MXPA01002759A

MXPA01002759A - 4-carboxyamino-2-substituted-1,2,3,4-tetrahydroquinolines as cetp inhibitors

Info

Publication number: MXPA01002759A
Application number: MXPA/A/2001/002759A
Authority: MX
Inventors: Michael Paul Deninno; George Tetteh Magnusaryitey; Roger Benjamin Ruggeri; Ronald Thure Wester
Original assignee: Pfizer Products Inc
Priority date: 1998-09-17
Filing date: 2001-03-15
Publication date: 2001-11-21

Abstract

Cholesteryl ester transfer protein inhibitors of the Formula (I), a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug, pharmaceutical compositions containing such inhibitors and the use of such inhibitors to elevate certain plasma lipid levels, including high density lipoprotein-cholesterol and to lower certain other plasma lipid levels, such as LDL-cholesterol and triglycerides and accordingly to treat diseases which are exacerbated by low levels of HDL cholesterol and/or high levels of LDL-cholesterol and triglycerides, such as atherosclerosis and cardiovascular diseases in some mammals, including humans.

Description

4-CARBOXYAMINO-1.2.3.4-TETRAHIPROQUFNQLINAS 2-SUBSTITUTED AS ESTER TRANSFER PRQTEIN INHIBITORS CHOLESTERILIC BACKGROUND OF THE INVENTION This invention relates to inhibitors of cholesteryl ester transfer protein (CETP), to pharmaceutical compositions containing such inhibitors and to the use of such inhibitors to elevate certain levels of plasma lipids, including high density lipoprotein cholesterol ( HDL), and to reduce other levels of plasma lipids, such as cholesterol associated with low density lipoproteins and triglycerides and, therefore, to treat diseases that are affected by low levels of HDL cholesterol and / or high cholesterol levels LDL and triglycerides, such as atherosclerosis and cardiovascular diseases in certain mammals (ie, those that have CETP in their plasma), including humans. Atherosclerosis, and coronary artery disease (CAD) associated with it, is the leading cause of mortality in the industrialized world. Despite attempts to modify secondary risk factors (smoking, obesity, and lack of exercise) and the treatment of dyslipidemia with diet modification and drug therapy, coronary heart disease (CHD) continues being the most cardiovascular cause they produce 44% of all deaths, 53% of which are associated with coronary atherosclerotic heart disease. It has been shown that the risk of developing this condition is closely related to certain levels of plasma lipids. Although elevated levels of LDL-C may be the most recognized form of dyslipidemia, it is by no means the only significant lipid that contributes to CHD. A low level of HDL-C is also a known risk factor for CHD (Gordon, D.J., et al., "High-density Lipoprotein Cholesterol and Cardiovascular Disease", Circulation, (1989), 79: 8-15). 10 High levels of LDL cholesterol and triglycerides are positively correlated, while high levels of HDL cholesterol are negatively correlated with the risk of developing cardiovascular diseases. Thus, dyslipidemia is not a unit risk profile for CHD, but may be composed of one or more lipid aberrations. Among the many factors that control the plasma levels of these disease-dependent principles, the activity of the cholesteryl ester transfer protein (CETP) affects all three. The role of this plasma glycoprotein of 70,000 daltons found in several species animals, including humans, is transferring cholesteryl ester and triglycerides between lipoprotein particles, including high density lipoproteins (HDL), low density lipoproteins (LDL), very low density lipoproteins (VLDL) and the chylomicrons. The result Net of CETP activity is a reduction of HDL cholesterol and an increase in LDL cholesterol. It is believed that this effect on the lipoprotein profile is pro-atherogenic, especially in subjects whose lipid profile constitutes an increased risk of CHD. There is no totally satisfactory therapy to elevate the HDL Niacin can significantly increase HDL, but has severe tolerance problems that reduce acceptance. Fibrates and inhibitors of HMG CoA reductase only modestly raise HDL-C (~ 10-12%). As a result, there is a significant unmet medical need for an agent that is well tolerated and that can significantly raise plasma HDL levels, thereby reversing or slowing the progression of atherosclerosis. Thus, although there is a diversity of anti-atherosclerotic therapies, the need still exists and alternative therapy is still sought in this field of the art. EP0818448 (970624) describes the preparation of certain tetrahydroquinolines 5, 6,7,8 substituted and analogues thereof, as inhibitof the cholesteryl ester transfer protein. U.S. Patent No. 5,231,102 discloses a class of 1,4-substituted 2,4,4-tetrahydroquinolines possessing an acidic group (or a group convertible therein in vivo) in the 2-position, which they are specific antagonists of the N-methyl-D-aspartate (NMDA) receptand, therefore, are useful in the treatment and / or prevention of neurodegenerative disorders. U.S. Patent No. 5,288,725 discloses pyrroloquinoline bradykin antagonists.

BRIEF DESCRIPTION OF THE INVENTION The invention relates to compounds of formula Formula I 15 prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs; wherein R1 is hydrogen, Y, W-X or W-Y; where W is carbonyl, thiocarbonyl, sulfinyl or sulfonyl X is -O-Y, -S-Y, -N (H) -Y or -N- (Y) 2; Where Y, for each case, is independently Z or a linear branched carbon chain, from one to ten members, fully saturated, partially unsaturated or totally unsaturated, where the carbons other than the connecting carbon can be replaced optionally with one or two heteroatoms independently selected from oxygen, sulfur and nitrogen, and said carbon is optionally mono-, di- or tri- substituted independently with halo, said carbon is optionally mono-substituted with hydroxy, said carbon being optionally mono- substituted with oxo, said sulfur is optionally mono or di-substituted with oxo, said nitrogen is optionally mono or disubstituted with oxo, and said carbon chain is optionally mono-substituted with Z; where Z is a ring of three to eight members partially Saturated, fully saturated or totally unsaturated having optionally one to four heteroatoms independently selected from oxygen, sulfur or nitrogen, or a bicyclic ring that costs two condensed rings of three to six members, partially saturated, fully saturated or totally unsaturated, take two Independently, optionally having from one to four heteroatoms independently selected from nitrogen, sulfur and oxygen; wherein said substituent Z is optionally mono-, di- or tri- substituted independently with halo, (C2-C6) alkenyl, (C1-C6) alkyl, hydroxy, alkoxy (CiC-ß), alkylthio (C-? - C4) , amino, nitro, cyano, oxo, carboxy, Alkoxycarbonyl (Ci-Cß), mono-N- or di-N, N-alkylamino (Ci-Ce), wherein said alkyl substituent (Ci-Cß) is optionally mono-, di- or tri-substituted independently with halo, hydroxy, alkoxy (dC-6), alkylthio (CrC), amino, nitro, cyano, oxo, carboxy, alkoxycarbonyl (Ci-Cß), mono-N- or di-N, N- alkylamino (d-Cß), and said alkyl substituent (C-i-Cß) is also optionally substituted with one to nine fluorine atoms; R2 is a linear or branched carbon chain, from one to six members, partially saturated, fully saturated or totally unsaturated, in which the carbons other than the connecting carbon can optionally be replaced with one or two heteroatoms independently selected from oxygen, sulfur and nitrogen , wherein said carbon atoms are optionally mono-, or tri-substituted independently with halo, said carbon is optionally mono-substituted with oxo, said carbon is optionally mono-substituted with hydroxy, said sulfur is optionally mono- or di-substituted with oxo, said nitrogen is optionally mono- or di-substituted with oxo; or said R2 is a three to seven member ring partially saturated, fully saturated or totally unsaturated having optionally one or two heteroatoms independently selected from oxygen, sulfur and nitrogen, wherein said ring R2 is optionally linked through an alkyl group (C1 -C4); wherein said ring R2 is optionally mono-, di- or tri-substituted independently with halo, (C2-C6) alkenyl, (Ci-Cß) alkyl, hydroxy, alkoxy (Ci-Cß), alkylthio (C4), amino, nitro, cyano, oxo, carboxy, alkoxycarbonyl (Ci-Cß), mono-N- or di-N, N-alkylamino (Ci-Cß) wherein said alkyl substituent (Ci-Cß) is optionally mono-, di- or tri - independently substituted with halo, hydroxy, alkoxy (d-Cß), alkylthio (C 1 -C 4), oxo-alkyloxycarbonyl (Ci-Cd); with the proviso that R2 is not methyl; R3 is hydrogen or Q; where Q is a linear or branched carbon chain of one to six members fully saturated, partially unsaturated or totally unsaturated, wherein the carbons other than the connecting carbon can optionally be replaced with a heteroatom selected from oxygen, sulfur and nitrogen, and said carbon is optionally mono-, di- or tri- substituted independently with halo, said carbon being optionally mono-substituted with hydroxy, said carbon is optionally mono-substituted with oxo, said sulfur is optionally mono- or di-substituted with oxo, said nitrogen is optionally mono- or di-substituted with oxo, and said carbon chain is optionally mono-substituted with; where V is a three to eight member ring partially saturated, fully saturated or totally unsaturated having optionally one to four heteroatoms independently selected from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two condensed rings of three to six members partially saturated, fully saturated or totally unsaturated, taken independently, optionally having from one to three heteroatoms independently selected from nitrogen, sulfur and oxygen; wherein said substituent V is optionally mono-di-, tri-, or tetra independently substituted with halo, alkyl (Ci-Cß), alkenyl (C2-Cd), hydroxy, alkoxy (Ci-Ce), alkylthio (C1-C4) amino, nitro, cyano, oxo, carboxamoyl, mono-N or di-N, N-alkylcarboxamoyl (d-Ce), carboxy, alkoxycarbonyl (d-Cß), mono-N- or di-N, N-alkylamino (d-Cß) where said alkyl substituent ( C Cd) or (C2-C6) alkenyl is optionally mono-, di- or tri-substituted independently with hydroxy, alkoxy (dC-6), alkylthio (d- C4), amino, nitro, cyano, oxo, carboxy, alkoxycarbonyl (C Ce), mono-N- or di- N, N-alkylamino (d-Cß), and said alkyl (d-Cd) or alkenyl (C2-Ce) substituents are also optionally substituted with one to nine fluorine atoms; R4 is Q1 or V1; where Q1 is a carbon chain of one to six members, linear or branched, fully saturated, partially unsaturated or totally unsaturated, in which the carbons other than the connecting carbon can optionally be replaced with a heteroatom selected from oxygen, sulfur and nitrogen and said carbon is optionally mono-, di- or tri- substituted independently with halo, said carbon is optionally mono-substituted with hydroxy, said carbon is optionally mono-substituted with oxo, said sulfur is optionally mono- or di-substituted with oxo, said nitrogen is optionally mono- or di-substituted with oxo, and said carbon chain is optionally mono-substituted with V1; where V1 is a three to six member ring partially saturated, fully saturated or totally unsaturated having one to two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein said substituent V1 is optionally mono-, di-, tri- or tetra-substituted independently with halo, alkyl (d-Cß), alkoxy, (d-Cß), amino, nitro, cyano, alkoxycarbonyl (d-Cß), mono-N- or di-N, N-alkylamino (d-Cß), wherein said alkyl substituent (Ci-Ce) is optionally mono-substituted with oxo, and said alkyl substituent (d-Cß) is also optionally substituted with one to nine fluorine atoms; where R3 must contain V or R4 must contain V1; R5, R6, R7 and R8 are independently hydrogen, a bond, nitro or halo, where said bond is substituted with T or a straight or branched, partially saturated, fully saturated or fully unsaturated carbon chain (C1-C12), where the The carbon can optionally be replaced with one or two heteroatoms independently selected from oxygen, sulfur and nitrogen, where said carbon atoms are optionally mono-, di- or tri-substituted independently with halo, said carbon is optionally mono-substituted with hydroxy, said carbon is optionally mono-substituted with oxo, said sulfur is optionally mono- or di-substituted with oxo, said nitrogen being optionally mono- or di-substituted with oxo; and said carbon chain is optionally mono-substituted with T; where T is a three to eight member ring partially saturated, fully saturated or totally unsaturated having optionally one to four heteroatoms independently selected from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two condensed rings of three to six members partially saturated, fully saturated or totally unsaturated, taken independently, optionally having from one to four heteroatoms independently selected from nitrogen, sulfur and oxygen; wherein said substituent T is optionally mono-, di- or tri-substituted independently with halo, alkyl (d-Cß), alkenyl (C2-C6), hydroxy, alkoxy (C Ce), alkylthio (dd), amino, nitro, cyano, oxo, carboxy, alkoxycarbonyl (C -Cß), mono-N- or di-N, N-alkylamino (d-Cß) wherein said alkyl substituent (Ci-Cß) is optionally mono-, di- or tri-substituted independently with hydroxy, alkoxy (d-Cß), alkylthio (C 1 -C 4), amino, nitro, cyano, oxo, carboxy, alkoxycarbonyl (d-Cd), mono-N- or di-N, N-alkylamino (d-C &;) and said alkyl substituent (d-Cß) is also optionally substituted with one to nine fluorine atoms; and wherein R5 and R6, or R6 and R7, and / or R7 and R8 may also be taken together and may fat least one four to eight member ring that is partially saturated or fully unsaturated optionally having one to three independently selected heteroatoms between hydrogen, sulfur and oxygen; wherein said ring or rings formed by R5 and R6, or R6 and R7, and / or R7 and R8 are optionally mono-, di- or tri- substituted independently with halo, alkyl (d-C6), alkylsulfonyl (CrC4), alkenyl (C2-C6), hydroxy, alkoxy (Ci-Ce), alkylthio (C1-C4), amino, nitro, cyano, oxo, carboxy, alkoxycarbonyl (Ci-Ce), mono-N- or di-N, N- alkylamino (d-Cß) wherein said alkyl substituent (d-Cß) is optionally mono-, di- or trisubstituted independently with hydroxyp.splcoxy (Ci-Cd), alkylthio (dd), amino. nitro, cyano, oxo, carboxy, alkoxycarbonyl (dC-6), mono-N- or di-N, N-alkylamino (d-Ce) and said alkyl substituent (d-Cß) is also optionally substituted with one to nine atoms of fluorine. With the proviso that when R2 is carboxyl or alkylcarboxyl, then R1 is not hydrogen. A preferred group of compounds, referred to as group A, contains the compounds having the formula I shown above, wherein R2 is beta; nitrogen C4 is beta; R1 is W-X; W is carbonyl, thiocarbonyl or -SO2-; X is -O-Y-, S-Y-, N (H) -Y- or -N- (Y) 2-; And, for each case, independently Z or (C1-C4) alkyl, said (C? -C4) alkyl being optionally substituted with one to nine fluorine or hydroxy atoms, or said alkyl (d-Ce) being optionally mono- replaced with Z; where Z is a three to six member ring partially saturated, fully saturated or totally unsaturated having optionally one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; i- ^ iraas ^ afea' ^ where said substituent Z is optionally mono-, di- or tri- substituted independently with halo, (C? -C4) alkyl, alkoxy (dd), alkylthio (dd), nitro, cyano, oxo or alkyloxycarbonyl (d-Ce), said (C 1 -C 4) alkyl being optionally substituted with one to nine fluorine atoms; R 2 is a straight or branched partially saturated, fully saturated or fully unsaturated one to four membered carbon chain in which the carbons other than the connecting atom can optionally be replaced with a heteroatom independently selected from oxygen, sulfur and nitrogen, wherein said atoms of carbon are Optionally mono-, di- or tri-substituted independently with halo, said carbon is optionally mono-substituted with oxo, said carbon is optionally mono-substituted with hydroxy, said sulfur is optionally mono- or di-substituted with oxo, said nitrogen it is optionally mono- or di-substituted with oxo; or said R2 is a ring of three to five members Partially saturated, fully saturated or totally unsaturated optionally having a heteroatom independently selected from oxygen, sulfur and nitrogen; wherein said ring R2 is optionally mono-, di- or tri- substituted independently with halo, hydroxy, alkoxy (d-Cß) or Alkoxycarbonyl (d-Cß); R3 is Q-V where Q is alkyl (d-d) and V is a five to six member ring partially saturated, totally saturated or totally unsaturated which optionally has one to three heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein said ring V is optionally mono-, di-, tri- or tetra- substituted independently with halo, alkyl (Ci-Cß), hydroxy, (C 1 -C 4) alkoxy, nitro, cyano and oxo and wherein said alkyl substituent ( Ci-Cd) optionally has one to nine fluorine atoms; R 4 is alkyl (d-d); each of R6 and R7 is independently H, halo, T or alkyl (Ci-Cß), said alkyl (Ci-Cß) optionally having from one to nine fluorine atoms or said alkyl (C Ce) being optionally mono-substituted with T; where T is a partially saturated, fully saturated or fully unsaturated five to six member ring optionally having one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; Wherein said substituent T is optionally mono-, di- or tri- substituted independently with halo, alkyl (d-Cß), hydroxy, alkoxy (d-Cß), alkylthio (Crd), amino, oxo, carboxy, alkyloxycarbonyl (d) -Cβ), mono-N- or di- N, N-alkylamino (d-Cß), wherein said alkyl substituent (CrCβ) optionally has from one to nine fluorine atoms; and R5 and R8 are H; And pharmaceutically acceptable salts thereof. A group of compounds that is preferred among group A of compounds, designated group B, contains the compounds wherein W is carbonyl; ^^^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ^^^^^ & ^^^^^^^^^^^^^^^^^^^^^^^^^^^ X is OY where Y is alkyl, (Crd) , said alkyl substituent (CrC4) being optionally substituted with one nine fluorine or hydroxy atoms; Q is alkyl (CrC) and V is phenyl, pyridinyl or pyrimidinyl; wherein said ring V is optionally mono-, di- or tri- substituted independently with halo, alkyl (CrCe), hydroxy, alkoxy (d-Ce), nitro, cyano or oxo, wherein said alkyl substituent (d-Cß) optionally has from one to nine fluorine atoms; R2 is a straight or branched carbon chain (d-d), fully saturated; or said R2 is a fully saturated three to five member ring; wherein said ring or chain R2 is optionally mono-, di- or tri-substituted independently with halo; and each of R6 and R7 are independently hydrogen, halo or alkyl (d-Cß), said alkyl (d-Cß) optionally having from one to nine fluorine atoms; and the pharmaceutically acceptable salts thereof. A group of compounds that is preferred among group B of compounds, designated group c, contains the compounds wherein Q is methyl and V is phenyl or pyridinyl; wherein said ring V is optionally mono-, di- or tri- substituted independently with halo, (C1-C2) alkyl or nitro, wherein said (C1-C2) alkyl optionally has one to five fluorine atoms; and the pharmaceutically acceptable salts thereof.

Especially preferred compounds of formula I are the compounds: [2S, 4S] 4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-isopropyl-6-trifluoromethyl-3-isopropyl ester. 4-dihydro-2H-quinoline-1-carboxylic acid; [2S, 4S] 4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -6-chloro-2-cyclopropyl-3,4-dihydro-2H-quinoline-1 isopropyl ester -carboxylic; [2S, 4S] 2-cyclopropyl-4 - [(3,5-dichloro-benzyl-methoxycarbonyl-aminoj-? - trifluoromethyl-S-dihydro-H-quinoline-l-carboxylic acid isopropyl ester; tert-butyl ester of [2S, 4S] 4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl] amino] -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid [2S, 4S] 4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-isopropyl ester 2H-quinoline-1-carboxylic acid [2S, 4S] 4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-cyclobutyl-6-trifluoromethyl-3,4-dihydro isopropyl ester -2H-quinoline-1-carboxylic acid, and the pharmaceutically acceptable salts of said compounds.

Other especially preferred compounds of formula I are the compounds: [2S, 4S] 4- [1- (3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-ethyl-6-isopropyl acid ester -trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid; [2S, 4S] 4- [1- (3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl] amino] -2-methoxymethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline isopropyl ester -1-carboxylic; 2-hydroxy-ethyl ester of [2R, 4S] 4 - [(3,5-bis-trifluoromethyl-10-benzyl) -methoxycarbonyl-amino] -2-etl-6-trifluoromethyl-3,4- dihydro-2H-quinoline-1-carboxylic acid; [2S, 4S] 4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-ethyl ester - carboxylic; 15 [2R,? S] 4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-ethyl-6-trifluoromethyl-3,4-dih ethyl ester Dro-2H-quinoline-1-carboxylic acid; [2S, 4S] 4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-2-propyl ester carboxylic; [2S, 4S] 4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid propyl ester Ilic; and the pharmaceutically acceptable salts of said compounds. Especially preferred compounds within group C of compounds are compounds wherein 5 a. And it is isopropyl; R2 is isopropyl; R3 is 3,5-bis-trifluoromethylphenylmethyl; R4 is methyl; R6 is trifluoromethyl; and R7 is H; b. And it is isopropyl; R2 is cyclopropyl; R3 is 3,5-bis-trifluoromethylphenylmethyl; R4 is methyl; 15 R6 is chlorine; and R7 is H; c. And it is isopropyl; R2 is cyclopropyl; R3 is 3,5-dichlorophenylmethyl; R4 is methyl; R6 is trifluoromethyl; and R7 is H; d. And it's tert-butyl; ^ j ^^^^^^^^ »H« «-,» ".

