

Q _I-1 is a 1 to 6 membered fully saturated, partially unsaturated or fully unsaturated linear or branched carbon chain wherein carbon other than the linking carbon is substituted with one heteroatom selected from oxygen, sulfur and nitrogen. And the carbon may be independently mono-, di- or tri-substituted with halo, mono-substituted with hydroxy, mono-substituted with oxo, and the sulfur is mono- or di-substituted with oxo. -Can be substituted, the nitrogen can be mono- or di-substituted with oxo and the carbon chain can be mono-substituted with V _I-1 ; At this time

V _I-1 is a 3-6 membered partially saturated, fully saturated or fully unsaturated ring which may have one or two heteroatoms independently selected from oxygen, sulfur and nitrogen;

The V _1-1 substituent is independently halo, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, amino, nitro, cyano, (C ₁ -C ₆ ) alkyloxycarbonyl, mono -N- or di-N, N- (C ₁ -C ₆ ) alkylamino can be mono-, di- or tri-substituted, wherein the (C ₁ -C ₆ ) alkyl substituent is oxo-mono- May be substituted, and may also be substituted with 1 to 9 fluorine;

R _I-3 should include V _I , or R _I-4 should include V _1-1 ;

R _I-5 , R _I-6 , R _I-7 and R _I-8 are each independently hydrogen, hydroxy or oxy, wherein the oxy is substituted with T _I or is partially 1-12 membered Saturated, fully saturated, or fully unsaturated, linear or branched carbon chains, wherein carbon other than the linking carbon may be substituted with one or two heteroatoms independently selected from oxygen, sulfur and nitrogen, wherein the carbon is independently halo May be mono-, di- or tri-substituted, mono-substituted with hydroxy, mono-substituted with oxo, the sulfur may be mono- or di-substituted with oxo, and the nitrogen is May be mono- or di-substituted with oxo, and the carbon chain may be mono-substituted with T _I ; At this time

T _I is a 3-8 membered partially saturated, fully saturated or fully unsaturated ring which may have 1 to 4 heteroatoms independently selected from oxygen, sulfur and nitrogen, or independently selected from nitrogen, sulfur and oxygen A bicyclic ring formed by condensation of two independently selected rings of 3 to 6 members which are partially saturated, fully saturated or fully unsaturated, which may have 1 to 4 heteroatoms;

The T _I substituent is independently halo, (C ₁ -C ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl, hydroxy, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) alkylthio, Amino, nitro, cyano, oxo, carboxy, (C ₁ -C ₆ ) alkyloxycarbonyl, mono-N- or di-N, N- (C ₁ -C ₆ ) alkylaminoroyl-, di- Or tri-substituted, wherein the (C ₁ -C ₆ ) alkyl substituent is independently hydroxy, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) alkylthio, amino, nitro, To be mono-, di- or tri-substituted with cyano, oxo, carboxy, (C ₁ -C ₆ ) alkyloxycarbonyl, mono-N- or di-N, N- (C ₁ -C ₆ ) alkylamino May also be substituted with 1 to 9 fluorine.

The compounds of formula (I) and methods for their preparation are disclosed in commonly assigned US Pat. No. 6,140,342, US Pat. No. 6,362,198, and European Patent Publication No. 987251, all of which are incorporated herein by reference in their entirety for all purposes. do.

In a preferred embodiment, the CETP inhibitor is selected from the following compounds of formula (I):

[2R, 4S] 4-[(3,5-Dichloro-benzyl) -methoxycarbonyl-amino] -6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1 Carboxylic acid ethyl esters;

[2R, 4S] 4-[(3,5-Dynetrobenzyl) -methoxycarbonyl-amino] -6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline- 1-carboxylic acid ethyl ester;

[2R, 4S] 4-[(2,6-Dichloro-paradan-4-ylmethyl) -methoxycarbonyl-amino] -6,7-dimethoxy-2-methyl-3,4-dihydro -2H-quinoline-1-carboxylic acid ethyl ester;

[2R, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -6,7-dimethoxy-2-methyl-3,4-dihydro-2H -Quinoline-1-carboxylic acid ethyl ester;

[2R, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -6-methoxy-2-methyl-3,4-dihydro-2H-quinoline -1-carboxylic acid ethyl ester;

[2R, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -7-methoxy-2-methyl-3,4-dihydro-2H-quinoline -1-carboxylic acid ethyl ester;

[2R, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -6,7-dimethoxy-2-methyl-3,4-dihydro-2H -Quinoline-1-carboxylic acid isopropyl ester;

[2R, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -ethoxycarbonyl-amino] -6,7-dimethoxy-2-methyl-3,4-dihydro-2H -Quinoline-1-carboxylic acid ethyl ester;

[2R, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -6,7-dimethoxy-2-methyl-3,4-dihydro-2H -Quinoline-1-carboxylic acid 2,2,2-trifluoro-ethylester;

[2R, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -6,7-dimethoxy-2-methyl-3,4-dihydro-2H -Quinoline-1-carboxylic acid propyl ester;

[2R, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -6,7-dimethoxy-2-methyl-3,4-dihydro-2H -Quinoline-1-carboxylic acid t-butyl ester;

[2R, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-methyl-6-trifluoromethoxy-3,4-dihydro-2H -Quinoline-1-carboxylic acid ethyl ester;

[2R, 4S] (3,5-Bis-trifluoromethyl-benzyl)-(1-butyryl-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydro-quinoline- 4-yl) -carbamic acid methyl ester;

[2R, 4S] (3,5-Bis-trifluoromethyl-benzyl)-(1-butyl-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydro-quinoline-4 -Yl) -carbamic acid methyl ester; And

[2R, 4S] (3,5-Bis-trifluoromethyl-benzyl) -1-[(2-ethyl-butyl) -6,7-dimethoxy-2-methyl-1,2,3,4- Tetrahydro-quinolin-4-yl] -carbamic acid methyl ester, hydrochloride.

Another class of CETP inhibitors that can be used in the present invention are 4-carboxyamino-2-methyl-1,2,3,4-tetrahydroquinoline having the formula (II), and pharmaceutically acceptable salts of these compounds, Consists of enantiomers or stereoisomers:

Where

R _II-1 is hydrogen, Y _II , W _II -X _II or W _II -Y _II ; At this time

W _II is carbonyl, thiocarbonyl, sulfinyl or sulfonyl;

X _II is -OY _II , -SY _II , -N (H) -Y _II or -N (Y _II ) ₂ ;

Each Y _II is independently Z _II or a 1 to 10 membered fully saturated, partially unsaturated or fully unsaturated linear or branched carbon chain, wherein carbon other than the linking carbon is independently in oxygen, sulfur and nitrogen May be substituted with one or two heteroatoms selected, the carbon may be independently mono-, di- or tri-substituted with halo, mono-substituted with hydroxy, mono-substituted with oxo , The sulfur may be mono- or di-substituted with oxo, the nitrogen may be mono- or di-substituted with oxo, and the carbon chain may be mono-substituted with Z _II ; At this time

Z _II is a 3-12 membered partially saturated, fully saturated or fully unsaturated ring which may have 1 to 4 heteroatoms independently selected from oxygen, sulfur and nitrogen, or independently selected from nitrogen, sulfur and oxygen A bicyclic ring formed by condensation of two independently selected rings of 3 to 6 members which are partially saturated, fully saturated or fully unsaturated, which may have 1 to 4 heteroatoms;

The Z _II substituents are independently halo, (C ₂ -C ₆ ) alkenyl, (C ₁ -C ₆ ) alkyl, hydroxy, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) alkylthio, Amino, nitro, cyano, oxo, carboxy, (C ₁ -C ₆ ) alkyloxycarbonyl, mono-N- or di-N, N- (C ₁ -C ₆ ) alkylaminoroyl-, di- Or tri-substituted, wherein the (C ₁ -C ₆ ) alkyl substituent is independently halo, hydroxy, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) alkylthio, amino, nit Rho, cyano, oxo, carboxy, (C ₁ -C ₆ ) alkyloxycarbonyl, mono-N- or di-N, N- (C ₁ -C ₆ ) alkylamino as mono-, di- or tri- May be substituted, and may also be substituted with 1 to 9 fluorine;

R _II-3 is hydrogen or Q _II ; At this time

Q _II is a 1 to 6 membered fully saturated, partially unsaturated or fully unsaturated linear or branched carbon chain, wherein carbon other than the linking carbon may be substituted with one heteroatom selected from oxygen, sulfur and nitrogen, and Carbon may be independently mono-, di- or tri-substituted with halo, mono-substituted with hydroxy, mono-substituted with oxo, and the sulfur may be mono- or di-substituted with oxo. The nitrogen may be mono- or di-substituted with oxo and the carbon chain may be mono-substituted with V _II ; At this time

V _II is a 3-12 membered partially saturated or fully saturated or fully unsaturated ring which may have 1 to 4 heteroatoms independently selected from oxygen, sulfur and nitrogen, or independently selected from nitrogen, sulfur and oxygen A bicyclic ring formed by condensation of two independently selected rings of 3 to 6 members which are partially saturated, fully saturated or fully unsaturated, which may have 1 to 4 heteroatoms;

The V _II substituents are independently halo, (C ₁ -C ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl, hydroxy, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) alkylthio, Amino, nitro, cyano, oxo, carboxamoyl, mono-N- or di-N, N- (C ₁ -C ₆ ) alkylcarboxamoyl, carboxy, (C ₁ -C ₆ ) alkyloxycarbonyl , Mono-N- or di-N, N- (C ₁ -C ₆ ) alkylamino can be mono-, di-, tri- or tetra-substituted, wherein said (C ₁ -C ₆ ) alkyl or (C ₂ -C ₆ ) alkenyl substituents are independently hydroxy, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) alkylthio, amino, nitro, cyano, oxo, carboxy, (C ₁ -C ₆ ) alkyloxycarbonyl, mono-N- or di-N, N- (C ₁ -C ₆ ) alkylamino can be mono-, di- or tri-substituted, and also from 1 to 9 fluorine Can be substituted;

R _II-4 is Q _II-1 or V _II-1 ; At this time

Q _II-1 is a 1 to 6 membered fully saturated, partially unsaturated or fully unsaturated linear or branched carbon chain, wherein carbon other than the linking carbon may be substituted with one heteroatom selected from oxygen, sulfur and nitrogen Wherein the carbon may be independently mono-, di- or tri-substituted with halo, mono-substituted with hydroxy, mono-substituted with oxo, and the sulfur is mono- or di-substituted with oxo. May be substituted, the nitrogen may be mono- or di-substituted with oxo and the carbon chain may be mono-substituted with V _II-1 ; At this time

V _II-1 is a 3 to 6 membered partially saturated, fully saturated or fully unsaturated ring which may have one or two heteroatoms independently selected from oxygen, sulfur and nitrogen;

The V _II-1 substituents are independently halo, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, amino, nitro, cyano, (C ₁ -C ₆ ) alkyloxycarbonyl, mono -N- or di _{-N, N- (C 1 -C 6} ) alkylamino in one -, two -, three-or four-can be optionally substituted, where the (C ₁ -C ₆₎ alkyl substituent is oxo May be mono-substituted and may also be substituted with 1 to 9 fluorine;

R _II-3 should comprise V _II , or R _II-4 should comprise V _II-1 ;

R _II-5 , R _II-6 , R _II-7 and R _II-8 are each independently hydrogen, a bond, nitro or halo, wherein the bond is substituted with T _II or partially saturated or fully Saturated or fully unsaturated (C ₁ -C ₁₂ ) linear or branched carbon chain, wherein carbon may be substituted with one or two heteroatoms independently selected from oxygen, sulfur and nitrogen, the carbon atoms independently Can be mono-, di- or tri-substituted with halo, mono-substituted with hydroxy, mono-substituted with oxo, the sulfur can be mono- or di-substituted with oxo, the nitrogen May be mono- or di-substituted with oxo and the carbon may be mono-substituted with T _II ; At this time

T _II is a 3-12 membered partially saturated or fully saturated or fully unsaturated ring which may have 1 to 4 heteroatoms independently selected from oxygen, sulfur and nitrogen, or independently selected from nitrogen, sulfur and oxygen A bicyclic ring formed by condensation of two independently selected rings of 3 to 6 members which are partially saturated, fully saturated or fully unsaturated, which may have 1 to 4 heteroatoms;

The T _II substituents are independently halo, (C ₁ -C ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl, hydroxy, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) alkylthio, Amino, nitro, cyano, oxo, carboxy, ((C ₁ -C ₆ ) alkyloxycarbonyl, mono-N- or di-N, N- (C ₁ -C ₆ ) alkylaminoroyl-, is Or tri-substituted, wherein the (C ₁ -C ₆ ) alkyl substituent is independently hydroxy, ((C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) alkylthio, amino, nit Rho, cyano, oxo, carboxy, (C ₁ -C ₆ ) alkyloxycarbonyl, mono-N- or di-N, N- (C ₁ -C ₆ ) alkylamino as mono-, di- or tri- May be substituted and may also be substituted with 1 to 9 fluorine;

At least one of the substituents R _II-5 , R _II-6 , R _II-7 and R _II-8 is not hydrogen and is not linked to the quinoline moiety via oxy.

The compounds of formula (II) and methods for their preparation are disclosed in commonly assigned U. S. Patent No. 6,147, 090, U. S. Patent Application No. 09/671, 400, filed September 27, 2000, and PCT Publication No. WO00 / 17166. All of which are incorporated herein by reference in their entirety for all purposes.

In one preferred embodiment, the CETP inhibitor is selected from the following compounds of formula II:

[2R, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-methyl-7-trifluoromethyl-3,4-dihydro-2H -Quinoline-1-carboxylic acid ethyl ester;

[2R, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -7-chloro-2-methyl-3,4-dihydro-2H-quinoline- 1-carboxylic acid ethyl ester;

[2R, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -6-chloro-2-methyl-3,4-dihydro-2H-quinoline- 1-carboxylic acid ethyl ester;

[2R, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2,6,7-trimethyl-3,4-dihydro-2H-quinoline- 1-carboxylic acid ethyl ester;

[2R, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -6,7-diethyl-2-methyl-3,4-dihydro-2H -Quinoline-1-carboxylic acid ethyl ester;

[2R, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -6-ethyl-2-methyl-3,4-dihydro-2H-quinoline- 1-carboxylic acid ethyl ester;

[2R, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-methyl-6-trifluoromethyl-3,4-dihydro-2H -Quinoline-1-carboxylic acid ethyl ester; And

[2R, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-methyl-6-trifluoromethyl-3,4-dihydro-2H -Quinoline-1-carboxylic acid isopropyl ester.

Another class of CETP inhibitors that can be used in the present invention are cyclic 4-carboxyamino-2-methyl-1,2,3,4-tetrahydroquinoline having the formula III, and pharmaceutically acceptable compounds of this compound: Consists of salts, enantiomers or stereoisomers:

Where

R _III-1 is hydrogen, Y _III , W _III -X _III or W _III -Y _III ; At this time

W _III is carbonyl, thiocarbonyl, sulfinyl or sulfonyl;

X _III is -OY _III , -SY _III , -N (H) -Y _III or -N- (Y _III ) ₂ ; At this time

Each Y _III is independently Z _III or a 1 to 10 membered fully saturated, partially unsaturated or fully unsaturated linear or branched carbon chain, wherein carbon other than the linking carbon is independently in oxygen, sulfur and nitrogen May be substituted with one or two heteroatoms selected, the carbon may be independently mono-, di- or tri-substituted with halo, mono-substituted with hydroxy, mono-substituted with oxo , The sulfur may be mono- or di-substituted with oxo, the nitrogen may be mono- or di-substituted with oxo, and the carbon chain may be mono-substituted with Z _III ; At this time

Z _III is a 3-12 membered partially saturated or fully saturated or fully unsaturated ring which may have 1 to 4 heteroatoms independently selected from oxygen, sulfur and nitrogen, or independently selected from nitrogen, sulfur and oxygen A bicyclic ring formed by condensation of two independently selected rings of 3 to 6 members which are partially saturated, fully saturated or fully unsaturated, which may have 1 to 4 heteroatoms;

The Z _III substituents are independently halo, (C ₂ -C ₆ ) alkenyl, (C ₁ -C ₆ ) alkyl, hydroxy, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) alkylthio, Amino, nitro, cyano, oxo, carboxy, (C ₁ -C ₆ ) alkyloxycarbonyl, mono-N- or di-N, N- (C ₁ -C ₆ ) alkylaminoroyl-, di- Or tri-substituted, wherein the (C ₁ -C ₆ ) alkyl substituent is independently halo, hydroxy, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) alkylthio, amino, nit Rho, cyano, oxo, carboxy, (C ₁ -C ₆ ) alkyloxycarbonyl, mono-N- or di-N, N- (C ₁ -C ₆ ) alkylamino as mono-, di- or tri- May be substituted, and may also be substituted with 1 to 9 fluorine;

R _III-3 is hydrogen or Q _III ; At this time

Q _III is a 1 to 6 membered fully saturated, partially unsaturated or fully unsaturated linear or branched carbon chain, wherein carbon other than the linking carbon may be substituted with one heteroatom selected from oxygen, sulfur and nitrogen, The carbon may be independently mono-, di- or tri-substituted with halo, mono-substituted with hydroxy, mono-substituted with oxo, and the sulfur is mono- or di-substituted with oxo. The nitrogen may be mono- or di-substituted with oxo and the carbon chain may be mono-substituted with V _III ; At this time

V _III is a 3 to 12 membered partially saturated or fully saturated or fully unsaturated ring which may have 1 to 4 heteroatoms independently selected from oxygen, sulfur and nitrogen, or independently selected from nitrogen, sulfur and oxygen A bicyclic ring formed by condensation of two independently selected rings of 3 to 6 members which are partially saturated, fully saturated or fully unsaturated, which may have 1 to 4 heteroatoms;

The V _III substituents are independently halo, (C ₁ -C ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl, hydroxy, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) alkylthio, Amino, nitro, cyano, oxo, carboxamoyl, mono-N- or di-N, N- (C ₁ -C ₆ ) alkylcarboxamoyl, carboxy, (C ₁ -C ₆ ) alkyloxycarbonyl , Mono-N- or di-N, N- (C ₁ -C ₆ ) alkylamino can be mono-, di-, tri- or tetra-substituted, wherein said (C ₁ -C ₆ ) alkyl or (C ₂ -C ₆ ) alkenyl substituents are independently hydroxy, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) alkylthio, amino, nitro, cyano, oxo, carboxy, (C ₁ -C ₆ ) alkyloxycarbonyl, mono-N- or di-N, N- (C ₁ -C ₆ ) alkylamino can be mono-, di- or tri-substituted, and also from 1 to 9 fluorine Can be substituted;

R _III-4 is Q _III-1 or V _III-1 ; At this time

Q _III-1 is a 1-6 membered fully saturated, partially unsaturated or fully unsaturated linear or branched carbon chain, wherein carbon other than the linking carbon may be substituted with one heteroatom selected from oxygen, sulfur and nitrogen Wherein the carbon may be independently mono-, di- or tri-substituted with halo, mono-substituted with hydroxy, mono-substituted with oxo, and the sulfur is mono- or di-substituted with oxo. Can be substituted, the nitrogen can be mono- or di-substituted with oxo and the carbon chain can be mono-substituted with V _III-1 ; At this time

V _III-1 is a 3 to 6 membered partially saturated, fully saturated or fully unsaturated ring which may have 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen;

The V _III-1 substituents are independently halo, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, amino, nitro, cyano, (C ₁ -C ₆ ) alkyloxycarbonyl, mono -N- or di _{-N, N- (C 1 -C 6} ) alkylamino in one -, two -, three-or four-can be optionally substituted, where the (C ₁ -C ₆₎ alkyl substituent is oxo It may be substituted with 1, and may have 1 to 9 fluorine;

R _III-3 should include V _III , or R _III-4 should include V _III-1 ;

R _III-5 and R _III-6 , or R _III-6 and R _III-7 , and / or R _III-7 and R _III-8 together may be 1 to 3 heteroatoms independently selected from oxygen, sulfur and nitrogen To form at least one 4-8 membered partially saturated or fully unsaturated ring which may have; At this time

The ring formed by R _III-5 and R _III-6 , or R _III-6 and R _III-7 , and / or R _III-7 and R _III-8 is independently halo, (C ₁ -C ₆ ) alkyl , (C ₁ -C ₄ ) alkylsulfonyl, (C ₂ -C ₆ ) alkenyl, hydroxy, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) alkylthio, amino, nitro, between Mono-, di-, or tri-substituted with ano, oxo, carboxy, (C ₁ -C ₆ ) alkyloxycarbonyl, mono-N- or di-N, N- (C ₁ -C ₆ ) alkylamino Wherein the (C ₁ -C ₆ ) alkyl substituent is independently hydroxy, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) alkylthio, amino, nitro, cyano, oxo, carboxy, May be mono-, di- or tri-substituted with (C ₁ -C ₆ ) alkyloxycarbonyl, mono-N- or di-N, N- (C ₁ -C ₆ ) alkylamino, and also from 1 to 9 Can be substituted with fluorine; only,

When R _III-5 , R _III-6 , R _III-7 and / or R _III-8 do not form one or more rings, they are each independently hydrogen, halo, (C ₁ -C ₆ ) alkoxy or (C _1- C ₆ ) alkyl, wherein (C ₁ -C ₆ ) alkyl may have 1 to 9 fluorine.

The compounds of formula III and methods for their preparation are disclosed in commonly assigned US Pat. Nos. 6,147,089, 6,310,075, and European Patent Application No. 99307240, filed Sep. 14, 1999, all of which are intended for all purposes. Is hereby incorporated by reference in its entirety.

In a preferred embodiment, the CETP inhibitor is selected from the following compounds of formula III:

[2R, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-methyl-2,3,4,6,7,8-hexahydro- Cyclopenta [g] quinoline-1-carboxylic acid ethyl ester;

[6R, 8S] 8-[(3,5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -6-methyl-3,6,7,8-tetrahydro-1H-2- Thia-5-aza-cyclopenta [b] naphthalene-5-carboxylic acid ethyl ester;

[6R, 8S] 8-[(3,5-Bis-Trifluoromethyl-benzyl) -methoxycarbonyl-amino] -6-methyl-3,6,7,8-tetrahydro-2H-puro [ 2,3-g] quinoline-5-carboxylic acid ethyl ester;

[2R, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-methyl-3,4,6,8-tetrahydro-2H-furo [ 3,4-g] quinoline-1-carboxylic acid ethyl ester;

[2R, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-methyl-3,4,6,7,8,9-hexahydro- 2H-benzo [g] quinoline-1-carboxylic acid propyl ester;

[7R, 9S] 9-[(3,5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -7-methyl-1,2,3,7,8,9-hexahydro- 6-aza-cyclopenta [a] naphthalene-6-carboxylic acid ethyl ester; And

[6S, 8R] 6-[(3,5-Bis-Trifluoromethyl-benzyl) -methoxycarbonyl-amino] -8-methyl-1,2,3,6,7,8-hexahydro- 9-aza-cyclopenta [a] naphthalene-9-carboxylic acid ethyl ester.

Another class of CETP inhibitors that may be used in the present invention are 4-carboxyamino-2-substituted-1,2,3,4-tetrahydroquinoline having the formula IV, and pharmaceutically acceptable salts of these compounds, Consists of enantiomers or stereoisomers:

Where

R _IV-1 is hydrogen, Y _IV , W _IV -X _IV or W _IV -Y _IV ; At this time

W _IV is carbonyl, thiocarbonyl, sulfinyl or sulfonyl;

X _IV is -OY _IV , -SY _IV , -N (H) -Y _IV or -N- (Y _IV ) ₂ ; At this time

Y _IV is independently Z _IV or a 1 to 10 membered fully saturated, partially unsaturated or fully unsaturated linear or branched carbon chain, wherein carbon other than the linking carbon is independently selected from oxygen, sulfur and nitrogen May be substituted with one or two heteroatoms, the carbon may be independently mono-, di- or tri-substituted with halo, mono-substituted with hydroxy, mono-substituted with oxo, The sulfur may be mono- or di-substituted with oxo, the nitrogen may be mono- or di-substituted with oxo, and the carbon chain may be mono-substituted with Z _IV ; At this time

Z _IV is a 3-8 membered partially saturated or fully saturated or fully unsaturated ring which may have 1 to 4 heteroatoms independently selected from oxygen, sulfur and nitrogen, or independently selected from nitrogen, sulfur and oxygen A bicyclic ring formed by condensation of two independently selected rings of 3 to 6 members which are partially saturated, fully saturated or fully unsaturated, which may have 1 to 4 heteroatoms;

The Z _IV substituents are independently halo, (C ₂ -C ₆ ) alkenyl, (C ₁ -C ₆ ) alkyl, hydroxy, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) alkylthio, Amino, nitro, cyano, oxo, carboxy, (C ₁ -C ₆ ) alkyloxycarbonyl, mono-N- or di-N, N- (C ₁ -C ₆ ) alkylaminoroyl-, di- Or tri-substituted, wherein the (C ₁ -C ₆ ) alkyl substituent is independently halo, hydroxy, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) alkylthio, amino, nit Rho, cyano, oxo, carboxy, (C ₁ -C ₆ ) alkyloxycarbonyl, mono-N- or di-N, N- (C ₁ -C ₆ ) alkylamino as mono-, di- or tri- May be substituted, and may also be substituted with 1 to 9 fluorine;

R _IV-2 is a 1-6 membered partially saturated, fully saturated or fully unsaturated linear or branched carbon chain wherein carbon other than the linking carbon is one or two heteros independently selected from oxygen, sulfur and nitrogen. Can be substituted with an atom, and the carbon atom can be independently mono-, di- or tri-substituted with halo, mono-substituted with oxo, mono-substituted with hydroxy, and sulfur with oxo May be mono- or di-substituted and the nitrogen may be mono- or di-substituted with oxo; or

R _IV-2 is a 3-7 membered partially saturated, fully saturated or fully unsaturated ring which may have 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, wherein R _IV-2 The ring may be bonded via (C ₁ -C ₄ ) alkyl; At this time

The R _IV-2 ring is independently halo, (C ₂ -C ₆ ) alkenyl, (C ₁ -C ₆ ) alkyl, hydroxy, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) alkyl Thio, amino, nitro, cyano, oxo, carboxy, (C ₁ -C ₆ ) alkyloxycarbonyl, mono-N- or di-N, N- (C ₁ -C ₆ ) alkylaminoroyl-, Di- or tri-substituted wherein the (C ₁ -C ₆ ) alkyl substituents are independently halo, hydroxy, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) alkylthio, oxo Or mono-, di- or tri-substituted with (C ₁ -C ₆ ) alkyloxycarbonyl; only

R _IV-2 is not methyl;

R _IV-3 is hydrogen or Q _IV ; At this time

Q _IV is a 1 to 6 membered fully saturated, partially unsaturated or fully unsaturated linear or branched carbon chain, wherein carbon other than the linking carbon may be substituted with one heteroatom selected from oxygen, sulfur and nitrogen, The carbon may be independently mono-, di- or tri-substituted with halo, mono-substituted with hydroxy, mono-substituted with oxo, and the sulfur is mono- or di-substituted with oxo. The nitrogen may be mono- or di-substituted with oxo and the carbon chain may be mono-substituted with V _IV ; At this time

V _IV is a 3-8 membered partially saturated, fully saturated or fully unsaturated ring which may have 1 to 4 heteroatoms independently selected from oxygen, sulfur and nitrogen, or independently selected from nitrogen, sulfur and oxygen A bicyclic ring formed by condensation of two independently selected rings of 3 to 6 members which are partially saturated, fully saturated or fully unsaturated, which may have 1 to 4 heteroatoms;

The V _IV substituents are independently halo, (C ₁ -C ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl, hydroxy, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) alkylthio, Amino, nitro, cyano, oxo, carboxamoyl, mono-N- or di-N, N- (C ₁ -C ₆ ) alkylcarboxamoyl, carboxy, (C ₁ -C ₆ ) alkyloxycarbonyl , Mono-N- or di-N, N- (C ₁ -C ₆ ) alkylamino can be mono-, di-, tri- or tetra-substituted, wherein said (C ₁ -C ₆ ) alkyl or (C ₂ -C ₆ ) alkenyl substituents are independently hydroxy, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) alkylthio, amino, nitro, cyano, oxo, carboxy, (C ₁ -C ₆ ) alkyloxycarbonyl, mono-N- or di-N, N- (C ₁ -C ₆ ) alkylamino can be mono-, di- or tri-substituted, and also from 1 to 9 fluorine Can be substituted;

R _IV-4 is Q _IV-1 or V _IV-1 ; At this time

Q _IV-1 is a 1-6 membered fully saturated, partially unsaturated or fully unsaturated linear or branched carbon chain, wherein carbon other than the linking carbon may be substituted with one heteroatom selected from oxygen, sulfur and nitrogen Wherein the carbon may be independently mono-, di- or tri-substituted with halo, mono-substituted with hydroxy, mono-substituted with oxo, and the sulfur is mono- or di-substituted with oxo. Can be substituted, the nitrogen can be mono- or di-substituted with oxo and the carbon chain can be mono-substituted with V _IV-1 ; At this time

V _IV-1 is a 3 to 6 membered partially saturated, fully saturated or fully unsaturated ring which may have one or two heteroatoms independently selected from oxygen, sulfur and nitrogen;

The V _IV-1 substituents are independently halo, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, amino, nitro, cyano, (C ₁ -C ₆ ) alkyloxycarbonyl, mono -N- or di _{-N, N- (C 1 -C 6} ) alkylamino in one -, two -, three-or four-can be optionally substituted, where the (C ₁ -C ₆₎ alkyl substituent is oxo May be mono-substituted and may also be substituted with 1 to 9 fluorine;

R _IV-3 should comprise V _IV or R _IV-4 should comprise V _IV-1 ;

R _IV-5 , R _IV-6 , R _IV-7 and R _IV-8 are each independently hydrogen, a bond, nitro or halo, wherein the bond is substituted by T _IV or partially saturated or fully Saturated or fully unsaturated (C ₁ -C ₁₂ ) linear or branched carbon chain, wherein carbon may be substituted with one or two heteroatoms independently selected from oxygen, sulfur and nitrogen, wherein the carbon atoms are independently Can be mono-, di- or tri-substituted with halo, mono-substituted with hydroxy, mono-substituted with oxo, the sulfur can be mono- or di-substituted with oxo, the nitrogen May be mono- or di-substituted with oxo and the carbon may be mono-substituted with T _IV ; At this time

T _IV is a 3-8 membered partially saturated or fully saturated or fully unsaturated ring which may have 1 to 4 heteroatoms independently selected from oxygen, sulfur and nitrogen, or independently selected from nitrogen, sulfur and oxygen A bicyclic ring formed by condensation of two independently selected rings of 3 to 6 members which are partially saturated, fully saturated or fully unsaturated, which may have 1 to 4 heteroatoms;

The T _IV substituents are independently halo, (C ₁ -C ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl, hydroxy, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) alkylthio, Amino, nitro, cyano, oxo, carboxy, (C ₁ -C ₆ ) alkyloxycarbonyl, mono-N- or di-N, N- (C ₁ -C ₆ ) alkylaminoroyl-, di- Or tri-substituted, wherein the (C ₁ -C ₆ ) alkyl substituent is independently hydroxy, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) alkylthio, amino, nitro, To be mono-, di- or tri-substituted with cyano, oxo, carboxy, (C ₁ -C ₆ ) alkyloxycarbonyl, mono-N- or di-N, N- (C ₁ -C ₆ ) alkylamino May also be substituted with 1 to 9 fluorine;

R _IV-5 and R _IV-6 , or R _IV-6 and R _IV-7 and / or R _IV-7 and R _IV-8 together form 1 to 3 heteroatoms independently selected from oxygen, sulfur and nitrogen. May form one or more of the 4-8 membered partially saturated or fully unsaturated rings it may have; At this time

The ring formed by R _IV-5 and R _IV-6 , or R _IV-6 and R _IV-7 , and / or R _IV-7 and R _IV-8 is independently halo, (C ₁ -C ₆ ) alkyl , (C ₁ -C ₄ ) alkylsulfonyl, (C ₂ -C ₆ ) alkenyl, hydroxy, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) alkylthio, amino, nitro, between Mono-, di-, or tri-substituted with ano, oxo, carboxy, (C ₁ -C ₆ ) alkyloxycarbonyl, mono-N- or di-N, N- (C ₁ -C ₆ ) alkylamino Wherein the (C ₁ -C ₆ ) alkyl substituent is independently hydroxy, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) alkylthio, amino, nitro, cyano, oxo, carboxy , (C ₁ -C ₆₎ alkyloxycarbonyl, mono or di -N- _{-N, N- (C 1 -C 6} ) alkylamino days -, phenyl or phenoxy may be optionally substituted, and 1 to May be substituted with 9 fluorine; only,

When R _IV-2 is carboxyl or (C ₁ -C ₄ ) alkylcarboxyl, R _IV-1 is not hydrogen.

The compounds of formula IV and methods for their preparation are disclosed in commonly assigned US Pat. No. 6,197,786, US Patent Application No. 09 / 685,300, filed Oct. 10, 2000, and PCT Publication WO 00/17164. All of which are incorporated herein by reference in their entirety for all purposes.

In a preferred embodiment, the CETP inhibitor is selected from the following compounds of formula IV:

[2S, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-isopropyl-6-trifluoromethyl-3,4-dihydro- 2H-quinoline-1-carboxylic acid isopropyl ester;

[2S, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -6-chloro-2-cyclopropyl-3,4-dihydro-2H-quinoline -1-carboxylic acid isopropyl ester;

[2S, 4S] 2-Cyclopropyl-4-[(3,5-dichloro-benzyl) -methoxycarbonyl-amino] -6-trifluoromethyl-3,4-dihydro-2H-quinoline- 1-carboxylic acid isopropyl ester;

[2S, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro- 2H-quinoline-1-carboxylic acid t-butyl ester;

[2R, 4R] 4-[(3,5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro- 2H-quinoline-1-carboxylic acid isopropyl ester;

[2S, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro- 2H-quinoline-1-carboxylic acid isopropyl ester;

[2S, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-cyclobutyl-6-trifluoromethyl-3,4-dihydro- 2H-quinoline-1-carboxylic acid isopropyl ester;

[2R, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H -Quinoline-1-carboxylic acid isopropyl ester;

[2S, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-methoxymethyl-6-trifluoromethyl-3,4-dihydro -2H-quinoline-1-carboxylic acid isopropyl ester;

[2R, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H -Quinoline-1-carboxylic acid 2-hydroxy-ethyl ester;

[2S, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro- 2H-quinoline-1-carboxylic acid ethyl ester;

[2R, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H -Quinoline-1-carboxylic acid ethyl ester;

[2S, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro- 2H-quinoline-1-carboxylic acid propyl ester; And

[2R, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H -Quinoline-1-carboxylic acid propyl ester.

In a preferred embodiment, the CETP inhibitor is [2R, 4S] -4-[(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino]-, also known as tocetrapib. 2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester. Tocetrapib is represented by Formula A:

CETP inhibitors, in particular tocetrapib and methods of making such compounds are detailed in US Pat. Nos. 6,197,786 and 6,313,142, PCT Publications WO 01 / 40190A1, WO 02 / 088085A2 and WO 02 / 088069A2. And the disclosures thereof are incorporated herein by reference. Tocetrapib has a significantly lower solubility in aqueous environments such as the human GI tract. The water solubility of tocetrapib is less than about 0.04 μg / ml. Tocetrapib should be provided to the gastrointestinal tract in a solubility-enhancing form to achieve sufficient drug concentration in the gastrointestinal tract to achieve sufficient absorption into the blood to elicit the desired therapeutic effect.