R2 is cyclopropyl; R3 is 3,5-bis-trifluoromethylphenylmethyl; R4 is methyl; R6 is trifluoromethyl; and R7esH; to. And it is isopropyl; R2 is cyclopropyl; R3 is 3,5-bis-trifluoromethylphenylmethyl; R4 is methyl; R6 is trifluoromethyl; and R7esH; F. And it is sopropilo; R2 is cyclobutyl; R3 is 3,5-bis-trifluoromethylphenimethyl; R4 is methyl; R6 is trifluoromethyl; and R7esH; g. Yes, sopropyl; R2 is ethyl; R3 is 3,5-bis-trifluoromethylphenylmethyl; R4 is methyl; R6 is trifluoromethyl; and R7esH; ".» O »- Ik ^ J ^ & ^ tX ^ V ^ K h. And it is sopropilo; R2 is methoxymethyl; R3 is 3,5-bis-trifluoromethylphenylmethyl; R4 is methyl; R6 is trifluoromethyl; and R7 is H; i. And it is 2-hydroxyethyl; R2 is ethyl; R3 is 3,5-bis-trifluoromethylphenylmethyl; R4 is methyl; R6 is trifluoromethyl; and R7 is H; j. And it is ethyl; R2 is cyclopropyl; R3 is 3,5-bis-trifluoromethylphenylmethyl; R4 is methyl; R6 is trifluoromethyl; and R7 is H; k. And it is ethyl; R2 is ethyl; R3 is 3,5-bis-trifluoromethylphenylmethyl; R4 is methyl; R6 is trifluoromethyl; . ^ «¿Ü Aja." R7 is H; I. And it is n-propyl; R2 is cyclopropyl; R3 is 3,5-bis-trifluoromethylphenylmethyl; R4 is methyl; R6 is trifluoromethyl; and R7 is H; and m. And it is n-propyl; R2 is ethyl; R3 is 3,5-bis-trifluoromethylphenylmethyl; R4 is methyl; R6 is trifluoromethyl; and R7 is H; and pharmaceutically acceptable salts of said compounds. Another preferred group of compounds are the isopropyl ester compounds of [2S, 4S] 4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-isopropyl-6-trifluoromethyl isopropyl ester. -3,4-dihydro-2H-quinoline-1-carboxylic acid; [2S, 4S] 4 - [(3,5-bis-trifluoromethyl-benzyl-methoxycarbonyl-aminoj-d-chloro-1-cyclopropyl-S-dihydro-H-quinoline-1-carboxylic acid isopropyl ester; > a ^ > . ? cnz [2S, 4S] 2-Cyclopropyl-4 - [(3,5-dichloro-benzyl) -methoxycarbonyl-amino] -6-trifluoromethyl-3,4-dihydro-2H-quinoline isopropyl ester -1-carboxylic; [2S, 4S] 4 - [(3,5-bis-trifluoromethyl-benzyl-methoxycarbonyl-aminoj ^ -cyclopropyl-e-trifluoromethyl-S-dihydro-H-quinoline-1-carboxylic acid tert -butyl ester; isopropyl ester of [2S, 4S] 4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline -1-carboxylic acid [2S, 4S] 4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-cyclobutyl-6-trifluoromethyl-3,4-d isopropyl ester Hydro-2H-quinoline-1-carboxylic acid [2R, 4S] 4 - [(3,5-b? s-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-ethyl-6-isopropyl ester -trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid [2S, 4S] 4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] isopropyl ester] -2- Methoxymethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid [2R, 4S] 4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl- 2-hydroxyethyl ester] amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-qu Noline-1-carboxylic acid; ethyl ester of [2S, "4S] 4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-cyclopropyl-6-trifluoromethyl-3,4-d¡h! dro-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 [2S, 4S] 4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-cyclopropyl-6-propyl ester -trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ester [2R, 4S] 4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] - 2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid, and the pharmaceutically acceptable salts of said compounds A preferred group of compound, called group E, contains the compounds having the formula I shown above, in which R2 is beta, the nitrogen of C4 is beta, R1 is WX, W is carbonyl, thiocarbonyl or sulfonyl, X is -OY-, -SY-, N (H) -Y or N- (Y )2-; ^ gg Y for each case is independently Z or alkyl (d-d), said alkyl (d-d) being optionally substituted with one to nine fluorine atoms or said alkyl (d-d) being optionally mono- substituted with Z; where Z is a three to six member ring partially saturated, fully saturated or totally unsaturated having optionally one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein said substituent Z is optionally mono-, di- or tri- substituted independently with halo, alkyl (dd), alkoxy (dd), alkylthio (dd), nitro, cyano, oxo or alkoxycarbonyl (d-Cß), said substituent being alkyl (dd) optionally substituted with one to nine fluorine atoms; R2 is a linear or branched partially saturated saturated, fully saturated or fully unsaturated one to four carbon chain wherein the carbons other than the connecting carbon can optionally be replaced with a heteroatom independently selected from oxygen, sulfur and nitrogen, where said carbon atoms are optionally mono-, or di- or tri-substituted independently with halo, said carbon is optionally mono-substituted with oxo, said carbon is optionally mono-substituted with hydroxy, said sulfur is optionally mono- or di-substituted with oxo, said nitrogen is optionally mono- or di-substituted with oxo; or said R2 is a ring of three to five members partially saturated, fully saturated or totally unsaturated optionally having a heteroatom independently selected from oxygen, sulfur and nitrogen; wherein said ring R2 is optionally mono-, di- or tri- substituted independently with halo, hydroxy, alkoxy (CrCe) or alkoxycarbonyl (C Ce); R3 is Q-V, where Q is alkyl (d-d) and V is a five to six member ring partially saturated, fully saturated or totally unsaturated, optionally having from one to three heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein said ring V is optionally mono-, di-, tri- or tetra-substituted independently with halo, alkyl (CrCe), hydroxy, alkoxy (d-Ce), nitro, cyano or oxo, wherein said alkyl substituent (d-Cß) ) optionally has from one to nine fluorine atoms; R4 is alkyl (d-C4); and R5 and Rd, or R6 and R7, or R7 and R8 are taken together and form a ring that is a five or six member ring that is partially saturated or fully unsaturated, optionally having one or two heteroatoms independently selected from nitrogen , sulfur and oxygen; wherein said ring formed by R5 and R6, or R6 and R7, or R7 and R8 is optionally mono-, di-, or tri-substituted independently with halo, alkyl (dd), alkylsulfonyl (CrC4), alkenyl (C2-d) , hydroxy, alkoxy (CC), alkylthio (Crd), amino, nitro, cyano, oxo, carboxy, alkoxycarbonyl (dd), mono-N- or di? /, / V-alkylamino (C1-C4) where said alkyl substituent (dd) is optionally mono-, di-, or tri-substituted independently with hydroxy, alkoxy (dd), alkylthio (dd), amino, nitro, cyano, oxo, carboxy, alkoxycarbonyl (dd), mono- / V- or di? /, / V-alkylamino (dd) or said alkyl substituent (dd) optionally has from one to nine fluorine atoms. With the proviso that R5, R6, R7 and / or R8, as may be the case, that do not form the ring, are hydrogens; and pharmaceutically acceptable salts thereof. A preferred group of compounds, called group F, contains the compounds having the formula I as shown above, wherein R2 is beta; the nitrogen of C4 is beta; R1 is W-Y, W is carbonyl, thiocarbonyl or sulfonyl; Y is alkyl (d-Ce), optionally having said alkyl (d-C &) of one to nine fluorine atoms or said alkyl (d-Ce) being optionally mono-substituted with Z; where Z is a three to six member ring partially saturated, totally saturated or totally unsaturated that has optionally one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein said substituent Z is optionally mono-, di-, tri-substituted independently with halo, alkyl (dd), alkoxy (dd), alkylthio (dd), nitro, cyano, oxo or alkoxycarbonyl (CrCe), said alkyl substituent ( dd) optionally substituted with one to nine fluorine atoms; R2 is a linear or branched partially saturated, fully saturated or fully unsaturated one to four membered carbon chain in which the carbons other than the connecting carbon can optionally be replaced with a heteroatom independently selected from oxygen, sulfur and nitrogen, wherein said carbon atoms are carbon are optionally mono-, di- or tri-substituted independently with halo, said carbon is optionally mono-substituted with oxo, said carbon is optionally mono-substituted with hydroxy, said sulfur is optionally mono- or di-substituted with oxo, said nitrogen is optionally mono- or di-substituted with oxo; or said R2 is a three to five member ring partially saturated, fully saturated or fully unsaturated optionally having a heteroatom independently selected from oxygen, sulfur and nitrogen; wherein said ring R2 is optionally mono-, di- or tri-substituted independently with halo, hydroxy, alkoxy (d-Cß) or alkoxycarbonyl (d-Cß); R3 is Q-V, where Q is alkyl (d-d) and V is a five or six member partially saturated, fully saturated or fully unsaturated ring optionally having one to three heteroatoms independently selected from oxygen, sulfur and nitrogen; Wherein said ring V is optionally mono-, di-, tri- or tetra-substituted independently with halo, alkyl (CrCe), hydroxy, alkoxy (d-Cß), nitro, cyano or oxo, wherein said alkyl substituent (d- Cß) optionally has from one to nine fluorine atoms; R4 is alkyl (d-C4); Each of R6 and R7 is independently alkyl (CrCβ) or alkoxy (d-Cβ), said substituent optionally having alkoxy (CrCβ) or alkyl (dC-6) of one to nine fluorine atoms or said alkoxy substituent (d) being -Cβ) or alkyl (d-Cß) optionally mono-substituted with T; where T is a partially saturated or fully unsaturated five or six part saturated ring optionally having one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein said substituent T is optionally mono-, di- or tri- substituted independently with halo, alkyl (CrCß), hydroxy, alkoxy (d-Cß), alkylthio (dd), amino, oxo, carboxy, alkoxycarbonyl (d-Cß) ), mono -? / - or di-? /,? - alkylamino (d-Cß), wherein said alkyl substituent (d-Cß) optionally has from one to nine fluorine atoms; or R6 and R7 are taken together and form a ring which is a partially or fully unsaturated five or six member ring optionally having one or two heteroatoms independently selected from nitrogen, sulfur and oxygen; wherein said ring formed by R6 and R7 is optionally mono-, di- or tri-substituted independently with halo, alkyl (dd), alkylsulfonyl (dd), alkenyl (dd), hydroxy, alkoxy (dd), alkylthio (dd), amino, nitro, cyano, oxo, carboxy, alkyloxycarbonyl (dd), mono-? / - or di-? /,? / - alkylamino (dd), wherein said alkyl substituent (dd) optionally has one to nine fluorine atoms; R5 and R8 are H; and the pharmaceutically acceptable salts thereof. A preferred group of compounds, designated group G, contains the compounds having the formula I as shown here above, wherein R2 is beta; the nitrogen of C4 is beta; R1 is Y; Y is alkenyl (C2-Cß) or alkyl (dd), said alkenyl (dd) or alkyl (dd) optionally having from one to nine fluorine atoms or said alkenyl (dd) or alkyl (dd) being optionally mono-substituted with Z; M t rilr 4Med "MJftafe * and J9 &-« * ».. where Z is a three to six member ring partially saturated, fully saturated or totally unsaturated having optionally one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; Wherein said substituent Z is optionally mono-, di- or tri- substituted independently with halo, alkyl (dd), alkoxy (dd), alkylthio (dd), nitro, cyano, oxo or alkoxycarbonyl (Crd), said alkyl substituent being (dd) optionally substituted with one to nine fluorine atoms; R2 is a linear or branched partially saturated saturated, fully saturated or totally unsaturated one to four membered carbon chain, wherein the carbons other than the connecting carbon can optionally be replaced with a heteroatom independently selected from oxygen, sulfur and nitrogen, where said atoms carbon are optionally mono-, di- or tri-substituted independently with halo, said carbon is optionally mono-substituted with oxo, said carbon is optionally mono-substituted with hydroxy, said sulfur is optionally mono-, or di-substituted with oxo, said nitrogen is optionally mono- or di-substituted with oxo; or said R2 is a A three to five member ring partially saturated, fully saturated or totally unsaturated optionally having a heteroatom independently selected from oxygen, sulfur and nitrogen; wherein said ring R2 is optionally mono-, di- or tri- substituted independently with halo, hydroxy, alkoxy (d-d) or alkoxycarbonyl (d-d); R3 is Q-V, where Q is alkyl (d-d) and V is a partially saturated, fully saturated or fully unsaturated five to six member ring optionally having one to three heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein said ring V is optionally mono-, di-, tri- or tetra-substituted independently with halo, alkyl (CrCe), hydroxy, alkoxy (dd), nitro, cyano or oxo, wherein said alkyl substituent (dd) optionally has one to nine fluorine atoms; R 4 is alkyl (d-d); each of R6 and R7 are independently alkyl (dd) or alkoxy (dd), said alkyl (dd) or alkoxy (dd) substituent optionally having from one to nine fluorine atoms or said substituent being alkoxy (dd) or alkyl (dd) optionally mono-substituted with T; where T is a partially saturated, or fully unsaturated, five or six member ring having optionally one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein said substituent Y is optionally mono-, di- or tri- substituted independently with halo, alkyl (dd), hydroxy, alkoxy (Crd), alkylthio (dd), amino, oxo, carboxy, alkoxycarbonyl, (dd), mono- I did not give- N, N-alkylamino (Crd), wherein said alkyl substituent (d-d) optionally has one to nine fluorine atoms; or R6 and R7 are taken together and form a ring that is a partially saturated or fully unsaturated five to six member ring optionally having one or two heteroatoms independently selected from nitrogen, sulfur and oxygen; wherein said ring formed by R6 and R7 is optionally mono-, di- or tri-substituted independently with halo, alkyl (dd), alkylsulfonyl (dd), alkenyl (dd), hydroxy, alkoxy (dd), alkylthio (d-C4) ), amino, nitro, cyano, oxo, carboxy, alkyloxycarbonyl (dd), mono-N- or di-N, N-alkylamino (dd), wherein said alkyl substituent (dd) optionally has one to nine fluorine atoms; R5 and R8 are H; and the pharmaceutically acceptable salts thereof. A preferred group of compounds, designated group H, contains the compounds having the formula I as shown here above, wherein R2 is beta; the nitrogen of C4 is beta; R1 is Z; Z is a three to six member ring partially saturated, fully saturated or totally unsaturated having optionally one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein said substituents Z is optionally mono-, di- or tri-substituted independently with halo, alkyl (d-C4), alkoxy (dd), alkylthio (dd), nitro, cyano, oxo or alkoxycarbonyl (CrCe), said substituent having alkyl (dd) optionally from one to nine fluorine atoms; R 2 is a straight or branched partially saturated, fully saturated or fully unsaturated one to four membered carbon chain in which the carbons other than the connecting carbon can optionally be replaced with a heteroatom independently selected from oxygen, sulfur and nitrogen, where said carbon atoms are optionally mono-, di- or tri-substituted independently with halo, said carbon is optionally mono-substituted with oxo, said carbon is optionally mono-substituted with hydroxy, said sulfur is optionally mono- or di-substituted cone oxo said nitrogen is optionally mono- or di-substituted with oxo; or said R2 is a three to five member ring partially saturated, fully saturated or totally unsaturated optionally having a heteroatom independently selected from oxygen, sulfur and nitrogen; wherein said ring R2 is optionally mono-, di- or tri-substituted independently with halo, hydroxy, alkoxy (d-Cß) or alkoxycarbonyl (d-d); R3 is Q-V, where Q is alkyl (d-d) and V is a five or six member partially saturated, fully saturated or fully unsaturated ring optionally having one to three heteroatoms independently selected from oxygen, sulfur and nitrogen; Wherein said ring V is optionally mono-, di-, tri- or tetra-substituted independently with halo, alkyl (dd), hydroxy, alkoxy (dd), nitro, cyano or oxo, wherein said alkyl substituent (dd) optionally has from one to nine fluorine atoms; R 4 is alkyl (d-d); Each of R6 and R7 are independently alkyl (dd) or alkoxy (dd), said alkyl (dd) or alkoxy (CrCe) substituent optionally having one to nine fluorine atoms or said alkoxy (d-) or alkyl substituent being (dd) optionally mono-substituted with T; where T is a partially saturated, or fully unsaturated, five to six membered partially saturated ring optionally having one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein said substituent T is optionally mono-, di- or tri- substituted independently with halo, alkyl (dd), hydroxy, alkoxy (Crd), alkylthio (dd), amino, oxo, carboxy, alkoxycarbonyl (Crd), mono- N- or di- N, N-alkylamino (CrCe), wherein said alkyl substituent (dd) optionally has from one to nine fluorine atoms; or R6 and R7 are taken together and form a ring that is a five or six member ring partially saturated or totally unsaturated having optionally one or two heteroatoms independently selected from nitrogen, sulfur and oxygen; Wherein said ring formed by R6 and R7 is optionally mono-, di- or tri-substituted independently with halo, alkyl (dd), alkylsulfonyl (dd), alkenyl (C2-d), hydroxy, alkoxy (dd), alkylthio ( d- d), amino, nitro, cyano, oxo, carboxy, alkyloxycarbonyl (dd), mono-N- od- N, N, alkylamino (dd), wherein said alkyl substituent (dd) optionally has from one to nine fluorine atoms; R5 and R8 are H; and the pharmaceutically acceptable salts thereof. A preferred group of compounds, called group I, contains the compounds having the formula I as shown hereinabove, wherein R2 is beta; the nitrogen of C4 is beta; R1 is W-Z; W is carbonyl; thiocarbonyl or sulfonyl; Z is a fully saturated or fully unsaturated saturated three to six member ring optionally having one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; ^^^^^^^^^^^^^^ ^^^^ j ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ where said substituent Z is optionally mono-, di- or tri-substituted independently with halo, alkyl ( dd), alkoxy (dd), alkylthio (dd), nitro, cyano, oxo or alkoxycarbonyl (dd), said alkyl substituent (dd) having optionally from one to nine fluorine atoms; R2 is a linear or branched partially saturated, fully saturated or fully unsaturated, one to four membered carbon chain in which the carbons other than the connecting carbon can optionally be replaced with a heteroatom independently selected from oxygen, sulfur and nitrogen, wherein said atoms of carbon are optionally mono-, di- or tri-substituted independently with halo, said carbon is optionally mono-substituted with oxo, said carbon is optionally mono-substituted with hydroxy, said sulfur is optionally mono- or di-substituted with oxo, said nitrogen is optionally mono- or di-substituted with oxo; or said R2 is a three to five member ring partially saturated, fully saturated or fully unsaturated optionally having a heteroatom independently selected from oxygen, sulfur and nitrogen; wherein said ring R2 is optionally mono-, di- or tri-substituted independently with halo, hydroxy, alkoxy (d-Cß) or alkoxycarbonyl (d-d); R3 is Q-V, where Q is alkyl (d-d) and V is a five or six member ring partially saturated, totally saturated or totally ^^ ßmZÍdau ^ -í'Zt ^^ S ^ a¡S? & zz ^ 7, ^.

Unsaturated having optionally from one to three heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein said ring V is optionally mono-, di-, tri- or tetra-substituted independently with halo, alkyl (CrCe), hydroxy, alkoxy (dd), nitro, cyano or oxo, wherein said alkyl substituent (dd) optionally has one to nine fluorine atoms; R 4 is alkyl (d-d); each of R6 and R7 are independently alkyl (dd) or alkoxy (dd), said substituent optionally having alkyl (dd) or alkoxy (dd) of one to nine fluorine atoms or said substituent being alkoxy (dd) or alkyl (CrCe) optionally mono-substituted with T; where T is a partially saturated, fully unsaturated or fully saturated five or six member ring optionally having one or two heteroatoms selected independently from oxygen, sulfur and nitrogen; wherein said substituent T is optionally mono-, di- or tri-substituted independently with halo, alkyl (CrCe), hydroxy, alkoxy (dd), alkylthio (dd), amino, oxo, carboxy, alkoxycarbonyl (dd), mono-N - or di-N, N-alkylamino (dd), wherein said alkyl substituent (dd) optionally has one to nine fluorine atoms; or R6 and R7 are taken together and form a ring which is a five or six member ring partially saturated or fully unsaturated having optionally one or two heteroatoms independently selected from nitrogen, sulfur and oxygen; wherein said ring formed by R6 and R7 is optionally mono-, di- or tri-substituted independently with halo, alkyl (dd), alkylsulfonyl (dd), alkenyl (dd), hydroxy, (C1-C4) alkoxy, alkylthio (d) -d), amino, nitro, cyano, oxo, carboxy, alkyloxycarbonyl (dd), mono-N-od-NN-alkylamino (dd), wherein said alkyl substituent (dd) optionally has from one to nine fluorine atoms; R5 and R8 are H; and the pharmaceutically acceptable salts thereof. A preferred group of compounds, called group J, contains the compounds having the formula I as shown here above, wherein R2 is beta; the nitrogen of C4 is beta; R1 is W-X; W is carbonyl, thiocarbonyl or sulfonyl; X is -O-Y-, S-Y-, N (H) -Y- or -N- (Y) 2-; And, for each case, it is independently Z or alkyl (C d); said alkyl (d-d) optionally having from one to nine fluorine atoms or said alkyl (d-d) being optionally mono-substituted with Z; where Z is a three to six member ring partially saturated, totally saturated or totally unsaturated that has optionally one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein said substituent Z is optionally mono-, di- or tri-substituted independently with halo, alkyl (dd), alkoxy (dd), alkylthio (dd), nitro, cyano, oxo or alkoxycarbonyl (dd), said alkyl substituent ( dd) optionally substituted with one to nine fluorine atoms; R 2 is a straight or branched partially saturated, fully saturated or fully unsaturated one to four membered carbon chain in which the carbons other than the connecting carbon can optionally be replaced with a heteroatom independently selected from oxygen, sulfur and nitrogen, where said carbon atoms are optionally mono-, di- or tri-substituted independently with halo, said carbon is optionally mono-substituted with oxo, said carbon is optionally mono-substituted with hydroxy, said sulfur is optionally mono- or di-substituted with oxo said nitrogen is optionally mono- or di-substituted with oxo; or said R2 is a three to five member ring partially saturated, fully saturated or totally unsaturated optionally having a heteroatom independently selected from oxygen, sulfur and nitrogen; wherein said ring R2 is optionally mono-, di- or tri-substituted independently with halo, hydroxy, alkoxy (d-Cß) or alkoxycarbonyl (d-d); R3 is Q-V, where Q is alkyl (d-d) and V is a five or six member ring partially saturated, fully saturated or fully unsaturated having optionally one to three heteroatoms independently selected from oxygen, sulfur and nitrogen; Wherein said ring V is optionally mono-, di-, tri- or tetra-substituted independently with halo, alkyl (dd), hydroxy, alkoxy (dd), nitro, cyano or oxo, wherein said alkyl substituent (dd) optionally has from one to nine fluorine atoms; R 4 is alkyl (d-d); At least one of R6 and R7 is alkoxy (dd) and at least one of R6 and R7 is alkyl (dd), said alkyl (d- d) or alkoxy (dd) substituent optionally having one to nine fluorine atoms or said substituent being alkoxy (dd) or alkyl (dd) optionally mono-substituted with T; Wherein T is a partially saturated, or fully unsaturated, five or six member ring having optionally one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein said substituent T is optionally mono-, di- or tri-substituted independently with halo, alkyl (Crd), hydroxy, alkoxy (dd), alkylthio (Crd), amino, oxo, carboxy, alkoxycarbonyl (CrCe), mono- N- or N- N, N-alkylamino (dd), wherein said alkyl substituent (Crd) optionally has from one to nine fluorine atoms; R5 and R8 are H; and the pharmaceutically acceptable salts thereof. Yet another aspect of this invention relates to methods for the treatment of atherosclerosis, peripheral vascular disease, dyslipidemia, hyperbetalipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemin, hypertriglyceridemia, familial hypercholesterolemia, cardiovascular disorders, angina, ischemia, cardiac ischemia, stroke, myocardial infarction, reperfusion injury, angioplastic restenosis, hypertension, vascular complications of diabetes, obesity or endotoxemia in a mammal (including a human being, both male and female) by administering to a mammal in need of such treatment an amount for the treatment of atherosclerosis, peripheral vascular disease, dyslipidemia, hyperbetalipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial hypercholesterolemia, cardiovascular disorders, angina, ischemia, cardiac ischemia, stroke, myocardial infarction, reperfusion, angioplastic restenosis, hypertension, vascular complications of diabetes, obesity or endotoxemia of a compound of formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug. Another aspect of this invention relates to a method for the treatment of atherosclerosis in a mammal (including humans) by administration to a mammal in need of such a treatment. .-t. . "Ef - > treatment of an amount for treating atherosclerosis of a compound of formula I or a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug. Another aspect of this invention relates to a method for the treatment of a peripheral vascular disorder in a mammal (including the human) by administering to a mammal in need of such treatment an amount to treat the peripheral vascular disorder of a compound of formula I or a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug. Another aspect of this invention relates to a method for the treatment of dyslipidemia in a mammal (including the human) by administering to a mammal in need of such treatment an amount to treat the dyslipidemia of a compound of formula I or a prodrug thereof, or a pharmaceutically acceptable salt of said compound or said prodrug. Another aspect of this invention relates to a method for the treatment of hyperbetalipoproteinemia in a mammal (including the human) by administering to a mammal in need of such treatment an amount to treat hyperbetalipoproteinemia of a compound of formula I or a prodrug thereof, or a pharmaceutically acceptable salt of said compound or said prodrug. Another aspect of this invention relates to a method for the treatment of hypoalphalipoproteinemia in a mammal (including * gi f. '^^^^ fe = ^. teffi ^ ^ ^ ^ ^ ^ j ^ a ^ .yj Z ^ r &Z3i »£ Z7S £ 7¿7 ^ the human being) by administering to a mammal in the need for such treatment of an amount for treating hypoalphalipoproteinemia of a compound of formula I or a prodrug thereof, or a pharmaceutically acceptable salt of said compound or said prodrug. Another aspect of this invention relates to a method for the treatment of hypercholesterolemia in a mammal (including human) by administering to a mammal in need of such treatment an amount to treat hypercholesterolemia of a compound of formula I or a prodrug thereof, or a pharmaceutically acceptable salt of said compound or said prodrug. Another aspect of this invention relates to a method for the treatment of hypertriglyceridemia in a mammal (including the human) by administering to a mammal in need of such treatment an amount to treat the hypertriglyceridemia of a compound of formula I or a prodrug thereof, or a pharmaceutically acceptable salt of said compound or said prodrug. Another aspect of this invention relates to a method for the treatment of familial hypercholesterolemia in a mammal (including the human) by administering to a mammal in need of such treatment an amount to treat familial hypercholesterolemia of a compound of formula I or a prodrug thereof, or an acceptable pharmaceutical salt of said compound or of said prodrug.

Another aspect of this invention relates to a method for the treatment of cardiovascular disorders in a mammal (including humans) by administering to a mammal in need of such treatment an amount for treating cardiovascular disorders of a compound of formula I or a prodrug thereof, or a pharmaceutically acceptable salt of said compound or said prodrug. Another aspect of this invention relates to a method for the treatment of angina in a mammal (including the human) by administering to a mammal in need of such treatment an amount to treat angina of a compound of formula I or a prodrug thereof, or a pharmaceutically acceptable salt of said compound or said prodrug. Another aspect of this invention relates to a method for the treatment of ischemia in a mammal (including humans) by administering to a mammal in need of such treatment an amount to treat ischemic disease of a compound of formula I or a prodrug thereof, or a pharmaceutically acceptable salt of said compound or said prodrug. Another aspect of this invention relates to a method for the treatment of cardiac ischemia in a mammal (including the human) by administering to a mammal in need of such treatment an amount to treat cardiac ischemia of a compound of formula I or a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug. Another aspect of this invention relates to a method for the treatment of stroke in a mammal (including the human) by administering to a mammal in need of such treatment an amount to treat stroke of a compound of formula I or a prodrug thereof, or a pharmaceutically acceptable salt of said compound or said prodrug. Another aspect of this invention relates to a method for the treatment of myocardial infarction in a mammal (including human) by administering to a mammal in need of such treatment an amount to treat myocardial infarction of a compound of Formula I or a prodrug thereof, or a pharmaceutically acceptable salt of said compound or said prodrug. Another aspect of this invention relates to a method for the treatment of reperfusion injury in a mammal (including human) by administering to a mammal in need of such treatment an amount to treat the reperfusion injury of a compound of formula I or a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug. Another aspect of this invention relates to a method for the treatment of angioplastic restenosis in a mammal (including the human) by administration to a mammal in need of such treatment. »» - > -TO-. Bfc ^,, - - .- ^^^ £ S ^ t ^^^^ & ^ l ^^ B ?. & e ^ > ri: ^ > < ^ t? ¿? ¿8 .¿ »*. -ae.r "". ».-« .. treatment of an amount for treating angioplastic restenosis of a compound of formula I or a prodrug thereof, or a pharmaceutically acceptable salt of said compound or said prodrug. Another aspect of this invention relates to a method for the treatment of hypertension in a mammal (including the human) by administering to a mammal in need of such treatment an amount to treat hypertension of a compound of formula I or a prodrug thereof, or a pharmaceutically acceptable salt of said compound or said prodrug. Another aspect of this invention relates to a method for the treatment of vascular complications of diabetes in a mammal (including humans) by administering to a mammal in need of such treatment an amount to treat vascular complications of the diabetes of a compound of formula I or a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug. Another aspect of this invention relates to a method for the treatment of obesity in a mammal (including the human) by administering to a mammal in need of such treatment an amount to treat obesity of a compound of formula I or a prodrug thereof, or a pharmaceutically acceptable salt of said compound or said prodrug.