Another class of CETP inhibitors that can be used in the present invention is 4-amino substituted-2-substituted-1,2,3,4-tetrahydroquinoline having the formula (V), and pharmaceutically acceptable compounds of this compound: Possible salts, enantiomers or stereoisomers consist of:

Where

R _V-1 is Y _V , W _V -X _V or W _V -Y _V ; At this time

W _V is carbonyl, thiocarbonyl, sulfinyl or sulfonyl;

X _V is -OY _V , -SY _V , -N (H) -Y _V or -N (Y _V ) ₂ ; At this time

Each Y _V is independently Z _V or a 1 to 10 membered fully saturated, partially unsaturated or fully unsaturated linear or branched carbon chain, wherein carbon other than the linking carbon is independently in oxygen, sulfur and nitrogen May be substituted with one or two heteroatoms selected, the carbon may be independently mono-, di- or tri-substituted with halo, mono-substituted with hydroxy, mono-substituted with oxo , The sulfur may be mono- or di-substituted with oxo, the nitrogen may be mono- or di-substituted with oxo, and the carbon chain may be mono-substituted with Z _V ; At this time

Z _V is a 3-8 membered partially saturated or fully saturated or fully unsaturated ring which may have 1 to 4 heteroatoms independently selected from oxygen, sulfur and nitrogen, or independently selected from nitrogen, sulfur and oxygen A bicyclic ring formed by condensation of two independently selected rings of 3 to 6 members which are partially saturated, fully saturated or fully unsaturated, which may have 1 to 4 heteroatoms;

The Z _V substituents are independently halo, (C ₂ -C ₆ ) alkenyl, (C ₁ -C ₆ ) alkyl, hydroxy, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) alkylthio, Amino, nitro, cyano, oxo, carboxy, (C ₁ -C ₆ ) alkyloxycarbonyl, mono-N- or di-N, N- (C ₁ -C ₆ ) alkylaminoroyl-, di- Or tri-substituted, wherein the (C ₁ -C ₆ ) alkyl substituent is independently halo, hydroxy, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) alkylthio, amino, nitro , Cyano, oxo, carboxy, (C ₁ -C ₆ ) alkyloxycarbonyl, mono-N- or di-N, N- (C ₁ -C ₆ ) alkylamino to mono-, di- or tri-substituted May also be substituted with 1 to 9 fluorine;

R _V-2 is a 1-6 membered partially saturated, fully saturated, or fully unsaturated linear or branched carbon chain, wherein carbon other than the linking carbon is one or two heteros, independently selected from oxygen, sulfur and nitrogen. Can be substituted with an atom, and the carbon atom can be independently mono-, di- or tri-substituted with halo, mono-substituted with oxo, mono-substituted with hydroxy, and sulfur with oxo May be mono- or di-substituted and the nitrogen may be mono- or di-substituted with oxo; or

Wherein R _V-2 is a 3-7 membered partially saturated, fully saturated or fully unsaturated ring which may have one or two heteroatoms independently selected from oxygen, sulfur and nitrogen, wherein R _V-2 The ring may be bonded via (C ₁ -C ₄ ) alkyl; At this time

The R _V-2 ring is independently halo, (C ₂ -C ₆ ) alkenyl, (C ₁ -C ₆ ) alkyl, hydroxy, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) alkyl Thio, amino, nitro, cyano, oxo, carboxy, (C ₁ -C ₆ ) alkyloxycarbonyl, mono-N- or di-N, N- (C ₁ -C ₆ ) alkylaminoroyl-, Di- or tri-substituted wherein the (C ₁ -C ₆ ) alkyl substituents are independently halo, hydroxy, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) alkylthio, oxo Or mono-, di- or tri-substituted with (C ₁ -C ₆ ) alkyloxycarbonyl;

R _V-3 is hydrogen or Q _V ; At this time

Q _V is a 1-6 membered fully saturated, partially unsaturated or fully unsaturated linear or branched carbon chain, wherein carbon other than the linking carbon may be substituted with one heteroatom selected from oxygen, sulfur and nitrogen, The carbon may be independently mono-, di- or tri-substituted with halo, mono-substituted with hydroxy, mono-substituted with oxo, and the sulfur is mono- or di-substituted with oxo. The nitrogen may be mono- or di-substituted with oxo and the carbon chain may be mono-substituted with V _V ; At this time

V _V is a 3-8 membered partially saturated or fully saturated or fully unsaturated ring which may have 1 to 4 heteroatoms independently selected from oxygen, sulfur and nitrogen, or independently selected from nitrogen, sulfur and oxygen A bicyclic ring formed by condensation of two independently selected rings of 3 to 6 members which are partially saturated, fully saturated or fully unsaturated, which may have 1 to 4 heteroatoms;

The V _V substituents are independently halo, (C ₁ -C ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl, hydroxy, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) alkylthio, Amino, nitro, cyano, oxo, carboxamoyl, mono-N- or di-N, N- (C ₁ -C ₆ ) alkylcarboxamoyl, carboxy, (C ₁ -C ₆ ) alkyloxycarbonyl , Mono-N- or di-N, N- (C ₁ -C ₆ ) alkylamino can be mono-, di-, tri- or tetra-substituted, wherein (C ₁ -C ₆ ) alkyl or ( C ₂ -C ₆ ) alkenyl substituents are independently hydroxy, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) alkylthio, amino, nitro, cyano, oxo, carboxy, (C _1- C ₆ ) alkyloxycarbonyl, mono-N- or di-N, N- (C ₁ -C ₆ ) alkylamino can be mono-, di- or tri-substituted, and also substituted with 1 to 9 fluorine Can be;

R _V-4 is cyano, formyl, W _V-1 Q _V-1 , (C ₁ -C ₄ ) alkylene V _V-1 or V _V-2 ; At this time

W _V-1 is carbonyl, thiocarbonyl, SO or SO ₂ ;

Q _V-1 is a 1-6 membered fully saturated, partially unsaturated or fully unsaturated linear or branched carbon chain wherein carbon other than the linking carbon may be substituted with one heteroatom selected from oxygen, sulfur and nitrogen Wherein the carbon may be independently mono-, di- or tri-substituted with halo, mono-substituted with hydroxy, mono-substituted with oxo, and the sulfur is mono- or di-substituted with oxo. Can be substituted, the nitrogen can be mono- or di-substituted with oxo and the carbon chain can be mono-substituted with V _V-1 ; At this time

V _V-1 is a 3-6 membered partially saturated, fully saturated or fully unsaturated ring which may have one or two heteroatoms independently selected from oxygen, sulfur and nitrogen, or is independent from nitrogen, sulfur and oxygen A bicyclic ring formed by condensation of two partially saturated, fully saturated or fully unsaturated two to six membered rings which may have 1 to 4 heteroatoms selected from;

The V _V-1 substituent is independently halo, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, hydroxy, oxo, amino, nitro, cyano, (C ₁ -C ₆ ) alkyl May be mono-, di-, tri- or tetra-substituted with oxycarbonyl, mono-N- or di-N, N- (C ₁ -C ₆ ) alkylamino, wherein the (C ₁ -C ₆ Alkyl substituents may be mono-substituted with oxo and may also be substituted with 1 to 9 fluorine;

V _V-2 is a 5 to 7 membered partially saturated or fully saturated or fully unsaturated ring having 1 to 4 heteroatoms independently selected from oxygen, sulfur and nitrogen;

The V _V-2 substituents may be independently mono-, di- or tri-substituted with halo, (C ₁ -C ₂ ) alkyl, (C ₁ -C ₂ ) alkoxy, hydroxy or oxo, wherein ( C ₁ -C ₂ ) alkyl may have 1 to 5 fluorine;

R _V-4 does not comprise oxycarbonyl directly linked to C ₄ nitrogen;

R _V-3 must comprise V _V or R _V-4 must comprise V _V-1 ;

R _V-5 , R _V-6 , R _V-7 and R _V-8 are independently hydrogen, a bond, nitro or halo, wherein the bond is substituted by T _V or partially saturated or fully saturated Or fully unsaturated (C ₁ -C ₁₂ ) linear or branched carbon chain, wherein carbon may be substituted with one or two heteroatoms independently selected from oxygen, sulfur and nitrogen, wherein the carbon atoms are independently halo May be mono-, di- or tri-substituted, mono-substituted with hydroxy, mono-substituted with oxo, the sulfur may be mono- or di-substituted with oxo, and the nitrogen is May be mono- or di-substituted with oxo, and the carbon may be mono-substituted with T _V ; At this time

T _V is a 3 to 12 membered partially saturated or fully saturated or fully unsaturated ring which may have 1 to 4 heteroatoms independently selected from oxygen, sulfur and nitrogen, or independently selected from nitrogen, sulfur and oxygen A bicyclic ring formed by condensation of two independently selected rings of 3 to 6 members which are partially saturated, fully saturated or fully unsaturated, which may have 1 to 4 heteroatoms;

The T _V substituents are independently halo, (C ₁ -C ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl, hydroxy, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) alkylthio, Amino, nitro, cyano, oxo, carboxy, (C ₁ -C ₆ ) alkyloxycarbonyl, mono-N- or di-N, N- (C ₁ -C ₆ ) alkylaminoroyl-, di- Or tri-substituted, wherein the (C ₁ -C ₆ ) alkyl substituent is independently hydroxy, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) alkylthio, amino, nitro, between Mono-, di-, or tri-substituted with ano, oxo, carboxy, (C ₁ -C ₆ ) alkyloxycarbonyl, mono-N- or di-N, N- (C ₁ -C ₆ ) alkylamino May also have from 1 to 9 fluorine;

R _V-5 and R _V-6 , or R _V-6 and R _V-7 , and / or R _V-7 and R _V-8 together are 1 to 3 heteroatoms independently selected from oxygen, sulfur and nitrogen May form one or more 4-8 membered partially saturated or fully unsaturated rings which may have; At this time

The ring formed by R _V-5 and R _V-6 , or R _V-6 and R _V-7 , and / or R _V-7 and R _V-8 is independently halo, (C ₁ -C ₆ ) alkyl , (C ₁ -C ₄ ) alkylsulfonyl, (C ₂ -C ₆ ) alkenyl, hydroxy, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) alkylthio, amino, nitro, between Mono-, di-, or tri-substituted with ano, oxo, carboxy, (C ₁ -C ₆ ) alkyloxycarbonyl, mono-N- or di-N, N- (C ₁ -C ₆ ) alkylamino Wherein the (C ₁ -C ₆ ) alkyl substituent is independently hydroxy, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) alkylthio, amino, nitro, cyano, oxo, carboxy, May be mono-, di- or tri-substituted with (C ₁ -C ₆ ) alkyloxycarbonyl, mono-N- or di-N, N- (C ₁ -C ₆ ) alkylamino, and also from 1 to 9 Fluorine.

The compounds of formula (V) and methods for their preparation are disclosed in commonly assigned U. S. Patent No. 6,140, 343, U. S. Patent Application Serial No. 09/671, 221, filed Sep. 27, 2000 and PCT Publication No. WO 00/17165. All of which are incorporated herein by reference in their entirety for all purposes.

In a preferred embodiment, the CETP inhibitor is selected from the following compounds of Formula (V):

[2S, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -formyl-amino] -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline -1-carboxylic acid isopropyl ester;

[2S, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -formyl-amino] -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline -1-carboxylic acid propyl ester;

[2S, 4S] 4- [acetyl- (3,5-bis-trifluoromethyl-benzyl) -amino] -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline -1-carboxylic acid t-butyl ester;

[2R, 4S] 4- [acetyl- (3,5-bis-trifluoromethyl-benzyl) -amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline- 1-carboxylic acid isopropyl ester;

[2R, 4S] 4- [acetyl- (3,5-bis-trifluoromethyl-benzyl) -amino] -2-methyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline- 1-carboxylic acid ethyl ester;

[2S, 4S] 4- [1- (3,5-Bis-trifluoromethyl-benzyl) -ureido] -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H- Quinoline-1-carboxylic acid isopropyl ester;

[2R, 4S] 4- [acetyl- (3,5-bis-trifluoromethyl-benzyl) -amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline- 1-carboxylic acid ethyl ester;

[2S, 4S] 4- [acetyl- (3,5-bis-trifluoromethyl-benzyl) -amino] -2-methoxymethyl-6-trifluoromethyl-3,4-dihydro-2H- Quinoline-1-carboxylic acid isopropyl ester;

[2S, 4S] 4- [acetyl- (3,5-bis-trifluoromethyl-benzyl) -amino] -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline -1-carboxylic acid propyl ester;

[2S, 4S] 4- [acetyl- (3,5-bis-trifluoromethyl-benzyl) -amino] -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline -1-carboxylic acid ethyl ester;

[2R, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -formyl-amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline- 1-carboxylic acid isopropyl ester;

[2R, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -formyl-amino] -2-methyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline- 1-carboxylic acid ethyl ester;

[2S, 4S] 4- [acetyl- (3,5-bis-trifluoromethyl-benzyl) -amino] -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline -1-carboxylic acid isopropyl ester;

[2R, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -formyl-amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline- 1-carboxylic acid ethyl ester;

[2S, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -formyl-amino] -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline -1-carboxylic acid ethyl ester;

[2R, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -formyl-amino] -2-methyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline- 1-carboxylic acid isopropyl ester; And

[2R, 4S] 4- [acetyl- (3,5-bis-trifluoromethyl-benzyl) -amino] -2-methyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline- 1-carboxylic acid isopropyl ester.

Another class of CETP inhibitors that may be used in the present invention consists of cycloalkano-pyridine having the formula VI and pharmaceutically acceptable salts, enantiomers, stereoisomers or N-oxides of this compound:

Where

A _VI is halogen, nitro, hydroxyl, trifluoromethyl, trifluoromethoxy, or straight or branched chain alkyl, acyl, hydroxyalkyl or alkoxy containing up to 7 carbon atoms, or formula -BNR _VI Aryl containing 6 to 10 carbon atoms which may be substituted with up to 5 substituents, identical or different, selected from the group _-3 R _VI-4 ; At this time

R _VI-3 and R _VI-4 are the same or different and represent hydrogen, phenyl or straight or branched chain alkyl containing up to 6 carbon atoms;

D _VI is phenyl, nitro, halogen, trifluoromethyl or trifluoromethoxy, or formula R _VI-5 -L _VI- , Or aryl containing 6 to 10 carbon atoms which may be substituted by R _VI-9 -T _VI -V _VI -X _VI ; At this time

R _VI-5 , R _VI-6 and R _VI-9 are independently of each other cycloalkyl containing 3 to 6 carbon atoms, aryl containing 6 to 10 carbon atoms, or at S, N and / or O It represents a 5-7 membered saturated or unsaturated mono-, di- or tricyclic heterocycle containing up to 4 heteroatoms selected and which can be benzo-condensed, wherein the ring is an N functional group in the case of a nitrogen-containing ring Via halogen, trifluoromethyl, nitro, hydroxyl, cyano, carboxyl, trifluoromethoxy, straight or branched acyl containing up to 6 carbon atoms each, alkyl, alkylthio, alkylalkoxy, alkoxy Or alkoxycarbonyl, containing at most 3 heteroatoms selected from aryl or trifluoromethyl substituted aryl containing 6 to 10 carbon atoms each, S, N and / or O and capable of being benzo condensed Up to 5 identical or different substituents selected from the group 5-7 membered heterocycle and / or groups BOR _VI-10 , -SR _VI-11 , -SO ₂ R _VI-12 or BNR _VI-13 R _VI-14 May be substituted with; At this time

R _VI-10 , R _VI-11 and R _VI-12 are independently of each other substituted with the same or different up to 2 substituents selected from phenyl, halogen or straight or branched chain alkyl containing up to 6 carbon atoms, Aryl containing 6 to 10 carbon atoms;

R _VI-13 and R _VI-14 are the same or different and have the meanings defined above for R _VI-3 and R _VI-4 ; or

R _VI-5 and / or R _VI-6 is a chemical formula Represents a radical according to; At this time

R _VI-7 represents hydrogen or halogen;

R _VI-8 is hydrogen, halogen, azido, trifluoromethyl, hydroxyl, trifluoromethoxy, straight or branched chain alkoxy or alkyl containing up to 6 carbon atoms, or formula -NR _VI-15 R _Represent a radical according to _VI-16 , wherein NR _VI-15 and R _VI-16 are the same or different and have the meanings defined above for R _VI-3 and R _VI-4 ; or

R _VI-7 and R _VI-8 together represent a formula = O or = NR _{VI-17 wherein} R _VI-17 is hydrogen or straight or branched chain alkyl, alkoxy or acyl containing up to 6 carbon atoms. To form a radical according to the invention;

L _VI represents a straight or branched chain alkylene or alkenylene containing up to 8 carbon atoms each, which may be substituted with up to 2 hydroxyl groups;

T VI and X VI represent the same or different, straight or branched chain alkylene containing up to 8 carbon atoms, or

T _VI or X _VI represents a bond;

V _VI represents a group of an oxygen or sulfur atom, or BN _RVI-18 , wherein R _VI-18 represents hydrogen or straight or branched chain alkyl containing up to 6 carbon atoms, or phenyl;

E _VI is a straight or branched chain alkyl containing up to 8 carbon atoms which may be substituted by cycloalkyl containing 3 to 8 carbon atoms, or cycloalkyl or hydroxyl containing 3 to 8 carbon atoms, Or phenyl which may be substituted with halogen or trifluoromethyl;

R _VI-1 and R _VI-2 together represent a carbonyl group and / or a chemical formula To form straight or branched chain alkylene containing up to 7 carbon atoms which are substituted with radicals according to; At this time

a and b are the same or different and represent 1, 2 or 3;

R _VI-19 is hydrogen atom, cycloalkyl containing 3 to 7 carbon atoms, straight or branched chain silylalkyl containing up to 8 carbon atoms, or straight or branched chain containing up to 8 carbon atoms Alkyl (these are linear or branched alkoxy or phenyl containing up to 6 carbon atoms which may be substituted by hydroxyl; halogen, nitro, trifluoromethyl, trifluoromethoxy, phenyl or tetrazol substituted phenyl) May be substituted), or the formula BOR _IV-22 , wherein R _IV-22 represents a straight or branched chain acyl or benzyl containing up to 4 carbon atoms; or

R _VI-19 contains straight or branched chain acyl or benzoyl containing up to 20 carbon atoms which may be substituted by halogen, trifluoromethyl, nitro or trifluoromethoxy, or up to 8 carbon atoms To straight or branched chain fluoroacyl;

R _VI-20 and R _VI-21 are the same or different and represent hydrogen, phenyl or straight or branched chain alkyl containing up to 6 carbon atoms; or

R _VI-20 and R _VI-21 together form a 3 to 6 membered carbocyclic ring, wherein the carbocyclic ring thus formed is trifluoromethyl, hydroxyl, nitrile, halogen, carboxyl, nitro, azido, inter Ano, cycloalkyl or cycloalkoxy containing 3 to 7 carbon atoms each, straight or branched alkoxycarbonyl, alkoxy or alkylthio containing up to 6 carbon atoms each, or containing up to 6 carbon atoms Linear or branched alkyl, wherein the alkyl is hydroxyl, benzyloxy, trifluoromethyl, benzoyl, straight or branched alkoxy, oxyacyl or carboxyl containing up to 4 carbon atoms, and / or halogen , May be substituted with phenyl which may be substituted with trifluoromethyl or trifluoromethoxy). Optionally up to six identical or different substituents may be optionally substituted in pairs and / or the carbocyclic ring formed is phenyl, benzoyl, which may be substituted by halogen, trifluoromethyl, trifluoromethoxy or nitro; Thiophenyl or sulfonylbenzyl forms and / or formulas

[Wherein,

c is 1, 2, 3 or 4;

d is 0 or 1;

R _VI-23 and R _VI-24 are the same or different and represent hydrogen, cycloalkyl containing 3 to 6 carbon atoms, straight or branched chain alkyl containing up to 6 carbon atoms, benzyl or phenyl, They may also be substituted with up to two identical or different substituents in the form of halogen, trifluoromethyl, cyano, phenyl or nitro]

Optionally optionally in pairs with up to 5 identical or different substituents selected from radicals according to;

The formed carbocyclic ring has the following formula

[Wherein,

W _VI represents an oxygen atom or a sulfur atom;

Y _VI and Y ′ _VI together represent a 2-6 membered straight or branched chain alkylene;

e is 1, 2, 3, 4, 5, 6 or 7;

f is 1 or 2;

R _VI-25 , R _VI-26 , R _VI-27 , R _VI-28 , R _VI-29 , R _VI-30 and R _VI-31 are the same or different and are hydrogen, trifluoromethyl, phenyl or halogen Or straight or branched chain alkyl or alkoxy containing up to 6 carbon atoms; or

R _VI-25 and R _VI-26 or R _VI-27 and R _VI-28 each represent straight or branched chain alkyl containing up to 6 carbon atoms; or

R _VI-25 and R _VI-26 or R _VI-27 and R _VI-28 together represent the formula

[Wherein,

W _VI has the meaning defined above;

g is 1, 2, 3, 4, 5, 6 or 7]

To form radicals according to;

R _VI-32 and R _VI-33 together form a 3-7 membered heterocycle containing an oxygen or sulfur atom or a group of formula SO, SO ₂ or BNR _VI-34 ; At this time

R _VI-34 represents a hydrogen atom, phenyl, benzyl, or straight or branched chain alkyl containing up to 4 carbon atoms]

Can be substituted with spiro-linked radicals according to; only

5 (6H) -quinolone, 3-benzoyl-7,8-dihydro-2,7,7-trimethyl-4-phenyl is excluded.

The compounds of formula VI and methods for their preparation are disclosed in European Patent Application Publication Nos. EP 818448 A1, US Pat. Nos. 6,207,671 and 6,069,148, all of which are incorporated herein by reference in their entirety for all purposes.

In one preferred embodiment, the CETP inhibitor is selected from the following compounds of Formula VI:

2-cyclopentyl-4- (4-fluorophenyl) -7,7-dimethyl-3- (4-trifluoromethylbenzoyl) -4,6,7,8-tetrahydro-1H-quinoline-5 -On;

2-cyclopentyl-4- (4-fluorophenyl) -7,7-dimethyl-3- (4-trifluoromethylbenzoyl) -7,8-dihydro-6H-quinolin-5-one;

[2-cyclopentyl-4- (4-fluorophenyl) -5-hydroxy-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-3-yl]-(4-trifluoro Romethylphenyl) -methanone;

[5- (t-Butyldimethylsilanyloxy) -2-cyclopentyl-4- (4-fluorophenyl) -7,7-dimethyl-5,6,7,8-tetrahydroquinoline-3- Il]-(4-trifluoromethylphenyl) -methanone;

[5- (t-Butyldimethylsilanyloxy) -2-cyclopentyl-4- (4-fluorophenyl) -7,7-dimethyl-5,6,7,8-tetrahydroquinoline-3- Il]-(4-trifluoromethylphenyl) -methanol;

[5- (t-Butyldimethylsilanyloxy) -2-cyclopentyl-4- (4-fluorophenyl) -3- [fluoro- (4-trifluoromethylphenyl) -methyl] -7,7 -Dimethyl-5,6,7,8-tetrahydroquinoline; And

2-cyclopentyl-4- (4-fluorophenyl) -3- [fluoro- (4-trifluoromethylphenyl) -methyl] -7,7-dimethyl-5,6,7,8-tetrahydro Quinoline-5-ol.

Another class of CETP inhibitors that may be used in the present invention consists of substituted-pyridine having the general formula (VII), and pharmaceutically acceptable salts or tautomers thereof:

Where

R _VII-2 and R _VII-6 are hydrogen, hydroxy, alkyl, fluorinated alkyl, fluorinated aralkyl, chlorofluorinated alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, alkoxyalkyl and alkoxycarbo Independently selected from the group consisting of N, wherein at least one of R _VII-2 and R _VII-6 is fluorinated alkyl, chlorofluorinated alkyl or alkoxyalkyl;

R _VII-3 is hydroxy, amido, arylcarbonyl, heteroarylcarbonyl, hydroxymethyl, -CHO, -CO ₂ R _VII-7 wherein R _VII-7 is hydrogen, alkyl and cyanoalkyl Selected from the group consisting of

[Wherein,

R _VII-15a is hydroxy, hydrogen, halogen, alkylthio, alkenylthio, alkynylthio, arylthio, heteroarylthio, heterocyclylthio, alkoxy, alkenoxy, alkynoxy, aryloxy, heteroaryloxy and Heterocyclyloxy;

R _VII-16a is selected from the group consisting of alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, heterocyclyl, arylalkoxy and trialkylsilyloxy]

It is selected from the group consisting of;

R _VII-4 is hydrogen, hydroxy, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, aryl, heteroaryl, heterocyclyl, cycloalkylalkyl Cycloalkenylalkyl, aralkyl, heteroarylalkyl, heterocyclylalkyl, cycloalkylalkenyl, cycloalkenylalkenyl, aralkenyl, heteroarylalkenyl, heterocyclylalkenyl, alkoxy, alkenoxy, alkynoxy, Aryloxy, heteroaryloxy, heterocyclyloxy, alkanoyloxy, alkenoyloxy, alkinoyloxy, arylloyloxy, heteroaroyloxy, heterocyclylyloxy, alkoxycarbonyl, alkenoxycarbonyl, Alkynoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, heterocyclyloxycarbonyl, thio, alkylthio, alkenylthio, alkynylthio, arylthio, heteroarylthio, heterocyclylthio, Cycloalkylthio, cycloalkenylthio, alkylthioalkyl, alkenylthioalkyl, alkynylthioalkyl, arylthioalkyl, heteroarylthioalkyl, heterocyclylthioalkyl, alkylthioalkenyl, alkenylthioalkenyl, alkyne Ylthioalkenyl, arylthioalkenyl, heteroarylthioalkenyl, heterocyclylthioalkenyl, alkylamino, alkenylamino, alkynylamino, arylamino, heteroarylamino, heterocyclylamino, aryldialkylamino , Diarylamino, diheteroarylamino, alkylarylamino, alkylheteroarylamino, arylheteroarylamino, trialkylsilyl, trialkenylsilyl, triarylsilyl, -CO (O) N (R _VII-8a R _{VII -8b} ) wherein R _VII-8a and R _VII-8b are independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl), -SO ₂ R _VII-9 ( _Wherein R _VII-9 is hydroxy, alkyl, Independently selected from the group consisting of alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl), OP (O) (OR _VII-10a ) (OR _VII-10b ), wherein R _VII-10a and R _{VII -10b} is independently selected from the group consisting of hydrogen, hydroxy, alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl) and OP (S) (OR _VII-11a ) (OR _VII-11b ) ( _Wherein R _VII-11a and R _VII-11b are independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl);

R _VII-5 is hydrogen, hydroxy, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, aryl, heteroaryl, heterocyclyl, alkoxy, alkene Oxy, alkynoxy, aryloxy, heteroaryloxy, heterocyclyloxy, alkylcarbonyloxyalkyl, alkenylcarbonyloxyalkyl, alkynylcarbonyloxyalkyl, arylcarbonyl oxyalkyl, heteroarylcarbonyloxyalkyl, Heterocyclylcarbonyloxyalkyl, cycloalkylalkyl, cycloalkenylalkyl, aralkyl, heteroarylalkyl, heterocyclylalkyl, cycloalkylalkenyl, cycloalkenylalkenyl, aralkenyl, heteroarylalkenyl, heterocycle Arylalkenyl, alkylthioalkyl, cycloalkylthioalkyl, alkenylthioalkyl, alkynylthioalkyl, arylthioalkyl, heteroarylthioalkyl, heterocyclylthioalkyl, alkylthioalkenyl, alkenyl Oalkenyl, alkynylthioalkenyl, arylthioalkenyl, heteroarylthioalkenyl, heterocyclylthioalkenyl, alkoxyalkyl, alkenoxyalkyl, alkynoxyalkyl, aryloxyalkyl, heteroaryloxyalkyl, heterocyclyl Oxyalkyl, alkoxyalkenyl, alkenoxyalkenyl, alkynoxyalkenyl, aryloxyalkenyl, heteroaryloxyalkenyl, heterocyclyloxyalkenyl, cyano, hydroxymethyl, -CO ₂ R _VII-14 ( Wherein R _VII-14 is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl),

[Wherein,

R _VII-15b is hydroxy, hydrogen, halogen, alkylthio, alkenylthio, alkynylthio, arylthio, heteroarylthio, heterocyclylthio, alkoxy, alkenoxy, alkynoxy, aryloxy, heteroaryloxy, Heterocyclyloxy, aroyloxy and alkylsulfonyloxy;

R _VII-16b is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkoxy and trialkylsilyloxy],

Formula

[Wherein,

R _VII-7 and R _VII-8 are independently selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl],

Formula

[Wherein,

R _VII-19 is alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, -SR _VII-20 , -OR _VII-21 and BR _VII-22 CO ₂ R _{VII-23 wherein} , R _VII-20 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aminoalkyl, aminoalkenyl, aminoalkynyl, aminoaryl, aminoheteroaryl, aminoheterocyclyl, alkylheteroarylamino And arylheteroarylamino; R _VII-21 is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl; R _VII-22 is alkylene or arylene R _VII-23 is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl),

Formula

[Wherein,

R _VII-24 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, aralkenyl and aralkinyl],

Formula

[Wherein,

R _VII-25 is heterocyclyldenylyl],

Formula

[Wherein,

R _VII-26 and R _VII-27 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl],

Formula

[Wherein,

R _VII-28 and R _VII-29 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl],

Formula

[Wherein,

R _VII-30 and R _VII-31 are independently selected from the group consisting of alkoxy, alkenoxy, alkynoxy, aryloxy, heteroaryloxy and heterocyclyloxy],

Formula

[Wherein,

R _VII-32 and R _VII-33 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl),

Formula

[Wherein,

R _VII-36 is selected from the group consisting of alkyl, alkenyl, aryl, heteroaryl and heterocyclyl],

Formula

[Wherein,

R _VII-37 and R _VII-38 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl],

Formula

[Wherein,

R _VII-39 is hydrogen, alkoxy, alkenoxy, alkynoxy, aryloxy, heteroaryloxy, heterocyclyloxy, alkylthio, alkenylthio, alkynylthio, arylthio, heteroarylthio and heterocyclylthio Selected from the group consisting of;

R _VII-40 represents haloalkyl, haloalkenyl, haloalkynyl, haloaryl, haloheteroaryl, haloheterocyclyl, cycloalkyl, cycloalkenyl, heterocyclylalkoxy, heterocyclylalkenoxy, heterocyclylalkyne Oxy, alkylthio, alkenylthio, alkynylthio, arylthio, heteroarylthio and heterocyclylthio;

-N = R _VII-41 , wherein R _VII-41 is heterocyclylideneyl,

Formula

[Wherein,

R _VII-42 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl;

R _VII-43 is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkinyl, haloaryl, haloheteroaryl and halo Heterocyclyl;

Formula

[Wherein,

R _VII-44 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl],

-N = S = O, -N = C = S, -N = C = O, -N ₃ , -SR _VII-45 wherein R _VII-45 is hydrogen, alkyl, alkenyl, alkynyl, aryl , Heteroaryl, heterocyclyl, haloalkyl, haloalkenyl, haloalkynyl, haloaryl, haloheteroaryl, haloheterocyclyl, heterocyclyl, cycloalkylalkyl, cycloalkenylalkyl, aralkyl, heteroarylalkyl , Heterocyclylalkyl, cycloalkylalkenyl, cycloalkenylalkenyl, aralkenyl, heteroarylalkenyl, heterocyclylalkenyl, alkylthioalkyl, alkenylthioalkyl, alkynylthioalkyl, arylthioalkyl, heteroaryl Thioalkyl, heterocyclylthioalkyl, alkylthioalkenyl, alkenylthioalkenyl, alkynylthioalkenyl, arylthioalkenyl, heteroarylthioalkenyl, heterocyclylthioalkenyl, aminocarbonylalkyl, amino Carbonylalkenyl, aminocarbonylalkynyl, aminocarbonylaryl, aminocarbonylhetero Aryl and aminocarbonylheterocyclyl),

SR _VII-46 and —CH ₂ R _VII-47 , wherein R _VII-46 is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl; R _VII-47 is hydrogen, Is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl),

Formula

[Wherein,

R _VII-48 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl;

R _VII-49 is selected from the group consisting of alkoxy, alkenoxy, alkynoxy, aryloxy, heteroaryloxy, heterocyclyloxy, haloalkyl, haloalkenyl, haloalkynyl, haloaryl, haloheteroaryl and haloheterocyclyl Is chosen],

Formula

[Wherein,

R _VII-50 in the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, alkoxy, alkenoxy, alkynoxy, aryloxy, heteroaryloxy and heterocyclyloxy Is chosen],

Formula

[Wherein,

R _VII-51 is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, haloalkyl, haloalkenyl, haloalkinyl, haloaryl, haloheteroaryl and haloheterocyclyl) , And

Formula

[Wherein,

R _VII-53 is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl]

It is selected from the group consisting of; only

When R _VII-5 is selected from the group consisting of heterocyclylalkyl and heterocyclylalkenyl, the heterocyclyl radical of the corresponding heterocyclylalkyl or heterocyclylalkenyl is not ??-lactone;

The R _VII-4 aryl, heteroaryl, or heteroaryl and heterocyclyl, R _VII-2 and R _VII-6, if one is a trifluoromethyl, R _VII-2 and R _VII-6 of the other is difluoromethyl Methyl.

The compounds of formula (VII) and methods for their preparation are disclosed in PCT Publication No. WO 9941237-A1, which is incorporated herein by reference in its entirety for all purposes.

In a preferred embodiment, the CETP inhibitor of Formula (VII) is dimethyl 5,5-dithiobis- [2-difluoromethyl-4- (2-methylpropyl) -6- (trifluoromethyl) -3- Pyridine-carboxylate].

Another class of CETP inhibitors that may be used in the present invention consists of substituted biphenyls having the general formula (VIII), and pharmaceutically acceptable salts, enantiomers or stereoisomers thereof:

Where

A _VIII is halogen, hydroxy, trifluoromethyl, trifluoromethoxy, straight or branched chain alkyl, acyl or alkoxy containing up to 7 carbon atoms each, or a formula -NR _VIII-1 R _VIII-2 ( Wherein R _VIII-1 and R _VIII-2 are the same or different and represent hydrogen, phenyl or straight or branched chain alkyl containing up to 6 carbon atoms) Aryl having 6 to 10 carbon atoms, which may be substituted with a substituent;

D _VIII represents straight or branched chain alkyl containing up to 8 carbon atoms substituted with hydroxy;

E _VIII and L _VIII are the same or different and are straight or branched chain alkyls containing up to 8 carbon atoms, which may be substituted with cycloalkyl containing 3 to 8 carbon atoms, or 3 to 8 carbon atoms Cycloalkyl containing; or

E _VIII has the meaning defined above;

L _VIII is halogen, hydroxy, trifluoromethyl, trifluoromethoxy, straight or branched chain alkyl, acyl or alkoxy containing up to 7 carbon atoms each, or a formula -NR _VIII-3 R _VIII-4 ( _Wherein R _VIII-3 and R _VIII-4 are the same or different and have the same or different three or less substituents selected from the group of R _VIII-1 and R _VIII-2 ) Or aryl of 6 to 10 carbon atoms; or

E _VIII represents a straight or branched chain alkyl containing up to 8 carbon atoms, or halogen, hydroxy, trifluoromethyl, trifluoromethoxy, straight or branched each containing up to 7 carbon atoms Chain alkyl, acyl or alkoxy, or the formula -NR _VIII-5 R _VIII-6 , wherein R _VIII-5 and R _VIII-6 are the same or different and are defined above for R _VIII-1 and R _VIII-2 Aryl of 6 to 10 carbon atoms, which may be substituted with up to 3 substituents, identical or different, selected from the group;

L _VIII in this case represents straight or branched chain alkoxy containing up to 8 carbon atoms, or cycloalkoxy of 3 to 8 carbon atoms;

T _VIII is a chemical formula Represents a radical of; At this time,

R _VIII-7 and R _VIII-8 are the same or different and represent cycloalkyl having 3 to 8 carbon atoms or aryl having 6 to 10 carbon atoms, or trifluoromethyl, trifluoromethoxy, Halogen, hydroxy, carboxyl, straight or branched chain alkyl, acyl, alkoxy or alkoxycarbonyl containing up to 6 carbon atoms each, or phenyl which may be substituted by halogen, trifluoromethyl or trifluoromethoxy, Can be substituted with up to 3 substituents, identical or different, selected from phenoxy or thiophenyl, and can be benzo-condensed of 5 to 7 membered aromatics having up to 3 heteroatoms selected from S, N and / or O Heterocyclic compound, and / or wherein the rings are of the formula -NR _VIII-11 R _{VIII-12 wherein} R _VIII-11 and R _VIII-12 are the same or different and R _VIII-1 And has the meanings defined above for R _VIII-2 ;

X _VIII represents straight or branched chain alkyl or alkenyl having 2 to 10 carbon atoms which may be substituted with up to 2 hydroxy;

R _VIII-9 represents hydrogen;

R _VIII-10 is hydrogen, halogen, azido, trifluoromethyl, hydroxy, mercapto, trifluoromethoxy, straight or branched alkoxy having up to 5 carbon atoms, or -NR _VIII-13 R _{VIII -14} , wherein R _VIII-13 and R _VIII-14 are the same or different and have the meanings defined above for R _VIII-1 and R _VIII-2 ; or

R _VIII-9 and R _VIII-10 together with the carbon atom form a carbonyl group.