Another aspect of this invention relates to a method for the treatment of endotoxemia in a mammal (including human) by administering to a mammal in need of such treatment an amount to treat endotoxemia of a compound of formula I or a prodrug thereof, or a pharmaceutically acceptable salt of said compound or said prodrug. A preferred dose is from about 0.001 to 100 mg / kg / day of a compound of formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug. An especially preferred dose is from about 0.01 to 10 mg / kg / day of a compound of formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug. This invention also relates to pharmaceutical compositions comprising a therapeutically effective amount of a compound of formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug, and a pharmaceutically acceptable carrier. This invention also relates to pharmaceutical compositions for the treatment of atherosclerosis, peripheral vascular disease, dyslipidemia, hyperbetalipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial hypercholesterolemia, cardiovascular disorders, angina, ischemia, cardiac ischemia, stroke, myocardial infarction, reperfusion, angioplastic restenosis, --j? -i ¿¡»3t» 6 -, - < ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ »• # Seá? ßS = **» -. hypertension, vascular complications of diabetes, obesity or endotoxemia in a mammal (including a human), comprising a therapeutically effective amount of a compound of formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug and a pharmaceutically acceptable vehicle. This invention also relates to pharmaceutical compositions for the treatment of atherosclerosis in a mammal (including a human), which comprises an amount for treating atherosclerosis of a compound of formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or said prodrug and a pharmaceutically acceptable carrier. This invention also relates to pharmaceutical compositions for the treatment of peripheral vascular disease in a mammal (including a human), which comprises an amount for treating the peripheral vascular disease of a compound of formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or said prodrug and a pharmaceutically acceptable carrier. This invention also relates to pharmaceutical compositions for the treatment of dyslipidemia in a mammal (including a human), which comprises an amount to treat the dyslipidemia of a compound of formula I, a prodrug thereof, or a salt Pharmaceutically acceptable means of said compound or said prodrug and a pharmaceutically acceptable carrier. This invention also relates to pharmaceutical compositions for the treatment of hyperbetalipoproteinemia in a mammal (including a human), which comprises an amount for treating hyperbetalipoproteinemia of a compound of formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or said prodrug and a pharmaceutically acceptable carrier. This invention also relates to pharmaceutical compositions for the treatment of hypoalphalipoproteinemia in a mammal (including a human), which comprises an amount for treating hypoalphalipoproteinemia of a compound of formula I, a prodrug thereof, or a pharmaceutically acceptable salt thereof. said compound or said prodrug and a pharmaceutically acceptable carrier. This invention also relates to pharmaceutical compositions for the treatment of hypercholesterolemia in a mammal (including a human), comprising an amount for treating hypercholesterolemia of a compound of formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or said prodrug and a pharmaceutically acceptable carrier. This invention also relates to pharmaceutical compositions for the treatment of hypertriglyceridemia in a mammal (including a human), which comprises an amount to treat hypertriglyceridemia ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ^^^^^^^^^^ _ ^^^^^^^^^^ _ ^^^^^^ of a compound of formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or said prodrug and a pharmaceutically acceptable carrier. This invention also relates to pharmaceutical compositions for the treatment of familial hypercholesterolemia in a mammal (including a human), comprising an amount for treating familial hypercholesterolemia of a compound of formula I, a prodrug thereof, or a pharmaceutically salt acceptable of said compound or said prodrug and a pharmaceutically acceptable carrier. This invention also relates to pharmaceutical compositions for the treatment of angina in a mammal (including a human), comprising an amount for angina of a compound of formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug and a pharmaceutically acceptable carrier. This invention also relates to pharmaceutical compositions for the treatment of ischemia in a mammal (including a human), which comprises an amount for treating the ischemia of a compound of formula I, a prodrug thereof, or a pharmaceutically acceptable salt thereof. said compound or said prodrug and a pharmaceutically acceptable carrier. This invention also relates to pharmaceutical compositions for the treatment of cardiac ischemia in a mammal (including a human), which comprises an amount for treating cardiac ischemia of a compound of the formula I, a prodrug thereof, or a salt pharmaceutically acceptable of said compound or said prodrug and a pharmaceutically acceptable carrier. This invention also relates to pharmaceutical compositions for the treatment of stroke in a mammal (including a human), comprising an amount for treating stroke of a compound of formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or said prodrug and a pharmaceutically acceptable carrier. This invention also relates to pharmaceutical compositions for the treatment of myocardial infarction in a mammal (including a human), comprising an amount for treating myocardial infarction of a compound of formula I, a prodrug thereof, or a salt pharmaceutically acceptable of said compound or said prodrug and a pharmaceutically acceptable carrier. This invention also relates to pharmaceutical compositions for the treatment of reperfusion injury in a mammal (including a human), comprising an amount for treating the reperfusion injury of a compound of formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or said prodrug and a pharmaceutically acceptable carrier.

This invention also relates to pharmaceutical compositions for the treatment of angioplastic restenosis in a mammal (including a human), comprising an amount for treating angioplastic restenosis of a compound of formula I, a prodrug thereof, or a pharmaceutically salt acceptable of said compound or said prodrug and a pharmaceutically acceptable carrier. This invention also relates to pharmaceutical compositions for the treatment of hypertension in a mammal (including a human), comprising an amount for treating hypertension of a compound of formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or said prodrug and a pharmaceutically acceptable carrier. This invention also relates to pharmaceutical compositions for the treatment of vascular complications of diabetes in a mammal (including a human), which comprises an amount to treat the vascular complications of diabetes of a compound of formula I, a prodrug of the same, or a pharmaceutically acceptable salt of said compound or of said prodrug and a pharmaceutically acceptable carrier. This invention also relates to pharmaceutical compositions for the treatment of obesity in a mammal (including a human), comprising an amount for treating obesity of a compound of formula I, a prodrug thereof, or a salt pharmaceutically acceptable of said compound or said prodrug and a pharmaceutically acceptable carrier. This invention also relates to pharmaceutical compositions for the treatment of endotoxemia in a mammal (including a human), which comprises an amount for treating the endotoxemia of a compound of formula I, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug and a pharmaceutically acceptable carrier. This invention also relates to a combination pharmaceutical composition comprising: a therapeutically effective amount of a composition comprising a first compound, said first compound being a compound of formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug; a second compound, said second compound being an inhibitor of HMG-CoA reductase, an inhibitor of the secretion of the microsomal triglyceride transfer protein (MTP) / ApoB, a PPAR activator, a bile acid reuptake inhibitor, an inhibitor of cholesterol absorption, an inhibitor of cholesterol synthesis, a fibrate, niacin, an ion exchange resin, an antioxidant, an ACAT inhibitor or a bile acid complexing agent; and / or, optionally, a pharmaceutical carrier.

Among the second compounds, an inhibitor of HMG-CoA reductase and an inhibitor of MTO / Apo B secretion is preferred. A particularly preferred inhibitor of HMG-CoA reductase is lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin or rivastatin. Another aspect of this invention is a method for the treatment of atherosclerosis in a mammal comprising administering to a mammal suffering from atherosclerosis; a first compound, said first compound being a compound of formula I, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug; and a second compound, said second compound being an inhibitor of MTP-CoA reductase, an inhibitor of MTP / ApoB secretion, an inhibitor of cholesterol absorption, an inhibitor of cholesterol synthesis, a fibrate, niacin, an ion exchange resin, an antioxidant, an ACAT inhibitor or a bile acid complexer, where the amounts of the first and second compounds produce therapeutic effect. A preferred aspect of the above process is that in which the second compound is an HMG-CoA reductase inhibitor of MTP / Apo B secretion.

A particularly preferred aspect of the above process is that in which the HMG-CoA reductase inhibitor is lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin or rivastatin. Yet another aspect of this invention is a team comprising: a. a first compound, said first compound being a compound of formula-I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or said prodrug and a pharmaceutically acceptable carrier, in a first unit dosage form; b. a second compound, said second compound being an inhibitor of HMG CoA reductase, an inhibitor of MTP / Apo B secretion, an inhibitor of cholesterol absorption, an inhibitor of cholesterol synthesis, a fibrate, niacin, a resin ion exchange, an antioxidant, an ACAT inhibitor or a bile acid complex and an acceptable vehicle in a second unit dosage form; and c. means for containing said first and second dosage unit forms, wherein the amounts of the first and second compounds produce a therapeutic effect. A second preferred compound is an inhibitor of HMG-CoA reductase or an inhibitor of MTP / Apo B secretion. < *? '^. "üí» j ^ ugly «.fej».

A particularly preferred inhibitor of HMG-CoA reductase is lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin or rivastatin. As used herein, it is understood that the term mammals refers to all mammals that contain CETP in their plasma, for example, rabbits and primates such as monkeys and humans: Certain other mammals, for example, dogs, cats, cows, goats, sheep and horses do not contain CETP in their plasma and, therefore, are not included here. The term "treatment" as used herein includes preventive (e.g., prophylactic) and palliative treatment. By "pharmaceutically acceptable salts" is meant the carrier, diluent, excipients and / or salts which have to be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. The term "prodrug" refers to compounds that are drug precursors, which after administration, release the drug in vivo by some chemical or physiological processes (for example, a prodrug which, when carried to physiological pH or by an enzymatic action, is converts to the desired drug form). Exemplary prodrugs, upon cleavage, release the corresponding free acid, and such hydrolyzable ester formed moieties of the compounds of formula I include, but are not limited to, those having a carboxyl radical in which the free hydrogen has been replaced by alkyl (dd), alkanoyloxymethyl (C2-) • ^ - .. * ~. ", D), 1- (alkanoyloxy) ethyl having from 4 to 9 carbon atoms, 1-methyl-1- (alkanoyloxy) -ethyl having from 5 to 10 carbon atoms , alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1- (alkoxycarbonyloxy) ethyl having from 4 to 7 carbon atoms, 1-methyl-1- (alkoxycarbonyloxy) ethyl having from 5 to 8 carbon atoms, N- (alkoxycarbonyl) aminomethyl having from 3 to 9 carbon atoms, 1- (N- (alkoxycarbonyl) amino) ethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4-crotonolactonyl, gamma-butyroacton-4-yl , di-NN-alkylaminoCrd) -alkyl-d), (such as b-dimethylaminoethyl), carbamoyl-(C1-C2) alkyl, N, N-di-alkylcarbamoyl (d-C4) -alkyl (C1-C2) and piperidino-, pyrrolidino- or morpholino ((C2-d) alkyl). The following paragraphs describe exemplary rings for the descriptions of generic rings contained in this document. Exemplary five- or six-membered aromatic rings optionally having one or two heteroatoms independently selected from oxygen, nitrogen and sulfur include phenyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrimidinyl and pyrazinyl. Rings of five to eight partially saturated, fully saturated or fully unsaturated, optionally having one to four heteroatoms independently selected from oxygen, sulfur and nitrogen include cyclopenty, cyclohexyl, cycloheptyl, cyclooctyl and phenyl. Other exemplary rings of five members include 2H-pyrrolyl, 3H-pyrrolyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, 1,3-dioxolanyl, oxazolyl, thiazolyl, imidazolyl, 2H-imidazolyl, 2-yl idozolyl, imidazolidinyl, pyrazolyl, 2-pyrazolinyl, pyrazolidinyl. , isoxazolyl, isothiazolyl, 1,2-dithiolyl, 1,3-dithiolyl, 3H-1,2-oxathiolyl, 1,2,3-oxadiazolyl, 1,4-oxadiazolyl, 1, 2,5-oxadiazolyl, 1 , 3,4-oxadiazolyl, 1,2,3-triazolyl, 1,4-triazolyl, 1,4-thiadiazolyl, 1, 2,3,4-oxatriazolyl, 1, 2,3,5-oxatriazolyl , 3H-1, 2,3-dioxazolyl, 1,4-dioxazolyl, 1,2-dioxazolyl, 1,4-dioxazolyl, 5H-1, 2,5-oxathiazolyl and 1,3-oxathiolyl . Other exemplary six membered rings include 2H-pyranyl, 4H-pyranyl, pyridinyl, piperidinyl, 1,2-dioxinyl, 1,3-dioxinyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl, thiomorinolinyl, pyridazinyl, pyrimidinyl. , pyrazinyl, piperazinyl, 1, 3,5-triazinyl, 1,4-triazinyl, 1, 2,3-triazinyl, 1, 3,5-trityanyl, 4H-1,2-oxazinyl, 2H-1, 3 -oxazinyl, 6H-1, 3-oxazinyl, 6H-1,2-oxazinyl, 1,4-oxazinyl, 2H-1,2-oxazinyl, 4H-1,4-oxazinyl, 1, 2,5-oxathiazinyl, , 4-oxazinyl, or isoxazinyl, p-isoxazinyl, 1, 2,5-oxathiazinyl, 1, 2,6-oxathiazinyl, 1,4,2-oxadiazinyl and 1, 3,5,2-oxadiazinyl. Other exemplary seven-membered rings include azepinyl, oxepinyl and thiepinyl. Other exemplary rings of eight members include cyclooctyl, cyclooctyl and cyclooctadienyl. The exemplary bicyclic rings consisting of two fused rings of five or six members, partially saturated, fully saturated or totally unsaturated, taken independently, having ..Safe *? -. ZSH a & X. "ZT ^. * TSihZ.> Optionally from one to four heteroatoms independently selected from nitrogen * sulfur and oxygen include indolizinyl, indolyl, isoindolyl, 3H-indolyl, 1 H-isoindolyl, indolinyl, cyclopenta (b) pyridinyl. , pyran (3,4-b) pyrrolyl, benzofuryl, isobenzofuryl, benzo (b) thienyl, benzo (c) thienyl, 1 H-indazolyl, indoxazinyl, benzoxazolyl, benzoimidazolyl, benzothiazolyl, purinyl, 4H-quinolizinyl, quinolinyl, isoquinolinyl, cinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridyl, pteridinyl, indenyl, isoindenyl, naphthyl, tetralinyl, decalinyl, 2H-1-benzopyranyl, pyrido (3,4-b) -pyridinyl, pyrido (3,2-b) ) -pyridinium, pyridine (4,3-b) -pyridinium, 2H-1,3-benzoxazinyl, 2H-1,4-benzoxazinyl, 1 H-2,3-benzoxazinyl, 4H- 3,1-benzoxazinyl, 2H-1,2-benzoxazinyl and 4H-1,4-benzoxazinyl Acyl alkylene is understood to mean a saturated hydrocarbon (straight or branched chain) in which a hydrogen atom has been removed from each of the terminal carbons. Examples of such groups (assuming that the designated length encompasses the particular example) are methylene, ethylene, propylene, butylene, pentylene, hexylene and heptylene). Halo means chlorine, bromine, iodine or fluorine. By "alkyl" is meant a straight chain saturated hydrocarbon or a branched chain saturated hydrocarbon. Examples are such alkyl groups (assuming that the designated length encompasses the particular example) methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tertiary butyl, pentyl, stilpentyl, neopentyl, tertiary pentyl, 1-methylbutyl, 2-methylbutyl , 3-methylbutyl, hexyl, isohexyl, heptyl and octyl.

By "alkoxy" is meant straight chain saturated alkyl or branched chain saturated alkyl attached through an oxy group. Examples of such alkoxy groups (assuming that the designated length encompasses the particular example) are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutyloxy, tertiary butoxy, pentoxy, isopentoxy, neopentoxy, tertiary pentoxy, hexoxy, isohexoxy, heptoxy and octoxy. As used herein, the term mono-N- or di-N, N-alkyl (d-Cx) ... refers to the alkyl radical (dd) taken independently when it is di-N, N-alkyl (CrCx) ) ... (x refers to integers). It will be understood that if a carbocyclic or heterocyclic radical can be linked or otherwise bound to a designated substrate through different ring atoms without indicating a specific point of attachment, all possible points are referred to, either through a carbon atom or, for example, a trivalent nitrogen atom. For example, the term "pyridyl" means 2-, 3- or 4-pyridyl, the term "thienyl" means 2- or 3-thienyl, and so on. The references (e.g., in claim 1) to "said carbon" in the phrase "said carbon is optionally mono-, di- or tri-substituted independently with halo, said carbon being optionally mono-substituted with hydroxy, said carbon being optionally mono-substituted with oxo "refers to the carbons of the carbon chain including the connecting carbon.

References to a "nitrogen ... di-substituted with oxo" in this document (e.g., in claim 1) refer to a terminal nitrogen that constitutes a nitro functionality. The term "pharmaceutically acceptable salt" refers to non-toxic anionic salts containing anions such as (but not limited to) chloride, bromide, iodide, sulfate, bisulfate, acetate, maleate, fumarate, oxalate, lactate, tartrate, citrate, gluconate , methanesulfonate and 4-toluene sulfonate. The term also refers to non-toxic cationic salts such as (but not limited to) sodium, potassium, calcium, magnesium, ammonium or protonated benzathine (N.N'-dibenzylethylenediamine), choline, ethanolamine, diethanolamine, ethylenediamine, meglumine ( N-methyl-glucamine), benetamine (N-benzylphenethylamine), piperazine or tromethamine (2-amino-2-hydroxymethyl-1,3-propanediol). As used in this document, the terms "solvent" "Inert to the reaction" and "inert solvent" refer to a solvent or a mixture thereof that does not interact with the starting materials, reagents, intermediates or prodrugs in a manner that adversely affects the yield of the desired product. "cis" refers to the orientation of two substituents with each other and with respect to the plane of the ring (both "up" or both "down"). Analogously, the term "trans" refers to the orientation of two substituents with respect to each other and with respect to the plane of the ring (the substituents being on opposite sides of the ring).

Alpha and beta refer to the orientation of a substituent with respect to the plane of the ring (ie, the page). Beta is above the plane of the ring (that is, the page) and alpha is below the plane of the ring (ie, the page). The chemists of ordinary experience will recognize that certain compounds of this invention will contain one or more atoms that can be in a particular stereochemical or geometric configuration, giving rise to stereoisomers and configurational isomers. All such isomers and mixtures thereof are included in this invention. They are also including the hydrates and solvates of the compounds of this invention. It will be recognized that the compounds of this invention can exist in radiolabelled forms, that is, said compounds can contain one or more atoms containing an atomic mass or mass number different from the atomic mass or mass number found usually in nature. The radioisotopes of hydrogen, carbon, phosphorus, fluorine and chlorine include 3H, 14C, 32P, 35S, 18F and 36CI, respectively. The compounds of this invention, or prodrugs thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug containing these radioisotopes and / or other radioisotopes of other atoms, are within the scope of this invention. Particularly preferred are tritiated radioisotopes, i.e., 3 H and carbon-14, i.e., 14C, for their easy preparation and detectability. The radiolabelled compounds of formula I of this invention and the prodrugs thereof can be prepared generally by procedures well known to those skilled in the art. Conveniently, such radiolabelled compounds can be prepared by performing the procedures described in the schemes and / or in the examples and preparations shown below, by replacing a non-radiolabelled reagent with a readily available radiolabelled reagent. DTT means dithiothreitol, DMSO means dimethyl sulfoxide, EDTA means ethylenediamine tetraacetic acid. Other features and advantages of this invention will be apparent from this specification and the appended claims describing the invention.

DETAILED DESCRIPTION OF THE INVENTION In general, the compounds of this invention can be obtained by processes that include processes analogous to those known in the chemical arts, particularly in light of the description contained herein. Certain processes for the manufacture of the compounds of this invention are provided as further features of the invention and are illustrated by the following reaction schemes. In the experimental section, other procedures can be described. * - »faith. FsJ, t.

SCHEME I Vil VI ^ ¿IgigjS ^ gj ^ g ^ gí ^ Aí ^ 'SCHEME lll SCHEME IV ajsjfe.7".- ..," .. a * s £ * ^. j e¡ 8 ^ * £ rfl lSílk.7il * < * r *. ^ -S «... AAri» l) < «» .-? ^ »» I ... Sáí ^ ixjioitSi • SCHEME V LVI LVIII LV Lili SCHEME VI LXIV gj > ifc ..? = éfeaifeA a -, t.wta '"..'? cÜa». »» C A, Ait- 'A? sü.jr ..,: SCHEME Vil LXX LXXI LXXII - ^ áfe ^ - ^^ - g ^ i & "£ -« =: SCHEME VIII LXXXII LXXXIII LXXXV LXXXVI As an initial note, it should be noted that in the preparation of the compounds of formula I some of the preparation methods useful for the preparation of the compounds described herein require protection of a remote functionality (eg, primary amine, secondary amine or carboxyl in the precursors of formula I). The need for such protection will vary depending on the nature of the remote functionality and of the conditions of the preparation procedures. The need for such protection is easily determined by one skilled in the art. The use of such protection / deprotection procedures is also within the skill in the art. As a general description of the protective groups and their use, see T.W. Greene, Protective Groups in Orqanic Synthesis. John Wiley & Sons, New York, 1991. For example, in reaction schemes I and II certain compounds of formula I contain primary amine or carboxylic acid functionalities that can interfere with reactions and other sites of the molecule if left unprotected. Accordingly, such functionalities can be protected by an appropriate protective group that can be removed at a later stage. Suitable protecting groups for the protection of the amine and the carboxylic acid include the protecting groups commonly used in the synthesis of peptides (such as Nt-butoxycarbonyl, benzyloxycarbonyl and 9-fluorenylmethyleneoxycarbonyl for amines, and lower alkyl or benzyl esters for acids carboxylic acids) which are generally not chemically reactive under the described reaction conditions and can typically be removed without chemically altering other functionalities of the compound of formula I. According to reaction scheme I, the compounds of formula III in which R2, R5, R6, R7 and R8 are as described above and P2 is a suitable protecting group, they can be prepared from the appropriate aromatic amine of formula II wherein R5, R6, R7 and R8 are as described above. The tetrahydroquinoline of formula III is prepared by treating the appropriate aromatic amine of formula II with the required carboxaldehyde, in an inert solvent such as a hydrocarbon (eg, hexanes, pentanes or cyclohexane), an aromatic hydrocarbon (eg, benzene) , toluene or xylene), a halocarbon (e.g., dichloromethane, chloroform, carbon tetrachloride or dichloroethane), an ether (e.g., diethyl ether, diisopropyl ether, tetrahydrofuran, tetrahydropyran, dioxane, dimethoxyethane, methyl tert-butyl ether, etc. .), a nitrile (e.g., acetonitrile or propionitrile), a nitroalkane (e.g., nitromethane or nitrobenzene), preferably dichloromethane, with a dehydrating agent (e.g., sodium sulfate or magnesium sulfate), at a temperature of about 0 ° C at about 100 ° C (preferably at room temperature) for 1-24 hours (preferably 1 hour). The resulting solution is treated with a conveniently substituted N-vinyl species (for example, benzyloxycarbonyl, t-butoxycarbonyl, methoxycarbonyl, formyl-, acetyl-, diallyl- or dibenzyl-N-vinyl) preferably carboxybenzyloxy-N-vinyl and with a Lewis acid (for example, boron trifluoride, boron trifluoride etherate, zinc chloride, titanium tetrachloride, iron trichloride, aluminum trichloride, aluminum alkyl dichloride, dialkyl aluminum chloride or ytterbium triflate (II); preferably boron trifluoride etherate) or a protic acid such as hydrohalogenic acid (eg, fluorine, chlorine, bromine or iodine), an alkyl sulfonic acid (eg, p-toluene, methane or trifluoromethane) or carboxylic acid (e.g. formic, acetic, trifluoroacetic or benzoic), at a temperature from about -78 ° C to about 50 ° C (preferably at room temperature), for 0.1 to 24 hours (preferably for 1 hour). Alternatively, the amine of formula II and the appropriate carboxaldehyde can be condensed by treating a solution of the amine and an alkyl amine base (preferably triethylamine) in a polar aprotic solvent (preferably dichloromethane) with titanium tetrachloride, in an aprotic solvent. polar (preferably in dichloromethane), at a temperature between about -78 ° C and about 40 ° C (preferably 0 ° C), followed by treatment with the carboxaldehyde at a temperature between about -78 ° C and about 40 ° C C (preferably 0 ° C). The reaction is allowed to proceed for about 0.1 to about 10 hours (preferably for 1 hour), at a temperature between about 0 ° C and about 40 ° C (preferably at room temperature), producing the amine, which is reacted with the N-vinyl species as described above. Compounds of formula IV in which R1, R2, R5, R6, R7 and R8 are as described above P1 and P2 are protective groups, can be prepared from the corresponding amine of formula III by various reaction routes of amines known to those skilled in the art.

Thus, the compounds of formula IV in which R1, R2, R5, R6, R7 and R8 are as described above and P1 and P2 are protective groups appropriately differentiated for the amine radicals, are prepared from the corresponding tetrahydroquinoline of formula III using standard procedures for transforming amines into the functional groups described for R1 above, see Richard Larock, Comprehensive Organic Transformations. VCH Publishers Inc., New York, 1989 and Jerry March, Advanced Organic Chemistry. John Wiley & Sons, New York, 1985. For example, a compound of formula III is treated with the appropriate carbonyl chloride, sulfonyl chloride or sulfinyl chloride, isocyanate or thiocyanate, in a polar aprotic solvent (preferably dichloromethane), in the presence of a base (preferably pyridine), at a temperature of about -78 ° C to about 100 ° C (preferably starting at 0 ° C and allowing to warm to room temperature) for a period of 1 to 24 hours (preferably 12 hours). The carbamate of formula IV and the urea compounds (where R1 is W = C (0), X = OY, SY, N (H) -Y or NY2) can be prepared from the amines of formula III by means of the corresponding carbamoyl chlorides, by treating the amine of formula III with a solution of phosgene in a hydrocarbon solvent (preferably toluene) at a temperature comprised between about 0 ° C and about 200 ° C (preferably under reflux) for a period comprised between 0.1 and 24 hours (preferably 2 hours).

The corresponding ureas can be prepared by treating a solution of the carbamoyl chlorides (prepared as described above) with the appropriate amine in a polar solvent (preferably dichloromethane), at a temperature ranging from about -78 ° C to about 100 ° C. ° C (preferably at room temperature), for a period comprised between 1 and 24 hours (preferably 12 hours). The corresponding carbamate can be prepared by treating a solution of the carbamoyl chlorides (prepared as described above) with the appropriate alcohol and a suitable base (preferably sodium hydride) in a polar solvent (preferably dioxane), at a temperature comprised between about -78 ° C and about 100 ° C (preferably at room temperature), for a period comprised between 1 and 24 hours (preferably 12 hours). Alternatively, the corresponding carbamate can be prepared by treating a solution of the carbamoyl chlorides at a temperature between about 0 ° C and about 200 ° C in the appropriate alcohol, for a period of between 1 and 240 hours (preferably 24 hours). hours). The compound of formula IV in which R1 is Y, can be prepared using methods known to those skilled in the art to introduce Y substituents such as an alkyl or alkyl-linked substituent. The methods include, for example, the formation of the amide from the amine of formula III and a carbon acid? activated fco, followed by reduction X * of the amide with borane in an ethereal solvent such as tetrahydrofuran. Alternatively, the alkyl or alkyl-linked substituent may be attached by reduction after condensation of the amine of formula III with the required carbonyl-containing reagent. In addition, the amine of formula III can be reacted with the appropriate alkyl or aryl halide according to procedures known to those skilled in the art. Thus, the amine of formula III and an acid (eg, halogenic, sulfuric, sulfonic or carboxylic, preferably acetic) are treated with the appropriate carbonyl-containing reagent, in a polar solvent (preferably ethanol), at a temperature of about 0 ° C to approximately 100 ° C (preferably at room temperature), for a period of about 0.1 to 24 hours (preferably 1 hour), followed by treatment with a hydride source (eg, sodium borohydride, sodium cyanoborohydride or preferably sodium triacetoxyborohydride), at a temperature of about 0 ° C to about 100 ° C (preferably at room temperature) for a period of 0.1 to 100 hours (preferably 5 hours). The amine of formula V in which R1, R2, R5, R6, R7 and R8 are as described above P1 is a protecting group, can be prepared from the corresponding compound of formula IV by deprotection (P2) using known procedures by those skilled in the art, including hydrogenolysis, treatment with an acid (e.g., trifluoroacetic or hydrobromic acid), a base (sodium hydroxide), or the reaction with a nucleophile (for example, sodium methylthiolate, sodium cyanide, etc.) and for the trialkylsilylethoxycarbonyl group a fluoride (for example, tetrabutyl ammonium fluoride) is used ). For the removal of a benzyloxycarbonyl group, hydrogenolysis is carried out by treating the compound of formula IV with a hydride source (for example, 1 to 10 atmosphere of hydrogen gas, cyclohexene or ammonium formate) in the presence of a suitable catalyst ( for example, palladium of 5-20% on carbon, palladium hydroxide, preferably 10% palladium on carbon), in a The polar solvent (for example, methanol, ethanol or ethyl acetate, preferably ethanol), at a temperature between about -78 ° C and about 100 ° C, preferably at room temperature, for a period of 0.1 to 24 hours, preferably 1 hour. The compounds of formula IV in which R 1, R 2, R 3, R 5, R 6, R 7 and R8 are as described above P1 is a protecting group as described above, can be prepared from the corresponding amine of formula V by various amine reaction routes known to those skilled in the art. Compounds of formula VI wherein R3 is as described above, can be prepared using methods known to those skilled in the art to introduce R3 substituents; including, for example, the procedures described for the introduction of the substituent R1 SA ^^^^^^^^ | ^ j ^ '«K Mgsß ^^^^^ A ^^^^^^ 3¡ ^^^? in the transformation of the compounds of formula III in the compounds of formula IV. The methods include, for example, the formation of an amide from the amine of formula V and an activated carboxylic acid, followed by reduction of the amide with borane in an ether solvent such as tetrahydrofuran. Alternatively, an alkyl or alkyl-linked substituent may be added by reduction of the appropriate mine, the mine being formed by condensation of the amine of formula V with the required carbonyl-containing reagent. In addition, the amine of formula V can be reacted with the appropriate alkyl halide according to methods known to those skilled in the art. Thus, the amine of formula V and an acid (eg, halogenic, sulfuric, sulfonic or carboxylic, preferably hydrochloric) are treated with the appropriate carbonyl-containing reagent in a polar solvent (preferably dichloromethane), at a temperature of about 0. ° C at about 100 ° C (preferably at room temperature), for a period of about 0.1 to 24 hours (preferably 1 hour), followed by treatment with a hydride source (eg, sodium borohydride or sodium cyanoborohydride, preferably sodium triacetoxyborohydride) ), at a temperature from about 0 ° C to about 100 ° C (preferably at room temperature), for 0.1 to 100 hours (preferably for 5 hours). The compound of formula VII in which R1, R2, R3, R5, R6, R7 and R8 are as described above P1 and P2 are protective groups, can be prepared from the corresponding compound of formula IV by procedures known to the experts in the art; for example, the methods described for the introduction of the above substituent R3 in the transformation of the compound of formula V into the compound of formula VI. After this, the corresponding compound of formula VI can be prepared from the compound of formula VII by appropriate deprotection, such as the procedures described above for the transformation of the compound of formula IV into the compound of formula V. When R3 is H and R4 is as described above, R4 can be represented by R3 in formulas VI and VII of Scheme I, thus providing a synthetic scheme for such compounds. According to scheme II, the dihydroquinolone compounds of formula XI wherein R2, R5, R6, R7 R8 and Y are as described above and P1 is a protecting group, can be prepared from the corresponding quinolines of formula X by treatment with species organometallic and a chloroformate followed by hydrolysis. Thus, a mixture of the quinoiin of formula X and an excess (preferably 1.5 equivalents) of an organomagnesium species (Grignard reagent) in a polar aprotic solvent (e.g., diethyl ether or dichloromethane) is treated.; preferably tetrahydrofuran), with an excess (preferably 1.5 equivalents) of Y- or P1-chloroformate, at a temperature comprised between about -100 ° C and about 70 ° C (preferably -78 ° C), followed by heating to -Tazara - - .. - ^ ~ ^ í & Si¡ ¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡e ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ environment) for a period between 0.1 and 24 hours (preferably 1 hour). The resulting mixture is combined with excess (preferably 2 equivalents) of an aqueous acid (preferably 1 molar hydrochloric acid) and mixed vigorously for a period between 0.1 and 24 hours (preferably 1 hour, or until it is determined to have been completed) the hydrolysis of the intermediate enol ether). Of course, the compounds of formula XI are the compounds of formula XVI wherein R1 is -C (O) OY or p1 is C (O) OP1 without further transformation. Compounds of formula XV wherein R2, R5, R6, R7 and R8 are as described above, can be prepared from the corresponding dihydroquinolone of formula XI (wherein the compound of formula XI contains P1) by appropriate deprotection ( including spontaneous decarboxylation) as described for the transformation of the compound of formula VI into the compound of formula V. Compounds of formula XVI wherein R1, R2, R5, R6, R7 and R8 are as described above and P1 is a protecting group, can be prepared from the corresponding dihydroquinolone of formula XV as described for the transformation of the compound of formula III into the compound of formula IV. In certain cases in which the reagent has also reacted on the carbonyl oxygen in position 4, the substituent can be conveniently removed by treatment with an acid (for example HCl) or a base (for example, aqueous sodium hydroxide). Again for the compounds of formula XVI wherein R1 or P1 is the same as for the compound of formula XI, such a transformation as described above is not necessary. The amine compounds of formula VI in which R1, R2, R3, R5, R6, R7 and R8 are as described above and P1 is a protecting group, can be prepared from the corresponding dihydroquinolone of formula XVI by a sequence of reductive amination. The dihydroquinolone of formula XVI, an excess (preferably 1.1 equivalents) of an R3-amine and an excess (preferably 7 equivalents) of an amine base (preferably triethylamine) in a polar solvent (preferably dichloromethane), is treated with 0.5 to 1.0 equivalents (preferably 0.55 equivalents) of titanium tetrachloride in the form of a solution in a suitable polar solvent (preferably dichloromethane), at a temperature comprised between about 0 ° C and about 40 ° C (preferably at room temperature), for a period comprised between 1 and 24 hours (preferably 12 hours). The resulting imine of formula XII is reduced by treatment with a reducing agent (preferably sodium borohydride) in an appropriate polar solvent (preferably ethanol), at a temperature between about 0 ° C and about 80 ° C (preferably at room temperature) , for a period between 1 and 24 hours (preferably 12 hours), resulting in a mixture of diastereomeric amines of formula VI, generally with a greater amount of the trans isomer. Alternatively, the reduction can be carried out by treating the imine of formula XII directly with an excess (preferably 5 equivalents) of zinc borohydride as a solution in ether (preferably 0.2 molar), at a temperature comprised between about 0 ° C and about 40 ° C (preferably room temperature), for a period of between 1 and 24 hours (preferably 12 hours), resulting in a mixture of diastereomeric amines of formula VI, generally with a greater proportion of the cis isomer. Alternatively, the amine of formula VI in which R1, R2, R3, R5, R6, R7 and R8 are as described above and P1 is a protecting group, can be prepared from the corresponding dihydroquinolines of formula XVI by the formation of an oxime, reduction and substitution of the amine. Thus, the dihydroquinolone of formula XVI, an excess (preferably 3 equivalents) of hydroxylamine hydrochloride and an excess (preferably 2.5 equivalents) of a base (preferably sodium acetate) are reacted at a temperature between about 0 ° C and about 100 ° C (preferably at reflux) for a period between about 1 and 24 hours (preferably 2 hours), in a polar solvent (preferably ethanol). The resulting oxime of formula XIII is treated with an excess (preferably 6). equivalents) of aqueous base (preferably 2 N potassium hydroxide), in a polar solvent (preferably ethanol) and an excess (preferably 4 equivalents) of a nickel-aluminum alloy (preferably 1: 1 by weight), at a temperature between about 0 ° C and about 100 ° C (preferably at room temperature), for a period between 0.25 and 24 hours (preferably 1 hour). The resulting amine of formula V is obtained in the form of a diastereomeric mixture (the cis isomer generally predominating). The secondary amine of formula VI in which R1, R2, R3, R5, R6, R7 and R8 are as described above and P1 is a protecting group, can be prepared from the amine of appropriate formula V as described in scheme I for the transformation of the compound of formula V into the compound of formula VI. According to scheme III, the compounds of formula I, as described above, can be prepared from the appropriate compounds of formula VI by conversion of the desired carbamate. Thus, the amine of formula VI is treated with the appropriate activated carbonate (eg, chloroformate, dicarbonate or carbonyl imidazole followed by the appropriate alcohol) in a polar solvent (preferably dichloromethane) in the presence of an excess of amine base (preferably pyridine) at a temperature between about -20 ° C and about 40 ° C (preferably room temperature) for between 1 and 24 hours (preferably 12 hours) to produce the compound of formula I.

Alternatively, according to scheme III, when appropriate, if the functionality in R1 is incompatible with the reaction to form the compound of formula I, then the compound of formula VI with protected P1 can be transformed into the compound of formula I by the protection / deprotection sequences and the introduction of the desired substituents. Thus, the amine of formula VI is treated with the appropriate reagent (for example, precursor of the protecting group, activated carbonate (for example chloroformate, dicarbonate or carbonyl imidazole)) in a polar solvent (preferably dichloromethane), in the presence of an excess of amine base (preferably pyridine), at a temperature comprised between about -20 ° C and about 40 ° C (preferably at room temperature), for a period comprised between 1 and 24 hours (preferably 12 hours), to produce the compound of formula XX. In addition, compounds of formula XX, in which P2 is present, can be obtained as shown in scheme I for compounds of formula VII (having P1). The amines of formula XXI wherein R2, R3, R5, R6, R7, R8 and R4 are as described above and P2 is a protecting group, can be prepared from the compound of formula XX by selective deprotection of P1. When P1 is, for example, t-butoxycarbonyl, the compound of formula XXI is conveniently prepared by treatment with an acid (preferably trifluoroacetic acid), at a temperature comprised between about 0 ° C and 100 ° C (preferably at room temperature), for a period of 0.1 to 24 hours (preferably 1 hour). The compounds of the formula I or the compounds of the formula XXII (in which R1 is as described above), can be prepared from the corresponding amine of formula XXI (in which R4 or P2 is present respectively) by various routes of amine reaction known to those skilled in the art, for example, those described in scheme I for the transformation of the compound of formula III into the compound of formula IV. The amines of formula XXIII can be prepared from the compounds of formula XXII by suitable deprotection. When P2 is, for example, benzyloxycarbonyl, the compound of formula XXIII is prepared by treatment with an excess of a hydride source (e.g., cyclohexane, hydrogen gas or preferably ammonium formate) in the presence of 0.01 to 2 equivalents (preferably 0.1 equivalents) of a suitable catalyst (preferably 10% palladium on carbon), in a polar solvent (preferably ethanol), at a temperature comprised between about 0 ° C and about 100 ° C (preferably at room temperature), for a period of 0.1 to 24 hours (preferably 1 hour). The compound of formula I in which R4 is as described above, can be prepared using the methods described for the conversion of the compound of formula VI into the compound of formula I of scheme III above.

According to scheme IV, the compounds of formula V in which R1, R2, R5, R7 and R8 are as described above, and R6 is an ether-linked radical, can be obtained from the quinolones of formula XXX having a radical OP3, where P3 is a protecting group, in the Re position, employing the following procedures. Furthermore, in an analogous manner, such methods can be used to prepare the corresponding compounds wherein R5, R7 or R8 are an ether-linked radical starting from the corresponding compound of formula XXX having an OP3 radical at positions R5, R7 or R8 . Thus, the quinolone of formula XXX is combined with hydroxylamine hydrochloride and a mineral base (preferably sodium acetate) in a polar solvent (preferably ethanol), at a temperature between about 0 ° C and about 100 ° C (preferably at reflux ), for a period of between 1 and 24 hours (preferably 2 hours), to produce the oxime of formula XXXI. The oxime of formula XXXI is treated with an excess (preferably six equivalents) of an aqueous base (preferably 2 N potassium hydroxide) and an excess (preferably four equivalents) of a nickel-potassium alloy (preferably 1: 1 by weight) in a polar solvent (preferably ethanol), at a temperature comprised between about 0 ° C and about 100 ° C (preferably at room temperature), for a period between 0.25 and 24 hours (preferably 2 hours), to prepare the corresponding amine from formula XXXII. If necessary, the protecting group P3 can be removed using conventional procedures if the transformation of the oxime does not produce such cleavage. Alternatively, the compound of formula XXX can be deprotected (removal of P3) by methods known to those skilled in the art, prior to the formation of the oxime of formula XXXI wherein P3 is H, which can then be reduced to form the amine of formula XXXII. The compound of formula V in which R6 is an oxy-linked radical can be prepared by treating the alcohol of formula XXXII under, for example, Mitsunobu conditions. Thus, the phenol of formula XXXII is treated with a phosphine (preferably triphenylphosphine) and an azodicarboxylate (preferably bis- (N-methyl-piperazinyl) -azodicarboxamide) and the required alcohol in a polar solvent (preferably benzene). Of course, by means of Schemes I and II, the resulting compound of formula V can be transformed into the precursors of formula VI or formula VIII for the compounds of formula I of this invention. Alternatively, the compound of formula XX in which R6 is an ether-linked radical, wherein R1, R2, R3 and R4 are as described above and P1 and P2 are protecting groups, can be prepared from the alcohols of formula XXXII as described later. In addition, in an analogous way, such procedures can be used to prepare the corresponding compounds wherein R5, R7 or R8 are an ether bound radical starting from the corresponding compound of formula XXXII and, therefore, finally, the compound of formula XXX (ie, the compound of formula XXX having a P30- in positions R5, R7 or R8). The secondary amine of formula XXXIII wherein R3 is as described above, can be prepared from the corresponding compound of formula XXXII according to the procedures of Scheme I described above for the conversion of the compound of formula V to the compound of formula SAW. Compounds of formula XXXIV in which R4 is as described above, can be prepared from the amines of formula XXXIII by procedures analogous to those described in scheme III for the transformation of the compound of formula VI into the compound of formula I The phenol of formula XXXV can be selectively deprotected, for example, when R4O2CO- is present by treatment of the carbonate of formula XXXIV with potassium carbonate in a polar solvent (preferably methanol)., at a temperature comprised between about 0 ° C and about 100 ° C (preferably at room temperature) for a period comprised between 1 and 24 hours (preferably 12 hours). The corresponding XX ethers can be prepared from the phenol of formula XXXV using, for example, the Mitsunobu conditions described above for the conversion of the compounds of formula XXXII into the compounds of formula V.

* J ^ K ^^ fá¡ßi ^ ¡&amp! A! ^ e-7k & ^ ÍtÁ'i '^ Xs; g & i * - 4¡j £ &&J! Of course, one skilled in the art will appreciate that phenol can be transformed into a variety of functional groups using conventional procedures, for example, as described in March or Larock, or by conversion into the corresponding triflate for use in a variety of reactions including transition metal catalysis. Although the following description of scheme V refers to the modifications of position R6 (position R6 described in formula I above), those skilled in the art will appreciate that analogous procedures can be applied to positions R5, R7 and R8. According to scheme V, the alcohol of formula Ll in which R1, R2, R3, R4, R5, R7 and R8 are as described above, P1 and P2 are protecting groups and X1 is a linking group in which a carbon (for example methylene) is directly attached to the carbonyl radical, they can be prepared from the corresponding ester (where R12 is a convenient alkyl radical) by reduction. Thus, the ester of formula L is treated with sodium borohydride / methanol or a complex of borane-dimethisulfide in a polar solvent (preferably tetrahydrofuran), at a temperature comprised between about 0 ° C and about 100 ° C (preferably under reflux), for a period comprised between 1 and 24 hours (preferably 3 hours). Compounds of formula Lll in which R1, R2, R3, R4, R5, R7 and R8 are as described above, P1 and P2 are protecting groups and wherein the R6 position includes an alkyl halide functionality, can prepare from the corresponding alcohol of formula Ll by treatment with trialkylphosphine (preferably triphenylphosphine) and a dihalogen (for example, bromine), in polar solvent (preferably dichloromethane), at a temperature between about -78 ° C and about 100 ° C (preferably at 0 ° C), for a period comprised between 0.1 to 10 hours (preferably 0.5 hours), followed by heating to room temperature for a period between 0.1 and 10 hours (preferably 3 hours). Compounds of formula Lili wherein R1, R2, R3, R4, R5, R7 and R8 are as described above, P1 and P2 are protective groups, position R6 includes ether and thioether radicals (ie, Y1 is S or O) and R13 is a carbon-bonded substituent, can be prepared by treating the alkyl halide of formula Lll in a polar solvent (preferably N, N-dimethylformamide) with the required alkoxide or thioalkoxide, at a temperature comprised between about 0 ° C and approximately 100 ° C (preferably at room temperature), for a period comprised between 1 and 24 hours (preferably 6 hours). Alternatively, the ethers and thioethers of formula Lili can be prepared by treating the corresponding alcohols and thiols of formula LIV (ie, Y1 is S or O), wherein X1 is a substituent directly attached through carbon to the methylene moiety , with a base (preferably sodium hydride) and the required alkylating agent in a polar solvent (preferably N, N-dimethylformamide), at a temperature comprised between about 0 ° C and about 100 ° C (preferably at room temperature), for a period comprised between 1 and 50 hours (preferably 18 hours). The compounds of formula LV in which R1, R2, R3, R4, R5, R7 and R8 are as described above, P1 and P2 are protective groups, position R6 includes alkyl halides (for example fluorides) and X1 is a substituent which is carbon directly attached to the methylene radical, can be prepared by treating the corresponding alcohol of formula Ll with a halogenating agent. For example, the alcohol is treated with a fluorinating agent (preferably diethylaminosulfur trifluoride) in a polar solvent (preferably 1,2-dichloroethane), at a temperature between about 0 ° C and about 100 ° C (preferably at 80 ° C). C), for a period comprised between 1 and 10 hours (preferably 0.75 hours). The amine compounds of formula LVII wherein R1, R2, R3, R4, R5, R7 and R8 are as described above, P1 and P2 are protecting groups and wherein R6 includes an amide functionality (such that X is a substituent that is carbon directly attached to the carbonyl radical and R10 and R11 are substituents selected for producing the desired R6 substituent defined above), can be prepared from the corresponding carboxylic acid of formula LVI which, in turn, can be prepared from the corresponding carboxylic ester of formula L.

JUME !.

Thus, the ester of formula L is treated with an aqueous hydroxide (preferably lithium, sodium or potassium) in a polar solvent (preferably tetrahydrofuran and / or methanol), at a temperature between about 0 ° C and about 100 ° C ( preferably at room temperature), for a period comprised between 0.1 and 100 hours (preferably 1 hour). The amide of formula LVII can be prepared from the corresponding acid of formula LVI by conventional procedures. The conversion of the carboxylic acid to the acid chloride is preferred by dissolving the acid in thionyl chloride and maintaining the solution at a temperature between about 0 ° C and about 80 ° C (preferably under reflux), for a period of time between 0.1 and 24 hours (preferably 1 hour), before the evaporation of the excess of thionyl chloride. This step is continued by treatment of the resulting acid chloride residue in a polar solvent (preferably dichloromethane) with the appropriate amine, selected to produce the amide functionality, and optionally an amine base (preferably triethylamine) at a temperature comprised between about -78 ° C and approximately 100 ° C (preferably at room temperature), for a period comprised between 0.1 and 100 hours (preferably 1 hour).

Although the following description of Scheme VI refers to the modifications of the R8 position, those skilled in the art will appreciate that analogous procedures can be applied for the positions R5, R6 and R7. According to Scheme VI, the compound of formula LXI in the that R1, R2, R3, R4, R5, R6 and R7 are as described above and P1 and P2 are protective groups, can be prepared from the corresponding compound of formula LX by nitration. The compound of formula LX is treated with nitrosyltriflate in a halogenated solvent, such as dichloromethane, at a temperature from about -78 ° C to about 0 ° C, for a period of from about 0.5 hours to about 3 hours, followed by heating to temperature ambient. The amine of formula LXII wherein R1, R2, R3, R4, R5, R6 and R7 are as described above and P1 and P2 are protecting groups, can be prepared from the corresponding compound of formula LXI by reduction. The compound of formula LXI is hydrogenated by treatment with hydrogen gas in the presence of a noble metal catalyst (eg, palladium on carbon) in a polar solvent such as ethanol, at a temperature of from about 0 ° C to about 100 ° C. for about 1 to 24 hours at elevated pressure (eg, 1 to 3 atmospheres). The compound of formula LXIII in which R1, R2, R3, R4, R5, R6 and R7 are as described above and P1 and P2 are protective groups and R8 is an amine-linked functionality, can be prepared from the corresponding formula LXII. Briefly, the amine of formula LXII is transformed following procedures analogous to those described in Scheme I for the conversion of the compound of formula III into the compound of formula IV. The compound of formula LXIV wherein R1, R2, R3, R4, R5, R6 and R7 are as described above and P1 and P2 are protective groups, can be prepared from the corresponding compound of formula LXII. The amine of formula LXII is treated with t-butyl nitrate and anhydrous cupric halide in a polar solvent at a temperature of about 30 ° C to about 100 ° C., for a period of about 1 hour to about 24 hours. Of course, one skilled in the art will understand that the halide can be transformed into a variety of functional groups using conventional methods, for example, as described in Larock or March. According to scheme VII, heterocycles of formula LXXI wherein R1, R2, R3, R4, R5 and R8 are as described above, P1 and P2 are protecting groups and R20 is a nitrogen-containing heterocycle condensed with the Quinoline ring structure, can be prepared from the compound of formula LXX, wherein P3 is a protecting group, by selective deprotection.

? * Afe »» 4jj $ stt. -l? c.