The compounds of formula (VIII) are disclosed in PCT Publication No. WO 9804528, which is incorporated herein by reference in its entirety for all purposes.

Another class of CETP inhibitors that can be used in the present invention consists of substituted 1,2,4-triazoles having the general formula (IX), and pharmaceutically acceptable salts or tautomers thereof:

Where

R _IX-1 is selected from higher alkyl, higher alkenyl, higher alkynyl, aryl, aralkyl, aryloxyalkyl, alkoxyalkyl, alkylthioalkyl, arylthioalkyl and cycloalkylalkyl;

R _IX-2 is selected from aryl, heteroaryl, cycloalkyl and cycloalkenyl, and R _IX-2 is alkyl, haloalkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkoxy, halo, aryl at substitutable positions May be substituted with one or more radicals independently selected from oxy, aralkyloxy, aryl, aralkyl, aminosulfonyl, amino, monoalkylamino and dialkylamino;

R _IX-3 is selected from hydrido, -SH and halo; only

When R _IX-1 is higher alkyl and R _IX-3 is BSH, R _IX-2 is not phenyl or 4-methylphenyl.

The compounds of formula IX and methods for their preparation are disclosed in PCT Publication WO 9914204, which is incorporated herein by reference in its entirety for all purposes.

In one preferred embodiment, the CETP inhibitor is selected from the following compounds of Formula (IX):

2,4-dihydro-4- (3-methoxyphenyl) -5-tridecyl-3H-1,2,4-triazole-3-thione;

2,4-dihydro-4- (2-fluorophenyl) -5-tridecyl-3H-1,2,4-triazole-3-thione;

2,4-dihydro-4- (2-methylphenyl) -5-tridecyl-3H-1,2,4-triazole-3-thione;

2,4-dihydro-4- (3-chlorophenyl) -5-tridecyl-3H-1,2,4-triazole-3-thione;

2,4-dihydro-4- (2-methoxyphenyl) -5-tridecyl-3H-1,2,4-triazole-3-thione;

2,4-dihydro-4- (3-methylphenyl) -5-tridecyl-3H-1,2,4-triazole-3-thione;

4-cyclohexyl-2,4-dihydro-5-tridecyl-3H-1,2,4-triazole-3-thione;

2,4-dihydro-4- (3-pyridyl) -5-tridecyl-3H-1,2,4-triazole-3-thione;

2,4-dihydro-4- (2-ethoxyphenyl) -5-tridecyl-3H-1,2,4-triazole-3-thione;

2,4-dihydro-4- (2,6-dimethylphenyl) -5-tridecyl-3H-1,2,4-triazole-3-thione;

2,4-dihydro-4- (4-phenoxyphenyl) -5-tridecyl-3H-1,2,4-triazole-3-thione;

4- (1,3-benzodioxol-5-yl) -2,4-dihydro-5-tridecyl-3H-1,2,4-triazole-3-thione;

4- (2-chlorophenyl) -2,4-dihydro-5-tridecyl-3H-1,2,4-triazole-3-thione;

2,4-dihydro-4- (4-methoxyphenyl) -5-tridecyl-3H-1,2,4-triazole-3-thione;

2,4-dihydro-5-tridecyl-4- (3-trifluoromethylphenyl) -3H-1,2,4-triazole-3-thione;

2,4-dihydro-5-tridecyl-4- (3-fluorophenyl) -3H-1,2,4-triazole-3-thione;

4- (3-chloro4-methylphenyl) -2,4-dihydro-5-tridecyl-3H-1,2,4-triazole-3-thione;

2,4-dihydro-4- (2-methylthiophenyl) -5-tridecyl-3H-1,2,4-triazole-3-thione;

4- (4-benzyloxyphenyl) -2,4-dihydro-5-tridecyl-3H-1,2,4-triazole-3-thione;

2,4-dihydro-4- (2-naphthyl) -5-tridecyl-3H-1,2,4-triazole-3-thione;

2,4-dihydro-5-tridecyl-4- (4-trifluoromethylphenyl) -3H-1,2,4-triazole-3-thione;

2,4-dihydro-4- (1-naphthyl) -5-tridecyl-3H-1,2,4-triazole-3-thione;

2,4-dihydro-4- (3-methylthiophenyl) -5-tridecyl-3H-1,2,4-triazole-3-thione;

2,4-dihydro-4- (4-methylthiophenyl) -5-tridecyl-3H-1,2,4-triazole-3-thione;

2,4-dihydro-4- (3,4-dimethoxyphenyl) -5-tridecyl-3H-1,2,4-triazole-3-thione;

2,4-dihydro-4- (2,5-dimethoxyphenyl) -5-tridecyl-3H-1,2,4-triazole-3-thione;

2,4-dihydro-4- (2-dimethoxy-5-chlorophenyl) -5-tridecyl-3H-1,2,4-triazole-3-thione;

4- (4-aminosulfonylphenyl) -2,4-dihydro-5-tridecyl-3H-1,2,4-triazole-3-thione;

2,4-dihydro-5-dodecyl-4- (3-methoxyphenyl) -3H-1,2,4-triazole-3-thione;

2,4-dihydro-4- (3-methoxyphenyl) -5-tetradecyl-3H-1,2,4-triazole-3-thione;

2,4-dihydro-4- (3-methoxyphenyl) -5-undecyl-3H-1,2,4-triazole-3-thione; And

2,4-dihydro- (4-methoxyphenyl) -5-pentadecyl-3H-1,2,4-triazole-3-thione.

Another class of CETP inhibitors that may be used in the present invention consists of hetero-tetrahydroquinolines having Formula X, and pharmaceutically acceptable salts, enantiomers, stereoisomers or N-oxides thereof:

Where

A _X is no more than 3 selected from cycloalkyl containing 3 to 8 carbon atoms, or S, N and / or O, which may be bonded to a nitrogen functional group and bridged thereon if it is a saturated heterocyclic ring To a 5-7 membered benzo-condensed saturated, partially saturated or unsaturated heterocyclic ring containing a heteroatom of which the aforementioned aromatic systems are halogen, nitro, hydroxy, trifluoromethyl , Trifluoromethoxy, straight or branched chain alkyl containing up to 7 carbon atoms, acyl, hydroxyalkyl or alkoxy, or the formula BNR _X-3 R _{X-4 wherein} R _X-3 and R _{X -4} are the same or different, itgeo may be substituted with hydrogen, the same or different substituents selected from the following five represents a linear or branched alkyl containing up to 6 carbon atoms or phenyl), .; or

A _X is a chemical formula Represents a radical of;

D _X represents aryl containing 6 to 10 carbon atoms, which may be substituted with phenyl, nitro, halogen, trifluoromethyl or trifluoromethoxy, or

Represents a radical of; At this time

R _X-5 , R _X-6 and R _X-9 are independently of each other cycloalkyl containing 3 to 6 carbon atoms, aryl containing 6 to 10 carbon atoms, or at S, N and / or O A 5- to 7-membered aromatic, benzo-condensed, saturated or unsaturated mono-, di-, or tricyclic heterocyclic ring containing a selected heteroatom, wherein the ring is a nitrogen-containing aromatic ring Halogen, trifluoromethyl, nitro, hydroxy, cyano, carbonyl, trifluoromethoxy, straight or branched chain acyl containing up to 6 carbon atoms, alkyl, alkylthio, Alkylalkoxy, alkoxy or alkoxycarbonyl, aryl or trifluoromethyl substituted aryl having 6 to 10 carbon atoms, or benzo condensed containing up to 3 heteroatoms selected from S, N and / or O May be substituted and / or the same or different substituent groups of less than 5 selected from the group consisting of an aromatic heterocyclic ring of 5 to 7 members, the formula _{BOR X-10, -SR X-} 11, SO 2 R X-12 or BNR _{X -13} may be substituted by R _X-14 ; At this time

R _X-10 , R _X-11 and R _X-12 are independently of each other substituted with the same or different up to 2 substituents selected from phenyl, halogen, or straight or branched chain alkyl containing up to 6 carbon atoms Aryl containing 6 to 10 carbon atoms;

R _X-13 and R _X-14 are the same or different and have the meanings defined above for R _X-3 and R _X-4 ;

R _X-5 and / or R _X-6 is a chemical formula

Represents a radical of; or

R _X-7 represents hydrogen or halogen;

R _X-8 is hydrogen, halogen, azido, trifluoromethyl, hydroxy, trifluoromethoxy, straight or branched chain alkoxy or alkyl containing up to 6 carbon atoms, or formula BNR _X-15 R _X Or _-16 , wherein R _X-15 and R _X-16 are the same or different and have the meanings defined above for R _X-3 and R _X-4 ; or

R _X-7 and R _X-8 together represent the formula = O or = NR _X-17 , wherein R _X-17 represents straight or branched chain alkyl, alkoxy or acyl containing up to 6 carbon atoms Forms a radical of;

L _X represents a straight or branched chain alkylene or alkenylene containing up to 8 carbon atoms, which may be substituted with up to 2 hydroxyl groups;

T _X and X _X are the same or different and represent straight or branched chain alkylene containing up to 8 carbon atoms; or

T _X or X _X represents a bond;

V _X represents a group of an oxygen or sulfur atom, or BNR _X-18 , wherein R _X-18 represents hydrogen, straight or branched chain alkyl containing up to 6 carbon atoms, or phenyl;

E _X represents straight or branched chain alkyl containing up to 8 carbon atoms which may be substituted by cycloalkyl of 3 to 8 carbon atoms, or cycloalkyl or hydroxy of 3 to 8 carbon atoms, or Phenyl which may be substituted by halogen or trifluoromethyl;

R _X-1 and R _X-2 are together a carbonyl group and / or a chemical formula

To form a straight or branched chain alkylene having up to 7 carbon atoms, substituted by a radical of; At this time

a and b are the same or different and represent 1, 2 or 3;

R _X-19 is hydrogen; Hydroxyl, straight or branched alkoxy containing up to 6 carbon atoms, or phenyl, which may in turn be substituted by halogen, nitro, trifluoromethyl, trifluoromethoxy, phenyl or tetrazol substituted phenyl Cycloalkyl of 3 to 7 carbon atoms, straight or branched chain silylalkyl having up to 8 carbon atoms, or straight or branched chain alkyl containing up to 8 carbon atoms, or formula BOR Alkyl which may be substituted by _X-22 ; At this time

R _X-22 represents straight or branched chain acyl or benzyl containing up to 4 carbon atoms; or

R _X-19 represents straight or branched chain acyl or benzoyl containing up to 20 carbon atoms which may be substituted by halogen, trifluoromethyl, nitro or trifluoromethoxy, or up to 8 Linear or branched fluoroacyl containing up to 9 carbon atoms and fluorine atoms;

R _X-20 and R _X-21 are the same or different and represent hydrogen, phenyl, or straight or branched chain alkyl containing up to 6 carbon atoms; or

R _X-20 and R _X-21 together form a 3 to 6 membered carbocyclic ring, wherein the carbocyclic ring thus formed is trifluoromethyl, hydroxy, nitrile, halogen, carboxyl, nitro, azido, inter Ano, cycloalkyl or cycloalkyloxy having 3 to 7 carbon atoms, straight or branched chain alkoxycarbonyl having up to 6 carbon atoms, alkoxy or alkylthio, straight or branched containing up to 6 carbon atoms Chain alkyl (these are hydroxyl, benzyloxy, trifluoromethyl, benzoyl, straight or branched alkoxy, oxyacyl or carbonyl and / or phenyl containing up to 4 carbon atoms (these are again halogen, trifluoromethylphenyl Or substituted with up to two identical or different substituents selected from (or may be substituted with trifluoromethoxy) up to six identical or selected from These substituents may optionally also be substituted in pairs, and / or the carbocyclic rings formed may be substituted with phenyl, benzoyl, thiophenyl or sulfonylbenzyl, which in turn may be substituted with halogen, trifluoromethyl, trifluoromethoxy or nitrate. And optionally also in pairs with up to 5 identical or different substituents selected from the group consisting of

May be substituted with a radical of; At this time

c is 1, 2, 3 or 4;

d is 0 or 1;

R _X-23 and R _X-24 are the same or different and are hydrogen, cycloalkyl of 3 to 6 carbon atoms, straight or branched chain alkyl, benzyl or phenyl containing up to 6 carbon atoms (these are again halogen, And may be substituted with up to two identical or different substituents selected from among trifluoromethyl, cyano, phenyl and nitro), and / or the carbocyclic ring formed is

May be substituted by a spiro-linked radical of; At this time

W _X is oxygen or sulfur atom;

Y _X and Y ′ _X together form a 2-6 membered straight or branched alkylene chain;

e is 1, 2, 3, 4, 5, 6 or 7;

f is 1 or 2;

R _X-25 , R _X-26 , R _X-27 , R _X-28 , R _X-29 , R _X-30 and R _X-31 are the same or different and represent hydrogen, trifluoromethyl, phenyl, halogen, Or straight or branched chain alkyl or alkoxy each containing up to 6 carbon atoms; or

R _X-25 and R _X-26 or R _X-27 and R _X-28 together form a straight or branched chain alkyl each containing up to 6 carbon atoms; or

R _X-25 and R _X-26 or R _X-27 and R _X-28 are each together

Forms a radical of; At this time

W _X has the above meaning;

g is 1, 2, 3, 4, 5, 6 or 7;

R _X-32 and R _X-33 together form a 3-7 membered heterocycle having an oxygen or sulfur atom or a group of SO, SO ₂ or -NR _X-34 ; At this time

R _X-34 is hydrogen, phenyl, benzyl, or straight or branched chain alkyl containing up to 4 carbon atoms.

The compounds of formula (X) and methods for their preparation are disclosed in PCT Publication No. WO 9914215, which is incorporated herein by reference in its entirety for all purposes.

In one preferred embodiment, the CETP inhibitor is selected from the following compounds of Formula (X):

2-cyclopentyl-5-hydroxy-7,7-dimethyl-4- (3-thienyl) -3- (4-trifluoromethylbenzoyl) -5,6,7,8-tetrahydroquinoline;

2-cyclopentyl-3- [fluoro- (4-trifluoromethylphenyl) methyl] -5-hydroxy-7,7-dimethyl-4- (3-thienyl) -5,6,7,8 Tetrahydroquinoline; And

2-cyclopentyl-5-hydroxy-7,7-dimethyl-4- (3-thienyl) -3- (trifluoromethylbenzyl) -5,6,7,8-tetrahydroquinoline.

Another class of CETP inhibitors that can be used in the present invention consists of substituted tetrahydronaphthalin and similar compounds having the general formula (XI) and stereoisomers, stereoisomer mixtures or salts thereof:

Where

A _XI is cycloalkyl having 3 to 8 carbon atoms, aryl having 6 to 10 carbon atoms, or 5 to benzo condensable containing up to 4 heteroatoms selected from S, N and / or O A 7-membered saturated, partially saturated or unsaturated heterocycle, wherein the aryl and heterocycle ring systems are cyano, halogen, nitro, carboxyl, hydroxy, trifluoromethyl, trifluoromethoxy, or Straight or branched chain alkyl, acyl, hydroxyalkyl, alkylthio, alkoxycarbonyl, oxyalkoxycarbonyl or alkoxy, each containing up to seven carbon atoms, or in formula NR _XI-3 R _XI-4 , wherein R _XI-3 and R _XI-4 are the same or different and are hydrogen, phenyl, or a six or less in a straight or branched chain alkyl containing a carbon atom) in the same five or less selected from the group of substituted or different Which is substituted by;

D _XI is a chemical formula

Is a radical of; At this time

R _XI-5 , R _XI-6 and R _XI-9 are independently of each other cycloalkyl having 3 to 6 carbon atoms, aryl having 6 to 10 carbon atoms, or 4 selected from S, N and / or O Is a benzo-condensed 5-7 membered saturated or unsaturated mono-, di-, or tricyclic heterocycle containing up to 2 heteroatoms, wherein the ring is halogen via an N functional group if it is a nitrogen containing ring; , Trifluoromethyl, nitro, hydroxy, cyano, carboxyl, trifluoromethoxy, straight or branched chain acyl containing up to 6 carbon atoms each, alkyl, alkylthio, alkylalkoxy, alkoxy or alkoxycarbo Of a benzo-condensable aromatic 5 to 7 membered group containing aryl or trifluoromethyl substituted aryl of 6 to 10 carbon atoms each, or up to 3 heteroatoms selected from S, N and / or O Hetero May be substituted and / or the same or different substituents selected from the following five cycles, by the formula _{-OR XI-10, -SR XI-} 11, -SO 2 R XI-12 or -NR _XI-13 R _XI-14 May be substituted; or

R _XI-10 , R _XI-11 and R _XI-12 are each independently substituted with up to 2 identical or different substituents selected from phenyl, halogen or straight or branched chain alkyl containing up to 6 carbon atoms Aryl having from 10 to 10 carbon atoms;

R _XI-13 and R _XI-14 are the same or different and have the meanings defined above for R _XI-3 and R _XI-4 ; or

R _XI-5 and / or R _XI-6 are of the formula

Is a radical of;

R _XI-7 is hydrogen, halogen or methyl;

R _XI-8 is hydrogen, halogen, azido, trifluoromethyl, hydroxy, trifluoromethoxy, straight or branched chain alkoxy or alkyl containing up to 6 carbon atoms each, or formula -NR _XI-15 R _XI-16 (at this time, R _XI-15 and R _XI-16 are identical or different, R _XI-3 and has the above-defined meaning for R _XI-4) a radical or; or

R _XI-7 and R _XI-8 together represent a formula = O or = NR _{XI-17 wherein} R _XI-17 is hydrogen, or straight or branched chain alkyl, alkoxy containing up to 6 carbon atoms each, or Acyl);

L _XI is a straight or branched chain alkylene or alkenylene containing up to 8 carbon atoms each, which may be substituted by up to 2 hydroxy;

T _XI and X _XI are the same or different and are straight or branched chain alkylene chains containing up to 8 carbon atoms; or

T _XI and X _XI are bonds;

V _XI is an oxygen or sulfur atom, or a group of —NR _{XI-18 wherein} R _XI-18 is hydrogen, straight or branched chain alkyl containing up to 6 carbon atoms, or phenyl;

E _XI represents a straight or branched chain alkyl having up to 8 carbon atoms which may represent cycloalkyl having 3 to 8 carbon atoms or may be substituted with cycloalkyl or hydroxy having 3 to 8 carbon atoms Or phenyl which may be substituted with halogen or trifluoromethyl;

R _XI-1 and R _XI-2 together represent a carbonyl group and / or a chemical formula

To form a straight or branched chain alkylene chain containing up to 7 carbon atoms, substituted with radicals of; At this time

a and b are the same or different and are 1, 2 or 3;

R _XI-19 is hydrogen, cycloalkyl having 3 to 7 carbon atoms, straight or branched chain silylalkyl having up to 8 carbon atoms, or hydroxy, straight or branched chain containing up to 6 carbon atoms Containing up to 8 carbon atoms, which may be substituted by alkoxy or phenyl, which may be substituted by halogen, nitro, trifluoromethyl, trifluoromethoxy, or phenyl substituted by phenyl or tetrazole Straight or branched alkyl, alkyl may be substituted by a group of the formula -OR _XI-22 wherein R _XI-22 is straight or branched acyl containing 4 or fewer carbon atoms, or benzyl ; or

R _XI-19 is straight or branched chain acyl or benzoyl containing up to 20 carbon atoms which may be substituted by halogen, trifluoromethyl, nitro or trifluoromethoxy, or up to 8 carbon atoms and Straight or branched chain fluoroacyl containing up to 9 fluorine atoms;

R _XI-20 and R _XI-21 are the same or different and are straight chain or branched chain alkyl containing hydrogen, phenyl or up to 6 carbon atoms; or

R _XI-20 and R _XI-21 together form a 3-6 membered carbocyclic ring, and the alkylene chains formed by R _XI-1 and R _XI-2 are selected from trifluoromethyl, hydroxy, nitrile, halogen, Carboxyl, nitro, azido, cyano, cycloalkyl or cycloalkyloxy having 3 to 7 carbon atoms each, straight or branched alkoxycarbonyl containing up to 6 carbon atoms, alkoxy or alkoxythio, Or straight or branched chain alkyl containing up to 6 carbon atoms (which is hydroxy, benzyloxy, trifluoromethyl, benzoyl, straight or branched chain alkoxy, oxyacyl or carboxyl containing up to 4 carbon atoms each) And / or phenyl (which may be substituted with halogen, trifluoromethyl or trifluoromethoxy) up to two identical or different substituents selected from And optionally also in pairs with up to 6 identical or different substituents, and / or the alkylene chains formed by R _XI-1 and R _XI-2 may be halogen, trifluoromethyl, trifluoromethoxy or Optionally up to 5 identical or different substituents selected from phenyl, benzoyl, thiophenyl or sulfobenzyl, which may be substituted with nitro, and may also be optionally substituted in pairs and / or formed by R _XI-1 and R _XI-2 The alkylene chain is of the formula

[Wherein,

c is 1, 2, 3 or 4;

d is 0 or 1;

R _XI-23 and R _XI-24 are the same or different and are hydrogen, cycloalkyl of 3 to 6 carbon atoms, straight or branched chain alkyl, benzyl or phenyl containing up to 6 carbon atoms (these are halogen, tri May be substituted with up to two identical or different substituents selected from among fluoromethyl, cyano, phenyl and nitro).

May be substituted by a radical of and / or;

The alkylene chain formed by R _XI-1 and R _XI-2 has the following formula

[Wherein,

W _XI is oxygen or sulfur atom;

Y _XI and Y ′ _XI together form a 2-6 membered straight or branched chain alkylene;

e is 1, 2, 3, 4, 5, 6 or 7;

f is 1 or 2;

R _XI-25 , R _XI-26 , R _XI-27 , R _XI-28 , R _XI-29 , R _XI-30 and R _XI-31 are the same or different and are hydrogen, trifluoromethyl, phenyl, halogen Or straight or branched chain alkyl or alkoxy containing up to 6 carbon atoms each; or

R _XI-25 and R _XI-26 or R _XI-27 and R _XI-28 together form a straight or branched chain alkyl containing up to 6 carbon atoms; or

R _XI-25 and R _XI-26 or R _XI-27 and R _XI-28 together are

[Wherein,

W _XI has the meaning defined above;

g is 1, 2, 3, 4, 5, 6 or 7]

Forms a radical of;

R _XI-32 and R _XI-33 together represent an oxygen or sulfur atom, or of the formula SO, SO ₂ or -NR _XI-34 , wherein R _XI-34 is hydrogen, phenyl, benzyl, or up to 4 carbon atoms A straight or branched chain alkyl containing a 3 to 7 membered heterocycle containing

It may be substituted by a spiro-bonded radical of.

The compounds of formula (XI) and methods for their preparation are disclosed in PCT Publication No. WO 9914174, which is incorporated herein by reference in its entirety for all purposes.

Another class of CETP inhibitors that may be used in the present invention consists of 2-aryl-substituted pyridine having the formula XII and pharmaceutically acceptable salts, enantiomers or stereoisomers of this compound:

Where

A _XII and E _XII are the same or different and are halogen, hydroxy, trifluoromethyl, trifluoromethoxy, nitro, straight or branched chain alkyl, acyl, hydroxyalkyl containing up to 7 carbon atoms each Or alkoxy, or the formula -NR _XII-1 R _XII-2 , wherein R _XII-1 and R _XII-2 are the same or different and are straight, branched or branched containing hydrogen, phenyl, or up to 6 carbon atoms Aryl having 6 to 10 carbon atoms, which may be substituted with up to 5 identical or different substituents selected from the group of the alkyl;

D _XII is straight or branched chain alkyl containing up to 8 carbon atoms, substituted by hydroxy;

L _XII is cycloalkyl of 3 to 8 carbon atoms or straight or branched chain alkyl containing up to 8 carbon atoms which may be substituted with cycloalkyl or hydroxy of 3 to 8 carbon atoms;

T _XII is represented by the formula R _XII-3 -X _XII -or

Is a radical of; At this time

R _XII-3 and R _XII-4 are the same or different and are cycloalkyl of 3 to 8 carbon atoms, aryl having 6 to 10 carbon atoms, or up to 3 heteros selected from S, N and / or O Benzo-condensed 5-7 membered aromatic heterocycles with atoms, which are trifluoromethyl, trifluoromethoxy, halogen, hydroxy, carboxyl, nitro, straight chains containing up to 6 carbon atoms or With up to three identical or different substituents selected from branched chain alkyl, acyl, alkoxy or alkoxycarbonyl, or phenyl, phenoxy or phenylthio, which may be substituted with halogen, trifluoromethyl or trifluoromethoxy And / or the ring is of the formula -NR _XII-7 R _{XII-8 wherein} R _XII-7 and R _XII-8 are the same or different and for R _XII-1 and R _XII-2 Having the meaning defined above ) It may be substituted with a;

X _XII is straight or branched chain alkyl or alkenyl having 2 to 10 carbon atoms each, which may be substituted by up to 2 selected from hydroxy and halogen;

R _XII-5 is hydrogen;

R _XII-6 is hydrogen, halogen, mercapto, azido, trifluoromethyl, hydroxy, trifluoromethoxy, straight or branched chain alkoxy having up to 5 carbon atoms, or formula BNR _XII-9 R _{XII -10} radicals wherein R _XII-9 and R _XII-10 are the same or different and have the meanings defined above for R _XII-1 and R _XII-2 ; or

R _XII-5 and R _XII-6 together with the carbon atom form a carbonyl group.

The compounds of formula XII and methods for their preparation are disclosed in European Patent Publication Nos. EP 796846-A1, US Pat. Nos. 6,127,383 and 5,925,645, all of which are incorporated herein by reference in their entirety for all purposes.

In a preferred embodiment, the CETP inhibitor is selected from the following compounds of formula XII:

4,6-bis- (p-fluorophenyl) -2-isopropyl-3-[(p-trifluoromethylphenyl)-(fluoro) -methyl] -5- (1-hydroxyethyl) pyridine;

2,4-bis- (4-fluorophenyl) -6-isopropyl-5- [4- (trifluoromethylphenyl) -fluoromethyl] -3- (hydroxymethyl) pyridine; And

2,4-bis- (4-fluorophenyl) -6-isopropyl-5- [2- (3-trifluoromethylphenyl) vinyl] -3- (hydroxymethyl) pyridine.

Another class of CETP inhibitors that may be used in the present invention consists of a compound having Formula XIII, and a pharmaceutically acceptable salt, enantiomer, stereoisomer, hydrate or solvate thereof:

Where

R _XIII is straight or branched chain C _1-10 alkyl; Straight or branched C _2-10 alkenyl; Halogenated C _1-4 lower alkyl; C _3-10 cycloalkyl which may be substituted; C _5-8 cycloalkenyl which may be substituted; C _3-10 cycloalkyl C _1-10 alkyl which may be substituted; Aryl which may be substituted; Aralkyl which may be substituted; A 5 or 6 membered heterocyclic group having 1 to 3 nitrogen atoms, oxygen atoms or sulfur atoms which may be substituted;

X _XIII-1 , X _XIII-2 , X _XIII-3 and X _XIII-4 may be the same or different and respectively represent a hydrogen atom, a halogen atom, C _1-4 lower alkyl, halogenated C _1-4 lower alkyl, C _1-4 lower alkoxy, cyano group, nitro group, acyl or aryl group;

Y _XIII is -CO- or BSO _2- ;

Z _XIII is a hydrogen atom or a mercapto protecting group.

The compounds of formula (XIII) and methods for their preparation are disclosed in PCT Publication No. WO 98/35937, which is hereby incorporated by reference in its entirety for all purposes.

In a preferred embodiment, the CETP inhibitor is selected from the following compounds of formula (XIII):

N, N '-(dithiodi-2,1-phenylene) bis [2,2-dimethyl-propanamide];

N, N '-(dithiodi-2,1-phenylene) bis [1-methyl-cyclohexanecarboxamide];

N, N '-(dithiodi-2,1-phenylene) bis [1- (3-methylbutyl) -cyclopentanecarboxamide];

N, N '-(dithiodi-2,1-phenylene) bis [1- (3-methylbutyl) -cyclohexanecarboxamide];

N, N '-(dithiodi-2,1-phenylene) bis [1- (2-ethylbutyl) -cyclohexanecarboxamide];

N, N '-(dithiodi-2,1-phenylene) bis-tricyclo [3.3.1.1 ^3.7 ] decane-1-carboxamide];

Propanethio acid, 2-methyl-, S- [2-[[[1- (2-ethylbutyl) cyclohexyl] carbonyl] amino] phenyl] ester;

Propanethio acid, 2,2-dimethyl-, S- [2-[[[1- (2-ethylbutyl) cyclohexyl] carbonyl] amino] phenyl] ester; And

Ethanethioic acid, S- [2-[[[1- (2-ethylbutyl) cyclohexyl] carbonyl] amino] phenyl] ester.

Another class of CETP inhibitors that may be used in the present invention consists of polycyclic aryl and heteroaryl tert-heteroalkylamines having the formula XIV, and pharmaceutically acceptable forms thereof:

Where

n _XIV is an integer from 0 to 5;

R _XIV-1 is selected from the group consisting of haloalkyl, haloalkenyl, haloalkenylalkyl and haloalkenyloxyalkyl;

X _XIV is selected from the group consisting of O, H, F, S, S (O), NH, N (OH), N (alkyl) and N (alkoxy);

R _XIV-16 is hydrido, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, alkoxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, aralkoxyalkyl, heteroaralkoxyalkyl , Alkylsulfinylalkyl, alkylsulfonylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxy Alkyl, haloalkenyloxyalkyl, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, heteroarylalkyl, monocarboalkoxyalkyl, monocarboalkoxy , Dicarboalkoxyalkyl, monocarboxamide, monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl, acyl, aroyl, heteroaroyl, heteroaryloxyalkyl, di Koksi phosphono alkyl, trialkylsilyl, and share a single bond, and _{R XIV-4, R XIV-} 8, 1 to 4 contiguous atoms linked to the coupling point of the selected aromatic substituents from the group consisting of R _XIV-9 and RXIV-13 A spacer selected from the group consisting of linear spacer moieties that contain heterocyclyl having 5 to 10 adjacent members, provided that when R _XIV-2 is alkyl, the spacer moiety is not a covalent single bond; , When X is H or F, R _XIV-16 is absent;

D _XIV-1 , D _XIV-2 , J _XIV-1 , J _XIV-2 and K _XIV-1 are independently selected from the group consisting of C, N, O, S and covalent bonds, but D _XIV-1 , D Only one or less of _XIV-2 , J _XIV-1 , J _XIV-2 and K _XIV-1 is a covalent bond, and D _XIV-1 , D _XIV-2 , J _XIV-1 , J _XIV-2 and K _XIV Only one or less of _-1 is O, only one or less of D _XIV-1 , D _XIV-2 , J _XIV-1 , J _XIV-2 and K _XIV-1 is S and D _XIV-1 , D _{If two of XIV-2} , J _XIV-1 , J _XIV-2 and K _XIV-1 are O and S, then D _XIV-1 , D _XIV-2 , J _XIV-1 , J _XIV-2 and K _{XIV- One} of 1 must be a covalent bond and no more than 4 of D _XIV-1 , D _XIV-2 , J _XIV-1 , J _XIV-2 and K _XIV-1 are N;

D _XIV-3 , D _XIV-4 , J _XIV-3 , J _XIV-4 and K _XIV-2 are independently selected from the group consisting of C, N, O, S and covalent bonds, but D _XIV-3 , D Only one or less of _XIV-4 , J _XIV-3 , J _XIV-4 and K _XIV-2 is a covalent bond, and D _XIV-3 , D _XIV-4 , J _XIV-3 , J _XIV-4 and K _{XIV At} most one of _-2 is O, at most one of D _XIV-3 , D _XIV-4 , J _XIV-3 , J _XIV-4 and K _XIV-2 is S, D _XIV-3 , D _{If two of XIV-4} , J _XIV-3 , J _XIV-4 and K _XIV-2 are O and S, then D _XIV-3 , D _XIV-4 , J _XIV-3 , J _XIV-4 and K _{XIV- One} of the two is a covalent bond and no more than four of D _XIV-3 , D _XIV-4 , J _XIV-3 , J _XIV-4 and K _XIV-2 are N;

R _XIV-2 is hydrido, hydroxy, hydroxyalkyl, amino, aminoalkyl, alkylamino, dialkylamino, alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkoxyalkyl, aryloxyalkyl, alkoxy Alkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, aralkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, Haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxy, alloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, perhaloaryl, perhaloaralkyl , Perhaloaryloxyalkyl, heteroaryl, heteroarylalkyl, heteroarylthioalkyl, heteroaralkylthioalkyl, monocarboalkoxyalkyl, dicarboalkoxyalkyl, monocya Alkyl, dicyanoalkyl, carboalkoxycyanoalkyl, alkylsulfinyl, alkylsulfonyl, alkylsulfinylalkyl, alkylsulfonylalkyl, haloalkylsulfinyl, haloalkylsulfonyl, arylsulfinyl, arylsulfinylalkyl, Arylsulfonyl, arylsulfonylalkyl, aralkylsulfinyl, aralkylsulfonyl, cycloalkylsulfinyl, cycloalkylsulfonyl, cycloalkylsulfinylalkyl, cycloalkylsulfonylalkyl, heteroarylsulfonylalkyl, heteroarylsul Pinyl, heteroarylsulfonyl, heteroarylsulfinylalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl, carboxy, carboxyalkyl, carboalkoxy, carboxamide, carboxamidoalkyl, carboalkoxy, dialkoxyphosphono , Dialkoxyphosphono, dialkoxyphosphonoalkyl and dialkoxyphosphonoalkyl, independently selected from the group consisting of

R _XIV-2 and R _XIV-3 together contain a covalent single bond, and cycloalkyl having 3 to 8 contiguous members, containing 1 to 6 contiguous members, cycloalkenyl having 5 to 8 contiguous members, and 4 to To form a linear spacer moiety selected from the group consisting of moieties that form a ring selected from the group consisting of heterocyclyls having eight adjacent members;

R _XIV-3 is hydrido, hydroxy, halo, cyano, aryloxy, hydroxyalkyl, amino, alkylamino, dialkylamino, acyl, sulfhydryl, acylamido, alkoxy, alkylthio, arylthio , Alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, alkoxyalkyl, heteroarylthio, aralkylthio, alkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, aroyl, heteroaroyl, Aralkylthioalkyl, heteroaralkylthioalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, Haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyl Cyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, heteroarylalkyl, heteroarylthioalkyl, monocarboalkoxyalkyl, dicarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl, Carboalkoxycyanoalkyl, alkylsulfinyl, alkylsulfonyl, haloalkylsulfinyl, haloalkylsulfonyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylalkyl, aralkylsulfinyl, aralkylsulfonyl Ponyl, cycloalkylsulfinyl, cycloalkylsulfonyl, cycloalkylsulfinylalkyl, cycloalkylsulfonylalkyl, heteroarylsulfonylalkyl, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylsulfinylalkyl, aralkylsulfinyl Alkyl, aralkylsulfonylalkyl, carboxy, carboxyalkyl, carboalkoxy, carboxamide, carboxamidoalkyl, carboalkoxy, dialkoxyphosphono, dialkoxyphosphono, dialkoxyphospho Alkyl and dies are selected from the group consisting of alkoxy phosphono-alkyl;

Y _XIV is sharing a single _{bond, (C (R XIV-14} ) 2) qXIV ( At this time, _qXIV is 1 or 2) and _{(CH (R XIV-14)} ) gXIV -W XIV - (CH (R XIV- ₁₄ )) _pXIV , wherein _gXIV and _pXIV are independently 1 or 2;