When P3 is, for example, benzyloxycarbonyl, the compound of formula LXX is conveniently cleaved to produce the compound of formula LXXI by treatment with a source of hydrogen (preferably 3 atmospheres of hydrogen gas), in the presence of a suitable catalyst (preferably palladium). at 10% on carbon) in a polar solvent (preferably ethanol) at a temperature between about 0 ° C and about 100 ° C (preferably at room temperature), for a period of 0.1 to 24 hours (preferably 1 hour) . Compounds of formula LXXII, wherein R1, R2, R3, R4, R5 and R8 are as described above, P1 and P2 are protecting groups, R20 is a nitrogen containing a fused heterocycle with the quinoline ring structure , and the "Substituent" is selected to produce the desired compounds described above, can be prepared from the corresponding amine of formula LXXI by various amine reaction routes known to those skilled in the art, for example, those described in the scheme I for the transformation of the compounds of formula III into the compounds of formula IV. The compounds of formula LXX can be prepared according to the procedures described in Schemes I, II and III. For example, in Scheme II, quinolines of formula X are formed by procedures known to those skilled in the art from the arylamines of formula II wherein R5 and R6, R6 and R7 or R7 and R8 comprise a ring as described above. These bicyclic arylamines are also synthesized by a variety of methods known to those skilled in the art. Such bicyclic arylamines are used in the sequence of transformations as illustrated in Schemes I and III to prepare the desired compounds. The compounds of formula LXX can also be obtained from the compounds of formula I, wherein R5 and R6, R6 and R7 or R7 and R8 contain a functionality susceptible to cyclization, for example Scheme VIII, thus forming the desired ring , using procedures known to those skilled in the art to cyclize such substituents. For example, the compound of formula LXXXII of scheme VIII is reacted with P3NH2 to give the protected P3 isoindoline. According to scheme VIII, the diesters of formula LXXX are reduced by producing the corresponding dialcohols of formula LXXXI according to procedures analogous to those described in scheme V for the transformation of the compounds of formula L into the compounds of formula Ll. Activation of these alcohols by electrophilic attack can be performed by several conventional methods, such as conversion to a halide or sulfate (preferably the conversion to the bis-bromide of formula LXXXII by treatment with two equivalents of dibromotriphenylphosphorane). The formation of the cyclohexane of formula LXXXIII can be achieved by treating the bis-bromide with sulfur (preferably sodium sulphide) in an aqueous / organic solvent system (Preferably a mixture of water and toluene) containing a suitable phase transfer catalyst (preferably triethylhexylammonium bromide), at a temperature between about 0 ° C and about 100 ° C (preferably at room temperature) for a period of time from 1 to 100 hours (preferably 12 hours). The oxygen heterocycles of formula LXXXIV can be formed using conventional etherification procedures including a nucleophilic displacement reaction with a bis-electrophile appropriate from the corresponding compound of formula LXXXII. For example, oxaciclo formation can be achieved by the treatment of a bis-bromide in an aqueous transparent solvent (preferably benzene) with an aqueous solution of hydroxide (preferably 30% sodium hydroxide) containing a suitable phase transfer catalyst. (preferably benzyl tri-n-butylammonium chloride) at a temperature comprised between about 0 ° C and about 100 ° C (preferably at 80 ° C), for a period between 1 and 100 hours (preferably 4 hours). The lactones of formula LXXXV and LXXXVI, wherein R1, R2, R3, R4, R5 and R8 are as described above and P1 and P2 are protective groups, can be formed using conventional lactonization process including an oxidative cyclization of the corresponding dialcohol of the formula LXXXI. Thus, a suitable bis-alcohol is treated with an oxidizing agent (preferably pyridinium chloroformate) in a solvent . . ».- > AA > a «?," Jii- * A. Z ^ iSS Mk see *. polar aprotic (preferably dichloromethane), at a temperature comprised between about 0 ° C and about 100 ° C (conveniently at room temperature), for a period comprised between 1 and 100 hours (preferably 24 hours) to prepare a mixture of the lactones of formula LXXXV and of formula LXXXVI which can be separated by conventional processes. The prodrugs of the compounds of the formula I can be prepared according to methods known to those skilled in the art. Exemplary procedures are described below. The prodrugs of this invention in which a carboxyl group of a carboxylic acid of formula I is replaced by an ester, can be prepared by combining the carboxylic acid with the appropriate alkyl halide, in the presence of a base such as potassium carbonate in a inert solvent such as dimethylformamide, at a temperature of about 0 to 100 ° C for a period of about 1 to about 24 hours. Alternatively the acid is combined with appropriate alcohol as solvent in the presence of a catalytic amount of acid such as concentrated sulfuric acid, at a temperature of about 20 to 100 ° C, preferably at the reflux temperature for a period of about 1 hour to approximately 24 hours. Another method is the reaction of the acid with a stoichiometric amount of the alcohol in the presence of a catalytic amount of acid in an inert solvent such as toluene or tetrahydrofuran, with the joint removal of the * > eu c ~ s. »-« -. ^. ¿Fc '& ».,' •? •. "~ S,. - ^ -i water produced by physical (eg Dean-Stark trap) or chemical (eg molecular sieves) The prodrugs of this invention in which an alcohol function has become as an ether , can be prepared by combining the alcohol with the appropriate alkyl bromide or iodide, in the presence of a base such as potassium carbonate, in an inert solvent such as dimethylformamide, at a temperature of about 0 to 100 ° C, for about 1 hour. at about 24 hours The alkanoylaminomethyl esters can be obtained by reaction of the alcohol with a bis- (alkanoylamino) methane in the presence of a catalytic amount of acid in an inert solvent such as tetrahydrofuran, according to a procedure described in the EUA document No. 4,997,984 Alternatively, these compounds can be prepared by the procedures described by Hoffman et al., In J. Org. Chem. 1994, 59, 3530. The glycos These are prepared by reacting the alcohol and a carbohydrate in an inert solvent such as toluene in the presence of acid. Typically, the water formed in the reaction is removed as it is being formed, as described above. An alternative procedure is the reaction of the alcohol with a suitable protected glycosyl halide in the presence of base followed by deprotection. The N- (1-hydroxyalkyl) amides, N- (1-hydroxy-1- (alkoxycarbonyl) methyl) amides can be prepared by reaction of the parent amine with the appropriate aldehyde under neutral or basic conditions (e.g., sodium ethoxide) in ethanol), at temperatures between 25 and 70 ° C. The N-alkoxymethyl or N-1- (alkoxy) alkyl derivatives can be obtained by the reaction of the N-unsubstituted compound with the necessary alkyl halide in the presence of a base in an inert solvent. The compounds of this invention may also be used in conjunction with other pharmaceutical agents (eg, LDL-cholesterol reducing agents or triglyceride reducing agents) for the treatment of the diseases / conditions described herein. For example, they can be used in combination with inhibitors of cholesterol synthesis, cholesterol absorption inhibitors, inhibitors of MTP / Apo B secretion and other cholesterol lowering agents such as fibrates., niacin, ion exchange resins, antioxidants, ACAT inhibitors and bile acid complexers. In treatment with combination therapies, the two compounds of this invention and the other drug therapies are administered to mammals (e.g., humans, men and women) by conventional procedures. In the combination aspect of this invention, any HMG-CoA reductase inhibitor can be used as the second compound. The term "HMG-CoA reductase inhibitor" refers to compounds that inhibit the bioconversion of hydroxymethylglutaryl coenzyme A to mevalonic acid catalyzed by the enzyme HMG-CoA reductase. Such inhibition is easily determined by those skilled in the art according to conventional tests (eg, Meth. Enzymol, 1981).; 71: 455-509 and references > > aaú ^ »cited here). A variety of these compounds are described and mentioned below, however, other HMG-CoA reductase inhibitors will be known to those skilled in the art. U.S. Patent No. 4,231,938 (the disclosure of which is incorporated herein by reference) discloses certain compounds isolated after culturing a microorganism belonging to the genus Aspergillus, such as lovastatin. Also, U.S. Patent No. 4,444,784 (the disclosure of which is incorporated herein by reference) discloses synthetic derivatives of the aforementioned compounds, such as simvastatin. In addition, U.S. Patent No. 4,739,073 (the disclosure of which is incorporated herein by reference) discloses certain substituted characters, such as fluvastatin. In addition, U.S. Patent No. 4,346,227 (the disclosure of which is incorporated herein by reference) discloses ML-236B derivatives, such as pravastatin. In addition, EP-491226A (the disclosure of which is incorporated herein by reference) discloses certain pyridylhydroxyheptenoic acids, such as rivastatin. In addition, U.S. Patent No. 5,237,995 (the disclosure of which is incorporated herein by reference) discloses certain 6- [2-substituted-pyrrol-1-yl) alkyl] pyran-2-ones such as atorvastatin. In the combination aspect of this invention, any inhibitor of MTP / Apo B secretion (microsomal triglyceride transfer protein and / or apolipoprotein B) can be used as the second compound. The term inhibitor of MTP / Apo B secretion refers to compounds that inhibit the secretion of triglycerides, cholesteryl ester and phospholipids. Such inhibition will be readily determined by those skilled in the art in accordance with conventional assays (eg, J.R. 1992; Science 258: 99). A variety of these compounds are described and mentioned below, however, other inhibitors of MTP / Apo A secretion will be known to those skilled in the art. WO 96/40640 and WO / 98/23593 are two exemplary publications. For example, the following inhibitors of MTP / Apo B secretion are particularly useful: [2- (1 H- [1, 2,4] triazol-3-llmethyl) -1, 2,3,4-tetahydro -isoquinolin-6-yl] -amide of 4'-trifluoromethyl-biphenyl carboxylic acid; [2- (2-Acetylamino-ethyl) -1,2,3,4-tetrahydro-isoquinolin-6-yl] -amide of 4'-trifluoromethyl-biphenyl-2-carboxylic acid; (2- {6 - [(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -3,4-dihydro-1H-isoquinolin-2-yl} -ethyl} -carbamic acid methyl ester; 4'-trifluoromethyl-2-phenyl-2-carboxylic acid [2- (1 H-imidazol-2-ylmethyl) -1,2,3,4-tetrahydro-isoquinolin-6-yl] -amide; 4-trifluoromethyl-biphenyl-2-carboxylic acid [2- (2,2-diphenyl-ethyl) -1,2,3,4-tetrahydro-isoquinolin-6-yl] -amide; and 4'-trifluoromethyl-biphenyl-2-carboxylic acid [2- (2-ethoxy-ethyl) -1,2,3,4-tetrahydro-isoquinolin-6-yl] -amide. In the combination aspect of this invention, any inhibitor of HMG-CoA synthase can be used as the second compound. The term "HMG-CoA synthase inhibitor" refers to compounds that inhibit the biosynthesis of hydroxymethylglutaryl-coenzyme A from acetyl-coenzyme A and acetoacetyl-coenzyme A, catalyzed by the enzyme HMG-CoA synthase. Such inhibition is easily determined by those skilled in the art according to conventional assays (Meth, Enzymol, 1975; 35: 155-160: Meth, Enzymol, 1985; 110: 19-26 and references cited here). A variety of these compounds are described and mentioned below, however, other HMG-CoA synthase inhibitors will be known to those skilled in the art. U.S. Patent No. 5,120,729 (the disclosure of which is incorporated herein by reference) discloses certain beta-lactam derivatives. U.S. Patent No. 5,064,856 (the disclosure of which is incorporated herein by reference) discloses certain spiro-lactone derivatives prepared by culturing a microorganism (MF5253). U.S. Patent No. 4, 847,271 (the disclosure of which is incorporated herein by reference) discloses certain oxetane compounds such as 11- (3-hydroxymethyl-4-oxo-2-oxethyl) -3,5,7-trimethyl-2,4-undeca acid derivatives -dienoco. Any compound that decreases the expression of the HMG-CoA reductase gene can be used as the second compound in the combination aspect of this invention. These agents can be transcription inhibitors of HGM-CoA reductase that block transcription of DNA or translational inhibitors that prevent the translation of the mRNA coding for HMG-CoA into proteins. Such compounds can directly affect transcription and translation, or they can be biotransformed into compounds having the aforementioned activities by one or more enzymes of the cholesterol biosynthetic cascade, or they can lead to the accumulation of an insoluble metabolite of the drug. activities mentioned above. Such regulation is easily determined by those skilled in the art according to conventional tests (Meth, Enzymol, 1985).; 110: 9-19). Next, several compounds are described and referenced, however, other inhibitors of the expression of the HGM-CoA reductase gene will be known to those of skill in the art. U.S. Patent No. 5,041, 432 (the disclosure of which is incorporated by reference) discloses certain 15-substituted lanosterol derivatives. He. Mercer (Prog. Lip. Res 1993; 32: 357-416) describes other oxygenated sterols that repress the synthesis of HGM-CoA reductase. Any squalene synthetase inhibitor can be used as the second compound of this invention. The term "squalene synthetase" refers to compounds that inhibit the condensation of 2 molecules of famesylpyrrophosphate to form squalene, catalyzed by the enzyme squalene synthetase. Such inhibition is readily determined by those skilled in the art in accordance with conventional assays (Meth, Enzymol, 1969; 15: 393-454 and Meth, Enzymol, 1985; 110: 359-373 and references contained herein). A variety of these compounds are described and mentioned below, however, other inhibitors of squalene synthetase will be known to those skilled in the art. U.S. Patent No. 5, 026, 554 (the disclosure of which is incorporated herein by reference) discloses fermentation products of microorganism MF5465 (ATCC 74011) including zaragozic acid. A summary of other patented squalene synthetase inhibitors has been compiled (Curr Op. Ther.Patents (1993) 861-4). Any squalene epoxidase inhibitor can be used as the second compound in the combination aspect of this invention. The term "squalene epoxidase inhibitor" refers to compounds that inhibit the bioconversion of squalene and molecular oxygen in squalene-2,3-epoxide, catalyzed by the enzyme squalene epoxidase. Such inhibition is easily determined by those skilled in the art of using conventional assays (Biochim, Biophys, Acta 1984; 794: 466-471). Next, several of these compounds are described and mentioned, however, other squalene epoxidase inhibitors will be known to those skilled in the art. U.S. Patent Nos. 5,011,859 and 5,064,864 (the descriptions of which are incorporated by reference) describe certain fluoro analogues of squalene. EP 395,768 A (the disclosure of which is incorporated by reference) discloses certain substituted allylamine derivatives. PCT publication WO 9312069 (the disclosure of which is incorporated herein by reference) discloses certain amino alcohol derivatives. U.S. Patent No. 5,051, 534 (the disclosure of which is incorporated herein by reference) discloses certain cyclopropyl-squalene derivatives. Any squalene cyclase inhibitor can be used as a second component in the combination aspect of this invention. The term "squalene cyclase inhibitor" refers to compounds that inhibit the bioconversion of squalene-2,3-epoxide to lanosterol, catalyzed by the squalene cyclase enzyme. Such inhibition is easily determined by those skilled in the art with conventional assays (FEBS Lett 1989, 244: 347-350). In addition, the compounds described and cited below are inhibitors of the school cyclase, however, those skilled in the art will also know other inhibitors of squalene cyclase. PCT Publication 9410150 (the disclosure of which is incorporated herein by reference) discloses certain derivatives of 1, 2,3,5,6,7,8,8a-octahydro-5-5,8a (beta) -trimethyl-6-isoquinolinamine, such as N -trifluoroacetyl-1, 2,3,5,6,7,8,8a-octahydro-2-allyl-5,5,8a (beta) -trimethyl-6-isoquinolinamine. The French patent publication 2697250 (the disclosure of which is incorporated herein by reference) discloses certain beta, beta-dimethyl-4-piperidine ethanol derivatives such as 1- (1, 5,9-trimethylmethyl) -beta, beta-dimethyl-4-piperidineethanol. Any combination inhibitor of squalene epoxidase / squalene cyclase can be used as a second component in the aspect of combination of this invention. The term combined squalene epoxidase / squalene cyclase inhibitor refers to compounds that inhibit the bioconversion of squalene to lanosterol by a squalene-2,3-epoxide intermediate. In some trials it is not possible to distinguish between squalene epoxidase inhibitors and squalene inhibitors Cyclase, however, these assays are recognized by those skilled in the art. Thus, the inhibition by combined inhibitors of the squalene epoxidase / squalene cyclase is easily determined by those skilled in the art in accordance with conventional tests mentioned previously for the squalene epoxidase or squalene cyclase inhibitors. A variety of these compounds are described and mentioned below, however, other inhibitors of squalene epoxidase and squalene cyclase will be known to those skilled in the art. U.S. Patent Nos. 5,084,461 and 5,278,171 (the disclosures of which are incorporated by reference) disclose certain azadecalin derivatives. EP 468,434 (the disclosure of which is incorporated by reference) discloses certain piperidyl ether and thio ether derivatives such as 2- (1-piperidyl) pentyl isopentyl sulfoxide and 2- (1-piperidyl) ethyl sulfide. PCT publication WO 9401404 (the disclosure of which is incorporated herein by reference) discloses certain acyl-piperidines such as 1- (1-oxopentyl-5-phenylthio) -4- (2-hydroxy-1-methyl) -eti) piperidine. U.S. Patent No. 5,102,915 (the disclosure of which is incorporated herein by reference) discloses certain cyclopropyloxy-squalene derivatives. The starting materials and reagents for the compounds described above of formula I, are also readily available or can be easily synthesized by those skilled in the art using conventional methods of organic synthesis. For example, many of the compounds used herein are related or come from compounds in which there is a broad scientific interest and commercial need and, consequently, many such compounds are commercially available, are presented in the literature or are easily obtainable from other - > ~ j »« jafay ». -. a »A - ~« «fc > «JS ~ jii. «A * 8. Rf ZÍVtMßü¡ * d £? ¡& z * S% »3¡-. * ^ ¡& *; > , 5 < * u > . - - • '** & «C. FAITH OVER S __ Substances commonly acquired by procedures presented in the literature. Some compounds of formula I of this invention or intermediates in their synthesis have asymmetric carbon atoms and, therefore, are enantiomers or diastereomers. Diastereomeric mixtures can be separated into their individual diastereomers based on their physicochemical differences by methods known per se. for example, by chromatography and / or fractional crystallization. The enantiomers can be separated, for example, by chiral HPLC methods or by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (eg, alcohol), separating the diastereomers and converting (eg, hydrolyzing) the individual diastereomers in the corresponding pure enantiomers. In addition, an enantiomeric mixture of the compounds of formula I or an intermediate in their synthesis containing an acidic or basic radical can be separated into their corresponding pure enantiomers by the formation of a diastereomic salt with an optically pure base or chiral acid (e.g. 1-phenylethylamine or tartaric acid) and the separation of the diastereomers by fractional crystallization followed by neutralization to break the salt, thus providing the corresponding pure enantiomers. All such isomers, including diastereomers, enantiomers and mixtures thereof are considered part of this invention. In addition, some of the Compounds of this invention are atropisomers (e.g., substituted biaryls) and are considered part of this invention. More specifically, the compounds of formula I of this invention can be obtained in an enantiomerically enriched form by resolution of the racemate of the final compound or an intermediate of its synthesis (preferably the final compound), using chromatography (preferably high pressure liquid chromatography [HPLC] ]) or an asymmetric resin (preferably Chiralcel ™ AD or OD [obtained from Chiral Technologies, Exton, Pennsylvania]) with a mobile phase consisting of a hydrocarbon (preferably heptane or hexane) containing between 0 and 50% isopropanol (preferably between 2 and 20%) and between 0 and 5% of an alkyl amine (preferably 0.1% of diethylamine). The concentration of the product containing the fractions produces the desired materials. Some compounds of the formula I of this invention are acidic and form a salt with a pharmaceutically acceptable cation. Some of the compounds of formula I of this invention are basic and form a salt with a pharmaceutically acceptable anion. All such salts are within the scope of this invention and can be prepared by conventional procedures such as the combination of the acidic and basic entities, usually in a stoichiometric ratio, in an aqueous, non-aqueous or partially aqueous medium, as appropriate. The salts are recovered by filtration, by precipitation with a non-solvent followed by filtration, by evaporation of the solvent, or, in the case of aqueous solutions, by lyophilization, as appropriate. The compounds can be obtained in crystalline form by dissolving in an appropriate solvent such as ethanol, hexanes or water / ethanol mixtures. In addition, when the compounds of formula I of this invention form hydrates or solvates, they are also within the scope of the invention. The compounds of formula I of this invention, their prodrugs and the salts of such compounds and prodrugs are adapted for therapeutic use as agents that inhibit the activity of cholesterol ester transfer protein in mammals, particularly in humans. Thus, the compounds of this invention elevate plasma HDL cholesterol, its associated components and the functions performed by them in mammals, particularly in humans. By virtue of their activity, these agents also reduce plasma levels of triglycerides, VLDL cholesterol, LDL cholesterol and their associated components in mammals, particularly in humans. Therefore, these compounds are useful in the treatment and correction of the various dyslipidemias observed that are associated with the development and incidence of atherosclerosis and cardiovascular diseases, including hypoalphalipoproteinemia, hyperbetalipoproteinemia, hypertriglyceridemia and familial hypercholesterolemia. In addition, the introduction of a functional CETP gene in an animal that lacks CETP (mouse) results in the reduction of HDL levels (Angellon, L. B., et al: J. Biol. Chem. (1991) 266: 10796-10801) and increases susceptibility to atherosclerosis. (Marotti, K. R. et al: Nature (1993) 364: 73-75). In addition, inhibition of CETP activity with an inhibitory antibody increases HDL cholesterol in hamsters (Evans, GF et al: J of Lipid Research (1994) 35: 1634-1645) and rabbits (Whitlock, ME, et al: J. Clin. Invest. (1989) 84: 129-137). Suppression of plasma CETP increase by intravenous injection with antisense oligodeoxynucleotides against CETP mRNA reduced atherosclerosis in rabbits fed cholesterol (Sugano, M. et al: J. of Biol. Chem. (1988) 273: 5033-5026 ). Importantly, humans with plasma CETP deficiency due to a genetic mutation have markedly elevated levels of HDL cholesterol and apolipoprotein A-1 in plasma, the main component of HDL apoprotein. In addition, most demonstrate a marked reduction in LDL cholesterol and apolipoprotein B in plasma (the main component of LDL apolipoprotein). (Inazu, A., Brown, M.L., Hesler, C.B., et al: N. Engl. J. Med. (1990) 323: 1234-1238). Given the negative correlation between levels of HDL cholesterol and HDL-associated lipoproteins and the positive correlation between triglycerides, LDL cholesterol and its associated apolipoproteins in blood with the development of cardiovascular, cerebrovascular and peripheral vascular diseases, the compounds of formula I of this invention , their prodrugs and the salts of such compounds and prodrugs, by virtue of their pharmacological action, are useful for the prevention, arrest and / or regression of atherosclerosis and its associated disease states. These include cardiovascular disorders (eg, angina, cardiac ischemia and myocardial infarction), complications due to therapies of cardiovascular diseases (eg, reperfusion injury and angioplastic restenosis), hypertension, stroke and atherosclerosis associated with organ transplantation. Because of the beneficial effects widely associated with elevated HDL levels, an agent that inhibits CETP activity in humans, by virtue of its ability to increase HDL, also provides valuable avenues for therapy in several distinct disease areas. . Thus, given the ability of the compounds of formula I of this invention, their prodrugs and the salts of such compounds and prodrugs to alter the lipoprotein composition by inhibiting cholesterol ester transfer, are useful in the treatment of vascular complications associated with diabetes. Hyperlipidemia is present in the majority of subjects with diabetes mellitus (Howard, B.V. 1987, J. Lipid, Res. 28, 613). Even in the presence of normal lipid levels, diabetic subjects experience an increased risk of cardiovascular diseases (Kannel, W.B. and McGee, D.L. 1979. Diabetes Care 2, 120). It is known that the transfer of the cholesteryl ester mediated by CETP is abnormally increased in both insulin-dependent diabetes (Bagdade, J.D. Subbaiah, P.V. and Ritter, M.C., 1991. Eur. J. Clin. . ~~~~. ^^. ^^ iii ^ g ^ aaaiSgi feA &AA ^ saci * s ^ .ni; j »& M & Í8 «Bte .--. J Invest. 21, 161) as in non-insulin dependent diabetes (Bagdade J.D., Ritter, M.C., Lane, J. and Subbaiah, 1993. Atherosclerosis 104, 69). It has been suggested that the abnormal increase in cholesterol transfer produces changes in lipoprotein composition, particularly for VLDL and LDL, which are more atherogenic (Bagdade, JD, Wagner, JD, Rudel, LL, and Clarkson, TB 1995 J Lipid, Res., 36, 759). These changes are not necessarily observed during routine lipid analysis. Thus, the present invention will be useful to reduce the risk of vascular complications as a result of diabetes. The described agents are useful in the treatment of obesity.

Both in humans (Radeau, T., Lau, P., Robb, M., McDonnell, M., Ailhaud, G. and McPherson, R., 1995. Journal of Lipid Research, 36 (12): 2552-61) as in non-human primates (Quinet, E. Tall, A., Ramakrishnan, R. and Rudel, L., 1991. Journal of Clinical Investigation, 87 (5): 1559-66), the mRNA for CETP is expressed at high levels in the adipose tissue. The adipose messenger increases the fat intake (Martin, LJ, Connelly, PW, Nancoo, D., Wood, N., Zhang, ZJ Maguire, G., Quinet, E., Tall, AR, Marcel, YL and McPherson , R., 1993. Journal of Lipid Research, 34 (3): 437-46) and translates into functional transfer proteins and, by secretion, contributes significantly to plasma CETP levels. In human adipocytes, the majority of cholesterol is provided by plasma LDL and HDL (Fong B. S., and Angel, A., 1989. Biochimica et Biophysica Acta. 1004 (1): 53-60). The uptake of HDL cholesteryl ester depends largely C »? ¿¿& lJéA Z.,? Measurement of CETP (Benoist, F., Lau, P., McDonnell, M., Doelle, H., Milne, R. and McPherson, R., 1997. Journal of Biological Chemistry 272 (38): 2357-7 ). This ability of CETP to stimulate the uptake of HDL cholesteril together with the greater binding of HDL to adipocytes in obese subjects (Jiménez, 5 JG, Fong., Julien, P., Despres, JP, Rotstein, L., and Angel, A., 1989. International Journal of Obesity 13 (5): 699-709), suggests a role for CETP not only in the generation of the phenotype of low HDL levels for these subjects, but also in the development of the obesity, promoting the accumulation of cholesterol. Inhibitors of blocking activity of CETP This process, therefore, serve as useful adjuvants for diet therapy for the purpose of reducing weight. CETP inhibitors are useful in the treatment of inflammation due to gram-negative sepsis and septic shock. For example, the systemic toxicity of gram-negative sepsis is due in large part to a endotoxin, a lipopolysaccharide (LPS) released from the outer surface of the bacteria, which causes an extensive inflammatory response. The lipopolysaccharides can form complexes with lipoproteins (Ulevitch, R.J., Johhston, A.R., and Weinstein, D.B., 1981. J. Clin.Invest.667, 827-37). Certain in vitro studies have shown that the binding of LPS to HDL reduces The production and release of mediators of inflammation (Ulevitch, R.J., Johhston, A.R., 1978, J. Clin.Research 62, 1313-24) is substantially substantial. Certain in vivo studies show that transgenic mice expressing human apo-AI and elevated HDL levels are protected from septic shock < a, ,, a =. »« Sfef '< . * -? x ^. t. . .. j ^ í ^ i? f < c.i & & amp; s ^ Ü: jto? ~? t '& ^ ^ l ^. ^.' «AataA - '^ i ^ S (Levine, D.M., Parker, T.S., Donnelly, T.M., Walsh, A.M. and Rubin, A.L. 1993. Proc. Nati, Acad.Sci.90, 12040-44). Importantly, the administration of reconstituted HDL to humans exposed to endotoxins, resulted in a lower inflammatory response (Pajkrt, D., Doran, JE, Koster, F., Lerch, PG, Arnet, B., Van der Poli , T., ten Cate, JW, and van Deventer, S.J.H. 1996. J. Exp. Med. 184, 1601-08). CETP inhibitors, by virtue of the fact that they raise HDL levels, attenuate the development of inflammation and septic shock. The utility of the compounds of formula I of the invention, their prodrugs and the salts of such compounds and prodrugs as medical agents in the treatment of the diseases / conditions described above in mammals (e.g., humans, men or women) is demonstrated by the activity of the compounds of this invention in conventional tests and in the in vivo assay described below. The in vivo assay (with appropriate modifications within the skill of the art) can be used to determine the activity of other lipid and triglyceride control agents as well as the compounds of this invention. The combination protocol described below is useful to demonstrate the utility of combinations of lipids and triglycerides (e.g., the compounds of this invention) described herein. Such assays also provide a means by which the activities of the compounds of formula I of this invention, their prodrugs and the salts of such compounds and prodrugs (or the other agents described herein) can be compared with each other and with the activities of other compounds known. The results of these comparisons are useful for determining dosage levels in mammals, including humans, for the treatment of such diseases. Of course, the following protocols may be varied by those skilled in the art. The hyperalphacholesterolemic activity of the compounds of formula I can be determined by evaluating the effect of these compounds on the action of the cholesteryl ester transfer protein by measuring the relative transfer ratio of radiolabeled lipids between lipoprotein fractions, essentially as previously described by Morton. in J. Biol. Chem. 256, 11992, 1981 and by Dias in Clin. Chem. 34, 2322, 1988.

In vitro CETP assay The following is a brief description of the cholesteryl ester transfer assay in human plasma (in vitro) and the animal plasma (ex vivo): the CETP activity in the presence or absence of the drug is assayed determined the transfer of oleate of cholesteryl labeled with 3H (CO) from an exogenous indicator of HDL to the lipoprotein fraction that is not HDL in human plasma, or from LDL labeled with 3H to the HDL fraction in transgenic mouse plasma. The labeled human lipoprotein substrates are prepared analogously to the method described by Morton in which the endogenous plasma CETP activity is employed to transfer 3H-CO from the phospholipid liposomes to all lipoprotein fractions in plasma. Subsequently, LDL and HDL labeled with 3H are isolated by sequential ultracentrifugation with density cuts of 1019-1.063 and 1.10-1.21 g / ml, respectively. For the activity assay, 3 H-labeled lipoprotein is added to the plasma at concentrations of 10-25 nmoles CO / ml and the samples are incubated at 37 ° C for 2.5-3 hours. Then, the non-HDL proteins are precipitated by the addition of an equal volume of polyethylene glycol 80000 (Dias) at 20% (w / v). The samples are centrifuged at 750 g x 20 minutes and the radioactivity contained in the HDL-containing supernatant is determined by liquid scintillation. The introduction of variable amounts of the compounds of this invention as a solution in dimethisulfoxide to human plasma, before the addition of the radiolabelled cholesteryl oleate, and the comparison of the relative amounts of radiolabel transferred, allow the determination of the inhibitory activities of the transfer of cholesteryl ester.