R _XIV-14 is hydrido, hydroxy, halo, cyano, aryloxy, amino, alkylamino, dialkylamino, hydroxyalkyl, acyl, aroyl, heteroaroyl, heteroaryloxyalkyl, sulfhydryl , Acyl amido, 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, halocycloalkenyl jade Cyalkyl, Perhaloaryl, Perhaloaralkyl, Perhaloaryloxyalkyl, Heteroaryl, Heteroarylalkyl, Heteroarylthioalkyl, Heteroaralkylthioalkyl, Monocarboalkoxyalkyl, Dicarboalkoxyalkyl, Monocyanoalkyl , Dicyanoalkyl, carboalkoxycyanoalkyl, alkylsulfinyl, alkylsulfonyl, haloalkylsulfinyl, haloalkylsulfonyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylalkyl, aralkyl Sulfinyl, aralkylsulfonyl, cycloalkylsulfinyl, cycloalkylsulfonyl, cycloalkylsulfinylalkyl, cycloalkylsulfonylalkyl, heteroarylsulfonylalkyl, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylsulfinyl Alkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl, carboxy, carboxyalkyl, carboalkoxy, carboxamide, carboxamidoalkyl, carboalkoxy, dialkoxyphosphono, diaalkoxypo Phono, di-alkoxy phosphono-alkyl, di-aralkoxy phosphono-alkyl; Cycloalkenyl having 5 to 8 contiguous members and heterocycle having 5 to 8 contiguous members having a chain length of 3 to 6 atoms linked to a point of attachment selected from the group consisting of R _XIV-9 and R _XIV-13 A heterocyclyl having 5 to 8 contiguous members, having a chain length of 2 to 5 atoms linked to a bonding point selected from the group consisting of R _XIV-4 and R _XIV-8 and a spacer selected from the portion forming the reel; But independently selected from the group consisting of spacers selected from: provided that when Y _XIV is a covalent bond, the R _XIV-14 substituent is not bonded to Y _XIV ;

When R _XIV-14 and R _XIV-14 are bonded to different elements, they together form a covalent bond, alkylene, haloalkylene, and saturated cycloalkyl having 5 to 8 contiguous members, 5 to 8 contiguous members To form a group selected from the group consisting of a cycloalkenyl having and a spacer selected from the group consisting of moieties having a chain length of 2 to 5 atoms linked to form a ring selected from the group consisting of heterocyclyls having 5 to 8 adjacent members and;

When R _XIV-14 and R _XIV-14 are bonded to the same element, they are oxo, thiono, alkylene, haloalkylene, and cycloalkyl having 4 to 8 contiguous members, 4 to 8 contiguous members A group selected from the group consisting of a cycloalkenyl group having a portion selected from the group consisting of a portion having a chain length of 3 to 7 atoms connected to form a ring selected from the group consisting of heterocyclyl having 4 to 8 adjacent members Forming;

W _XIV is O, C (O), C (S), C (O) N (R _XIV-14 ), C (S) N (R _XIV-14 ), (R _XIV-14 ) NC (O), (R _XIV-14 ) NC (S), S, S (O), S (O) ₂ , S (0) ₂ N (R _XIV-14 ), (R _XIV-14 ) NS (0) ₂ and N (R _XIV-14 ), provided that R _XIV-14 is not halo and cyano;

Z _XIV is a covalent single bond, (C (R _XIV-15 ) ₂ ) _qXIV-2 , wherein _qXIV-2 is 1 or 2 and (CH (R _XIV-15 )) _jXIV -W- (CH ( R _XIV-15 )) _kXIV , wherein _jXIV and kXIV are independently 0 or 1, provided that if Z _XIV is a covalent single bond, then the R _XIV-15 substituent is not bonded to Z _XIV Without;

When Z _XIV is (C (R _XIV-15 ) ₂ ) _qXIV (where _qXIV is 1 or 2), R _XIV-15 is hydrido, hydroxy, halo, cyano, aryloxy, amino, alkyl Amino, 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, aryl Thioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyl Oxyalkyl, halocycloal Halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, heteroarylalkyl, heteroarylthioalkyl, heteroaralkylthioalkyl, monocarboalkoxy Alkyl, dicarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl, alkylsulfinyl, alkylsulfonyl, haloalkylsulfinyl, haloalkylsulfonyl, arylsulfinyl, arylsulfinylalkyl, Arylsulfonyl, arylsulfonylalkyl, aralkylsulfinyl, aralkylsulfonyl, cycloalkylsulfinyl, cycloalkylsulfonyl, cycloalkylsulfinylalkyl, cycloalkylsulfonylalkyl, heteroarylsulfonylalkyl, heteroarylsul Pinyl, heteroarylsulfonyl, heteroarylsulfinylalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl, carboxy, carboxyalkyl, carboalkoxy, carboxamide, carboxamidoalkyl, carbo Le alkoxy, di-alkoxy phosphono, di-aralkoxy phosphono, di-alkoxy phosphono-alkyl, di-aralkoxy phosphono-alkyl; Cycloalkenyl having 5 to 8 contiguous members and heterocycle having 5 to 8 contiguous members having a chain length of 3 to 6 atoms linked to a bonding point selected from the group consisting of R _XIV-4 and R _XIV-8 A spacer selected from the portion forming the ring selected from the reel, and a chain length of 2 to 5 atoms linked to a bonding point selected from the group consisting of R _XIV-9 and R _XIV-13 having 5 to 8 adjacent members Independently selected from the group consisting of spacers selected from the portion forming the heterocyclyl;

When R _XIV-15 and R _XIV-15 are bonded to different elements, they together form a covalent bond, alkylene, haloalkylene, and saturated cycloalkyl having 5 to 8 contiguous members, 5 to 8 contiguous members To form a group selected from the group consisting of a cycloalkenyl having and a spacer selected from the group consisting of moieties having a chain length of 2 to 5 atoms linked to form a ring selected from the group consisting of heterocyclyls having 5 to 8 adjacent members and;

When R _XIV-15 and R _XIV-15 are bonded to the same element, they together form oxo, thiono, alkylene, haloalkylene, and cycloalkyl having 4 to 8 contiguous members, 4 to 8 contiguous members. Form a group selected from the group consisting of a cycloalkenyl having and a spacer selected from the group consisting of moieties having a chain length of 3 to 7 atoms linked to form a ring selected from the group consisting of heterocyclyls having 4 to 8 adjacent members and;

If Z _XIV is (CH (R _XIV-15 )) _jXIV -W- (CH (R _XIV-15 )) _kXIV , where _jXIV and _kXIV are independently 0 or 1, then R _XIV-15 is _hydride Also, 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, cyclo Alkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, halo Cycloalkoxy, halocycloalkoxyalkyl, halocyclo Alkenyloxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, heteroarylalkyl, heteroarylthioalkyl, heteroaralkylthioalkyl, monocarboalkoxyalkyl, dicarboalkoxyalkyl, monocy Anoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl, alkylsulfinyl, alkylsulfonyl, haloalkylsulfinyl, haloalkylsulfonyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylalkyl, Aralkylsulfinyl, aralkylsulfonyl, cycloalkylsulfinyl, cycloalkylsulfonyl, cycloalkylsulfinylalkyl, cycloalkylsulfonylalkyl, heteroarylsulfonylalkyl, heteroarylsulfinyl, heteroarylsulfonyl, heteroaryl Sulfinylalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl, carboxyalkyl, carboalkoxy, carboxamide, carboxamidoalkyl, carboalkoxy, dialkoxyphosphonoalkyl, dialkoxy Phosphono-alkyl; Cycloalkenyl having 5 to 8 contiguous members and heterocycle having 5 to 8 contiguous members having a chain length of 3 to 6 atoms linked to a bonding point selected from the group consisting of R _XIV-4 and R _XIV-8 A spacer selected from a linear portion forming a ring selected from the group consisting of reels, and a chain length of 2 to 5 atoms linked to a bond point selected from the group consisting of R _XIV-9 and R _XIV-13 and having from 5 to 8 adjacent submembers Is selected from the group consisting of a spacer selected from a linear moiety forming a heterocyclyl having;

R _XIV-4 , R _XIV-5 , R _XIV-6 , R _XIV-7 , R _XIV-8 , R _XIV-9 , R _XIV-10 , R _XIV-11 , R _XIV-12 and R _XIV-13 Perhaloaryloxy, alkanoylalkyl, alkanoylalkoxy, alkanoyloxy, N-aryl-N-alkylamino, heterocyclylalkoxy, heterocyclylthio, hydroxyalkoxy, carboxamidoalkoxy, alkoxycarbonylalkoxy, Alkoxycarbonylalkenyloxy, aralkanoylalkoxy, aralkenoyl, N-alkylcarboxamido, N-haloalkylcarboxamido, N-cycloalkylcarboxamido, N-arylcarboxamidoalkoxy, cycloalkylcarbo Nyl, cyanoalkoxy, heterocyclylcarbonyl, hydrido, carboxy, heteroaralkylthio, heteroaralkoxy, cycloalkylamino, acylalkyl, acylalkoxy, aroylalkoxy, heterocyclyloxy, aralkylaryl, Aralkyl, aralkenyl, aralkynyl, heterocyclyl, perhaloaralkyl, aralkylsulfonyl, aralkyl Sulfonylalkyl, 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, heteroaralkoxyal Alkyl, sulfinylalkyl, arylsulfinylalkyl, arylsulfonylalkyl, heteroarylsulfinylalkyl, heteroarylsulfonylalkyl, alkylsulfonyl, alkylsulfonylalkyl, haloalkylsulfinylalkyl, haloalkyl Sulfonylalkyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkylamidosulfonyl, dialkylamidosulfonyl, monoarylamidosulfonyl, arylsulfonamido, diarylamidosulfonyl, monoalkyl mono Arylamidosulfonyl, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, heterocyclylsulfonyl, heterocyclylthio, alkanoyl, alkenoyl, aroyl, heteroaroyl, Aralkanoyl, heteroarkanoyl, haloalkanoyl, alkyl, alkenyl, alkynyl, alkenyloxy, alkenyloxyalkyl, alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkylalkanoyl, cycloal 1, lower cycloalkylalkyl, lower cycloalkenylalkyl, halo, haloalkyl, haloalkenyl, haloalkoxy, hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, hydroxyheteroaralkyl, haloalkoxyalkyl, Aryl, heteroaralkynyl, aryloxy, aralkoxy, aryloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkenyl, heteroarylal Kenyl, carboxyalkyl, carboalkoxy, alkoxycarboxamido, alkylamidocarbonylamido, arylamidocarbonylamido, carboalkoxyalkyl, carboalkoxyalkenyl, carboalkoxy, carboxamido, carboxamidoalkyl Independently selected from the group consisting of, cyano, carbohaloalkoxy, phosphono, phosphonoalkyl, diaalkoxyphosphono and diaalkoxyphosphonoalkyl, 1 To 5 non-hydrido ring substituents R _XIV-4 , R _XIV-5 , R _XIV-6 , R _XIV-7 and R _XIV-8 , and from 1 to 5 non-hydrido ring substituents R _XIV-9 , R _XIV-10 , R _XIV-11 , R _XIV-12 and R _XIV-13 are present and R _XIV-4 , R _XIV-5 , R _XIV-6 , R _XIV-7 , R _{XIV- 8} , R _XIV-9 , R _XIV-10 , R _XIV-11 , R _XIV-12 and R _XIV-13 are each independently to maintain carbon tetravalent, nitrogen trivalent, sulfur divalent and oxygen divalent Is selected;

R _XIV-4 and R _XIV-5 , R _XIV-5 and R _XIV-6 , R _XIV-6 and R _XIV-7 , R _XIV-7 and R _XIV-8 , R _XIV-8 and R _XIV-9 , R _XIV-9 and R _XIV-10 , R _XIV-10 and R _XIV-11 , R _XIV-11 and R _XIV-12 , and R _XIV-12 and R _XIV-13 are independently selected to form a spacer pair Wherein the spacer pair is together a cycloalkenyl having 5 to 8 contiguous members, partially saturated heterocyclyl having 5 to 8 contiguous members, a heteroaryl ring having 5 to 6 contiguous members, and aryl To form a ring selected from the group consisting of a linear moiety having 3 to 6 adjacent atoms connecting the point of attachment of the spacer pair members, provided that the spacer pairs R _XIV-4 and R _XIV-5 , R _XIV-5 And no more than one crowd consisting of R _XIV-6 , R _XIV-6 and R _XIV-7 , and R _XIV-7 and R _XIV-8 are used simultaneously and the spacer pairs R _XIV-9 and R _XIV-10 , R _XIV-10 and R _XIV-11 , R _XIV-11 and R _XIV-12, and R _XIV-12 and R but less than one from the group of _XIV-13 are used at the same time;

R _XIV-4 and R _XIV-9 , R _XIV-4 and R _XIV-13 , R _XIV-8 and R _XIV-9 , and R _XIV-8 and R _XIV-13 are independently selected to form a spacer pair Wherein the spacer pair together form a linear moiety that forms a ring selected from the group consisting of partially saturated heterocyclyl having 5 to 8 contiguous members and a heteroaryl ring having 5 to 6 contiguous members, No more than _one in a crowd of spacer pairs R _XIV-4 and R _XIV-9 , R _XIV-4 and R _XIV-13 , R _XIV-8 and R _XIV-9 , and R _XIV-8 and R _XIV-1 This is used at the same time.

The compounds of formula (XIV) and methods for their preparation are disclosed in PCT Publication No. WO 00/18721, which is incorporated herein by reference in its entirety for all purposes.

In one preferred embodiment, the CETP inhibitor is selected from the following compounds of Formula XIV:

3-[[3- (3-trifluoromethoxyphenoxy) phenyl] [[3- (1,1,2,2-tetrafluoroethoxy) phenyl] methyl] amino] -1,1,1- Trifluoro-2-propanol;

3-[[3- (3-isopropylphenoxy) phenyl] [[3- (1,1,2,2-tetrafluoroethoxy) phenyl] -methyl] amino] -1,1,1-tri Fluoro-2-propanol;

3-[[3- (3-cyclopropylphenoxy) phenyl] [[3- (1,1,2,2-tetrafluoroethoxy) phenyl] methyl] amino] -1,1,1-trifluoro Ro-2-propanol;

3-[[3- (3- (2-furyl) phenoxy) phenyl] [[3- (1,1,2,2-tetrafluoroethoxy) phenyl] methyl] amino] 1,1,1- Trifluoro-2-propanol;

3-[[3- (2,3-dichlorophenoxy) phenyl] [[3- (1,1,2,2-tetrafluoroethoxy) phenyl] -methyl] amino] -1,1,1 -Trifluoro-2-propanol;

3-[[3- (4-fluorophenoxy) phenyl] [[3- (1,1,2,2-tetrafluoroethoxy) phenyl] -methyl] amino] -1,1,1-tri Fluoro-2-propanol;

3-[[3- (4-methylphenoxy) phenyl] [[3- (1,1,2,2-tetrafluoroethoxy) phenyl] -methyl] amino] -1,1,1-trifluoro Ro-2-propanol;

3-[[3- (2-fluoro-5-bromophenoxy) phenyl] [[3- (1,1,2,2-tetrafluoroethoxy) phenyl] -methyl] amino] -1, 1,1-trifluoro-2-propanol;

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

3-[[3- [3- (1,1,2,2-tetrafluoroethoxy) phenoxy] phenyl] [[3- (1,1,2,2-tetrafluoroethoxy) phenyl] Methyl] amino] -1,1,1-trifluoro-2-propanol;

3-[[3- [3- (pentafluoroethyl) phenoxy] phenyl] [[3- (1,1,2,2-tetrafluoroethoxy) -phenyl] methyl] amino] -1,1 , 1-trifluoro-2-propanol;

3-[[3- (3,5-dimethylphenoxy) phenyl] [[3- (1,1,2,2-tetrafluoroethoxy) phenyl] -methyl] amino] -1,1,1 -Trifluoro-2-propanol;

3-[[3- (3-ethylphenoxy) phenyl] [[3- (1,1,2,2-tetrafluoroethoxy) phenyl] -methyl] amino] -1,1,1-trifluoro Ro-2-propanol;

3-[[3- (3-t-butylphenoxy) phenyl] [[3- (1,1,2,2-tetrafluoroethoxy) phenyl] -methyl] amino] -1,1,1- Trifluoro-2-propanol;

3-[[3- (3-methylphenoxy) phenyl] [[3- (1,1,2,2-tetrafluoroethoxy) phenyl] -methyl] amino] -1,1,1-trifluoro Ro-2-propanol;

3-[[3- (5,6,7,8-tetrahydro-2-naphthoxy) phenyl] [[3- (1,1,2,2-tetrafluoroethoxy) phenyl] methyl] amino] -1,1,1-trifluoro-2-propanol;

3-[[3- (phenoxy) phenyl] [[3- (1,1,2,2-tetrafluoroethoxy) phenyl] methyl] amino] -1,1,1-trifluoro-2- Propanol;

3-[[3- [3- (N, N-dimethylamino) phenoxy] phenyl] [[3- (1,1,2,2-tetrafluoroethoxy) phenyl] methyl] amino] -1 , 1,1-trifluoro-2-propanol;

3-[[[3- (1,1,2,2-tetrafluoroethoxyphenyl] methyl] [3-[[3- (trifluoromethoxy) -phenyl] methoxy] phenyl] amino] -1 , 1,1-trifluoro-2-propanol;

3-[[[3- (1,1,2,2-tetrafluoroethoxy) phenyl] methyl] [3-[[3- (trifluoromethyl) phenyl] methoxy] phenyl] amino] -1 , 1,1-trifluoro-2-propanol;

3-[[[3- (1,1,2,2-tetrafluoroethoxy) phenyl] methyl] [3-[[3,5-dimethylphenyl] methoxy] phenyl] amino] -1,1, 1-trifluoro-2-propanol;

3-[[[3- (1,1,2,2-tetrafluoroethoxy) phenyl] methyl] [3-[[3- (trifluoromethylthio) -phenyl] methoxy] phenyl] amino] -1,1,1-trifluoro-2-propanol;

3-[[[3- (1,1,2,2-tetrafluoroethoxy) phenyl] methyl] [3-[[3,5-difluorophenyl] methoxy] phenyl] amino] -1, 1,1-trifluoro-2-propanol;

3-[[[3- (1,1,2,2-tetrafluoroethoxy) phenyl] methyl] [3- [cyclohexylmethoxy] -phenyl] amino] -1,1,1-trifluoro -2-propanol;

3-[[3- (2-difluoromethoxy-4-pyridyloxy) phenyl] [[3- (1,1,2,2-tetrafluoroethoxy) -phenyl] methyl] amino] -1 , 1,1-trifluoro-2-propanol;

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

3-[[3- (3-difluoromethoxyphenoxy) phenyl] [[3- (1,1,2,2-tetrafluoroethoxy) phenyl] methyl] amino] -1,1,1- Trifluoro-2-propanol;

3-[[[3- (3-trifluoromethylthio) phenoxy] phenyl] [[3- (1,1,2,2-tetrafluoroethoxy) -phenyl] methyl] amino] -1, 1,1-trifluoro-2-propanol;

3-[[3- (4-chloro-3-trifluoromethylphenoxy) phenyl] [[3- (1,1,2,2-tetrafluoroethoxy) phenyl] methyl] amino] -1, 1,1-trifluoro-2-propanol;

3-[[3- (3-trifluoromethoxyphenoxy) phenyl] [[3- (pentafluoroethylmethyl] amino] -1,1,1-trifluoro-2-propanol;

3-[[3- (3-isopropylphenoxy) phenyl] [[3- (pentafluoroethyl) phenyl] methyl] -amino] -1,1,1-trifluoro-2-propanol;

3-[[3- (3-cyclopropylphenoxy) phenyl] [[3- (pentafluoroethyl) phenyl] methyl] -amino] -1,1,1-trifluoro-2-propanol;

3-[[3- (3- (2-furyl) phenoxy) phenyl] [[3- (pentafluoroethyl) phenyl] methyl] -amino] -1,1,1-trifluoro-2-propanol ;

3-[[3- (2,3-dichlorophenoxy) phenyl] [[3- (pentafluoroethyl) phenyl] methyl] -amino] -1,1,1-trifluoro-2-propanol;

3-[[3- (4-fluorophenoxy) phenyl] [[3- (pentafluoroethyl) phenyl] methyl] amino] -1,1,1-trifluoro-2-propanol;

3-[[3- (4-methylphenoxy) phenyl] [[3- (pentafluoroethyl) phenyl] methyl] amino] -1,1,1-trifluoro-2-propanol;

3-[[3- (2-fluoro-5-bromophenoxy) phenyl] [[3- (pentafluoroethyl) phenyl] methyl] -amino] -1,1,1-trifluoro-2 Propanol;

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

3-[[3- [3- (1,1,2,2-tetrafluoroethoxy) phenoxy] phenyl] [[3- (pentafluoroethyl) -phenyl] methyl] amino] -1,1 , 1-trifluoro-2-propanol;

3-[[3- [3- (pentafluoroethyl) phenoxy] phenyl] [[3- (pentafluoroethyl) phenyl] -methyl] amino] -1,1,1-trifluoro-2- Propanol;

3-[[3- (3,5-dimethylphenoxy) phenyl] [[3- (pentafluoroethyl) phenyl] methyl] -amino] -1,1,1-trifluoro-2-propanol;

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

3- [3- (3-t-butylphenoxy) phenyl] [[3- (pentafluoroethyl) phenyl] methyl] amino] -1,1,1-trifluoro-2-propanol;

3-[[3- (3-methylphenoxy) phenyl] [[3-pentafluoroethyl) phenyl] methyl] amino] -1,1,1-trifluoro-2-propanol;

3-[[3- (5,6,7,8-tetrahydro-2-naphthoxy) phenyl] [[3- (pentafluoroethyl) phenyl] -methyl] amino] -1,1,1-tri Fluoro-2-propanol;

3-[[3- (phenoxy) phenyl] [[3- (pentafluoroethyl) phenyl] methyl] amino] -1,1,1-trifluoro-2-propanol;

3-[[3- [3- (N, N-dimethylamino) phenoxy] phenyl] [[3- (pentafluoroethyl) phenyl] -methyl] amino] -1,1,1-trifluoro -2-propanol;

3-[[[3- (pentafluoroethyl) phenyl] methyl] [3-[[3- (trifluoromethoxy) phenyl] methoxy] phenyl] amino] -1,1,1-trifluoro- 2-propanol;

3-[[[3- (pentafluoroethyl) phenyl] methyl] [3-[[3- (trifluoromethyl) phenyl] methoxy] phenyl] amino] -1,1,1-trifluoro- 2-propanol;

3-[[[3- (pentafluoroethyl) phenyl] methyl] [3-[[3,5-dimethylphenyl] methoxy] -phenyl] amino] -1,1,1-trifluoro-2- Propanol;

3-[[[3- (pentafluoroethyl) phenyl] methyl] [3-[[3- (trifluoromethylthio) phenyl] -methoxy] phenyl] amino] -1,1,1-trifluoro Ro-2-propanol;

3-[[[3- (pentafluoroethyl) phenyl] methyl]] 3-[[3,5-difluorophenyl] methoxy] -phenyl] amino] -1,1,1-trifluoro- 2-propanol;

3-[[[3- (pentafluoroethyl) phenyl] methyl] [3- [cyclohexylmethoxy] phenyl] -amino] -1,1,1-trifluoro-2-propanol;

3-[[3- (2-difluoromethoxy-4-pyridyloxy) phenyl] [[3- (pentafluoroethyl) phenyl] -methyl] amino] -1,1,1-trifluoro- 2-propanol;

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

3-[[3- (3-difluoromethoxyphenoxy) phenyl] [[3- (pentafluoroethyl) phenyl] methyl] amino] -1,1,1-trifluoro-2-propanol;

3-[[[3- (3-trifluoromethylthio) phenoxy] phenyl] [[3- (pentafluoroethyl) phenyl] -methyl] amino] -1,1,1-trifluoro-2 Propanol;

3-[[3- (4-chloro-3-trifluoromethylphenoxy) phenyl] [[3- (pentafluoroethyl) phenyl] methyl] amino] -1,1,1-trifluoro-2 Propanol;

3-[[3- (3-trifluoromethoxyphenoxy) phenyl] [[3- (heptafluoropropyl) phenyl] -methyl] amino] -1,1,1-trifluoro-2-propanol;

3-[[3- (3-isopropylphenoxy) phenyl] [[3- (heptafluoropropyl) phenyl] methyl] -amino] -1,1,1-trifluoro-2-propanol;

3-[[3- (3-cyclopropylphenoxy) phenyl] [[3- (heptafluoropropyl) phenyl] methyl] -amino] -1,1,1-trifluoro-2-propanol;

3-[[3- (3- (2-furyl) phenoxy) phenyl] [[3- (heptafluoropropyl) phenyl] methyl] -amino] -1,1,1-trifluoro-2-propanol ;

3-[[3- (2,3-dichlorophenoxy) phenyl] [[3- (heptafluoropropyl) phenyl] methyl] -amino] -1,1,1-trifluoro-2-propanol;

3-[[3- (4-fluorophenoxy) phenyl] [[3- (heptafluoropropyl) phenyl] methyl] amino] -1,1,1-trifluoro-2-propanol;

3-[[3- (4-methylphenoxy) phenyl] [[3- (heptafluoropropyl) phenyl] methyl] amino] -1,1,1-trifluoro-2-propanol;

3-[[3- (2-fluoro-5-bromophenoxy) phenyl] [[3- (heptafluoropropyl) phenyl] methyl] -amino] -1,1,1-trifluoro-2 Propanol;

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

3-[[3- [3- (1,1,2,2-tetrafluoroethoxy) phenoxy] phenyl] [[3- (heptafluoropropyl) -phenyl] methyl] amino] -1,1 , 1-trifluoro-2-propanol;

3-[[3- [3- (pentafluoroethyl) phenoxy] phenyl] [[3- (heptafluoropropyl) phenyl] -methyl] amino] -1,1,1-trifluoro-2- Propanol;

3- [3- (3,5-dimethylphenoxy) phenyl] [[3- (heptafluoropropyl) phenyl] methyl] -amino] -1,1,1-trifluoro-2-propanol;

3-[[3- (3-ethylphenoxy) phenyl] [[3- (heptafluoropropyl) phenyl] methyl] -amino] -1,1,1-trifluoro-2-propanol;

3-[[3- (3-t-butylphenoxy) phenyl] [[3- (heptafluoropropyl) phenyl] methyl] -amino] -1,1,1-trifluoro-2-propanol;

3-[[3- (3-methylphenoxy) phenyl] [[3- (heptafluoropropyl) phenyl] methyl] amino] -1,1,1-trifluoro-2-propanol;

3-[[3- (5,6,7,8-tetrahydro-2-naphthoxy) phenyl] [[3- (heptafluoropropyl) phenyl] -methyl] amino] -1,1,1-tri Fluoro-2-propanol;

3-[[3- (phenoxy) phenyl] [[3- (heptafluoropropyl) phenyl] methyl] amino] -1,1,1-trifluoro-2-propanol;

3-[[3- [3- (N, N-dimethylamino) phenoxy] phenyl] [[3- (heptafluoropropyl) phenyl] -methyl] amino] -1,1,1-trifluoro -2-propanol;

3-[[[3- (heptafluoropropyl) phenyl] methyl] [3-[[3- (trifluoromethoxy) phenyl] -methoxy] phenyl] amino] -1,1,1-trifluoro -2-propanol;

3-[[[3- (heptafluoropropyl) phenyl] methyl] [3-[[3- (trifluoromethyl) phenyl] methoxy] phenyl] amino] -1,1,1-trifluoro- 2-propanol;

3-[[[3- (heptafluoropropyl) phenyl] methyl] [3-[[3,5-dimethylphenyl] methoxy] -phenyl] amino] -1,1,1-trifluoro-2- Propanol;

3-[[[3- (heptafluoropropyl) phenyl] methyl] [3-[[3 (trifluoromethylthio) phenyl] -methoxy] phenyl] amino] -1,1,1-trifluoro -2-propanol;

3-[[[3- (heptafluoropropyl) phenyl] methyl] [3-[[3,5-difluorophenyl] methoxy] -phenyl] amino] -1,1,1-trifluoro- 2-propanol;

3-[[[3- (heptafluoropropyl) phenyl] methyl] [3-[[3- [cyclohexylmethoxy] phenyl] -amino] -1,1,1-trifluoro-2-propanol;

3-[[3- (2-Difluoromethoxy-4-pyridyloxy) phenyl] [[3- (heptafluoropropyl) phenyl] -methyl] amino] -1,1,1-trifluoro- 2-propanol;

3-[[3- (2-trifluoromethyl-4-pyridyloxy) phenyl] [[3- (heptafluoropropyl) phenyl] methyl] amino] -1,1,1-trifluoro-2 Propanol;

3-[[3- (3-difluoromethoxyphenoxy) phenyl] [[3- (heptafluoropropyl) phenyl] -methyl] amino] -1,1,1-trifluoro-2-propanol;

3-[[[3- (3-trifluoromethylthio) phenoxy] phenyl] [[3- (heptafluoropropyl) phenyl] -methyl] amino] -1, 1, 1-trifluoro-2 Propanol;

3-[[3- (4-chloro-3-trifluoromethylphenoxy) phenyl] [[3- (heptafluoropropyl) phenyl] methyl] amino] -1,1,1-trifluoro-2 Propanol;

3-[[3- (3-trifluoromethoxyphenoxy) phenyl] [[2-fluoro-5- (trifluoromethyl) -phenyl] methyl] amino] -1,1,1-trifluoro -2-propanol;

3-[[3- (3-isopropylphenoxy) phenyl] [[2-fluoro-5- (trifluoromethyl) phenyl] -methyl] amino] -1,1,1-trifluoro-2 Propanol;

3-[[3- (3-cyclopropylphenoxy) phenyl] [[2-fluoro-5 (trifluoromethyl) phenyl] -methyl] amino] -1,1,1-trifluoro-2- Propanol;

3-[[3- (3- (2-furyl) phenoxy) phenyl] [[2-fluoro-5- (trifluoromethyl) phenyl] -methyl] amino] -1,1,1-trifluoro Ro-2-propanol;

3-[[3- (2,3-dichlorophenoxy) phenyl] [[2-fluoro-5- (trifluoromethyl) phenyl] -methyl] amino] -1,1,1-trifluoro -2-propanol;

3-[[3- (4-fluorophenoxy) phenyl] [[2-fluoro-5- (trifluoromethyl) phenyl] -methyl] amino] -1,1,1-trifluoro-2 Propanol;

3-[[3- (4-methylphenoxy) phenyl] [[2-fluoro-5- (trifluoromethyl) phenyl] -methyl] amino] -1,1,1-trifluoro-2- Propanol;

3-[[3- (2-fluoro-5-bromophenoxy) phenyl] [[2-fluoro-5- (trifluoromethyl) phenyl] methyl] amino] -1,1,1-tri Fluoro-2-propanol;

3-[[3- (4-chloro-3-ethylphenoxy) phenyl] [[2-fluoro-5- (trifluoromethyl) phenyl] methyl] amino] -1,1,1-trifluoro -2-propanol;

3-[[3- [3- (1,1,2,2-tetrafluoroethoxy) phenoxy] phenyl] [[2-fluoro-5- (trifluoromethyl) phenyl] methyl] amino] -1,1,1-trifluoro-2-propanol;

3-[[3- [3- (pentafluoroethyl) phenoxy] phenyl] [[2-fluoro-5- (trifluoromethyl) -phenyl] -methyl] amino] -1,1,1- Trifluoro-2-propanol;

3-[[3- (3,5-dimethylphenoxy) phenyl] [[2-fluoro-5- (trifluoromethyl) phenyl] -methyl] amino] -1,1,1-trifluoro -2-propanol;

3-[[3- (3-ethylphenoxy) phenyl] [[2-fluoro-5- (trifluoromethyl) phenyl] methyl] -amino] -1,1,1-trifluoro-2- Propanol;

3-[[3- (3-t-butylphenoxy) phenyl] [[2-fluoro-5- (trifluoromethyl) phenyl] methyl] -amino] -1,1,1-trifluoro- 2-propanol;

3-[[3- (3-methylphenoxy) phenyl] [[2-fluoro-5- (trifluoromethyl) phenyl] methyl] -amino] -1,1,1-trifluoro-2- Propanol;

3-[[3- (5,6,7,8-tetrahydro-2-naphthoxy) phenyl] [[2-fluoro-5- (trifluoromethyl) -phenyl] methyl] amino] -1, 1,1-trifluoro-2-propanol;

3-[[3- (phenoxy) phenyl] [[2-fluoro-5- (trifluoromethyl) phenyl] methyl] amino] -1,1,1-trifluoro-2-propanol;

3-[[3- [3- (N, N-dimethylamino) phenoxy] phenyl] [[2-fluoro-5- (trifluoromethyl) -phenyl] methyl] amino] -1,1, 1-trifluoro-2-propanol;

3-[[[2-fluoro-5- (trifluoromethyl) phenyl] methyl] [3-[[3- (trifluoromethoxy) phenyl] methoxy] phenyl] amino] -1,1,1 -Trifluoro-2-propanol;

3-[[[2-fluoro-5- (trifluoromethyl) phenyl] methyl] [3-[[3- (trifluoromethyl) -phenyl] methoxy] phenyl] amino] -1,1, 1-trifluoro-2-propanol;

3-[[[2-fluoro-5- (trifluoromethyl) phenyl] methyl] [3-[[3,5-dimethylphenyl] methoxy] phenyl] amino] -1,1,1-trifluoro Ro-2-propanol;

3-[[[2-fluoro-5- (trifluoromethyl) phenyl] methyl] [3-[[3- (trifluoromethylthio) -phenyl] methoxy] phenyl] amino] -1,1 , 1-trifluoro-2-propanol;

3-[[[2-fluoro-5- (trifluoromethyl) phenyl] methyl] [3-[[3,5-difluorophenyl] methoxy] phenyl] amino] -1,1,1- Trifluoro-2-propanol;

3-[[[2-fluoro-5- (trifluoromethyl) phenyl] methyl] [3- [cyclohexylmethoxy] -phenyl] amino] -1,1,1-trifluoro-2-propanol ;

3-[[3- (2-difluoromethoxy-4-pyridyloxy) phenyl] [[2-fluoro-5- (trifluoromethyl) -phenyl] methyl] amino] -1,1,1 -Trifluoro-2-propanol;

3-[[3- (2-trifluoromethyl-4-pyridyloxy) phenyl] [[2-fluoro-5- (trifluoromethyl) -phenyl] methyl] amino] -1,1,1 -Trifluoro-2-propanol;

3-[[3- (3-difluoromethoxyphenoxy) phenyl] [[2-fluoro-5- (trifluoromethyl) phenyl] methyl] amino] -1,1,1-trifluoro- 2-propanol;

3-[[[3- (3-tdfluoromethylthio) phenoxy] phenyl] [[2-fluoro-5- (trifluoromethyl) -phenyl] methyl] amino] -1,1,1- Trifluoro-2-propanol;

3-[[3- (4-chloro-3-trifluoromethylphenoxy) phenyl] [[2-fluoro-5- (trifluoromethyl) phenyl] methyl] amino] -1,1,1- Trifluoro-2-propanol;

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

3-[[3- (3-isopropylphenoxy) phenyl] [[2-fluoro-4- (trifluoromethyl) phenyl] -methyl] amino] -1,1,1-trifluoro-2 Propanol;

3-[[3- (3-cyclopropylphenoxy) phenyl] [[2-fluoro-4- (trifluoromethyl) phenyl] -methyl] amino] -1,1,1-trifluoro-2 Propanol;

3-[[3- (3- (2-furyl) phenoxy) phenyl] [[2-fluoro-4- (trifluoromethyl) phenyl] -methyl] amino] -1,1,1-trifluoro Ro-2-propanol;

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

3-[[3- (4-fluorophenoxy) phenyl] [[2-fluoro-4- (trifluoromethyl) phenyl] -methyl] amino] -1,1,1-trifluoro-2 Propanol;

3-[[3- (4-methylphenoxy) phenyl] [[2-fluoro-4- (trifluoromethyl) phenyl] -methyl] amino] -1,1,1-trifluoro-2- Propanol;

3-[[3- (2-fluoro-5-bromophenoxy) phenyl] [[2-fluoro-4- (trifluoromethyl) -phenyl] methyl] amino] -1,1,1- Trifluoro-2-propanol;

3-[[3- (4-chloro-3-ethylphenoxy) phenyl] [[2-fluoro-4- (trifluoromethyl) phenyl] methyl] amino] -1,1,1-trifluoro -2-propanol;

3-[[3- [3- (1,1,2,2-tetrafluoroethoxy) phenoxy] phenyl] [[2-fluoro-4- (trifluoromethyl) phenyl] methyl] amino] -1,1,1-trifluoro-2-propanol;

3-[[3- [3- (pentafluoroethyl) phenoxy] phenyl] [[2-fluoro-4- (trifluoromethyl) -phenyl] methyl] amino] -1,1,1-tri Fluoro-2-propanol;

3-[[3- (3,5-dimethylphenoxy) phenyl] [[2-fluoro-4- (trifluoromethyl) phenyl] -methyl] amino] -1,1,1-trifluoro -2-propanol;

3-[[3- (3-ethylphenoxy) phenyl] [[2-fluoro-4- (trifluoromethyl) phenyl] methyl] -amino] -1,1,1-trifluoro-2- Propanol;

3-[[3- (3-t-butylphenoxy) phenyl] [[2-fluoro-4- (trifluoromethyl) phenyl] methyl] -amino] -1,1,1-trifluoro- 2-propanol;

3-[[3- (3-methylphenoxy) phenyl] [[2-fluoro-4- (trifluoromethyl) phenyl] methyl] -amino] -1,1,1-trifluoro-2- Propanol;

3-[[3- (5,6,7,8-tetrahydro-2-naphthoxy) phenyl] [[2-fluoro-4- (trifluoromethyl) phenyl] methyl] amino] -1,1 , 1-trifluoro-2-propanol;

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

3-[[3- [3- (N, N-dimethylamino) phenoxy] phenyl] [[2-fluoro-4- (trifluoromethyl) -phenyl] methyl] amino] -1,1, 1-trifluoro-2-propanol;

3-[[[2-fluoro-4- (trifluoromethyl) phenyl] methyl] [3-[[3- (trifluoromethoxy) phenyl] methoxy] phenyl] amino] -1,1,1 -Trifluoro-2-propanol;

3-[[[2-fluoro-4- (trifluoromethyl) phenyl] methyl] [3-[[3- (trifluoromethyl) phenyl] methoxy] phenyl] amino] -1,1,1 -Trifluoro-2-propanol;

3-[[[2-fluoro-4- (trifluoromethyl) phenyl] methyl] [3-[[3,5-dimethylphenyl] methoxy] phenyl] amino] -1,1,1-trifluoro Ro-2-propanol;

3-[[[2-fluoro-4- (trifluoromethyl) phenyl] methyl] [3-[[3- (trifluoromethylthio) -phenyl] methoxy] phenyl] amino] -1,1 , 1-trifluoro-2-propanol;

3-[[[2-fluoro-4- (trifluoromethyl) phenyl] methyl] [3-[[3,5-difluorophenyl] methoxy] phenyl] amino] -1,1,1- Trifluoro-2-propanol;

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

3-[[3- (2-difluoromethoxy-4-pyridyloxy) phenyl] [[2-fluoro-4- (trifluoromethyl) -phenyl] methyl] amino] -1,1,1 -Trifluoro-2-propanol;

3-[[3- (2-trifluoromethyl-4-pyridyloxy) phenyl] [[2-fluoro-4- (trifluoromethyl) -phenyl] methyl] amino] -1,1,1 -Trifluoro-2-propanol;

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

3-[[[3- (3-trifluoromethylthio) phenoxy] phenyl] [[2-fluoro-4- (trifluoromethyl) -phenyl] methyl] amino] -1,1,1- Trifluoro-2-propanol; And

3-[[3- (4-chloro-3-trifluoromethylphenoxy) phenyl] [[2-fluoro-4- (trifluoromethyl) phenyl] methyl] amino] -1,1,1- Trifluoro-2-propanol.