In vivo CETP assay The activity of these compounds in vivo can be determined by the amount of agent required to be administered, with respect to the control, to inhibit the transfer activity of the cholesteryl ester by 50% at various ex vivo time points, or to raise HDL cholesterol by a given percentage in an animal species that contains CETP. Transgenic mice expressing both human CETP and apolipoprotein can be used To the human (Charles River, Boston, MA) to evaluate the compounds in vivo. The compounds to be examined are administered by an oral probe in an emulsion vehicle containing olive oil and sodium taurocholate. It is removed from the mice retroorbitally before the dose is administered. At 5 different times after dosing, which vary between 4 hours and 24 hours, the animals are sacrificed, blood is extracted by cardiac puncture and the lipid parameters are measured including total cholesterol, HDL cholesterol, LDL cholesterol and triglycerides. . The CETP activity is determined by a procedure similar to that described above with the exception that LDL containing cholesteryl oleate labeled with 3H is used as a donor source instead of HDL. The values obtained for the lipids and the transfer activity are compared with those obtained before dosing and / or with those from mice that received only vehicle.

Plasma lipid assay The activity of these compounds can also be demonstrated by determining the amount of agent needed to alter plasma lipid levels, for example, HDL cholesterol levels, LDL cholesterol levels, VLDL cholesterol levels or triglycerides, in the plasma of certain mammals, for example, marmosets, which possess CETP activity and a plasma lipoprotein profile similar to that of humans (Crook et al., Arteriosclerosis 10, 625, 1990). Adult marmosets are assigned to treatment groups so that each group has a similar SD mean for the groups. ^^^ te ^^ g ^^^^^ i ^^^^^^^^^^^^ g ^^^^^^^^^^^^^^ * ** ^^^^^^^^^^^^^^^^^^ 4 ^^^^ concentrations of total cholesterol, HDL and / or LDL in plasma. After the group assignment, the marmosets receive daily doses of compound as a mixture with the diet or by intragastric intubation from days 1 to 8. The control marmosets receive only the dosing vehicle. The values of total cholesterol, LDL, VLDL and HDL can be determined at any time during the study by obtaining blood from an antecubital vein, separating the plasma lipoproteins in their individual subclasses by centrifugation with density gradient, and measuring the concentration of cholesterol as it has been previously described (Crook et al., Arteriosclerosis 10, 625, 1990).

Atherosclerosis test in vivo The anti-atherosclerotic effects of the compounds can be determined by the amount of the compound necessary to reduce the deposition of lipids in the aorta of rabbits. A diet containing 0.2% cholesterol and 10% coconut oil is supplied for 4 days (once a day) to New Zealand white rabbits. Blood is drawn from the rabbits from the marginal vein of the ear and the plasma cholesterol levels are determined from these samples. Then, the rabbits are assigned to treatment groups so that each group has a similar SD mean for total plasma cholesterol concentration, HDL cholesterol concentration, triglyceride concentration and / or protein transfer activity. cholesteryl ester. After group allocation, the rabbits receive daily the dose of the compound administered as a mixture with the diet or on a small piece of gelatin-based confection. The control rabbits only receive the dosing vehicle, either the food or the gelatin preparation. The cholesterol / coconut oil diet is continued, along with the administration of the compound throughout the entire study. The plasma cholesterol values and the activity of the cholesteryl ester transfer protein can be determined at any time during the study by drawing blood from the marginal vein of the ear. After 3-5 months, the rabbits are sacrificed and the aortas are removed from the thoracic arch in the branch of the iliac arteries. The aortas are cleared of adventitia, open longitudinally and then stained with Sudan IV as described by Holman et al. (Lab. Invest. 1958, 7, 42-47). The percentage of the stained surface area is quantified by densitometry using an Optimal Image Analyzing System (Image Processing Systems). The reduction in lipid deposition is indicated by a reduction in the percentage of the specific surface stained in the group receiving the compound compared to the control rabbits.

Anti-obesity Protocol The ability of CETP inhibitors to cause weight loss can be evaluated in obese humans with a body mass index (BMI) > 30 kg / m2. The doses of inhibitor are administered in an amount sufficient to produce an increase of > 25% of the levels of HDL cholesterol. The BMI and body fat distribution, defined as a ratio between waist (W) and hip (H) (WHR), are controlled during the course of the 3-6 month studies, and the results for the groups of treatment are compared with those obtained with subjects receiving placebo.

In vivo sepsis assay Certain in vivo studies show that transgenic mice expressing human apo-AI and high HDL levels are protected from septic shock. Thus, the ability of CETP inhibitors to protect from septic shock can be demonstrated in transgenic mice expressing both human apo-AI and human transgenes from CETP (Levine, DM, Parker, TS, Donnelly, TM Walsh, AM and Rubin, AL, 1993. Proc. Nati, Acad. Sci. 90, 12040-44). LPS derived from E. coli, at a concentration of 30 mg / kg, is administered by i.p. injection to animals that have received a CETP inhibitor at an appropriate dose to result in the elevation of HDL. The number of surviving mice is determined at times up to 48 hours after injection of LPS and compared to mice that received only vehicle (less CETP inhibitor). The administration of the compounds of this invention can be carried out by any method that releases a compound of this invention systemically and / or locally. These procedures include routes oral, parenteral, intraduodenal, etc. Generally, the compounds of this invention are administered orally, but parenteral administration (eg, intravenous, intramuscular, subcutaneous or intramedullary) can be used, for example, when oral administration is inappropriate for the recipient or when the patient is not You can ingest the drug. * In general, an amount of a compound of this invention that is sufficient to achieve the desired therapeutic effect (e.g., elevation of HDL) is used. In general, an effective dose for the compounds of formula I of This invention, its prodrugs and the salts of such compounds and prodrugs are in the range of 0.01 to 10 mg / kg / day, preferably 0.1 to 5 mg / kg / day. A dose of the combination pharmaceutical agents to be used in conjunction with the CETP inhibitors is used which is effective for the indication to be treated. For example, typically an effective dose for the HMG-CoA reductase inhibitors is in the range of 0.01 to 100 mg / kg / day. In general, a dose of effect for inhibitors of MTP / ApoB secretion is in the range of 0.01 to 100 mg / kg / day. The compounds of the present invention are generally administered in the form of a pharmaceutical composition comprising at least one of the compounds of this invention together with a pharmaceutically acceptable carrier, diluent or excipient. So, the The compounds of this invention can be administered individually or in combination in any conventional oral, parenteral, rectal or transdermal dosage form. For oral administration, a pharmaceutical composition can take the form of solutions, suspensions, tablets, pills, capsules, powders and the like. Tablets containing various excipients such as sodium cipher, calcium carbonate and calcium phosphate are used, together with various disintegrants such as starch and preferably potato starch or tapioca, and certain complex silicates, together with binding agents such as polyvinylpyrrolidone, sucrose, gelatin and gum arabic. In addition, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for forming tablets. Solid compositions of a similar type are also employed as fillers in soft and hard gelatin capsules; Preferred materials in this regard also include lactose or milk sugar, as well as high molecular weight polyethylene glycols. A preferred formulation is a solution or suspension in an oil, for example, olive oil, Miglyol ™, or Capmul ™ in a soft gelatin capsule. When appropriate, antioxidants can be added to prevent long-term degradation. When aqueous suspensions and / or elixirs are desired for oral administration, the compounds of this invention can be combined with various sweetening agents, flavoring agents, coloring agents, agents -'jiiSfc ?. ^ »*,. «Faith.« Js. - ^. «_» • > . 7 u. Art »a,» «SaMjfe-. emulsifiers and / or suspending agents, as well as diluents such as water, ethanol, propylene glycol, glycerin and various combinations thereof. For the purposes of parenteral administration, solutions in sesame or peanut oil or aqueous propylene glycol, as well as sterile aqueous solutions of the corresponding water-soluble salts may be employed. Such aqueous solutions may conveniently be buffered, if necessary, and the liquid diluent may first be made isotonic with sufficient saline or glucose. These aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal injection purposes. In this regard, all of the sterile aqueous media employed can be readily obtained by conventional techniques well known to those skilled in the art. For the purposes of transdermal administration (eg, topical), dilute, aqueous or partially aqueous solutions are prepared (normally at a concentration of about 0.1% to 5%), otherwise similar to the parenteral solutions above. The methods for preparing various pharmaceutical compositions with a certain amount of active ingredient are known or will be apparent in light of this description for those skilled in the art. As examples of processes for preparing pharmaceutical compositions, see Remington's Pharmaceutical Sciences. Mack Publishing Company, Easter, Pa., 15th Edition (1975).

The pharmaceutical compositions according to this invention may contain from 0.1% to 95% of the compound (s) of this invention, preferably from 1% to 70%. In any case, the composition or formulation to be administered will contain an amount of compound (s) according to the invention effective to treat the disease / condition of the subject being treated, for example, atherosclerosis. As the present invention has an aspect that relates to the treatment of the diseases / conditions described herein with a combination of active ingredients that can be administered separately, the invention also relates to a combination of the separate pharmaceutical compositions in the form of a kit. The kit includes two separate pharmaceutical compositions: a compound of the formula I or a prodrug thereof, or a salt of such a compound or prodrug, and a second compound as described above. The equipment comprises means for containing the separate compositions, such as a container, a bottle divided into a container divided with a sheet. Typically, the equipment includes instructions for the administration of the separate components. The form of the kit is particularly advantageous when the separate components are preferably administered in different dosage forms (eg, oral and parenteral), administered at different dosage intervals, or when the corresponding physician wishes to concentrate the individual components of the combination. , «< - .- »». . ~ 7 ^ ^ ¡^ & 3 & ^ ^^^ & ^ ¡Fi > ? l & S ^ b £. &? ^ J -.?. j / g »• g -% a« sl ^.

An example of such equipment is called a blister. Blisters are well known in the packaging industry and are widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules and the like). Blisters generally consist of a sheet of relatively rigid material covered with a sheet of preferably transparent plastic material. During the packaging process, cavities are formed in the plastic sheet. The cavities have the size and shape of the tablets or capsules to be packaged. Then, the tablets or capsules are placed in the cavities and the sheet of relatively rigid material is sealed with the plastic sheet on the side of the sheet opposite the direction in which the cavities were formed. As a result, the tablets or capsules are sealed in the cavities between the plastic sheet and the sheet. Preferably, the strength of the sheet is such that the tablets or capsules can be removed from the blister by manually pressing on the cavity, whereby an opening is formed in the sheet at the cavity site. The tablet or capsule can then be removed through said opening. It may be desirable to provide a reminder in the assembly, for example, in the form of numbers near the tablets or capsules, the numbers corresponding to the days of the regimen in which the tablets or capsules so specified should be ingested. Another example of such a reminder is a calendar printed on the card, for example, as indicated below: "first week, Monday, Tuesday, ... etc ... second week Monday, Tuesday ... "etc. Other variations of reminders will be evident: a" daily dose "can be a single tablet or capsule or several tablets or capsules to be taken on a given day In addition, a daily dose of the formula compound I may consist of a tablet or capsule, while a daily dose of the second compound may consist of several tablets or capsules and vice versa.The reminder should reflect this.In another specific embodiment of this invention, a dispenser designed to supply the daily doses, once, in the / ** desired use order. Preferably, the distributor has a reminder, in a way that additionally facilitates compliance with the regime. An example of such a reminder is a mechanical counter that indicates the number of daily doses that have been delivered. Another example of such a reminder in a microchip memory that runs on batteries, coupled to a liquid crystal display, or a reminder auditory signal that, for example, shows the data of the last daily dose and / or remember when the next dose should be taken. The compounds of this invention, either alone or in combination with each other or with other compounds, will generally be administered in a convenient formulation. The following formulation examples are only illustrative and are not intended to limit the scope of the present invention. In the formulations shown below, "active ingredient" means a compound of this invention.

FORMULATION 1 Gelatin capsules Hard gelatin capsules are prepared using the following: Ingredient Quantity (mg / capsule) Active ingredient 0.25-100 Starch, NF 0-650 Fluid starch powder 0-50 Silicone fluid 350 centistokes 0-15 * \ A tablet formulation is prepared using the 7 10 following ingredients: FORMULATION 2 Tablets Ingredient Quantity (mg / tablet) Active ingredient 0.25-100 Cellulose, microcrystalline 200-650 Silicon dioxide, pyrolyzed 10-650 Stearic acid 5-15 The components are mixed and pressed to form 20 tablets. Alternatively, tablets are made which each contain 0.25-100 mg of active ingredients, as indicated below: FORMULATION 3 Tablets Ingredient Quantity (mg / tablet) Active ingredient 0.25-100 Starch 45 Cellulose, microcrystalline 35 Polyvinylpyrrolidone (in the form of a 10% solution in water) 4 Carboxymethylcellulose sodium 4.5 Magnesium stearate 0.5 Talcum 1 The active ingredients, starch and cellulose are passed through a U.S. No. 45 and mix thoroughly. The solution of polyvinylpyrrolidone is mixed with the resulting powders and mixed then passed through a U.S. No. 14. The granules thus produced are dried at 50 ° C-60 ° C and passed through a U.S. mesh screen. No. 18. Next, the sodium carboxymethyl starch, the Magnesium stearate and talc, previously passed through a U.S. mesh screen No. 60, are added to granules which, after mixing, are pressed into a tablet machine to produce tablets. The suspensions they contain, each 0.25-100 mg of active ingredient per 5 ml dose, are manufactured as indicated below: FORMULATION 4 Suspensions Ingredient Quantity (mg / 5 ml) Active ingredient 0.25-100 mg Carboxymethromellose sodium 50 mg Syrup 1.25 mg Benzoic acid solution 0.10 ml Flavoring agent c.v. Colorant c.v. Purified water, up to 5 ml The active ingredient is passed through a No. 45 mesh screen and mixed with the sodium carboxymethylcellulose and the syrup to form a uniform paste. The benzoic acid, flavoring and coloring solution is diluted with some water and added, with stirring. Then enough water is added to produce the necessary volume. An aerosol solution is prepared containing the following ingredients: FORMULATION 5 Aerosol Ingredient Quantity (% by weight) Active ingredient 0.25 Ethanol 25.75 Propellant 22 (Chlorodifluoromethanol) 70.00 The active ingredient is mixed with ethanol and the mixture is added to a portion of the propellant 22, cooled to 30 ° C and transferred to a refilling device. The necessary amount is then introduced into a stainless steel container and diluted with the rest of the propellant. Then the valve units in the container are adjusted. Suppositories are prepared as follows: FORMULATION 6 Suppositories 10 Ingredient Quantity (mg / suppository) Active ingredient 250 Glycerides of saturated fatty acids 2,000 The active ingredient is passed through a U.S. mesh screen.

No. 60 and is suspended in the glycerides of saturated fatty acids, previously melted using the minimum necessary heat. The mixture is then poured into a suppository mold with a nominal capacity of 2 g and allowed to cool. An intravenous formulation is prepared as indicated continuation: FORMULATION 7 Intravenous solution Ingredient Quantity Active ingredient 20 mg Intralipid ™ Emulsion 1,000 ml The solution of the above ingredients is administered intravenously to a patient at a rate of about 1 ml per v-j »minute. f \ 10 Soft gelatin capsules are prepared using the following: FORMULATION 8 Soft gelatin capsules with oil formulation 15 Ingredient Quantity (mg / capsule) Active ingredient 10-500 Olive oil or Miglyol ™ 500-1000 The above active ingredient can also be a combination of agents.

General experimental procedures The NMR spectra were recorded on a Varian XL-300 spectrometer (Varian Co., Palo Alto, California, a Bruker AM-300 spectrometer (Bruker Co., Billerica, Massachusetts) or a Varian Unity spectrometer, at approximately 23 ° C, at 300 MHz for protons and at 75.4 mHz for carbon nuclei Chemical shifts are expressed in parts per million downfield of tetramethylsilane The shapes of the peaks are referred to as follows: s, singlet; , doublet, t, triplet, q, quadruplet, m, multiplet, sa = broad singlet The interchangeable designated resonances did not appear in a different experiment in which the samples were shaken with several drops of D20 in the same solvent. Chemical ionization masses at atmospheric pressure (APCI) were obtained on a Fisons Platform II Spectrometer Chemical mass spectra were obtained on a Hewlett-Pack instrument ard 5989 (Hewlett-Packard Co., Palo Alto, California) (ammonia ionization, PBMS). When the intensity of the ions containing chlorine or bromine is described, the expected intensity ratio is that observed (approximately 3: 1 for ions containing 35CI / 37CI and 1: 1 for ions containing 79Br / 81Br) and only the intensity of the lower mass ion is provided. Column chromatography was performed with Baker silica gel (40 μm) (J.T. Baker, Phillipsburg, N.J.) or silica gel 60 (EM Sciences, Gibbstown, N.J.) on glass columns under low nitrogen pressure. Radial chromatography was performed using a Chromatron (model 7924T, Harrison Research). Unless otherwise specified, the reagents were used as obtained from commercial sources. The dimethylformamide, the 2-propanol, the tetrahydrofuran and the dichloromethane used as reaction solvents, were of the anhydrous quality supplied by Aldrich Chemical Company (Milwaukee, Wisconsin). Microanalyses were performed by Schwarzkopf Microanalytical Laboratory, Woodside, NY. The terms "concentrated" and "evaporated" refer to the removal of the solvent at the pressure of a water aspirator in a rotary evaporator with a bath temperature of less than 45 ° C. Reactions performed at "0-20 ° C" or "0-25 ° C" were performed with initial cooling of the vessel in an isolated ice bath that was allowed to warm to room temperature for several hours. The abbreviation "min" and "h" mean "minutes" and "hours" respectively.

EXAMPLES EXAMPLE 1 C / S-4-Benzylloxycarbonylamino-6,7-dimethoxy-1,2.3.4-tetrahydro-quinoline-2-carboxylic acid butyl ester 3,4-Dimethoxyaniline (7.5 g, 49.0 mmol), n-butyl glyoxylate (6.5 g, 49.0 mmol) and anhydrous sodium sulfate (20 g) in anhydrous dichloromethane (100 mL) were stirred at room temperature. After 90 minutes, the sulfate Sodium was removed by filtration, and O-benzyl-N-vinyl carbamate (5.0 g, 28.2 mmol) was added to the filtrate, followed by diethyl etherate boron trifluoride (1.0 ml). After stirring at room temperature for 18 hours, the reaction mixture was concentrated and the crude product was purified by chromatography on silica gel using 25% ethyl acetate / hexanes as eluent to yield 7.0 g of the title compound. 1 H NMR (CDCl 3) d 0.95 (t, 3 H), 1.4 (m, 2 H), 1.6 (m, 2 H), 2.3 (m, 1 H), 2.5 (m, 1 H), 3.8 (s, 3 H), 3.9 (s, 3H), 5.2 (q, 2H), 6.2 (s, 1 H), 6.6 (s, 1 H), 7.4 (m, 5H).

EXAMPLE 2 C-S-4-benzyloxycarbonylamino-6,7-dimethoxy-3,4-dihydro-2H-quinoline-1,2-dicarboxylic acid 2-butyl ester To a solution of butyl ester of c / s-4-benzylcarbonylamino-6,7-dimethoxy-1, 2,3,4-tetrahydro-quinoline-2-carboxylic acid ester (example 1) (3.0 g, 6.8 mmol) in anhydrous dichloromethane (100 ml) was added pyridine (1.34 g, 16.9). The mixture was cooled to 0 ° C and ethyl chloroformate (1.47 g, 13.6 mmol) was slowly added. The reaction was stirred at 0 ° C for 30 minutes and then at room temperature for 18 hours. The reaction mixture was washed twice with 2N HCl and the organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by jtentehai * - jn ">» • »* $ &j3Ví £ ma £? ^ £ t * chromatography on silica gel using 20% ethyl acetate hexanes as eluents yielded the title compound (3.1 g). NMR (CDCl 3) d 0.85 (t, 3 H), 1.3 (m, 5 H), 1.5 (m, 2 H), 3.7 (s, 3 H), 3.8 (s, 3 H), 6.65 (s, 1 H), 7.4 ( m, 6H) 5 EXAMPLE 3 C-S-4-amino-6,7-dimethoxy-3,4-dihydro-2H-quinoline-1,2-dicarboxylic acid 2-butyl ester ester 1-ethyl ester of 2-butyl ester of c / s-4-benzyloxycarbonylamino-6,7-dimethoxy-3,4-dihydro-2H-quinolin-1, 2-ethyl ester was heated. -dicarboxylic acid (example 2) (800 mg), 10% palladium on carbon (800 mg) and a mixture of methanol-cyclohexene (2; 1, 60 ml) at 70 ° C for 2 hours. The reaction mixture was cooled to room temperature, filtered through Celite® and concentrated in vacuo. Purification by chromatography on silica gel using 5% methanol / ethyl acetate yielded the title compound (500 mg). 1 H NMR (CDCl 3) d 0.9 (t, 3 H), 1.4 (m, 5 H), 2.5 (m, 1 H), 3.9 (d, 6 H), 6.9 (s, 1 H), 7.2 (s, 1 H) . j * ^ .. 3-. - A a ^. U f '. i '^^ l- -fe.x »^ > A- < ¿Sa6M ^ < ^ AA..Aj < . ^ ..AS ». . »I .. Chief *» »** .., EXAMPLE 4 Ester-1-ethyl 2-butyl ester of c / s-4- (3,5-bis-trifl? Oromethyl-benzylamino) -6.7-d methoxy-3,4-dihydro-2H-quinoline-1,2-dicarboxylic acid To a solution of 1-ethyl ester of cis-4-amino-6,7-dimethoxy-3,4-dihydro-2H-quinoline-1,2-dicarboxylic acid 2-butyl ester (example 3) (500 mg , 1.30 mmol) in anhydrous dichloroethane (30 ml) was added acetic acid (79 mg, 1.30 mmol), followed by 3,5-bis (trifluoromethyl) benzaldehyde s * (318 mg, 1.30 mmol) and sodium triacetoxyborohydride (418 mg, 1.97 mmoles).

The reaction was stirred at room temperature for 30 minutes. The reaction mixture was then diluted with chloroform and washed with 1 N NaOH. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated in vacuo to yield the crude title compound (approximately 500 mg) which it was used directly in Example 5. 15 EXAMPLE 5 1-ethyl ester of 2-butyl ester of c / s-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -6,7-dimethoxy-3,4- dihydro-2H-quinoline-1,2-dicarboxylic acid 1-ethyl ester of 2-butyl ester of c / s-4- (3,5-bis-trifluoromethyl-benzylamine) -6,7-dimethoxy ester 3,4,4-dihydro-2H-quinolin-1, 2-dicarboxylic acid (example 4) (approximately 500 mg, 0.83 mmol) and pyridine (195 mg, 2.5 mmol) in anhydrous dichloromethane (100 ml) were added. cooled to 0 ° C. Methyl chloroformate (195 mg, 2.1 mmol) was added slowly. The reaction was stirred at 0 ° C for 1 hour and then at room temperature for 18 hours. The reaction mixture was then diluted with chloroform and washed with 1 N HCl. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. Pyrification by chromatography on silica gel using 15% ethyl acetate / hexanes as eluent afforded the title product (400 mg). MS m / z 664.2 (M +); 1 H NMR (CDCl 3) d 0.9 (t, 3 H), 1.3 (t, 3 H), 1.5 (m, 2 H), 3.85 (s, 3H), 4.0 (t, 2H), 6.3 (s, 1 H), 7.8 (s, 1H).

EXAMPLE 6 1-ethyl ester of frans-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amyno] -6,7-dimethoxy-3,4-dihydro-2H-quinoline-1,2-dicarboxylic acid 2-butyl ester 1-ethyl ester of trans-4-amino-6,7-dimethoxy-3,4-dihydro-2H-quinoline-1,2-dicarboxylic acid 2-butyl ester was isolated as a minor component during the precipitation of Example 3 , and was transformed into the desired product as described in Examples 4 and 5. 1 H NMR (CDCl 3) d 0.9 (t, 3 H), 1, 3 (t, 3 H), 3.9 (s, 3 H), 4.1 ( t, 2H), 6.3 (s, 1 H), 7.8 (s, 1 H).

EXAMPLE 7A Propylene- (4-trifluoromethyl-phenyl) -amine To a solution of 4-trifluoromethylaniline (3.3 g, 20.5 mmol) and 5 triethylamine (8.3 g, 83 mmol) in 100 ml of dichloromethane, cooled in an ice / water bath, was added titanium tetrachloride (11.4 ml. a 1.0 M solution in dichloromethane, 11.4 mmol). After 25 minutes, propionaldehyde (1.8 g, 25.6 mmol) was slowly added in the form of a > *, dichloromethane solution. After one more hour of stirring in an ice / water bath, an aqueous potassium carbonate solution (-100 ml of a 1 M solution) was added. The organic phase was separated, dried over magnesium sulfate, filtered and concentrated in vacuo to yield the crude title product which was used without further purification. 1 H NMR (CDCl 3) d 1.2 (t, 3 H), 2.5 (dq, 2 H), 7.05 (d, 2 H), 7.56 (d, 15 2 H), 7.84 (t, 1 H, J = 4.4 Hz).

EXAMPLE 7B C / s- (2-Ethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-4-yl) -carbamic acid benzyl ester. Crude propylene- (4-trifluoromethyl-phenyl) -amine. Example 7A and O-benzyl-N-vinyl carbamate (3.1 g, 17.4 mmol) were combined in 200 ml of dichloromethane and the mixture was cooled in an ice / water bath as described. added diethyl ether boron trifluoride (0.25 g, 1.7 mmol). After stirring at room temperature for 1 hour, the reaction mixture was concentrated to -50 ml and purified directly by chromatography on silica gel using 50% dichloromethane / hexanes as eluent to yield 2.5 g of title product. 1 H NMR (CDCl 3) d 0.96 (t, 3 H), 1.42 (q, 1 H), 1.53 (m, 2 H), 2.29 (m, 1 H), 3.37 (m, 1 H), 4.05 (s, 1 H ), 4.88 (d, 1 H), 5.00 (m, 1H), 5.16 (s, 2H), 6.44 (d, 1 H), 7.20 (dd, 1H), 7.38 (m, 6H).

EXAMPLE 7C c / s-4-benzyloxycarbonylamino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester A solution of c / 's - (2-ethyl-6-trifluoromethyl-1, 2,3,4-tetrahydro-quinol? N-4-yl) -carbamic acid benzyl ester (Example 7B) (37.0 g), 97.9 mmoles) and pyridine (23.2 g, 293.7 mmoles) in dichloromethane (1 L) was cooled in an ice / water bath as slowly added ethyl chloroformate (37.2 g, 342.6 mmoles). After stirring at room temperature overnight, the mixture was cooled in an ice / water bath as a 1M solution of potassium hydroxide was added to interrupt the reaction. The organic phase was washed twice with a 2M solution of hydrochloric acid, dried over magnesium sulfate, filtered and concentrated in vacuo to yield the crude product which was purified by chromatography on silica gel using j * -. * i tti »Baagií fr fe» '10-15% ethyl acetate / hexanes as eluent to produce 40 g of the title product. 1 H NMR (CDCl 3) d 0.83 (t, 3 H), 1.28 (t, 3 H), 1.4-1.6 (m, 3 H), 2.53 (m, 1 H), 4.23 (m, 2 H), 4.47 (m, 1 H ), 4.80 (m, 1 H), 4.94 (m, 1 H), 5.18 (s, 2H), 7.3-7.6 (m, 8H).

EXAMPLE 7D c / s-4-amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester A solution of c / 's-4-benzylcarbonylamino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (Example 7C) ( 18.0 g, 40 mmol) in 150 ml of cyclohexane and 150 ml of methanol was treated with 10% palladium on carbon (10.0 g, 50% by weight of water). After heating to reflux for 1 hour, the cooled mixture was filtered through Celite® and concentrated in vacuo to yield the crude product, which was purified by silica gel chromatography using 25-50% ethyl acetate / hexanes as eluent to produce 8.8 g of the title product. 1 H NMR (CDCl 3) d 0.83 (t 3 H), 1.25 (m, 4 H), 1.45 (m, 1 H), 1.6 (m, 1H), 2.49 (m, 1 H), 3.81 (m, 1 H), 4.2 (m, 2H), 4.4 (m, 1 H), 7.47 (m, 2H), 7.69 (s, 1 H) ).

EXAMPLE 7E c / s-4- (3,5-bis-trifluoromethyl-benzylamino) -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester A solution of c / s-4-amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (Example 7D) (8.8 g, 27.8 mmol) was treated sequentially with acetic acid (5.0 g, 83.5 mmole) and 3,5-bis-trifluoromethyl-benzaldehyde (6.74 g, 27.8 mmole), followed by sodium triacetoxyborohydride (29.5 g, 139.2 mmole). After stirring at room temperature for 24 hours, the mixture was combined with 500 ml of 1 M potassium hydroxide and the aqueous layer was extracted with dichloromethane (2 x 200 ml). The combined organic phases were dried over magnesium sulfate, filtered and concentrated in vacuo to yield the crude product, which was purified by chromatography on silica gel using 5-10% ethyl acetate / hexanes as eluent to yield 13.8 g. of the product of the title. 1 H NMR (CDCl 3) d 0.85 (t, 3 H), 1.27 (m, 4 H), 1.45 (m, 2 H), 1.67 (m, 1 H), 2.66 (m, 1 H), 3.56 (m, 1 H), 4.1-4.3 (m, 4H), 4.42 (m, 1 H), 7.49 (d, 1 H, J = 8.5 Hz), 7.52 (d, 1 H, J = 8.5 Hz), 7.76 (s, 1 H) 7.79 (s, 1 H), 7.91 (s, 2H).

Ethyl ester of c / s-4 - [(3,5-bi-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 - carboxylic A solution of c / s-4- (3,5-bis-trifluoromethyl-benzylamino) -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (Example 7E) (2.0 g, 3.7 mmol) and pyridine (0.58 g, 7.4 mmol) in 100 mL of dichloromethane was cooled in an ice / water bath as slowly added methyl chloroformate (0.87 g, 9.2 mmol). After stirring overnight at room temperature, the reaction mixture was washed twice with a 2 N solution of hydrochloric acid, dried over magnesium sulfate, filtered and concentrated in vacuo to yield the crude product, which was purified by chromatography on silica gel using 5-10% ethyl acetate / hexanes as eluent to yield 1.8 g of the title product. MS m / z 601 (M + + 1); 1 H NMR (coalescent mixture of conformers, CDCl 3) d 0.6-0.8 (ma, 3H), 1.2-1.3 (ma, 3H), 1.3-1.5 (ma, 2H), 1.6-1.75 (ma, 1 H), 2.1- 2.3 (ma, 1H), 3.7-3.9 (sa, 3H), 4.0-4.4 (ma, 4H), 5.0-5.6 (ma, 2H), 7.1 (s, 1H), 7.4-7.6 (ma, 2H), 7.6-7.8 (ma, 3H). Using the appropriate starting materials, Examples 8-91 were prepared in a manner analogous to the sequence of reactions described in Examples 1-5 or 7A-7F, as appropriate. ^^^^^ 25 ^^ EXAMPLE 8 Ethyl ester of c / s-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-cyclopropyl-6-trifluoromethoxy-3,4- dihydro-2H-quinoline-1-carboxylic acid MS m / z 628.3 (M +); 1 H NMR (CDCl 3) d 6.85 (s, 1 H).

EXAMPLE 9 C / s-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-cyclopropyl-6,7-difluoro-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester MS m / z 580.2 (M +); 1 H NMR (CDCl 3) d 3.8 (s, 3 H), 6.8 (t, 1 H).

EXAMPLE 10 Isopropyl ester of c / s-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid MS m / z 626.5 (M +); 1 H NMR (CDCl 3) d 3.75 (s, 3 H), 7.1 (s, 1 H). - • - & & amp; - EXAMPLE 11 Isopropyl ester of c / s-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-cyclopropyl-6,7-dimethyl-3,4-dihydroxy acid 2H-quinoline-1-carboxylic acid MS m / z 586.3 (M +); 1 H NMR (CDCl 3) d 3.8 (s, 3 H), 6.7 (s, 1 H).

EXAMPLE 12 C / s-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-cyclopropyl-6-pentafluoroethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester MS m / z 662.4 (M +); 1 H NMR (CDCl 3) d 3.7 (s, 3 H), 7.1 (s, 1 H).

EXAMPLE 13 Isopropyl ester of c / s-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-cyclopropyl-6-trifluoromethoxy-3,4-dihydro-2H-quinoline-1-carboxylic acid MS m / z 642.3 (M +); 1 H NMR (CDCl 3) d 3.8 (s, 3 H), 6.75 (s, 1 H).

EXAMPLE 14 Isopropyl ester of c / s-4-f (3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-cyclopropyl-7-trifluoromethoxy-3,4-dihydro-2H-quinoline-1-carboxylic acid ester MS m / z 642.3 (M +); 1 H NMR (CDCl 3) d 3.8 (s, 3 H), 7.0 (m, 1 H).

EXAMPLE 15 Isopropyl ester of c / s-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 acid carboxylic MS m / z 614.5 (M +); 1 H NMR (CDCl 3) d 3.8 (s, 3 H), 7.1 (s, 1 H).

EXAMPLE 16 Isopropyl ester of c / s-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-propyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid MS m / z 328 (M + -300); 1 H NMR (CDCl 3) d 3.8 (s, 3 H), 7.1 (s, 1 H).

EXAMPLE 17 isopropyl ester of c / s-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-sec-butyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ester MS m / z 642.5 (M +); 1 H NMR (CDCl 3) d 3.8 (s, 3 H), 7.0 (s, 1 H).

EXAMPLE 18 10 Isopropyl ester of c / s-4 - [(3,5-bis-trifluoromethyl-benzyl) - sopropoxycarbonyl-amino] -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid MS / t? / Z655 (M ++ 1); 15 1 H NMR (CDCl 3) d 0.8 (a, 1 H), 2.4 (a, 1 H), 7.1 (s, 1 H), 7.1 (s, 1 H), 7.7 (s, 1 H), 7.8 (s, 1 H).

EXAMPLE 19 Isopropyl ester of c / s-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-isobutyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline- 1 -carboxylic MS m / z 342 (M + -300); 1 H NMR (CDCl 3) d 0.9 (m, 6 H), 1.1 (a, 1 H), 2.2 (a, 1 H), 3.8 (s, H), 7.1 (s, 1 H), 7.5-7.9 (m, 5H).

EXAMPLE 20 Isopropyl ester of c s-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-isopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid MS m / z 629.2 (M + + 1); 1 H NMR (CDCl 3) d 0.7 (d, 3 H), 3.8 (s, 3 H), 7.1 (s, 1 H), 7.6 (a, H), 7.8 (m, 3 H).

EXAMPLE 21 C / 's-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-isobutyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester MS m / z 328 (M + -300); 1 H NMR (CDCl 3) d 1.1 (a, 1 H), 2.1 (a, 1 H), 3.8 (s, 3 H), 7.1 (s, 1 H), 7.6 (a, 2 H).

EXAMPLE 22 10 isopropyl ester of c / 's-4 - [(3,5-bis-trifluoromethyl-benzyl) -ethoxycarbonyl-amino] -2-isopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline- 1 -carboxylic MS m / z 643.3 (M +); 15 1 H NMR (CDCl 3) d 0.7 (d, 3 H), 0.8 (d, 3 H), 2.1 (a, 2 H), 7.1 (s, 1 H), 7.5 (a, 2 H).

EXAMPLE 23 Isopropyl ester of c s-4 - [(3,5-bis-trifluoromethyl-benzyl) -isopropoxycarbonyl-amino] -2-isopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid 5 MS m / z 656.3 (M +); 1 H NMR (CDCl 3) d 0.7 (d, 3 H), 0.8 (d, 3 H), 1.2 (d, 3 H), 1.3 (d, 3 H), 7.1 (s, 1 H), 7.6 (a, 2 H), 7.8 (s, 2H).

EXAMPLE 24 C / s-6-acetyl-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-cyclopropyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester MS m / z 586.4 (M +); 1 H NMR (CDCl 3) d 2.6 (s, 3 H), 3.8 (s, 3 H), 7.5-8.0 (m, 6 H).

EXAMPLE 25 Ethyl ester of c s-4 - [(3,5-bis-trifl? Oromethyl-benzyl) -methoxycarbonyl-amino] -2-cyclopropyl-6-methoxy-7-trifluoromethyl-3,4-dihydro-2H-quinoline -1- carboxylic MS m / z 642.5 (M +); 1 H NMR (CDCl 3) d 1.3 (t, 3 H), 3.8 (s, 6 H), 6.5 (s, 1 H), 7.7 (s, 1 H), 7.8 (s, 2 H), 7.85 (s, 1 H).

EXAMPLE 26 C / s-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-cyclopropyl-5,6-dimethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester MS m / z 572.7 (M +); 1 H NMR (CDCl 3) d 1.3 (t, 3 H), 1.7 (d, 3 H), 1.8 (d, 3 H), 3.9 (d, 3 H). .3 (m, 2H), 6.9 (d, 1 H), 7.1 (d, 1H), 7.2 (s, 1 H), 7.3 (s, 1H), 7.5 (s, 1 H).

EXAMPLE 27 C / s-4 - [(3,5-bis-ferfluoromethyl-benzyl) -methoxycarbonyl-amino] -2-cyclopropyl-6,7-dimethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester MS m / z 272.7 (M + -300); 1 H NMR (CDCl 3) d 1.3 (t, 3 H), 2.3 (d, 6 H), 3.8 (s, 3 H), 6.6 (s, 1 H), 7.2 (s, 1 H), 7.7 (m, 3 H).

EXAMPLE 28 C / 's-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-cyclopropyl-7-trifluoromethoxy-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester MS m / z 642.2 (M +); 1 H NMR (CDCl 3) d 3.8 (s, 3 H), 7.4 (s, 1 H), 7.8 (s, 1 H).

J ^ iási ^^ sd ^^^? iiUMS ^^ & i ^ réisTZ »Sii7zMi¿ irwf¿ 7z ^ EXAMPLE 29 .2.2-Trichloro-1.1 -dimethyl-ethyl ester c / s-4 - [(3.5-bis-trifluoromethyl-benzyl) -metoxicarbonil-? amino] -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid MS m / z 743.2 (M +); 1 H NMR (CDCl 3) d 1.9 (s, 3 H), 2.0 (s, 3 H), 3.8 (s, 3 H), 7.1 (s, H), 7.8 (s, 1 H).

EXAMPLE 30 Isopropyl ester of c / s-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-cyclopropyl-6-methylsulfanyl-3,4-dihydro-2H-quinoline-1-carboxylic acid MS m / z 604.5 (M +); 1 H NMR (CDCl 3) d 2.2 (s, 3 H), 3.8 (s, 3 H), 6.8, (s, 1 H), 7.1 (d, H), 7.4 (s, 1 H), 7.7 (m, 3 H) .

EXAMPLE 31 Isopropyl Ester acid c / s-4 - [(3.5-bis-trifluoromethyl-benzyl) - methoxycarbonyl-am¡no] -2-cyclopropyl-6-methanesulfonyl-3.4-dihydro-2H- quinoline-1 -carboxylic acid MS m / z 637.5 (M + + 1); 1 H NMR (CDCl) d 1.2 (m, 6 H), 3.1 (s, 3 H), 3.8 (s, 3 H), 7.5 (s, H).

EXAMPLE 32 Isopropyl Ester acid c / s-4 - [(3.5-bis-trifluoromethyl-benzyl) - methoxycarbonyl-amino] -2-isobutyl-6-trifluoromethyl-3.4-dihydro-2H- quinoline-1 -carboxylic acid MS m / z 642.6 (M + + 1); 1 H NMR (CDCl 3) d 0.9 (d, 6H), 1.1 (a, 1 H), 7.1 (s, 1 H), 7.6 (m, H), 7.8 (m, 3H).

EXAMPLE 36 c acid isopropyl ester s-4 - [(3.5-bis-trifluoromethyl-benzyl) - methoxycarbonyl-amino] -7-chloro-2-cyclopropyl-6-trifluoromethyl-3.4-dihydro- 2H-quinoline-1 -carboxylic acid 1 H NMR (CDCl 3) d 7.18 (s, 1 H), 3.81 (s, 3H).

EXAMPLE 37 Crs-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-cyclopropyl-6,7-bis-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester MS m / z 695 (M + + 1), 712 (M + + 18); 1 H NMR (CDCl 3) d 8.01 (s, 1 H), 3.83 (s, 1 H).

EXAMPLE 38 Isopropyl Ester acid c / s-4 - [(3.5-bis-trifluoromethyl-benzyl) methoxycarbonyl-amino] -2-cyclopropyl-7-fluoro-6-trifluoromethyl-3.4-dihydro- 2H-quinoline-1 - carboxylic MS m / z 645 (M + + 1), 662 (M + + 18); 1 H NMR (CDCl 3) d 7.81 (s, 1H), 3.81 (s, 3H). » ^ a a ^ a «^ afe ^ Bt ^.« aM ^^^ 3ia ^ a8fcgttrt = ¿^ fc. /. afe &, * '% *. Z-CX,? * - á £? EXAMPLE 39 Cs-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -6,7-dimethoxy-2-phenyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester MS m / z 654.6 (M +), 1 H NMR (CDCl 3) d 1.1 (t, 3 H), 2.4 (m, 1 H) 3.8 (s, 3 H), 3.9 (s, 3 H), 6.5 (s, 1 H) , 7.6 (a, 2H), 7.7 (a, 1H). EXAMPLE 40 C / s-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -6,7-dimethoxy-2- (4-trifluoromethyl-phenyl) -3,4-dihydro-2H-quinoline- ethyl ester ethyl ester 1- carboxylic MS m / z 722.6 (M +), 1 H NMR (CDCl 3) d 1.2 (t, 3 H), 3.8 (s, 3 H) 3.9 (s, 3 H), 6.5 (s, 1 H), 7.3 (d, 2 H), 7.5 (d, 2H), 7.7 (a, 2H) 7.8 (a, 1 H).

EXAMPLE 44 Isopropyl Ester of c / s-2-cyclopropyl-4- (methoxycarbonyl-2-thiophen-ylmethyl-amino) -6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid MS r? / Z 496 (M +), 514 (M + + 18); 1 H NMR (CDCl 3) d 3.86 (s, 3 H), 7.26 (s, 1 H).

EXAMPLE 45 Isopropyl ester of c / s-2-cyclopropyl-4 - [(3,5-dichloro-benzyl) -methoxycarbonyl-amino] -6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid MS m / z 559 (M +), 1 H NMR (CDCl 3) d 2.40-2-34 (m, 1 H), 3.80 (s, 3H).

EXAMPLE 46 Isopropyl ester of c / s-4- (benzyl-methoxycarbonyl-amino) -2- c -clopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid MS m / z 492 (M + + 2), 509 (M + + 19); 1 H NMR (CDCl 3) d 2.30-2.35 (m, 1 H), 3.79 (s, 3H). ,: fc¿Í H *, -y-. -C, - AVg V2 ^ * ^^ k £ ^! ^^ - ~ '">. ^^^ & ^ Ba't EXAMPLE 47 Cs-2 (3,5-bis-trifluoromethyl-benzyl) - (2-cyclopropyl-trifluoroacetyl-6-methyl) methyl ester trifluoromethyl-1,2,3,4-tetrahydro-quinolin-4-yl) -carbamic acid MS m / z 655 (M + + 19); 1 H NMR (CDCl 3) d 7.25 (C5, s, 1 H).

EXAMPLE 48 Isopropyl Ester of c / s-2-cyclopropyl-4 - [(4-isopropenyl-1-enylmethyl) -methoxycarbonyl-amino] -6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid MS m / z 536 (M + + 2), 533 (M + + 19); 1 H NMR (CDCl 3) d 3.74 (s, 3 H), 7.18 (s, 1 H).

EXAMPLE 49 Isopropyl ester of c / s-2- (cyclohex-3-enylmethyl-methoxycarbonylamino) -2-cyclopripyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ester MS m / z 496 (M + + 2), 513 (M + + 19); 1 H NMR (CDCl 3) d 3.73 (s, 3 H), 5.68 (br s, 2 H).

EXAMPLE 50 Isopropyl ester of c / s-2-cyclopropyl - [(6,6-dimethyl-biciclof3.1.1] hept-2-en-2-ylmethyl) -methoxycarbonyl-amino] -6-trifluoromethyl-3,4-dihydro-2H- 1in-1 -carboxylic machine 5 MS m / z 536 (M + + 2), 553 (M + + 19); 1 H NMR (CDCl 3) d 3.74 (s, 3 H), 7.16 (s, 1 H).

EXAMPLE 51 10 Isopropyl ester of c / s-4- (bicyclo [2.2.1] hept-5-en-2-ylmethyl-methoxycarbonyl-amino) -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H - quinoline-1 -carboxylic MS m / z 508 (M + + 2), 525 (M + + 19); 1 H NMR (CDCl 3) d 1.30-1.42 (m, 6H), 3.73 (s, 3H).

EXAMPLE 52 Isopropyl ester of c / s-4 - [(2-bromo-3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-20 quinoline-1 acid -carboxylic MS m / z 706 (M + + 1), 724 (M + + 19); 1 H NMR (CDCl 3) d 3.78 (s, 3 H), 7.22 (s, 1 H).

EXAMPLE 53 Isobutyl ester of c / s-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2- (2-ethoxycarbonyl-cyclopropyl) -6-trifluoromethyl-3,4-dihydro-2H-quinoline- 1 -carboxylic MS m / z 698.6 (M +); 1 H NMR (CDCl 3) d 1.2 (t, 3 H), 2.3 (a, 1 H), 3.8 (s, 3 H), 4.1 (q, 4 H), .1 (s, 1 H), 7.5 (s, 2 H), 7.8 (s, 1H).

EXAMPLE 54 Isopropyl ester of c / s-4 - [(2,4-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid MS m / z 628 (M + + 2), 645 (M + + 19); 1 H NMR (CDCl 3) d 3.78 (s, 3 H), 7.20 (s, 1 H).

EXAMPLE 55 Isopropyl ester of c / s-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-cyclopropyl-7-methyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 - carboxylic MS m / z 642 (M + + 2), 659 (M + + 19); 1 H NMR (CDCl 3) d 2.46 (s, 3 H), 3.80 (3 H).

EXAMPLE 56 C / 's-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-tert-butyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester MS m / z 643 (M +); 1 H NMR (CDCl 3) d 0.6 (s, 9H), 1.1 (a, 6H), 3.8 (s, 3H), 7.1 (s, H), 7.5 (a, 1 H), 7.7 (s, 1 H), 7.8 (s, 2H). • * aZ * - ¿f3 £ »7j & * * -». . . A -, a ^, fe ^^ «^ feAaS? Teaj ^ ÍMs = ^^» »aa? ^ = Yg'i», ?? A¿ .... .. < ».« ... . ' .- .. ..-. ^; ..-- &> ,. ...

EXAMPLE 57 Isopropyl ester of c / s-4 - [(6-chloro-4-trifluoromethyl-pyridin-2-ylmethyl) -methoxycarbonyl-amino] -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline- 1 -carboxylic MS m / z 595 (M + + 2), 612 (M + + 19); 1 H NMR (CDCl 3) d 3.78 (s, 3 H), 7.15 (s, 1 H).

EXAMPLE 58 Isopropyl ester of c / s-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-cyclohexyl-6-trifluoromethyl-3,4-dhydro-2H-quinoline-1-carboxylic acid MS m / z 669.1 (M + + 1); 1 H NMR (CDCl 3) d 3.8 (s, 3 H), 7.1 (s, 1 H), 7.5 (a, 1 H), 7.7 (s, H), 7.8 (s, 2 H).

EXAMPLE 59 Isobutyl ester of c / s-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid MS / t? / Z318 (M + -300); 1 H NMR (CDCl 3) d 1.3 (t, 3 H), 2.9 (q, 2 H), 3.8 (s, 3 H), 6.9 (s, 1 H), .4 (s, 1 H), 7.6 (s, 1 H), 7.7 (s, 1H), 7.8 (s, 1H).

EXAMPLE 60 Isopropyl Ester of c / s-2-cyclopropyl - [(4-mercapto-3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid Em m / z657 (M + -i)? 658 (M +); 1 H NMR (CDCl 3) d 3.80 (s, 3 H), 7.15 (s, 1 H).

»Fc ... 1JA? /..safe it, t? "-". ". ¥ * ^ .- ^ Ta ^ te »^? 8fe« .g ^ a ^ 'A..A »^ > a ^ «. . ~ ? ? 7-s7? .iSíé iZí & EXAMPLE 61 Isopropenyl ester of c / s-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino-1-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid 5 MS m / z 625.5 (M +); 1 H NMR (CDCl 3) d 2.0 (s, 3 H), 3.8 (s, 3 H), 7.1 (s, 1 H).

EXAMPLE 62 10 isopropyl ester of c / s-4- [2- (3,5-bis-trifluoromethyl-ethyl) -methoxycarbonyl-amino] -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 acid -carboxylic MS m / z 657 (M + NH 3) +; 15 1 H NMR (CDCl 3) d 1.26 (d, 3 H), 1.31 (d, 3 H), 7.12 (s, 1 H), 7.50 (d, 1 H), 7.59 (d, 1 H), 7.65 (s, 2 H) ), 7.76 (s, 1 H).

EXAMPLE 63 C / s-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid propyl ester MS m / z 627 (M + + 1); 1 H NMR (CDCl 3) d 3.8 (s, 3 H), 7.1 (s, 1 H), 7.5-7.8 (m, 5 H).

EXAMPLE 64 C / s-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-cyclopropyl-2,3,4,6,7,8-hexahydro-cyclopenta [g] quinoline-1-carboxylic acid ethyl ester MS m / z 584 (M +); 1 H NMR (CDCl 3) d 3.8 (s, 3 H), 6.8 (s, 1 H), 7.3 (s, 1 H).

EXAMPLE 65 Isopropyl ester of c / s-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-cyclopropyl-6-ethanesulfinyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ester. 1 H NMR (CDCl 3) d 2.8 (m, 3 H), 4.1 (2 H), 3.8 (s, 3 H), 7.8 (s, 1 H).

^ ^ ^ ^ ^ ^ G ^ ^ EXAMPLE 66 Isopropyl ester of c / s-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-cyclopropyl-6-ethanesulfonyl-3,4-dihydro-2H- acid quinoline-1-carboxylic acid 5 MS m / z 651.1 (M +); 1 H NMR (CDCl 3) d 3.7 (s, H), 7.5 (s, 1 H).

EXAMPLE 67 10 Isopropyl ester of c / s-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-cyclopropyl-2,3,4,6,7,8-hexahydro-cyclopenta [g] quinoline-1-carboxylic acid ester MS m / z 298.3 (M + -300); 15 1 H NMR (CDCl 3) d 2.9 (t, 4 H), 3.8 (s, 3 H), 6.8 (s, 1 H), 7.6 (s, 1 H), 7.7 (s, 1 H), 7.8 (s, 1 H) ).

EXAMPLE 68 Isopropyl Ester of c / s-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-cyclopentyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid MS m / z 655.2 (M +); 1 H NMR (CDCl 3) d 3.8 (s, 3 H), 7.1 (s, 1 H), 7.5 (a, 2 H).

EXAMPLE 69 Isopropyl ester of c / s-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-cyclobutyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 - carboxylic MS m / z 640.1 (M +); 1 H NMR (CDCl 3) d 3.8 (s, 3 H), 7.1 (s, 1 H), 7.5 (a, 2 H).

EXAMPLE 70 Isopropyl ester of c / s-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-cyclopropyl-7-methoxy-6-trifluoromethyl-3,4-dihydro-2H-quinoline- 1 -carboxylic MS m / z 658 (M + + 2), 675 (M + + 19); 1 H NMR (CDCl 3) d 3.88 (s, 3 H), 3.79 (s, 3 H). "*» ** & j. -,. »F. serf && aM0 B3Bm ?? M £ t - »... ^ ... A ......

EXAMPLE 71 1-ethyl-propyl ester of c / s-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-cyclopropyl-2,3,4,6,7,8-hexahydro-cyclopenta [g] quinoline- 1 -carboxylic MS m / z 326.6 (M + -300); 1 H NMR (CDCl 3) d 3.8 (s, 3 H), 6.8 (s, 1 H), 7.3 (s, 1 H).

EXAMPLE 72 2.2.2-trifluoro-ethyl ester of c / s-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-cyclopropyl-2.3.4.6.7.8-hexahydro-cyclopenta [g] quinoline-1 -carboxylic MS m / z 338.1 (M + -300); 1 H NMR (CDCl 3) d 2.9 (m, 4 H), 3.8 (s, 3 H), 6.8 (s, 1 H).