Another class of CETP inhibitors that may be used in the present invention consists of substituted N-aliphatic-N-aromatic tert-heteroalkylamines having the general formula XV:

Where

n _XV is 1 or 2;

A _XV and Q _XV are the formula AQ-1, AQ-2 and _{-CH 2 (CR XV-37 R} XV-38) vXV - (CR XV-33 R XV-34) uXV -T XV - (CR XV- ₃₅ R _XV-36 ) _wXV -H

Are independently selected from the group consisting of: provided that one of A _XV and Q _XV is AQ-1 and one of A _XV and Q _XV is AQ-2 and -CH ₂ (CR _XV-37 R _XV-38 ) _{vXV- (CR XV-33 R XV-} 34) uXV -T XV - (CR XV-35 R XV-36) _wXV be selected from the group consisting of -H, and;

T _XV is selected from the group consisting of a single covalent bond, O, S, S (O), S (0) ₂ , C (R _XV-33 ) = C (R _XV-35 ) and C ?? C;

_vXV is 0 or 1, but when any one of R _XV-33 , R _XV-34 , R _XV-35 and R _XV-36 is aryl or heteroaryl, _vXV is 1;

_uXV and _wXV are integers independently selected from 0 to 6;

A _XV-1 is C (R _XV-30 );

D _XV-1 , D _XV-2 , J _XV-1 , J _XV-2 and K _XV-1 are independently selected from the group consisting of C, N, O, S and covalent bonds, but D _XV-1 , D Only one or less of _XV-2 , J _XV-1 , J _XV-2 and K _XV-1 is a covalent bond, and D _XV-1 , D _XV-2 , J _XV-1 , J _XV-2 and K _XV Only one or less of _-1 is O, only one or less of D _XV-1 , D _XV-2 , J _XV-1 , J _XV-2 and K _XV-1 is S, D _XV-1 , D _{If two of XV-2} , J _XV-1 , J _XV-2 and K _XV-1 are 0 and S, then D _XV-1 , D _XV-2 , J _XV-1 , J _XV-2 and K _{XV- One} of 1 must be a covalent bond and no more than 4 of D _XV-1 , D _XV-2 , J _XV-1 , J _XV-2 and K _XV-1 are N;

B _XV-1 , B _XV-2 , D _XV-3 , D _XV-4 , J _XV-3 , J _XV-4 and K _XV-2 are C, C (R _XV-30 ), N, O, S And covalently selected from the group consisting of up to 5 of B _XV-1 , B _XV-2 , D _XV-3 , D _XV-4 , J _XV-3 , J _XV-4 and K _XV-2 Only are covalent bonds, and no more than two of B _XV-1 , B _XV-2 , D _XV-3 , D _XV-4 , J _XV-3 , J _XV-4 and K _XV-2 are O, and B Only two or less of _XV-1 , B _XV-2 , D _XV-3 , D _XV-4 , J _XV-3 , J _XV-4 and K _XV-2 are S, B _XV-1 , B _{XV- Only two} or less of ₂ , D _XV-3 , D _XV-4 , J _XV-3 , J _XV-4 and K _XV-2 are O and S simultaneously, and B _XV-1 , B _XV-2 , D _{XV No} more than _two of _-3 , D _XV-4 , J _XV-3 , J _XV-4 and K _XV-2 are N;

B _XV-1 and D _XV-3 , D _XV-3 and J _XV-3 , J _XV-3 and K _XV-2 , K _XV-2 and J _XV-4 , J _XV-4 and D _XV-4 , And D _XV-4 and B _XV-2 are independently selected to form an in-ring spacer pair, wherein the spacer pair consists of C (R _XV-33 ) = C (R _XV-35 ) and N = N Selected from the group, but AQ-2 must be a ring of at least five adjacent members, at most two of the spacer pairs being C (R _XV-33 ) = C (R _XV-35 ) simultaneously, and the other spacer pair being C ( When R _XV-33 ) = C (R _XV-35 ), 0, N, and S, one of the pair of spacers may be N = N;

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

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

R _XV-3 is selected from the group consisting of hydrido, aryl, alkyl, alkenyl, haloalkyl and haloalkoxyalkyl;

Y _XV is a covalent single bond, (CH ₂ ) _q (where q is 1 or 2) and (CH ₂ ) _j -O- (CH ₂ ) _k , wherein j and k are independently 0 or 1 Is selected from the group consisting of;

Z _XV is a covalent single bond, (CH ₂ ) _q (where q is 1 or 2) and (CH ₂ ) _j -O- (CH ₂ ) _k , wherein j and k are independently 0 or 1 Is selected from the group consisting of;

R _XV-4 , R _XV-8 , R _XV-9 and R _XV-13 are independently selected from the group consisting of hydrido, halo, haloalkyl and alkyl;

R _XV-30 is selected from the group consisting of hydrido, alkoxy, alkoxyalkyl, halo, haloalkyl, alkylamino, alkylthio, alkylthioalkyl, alkyl, alkenyl, haloalkoxy and haloalkoxyalkyl, provided that R _{XV -30} is chosen to maintain tetravalent carbon, trivalent nitrogen, divalent sulfur and divalent oxygen;

When R _XV-30 is bonded to A _XV-1 , they together form A _XV-1 carbon present at the bond of R _XV-30 to R _XV-10 , R _XV-11 , R _XV-12 , R _{XV- 31} and R _XV-32 to form an in-ring linear spacer that connects to the point of attachment of a group selected from the group consisting of: a cycloalkyl having a single covalent bond, and 3 to 10 adjacent members, Selected from the group consisting of spacer moieties having from 1 to 6 adjacent atoms to form a ring selected from the group consisting of cycloalkenyl having from 5 to 10 adjacent members and heterocyclyl having from 5 to 10 adjacent members;

When R _XV-30 is bonded to A _XV-1 , they together form A _XV-1 carbon present at the point of attachment of R _XV-30 with a substituent pair R _XV-10 and R _XV-11 , R _XV-10 and R _XV-31 , R _XV-10 and R _XV-32 , R _XV-10 and R _XV-12 , R _XV-11 and R _XV-31 , R _XV-11 and R _XV-32 , R _XV-11 and R _XV-12 , R _XV-31 and R _XV-32 , R _XV-31 and R _XV-12 , and R _XV-32 and R _XV-12 each of the subunits of the substituent pair selected from the group consisting of Forming in-ring branched spacers, wherein the in-ring branched spacers are cycloalkyl having 3 to 10 contiguous members, cycloalkenyl having 5 to 10 contiguous members and 5 to 10 contiguous members. To form two rings selected from the group consisting of heterocyclyl having;

R _XV-4 , R _XV-5 , R _XV-6 , R _XV-7 , R _XV-8 , R _XV-9 , R _XV-10 , R _XV-11 , R _XV-12 , R _XV-13 , R _XV-31 , R _XV-32 , R _XV-33 , R _XV-34 , R _XV-35 and R _XV-36 are hydrido, carboxy, heteroaralkylthio, heteroaralkoxy, cycloalkylamino, acyl Alkyl, acylalkoxy, aroylalkoxy, heterocyclyloxy, aralkylaryl, aralkyl, aralkenyl, aralkynyl, heterocyclyl, perhaloaralkyl, aralkylsulfonyl, aralkylsulfonylalkyl, ar Alkylsulfinyl, aralkylsulfinylalkyl, halocycloalkyl, halocycloalkenyl, cycloalkylsulfinyl, cycloalkylsulfinylalkyl, cycloalkylsulfonyl, cycloalkylsulfonylalkyl, heteroarylamino, N-heteroarylamino -N-alkylamino, heteroarylaminoalkyl, haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl, haloalkoxyalkyl, heteroaralkoxy, cycloalkoxy, Chloalkenyloxy, 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, amidosul Ponyl, mono alkyl amidosulfonyl, dialkyl amidosulfonyl, monoarylamidosulfonyl, arylsulfonamido, diarylamidosulfonyl, monoalkyl monoaryl Amidosulfonyl, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, heterocyclylsulfonyl, heterocyclylthio, alkanoyl, alkenoyl, aroyl, heteroaroyl, ar Alkanoyl, heteroarkanoyl, haloalkanoyl, alkyl, alkenyl, alkynyl, alkenyloxy, alkenyloxyalkyl, alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkylalkanoyl, cycloalkenyl, Lower cycloalkylalkyl, lower cycloalkenylalkyl, halo, haloalkyl, haloalkenyl, haloalkoxy, hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, hydroxyheteroaralkyl, haloalkoxyalkyl, aryl, Heteroaralkynyl, aryloxy, aralkoxy, aryloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryl Cialkyl, arylalkenyl, heteroarylalkenyl, carboxyalkyl, carboalkoxy, alkoxycarboxamido, alkylamidocarbonylamido, alkylamidocarbonylamido, carboalkoxyalkyl, carboalkoxyalkenyl, carboar Independently selected from the group consisting of alkoxy, carboxamido, carboxamidoalkyl, cyano, carbohaloalkoxy, phosphono, phosphonoalkyl, diaalkoxyphosphono and _{diaalkoxyphosphonoalkyl} , R _{XV- 4} , R _XV-5 , R _XV-6 , R _XV-7 , R _XV-8 , R _XV-9 , R _XV-10 , R _XV-11 , R _XV-12 , R _XV-13 , R _{XV- 31} , R _XV-32 , R _XV-33 , R _XV-34 , R _XV-35 and R _XV-36 are independent to maintain tetravalent carbon, trivalent nitrogen, divalent sulfur and divalent oxygen, respectively And no more than three of the R _XV-33 and R _XV-34 substituents are simultaneously selected from the group except hydrido and halo, and only three or less of the R _XV-35 and R _XV-36 substituents are Lido and Halo It is selected from the group, except at the same time;

R _XV-9 , R _XV-10 , R _XV-11 , R _XV-12 , R _XV-13 , R _XV-31 and R _XV-32 are independently selected to form oxo, but B _XV-1 , B _XV-2 , D _XV-3 , D _XV-4 , J _XV-3 , J _XV-4 and K _XV-2 are independently selected from the group consisting of C and S, and R _XV-9 , R _XV-10 , Up to two of R _XV-11 , R _XV-12 , R _XV-13 , R _XV-31 and R _XV-32 are oxo simultaneously, and R _XV-9 , R _XV-10 , R _XV-11 , R _XV-12 , R _XV-13 , R _XV-31 and R _XV-32 are each independently selected to maintain tetravalent carbon, trivalent nitrogen, divalent sulfur and divalent oxygen;

R _XV-4 and R _XV-5 , R _XV-5 and R _XV-6 , R _XV-6 and R _XV-7 , R _XV-7 and R _XV-8 , R _XV-9 and R _XV-10 , R _XV-10 and R _XV-11 , R _XV-11 and R _XV-31 , R _XV-31 and R _XV-32 , R _XV-32 and R _XV-12 , and R _XV-12 and R _XV-13 Are independently selected to form a spacer pair, wherein the spacer pair together is cycloalkenyl having 5 to 8 contiguous members, partially saturated heterocyclyl having 5 to 8 contiguous members, 5 to 6 contiguous Form a linear moiety having from 3 to 6 adjacent atoms connecting the point of attachment of said spacer pair member to form a ring selected from the group consisting of heteroaryl having a secondary member and aryl, provided that the spacer pair R _XV-4 and R _{XV -5} , R _XV-5 and R _XV-6 , R _XV-6 and R _XV-7 and only one crowd of R _XV-7 and R _XV-8 are used simultaneously and spacer pairs R _XV-9 and R _XV-10 , R _XV-10 and R _XV-11 , R _XV-11 and R _XV-31 , R _XV-31 and R _XV-3 Only one of the group consisting of ₂ , R _XV-32 and R _XV-12 , and R _XV-12 and R _XV-13 is used simultaneously;

R _XV-9 and R _XV-11 , R _XV-9 and R _XV-12 , R _XV-9 and R _XV-13 , R _XV-9 and R _XV-31 , R _XV-9 and R _XV-32 , R _XV-10 and R _XV-12 , R _XV-10 and R _XV-13 , R _XV-10 and R _XV-31 , R _XV-10 and R _XV-32 , R _XV-11 and R _XV-12 , R _XV-11 and R _XV-13 , R _XV-11 and R _XV-32 , R _XV-12 and R _XV-31 , R _XV-13 and R _XV-31 , and R _XV-13 and R _XV-32 Are independently selected to form a spacer pair, wherein the spacer pair together form a cycloalkyl having a single covalent bond and 3 to 8 contiguous members, a cycloalkenyl having 5 to 8 contiguous members, 5 to 8 contiguous Linear spacer moieties selected from the group consisting of moieties having from 1 to 3 adjacent atoms to form a ring selected from the group consisting of saturated heterocyclyls having a member and partially saturated heterocyclyls having 5 to 8 adjacent members However, one or more crowds of the spacer pair At the same time used;

R _XV-37 and R _XV-38 are hydrido, alkoxy, alkoxyalkyl, hydroxy, amino, thio, halo, haloalkyl, alkylamino, alkylthio, alkylthioalkyl, cyano, alkyl, alkenyl, halo Independently selected from the group consisting of alkoxy and haloalkoxyalkyl.

The compounds of formula (XV) and methods for their preparation are disclosed in PCT Publication No. WO 00/18723, which is incorporated herein by reference in its entirety for all purposes.

In a preferred embodiment, the CETP inhibitor is selected from the following compounds of formula XV:

3-[[3- (4-chloro-3-ethylphenoxy) phenyl] (cyclohexylmethyl) amino] -1,1,1-trifluoro-2-propanol;

3-[[3- (4-chloro-3-ethylphenoxy) phenyl] (cyclopentylmethyl) amino] -1,1,1-trifluoro-2-propanol;

3-[[3- (4-chloro-3-ethylphenoxy) phenyl] (cyclopropylmethyl) amino] -1,1,1-trifluoro-2-propanol;

3-[[3- (4-chloro-3-ethylphenoxy) phenyl] [(3-trifluoromethyl) cyclohexyl-methyl] amino] -1,1,1-trifluoro-2-propanol;

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

3-[[3- (4-chloro-3-ethylphenoxy) phenyl] [(3-trifluoromethoxy) cyclohexyl-methyl] amino] -1,1,1-trifluoro-2-propanol;

3-[[3- (4-chloro-3-ethylphenoxy) phenyl] [[3- (1,1,2,2-tetrafluoroethoxy) cyclo-hexylmethyl] amino] -1,1, 1-trifluoro-2-propanol;

3-[[3- (3-trifluoromethoxyphenoxy) phenyl] (cyclohexylmethyl) amino] -1,1,1-trifluoro-2-propanol;

3-[[3- (3-trifluoromethoxyphenoxy) phenyl] (cyclopentylmethyl) amino] -1,1,1-trifluoro-2-propanol;

3-[[3- (3-trifluoromethoxyphenoxy) phenyl] (cyclopropylmethyl) amino] -1,1,1-trifluoro-2-propanol;

3-[[3- (3-trifluoromethoxyphenoxy) phenyl] [(3-trifluoromethyl) cyclohexyl-methyl] amino] -1,1,1-trifluoro-2-propanol;

3-[[3- (3-trifluoromethoxyphenoxy) phenyl]] (3-pentafluoroethyl) cyclohexyl-methyl] amino] -1,1,1-trifluoro-2-propanol;

3-[[3- (3-trifluoromethoxyphenoxy) phenyl] [(3-trifluoromethoxy) cyclohexyl-methyl] amino] -1,1,1-trifluoro-2-propanol;

3-[[3- (3-trifluoromethoxyphenoxy) phenyl] [[3- (1,1,2,2-tetrafluoroethoxy) cyclohexyl-methyl] amino] -1,1,1 -Trifluoro-2-propanol;

3-[[3- (3-isopropylphenoxy) phenyl] (cyclohexylmethyl) amino] -1,1,1-trifluoro-2-propanol:

3- [3- (3-isopropylphenoxy) phenyl] (cyclopentylmethyl) amino] -1,1,1-trifluoro-2-propanol;

3-[[3- (3-isopropylphenoxy) phenyl] (cyclopropylmethyl) amino] -1,1,1-trifluoro-2-propanol;

3- [3- (3-isopropylphenoxy) phenyl] [(3-trifluoromethyl) cyclohexyl-methyl] amino-l, 1,1-trifluoro-2-propanol;

3-[[3- (3-isopropylphenoxy) phenyl] [(3-pentafluoroethyl) cyclohexyl-methyl] amino] -1,1,1-trifluoro-2-propanol;

3-[[3- (3-isopropylphenoxy) phenyl] [(3-trifluoromethoxy) cyclohexyl-methyl] amino] -1,1,1-trifluoro-2-propanol;

3-[[3- (3-isopropylphenoxy) phenyl] [3- (1,1,2,2-tetrafluoroethoxy) cyclohexylmethyl] amino] -1,1,1-trifluoro -2-propanol;

3-[[3- (2,3-dichlorophenoxy) phenyl] (cyclohexylmethyl) amino] -1,1,1-trifluoro-2-propanol;

3-[[3- (2,3-dichlorophenoxy) phenyl] (cyclopentylmethyl) amino-1,1,1-trifluoro-2-propanol;

3-[[3- (2,3-dichlorophenoxy) phenyl] (cyclopropylmethyl) amino] -1,1,1-trifluoro-2-propanol;

3-[[3- (2,3-dichlorophenoxy) phenyl] [(3-trifluoromethyl) cyclohexyl-methyl] amino] -1,1,1-trifluoro-2-propanol;

3-[[3- (2,3-dichlorophenoxy) phenyl] [(3-pentafluoroethyl) cyclohexyl-methyl] amino] -1,1,1-trifluoro-2-propanol;

3-[[3- (2,3-dichlorophenoxy) phenyl] [(3-trifluoromethoxy) cyclohexyl-methyl] amino] -1,1,1-trifluoro-2-propanol;

3-[[3- (2,3-dichlorophenoxy) phenyl] [3- (1,1,2,2-tetrafluoroethoxy) cyclo-hexylmethyl] amino] -1,1,1- Trifluoro-2-propanol;

3-[[3- (4-fluorophenoxy) phenyl] (cyclohexylmethyl) amino] -1,1,1-trifluoro-2-propanol;

3-[[3- (4-fluorophenoxy) phenyl] (cyclopentylmethyl) amino] -1,1,1-trifluoro-2-propanol;

3-[[3- (4-fluorophenoxy) phenyl] (cyclopropylmethyl) amino] -1,1,1-trifluoro-2-propanol;

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

3-[[3- (4-fluorophenoxy) phenyl] [(3-pentafluoroethyl) cyclohexyl-methyl] amino] -1,1,1-trifluoro-2-propanol;

3-[[3- (4-fluorophenoxy) phenyl] [(3-trifluoromethoxy) cyclohexyl-methyl] amino] -1,1,1-trifluoro-2-propanol;

3-[[3- (4-fluorophenoxy) phenyl] [[3- (1,1,2,2-tetrafluoroethoxy) cyclohexyl-methyl] amino] -1,1,1-tri Fluoro-2-propanol;

3-[[3- (3-trifluoromethoxybenzyloxy] phenyl] (cyclohexylmethyl) amino] -1,1,1-trifluoro-2-propanol;

3-[[3- (3-trifluoromethoxybenzyloxy] phenyl] (cyclopentylmethyl) amino] -1,1,1-trifluoro-2-propanol;

3-[[3- (3-trifluoromethoxybenzyloxy) phenyl] (cyclopropylmethylamino] -1,1,1-trifluoro-2-propanol;

3-[[3- (3-trifluoromethoxybenzyloxy) phenyl] [(3-trifluoromethyl) cyclohexyl-methyl] amino] -1,1,1-trifluoro-2-propanol;

3-[[3- (3-trifluoromethoxybenzyloxy) phenyl] [(3-pentafluoroethyl) cyclohexyl-methyl] amino] -1,1,1-trifluoro-2-propanol;

3-[[3- (3-trifluoromethoxybenzyloxy] phenyl] [(3-trifluoromethoxy) cyclohexyl-methyl] amino] -1,1,1-trifluoro-2-propanol;

3-[[3- (3-trifluoromethoxybenzyloxy) phenyl] [3- (1,1,2,2-tetrafluoroethoxy) -cyclohexylmethyl] amino] -1,1,1- Trifluoro-2-propanol;

3-[[3- (3-trifluoromethylbenzyloxy) phenyl] (cyclohexylmethyl) amino] -1,1,1-trifluoro-2-propanol;

3-[[3- (3-trifluoromethylbenzyloxy) phenyl] (cyclopentylmethyl) amino] -1,1,1-trifluoro-2-propanol;

3-[(3- (3-trifluoromethylbenzyloxy) phenyl] (cyclopropylmethyl) amino] -1,1,1-trifluoro-2-propanol;

3-[(3- (3-trifluoromethylbenzyloxy) phenyl] [(3-trifluoromethyl) cyclohexyl-methyl] amino] -1,1,1-trifluoro-2-propanol;

3-[[3- (3-trifluoromethylbenzyloxy) phenyl] [(3-pentafluoroethyl) cyclohexyl-methyl] amino] -1,1,1-trifluoro-2-propanol;

3-[[3- (3-trifluoromethylbenzyloxy) phenyl] [(3-trifluoromethoxy) cyclohexyl-methyl] amino] -1,1,1-trifluoro-2-propanol;

3-[[3- (3-trifluoromethylbenzyloxy) phenyl] [3- (1,1,2,2-tetrafluoroethoxy) cyclohexyl-methyl] amino] -1,1,1- Trifluoro-2-propanol;

3-[[[(3-trifluoromethyl) phenyl] methyl] (cyclohexyl) amino] -1,1,1-trifluoro-2-propanol;

3-[[[(3-pentafluoroethyl) phenyl] methyl] (cyclohexyl) amino] -1,1,1-trifluoro-2-propanol;

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

3-[[[3- (1,1,2,2-tetrafluoroethoxy) phenyl] methyl] (cyclohexyl) amino] -1,1,1-trifluoro-2-propanol;

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

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

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

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

3-[[[(3-trifluoromethyl] phenyl] methyl] (3-trifluoromethylcyclohexyl) amino] -1,1,1-trifluoro-2-propanol;

3-[[[(3-pentafluoroethyl) phenyl] methyl] (3-trifluoromethylcyclohexyl) amino] -1,1,1-trifluoro-2-propanol;

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

3-[[[3- (1,1,2,2-tetrafluoroethoxy) phenyl] methyl] (3-trifluoromethylcyclohexyl) amino] -1,1,1-trifluoro-2 Propanol;

3-[[[(3-trifluoromethyl) phenyl] methyl] [3- (4-chloro-3-ethylphenoxy) cyclo-hexyl] amino] -1,1,1-trifluoro-2 Propanol;

3-[[[(3-pentafluoroethyl) phenyl] methyl] [3- (4-chloro-3-ethylphenoxy) cyclo-hexyl] amino] -1,1,1-trifluoro-2- Propanol;

3-[[[(3-trifluoromethoxy) phenyl] methyl] [3- (4-chloro-3-ethylphenoxy) cyclo-hexyl] amino] -1,1,1-trifluoro-2- Propanol;

3-[[[3- (1,1,2,2-tetrafluoroethoxy) phenyl] methyl] [3- (4-chloro-3-ethylphenoxy) cyclohexyl] amino] -1,1, 1-trifluoro-2-propanol;

3-[[[(3-trifluoromethyl] phenyl] methyl] (3-phenoxycyclohexyl) amino] -1,1,1-trifluoro-2-propanol;

3-[[[(3-pentafluoroethyl) phenyl] methyl] (3-phenoxycyclohexyl) amino] -1,1,1-trifluoro-2-propanol;

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

3-[[[3- (1,1,2,2-tetrafluoroethoxy) phenyl] methyl] (3-phenoxycyclohexyl) amino] -1,1,1-trifluoro-2-propanol ;

3-[[[(3-trifluoromethyl) phenyl] methyl] (3-isopropoxycyclohexyl) amino] -1,1,1-trifluoro-2-propanol;

3-[[[(3-pentafluoroethyl) phenyl] methyl] (3-isopropoxycyclohexyl) amino] -1,1,1-trifluoro-2-propanol;

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

3-[[[3- (1,1,2,2-tetrafluoroethoxy) phenyl] methyl] (3-isopropoxycyclohexyl) -amino] -1,1,1-trifluoro-2 Propanol;

3-[[[(3-trifluoromethyl) phenyl] methyl] (3-cyclopentyloxycyclohexyl) amino] -1,1,1-trifluoro-2-propanol;

3-[[[(3-pentafluoroethyl] phenyl] methyl] (3-cyclopentyloxycyclohexyl) amino] -1,1,1-trifluoro-2-propanol;

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

3-[[[3- (1,1,2,2-tetrafluoroethoxy) phenyl] methyl] (3-cyclopentyloxycyclohexyl) -amino] -1,1,1-trifluoro-2 Propanol;

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

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

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

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

3-[[[(2-trifluoromethyl) pyrid-6-yl] methyl] [3- (4-chloro-3-ethylphenoxy) cyclohexyl] amino] -1,1,1-trifluoro Ro-2-propanol;

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

3-[[[(2-trifluoromethyl) pyrid-6-yl] methyl] (3-pentafluoroethoxy) cyclohexyl) -amino] -1,1,1-trifluoro-2- Propanol;

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

3-[[[(3-trifluoromethyl) phenyl] methyl] [3- (4-chloro-3-ethylphenoxy) propyl] -amino] -1, 1, 1-trifluoro-2-propanol ;

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

3-[[[(3-trifluoromethoxy) phenyl] methyl] [3- (4-chloro-3-ethylphenoxy) propyl] -amino] -1, 1, 1-trifluoro-2-propanol ;

3-[[[3- (1,1,2,2-tetrafluoroethoxy) phenyl] methyl] [3- (4-chloro-3-ethylphenoxy) propyl] amino] -1,1,1 -Trifluoro-2-propanol;

3-[[[(3-trifluoromethyl) phenyl] methyl] [3- (4-chloro-3-ethylphenoxy) -2,2-difluoropropyl] amino] -1,1,1- Trifluoro-2-propanol;

3-[[[(3-pentafluoroethyl) phenyl] methyl] [3- (4-chloro-3-ethylphenoxy) -2,2-difluoropropyl] amino] -1,1,1- Trifluoro-2-propanol;

3-[[[(3trifluoromethoxy) phenyl] methyl] [3- (4-chloro-3-ethylphenoxy) -2,2-difluoropropyl] amino] -1,1,1-tri Fluoro-2-propanol;

3-[[[3- (1,1,2,2-tetrafluoroethoxy) phenyl] methyl] [3- (4-chloro-3-ethylphenoxy) -2,2, difluoropropyl] Amino] -1,1,1-trifluoro-2-propanol;

3-[[[(3-trifluoromethyl) phenyl] methyl] [3- (isopropoxy) propyl] amino] -1, 1, 1-trifluoro-2-propanol;

3-[[[(3-pentafluoroethyl) phenyl] methyl] [3- (isopropoxy) propyl] amino] -1,1,1-trifluoro-2-propanol;

3-[[[(3-trifluoromethoxy) phenyl] methyl] [3- (isopropoxy) propyl] amino] -1, 1, 1-trifluoro-2-propanol;

3-[[[3- (1,1,2,2-tetrafluoroethoxy) phenyl] methyl] [3- (isopropoxy) propyl] amino] -1,1,1-trifluoro-2 Propanol; And

3-[[[3- (1,1,2,2-tetrafluoroethoxy) phenyl] methyl] [3- (phenoxy) propyl] amino-1,1,1-trifluoro-2-propanol .

Another class of CETP inhibitors that may be used in the present invention are (R) -chiral halogenated 1-substituted amino- (n + l) -alkanols having the formula XVI: :

Where

n _XVI is an integer from 1 to 4;

X _XVI is oxy;

R _XVI-1 is selected from the group consisting of haloalkyl, haloalkenyl, haloalkenylmethyl and haloalkenyloxymethyl, provided that R _XVI-1 is R _XVI-2 and (CHR _XVI-3 ) _n -N (A _XVI ) Q _XVI , wherein A _XVI is of Formula XVI-II and Q is of Formula XVI-III, and has a Cahn-Ingold-Prelog stereochemical system grade,

R _XVI-16 represents hydrido, alkyl, acyl, aroyl, heteroaroyl, trialkylsilyl, and R _XVI-4 , R to form a heterocyclic ring having a single covalent bond and 5 to 10 adjacent members. Selected from the group consisting of spacers selected from the group consisting of linear spacer moieties having from 1 to 4 atomic chain lengths linked to the point of attachment of any aromatic substituent selected from the group consisting of _XVI-8 , R _XVI-9 and R _XVI-13 Become;

D _XVI-1 , D _XVI-2 , J _XVI-1 , J _XVI-2 and K _XVI-1 are independently selected from the group consisting of C, N, O, S and covalent bonds, provided that D _XVI-1 , Only one or less of D _XVI-2 , J _XVI-1 , J _XVI-2 and K _XVI-1 is a covalent bond, and D _XVI-1 , D _XVI-2 , J _XVI-1 , J _XVI-2 and K Only one or less of _XVI-1 is O, and only one or less of D _XVI-1 , D _XVI-2 , J _XVI-1 , J _XVI-2 and K _XVI-1 is S, D _XVI-1 , If _{two of} D _XVI-2 , J _XVI-1 , J _XVI-2 and K _XVI-1 are O and S, then D _XVI-1 , D _XVI-2 , J _XVI-1 , J _XVI-2 and K _{XVI One of -1} must be a covalent bond and at most four of D _XVI-1 , D _XVI-2 , J _XVI-1 , J _XVI-2 and K _XVI-1 are N;

D _XVI-3 , D _XVI-4 , J _XVI-3 , J _XVI-4 and K _XVI-2 are independently selected from the group consisting of C, N, O, S and covalent bonds, provided that D _XVI-3 , Only one or less of D _XVI-4 , J _XVI-3 , J _XVI-4 and K _XVI-2 is a covalent bond and D _XVI-3 , D _XVI-4 , J _XVI-3 , J _XVI-4 and K Only one or less of _XVI-2 is O, only one or less of D _XVI-3 , D _XVI-4 , J _XVI-3 , J _XVI-4 and K _XVI-2 is S, D _XVI-3 , Up to two of D _XVI-4 , J _XVI-3 , J _XVI-4 and K _XVI-2 are O and S, and D _XVI-3 , D _XVI-4 , J _XVI-3 , J _XVI-4 and K _{If two} of _XVI-2 are O and S, then one of D _XVI-3 , D _XVI-4 , J _XVI-3 , J _XVI-4 and K _XVI-2 is a covalent bond, and D _XVI-3 , D _No more than four of _XVI-4 , J _XVI-3 , J _XVI-4 and K _XVI-2 are N;

R _XVI-2 is hydrido, aryl, aralkyl, alkyl, alkenyl, alkenyloxyalkyl, haloalkyl, haloalkenyl, halocycloalkyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, halocyclo Alkoxy, halocycloalkoxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, dicyanoalkyl and carboalkoxycyanoalkyl, provided that R _XVI-2 is R _{XVI -1} and (CHR _XVI-3 ) _n -N (A _XVI ) Q _XVI having a lower can-ingold-prelog stereochemical system grade; At this time

R _XVI-3 represents hydrido, hydroxy, cyano, aryl, aralkyl, acyl, alkoxy, alkyl, alkenyl, alkoxyalkyl, heteroaryl, alkenyloxyalkyl, haloalkyl, haloalkenyl, haloal coxy , Haloalkoxyalkyl, haloalkenyloxyalkyl, monocyanoalkyl, dicyanoalkyl, carboxamide and carboxamidoalkyl, provided that (CHR _XVI-3 ) _n -N (A _XVI ) Q _XVI has a can-ingold-prelog stereochemistry system grade lower than R _XVI-1 and a can-ingold-prelog stereochemistry system grade higher than R _XVI-2 ;

Y _XVI is a single covalent bond, (C (R _XVI-14 ) ₂ ) _q (where q is 1 or 2) and (CH (R _XVI-14 )) _g -W _XVI- (CH (RX _{VI- 14} )) _p , wherein g and p are independently 0 or 1;

R _XVI-14 is hydrido, hydroxy, cyano, hydroxyalkyl, acyl, alkoxy, alkyl, alkenyl, alkynyl, alkoxyalkyl, haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloal Kenyloxyalkyl, monocarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl, carboxamide and carboxamidoalkyl;

Z _XVI is a single covalent _{bond, (C (R XVI-15} ) 2) q ( at this time, q is 1 or 2) and _{(CH (R XVI-15)} ) j -W XVI - (CH (R XVI- ₁₅ )) _k , wherein j and k are independently 0 or 1;

W _XVI is O, C (O), C (S), C (O) N (R _XVI-14 ), C (S) N (R _XVI-14 ), (R _XVI-14 ) NC (O), (R _XVI-14 ) NC (S), S, S (O), S (0) ₂ , S (O) ₂ N (R _XVI-14 ), (R _XVI-14 ) NS (0) ₂ and N (R _XVI-14 ), except that R _XVI-14 is not cyano;

R _XVI-15 represents hydrido, cyano, hydroxyalkyl, acyl, alkoxy, alkyl, alkenyl, alkynyl, alkoxyalkyl, haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl , Monocarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl, carboalkoxy, carboxamide and carboxamidoalkyl;

R _XVI-4 , R _XVI-5 , R _XVI-6 , R _XVI-7 , R _XVI-8 , R _XVI-9 , R _XVI-10 , R _XVI-11 , R _XVI-12 and R _XVI-13 Hydrido, carboxy, heteroaralkylthio, heteroaralkoxy, cycloalkylamino, acylalkyl, acylalkoxy, aroylalkoxy, heterocyclyloxy, aralkylaryl, aralkyl, aralkenyl, aralkynyl, hetero Cyclyl, perhaloaralkyl, aralkylsulfonyl, aralkylsulfonylalkyl, aralkylsulfinyl, aralkylsulfinylalkyl, halocycloalkyl, halocycloalkenyl, cycloalkylsulfinyl, cycloalkylsulfinylalkyl, Cycloalkylsulfonyl, cycloalkylsulfonylalkyl, heteroarylamino, N-heteroarylamino-N-alkylamino, heteroaralkyl, heteroarylaminoalkyl, haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl, haloalkoxy Alkyl, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy, Icycloalkoxyalkyl, cycloalkylalkoxy, cycloalkenyloxyalkyl, cycloalkylenedioxy, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxy, halocycloalkenyloxyalkyl, hydroxy, amino, thio, nit 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, aryl Pinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, heterocyclylsulfonyl, heterocyclylthio, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroarka Noyl, haloalkanoyl, alkyl, alkenyl, alkynyl, alkenyloxy, alkenyloxyalkyl, alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkylalkanoyl, cycloalkenyl, lower cycloalkylalkyl, lower Cycloalkenylalkyl, halo, haloalkyl, haloalkenyl, haloalkoxy, hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, hydroxyheteroaralkyl, haloalkoxyalkyl, aryl, heteroaralkynyl, aryl Oxy, aralkoxy, aryloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkenyl Heteroarylalkenyl, carboxyalkyl, carboalkoxy, alkoxycarboxamido, alkylamidocarbonylamido, arylamidocarbonylamido, carboalkoxyalkyl, carboalkoxyalkenyl, carboalkoxy, carboxamido, Independently selected from the group consisting of carboxamidoalkyl, cyano, carbohaloalkoxy, phosphono, phosphonoalkyl, diaalkoxyphosphono and diaalkoxyphosphonoalkyl, R _XVI-4 , R _XVI-5 , R _XVI-6 , R _XVI-7 , R _XVI-8 , R _XVI-9 , R _XVI-10 , R _XVI-11 , R _XVI-12 and R _XVI-13 are tetravalent carbon and 3 nitrogen Independently selected to maintain causticity, divalent sulfur and divalent oxygen;

R _XVI-4 and R _XVI-5 , R _XVI-5 and R _XVI-6 , R _XVI-6 and R _XVI-7 , R _XVI-7 and R _XVI-8 , R _XVI-9 and R _XVI-10 , R _XVI-10 and R _XVI-11 , R _XVI-11 and R _XVI-12 and R _XVI-12 and R _XVI-13 are independently selected to form a spacer pair, wherein the spacer pairs together are 5 to 8 The spacer to form a ring selected from the group consisting of cycloalkenyl having 4 contiguous members, partially saturated heterocyclyl having 5 to 8 contiguous members, heteroaryl ring having 5 to 6 contiguous members, and aryl Form a linear moiety with 3 to 6 adjacent atoms connecting the bond points of the paired members, with the exception of spacer pairs R _XVI-4 and R _XVI-5 , R _XVI-5 and R _XVI-6 , R _XVI-6 and Only one crowd of R _XVI-7 , R _XVI-7 and R _XVI-8 is used simultaneously and the spacer pairs R _XVI-9 and R _XVI-10 , R _XVI-10 and R _XVI-11 , R _{XVI- 11} and R _XVI-12 and R _XVI-12 and R _{XVI No} more than one crowd of _-13 may be used simultaneously;

R _XVI-4 and R _XVI-9 , R _XVI-4 and R _XVI-13 , R _XVI-8 and R _XVI-9 , and R _XVI-8 and R _XVI-13 are independently selected to form a spacer pair and Wherein the spacer pair together form a linear moiety that forms a ring selected from the group consisting of partially saturated heterocyclyl having 5 to 8 contiguous members and heteroaryl ring having 5 to 6 contiguous members, Only one crowd consisting of R _XVI-4 and R _XVI-9 , R _XVI-4 and R _XVI-13 , R _XVI-8 and R _XVI-9 , and R _XVI-8 and R _XVI-13 simultaneously Used.

The compounds of formula XVI and methods for their preparation are disclosed in PCT Publication WO 00/18724, which is incorporated herein by reference in its entirety for all purposes.

In a preferred embodiment, the CETP inhibitor is selected from the following compounds of formula XVI:

(2R) -3-[[3- (3-trifluoromethoxyphenoxy) phenyl] [[3- (1,1,2,2-tetrafluoroethoxy) phenyl] methyl] amino] -1, 1,1-trifluoro-2-propanol;

(2R) -3-[[3- (3-isopropylphenoxy) phenyl] [[3- (1,1,2,2-tetrafluoroethoxy) phenyl] -methyl] amino] -1,1 , 1-trifluoro-2-propanol;

(2R) -3-[[3- (3-cyclopropylphenoxy) phenyl) [[3- (1,1,2,2-tetrafluoroethoxy) phenyl] -methyl] amino] -1,1 , 1-trifluoro-2-propanol;

(2R) -3-[[3- (2-furyl) phenoxy) phenyl] [[3- (1,1,2,2-tetrafluoroethoxy) phenyl] methyl] amino] -1,1, 1-trifluoro-2-propanol;

(2R) -3-[[3- (2,3-dichlorophenoxy) phenyl] [[3- (1,1,2,2-tetrafluoroethoxy) phenyl] -methyl] amino] -1 , 1,1-trifluoro-2-propanol;

(2R) -3-[[3- (4-fluorophenoxy) phenyl] [[3- (1,1,2,2-tetrafluoroethoxy) phenyl] -methyl] amino] -1,1 , 1-trifluoro-2-propanol;

(2R) -3-[[3- (4-methylphenoxy) phenyl] [[3- (1,1,2,2-tetrafluoroethoxy) phenyl] -methyl] amino] -1,1, 1-trifluoro-2-propanol;

(2R) -3-[[3- (2-fluoro-5-bromophenoxy) phenyl] [[3- (1,1,2,2-tetrafluoroethoxy) phenyl] -methyl] amino ] -1,1,1-trifluoro-2-propanol;

(2R) -3-[[3- (4-chloro-3-ethylphenoxy) phenyl] [[3- (1,1,2,2-tetrafluoroethoxy) phenyl] -methyl] amino]- 1,1,1-trifluoro-2-propanol;

(2R) -3-[[3- [3- (1,1,2,2-tetrafluoroethoxy) phenoxy] phenyl] [[3- (1,1,2,2-tetrafluoro- Ethoxy) phenyl] methyl] amino] -1,1,1-trifluoro-2-propanol;

(2R) -3-[[3- [3- (pentafluoroethyl) phenoxyl] phenyl] [[3- (1,1,2,2-tetrafluoroethoxy) phenyl] methyl] amino] -1,1,1-trifluoro-2-propanol;

(2R) -3-[[3- (3,5-dimethylphenoxy) phenyl] [3- (1,1,2,2-tetrafluoroethoxy) phenyl] -methyl] amino] -1, 1,1-trifluoro-2-propanol;

(2R) -3-[[3- (3-ethylphenoxy) phenyl] [[3- (1,1,2,2-tetrafluoroethoxy) phenyl] -methyl] amino] -1,1, 1-trifluoro-2-propanol;

(2R) -3-[[3- (3-t-butylphenoxy) phenyl] [[3- (1,1,2,2-tetrafluoroethoxy) phenyl] -methyl] amino] -1, 1,1-trifluoro-2-propanol:

(2R) -3-[[3- (3-methylphenoxy) phenyl] [[3- (1,1,2,2-tetrafluoroethoxy) phenyl] -methyl] amino] -1,1, 1-trifluoro-2-propanol;

(2R) -3-[[3- (5,6,7,8-tetrahydro-2-naphthoxy) phenyl] [[3- (1,1,2,2-tetrafluoroethoxy) phenyl] Methyl] amino] -1,1,1-trifluoro-2-propanol;

(2R) -3-[[3- (phenoxy) phenyl] [[3- (1,1,2,2-tetrafluoroethoxy) phenyl] methyl] amino] -1,1,1-trifluoro Ro-2-propanol;

(2R) -3-[[3- [3- (N, N-dimethylamino) phenoxy] phenyl] [[3- (1,1,2,2-tetrafluoroethoxy) phenyl] methyl] Amino-1,1,1-trifluoro-2-propanol;

(2R) -3-[[[3- (1,1,2,2-tetrafluoroethoxy) phenyl] methyl] [3-[[3- (trifluoromethoxy) phenyl] methoxy] phenyl] Amino] -1,1,1-trifluoro-2-propanol;

(2R) -3-[[[3- (1,1,2,2-tetrafluoroethoxy) phenyl] methyl] [3-[[3- (trifluoromethyl) phenyl] methoxy] phenyl] Amino] -1,1,1-trifluoro-2-propanol;

(2R) -3-[[[3- (1,1,2,2-tetrafluoroethoxy) phenyl] methyl] [3-[[3,5-dimethylphenyl] methoxy] phenyl] amino]- 1,1,1-trifluoro-2-propanol;

(2R) -3-[[[3- (1,1,2,2-tetrafluoroethoxy) phenyl] methyl] [3-[[3- (trifluoromethylthio) phenyl] methoxy] phenyl ] Amino] -1,1,1-trifluoro-2-propanol;

(2R) -3-[[[3- (1,1,2,2-tetrafluoroethoxy) phenyl] methyl] [3-[[3,5-difluorophenyl] methoxy] phenyl] amino ] -1,1,1-trifluoro-2-propanol;

(2R) -3-[[[3- (1,1,2,2-tetrafluoroethoxy) phenyl] methyl] [3- [cyclohexylmethoxy] phenyl] amino] -1,1,1- Trifluoro-2-propanol;

(2R) -3-[[3- (2-difluoromethoxy-4-pyridyloxy) phenyl] [[3- (1,1,2,2-tetrafluoroethoxy) phenyl] methyl] amino ] -1,1,1-trifluoro-2-propanol;

(2R) -3-[[3- (2-trifluoromethyl-4-pyridyloxy) phenyl] [[3- (1,1,2,2-tetrafluoroethoxy) phenyl] methyl] amino ] -1,1,1-trifluoro-2-propanol;

(2R) -3-[[3- (3-difluoromethoxyphenoxy) phenyl] [[3- (1,1,2,2-tetrafluoroethoxy) -phenyl] methyl] amino] -1 , 1,1-trifluoro-2-propanol;

(2R) -3-[[[3- (3-trifluoromethylthio) phenoxy] phenyl] [[3- (1,1,2,2-tetrafluoroethoxy) phenyl] methyl] amino] -1,1,1-trifluoro-2-propanol;

(2R) -3-[[3- (4-chloro-3-trifluoromethylphenoxy) phenyl] [[3- (1,1,2,2-tetra fluoroethoxy) phenyl] methyl] amino ] -1,1,1-trifluoro-2-propanol;

(2R) -3-[[3- (3-trifluoromethoxyphenoxy) phenyl] [[3- (pentafluoroethyl) phenyl] -methyl] amino] -1,1,1-trifluoro- 2-propanol;

(2R) -3-[[3- (3-isopropylphenoxy) phenyl] [[3- (pentafluoroethyl) phenyl] methyl] -amino] -1,1,1-trifluoro-2- Propanol;

(2R) -3-[[3- (3-cyclopropylphenoxy) phenyl] [[3- (pentafluoroethyl) phenyl] methyl] -amino] -1,1,1-trifluoro-2- Propanol;

(2R) -3-[[3- (3- (2-furyl) phenoxy) phenyl] [[3- (pentafluoroethyl) phenyl] methyl] -amino] -1,1,1-trifluoro -2-propanol;

(2R) -3-[[3- (2,3-dichlorophenoxy) phenyl] [[3- (pentafluoroethyl) phenyl] methyl] -amino] -1,1,1-trifluoro- 2-propanol;

(2R) -3-[[3- (4-fluorophenoxy) phenyl] [[3- (pentafluoroethyl) phenyl] methyl] amino] -1,1,1-trifluoro-2-propanol ;

(2R) -3-[[3- (4-methylphenoxy) phenyl] [[3- (pentafluoroethyl) phenyl] methyl] amino] -1,1,1-trifluoro-2-propanol;

(2R) -3-[[3- (2-fluoro-5-bromophenoxy) phenyl] [[3- (pentafluoroethyl) phenyl] methyl] -amino] -1,1,1-tri Fluoro-2-propanol;

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

(2R) -3-[[3- [3- (1,1,2,2-tetrafluoroethoxy) phenoxy] phenyl] [[3- (pentafluoroethyl) phenyl] methyl] amino]- 1,1,1-trifluoro-2-propanol;

(2R) -3-[[3- (pentafluoroethyl) phenoxy] phenyl] [[3- (pentafluoroethyl) phenyl] -methyl] amino] -1,1,1-trifluoro-2 Propanol;

(2R) -3-[[3- (3,5-dimethylphenoxy) phenyl] [[3- (pentafluoroethyl) phenyl] methyl] -amino] -1,1,1-trifluoro- 2-propanol;

(2R) -3-[[3- (3-ethylphenoxy) phenyl] [[3- (pentafluoroethyl) phenyl] methyl] amino] -1,1,1-trifluoro-2-propanol;

(2R) -3-[[3- (3-t-butylphenoxy) phenyl] [[3- (pentafluoroethyl) phenyl] methyl] amino] -1,1,1-trifluoro-2- Propanol;

(2R) -3-[[3- (3-methylphenoxy) phenyl] [[3- (pentafluoroethyl) phenyl] methyl] amino] -1,1,1-trifluoro-2-propanol;

(2R) -3-[[3- (5,6,7,8-tetrahydro-2-naphthoxy) phenyl] [[3- (pentafluoroethyl) phenyl] -methyl] amino] -1,1 , 1-trifluoro-2-propanol;

(2R) -3-[[3- (phenoxy) phenyl] [[3- (pentafluoroethyl) phenyl] methyl] amino] -1,1,1-trifluoro-2-propanol;

(2R) -3-[[3- [3- (N, N-dimethylamino) phenoxy] phenyl] [[3- (pentafluoroethyl) phenyl] -methyl] amino] -1,1,1 -Trifluoro-2-propanol;

(2R) -3-[[[3- (pentafluoroethyl) phenyl] methyl] [3-[[3- (trifluoromethoxy) phenyl] -methoxy] phenyl] amino] -1,1,1 -Trifluoro-2-propanol;

(2R) -3-[[[3- (pentafluoroethyl) phenyl] methyl] [3- [3- (trifluoromethyl) -phenyl] methoxy] phenyl] amino-1, 1, 1-tri Fluoro-2-propanol;

(2R) -3-[[[3- (pentafluoroethyl) phenyl] methyl] [3-[[3,5-dimethylphenyl] methoxy] -phenyl] amino] -1,1,1-trifluoro Ro-2-propanol;

(2R) -3-[[[3- (pentafluoroethyl) phenyl] methyl] [3- [[3- (trifluoromethylthio) phenyl] -methoxy] phenyl] amino] -1, 1, 1-trifluoro-2-propanol;

(2R) -3-[[[3- (pentafluoroethyl) phenyl] methyl] [3-[[3,5-difluorophenyl] methoxy] -phenyl] amino] -1,1,1- Trifluoro-2-propanol;

(2R) -3-[[[3- (pentafluoroethyl) phenyl] methyl] [3- [cyclohexylmethoxy] phenyl] -amino] -1, 1, 1-trifluoro-2-propanol;

(2R) -3-[[3- (2-difluoromethoxy-4-pyridyloxy) phenyl] [[3- (pentafluoroethyl) phenyl] -methyl] amino] -1,1,1- Trifluoro-2-propanol;

(2R) -3-[[3- (2-trifluoromethyl-4-pyridyloxy) phenyl] [[3- (pentafluoroethyl) phenyl] -methyl] amino] -1,1,1- Trifluoro-2-propanol;

(2R) -3-[[3- (3-difluoromethoxyphenoxy) phenyl] [[3- (pentafluoroethyl) phenyl] -methyl] amino] -1,1,1-trifluoro- 2-propanol;

(2R) -3-[[[3- (3-trifluoromethylthio) phenoxy] phenyl] [[3- (pentafluoroethyl) phenyl] -methyl] amino] -1,1,1-tri Fluoro-2-propanol;

(2R) -3-[[3- (4-chloro-3-trifluoromethylphenoxy) phenyl] [[3- (pentafluoroethyl) -phenyl] methyl] amino] -1,1,1- Trifluoro-2-propanol;

(2R) -3-[[3- (3-trifluoromethoxyphenoxy) phenyl] [[3- (heptafluoropropyl) phenyl] -methyl] amino] -1,1,1-trifluoro- 2-propanol;

(2R) -3-[[3- (3-isopropylphenoxy) phenyl] [[3- (heptafluoropropyl) phenyl] methyl] -amino] -1,1,1-trifluoro-2- Propanol;

(2R) -3-[[3- (3-cyclopropylphenoxy) phenyl] [[3- (heptafluoropropyl) phenyl] methyl] -amino] -1,1,1-trifluoro-2- Propanol;

(2R) -3-[[3- (3- (2-furyl) phenoxy) phenyl] [[3- (heptafluoropropyl) phenyl] methyl] -amino] -1,1,1-trifluoro -2-propanol;

(2R) -3-[[3- (2,3-dichlorophenoxy) phenyl] [[3- (heptafluoropropyl) phenyl] methyl] -amino] -1,1,1-trifluoro- 2-propanol;

(2R) -3-[[3- (4-fluorophenoxy) phenyl] [[3- (heptafluoropropyl) phenyl] methyl] amino] -1,1,1-trifluoro-2-propanol ;

(2R) -3-[[3- (4-methylphenoxy) phenyl] [[3- (heptafluoropropyl) phenyl] methyl] amino] -1,1,1-trifluoro-2-propanol;

(2R) -3-[[3- (2-fluoro-5-bromophenoxy) phenyl] [[3- (heptafluoropropyl) phenyl] -methyl] amino] -1,1,1-tri Fluoro-2-propanol;

(2R) -3-[[3- (4-chloro-3-ethylphenoxy) phenyl] [[3- (heptafluoropropyl) phenyl] methyl] -amino] -1,1,1-trifluoro -2-propanol;

(2R) -3-[[3- [3- (1,1,2,2-tetrafluoroethoxy) phenoxy] phenyl] [[3- (heptafluoropropyl) phenyl] methyl] amino]- 1,1,1-trifluoro-2-propanol;

(2R) -3-[[3- [3- (pentafluoroethyl) phenoxy] phenyl] [[3- (heptafluoropropyl) phenyl] -methyl] amino] -1,1,1-trifluoro Ro-2-propanol;

(2R) -3-[[3- (3,5-dimethylphenoxy) phenyl] [[3- (heptafluoropropyl) phenyl] methyl] -amino] -1,1,1-trifluoro- 2-propanol;

(2R) -3-[[3- (3-ethylphenoxy) phenyl] [[3- (heptafluoropropyl) phenyl] methyl] amino] -1,1,1-trifluoro-2-propanol;

(2R) -3-[[3- (3-t-butylphenoxy) phenyl] [[3- (heptafluoropropyl) phenyl] methyl] amino] -1,1,1-trifluoro-2- Propanol;

(2R) -3-[[3- (3-methylphenoxy) phenyl] [[3- (heptafluoropropyl) phenyl] methyl] amino] -1,1,1-trifluoro-2-propanol;

(2R) -3-[[3- (5,6,7,8-tetrahydro-2-naphthoxy) phenyl] [[3- (heptafluoropropyl) phenyl] -methyl] amino] -1,1 , 1-trifluoro-2-propanol;

(2R) -3-[[3- (phenoxy) phenyl] [[3- (heptafluoropropyl) phenyl] methyl] amino] -1,1,1-trifluoro-2-propanol;

(2R) -3-[[3- [3- (N, N-dimethylamino) phenoxy] phenyl] [[3- (heptafluoropropyl) phenyl] -methyl] amino] -1,1,1 -Trifluoro-2-propanol;

(2R) -3-[[[3- (heptafluoropropyl) phenyl] methyl] [3-[[3- (trifluoromethoxy) phenyl] -methoxy] phenyl] amino] -1,1,1 -Trifluoro-2-propanol;

(2R) -3-[[[3- (heptafluoropropyl) phenyl] methyl] [3- [[3- (trifluoromethyl) phenyl] -methoxy] phenyl] amino] -1, 1, 1 -Trifluoro-2-propanol;

(2R) -3-[[[3- (heptafluoropropyl) phenyl] methyl] [3-[[3,5-dimethylphenyl] methoxy] -phenyl] amino] -1,1,1-trifluoro Ro-2-propanol;

(2R) -3-[[[3- (heptafluoropropyl) phenyl] methyl] [3-[[3- (trifluoromethylthio) phenyl] -methoxy] phenyl] amino] -1,1, 1-trifluoro-2-propanol;

(2R) -3-[[[3- (heptafluoropropyl) phenyl] methyl] [3-[[3,5-difluorophenyl] methoxy] -phenyl] amino] -1,1,1- Trifluoro-2-propanol;

(2R) -3-[[[3- (heptafluoropropyl) phenyl] methyl] [3- [cyclohexylmethoxy] phenyl] -amino] -1,1,1-trifluoro-2-propanol;

(2R) -3-[[3- (2-difluoromethoxy-4-pyridyloxy) phenyl] [[3- (heptafluoropropyl) phenyl] -methyl] amino] -1,1,1- Trifluoro-2-propanol;

(2R) -3-[[3- (2-trifluoromethyl-4-pyridyloxy) phenyl] [[3- (heptafluoropropyl) phenyl] -methyl] amino] -1,1,1- Trifluoro-2-propanol;

(2R) -3-[[3- (3-difluoromethoxyphenoxy) phenyl] [[3- (heptafluoropropyl) phenyl] -methyl] amino] -1,1,1-trifluoro- 2-propanol;

(2R) -3-[[[3- (3-trifluoromethylthio) phenoxy] phenyl] [[3- (heptafluoropropyl) phenyl] -methyl] amino] -1, 1, 1-tri Fluoro-2-propanol;

(2R) -3-[[3- (4-chloro-3-trifluoromethylphenoxy) phenyl] [[3- (heptafluoropropyl) -phenyl] methyl] amino] -1,1,1- Trifluoro-2-propanol;

(2R) -3-[[3- (3-trifluoromethoxyphenoxy) phenyl] [[2-fluoro-5- (trifluoromethyl) -phenyl] methyl] amino] -1,1,1 -Trifluoro-2-propanol;

(2R) -3-[[3- (3-isopropylphenoxy) phenyl] [[2-fluoro-5- (trifluoromethyl) phenyl] -methyl] amino] -1,1,1-tri Fluoro-2-propanol;

(2R) -3-[[3- (3-cyclopropylphenoxy) phenyl] [[2-fluoro-5- (trifluoromethyl) phenyl] -methyl] amino] -1,1,1-tri Fluoro-2-propanol;

(2R) -3-[[3- (3- (2-furyl) phenoxy) phenyl] [[2-fluoro-5- (trifluoromethyl) phenyl] methyl] amino] -1,1,1 -Trifluoro-2-propanol;

(2R) -3-[[3- (2,3-dichlorophenoxy) phenyl] [[2-fluoro-5- (trifluoromethyl) phenyl] -methyl] amino] -1,1,1 -Trifluoro-2-propanol;

(2R) -3-[[3- (4-fluorophenoxy) phenyl] [[2-fluoro-5- (trifluoromethyl) phenyl] -methyl] amino] -1,1,1-tri Fluoro-3-propanol;

(2R) -3-[[3- (4-methylphenoxy) phenyl] [[2-fluoro-5- (trifluoromethyl) phenyl] -methyl] amino] -1,1,1-trifluoro Ro-2-propanol;

(2R) -3-[[3- (2-fluoro-5-bromophenoxy) phenyl] [[2-fluoro-5- (trifluoromethyl) phenyl] methyl] amino] -1,1 , 1-trifluoro-2-propanol;

(2R) -3-[[3- (4-chloro-3-ethylphenoxy) phenyl] [[2-fluoro-5- (trifluoromethyl) phenyl] methyl] amino] -1,1,1 -Trifluoro-2-propanol;

(2R) -3-[[3- [3- (1,1,2,2-tetrafluoroethoxy) phenoxy] phenyl] [[2-fluoro-5- (trifluoro-methyl) phenyl ] Methyl] amino] -1,1,1-trifluoro-2-propanol;

(2R) -3-[[3- [3- (pentafluoroethyl) phenoxy] phenyl] [[2-fluoro-5- (trifluoromethyl) phenyl] methyl] amino] -1,1, 1-trifluoro-2-propanol;

(2R) -3-[[3- (3,5-dimethylphenoxy) phenyl] [[2-fluoro-5- (trifluoromethyl) phenyl] -methyl] amino] -1,1,1 -Trifluoro-2-propanol;

(2R) -3-[[3- (3-ethylphenoxy) phenyl] [[2-fluoro-5- (trifluoromethyl) phenyl] methyl] -amino] -1,1,1-trifluoro Ro-2-propanol;

(2R) -3-[[3- (3-t-butylphenoxy) phenyl] [[2-fluoro-5- (trifluoromethyl) phenyl] methyl] -amino] -1,1,1- Trifluoro-2-propanol;

(2R) -3-[[3- (3-methylphenoxy) phenyl] [[2-fluoro-5- (trifluoromethyl) phenyl] methyl] -amino] -1,1,1-trifluoro Ro-2-propanol;

(2R) -3-[[3- (5,6,7,8-tetrahydro-2-naphthoxy) phenyl] [[2-fluoro-5- (trifluoromethyl) -phenyl] methyl] amino ] -1,1,1-trifluoro-2-propanol;

(2R) -3-[[3- (phenoxy) phenyl] [[2-fluoro-5- (trifluoromethyl) phenyl] methyl] amino] -1,1,1-trifluoro-2- Propanol;

(2R) -3-[[3- [3- (N, N-dimethylaminophenoxy] phenyl] [[2-fluoro-5- (trifluoromethyl) phenyl] methyl] amino] -1, 1,1-trifluoro-2-propanol;

(2R) -3-[[[2-fluoro-5- (trifluoromethyl) phenyl] methyl] [3-[[3- (trifluoromethoxy) -phenyl] methoxy] phenyl] amino]- 1,1,1-trifluoro-3-propanol;

(2R) -3-[[[2-fluoro-5- (trifluoromethyl) phenyl] methyl] [3-[[3- (trifluoromethyl) -phenyl] methoxy] phenyl] amino]- 1,1,1-trifluoro-2-propanol;

(2R) -3-[[[2-fluoro-5- (trifluoromethyl) phenyl] methyl] [3-[[3,5-dimethylphenyl] methoxy] phenyl] amino] -1,1, 1-trifluoro-2-propanol;

(2R) -3-[[[2-fluoro-5- (trifluoromethyl) phenyl] methyl] [3-[[3- (trifluoromethylthio) phenyl] methoxy] phenyl] amino]- 1,1,1-trifluoro-2-propanol;

(2R) -3-[[[2-fluoro-5- (trifluoromethyl) phenyl] methyl] [3-[[3,5-difluorophenyl] methoxy] phenyl] amino] -1, 1,1-trifluoro-2-propanol;

(2R) -3-[[[2-fluoro-5- (trifluoromethyl) phenyl] methyl] [3- [cyclohexylmethoxy-phenyl] amino] -1,1,1-trifluoro- 2-propanol;

(2R) -3-[[3- (2-difluoromethoxy-4-pyridyloxy) phenyl] [[2-fluoro-5- (trifluoromethyl) phenyl] methyl] amino] -1, 1,1-trifluoro-2-propanol;

(2R) -3-[[3- (2-trifluoromethyl-4-pyridyloxy) phenyl] [[2-fluoro-5- (trifluoromethyl) -phenyl] methyl] amino] -1 , 1,1-trifluoro-2-propanol;

(2R) -3-[[3- (3-difluoromethoxyphenoxy) phenyl] [[2-fluoro-5- (trifluoromethyl) phenyl] methyl] amino] -1,1,1- Trifluoro-2-propanol;

(2R) -3-[[[3- (3-trifluoromethylthio) phenoxy] phenyl] [[2-fluoro-5- (trifluoromethyl) phenyl] methyl] amino-1,1, 1-trifluoro-2-propanol;

(2R) -3-[[3- (4-cyclo-3-trifluoromethylphenoxy) phenyl] [[2-fluoro-5- (trifluoromethyl) phenyl] methyl] amino] -1, 1,1-trifluoro-2-propanol;

(2R) -3-[[3- (3-trifluoromethoxyphenoxy) phenyl] [[2-fluoro-4- (trifluoromethyl) -phenyl] methyl] amino] -1,1,1 -Trifluoro-2-propanol;

(2R) -3-[[3- (3-isopropylphenoxy) phenyl] [[2-fluoro-4- (trifluoromethyl) phenyl] -methyl] amino] -1,1,1-tri Fluoro-2-propanol;

(2R) -3-[[3- (3-cyclopropylphenoxy) phenyl] [[2-fluoro-4- (trifluoromethyl) phenyl] methyl] amino] -1,1,1-trifluoro Ro-2-propanol;

(2R) -3-[[3- (3- (2-furyl) phenoxy) phenyl] [[2-fluoro-4- (trifluoromethyl) phenyl] methyl] amino] -1,1,1 -Trifluoro-2-propanol;

(2R) -3-[[3- (2,3-dichlorophenoxy) phenyl] [[2-fluoro-4- (trifluoromethyl) phenyl] -methyl] amino] -1,1,1 -Trifluoro-2-propanol;

(2R) -3-[[3- (4-fluorophenoxy) phenyl] [[2-fluoro-4- (trifluoromethyl) phenyl] -methyl] amino] -1,1,1-tri Fluoro-2-propanol;

(2R) -3-[[3- (4-methylphenoxy) phenyl] [[2-fluoro-4- (trifluoromethyl) phenyl] -methyl] amino] -1,1,1-trifluoro Ro-2-propanol;

(2R) -3-[[3- (2-fluoro-5-bromophenoxy) phenyl] [[2-fluoro-4- (trifluoromethyl) -phenyl] methyl] amino] -1, 1,1-trifluoro-2-propanol;

(2R) -3-[[3- (4-chloro-3-ethylphenoxy) phenyl] [[2-fluoro-4- (trifluoromethyl) -phenyl] methyl] amino] -1,1, 1-trifluoro-2-propanol;

(2R) -3-[[3- [3- (1,1,2,2-tetrafluoroethoxy) phenoxy] phenyl] [[2-fluoro-4- (trifluoromethyl) phenyl] Methyl] amino] -1,1,1-trifluoro-2-propanol;

(2R) -3-[[3- [3- (pentafluoroethyl) phenoxy] phenyl] [[2-fluoro-4- (trifluoromethyl) -phenyl] methyl] amino] -1,1 , 1-trifluoro-2-propanol;

(2R) -3-[[3- (3,5-dimethylphenoxy) phenyl] [[2-fluoro-4- (trifluoromethyl) phenyl] -methyl] aminol-1,1,1 -Trifluoro-2-propanol;

(2R) -3-[[3- (3-ethylphenoxy) phenyl] [[2-fluoro-4- (trifluoromethyl) phenyl] methyl] -amino] -1,1,1-trifluoro Ro-2-propanol;

(2R) -3-[[3- (3-t-butylphenoxy) phenyl] [[2-fluoro-4- (trifluoromethyl) phenyl] methyl] -amino] -1,1,1- Trifluoro-2-propanol;

(2R) -3-[[3- (3-methylphenoxy) phenyl] [[2-fluoro-4- (trifluoromethyl) phenyl] methyl] -amino] -1,1,1-trifluoro Ro-2-propanol;

(2R) -3-[[3- (5,6,7,8-tetrahydro-2-naphthoxy) phenyl] [[2-fluoro-4- (trifluoromethyl) -phenyl] methyl] amino ] -1,1,1-trifluoro-2-propanol;

(2R) -3-[[3- (phenoxy) phenyl] [[2-fluoro-4- (trifluoromethyl) phenyl] methyl] amino] -1,1,1-trifluoro-2- Propanol;

(2R) -3-[[3- [3- (N, N-dimethylamino) phenoxy] phenyl] [[2-fluoro-4- (trifluoromethyl) phenyl] methyl] amino] -1 , 1,1-trifluoro-2-propanol;

(2R) -3-[[[2-fluoro-4- (trifluoromethyl) phenyl] methyl] [3-[[3- (trifluoromethoxy) phenyl] methoxy] phenyl] amino] -1 , 1,1-trifluoro-2-propanol;

(3R) -3-[[[2-fluoro-4- (trifluoromethyl) phenyl] methyl] [3-[[3- (trifluoromethyl) phenyl] methoxy] phenyl] amino] -1 , 1,1-trifluoro-2-propanol;

(2R) -3-[[[2-fluoro-4- (trifluoromethyl) phenyl] methyl] [3-[[3,5-dimethylphenyl] methoxy] phenyl] amino] -1,1, 1-trifluoro-2-propanol;

(2R) -3-[[[2-fluoro-4- (trifluoromethyl) phenyl] methyl] [3-[[3- (trifluoromethylthio) -phenyl] methoxy] phenyl] amino] -1,1,1-trifluoro-2-propanol;

(2R) -3-[[[2-fluoro-4- (trifluoromethyl) phenyl] methyl] [3-[[3,5-difluorophenyl] methoxy] phenyl] amino] -1, 1,1-trifluoro-2-propanol;

(2R) -3-[[[2-fluoro-4- (trifluoromethyl) phenyl] methyl] [3- [cyclohexylmethoxy] -phenyl] amino] -1,1,1-trifluoro -2-propanol;

(2R) -3-[[3- (2-difluoromethoxy-4-pyridyloxy) phenyl] [[2-fluoro-4- (trifluoromethyl) phenyl] methyl] amino] -1, 1,1-trifluoro-2-propanol;

(2R) -3-[[3- (2-trifluoromethyl-4-pyridyloxy) phenyl] [[2-fluoro-4- (trifluoromethyl) phenyl] methyl] amino-1,1 , 1-trifluoro-2-propanol;

(2R) -3-[[3- (3-difluoromethoxyphenoxy) phenyl] [[2-fluoro-4- (trifluoromethyl) -phenyl] methyl] amino] -1,1,1 -Trifluoro-2-propanol;

(2R) -3-[[[3- (3-trifluoromethylthio) phenoxy] phenyl] [[2-fluoro-4- (trifluoromethyl) -phenyl] methyl] amino] -1, 1,1-trifluoro-2-propanol; And

(2R) -3-[[3- (4-chloro-3-trifluoromethylphenoxy) phenyl] [[2-fluoro-4- (trifluoromethyl) phenyl] methyl] amino] -1, 1,1-trifluoro-2-propanol.

Another class of CETP inhibitors that can be used in the present invention consists of quinoline of formula XVII and a pharmaceutically acceptable form thereof:

Where

A _XVII is halogen, nitro, hydroxyl, trifluoromethyl, trifluoromethoxy, or straight or branched chain alkyl, acyl, hydroxyalkyl or alkoxy containing up to 7 carbon atoms each, or formula -NR Aryl containing 6 to 10 carbon atoms which may be substituted with up to 5 identical or different substituents selected from the groups according to _XII-4 R _XVII-5 ; At this time

R _XVII-4 and R _XVII-5 are the same or different and represent hydrogen, phenyl, or straight or branched chain alkyl containing up to 6 carbon atoms;

D _XVII is aryl containing 6 to 10 carbon atoms, which may be substituted with phenyl, nitro, halogen, trifluoromethyl or trifluoromethoxy, or

Represents a radical according to; At this time

R _XVII-6 , R _XVII-7 and R _XVII-10 are independently of each other cycloalkyl having 3 to 6 carbon atoms, aryl having 6 to 10 carbon atoms, or 4 selected from S, N and / or O 5 to 7 membered benzo-condensed, saturated or unsaturated, mono-, di- or tricyclic heterocyclic containing up to 2 heteroatoms, wherein the ring is N in the case of a nitrogen containing ring Halogen, trifluoromethyl, nitro, hydroxyl, cyano, carboxyl, trifluoromethoxy, straight or branched chain acyl containing up to 6 carbon atoms each, alkyl, alkylthio, alkylalkoxy, Alkoxy or alkoxycarbonyl, aryl or trifluoromethyl substituted aryl each having 6 to 10 carbon atoms, or up to 3 heteroatoms selected from S, N and / or O and may be benzo condensed Up to 5 aromatics selected from aromatic 5-7 membered heterocycles and / or groups according to formula -OR _XVII-11 , -SR _XVII-12 , -SO ₂ R _XVII-13 or -NR _XVII-14 R _XVII-15 May be substituted with the same or different substituents; At this time

R _XVII-11 , R _XVII-12 and R _XVII-13 are independently of each other substituted with up to 2 identical or different substituents selected from phenyl, halogen, or straight or branched chain alkyl containing up to 6 carbon atoms Aryl containing 6 to 10 carbon atoms;

R _XVII-14 and R _XVII-15 are the same or different and have the meanings defined above for R _XVII-4 and R _XVII-5 ;

R _XVII-6 and / or R _XVII-7 have the formula

Represents a radical according to; At this time

R _XVII-8 represents hydrogen or halogen;

R _XVII-9 is hydrogen, halogen, azido, trifluoromethyl, hydroxyl, trifluoromethoxy, straight or branched chain alkoxy or alkyl containing up to 6 carbon atoms each, or formula NR _XVII-16 R _Represents a radical according to _XVII-17 ; At this time

R _XVII-16 and R _XVII-17 are the same or different and have the meanings defined above for R _XVII-4 and R _XVII-5 ;

R _XVII-8 and R _XVII-9 together form a radical according to formula = O or = NR _XVII-18 ; At this time

R _XVII-18 represents hydrogen or straight or branched chain alkyl, alkoxy or acyl containing up to 6 carbon atoms each;

L _XVII represents a straight or branched chain alkylene or alkenylene containing up to 8 carbon atoms which may be substituted with up to 2 hydroxyl groups;

T _XVII and X _XVII are the same or different and represent straight or branched chain alkylene containing up to 8 carbon atoms; or

T _XVII and X _XVII represent a bond;

V _XVII represents an oxygen or sulfur atom or -NR _XVII-19 ; At this time

R _XVII-19 represents hydrogen, straight or branched chain alkyl containing up to 6 carbon atoms, or phenyl;

E _XVII may be substituted with cycloalkyl containing 3 to 8 carbon atoms, or cycloalkyl or hydroxyl containing 3 to 8 carbon atoms and straight or branched chain alkyl containing up to 8 carbon atoms, Or phenyl which may be substituted with halogen or trifluoromethyl;

R _XVII-1 and R _XVII-2 are the same or different and contain cycloalkyl, hydrogen, nitro, halogen, trifluoromethyl, trifluoromethoxy, carboxy, hydroxy, between 3 to 8 carbon atoms Ano, straight or branched acyl containing up to 6 carbon atoms each, alkoxycarbonyl or alkoxy, or NR _XVII-20 R _XVII-21 , wherein R _XVII-20 and R _XVII-21 are the same or different Hydrogen, phenyl, or straight or branched chain alkyl containing up to 6 carbon atoms);

R _XVII-1 and / or R _XVII-2 contain up to 6 carbon atoms, which may be substituted by halogen, trifluoromethoxy, hydroxy or straight or branched alkoxy containing up to 4 carbon atoms Straight or branched chain alkyl, or halogen, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, nitro, straight or branched chain alkyl containing up to 7 carbon atoms, acyl, hydroxyalkyl or Alkoxy, and NR _XVII-22 R _XVII-23 , wherein R _XVII-22 and R _XVII-23 are the same or different and represent hydrogen, phenyl or straight or branched chain alkyl containing up to 6 carbon atoms Aryl containing 6 to 10 carbon atoms, which may be substituted with up to 5 identical or different substituents selected from; or

R _XVII-1 and R _XVII-2 together contain up to 6 carbon atoms, which may be substituted by halogen, trifluoromethoxy, hydroxy or straight or branched alkoxy containing up to 4 carbon atoms To form straight or branched alkene or alkanes;

R _XVII-3 is hydrogen, straight or branched chain acyl containing up to 20 carbon atoms; benzoyl, which may be substituted with halogen, trifluoromethyl, nitro or trifluoromethoxy; Straight or branched chain fluoroacyl containing up to 8 carbon atoms and 7 fluorine atoms; Cycloalkyl containing 3 to 7 carbon atoms; Straight or branched chain alkyl containing up to 8 carbon atoms which may be substituted with hydroxyl; Straight or branched chain alkoxy containing up to 6 carbon atoms, which may be substituted by halogen, nitro, trifluoromethyl, trifluoromethoxy, or phenyl which may be substituted with phenyl or tetrazol substituted phenyl And / or alkyl which may be substituted with a group of the formula -OR _XVII-24 ; At this time

R _XVII-24 is straight or branched acyl or benzyl containing up to 4 carbon atoms.

The compounds of formula (XVII) and methods for their preparation are disclosed in PCT Publication No. WO 98/39299, which is incorporated herein by reference in its entirety for all purposes.

Another class of CETP inhibitors that can be used in the present invention consists of 4-phenyltetrahydroquinoline of formula XVIII, N-oxides thereof and pharmaceutically acceptable forms thereof:

Where

A _XVIII represents phenyl which may be substituted with up to two identical or different substituents selected from halogen, trifluoromethyl or straight or branched chain alkyl or alkoxy containing up to 3 carbon atoms;

D _XVIII is represented by the formula

Represents; At this time

R _XVIII-5 and R _XVIII-6 together form ═O;

R _XVIII-5 represents hydrogen and R _XVIII-6 represents halogen or hydrogen; or

R _XVIII-5 and R _XVIII-6 represent hydrogen;

R _XVIII-7 and R _XVIII-8 are the same or different and are selected from halogen, trifluoromethyl, nitro, cyano, trifluoromethoxy, SO ₂ -CH ₃ or NR _XVIII-9 R _XVIII-10 Phenyl, naphthyl, benzothiazolyl, quinolinyl, pyrimidyl or pyridyl having up to 5 identical or different substituents;

R _XVIII-9 and R _XVIII-10 are the same or different and represent hydrogen or straight or branched chain alkyl containing up to 3 carbon atoms;

E _XVIII represents cycloalkyl containing 3 to 6 carbon atoms or straight or branched chain alkyl containing up to 8 carbon atoms;

R _XVIII-1 represents hydroxy;

R _XVIII-2 represents hydrogen or methyl;

R _XVIII-3 and R _XVIII-4 are the same or different and represent straight or branched chain alkyl containing up to 3 carbon atoms; or

R _XVIII-3 and R _XVIII-4 together form an alkenylene containing 2 to 4 carbon atoms.

The compounds of formula XVIII and methods for their preparation are disclosed in PCT Publication No. WO 99/15504 and US Pat. No. 6,291,477, both of which are incorporated herein by reference in their entirety for all purposes.

Amlodipine and related dihydropyridine compounds are disclosed as potent anti-ischemic and antihypertensive agents in US Pat. No. 4,572,909, which is incorporated herein by reference. US Pat. No. 4,879,303, incorporated herein by reference, discloses amlodipine benzelsulfonate salts (also called amlodipine besylate). Amlodipine and amlodipine besylate are potent and persistent calcium channel blockers. Thus, amlodipine, amlodipine besylate, and other pharmaceutically acceptable acid addition salts of amlodipine are useful as antihypertensive agents and as anti-ischemic agents. Amlodipine and its pharmaceutically acceptable acid addition salts are also disclosed in US Pat. No. 5,155,120 as useful in the treatment of congestive heart failure. Amlodipine besylate is currently sold as Novasc®. Amlodipine has the formula (B):

Calcium channel blockers within the scope of this invention include bepridil, which may be prepared as disclosed in U.S. Patent No. 3,962,238 or US Reissue Patent No. 30,577; Clentiazem, which may be prepared as disclosed in U.S. Patent No. 4,567,175; Diltiazem, which may be prepared as disclosed in U.S. Patent No. 3,562; Pendylin, which may be prepared as disclosed in U.S. Patent No. 3,262,977; Galopamil, which may be prepared as disclosed in U.S. Patent No. 3,261,859; Mibepradyl, which may be prepared as disclosed in U.S. Patent No. 4,808,605; Prenylamine, which may be prepared as disclosed in U.S. Patent No. 3,152,173; Semotiadil, which may be prepared as disclosed in U.S. Patent No. 4,786,635; Terodilin, which may be prepared as disclosed in U.S. Patent No. 3,371,014; Verapamil, which may be prepared as disclosed in U.S. Patent No. 3,261,859; Aranipine, which may be prepared as disclosed in U.S. Patent No. 4,572,909; Vanidipine, which may be prepared as disclosed in U.S. Patent No. 4,220,649; Benidipine, which may be prepared as disclosed in European Patent Application Publication No. 106,275; Silnidipine, which may be prepared as disclosed in U.S. Patent No. 4,672,068; Eponidipine, which may be prepared as disclosed in U.S. Patent No. 4,885,284; Elgodipine, which may be prepared as disclosed in U.S. Patent No. 4,952,592; Felodipine, which may be prepared as disclosed in U.S. Patent No. 4,264,611; Isradipine, which may be prepared as disclosed in U.S. Patent No. 4,466,972; Lacidipine, which may be prepared as disclosed in U.S. Patent No. 4,801,599; Rucanidipine, which may be prepared as disclosed in U.S. Patent No. 4,705,797; Manidipine, which may be prepared as disclosed in U.S. Patent No. 4,892,875; Nicadipine, which may be prepared as disclosed in U.S. Patent No. 3,985,758; Nifedipine, which may be prepared as disclosed in U.S. Patent No. 3,485,847; Nilvadipine, which may be prepared as disclosed in U.S. Patent No. 4,338,322; Nimodipine, which may be prepared as disclosed in U.S. Patent No. 3,799,934; Nisoldipine, which may be prepared as disclosed in U.S. Patent No. 4,154,839; Nirenedipine, which may be prepared as disclosed in U.S. Patent No. 3,799,934; Cinarizine, which may be prepared as disclosed in U.S. Patent No. 2,882,271; Flunarizine, which may be prepared as disclosed in U.S. Patent No. 3,773,939; Lidoprazine, which may be prepared as disclosed in U.S. Patent No. 3,267,104; Lomerizin, which may be prepared as disclosed in U.S. Patent No. 4,663,325; Bencycline, which may be prepared as disclosed in Hungarian Patent No. 151,865; Etaphenone, which may be prepared as disclosed in German Patent No. 1,265,758; And perhexylline, which may be prepared as disclosed in British Patent No. 1,025,578, but is not limited to these. The disclosures of all such US patents are incorporated herein by reference.

Angiotensin converting enzyme inhibitors (ACE-inhibitors) that fall within the scope of the present invention include alacepril, which may be prepared as disclosed in U.S. Patent No. 4,248,883; Benazepril, which may be prepared as disclosed in U.S. Patent No. 4,410,520; Captopril, which may be prepared as disclosed in U.S. Patent Nos. 4,046,889 and 4,105,776; Seronapril, which may be prepared as disclosed in U.S. Patent No. 4,452,790; Delapril, which may be prepared as disclosed in U.S. Patent No. 4,385,051; Enalapril, which may be prepared as disclosed in U.S. Patent No. 4,374,829; Posinopril, which may be prepared as disclosed in U.S. Patent No. 4,337,201; Imadapril, which may be prepared as disclosed in U.S. Patent No. 4,508,727; Ricinopril, which may be prepared as disclosed in U.S. Patent No. 4,555,502; Moveltopril, which may be prepared as disclosed in Belgian Patent No. 893,553; Perindopril, which may be prepared as disclosed in U.S. Patent No. 4,508,729; Quinapril, which may be prepared as disclosed in U.S. Patent No. 4,344,949; Ramipril, which may be prepared as disclosed in U.S. Patent No. 4,587,258; Spirapril, which may be prepared as disclosed in U.S. Patent No. 4,470,972; Temocapryl, which may be prepared as disclosed in U.S. Patent No. 4,699,905; And trandolapril, which may be prepared as disclosed in U.S. Patent No. 4,933,361. The disclosures of all these US patents are incorporated herein by reference.

Angiotensin-II receptor antagonists (A-II antagonists) that fall within the scope of the present invention include candesartan, which may be prepared as disclosed in U.S. Patent No. 5,196,444; Eprosatan, which may be prepared as disclosed in U.S. Patent No. 5,185,351; Avesatan, which may be prepared as disclosed in U.S. Patent No. 5,270,317; Losartan, which may be prepared as disclosed in U.S. Patent No. 5,138,069; And balsa, which may be prepared as disclosed in U.S. Patent 5,399,578, but is not limited to such. The disclosures of all such US patents are incorporated herein by reference.

Beta-adrenergic receptor blockers (beta- or ??-blockers) within the scope of the present invention include acebutolol, which may be prepared as disclosed in U.S. Patent No. 3,857,952; Alprenolol, which may be prepared as disclosed in Dutch Patent Application No. 6,605,692; Amosulalol, which may be prepared as disclosed in U.S. Patent No. 4,217,305; Arotinol, which may be prepared as disclosed in U.S. Patent No. 3,932,400; Atenolol, which may be prepared as disclosed in U.S. Patent No. 3,663,607 or 3,836,671; Befunolol, which may be prepared as disclosed in U.S. Patent No. 3,853,923; Betaxolol, which may be prepared as disclosed in U.S. Patent No. 4,252,984; Bevantolol, which may be prepared as disclosed in U.S. Patent No. 3,857,981; Bisoprolol, which may be prepared as disclosed in U.S. Patent No. 4,171,370; Bopindolol, which may be prepared as disclosed in U.S. Patent No. 4,340,541; Bucumolol, which may be prepared as disclosed in U.S. Patent No. 3,663,570; Bufetolol, which may be prepared as disclosed in U.S. Patent No. 3,723,476; Bufuralol, which may be prepared as disclosed in U.S. Patent No. 3,929,836; Bunitrolol, which may be prepared as disclosed in U.S. Patent Nos. 3,940,489 and 3,961,071; Bufrandolol, which may be prepared as disclosed in U.S. Patent No. 3,309,406; Butyridine hydrochloride, which may be prepared as disclosed in French Patent No. 1,390,056; Butofylolol, which may be prepared as disclosed in U.S. Patent No. 4,252,825; Carazolol, which may be prepared as disclosed in German Patent No. 2,240,599; Cateolol, which may be prepared as disclosed in U.S. Patent No. 3,910,924; Carvedilol, which may be prepared as disclosed in U.S. Patent No. 4,503,067; Celiprolol, which may be prepared as disclosed in U.S. Patent No. 4,034,009; Cetamolol, which may be prepared as disclosed in U.S. Patent No. 4,059,622; Chloranol, which may be prepared as disclosed in German Patent No. 2,213,044; Dilevalol, which may be prepared as disclosed in Clifton et al., Journal of Medicinal Chemistry, 1982 , 25 , 670; Epanolol, which may be prepared as disclosed in European Patent Application Publication No. 41,491; Indenolol, which may be prepared as disclosed in U.S. Patent No. 4,045,482; Labetalol, which may be prepared as disclosed in U.S. Patent No. 4,012,444; Levobunol, which may be prepared as disclosed in U.S. Patent No. 4,463,176; Seeman et al., Helv. Chim. Mepindolol, which may be prepared as disclosed in Acta, 1971 , 54 , 241; Metipranolol, which may be prepared as disclosed in Czechoslovakia Patent Application No. 128,471; Metoprolol, which may be prepared as disclosed in U.S. Patent No. 3,873,600; Morphrolol, which may be prepared as disclosed in U.S. Patent No. 3,501,769; Nadolol, which may be prepared as disclosed in U.S. Patent No. 3,935,267; Nadoxolol, which may be prepared as disclosed in U.S. Patent No. 3,819,702; Nebivalol, which may be prepared as disclosed in U.S. Patent No. 4,654,362; Nipradilol, which may be prepared as disclosed in U.S. Patent No. 4,394,382; Oxprenolol, which may be prepared as disclosed in British Patent No. 1,077,603; Perbutolol, which may be prepared as disclosed in U.S. Patent No. 3,551,493; Pindolol, which may be prepared as disclosed in Swiss Patent Nos. 469,002 and 472,404; Fructolol, which may be prepared as disclosed in U.S. Patent No. 3,408,387; Pronetalol, which may be prepared as disclosed in British Patent No. 909,357; Propranolol, which may be prepared as disclosed in U.S. Patent Nos. 3,337,628 and 3,520,919; Sotalol, which may be prepared as disclosed in Uloth et al., Journal of Medicinal Chemistry, 1966 , 9 , 88; Supinalol, which may be prepared as disclosed in German Patent No. 2,728,641; Tallindol, which may be prepared as disclosed in U.S. Patent Nos. 3,935,259 and 4,038,313; Tertatolol, which may be prepared as disclosed in U.S. Patent No. 3,960,891; Tilisolol, which may be prepared as disclosed in U.S. Patent No. 4,129,565; Timolol, which may be prepared as disclosed in U.S. Patent No. 3,655,663; Toliprolol, which may be prepared as disclosed in U.S. Patent No. 3,432,545; And givenolol, which may be prepared as disclosed in U.S. Patent No. 4,018,824. The disclosures of all these US patents are incorporated herein by reference.

Alpha-adrenergic receptor blockers (alpha- or a-blockers) within the scope of the present invention include amosulalol, which may be prepared as disclosed in U.S. Patent No. 4,217,307; Arotinol, which may be prepared as disclosed in U.S. Patent No. 3,932,400; Dapiprazole, which may be prepared as disclosed in U.S. Patent No. 4,252,721; Doxazosin, which may be prepared as disclosed in U.S. Patent No. 4,188,390; Fenspiride, which may be prepared as disclosed in U.S. Patent No. 3,399,192; Indoramine, which may be prepared as disclosed in U.S. Patent No. 3,527,761; Rabetolol, which may be prepared as disclosed above; Naphthopidyl, which may be prepared as disclosed in U.S. Patent No. 3,997,666; Naisergolin, which may be prepared as disclosed in U.S. Patent No. 3,228,943; Prazosin, which may be prepared as disclosed in U.S. Patent No. 3,511,836; Tamsulosin, which may be prepared as disclosed in U.S. Patent No. 4,703,063; Tolazoline, which may be prepared as disclosed in U.S. Patent No. 2,161,938; Trimazosine, which may be prepared as disclosed in U.S. Patent No. 3,669,968; And yohimbine, which can be isolated from natural sources according to methods well known to those skilled in the art. The disclosures of all these US patents are incorporated herein by reference.

As used herein, the term "vascular dilator" includes cerebral vascular dilators, coronary vascular dilators and peripheral vascular dilators. Cerebral vasodilators within the scope of the present invention include bencycline, which may be prepared as disclosed above; Cinarizine, which may be prepared as disclosed above; Isolated from natural sources as described in Kennedy et al., Journal of the American Chemical Society, 1955 , 77 , 250, or synthesized as disclosed in Kennedy, Journal of Biological Chemistry, 1956 , 222 , 185. Citicholine, which can be; Cyclodelate, which may be prepared as disclosed in U.S. Patent No. 3,663,597; Cyclonicates, which may be prepared as disclosed in German Patent No. 1,910,481; Diisopropylamine dichloroacetate, which may be prepared as disclosed in British Patent No. 862,248; Evernamonine, which may be prepared as disclosed in Hermann et al., Journal of the American Chemical Society, 1979 , 101 , 1540; Fasudil, which may be prepared as disclosed in U.S. Patent No. 4,678,783; Phenoxedil, which may be prepared as disclosed in U.S. Patent No. 3,818,021; Flunarizine, which may be prepared as disclosed in U.S. Patent No. 3,773,939; Ibudilast, which may be prepared as disclosed in U.S. Patent No. 3,850,941; Ifenprodil, which may be prepared as disclosed in U.S. Patent No. 3,509,164; Lomerizin, which may be prepared as disclosed in U.S. Patent No. 4,663,325; Napronyl, which may be prepared as disclosed in U.S. Patent No. 3,334,096; Nikamate, which may be prepared as disclosed in Blicke et al., Journal of the American Chemical Society, 1942 , 64 , 1722; Naisergolin, which may be prepared as disclosed above; Nimodipine, which may be prepared as disclosed in U.S. Patent No. 3,799,934; Goldberg, Chem. Prod. Chem. Papaverin, which may be prepared as disclosed in News, 1954 , 17 , 371; Pentiphylline, which may be prepared as disclosed in German Patent No. 860,217; Tinophedrine, which may be prepared as disclosed in U.S. Patent No. 3,563,997; Vincarmine, which may be prepared as disclosed in U.S. Patent No. 3,770,724; Vinpocetin, which may be prepared as disclosed in U.S. Patent No. 4,035,750; And biquidyl, which may be prepared as disclosed in U.S. Patent No. 2,500,444, including but not limited to. The disclosures of all these US patents are incorporated herein by reference.

Coronary vasodilators within the scope of the present invention include amotrifen, which may be prepared as disclosed in U.S. Patent No. 3,010,965; J. Chem. Soc. Bendazole, which may be prepared as disclosed in 1958, 2426; Benfurodil hemisuccinate, which may be prepared as disclosed in U.S. Patent No. 3,355,463; Bengiodarone, which may be prepared as disclosed in U.S. Patent No. 3,012,042; Chlorasizin, which may be prepared as disclosed in British Patent No. 740,932; Chromona, which may be prepared as disclosed in U.S. Patent No. 3,282,938; Clobenfural, which may be prepared as disclosed in British Patent No. 1,160,925; Clonitrate, which may be prepared in propanediol according to methods well known to those skilled in the art (see, eg, Annalen, 1870, 155, 165); Chlorichromen, which may be prepared as disclosed in U.S. Patent No. 4,452,811; Dilaze, which may be prepared as disclosed in U.S. Patent No. 3,532,685; Dipyridamole, which may be prepared as disclosed in British Patent No. 807,826; Droprenylamine, which may be prepared as disclosed in German Patent No. 2,521,113; Eproxate, which may be prepared as disclosed in British Patent Nos. 803,372 and 824,547; Erytrityl tetranitrate, which may be prepared by the nitrification of erythritol according to methods well known to those skilled in the art; Etaphenone, which may be prepared as disclosed in German Patent No. 1,265,758; Pendylin, which may be prepared as disclosed in U.S. Patent No. 3,262,977; Floredil, which may be prepared as disclosed in German Patent No. 2,020,464; Ganglefen, which may be prepared as disclosed in Soviet Patent No. 115,905; Hexestrol, which may be prepared as disclosed in U.S. Patent No. 2,357,985; Hexobendine, which may be prepared as disclosed in U.S. Patent No. 3,267,103; Itramine tosylate, which may be prepared as disclosed in Swedish Patent No. 168,308; Kelin, which may be prepared as disclosed in Baxter et al., Journal of the Chemical Society, 1949 , S 30; Lidoprazine, which may be prepared as disclosed in U.S. Patent No. 3,267,104; Mannitol hexanitrate, which may be prepared by nitrification of mannitol according to methods well known to those skilled in the art; Methazazine, which may be prepared as disclosed in U.S. Patent No. 3,119,826; Nitroglycerin; Pentaerythritol tetranitrate, which may be prepared by nitrification of bentaerythritol according to methods well known to those skilled in the art; Pentrinitrol, which may be prepared as disclosed in German Patent No. 638,422-3; Perhexylline, which may be prepared as disclosed above; Pimephylline, which may be prepared as disclosed in U.S. Patent No. 3,350,400; Prenylamine, which may be prepared as disclosed in U.S. Patent No. 3,152,173; Propatyl nitrate, which may be prepared as disclosed in French Patent No. 1,103,113; Trapidyl, which may be prepared as disclosed in East German Patent No. 55,956; Tricromyl, which may be prepared as disclosed in U.S. Patent No. 2,769,015; Trimetazidine, which may be prepared as disclosed in U.S. Patent No. 3,262,852; Trolnitrate phosphate, which may be prepared by nitrification of triethanolamine followed by precipitation with phosphoric acid according to methods well known to those skilled in the art; And bisnadine, which may be prepared as disclosed in U.S. Patent Nos. 2,816,118 and 2,980,699. The disclosures of all these US patents are incorporated herein by reference.

Peripheral vasodilators within the scope of this invention include aluminum nicotinate, which may be prepared as disclosed in U.S. Patent No. 2,970,082; Methane, which may be prepared as disclosed in Corrigan et al., Journal of the American Chemical Society, 1945 , 67 , 1894; Bencycline, which may be prepared as disclosed above; Walter et al .; Beta hisstin, which may be prepared as disclosed in Journal of the American Chemical Society, 1941 , 63 , 2771; Hamburg et al., Arch. Biochem. Bradykinin, which may be prepared as disclosed in Biophys., 1958 , 76 , 252; Brovincarmine, which may be prepared as disclosed in U.S. Patent No. 4,146,643; Bufeniode, which may be prepared as disclosed in U.S. Patent No. 3,542,870; Buflomethyl, which may be prepared as disclosed in U.S. Patent No. 3,895,030; Butalamine, which may be prepared as disclosed in U.S. Patent No. 3,338,899; Cetiethyl, which may be prepared as disclosed in French Patent No. 1,460,571; Cyclonicates, which may be prepared as disclosed in German Patent No. 1,910,481; Cinefazide, which may be prepared as disclosed in Belgian Patent No. 730,345; Cinarizine, which may be prepared as disclosed above; Cyclodelate, which may be prepared as disclosed above; Diisopropylamine dichloroacetate, which may be prepared as disclosed above; Eleodocin, which may be prepared as disclosed in British Patent No. 984,810; Phenoxedil, which may be prepared as disclosed above; Flunarizine, which may be prepared as disclosed above; Hepronicate, which may be prepared as disclosed in U.S. Patent No. 3,384,642; Ifenprodil, which may be prepared as disclosed above; Iloprost, which may be prepared as disclosed in U.S. Patent No. 4,692,464; Inositol niacinate, which may be prepared as disclosed in Baddett et al., Journal of the American Chemical Society, 1947 , 69 , 2907; Isoxsuprine, which may be prepared as disclosed in U.S. Patent No. 3,056,836; Biochem. Biophys. Res. Caliun, which may be prepared as disclosed in Commun., 1961 , 6 , 210; Kallikrein, which may be prepared as disclosed in German Patent No. 1,102,973; Moxisilite, which may be prepared as disclosed in German Patent No. 905,738; Napronyl, which may be prepared as disclosed above; Nikametate, which may be prepared as disclosed above; Naisergolin, which may be prepared as disclosed above; Nicofuranose, which may be prepared as disclosed in Swiss Patent No. 366,523; Nilidrin, which may be prepared as disclosed in U.S. Patent Nos. 2,661,372 and 2,661,373; Pentiphylline, which may be prepared as disclosed above; Pentoxifylline, which may be prepared as disclosed in U.S. Patent No. 3,422,107; Pyrivedyl, which may be prepared as disclosed in U.S. Patent No. 3,299,067; Prostaglandin E _1, which may be prepared according to any method referred to in the Merck Index, Twelfth Edition, Budaveri, Ed., New Jersey, 1996, p. 1353; Sulfoxidyl, which may be prepared as disclosed in German Patent No. 2,334,404; Tolazoline, which may be prepared as disclosed in U.S. Patent No. 2,161,938; And German Patent No. 1,102,750 or Korbonits et al., Acta. Pharm. Hung., 1968 , 38 , 98, includes but is not limited to xanthinyl niacinate, which may be prepared as disclosed. The disclosures of all these US patents are incorporated herein by reference.

The term "diuretic" within the scope of the present invention means diuretic benzothiadiazine derivatives, diuretic organic mercury, diuretic purine, diuretic steroids, diuretic sulfonamide derivatives, diuretic uracil and other diuretics such as those disclosed in Austrian Patent No. 168,063. Amanazine, which may be prepared; Amylolide, which may be prepared as disclosed in Belgian Patent No. 639,386; Arbutin, which may be prepared as disclosed in Tschitschibabin, Annalen, 1930 , 479 , 303; Chlorazanyl, which may be prepared as disclosed in Austrian Patent No. 168,063; Ethacrynic acid, which may be prepared as disclosed in U.S. Patent No. 3,255,241; Etozoline, which may be prepared as disclosed in U.S. Patent No. 3,072,653; Hydrcarbazine, which may be prepared as disclosed in British Patent No. 856,409; Isosorbide, which may be prepared as disclosed in U.S. Patent No. 3,160,641; Mannitol; Metokalcon, which may be prepared as disclosed in Freudenberg et al., Ber., 1957 , 90 , 957; Muzolimin, which may be prepared as disclosed in U.S. Patent No. 4,018,890; Perhexylline, which may be prepared as disclosed above; Ticlinafen, which may be prepared as disclosed in U.S. Patent No. 3,758,506; Triamterene, which may be prepared as disclosed in U.S. Patent No. 3,081,230; And urea. The disclosures of all these US patents are incorporated herein by reference.

Diuretic benzothiadiazine derivatives within the scope of the present invention include althiazide, which may be prepared as disclosed in British Patent No. 902,658; Bendroflumetiazide, which may be prepared as disclosed in U.S. Patent No. 3,265,573; McManus et al., 136 th Am. Soc. Benzthiazide, which may be prepared as disclosed in Meeting (Atlantic City, September 1959), Abstract of papers, pp 13-O; Benzylhydrochlorothiazide, which may be prepared as disclosed in U.S. Patent No. 3,108,097; Butiazide, which may be prepared as disclosed in British Patent Nos. 861,367 and 885,078; Chlorothiazide, which may be prepared as disclosed in U.S. Patent Nos. 2,809,194 and 2,937,169; Clotalidone, which may be prepared as disclosed in U.S. Patent No. 3,055,904; Cyclopentthiazide, which may be prepared as disclosed in Belgian Patent No. 587,225; Cyclothiazide, which may be prepared as disclosed in Whitehead et al., Journal of Organic Chemistry, 1961 , 26 , 2814; Epithiazide, which may be prepared as disclosed in U.S. Patent No. 3,009,911; Ethiazide, which may be prepared as disclosed in British Patent No. 861,367; Penquizone, which may be prepared as disclosed in U.S. Patent No. 3,870,720; Indamide, which may be prepared as disclosed in U.S. Patent No. 3,565,911; Hydrochlorothiazide, which may be prepared as disclosed in U.S. Patent No. 3,164,588; Hydroflumetiazide, which may be prepared as disclosed in U.S. Patent No. 3,254,076; Methiclothiazide, which may be prepared as disclosed in Close et al., Journal of the American Chemical Society, 1960 , 82 , 1132; Meticrane, which may be prepared as disclosed in French Patent Nos. M2790 and 1,365,504; Metolazone, which may be prepared as disclosed in U.S. Patent No. 3,360,518; Paraflutizide, which may be prepared as disclosed in Belgian Patent No. 620,829; Polythiazide, which may be prepared as disclosed in U.S. Patent No. 3,009,911; Quinetazone, which may be prepared as disclosed in U.S. Patent No. 2,976,289; Teclothiazide, which may be prepared as disclosed in Close et al., Journal of the American Chemical Society, 1960 , 82 , 1132; And triclomethiazide, which may be prepared as disclosed in deStevens et al., Experientia, 1960 , 16 , 113. The disclosures of all these US patents are incorporated herein by reference.

Diuretic sulfonamide derivatives within the scope of this invention include acetazolamide, which may be prepared as disclosed in U.S. Patent No. 2,980,679; Ambuside, which may be prepared as disclosed in U.S. Patent No. 3,188,329; Azosemide, which may be prepared as disclosed in U.S. Patent No. 3,665,002; Bumetanide, which may be prepared as disclosed in U.S. Patent No. 3,634,583; Butazolamide, which may be prepared as disclosed in British Patent No. 769,757; Chloraminophenamide, which may be prepared as disclosed in U.S. Patent Nos. 2,809,194, 2,965,655, and 2,965,656; Olivier, Rec. Trav. Clomamide, which may be prepared as disclosed in Chim., 1918 , 37 , 307; Clofamid, which may be prepared as disclosed in U.S. Patent No. 3,459,756; Clolexsolone, which may be prepared as disclosed in U.S. Patent No. 3,183,243; Disulfamide, which may be prepared as disclosed in British Patent No. 851,287; Ethoxolamide, which may be prepared as disclosed in British Patent No. 795,174; Furosemide, which may be prepared as disclosed in U.S. Patent No. 3,058,882; Mepruside, which may be prepared as disclosed in U.S. Patent No. 3,356,692; Metazolamide, which may be prepared as disclosed in U.S. Patent No. 2,783,241; Pyretanide, which may be prepared as disclosed in U.S. Patent No. 4,010,273; Torasemide, which may be prepared as disclosed in U.S. Patent No. 4,018,929; Tripamide, which may be prepared as disclosed in Japanese Patent No. 73-05,585; And xipamide, which may be prepared as disclosed in U.S. Patent No. 3,567,777. The disclosures of all these US patents are incorporated herein by reference.

The conversion of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) to mevalonate is an initial rate-limiting step in the cholesterol biosynthetic pathway. This step is catalyzed by the enzyme HMG-CoA reductase. Statins inhibit HMG-CoA reductase from catalyzing this conversion.

The atorvastatin calcium (i.e., atorvastatin hemicalcium) disclosed in U.S. Patent 5,273,995, which is incorporated herein by reference, is currently sold as Lipitor® and has the formula:

Atorvastatin calcium is a selective and competitive inhibitor of HMG-CoA. Thus, atorvastatin calcium is an effective lipid lowering compound. The free carboxylic acid form of atorvastatin is predominantly present as lactone of formula D and is disclosed in US Pat. No. 4,681,893, incorporated herein by reference:

Statins include simvastatin disclosed in US Pat. No. 4,444,784, which is incorporated herein by reference; Pravastatin, disclosed in US Pat. No. 4,346,227, which is incorporated herein by reference; Cerivastatin disclosed in US Pat. No. 5,502,199, which is incorporated herein by reference; Mevastatin, disclosed in US Pat. No. 3,983,140, which is incorporated herein by reference; Belostatin, disclosed in U.S. Patents 4,448,784 and 4,450,171, which are incorporated herein by reference; Fluvastatin disclosed in US Pat. No. 4,739,073, which is incorporated herein by reference; Compactin disclosed in US Pat. No. 4,804,770, which is incorporated herein by reference; Lovastatin, disclosed in US Pat. No. 4,231,938, which is incorporated herein by reference; Dalvastatin, disclosed in European Patent Application Publication No. 738510 A2, which is incorporated herein by reference; Fluindostatin, disclosed in European Patent Application Publication No. 363934 A1, which is incorporated herein by reference; Atorvastatin, disclosed in US Pat. No. 4,681,893, incorporated herein by reference; Atorvastatin calcium disclosed in US Pat. No. 5,273,995, which is incorporated herein by reference; And compounds such as dihydrocompactin, disclosed in US Pat. No. 4,450,171, which is incorporated herein by reference.

Given the positive correlation between lipid regulation and lipid fraction regulation in the blood with progression of various diseases / symptoms such as cardiovascular and cerebral vascular disease, the compounds / complexes of the present invention and salts of these compounds are pharmacological By action it is useful for the prevention, arrest and / or treatment of disease states / symptoms described above. This includes complications due to cardiovascular disorders and cardiovascular disease. In particular, assuming the correlation of HDL regulation and disease / symptoms described above, the CETP compounds and complexes thereof described herein may be prevented by their HDL-regulating pharmacological action (eg, HDL elevation) to prevent disease states / symptoms as described above. It is useful for preventing and / or treating.

The usefulness of the compounds / complexes of the invention and salts of such compounds as a medicament in the treatment of the diseases / symptoms described above in a mammal (eg, a human, male or female) is known in the art, including the assays described herein. It is demonstrated by the activity of the compounds of the invention in assays (e.g., in vivo assays and in vitro assays). In particular, the plasma lipid assay described below can be used to determine the level of HDL regulation for a given compound / complex and thus to determine the therapeutic impact on the disease / symptom described above. In addition, these assays provide a means by which the activity of the compounds / complexes of the present invention and salts of these compounds (or other drugs described herein) can be compared with each other and with other known compounds. The results of this comparison are useful for determining dosage levels in mammals, including humans, in the treatment of such diseases. For example, characterization of the effects of compounds / complexes of the invention and salts (or other drugs described herein) of the various lipid fractions is described in Methods in Enzymology, Vol. 129: Plasma Lipoproteins, Pt. B: Characterization, Cell Biology, and Metabolism. Albers, John J .; Segrest, Jere P .; Editors. USA. (1986), (Academic Press, Orlando, Fla.) And Methods in Enzymology, Vol. 128: Plasma Lipoproteins, Pt. A: Preparation, Structure, and Molecular Biology. Segrest, Jere P .; Albers, John J .; Editors. USA. (1986), 992 pp. Academic Press, Orlando, Fla.), As determined by methods known in the art. In particular, the plasma lipid assay described below can be used to determine the level of HDL regulation for a given compound / complex and thus the therapeutic impact on the aforementioned disease / symptoms.

The following is a typical assay.

CETP In Vitro Assay

Below is a brief description of assays for cholesteryl ester delivery of human plasma (in vitro) and animal plasma (ex vivo): exogenous tracer HDL to non-HDL lipoprotein fraction in human plasma, or genetic modification. CETP activity is assayed in the presence or absence of drug by measuring the delivery of ³ H-labeled cholesteryl oleate (CO) from ³ H-labeled LDL to the HDL fraction in mouse plasma. Labeled human lipoprotein substrates are prepared analogously to the method described in Morton's literature that delivers ³ H-CO from phospholipid liposomes to all lipoprotein fractions in plasma using exogenous CETP activity in plasma. Subsequently, ³ H-labeled LDL and HDL are isolated in density cuts of 1.019 to 1.063 and 1.10 to 1.21 g / ml, respectively, by continuous ultracentrifugation. For the activity assay, 3 H-labeled lipoproteins are added to the plasma at 10-25 mmol CO / ml and the samples are incubated at 37 ° for 2.5-3 hours. 20% (weight / volume) of polyethylene glycol 8000 (Dias) is then added in the same volume to precipitate the non-HDL lipoprotein. The sample is centrifuged at 750 gx20 minutes and the radioactivity contained in the HDL-containing supernatant is determined by liquid scintillation. Relative cholesteryl ester delivery by introducing various amounts of a compound of the invention into human plasma as a solution in dimethylsulfoxide before adding the radiolabeled cholesteryl oleate and comparing the relative amounts of radioisotopes delivered Determine inhibitory activity.

CETP In Vivo Assay

In vivo at various time points in vivo in the amount of drug required to inhibit cholesteryl ester transfer activity to the control group, or to increase HDL cholesterol to a given percentage in a CETP-containing animal species. The activity of the compounds of the invention can be determined. Transgenic mice expressing both human CETP and human apolipoprotein Al (Charles River, Boston, Mass.) Can be used to assess compounds in vivo. The compound to be tested is administered by oral gavage in an emulsion vehicle containing olive oil and sodium taurocholate. Blood is taken from the mice retroorbitally at various time points in the range of 4 to 24 hours after administration. Multiple times after dosing, in the range of 4 to 24 hours, the animal is sacrificed and blood is obtained by cardiac puncture to determine lipid parameters including total cholesterol, HDL and LDL cholesterol, and triglycerides. CETP activity is determined in a similar manner as described above, except that ³ H-cholesteryl oleate containing LDL is used as the donor source as opposed to HDL. The values obtained for lipid and delivery activity are compared with those obtained before administration and / or values obtained in mice receiving vehicle only.

Plasma lipid assay

Plasma mammalian lipid levels, such as HDL cholesterol levels, LDL cholesterol levels, VLDL cholesterol levels, or triglycerides of marmosets having similar CETP activity and plasma lipoprotein profiles similar to those of human mammals. By determining the amount of agent, the activity of the compounds can also be demonstrated (see Crook et al., Arteriosclerosis 10, 625, 1990). Mature silk monkeys are designated as treatment groups so that each group has a similar mean ± SD for total HDL and / or LDL plasma cholesterol concentrations. After group designation, the monkey is dosed with the compound for 1-8 days in admixture with the diet or by intubation. Control silk monkeys are given the dosing vehicle only. Blood is obtained from the main vein, and the plasma lipoproteins are separated into individual subclasses by density gradient centrifugation, as described above (see Crook et al., Arteriosclerosis 10, 625, 1990). By measuring, the plasma total LDL, VLDL and HDL cholesterol values can be determined at any point during the study.

Conventional clinical designs and methods to modify these clinical protocols to facilitate testing of compounds / complexes of the invention and salts of such compounds (or other drugs described herein) for the various diseases / symptoms described above are known in the art. It is known to those skilled in the art.

For example, in these clinical studies, the level of atherosclerotic plaques may vary with various imaging techniques such as intracardiac ultrasonography (ICE), quantitative coronary angiography, coronary intravascular ultrasound (IVUS), corrotide Corotid intimal medial thickness (CIMT) measurement, magnetic resonance imaging (MRI), magnetic resonance coronary angiography, flow-mediated dilatation, positron emission tomography, multi-section computed tomography , Electron beam computed tomography (EBT), mechanical multi-section spiral CT (MSCT), echocardiography, coronary angiography, radiography and radionucleotide imaging.

These imaging techniques and their interpretation are known and are described, for example, in "Measurement of Subclinical Atherosclerosis: beyond risk factor assessment", Current Opinion in Lipidology 13, 595-603 (2002); "A Comparison of Intravascular, Ultrasound With Coronary Angiography for Evaluation of Transplant Coronary Disease in Pediatric Heart Transplant Recipients", Journal of Heart & Lung Transplantation 22,44-49 (2003); And "Assessment of Calcium Scoring Performance in Cardiac Computed Tomography", European Radiology 13,484-97 (2003).

In general, the compounds of the present invention may be administered in the form of a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent together with one or more compounds of the present invention. Thus, the compounds of the present invention may be administered separately or together in any conventional oral, parenteral or transdermal dosage form.

For oral administration, the pharmaceutical compositions may take the form of solutions, suspensions, tablets, pills, capsules, powders and the like. Tablets containing various excipients, such as sodium citrate, calcium carbonate and calcium phosphate, may be used in various disintegrants such as starch, preferably potato or tapioca starch and certain complex silicates, and binders such as polyvinylpyrrolidone, sucrose, Used with gelatin and acacia. In addition, lubricants such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tableting purposes. Solid compositions of a similar form are also used as fillers in soft and hard-filled gelatin capsules, with preferred materials in this connection as well as high molecular weight polyethylene glycols as well as lactose or lactose. If aqueous suspensions and / or elixirs are preferred for oral administration, the compounds of the present invention may be used in various sweetening, flavoring, coloring, emulsifying and / or suspending agents as well as diluents such as water, ethanol, propylene glycol, glycerin and their It can be combined with various mixtures.

In addition, the complexes of the present invention may be administered in controlled release formulations, such as sustained or immediate release formulations. Such controlled release formulations of the composites of the present invention can be prepared using methods well known to those skilled in the art. The method of administration will be determined by the attending physician or other skilled in the art after evaluating the condition and requirements of the patient. A generally preferred formulation of amlodipine is Novasque®.

Many of the CETP inhibitors of the present invention have low solubility and dosing forms that increase solubility facilitate the administration of such compounds. One such dosage form is a dosage form comprising (1) a solid amorphous dispersion comprising a cholesteryl ester transfer protein (CETP) inhibitor and an acidic concentration-enhancing polymer, and (2) an acid-sensitive HMG-CoA reductase inhibitor to be. This dosage form is described in more detail in US Provisional Patent Application No. 60 / 435,345, filed December 20, 2002 entitled “Dosage Form Containing a CETP Inhibitor and a HMG-CoA Reductase Inhibitor,” the specification of which is incorporated herein by reference. Is incorporated herein by reference.

In general, the compounds of the invention are administered in a convenient formulation alone or in combination, or in combination with other compounds. The following formulation examples are merely illustrative and are not intended to limit the scope of the invention.

A complex tablet of amlodipine besylate, tocetrapib and atorvastatin hemicalcium was prepared following the procedure immediately following the table in an amount of about 1 kg. The dosages and compositions of the tablets made are detailed in Table 1 below:

Separate granules or mixtures of each active ingredient were first prepared and these three powder mixtures were mixed in different proportions to provide the desired dosage complex.

Atorvastatin hemicalcium granules were prepared by preparing a solution of hydroxypropyl cellulose and polysorbate 80 in water. The remaining ingredients (except magnesium stearate) were then charged into the fluidized bed granulator and wet granulated by spraying the binder solution onto the powder in the granulator, together with the binder solution in a warm air stream (30-60 °). After spraying all the binder solution, the granules were dried in the fluidized bed and milled to remove any large (> 1 mm) aggregates. The granules were lubricated by mixing with magnesium stearate.

Dissolution of tocetrapib and polymer hypromellose (hydroxypropyl methylcellulose) acetate succinate in acetone and the resulting solution by spray drying in a conventional spray drying apparatus (see US Patent Application No. 60 / 435,345). A dispersion of tocetrapib in promellose (hydroxypropyl methylcellulose) acetate succinate was prepared. Tocetrapib granules were prepared by mixing the resulting spray dried dispersion, microcrystalline cellulose, crospovidone and magnesium stearate together and dry granulating the powder mixture by roller compaction. Standard pharmaceutical roller compaction apparatus and operating conditions were used. The resulting compacted ribbons were ground and made into granules for further processing. Calcium phosphate and magnesium stearate were added and mixed with the granules to prepare the final lubricated tocetrapib mixture.

Amlodipine besylate was briefly mixed with excipients to produce a lubricated amlodipine powder mixture.

The three active granules / mixtures were mixed together using a low-shear biaxial mixer and compressed using a single punch eccentric tablet compressor. .

The compounds of the present invention can be administered via any method that delivers the compounds systemically and / or locally. Such methods include oral routes, parenteral routes, duodenum routes, and the like. In general, parenteral administration (eg, intravenous, intramuscular, subcutaneous or bone marrow) may be used if the compound of the invention is administered orally, but for example when oral administration is inappropriate for a target or the patient is not able to take the drug. have.

These methods and combinations are useful for treating mammals, including humans, depending on the symptoms / conditions. In addition, this includes men, women, the elderly (> 60), infants (<2), children, diabetics (type I and / or 11), patients without a history of coronary events (ie, primary prevention), once Patients with a history of abnormal coronary events (i.e. secondary prevention), patients with cerebrovascular events (e.g. seizure or transient ischemic events), patients with total cholesterol greater than 250, patients with total cholesterol greater than 200 , Patients with total cholesterol below 200, patients with HDL <30/40/50/60, patients with high HDL, various ethnic subgroups (African, Turkish, Hispanic, Asian), women ± HRT (menopausal) Before and after), smokers, patients with low HDL due to diet, patients undergoing secondary reductions in HDL due to other drug therapies (such as androgen agonists), patients with peripheral vascular disease, normal HDL-C such as Patients with 40 to 60 mg / dec, no history of coronary heart disease Advantageously and / or patients of various subgroups, including patients (with or without abnormal cholesterol levels), patients with metabolic syndrome, patients with apo-E4 alleles, patients with BMI greater than 30, and obese patients Or for selective treatment.

In general, the amount of the compound / complex of the present invention is used in an amount sufficient to achieve the desired therapeutic effect (eg, HDL elevation). Of course, this amount depends on the patient being treated, the severity of the disease, the mode of administration and the judgment of the prescribing physician.

In general, the effective dosages of the CETP inhibitors, prodrugs thereof, and salts of these compounds and prodrugs of the invention are from about 0.01 to about 100 mg / kg / day, preferably from about 0.1 to about 5 mg / kg / day. .

[2R, 4S] -4-[(3,5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro- A particularly preferred dose of 2H-quinoline-1-carboxylic acid ethyl ester (tocetrapib) is about 15 to about 240 mg per day, preferably about 30 to about 120 mg per day. This dosage may be administered in a single dose or in multiple doses (eg, twice daily).

Dosages of combination medications (eg antihypertensives, statins) used with CETP inhibitors are used in an amount effective for the condition being treated.

For example, typically an effective dosage of an HMG-CoA reductase inhibitor ranges from about 0.01 to about 100 mg / kg / day.

For example, typically an effective dosage of atorvastatin calcium (also known as atorvastatin hemicalcium or Lipitor®) or other salts of atorvastatin is about 10 to about 80 mg / day (eg 10 mg, 20 mg, 40 mg). Or 80 mg).

For example, typically an effective dosage of an antihypertensive agent ranges from about 0.01 to about 100 mg / kg / day.

For example, typically an effective dosage of amlodipine or a pharmaceutically acceptable salt thereof (eg, amlodipine besylate or amlodipine mesylate) is in the range of about 5 to about 10 mg / day.

Amlodipine and its pharmaceutically acceptable salts (eg amlodipine besylate) / atorvastatin and its pharmaceutically acceptable salts (eg atorvastatin hemicalcium) / and [2R, 4S] -4-[(3 , 5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester Exemplary dosages of the triple combination of cetrapib) range from 5 to 10 mg / day 10 to 80 mg / day 30 to 120 mg.

For parenteral administration, solutions in sesame oil or peanut oil, or solutions in aqueous propylene glycol, and also sterile aqueous solutions of the corresponding water soluble salts can be used. This aqueous solution is suitably buffered as necessary and the liquid diluent is first made isotonic with sufficient saline or glucose. Such aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal injection purposes. In this regard, the sterile aqueous medium used can be readily obtained by standard techniques well known to those skilled in the art.

Methods of preparing various pharmaceutical compositions having a predetermined amount of active ingredient are known to those skilled in the art or will be apparent in light of the present disclosure. See, eg, Remington's Pharmaceutical Sciences , Mack Publishing Company, Easter, Pa., 15th Edition (1975).

The pharmaceutical composition according to the present invention may comprise 0.1 to 95%, preferably 1 to 70%, of the compound of the present invention. In any event, the compositions or formulations to be administered will comprise the compounds according to the invention in an effective amount for treating a condition or condition of a subject to be treated.

Since the present invention relates to the treatment of the diseases / symptoms described herein using a combination of active ingredients that can be administered separately, the present invention also relates to the combination of kit forms of separate pharmaceutical compositions. The kit may comprise two separate pharmaceutical compositions, namely amlodipine or a pharmaceutically acceptable acid addition salt thereof, and statins or a pharmaceutically acceptable salt thereof. The kit includes container means containing separate compositions, such as separate bottles or separate foil packets, but separate compositions may also be contained in a single, non-separated container. Typically, the kit includes instructions for the administration of the separate components. The kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (eg oral and parenteral), administered at different intervals, or when the titration of the individual components in the combination is required by the prescribing physician.

While the invention is not limited to the specific embodiments described herein, it should be noted that various changes and modifications may be made therein without departing from the spirit and scope of the novel concepts herein as defined in the following claims. .

Claims (14)

Arteriosclerosis, peripheral vascular disease, dyslipidemia, hyperbetalipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial-hypercholesterolemia, cardiovascular disorders, angina pectoris, ischemia, myocardial ischemia, Cholesteryl ester delivery protein to mammals, including humans, in need of treatment for disorders or symptoms selected from the group consisting of seizures, myocardial infarction, reperfusion injury, post-vascular restenosis, hypertension, vascular complications of diabetes, obesity and endotoxins (CETP) inhibitors or pharmaceutically acceptable salts thereof, and antihypertensive agents or pharmaceutically acceptable salts thereof, optionally in combination with HMG CoA reductase inhibitors or pharmaceutically acceptable salts thereof, these active drugs A method for treating said disorder or condition in a mammal comprising administering in an amount effective for the treatment of. Arteriosclerosis, peripheral vascular disease, dyslipidemia, hyperbetalipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial-hypercholesterolemia, cardiovascular disorders, angina pectoris, ischemia, myocardial ischemia, A compound of formula (I) to a mammal, including a human, in need of treatment for a disorder or condition selected from the group consisting of seizures, myocardial infarction, reperfusion injury, post vascular restenosis, hypertension, vascular complications of diabetes, obesity and endotoxins, Prodrugs thereof, or pharmaceutically acceptable salts of these compounds or prodrugs, and antihypertensive agents or pharmaceutically acceptable salts thereof, optionally in combination with HMG CoA reductase inhibitors or pharmaceutically acceptable salts thereof Administering said disorder or disorder in a mammal comprising administering in an amount effective for the treatment of said disorder or condition How to treat the award: Formula I R ¹ is Y, WX or WY; W is carbonyl, thiocarbonyl, sulfinyl or sulfonyl; X is -OY, -SY, -N (H) -Y or -N- (Y) ₂ ; Y is each independently Z, or a 1 to 10 membered linear or branched carbon chain that is fully saturated, partially unsaturated, or fully unsaturated, wherein carbon other than the linking carbon is independently selected from oxygen, sulfur, and nitrogen; May be substituted with two heteroatoms, the carbon may be independently mono-, di- or tri-substituted with halo, mono-substituted with hydroxy, mono-substituted with oxo, and sulfur is Can be mono- or di-substituted with oxo, the nitrogen can be mono- or di-substituted with oxo, and the carbon chain can be mono-substituted with Z; Z is a partially saturated, fully saturated or fully unsaturated 3-8 membered ring which may have 1 to 4 heteroatoms independently selected from oxygen, sulfur and nitrogen, or 1 independently selected from nitrogen, sulfur and oxygen A bicyclic ring formed by condensation of two independently selected rings of 3 to 6 members which are partially saturated, fully saturated or fully unsaturated, which may have from 4 to 4 heteroatoms; The Z substituents are halo, (C ₂ -C ₆ ) alkenyl, (C ₁ -C ₆ ) alkyl, hydroxy, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) alkylthio, amino, nit , Cyano, oxo, carboxy, (C ₁ -C ₆ ) alkyloxycarbonyl, mono-N- (C ₁ -C ₆ ) alkylamino or di-N, N- (C ₁ -C ₆ ) alkylamino May be independently mono-, di-, or tri-substituted, wherein the (C ₁ -C ₆ ) alkyl substituent is halo, hydroxy, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) Alkylthio, amino, nitro, cyano, oxo, carboxy, (C ₁ -C ₆ ) alkyloxycarbonyl, mono-N- (C ₁ -C ₆ ) alkylamino or di-N, N- (C May be independently mono-, di- or tri-substituted with _1- C ₆ ) alkylamino and also substituted with 1 to 9 fluorine; R ² is a partially saturated, fully saturated, or fully unsaturated 1-6 membered linear or branched carbon chain, wherein carbon other than the linking carbon is selected from oxygen, sulfur and nitrogen as one or two heteroatoms independently selected from Can be substituted, the carbon atom may be independently mono-, di- or tri-substituted with halo, mono-substituted with oxo, mono-substituted with hydroxy, and sulfur is mono-substituted with oxo Or can be di-substituted and said nitrogen can be mono- or di-substituted with oxo; Or R ² is a partially saturated, fully saturated or fully unsaturated 3-7 membered ring which may have one or two heteroatoms independently selected from oxygen, sulfur and nitrogen, wherein the R ² ring is (C May be bonded via ₁ -C ₄ ) alkyl; The R ² ring is halo, (C ₂ -C ₆ ) alkenyl, (C ₁ -C ₆ ) alkyl, hydroxy, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) alkylthio, amino, Nitro, cyano, oxo, carboxy, (C ₁ -C ₆ ) alkyloxycarbonyl, mono-N- (C ₁ -C ₆ ) alkylamino or di-N, N- (C ₁ -C ₆ ) alkyl Independently mono-, di- or tri-substituted with amino, wherein the (C ₁ -C ₆ ) alkyl substituent is halo, hydroxy, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) may be independently mono-, di- or tri-substituted with alkylthio, oxo or (C ₁ -C ₆ ) alkyloxycarbonyl; R ³ is hydrogen or Q; Q is a fully saturated, partially unsaturated or fully unsaturated 1-6 membered linear or branched carbon chain, wherein carbon other than the linking carbon may be substituted with one heteroatom selected from oxygen, sulfur and nitrogen, and Carbon may be independently mono-, di- or tri-substituted with halo, mono-substituted with hydroxy, mono-substituted with oxo, and the sulfur may be mono- or di-substituted with oxo. Wherein the nitrogen may be mono- or di-substituted with oxo and the carbon chain may be mono-substituted with V; V is a partially saturated, fully saturated or fully unsaturated 3-8 membered ring which may have 1 to 4 heteroatoms independently selected from oxygen, sulfur and nitrogen, or 1 independently selected from nitrogen, sulfur and oxygen A bicyclic ring formed by condensation of two independently selected rings of 3 to 6 members which are partially saturated, fully saturated or fully unsaturated, which may have from 4 heteroatoms; The V substituent is halo, (C ₁ -C ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl, hydroxy, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) alkylthio, amino, nit Rho, cyano, oxo, carboxamoyl, mono-N- (C ₁ -C ₆ ) alkylcarboxamoyl, di-N, N- (C ₁ -C ₆ ) alkylcarboxamoyl, carboxy, (C ₁ -C ₆₎ alkyloxycarbonyl, mono -N- (C ₁ -C ₆₎ alkylamino or di _{-N, N- (C 1 -C 6} ) work independently alkyl amino-, a -, phenoxy or May be tetra-substituted, wherein the (C ₁ -C ₆ ) alkyl or (C ₂ -C ₆ ) alkenyl substituent is hydroxy, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) Alkylthio, amino, nitro, cyano, oxo, carboxy, (C ₁ -C ₆ ) alkyloxycarbonyl, mono-N- (C ₁ -C ₆ ) alkylamino or di-N, N- (C ₁ -C ₆ ) alkylamino can be independently mono-, di-, tri- or tetra-substituted, and can also be substituted with 1 to 9 fluorine; R ⁴ is cyano, formyl, W ¹ Q ¹ , W ¹ V ¹ , (C ₁ -C ₄ ) alkylene V ¹ or V ² ; W ¹ is carbonyl, thiocarbonyl, SO or SO ₂ ; Q ¹ is a fully saturated, partially unsaturated or fully unsaturated 1-6 membered linear or branched carbon chain, wherein carbon may be substituted with one heteroatom selected from oxygen, sulfur and nitrogen, the carbon being halo Can be independently mono-, di- or tri-substituted, mono-substituted with hydroxy, mono-substituted with oxo, the sulfur can be mono- or di-substituted with oxo, and Nitrogen may be mono- or di-substituted with oxo and the carbon chain may be mono-substituted with V ¹ ; V ¹ is a partially saturated, fully saturated or fully unsaturated 3-6 membered ring which may have 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, or 1 independently selected from nitrogen, sulfur and oxygen A bicyclic ring formed by condensation of two independently selected rings of 3 to 6 members which are partially saturated, fully saturated or fully unsaturated, which may have from 4 heteroatoms; The V ¹ substituent is halo, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, hydroxy, oxo, amino, nitro, cyano, (C ₁ -C ₆ ) alkyloxycarbonyl, mono -N- (C ₁ -C ₆₎ alkylamino or di _{-N, N- (C 1 -C 6} ) work independently alkyl amino-, a -, three-or four-can be optionally substituted, where , The (C ₁ -C ₆ ) alkyl substituent may be mono-substituted with oxo and may also be substituted with 1 to 9 fluorine; V ² is a partially saturated, fully saturated or fully unsaturated 5 to 7 membered ring containing 1 to 4 heteroatoms independently selected from oxygen, sulfur and nitrogen, The V ² substituents may be independently mono-, di- or tri-substituted with halo, (C ₁ -C ₂ ) alkyl, (C ₁ -C ₂ ) alkoxy, hydroxy or oxo, wherein the ( C ₁ -C ₂ ) alkyl may have 1 to 5 fluorine; R ³ must contain V or R ⁴ must contain V ¹ ; R ⁵ , R ⁶ , R ⁷ and R ⁸ are each independently hydrogen, a bond, nitro or halo, wherein the bond is substituted with T, or partially saturated or fully saturated or fully unsaturated (C _1- C ₁₂ ) linear or branched carbon chain, wherein carbon may be substituted with one or two heteroatoms independently selected from oxygen, sulfur and nitrogen, wherein the carbon atoms are independently one-, two- or three halo -Substituted, mono-substituted with hydroxy, mono-substituted with oxo, the sulfur can be mono- or di-substituted with oxo, and the nitrogen mono- or di-substituted with oxo The carbon chain may be mono-substituted with T; T is a partially saturated, fully saturated or fully unsaturated 3 to 12 membered ring which may have 1 to 4 heteroatoms independently selected from oxygen, sulfur and nitrogen, or 1 independently selected from nitrogen, sulfur and oxygen A bicyclic ring formed by condensation of two independently selected rings of 3 to 6 members which are partially saturated, fully saturated or fully unsaturated, which may have from 4 heteroatoms; The T substituent is halo, (C ₁ -C ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl, hydroxy, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) alkylthio, amino, nit , Cyano, oxo, carboxy, (C ₁ -C ₆ ) alkyloxycarbonyl, mono-N- (C ₁ -C ₆ ) alkylamino or di-N, N- (C ₁ -C ₆ ) alkylamino Can be independently mono-, di- or tri-substituted, wherein the (C ₁ -C ₆ ) alkyl substituent is hydroxy, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) alkyl Thio, amino, nitro, cyano, oxo, carboxy, (C ₁ -C ₆ ) alkyloxycarbonyl, mono-N- (C ₁ -C ₆ ) alkylamino or di-N, N- (C _1- C ₆ ) alkylamino may be independently mono-, di- or tri-substituted, and may also have 1 to 9 fluorine; R ⁵ and R ⁶ , or R ⁶ and R ⁷ , and / or R ⁷ and R ⁸ together may be partially saturated or fully unsaturated, which may have 1 to 3 heteroatoms independently selected from nitrogen, sulfur and oxygen. To form one or more to eight membered rings; R ⁵ and R ⁶ , or The ring formed by R ⁶ and R ⁷ , and / or R ⁷ and R ⁸ may be halo, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₄ ) alkylsulfonyl, (C ₂ -C ₆ ) alkenyl , Hydroxy, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) alkylthio, amino, nitro, cyano, oxo, carboxy, (C ₁ -C ₆ ) alkyloxycarbonyl, mono-N - (C ₁ -C ₆₎ alkylamino or di _{-N, N- (C 1 -C 6} ) work independently alkylamino -, phenyl or phenoxy may be optionally substituted, at this time, (C ₁ -C ₆ ) Alkyl substituents are hydroxy, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) alkylthio, amino, nitro, cyano, oxo, carboxy, (C ₁ -C ₆ ) alkyloxycarbonyl , Mono-, di-, or tri-substituted independently with mono-N- (C ₁ -C ₆ ) alkylamino or di-N, N- (C ₁ -C ₆ ) alkylamino, and also from 1 to 9 Fluorine. The method of claim 2, Wherein the compound of formula (I) is a compound of formula (I ′), a prodrug thereof, or a pharmaceutically acceptable salt of these compounds or prodrugs: Formula I ' Where R ¹ is Y, WX or WY; W is carbonyl; X is -O-Y; Each Y is independently Z or a fully saturated, partially unsaturated or fully unsaturated 1 to 10 membered linear or branched carbon chain, wherein carbon other than the linking carbon is independently selected from oxygen, sulfur and nitrogen. Or may be substituted with two heteroatoms, and the carbon may be mono-, di- or tri-substituted independently with halo, mono-substituted with hydroxy, mono-substituted with oxo, and Sulfur may be mono- or di-substituted with oxo and the nitrogen may be mono- or di-substituted with oxo; R ² is a partially saturated, fully saturated, or fully unsaturated 1-6 membered linear or branched carbon chain, wherein carbon other than the linking carbon may be substituted with one heteroatom independently selected from oxygen, sulfur and nitrogen. Wherein the carbon atom may be independently mono-, di- or tri-substituted with halo, mono-substituted with oxo, mono-substituted with hydroxy, and sulfur is mono- or di-substituted with oxo -Or a partially saturated, fully saturated or fully unsaturated 3 to 6 membered ring which may have 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen; R ³ is a fully saturated one or two membered carbon chain, where carbon may be mono-substituted with oxo, and the carbon chain is mono-substituted with V; V is a partially saturated, fully saturated or fully unsaturated 5 or 6 membered ring which may have from 1 to 3 heteroatoms independently selected from oxygen, sulfur and nitrogen; The V substituent may be independently mono-, di- or tri-substituted with halo or (C ₁ -C ₂ ) alkyl, wherein the (C ₁ -C ₂ ) alkyl substituent is substituted with 1 to 5 fluorine Can; R ⁴ is acetyl, formyl or (C ₁ -C ₆ ) alkoxy; R ⁵ and R ⁸ are hydrogen; R ⁶ and R ⁷ are each independently hydrogen, halo, (C ₁ -C ₂ ) alkoxy or saturated (C ₁ -C ₂ ) alkyl chains, wherein the (C ₁ -C ₂ ) alkyl chains are independent of fluorine And may be mono-, di- or tri-substituted. The method of claim 2, Compound [2S, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-isopropyl-6-trifluoromethyl-3,4-dihydro- 2H-quinoline-1-carboxylic acid isopropyl ester; [2S, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -6-chloro-2-cyclopropyl-3,4-dihydro-2H-quinoline -1-carboxylic acid isopropyl ester; [2S, 4S] 2-Cyclopropyl-4-[(3,5-dichloro-benzyl) -methoxycarbonyl-amino] -6-trifluoromethyl-3,4-dihydro-2H-quinoline- 1-carboxylic acid isopropyl ester; [2S, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro- 2H-quinoline-1-carboxylic acid t-butyl ester; [2S, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro- 2H-quinoline-1-carboxylic acid isopropyl ester; [2S, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-cyclobutyl-6-trifluoromethyl-3,4-dihydro- 2H-quinoline-1-carboxylic acid isopropyl ester; [2R, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H -Quinoline-1-carboxylic acid isopropyl ester; [2S, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-methoxymethyl-6-trifluoromethyl-3,4-dihydro -2H-quinoline-1-carboxylic acid isopropyl ester; [2R, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H -Quinoline-1-carboxylic acid 2-hydroxy-ethyl ester; [2S, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro- 2H-quinoline-1-carboxylic acid ethyl ester; [2R, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H -Quinoline-1-carboxylic acid ethyl ester; [2S, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro- 2H-quinoline-1-carboxylic acid propyl ester; [2R, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H -Quinoline-1-carboxylic acid propyl ester, [2S, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -formyl-amino] -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline -1-carboxylic acid isopropyl ester; [2S, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -formyl-amino] -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline -1-carboxylic acid propyl ester; [2S, 4S] 4- [acetyl- (3,5-bis-trifluoromethyl-benzyl) -amino] -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline -1-carboxylic acid t-butyl ester; [2R, 4S] 4- [acetyl- (3,5-bis-trifluoromethyl-benzyl) -amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline- 1-carboxylic acid isopropyl ester; [2R, 4S] 4- [acetyl- (3,5-bis-trifluoromethyl-benzyl) -amino] -2-methyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline- 1-carboxylic acid ethyl ester; [2S, 4S] 4- [l- (3,5-Bis-trifluoromethyl-benzyl) -ureido] -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H- Quinoline-1-carboxylic acid isopropyl ester; [2R, 4S] 4- [acetyl- (3,5-bis-trifluoromethyl-benzyl) -amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline- 1-carboxylic acid ethyl ester; [2S, 4S] 4- [acetyl- (3,5-bis-trifluoromethyl-benzyl) -amino] -2-methoxymethyl-6-trifluoromethyl-3,4-dihydro-2H- Quinoline-1-carboxylic acid isopropyl ester; [2S, 4S] 4- [acetyl- (3,5-bis-trifluoromethyl-benzyl) -amino] -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline -1-carboxylic acid propyl ester; [2S, 4S] 4- [acetyl- (3,5-bis-trifluoromethyl-benzyl) -amino] -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline -1-carboxylic acid ethyl ester; [2R, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -formyl-amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline- 1-carboxylic acid isopropyl ester; [2R, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -formyl-amino] -2-methyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline- 1-carboxylic acid ethyl ester; [2S, 4S] 4- [acetyl- (3,5-bis-trifluoromethyl-benzyl) -amino] -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline -1-carboxylic acid isopropyl ester; [2R, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -formyl-amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline- 1-carboxylic acid ethyl ester; [2S, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -formyl-amino] -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline -1-carboxylic acid ethyl ester; [2R, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl) -formyl-amino] -2-methyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline- 1-carboxylic acid isopropyl ester; [2R, 4S] 4- [acetyl- (3,5-bis-trifluoromethyl-benzyl) -amino] -2-methyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline- 1-carboxylic acid isopropyl ester; And pharmaceutically acceptable salts of these compounds. The method of claim 1, HMG CoA reductase inhibitors include lovastatin, simvastatin, pravastatin, fludostatin, belostatin, dihydrocompactin, compactin, fluvastatin, atorvastatin, glenvastatin, dalvastatin, carvastatin, krillvastatin, burva The method is selected from the group consisting of statins, cerivastatin, rosuvastatin, pitavastatin, mevastatin and rivastatin. The method of claim 1, The antihypertensive agent is selected from the group consisting of calcium channel blockers, ACE inhibitors, A-ll antagonists, diuretics, beta-adrenergic receptor blockers and alpha-adrenergic receptor blockers. The method of claim 6, A method comprising the hemicalcium salt of atorvastatin. The method of claim 7, wherein Antihypertensive agents include verapamil, diltiazem, mibepradil, isradiffine, lassipidine, nicadipine, nifedipine, nimodipine, nisoldipine, nitrendypine, avanidine, amlodipine, amlodipine besylate, manidipine, silidine And a calcium channel blocker selected from the group consisting of linidipine, lucanidipine, felodipine and pharmaceutically acceptable salts thereof. The method of claim 8, The calcium channel blocker is selected from the group consisting of felodipine, nifedipine, amlodipine and pharmaceutically acceptable salts thereof. The method of claim 7, wherein And wherein the antihypertensive agent is an A-ll antagonist selected from the group consisting of losartan, avesatan, telmisartan, balsa charcoal and pharmaceutically acceptable salts thereof. The method of claim 7, wherein And wherein the antihypertensive agent is a diuretic selected from the group consisting of amylolide, bendroflumetiazide, and pharmaceutically acceptable salts thereof. The method of claim 7, wherein The antihypertensive agent is beta-adrenergic receptor blocker, which is carvedilol or a pharmaceutically acceptable salt thereof. The method of claim 7, wherein Antihypertensive agents include benazepril, captopril, enalapril, posinopril, ricinopril, perindopril, quinapril, trandolapril, ramipril, estril, jofenopril, silapril, temocapril, spira A method that is an ACE inhibitor selected from the group consisting of prills, moexiprils, delapril, imidapril, ramipril, terrazosin, urapidine, indoramine, amolsuladol, alfuzosin and pharmaceutically acceptable salts thereof . The method of claim 7, wherein And wherein the antihypertensive agent is an alpha-adrenergic receptor blocker selected from the group consisting of doxazosin, prazosin, trimazosin and their pharmaceutically acceptable salts.