EXAMPLE 73 C / s-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-cyclopropyl-2,3,4,6,7,8-hexahydro-cyclopenta [g] quinoline-1-carboxylic acid dicyclopropylmethyl ester EM m / z 350.2 | (M + - 300); 1 H NMR (CDCl 3) d 3.8 (s, 3 H), 6.8 (s, 1 H).

EXAMPLE 74 C / S Acid methyl ester - [(3,5-bis-trifluoromethyl-benzyl) - (2-cyclopropyl-1-trifluoroacetyl-2.3.4.6.7.8-hexahydro-1 H-cyclopenta [g] quinoline-1-carbamic acid 1 H NMR (CDCl 3) d 3.8 (s, 3 H), 6.9 (a, 1 H), 7.8 (a, 21 H).

EXAMPLE 75 Isopropyl Ester of c / s-4 - [(4-chloro-3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 - carboxylic MS m / z 660 (M +); 1 H NMR (CDCl 3) d 3.81 (s, 3 H), 7.12 (s, 1 H).

EXAMPLE 76 C / s-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-isopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester 1 H NMR (CDCl 3) d 3.8 (s, 3 H), 7.1 (s, 1 H), 7.5 (a, 2 H).

EXAMPLE 77 C / s-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-isopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-propyl ester carboxylic 1 H NMR (CDCl 3) d 3.8 (s, 3 H), 7.1 (s, 1 H), 7.5 (a, 2 H).

EXAMPLE 78 C / s-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-ethyl ester carboxylic MS m / z 613.1 (M +); 1 H NMR (CDCl 3) d 3.8 (s, 3 H), 7.1 (s, 1 H).

EXAMPLE 79 C / s-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid propyl ester MS m / z 314.1 (M + -300); ? NMR (CDCl 3) d 3.8 (s, 3 H), 7.1 (s, 1 H).

EXAMPLE 80 2-Hydroxy-ethyl ester of c / s-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-isopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline- 1 -carboxylic 1 H NMR (CDCl 3) d 2.0 (a, 3 H), 3.8 (s, 5 H), 7.1 (s, 1 H), 7.5 (a, H). EXAMPLE 81 C / s-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-cyclobutyl-6-trifluoromethyl-3,4-dihydro-2H-q-inoline-1-carboxylic acid propyl ester 1 H NMR (CDCl 3) d 3.8 (s, 3 H), 7.1 (s, 1 H), 7.5 (s, 2 H).

EXAMPLE 82 2-Methoxy-ethyl ester of c / s-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-isopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 - carboxylic 1 H NMR (CDCl 3) d 3.3 (m, 4 H), 3.6 (m, 4 H), 3.8 (s, 3 H), 7.1 (s, H).

EXAMPLE 83 C / s-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-cyclobutyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline- ethyl ester 1 -carboxylic MS m / z 326 (M + -300); 1 H NMR (CDCl 3) d 3.8 (s, 3 H), 7.1 (s, 1 H), 7.5 (a, 2 H).

EXAMPLE 84 c-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ester 2-hydroxy-ethyl ester MS m / z 316.1 (M + -300); 1 H NMR (CDCl 3) d 3.8 (s, 3 H), 7.1 (s, 1 H).

EXAMPLE 85 2-Hydroxy-ethyl ester of c / s-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-cyclobutyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 - carboxylic MS m / z 643.1 (M + + 2); 1 H NMR (CDCl 3) d 3.8 (m, 5H), 7.1 (s, 1H), 7.5-7.8 (m, 5H).

EXAMPLE 86 Isopropyl ester of c / s-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-methoxymethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid 1 H NMR (CDCl 3) d 3.2 (s, 3 H), 3.8 (s, 3 H), 7.1 (s, 1 H).

EXAMPLE 87 C / s-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-methoxymethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester 1 H NMR (CDCl 3) d 3.1 (s, 3 H), 3.8 (s, 3 H), 7.1 (s, 1 H).

EXAMPLE 88 C / s-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-methoxymethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid propyl ester MS m / z 630.9 (M +); 1 H NMR (CDCl 3) d 3.2 (s, 3 H), 3.8 (s, 3 H), 7.1 (s, 1 H).

EXAMPLE 89 Cis-2-cyclopropyl-4- [methoxycarbonyl- (4-methyl-3,5-bis-trifluoromethyl-benzyl) -amino] -6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester MS m / z 640.8 (M +); 1 H NMR (CDCl 3) d 2.55 (s, 3 H), 3.79 (s, 3 H).

EXAMPLE 90 Isopropyl ester of c / s-4 - [(2,6-bis-trifluoromethyl-biphenyl-4-ylmethyl) -methoxycarbonyl-amino] -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline- 1 -carboxylic MS m / z 703 (M + + 1); 705 (M + + 3); 1 H NMR (CDCl 3) d 2.15-2.39 (m, 1 H), 3.83 (br s, 3 H).

EXAMPLE 91 Isopropyl ester of c / s-4 - [(3,5-bis-trifluoromethyl-cyclohexylmethyl) -methoxycarbonyl-amino] -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid MS m / z 633 (M + + 1); 1 H NMR (CDCl 3) d 3.74 (s, 3 H), 7.18 (s, 1 H).

EXAMPLE 92 Ethyl 6,7-dimethoxy-2-ylpropyl-4-oxo-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester 4,6,7-Trimethoxyquinoline (0.3 g, 1.4 mmol) was dissolved in anhydrous tetrahydrofuran (6 ml). The mixture was cooled to -78 ° C and ε-propionyl magnesium chloride (0.8 mL of a 2M solution in tetrahydrofuran, 1.6 mmol) was added. The mixture was stirred at -78 ° C for 10 minutes and then ethyl chloroformate (0.16 ml, 1.6 mmol) was added. The reaction was warmed to room temperature and stirred overnight and then 1 N HCl (6 mL) was added. After stirring for 1 hour, the tetrahydrofuran was removed in vacuo and the remaining aqueous phase was extracted with ethyl acetate (3 x 50 ml). The organic phases were combined and washed with water (15 ml), dried over sodium sulfate, filtered and concentrated in vacuo to give 0.26 g of crude product. Purification by chromatography on silica gel using 0-40% ethyl acetate / hexanes as eluent afforded the title product (0.23 g, 51%). 1 H NMR (CDCl 3) d 0.85 (d, 3 H), 0.9 (d, 3 H), 1.33 (t, 3 H), 1.8 (m, 1 H), 2.8 (dd, 1 H), 2.93 (dd, 1 H) , 3.9 (s, 3H), 3.95 (s, 3H), 4.3 (m, 2H), 4.5 (m, 1 H), 7.3 (sa, 1 H), 7.37 (s, 1 H).

EXAMPLES 93 AND 94 C / s-4-benzylamino-6,7-dimethoxy-2-isopropyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester and trans-4-benzylamino-6,7-dimethoxy- ethyl ester 2-isopropyl-3,4-dihydro-2H-quinoline-1-carboxylic acid 6,7-Dimethoxy-2-isopropyl-4-oxo-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (Example 92) (0.254 g, 0.79 mmol) was combined with triethylamine (0.75 mL, 5.4 mmol) and benzylamine (0.17 ml, 1.6 mmol) in anhydrous dichloromethane (4 ml). This solution was introduced into a water bath at room temperature and titanium tetrachloride (0.8 ml of a 1 M solution in dichloromethane, 0.8 mmol) was slowly added. After stirring overnight, a solution of sodium borohydride (0.27 g, 7.2 mmol) in methanol (6 mL) was carefully added to the mixture. After 3 days, the mixture was made basic with 2N KOH and extracted with ethyl acetate (3 x 50 ml), the combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo to yield 0.315 g of material. This material was purified by chromatography on silica gel eluting with 0-30% ethyl acetate in hexanes to yield 35 mg of cis product of the title of example 93. 1 H NMR (CDCl 3) d 0.78 (d, 3H), 0.88 ( d, 3H), 1.26 (t, 3H), 1.35 (m, 1 H), 1.9 (m, 1 H), 2.43 (ddd, 1 H), 3.57 (dd, 1 H), 3.85 (s, 3H), 3.87 (s, 3H), 3.95 (d, 1) H), 4.07 (d, 1 H), 4.15 (m, 1 H), 4.25 (m, 2H), 6.95 (s, 1 H), 7.03 (s, 1 H), 7.25-7.45 (m, 5H) . Further elution of silica gel with 40% ethyl acetate in hexanes yielded 130 mg of the trans product of the title of example 94. 1 H NMR (CDCl 3) d 0.78 (d, 3 H), 0.88 (d, 3 H), 1.28 (d. t, 3H), 1.8 (m, 1 H), 2.08 (t, 2H), 3.70-3.85 (m, 3H), 3.87 (s, 6H), 4.10-4.35 (m, 3H), 6.80 (s, 1 H), 7.10 (s, 1 H), 7.25-7.45 (m, 5H).

EXAMPLE 95 cis-4- (benzyl-methoxycarbonyl-amino) -2-isopropyl-6,7-dimethoxy-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester To a solution of cis-4-benzylamino-6,7-dimethoxy-2-isopropyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (example 93) (22 mg, 0.05 mmol) and pyridine (0.50 ml, 6.2 mmol) in anhydrous dichloromethane (1 ml) was added methyl chloroformate (0.10 ml, 1.3 mmol) while cooling in an ice bath. After stirring at room temperature overnight, water (10 ml) and aqueous 2 N KOH (10 ml) were added to the reaction mixture. The solution was stirred for 30 minutes and then the mixture was extracted with ethyl acetate (2 x 10 ml). The organic phases were combined and washed with 1 N HCl (2 x 10 ml), a saturated solution of sodium bicarbonate (10 ml) and brine (10 ml). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give 88 mg of crude product. Purification by chromatography on silica gel using 0-40% ethyl acetate / hexanes as eluent afforded the title product (12 mg, 50%). MS m / z 471 (M + + 1), 488 (M + + 18); 1 H NMR (CDCl 3) d 0.6-0.8 (m, 6H), 1.25 (t, 3H), 1.4 (m, 1H), 1.8-2.3 (m, 3H), 3.8 (s, 6H), 3.85 (s, 3H) ), 4.0-4.3 (m, 5H), 5.1 (m, 1 H), 6.96 (C8, sa, 1 H), 6.42 (C5, sa, 1 H), 7.2-7.4 (m, 5H). Example 96 was prepared from example 94 in a manner analogous to that of example 95.

EXAMPLE 96 Fra / 7S-4- (benzyl-methoxycarbonyl-amino) -2-isopropyl-6,7-dimethoxy-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester MS m / z 471 (M + + 1), 488 (M + + 18). 1 H NMR (CDCl 3) d 3.86 (C6-OMe, s, 3H), 3.77 (C7-OMe, s, 3H). Examples 97-99 were prepared in a manner analogous to the sequence of reactions described for Examples 92-95.

EXAMPLE 97 C / S-4- (Benzyl-ethoxycarbonyl-amino) -2-ethyl-6,7-dimethoxy-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester MS m / z 471 (M + + 1), 488 (M + + 18). 1 H NMR (CDCl 3) d 7.00 (C8, s, 1H), 6.42 (C5, s, 1H), 0.71 (C2-Et, m, 3H).

EXAMPLE 98 Fra / 7s-4- (benzyl-ethoxycarbonyl-amino) -2-ethyl-6,7-dimethoxy-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester MS m / z 471 (M + + 1), 488 (M + + 18). 1 H NMR (CDCl 3) d 6.47 (C5, s, 1 H), 0.86 (C2-Et, t, 3H).

EXAMPLE 99 C / s-2-allyl-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino) -6,7-dimethoxy-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester MS m / z 605 (M + + H); 1 H NMR (CDCl 3) d 7.7 (br s, 1 H), 7.5 (br, 2H), 7.2 (br, 2H), 6.3 (br, 1H), 3.6 (s, 3H), 1.35 (t, 3H, J = 7 Hz).

EXAMPLE 100A c / s-4-Amino-8-bromo-2-cyclopropyl-6-trifluoromethyl-1.2.3.4-tetrahydroquinoline To a solution of c / s-4-benzyloxycarbonylamino-8-bromo-2-cyclopropyl-6-trifluoromethyl-1, 2,3,4-tetrahydro-quinoline (1.0 g) (prepared from 2-bromo-4-trifluoroethylaniline and cyclopanecarboxaldehyde as in example 1) in 20 ml of dichloromethane, 30% HBr in HOAc (10 ml) was added over 5 minutes and the resulting mixture was stirred for 18 hours. The reaction was quenched with 1 M K2CO3 solution, the layers were separated and the aqueous layer was extracted with 50 ml of dichloromethane. The combined extracts were dried (MgSO), filtered and concentrated, and the residue was chromatographed (70% EtOAc / hexane) to yield the title product (500 mg). MS m / z 335.9 (M + + 1); 1 H NMR (CDCl 3) d 0.3 (m, 2 H), 0.6 (m, 2 H), 1.0 (m, 1 H), 4.0 (m, 1 H), 7.5 (s, 1 H), 7.6 (s, 1 H).

EXAMPLE 100B c / s-4 - [(3,5-Bis-trifluoromethyl-benzyl) -amino] -8-bromo-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline To a solution of c / s-4-amino-8-bromo-2-cyclopropyl-6-trifluoromethyl-1, 2,3,4-tetrahydroquinoline (example 100A) (250 mg, 0.75 mmol) in dichloromethane anhydrous (10 ml), acetic acid (112 mg, 1.90 mmol) was added followed by 3,5-bis (trifluoromethyl) benzaldehyde (180 mg, 0.75 mmol) and sodium triacetoxyborohydride (791 mg, 3.73 mmol). The reaction was stirred at room temperature for 5 hours. The reaction mixture was then diluted with dichloromethane and washed with 1 N NaOH. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated in vacuo to yield the crude title product (420 mg) which was used without further purification. 1 H NMR (CDCl 3) d 0.3 (m, 2 H), 0.6 (m, 2 H), 1.0 (m, 1 H), 7.5 (s, 1 H), 7.8 (s, 2H), 7.9 (s, 2H).

EXAMPLE 100C c / s-4 - [(3,5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -8-bromo-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline C / s-4 - [(3,5-bis-trifluoromethyl-benzyl) -amino] -8-bromo-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinolin (Example 10OB) was dissolved. ) (420 mg, 0.75 mmole) and pyridine (148 mg, 1.88 mmole) in anhydrous dichloromethane (15 ml) and the mixture was cooled to 0 ° C. Methyl chloroformate (142 mg, 1.5 mmol) was added for 1 minute. The reaction was stirred at 0 ° C for 1 hour and then at temperature for 24 hours. The reaction mixture was then diluted with 50 ml of dichloromethane and washed twice with 1N HCl. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo to yield the title product (400 mg) it was used without further purification. Em m / z 618.8 (M +).

EXAMPLE 100D c / s-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -8-bromo-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline- chloride 1 -carbonyl A solution of c / 's-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -8-bromo-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline ( Example 100C) (1.0 g) in 50 ml of a 20% solution of phosgene in toluene, was heated to reflux for 24 hours. Additional phosgene / toluene (50 ml) was added and heating continued for a further 24 hours. Excess phosgene was removed by purification with nitrogen. The resulting solution was concentrated to yield the crude title product that was used without further purification. Em m / z 618.5 (M +).

EXAMPLE 101 Isopropyl ester of c / s-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -8-bromo-2-c8-chloropropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 - carboxylic A solution of c / 's-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -8-bromo-2-cyclopropyl-6-trifluoromethyl-3 chloride, 4-dihydro-2H-quintilla-1 -carbonyl (example 100D) (1.5 g) in isopropanol, was heated to reflux for 48 hours. The reaction was cooled and concentrated and the residue was chromatographed (5-10% EtOAc / hexane) to yield the title product (1.09) -Em m / z 705.4 (M +); 1 H NMR (CDCl 3) d 3.8 (s, 3 H), 7.1 (s, 1 H), 7.8 (s 2 H).

EXAMPLE 102A c / 's-4 - [(3,5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline C / 's- (3,5-bis-trifluoromethyl-benzyl) - (2-cyclopropyl-1-trifluoroacetyl-6-trifluoromethyl-1, 2,3,4-tetrahydro-quinolin-4-methyl ester was dissolved. il) -carbamic (example 47) (900 mg, 1.41 mmol) in 20 ml of methanol and 60 ml of tetrahydrofuran, before the addition of lithium hydroxide (1.6 ml of a 1.0 M aqueous solution, 1.6 mmol) to the solution . After 2 hours to At room temperature, 100 ml of water was added and the mixture was extracted with ethyl acetate (3 x 100 ml). The combined organic extracts were washed with 50 ml of brine, dried over sodium sulfate, filtered and concentrated in vacuo to yield the title product (740 mg) as a colorless solid which was used without further purification. Em m / z 542 (M + 2) +. 1 H NMR (CDCl) d 0.2 (m, 2 H), 0.55 (m, 2 H), 0.8 (m, 1 H).

EXAMPLE 102B c / s-4 - [(3,5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-carbonyl chloride A solution of c / 's-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro- 2H-quinoline (example 102A) (180 mg, 0.33 mmol) in 2 ml of a 1.93 M solution of phosgene in toluene was heated to reflux for 1 hour. The excess phosgene was removed by purging with nitrogen and the resulting solution was concentrated to yield the crude title product (208 mg) which was used without further purification. Em m / z 621 (M + 19) +. 1 H NMR (CDCl 3) d 0.2 (m, 1 H), 0.45 (m, 2 H), 0.55 (1 H), 0.75 (m, 1 H). if-Si ^^^^^ - ^^ AASáSi ^ ^ J X7.,.:., j ¿-f ^ ^ EXAMPLE 102C 2.2.2-Trifluoro-ethyl ester of c / s - [(3.5-bis -trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid A solution of c / s-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H chloride was added at reflux. -quinoline-1 -carbonyl (example 102B) (20 g) in 2,2,2-trifluoroethanol (5 ml). After 1 hour, the reaction was cooled and concentrated and the residue was chromatographed (5-10% EtOAc / hexane) to yield the title product (22 mg, 77%). Em m / z 685 (M + 19) +; 1 H NMR (CDCl 3) d 3.82 (s, 3H), 7.17 (C5, s, 1H). Examples 103-106 were prepared using the appropriate alcohol in a manner analogous to the sequence of reactions used in Examples 102A-102C.

^, "'. . A & "J- ¿1 ¡A - jfa¿fc¡áw» ^ S teÉ < lbSiSS > «? Brihaá. i..gis ... -t- * JB- and. »». .. «jaft4? Flfe» »jrittSto.» - *, EXAMPLE 103 c / s-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-cyclopropyl-6-cyclopropyl methyl ester trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid MS m / z 640 (M + + 2). 657 (M + + 19); 1 H NMR (CDCl 3) d 3.81 (s, 3 H), 7.14 (C5, s, 1 H).

EXAMPLE 104 c / s-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid butyl ester MS m / z 642 (M + + 2), 659 (M + + 19); 1 H NMR (CDCl 3) d 3.81 (s, 3 H), 7.14 (C5, s, 1 H).

EXAMPLE 105 .2-Dimethyl-propyl ester of c / s-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 acid -carboxylic MS m / z 656 (M + + 2), 673 (M + + 19); 1 H NMR (CDCl 3) d 3.81 (s, 3 H), 7.14 (C5, s, 1 H).

-U »&» S. ». , j ». * »< * a ^^^^? ÁÉ ^ i &Á ^ ~ A Á '"*.'. - • 'iÁ S / ^? Te Satíi ,.

EXAMPLE 106 C / s-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino-1-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid pentylester.

MS m / z 656 (M + + 2), 673 (M + + 19); 1 H NMR (CDCl 3) d 3.81 (s, 3H), 7.14 (C5, s, 1H).

EXAMPLE 107A c / s-4- (N-benzyloxycarbonyl-N-tert-butoxycarbonyl) amino-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester To a solution of c / s- (2-cyclopropyl-6-trifluoromethyl-1, 2,3,4-tetrahydro-quinoline-4-yl) -carbamic acid benzyl ester (4.0 g, 10.3 mmol) (prepared from 4-trifluoromethylaniline and cyclopropanecarboxaldehyde as in Example 1) in 150 ml of anhydrous tetrahydrofuran, 4-dimethylaminopyridine (5.0 g) and di-tert-butyl dicarbonate (8.96 g, 41 mmol) were added and the resulting solution it stirred for 24 hours. The reaction mixture was poured into 100 ml of 2 N HCl and extracted with 2 x 200 ml EtOAc. The combined extracts were dried (MgSO), filtered and concentrated to yield the title product (6.5 g) which was used without further purification. - * »^^. &« ^ ^ * * * * * X ^ t "'• y? Foj k 1H NMR (CDCI3) d 1.4 (s, 9H), 1.5 (s, 9H), 2.35 (m , 1 H), 2.55 (m, 1H), 4.0 (q, 1 H), 7.3 (s, 5H), 7.5 (m, 3H).

EXAMPLE 107B c / s-4-tert-butoxycarbonyl-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester A mixture of tert-butyl ester of c / s-4- (N-benzyloxycarbonyl-N-tert-butoxycarbonyl) amino-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinolyl ester Na-1-carboxylic acid (example 107 A) (6.5 g) and 10% Pd / C in 50 ml of EtOH and 50 ml of cyclohexene was refluxed for 1 hour. The cooled reaction mixture was filtered through Celite® and concentrated to yield the title product (3.4 g) which was used without further purification. 1 H NMR (CDCl 3) d 1.5 (d, 18 H), 1.7 (m, 1 H), 2.5 (m, 1 H), 4.0 (q, 1 H), 7.6 (m, 3 H).

EXAMPLE 107C c / s-4-amino-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quintile-1-carboxylic acid tert-butyl ester Trifluoroacetic acid (3.4 g) was added portionwise to a solution of c / s-4-tert-butoxycarbonylamino-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-tert-butyl ester. carboxylic (example -. > -, ßt? K & f? tél & , -? x & sx ^, .vBi.t -: «,. . t y- ... ... - »,« - íi ex. '-g, ~. -107B) (3.4 g, 7.4 mmol) in 150 ml of dichloromethane and the reaction was stirred until no starting material was observed by thin layer chromatography. A small amount of 1 N NaOH was added and the reaction mixture was dried (MgSO4), filtered and concentrated. Chromatography on silica gel (50% ethyl acetate: hexane, through 5% MeOH / dichloromethane) yielded the title product (1.0 g). 1 H NMR (CDCl 3) d 1.5 (s, 9 H), 1.7 (m, 1 H), 2.5 (m, 1 H), 4.1 (q, 1 H), 7.6 (m, 3 H).

EXAMPLE 107D c / s-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester The c / s-4-amino-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester (Example 107C) (1.0 g) was subjected to to reductive amination (with 3,5-bis (trifluoromethyl) benzaldehyde as in Example 4 and acylation with methyl chloroformate as in example 5) to yield 2.4 g of the title compound. MS m / z 640 (M +); 1 H NMR (CDCl 3) d 1.5 (s, 9 H), 3.8 (s, 3 H), 7.1 (s, 1 H), 7.5-8.0 (m, 4 H).

Examples 108-111 were prepared from the appropriate starting materials in a manner analogous to the sequence of reactions described in Examples 107A-107D.

EXAMPLE 108 c / s-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester MS m / z 657.3 (M +); 1 H NMR (CDCl 3) d 3.8 (s, 3 H), 6.8 (t, 1 H).

EXAMPLE 109 c-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester MS m / z 529.1 (M + -CO2-tBu); 1 H NMR (CDCl 3) d 0.9 (t, 3 H), 1.4 (s, 9 H), 8 (s, 3 H), 7.4 (s, 1 H).

EXAMPLE 110 c / s-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-isopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester 1 H NMR (CDCl 3) d 1.4 (s, 9 H), 3.8 (s, 3 H), 7.1 (s, 1 H), 7.8 (a, 2 H).

EXAMPLE 111 c / s-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-cyclopropyl-2,3,4,6,7,8-hexahydro-cyclopenta [g] quinoline-1-tert-butyl ester carboxylic MS m / z 513.2 (M + - CO2tBu)); 1 H NMR (CDCl 3) d 2.1 (t, 2 H), 2.9 (m, 4 H), 3.8 (s, 3 H), 6.8 (s, 1 HOUR).

EXAMPLE 112A (3,5-bis-trifluoromethyl-benzyl) - (7,8-dimethoxy-1-oxo-3,3a.4,5-tetrahydro-2-oxa-9b-aza-cyclopenta [a] naphthalene-5) methyl ester il) -carbamic To a solution of 1-ethyl ester of 4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -6,7-dimethoxy-3,4-dihydroxy-2-butyl ester. «.- * _ = 2H-quinoline-1,2-dicarboxylic acid (example 5) (100 mg, 0.15 mmol) in 8.5 ml of methanol at 0 ° C, sodium borohydride (57 mg, 1.5 mmol) was added and the mixture The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water and extracted twice with ethyl acetate. The combined extracts were dried over magnesium sulfate, filtered and concentrated. The residue was chromatographed using 80% ethyl acetate / hexanes to yield the title product (70 mg). 1 H NMR (CDCl 3) d 1.8 (a, 1 H), 2.4 (a, 1 H), 3.6 (s, 3 H), 6.5 (a, 1 H), 7.6 (a, 2 H), 7.9 (s, 1 H).

EXAMPLE 112B c / s- (3,5-Bis-trifluoromethyl-benzyl) - (6,7-dimethoxy-2-methylsulfanylmethyl-1,2,3,4-tetrahydro-quinolin-4-yl) -amine To a solution of (3,5-bis-trifluoromethyl-benzyl) - (7,8-dimethoxy-1-oxo-3, 3a, 4,5-tetrahydro-2-oxa-9b-aza-c) methyl ester. Clopenta [a] naphthalen-5-yl) -carbamic acid (example 112A) (700 mg) in dimethyl formamide (15 ml), sodium methylthiolate (105 mg, 1.5 mmol) was added and the resulting solution was heated to 90 °. C for 15 hours. The reaction was cooled, water was added and the mixture was extracted twice with ethyl acetate. The extracts were dried (MgSO4), filtered and concentrated. The residue was chromatographed using 25% ethyl acetate / hexanes to yield the title product (120 mg).

EXAMPLE 112C c / s ^ 4 - [(3,5-bis-trifluoromethyl-benzyl) -ethoxycarbonyl-amino] -6,7-dimethoxy-2-methylsulfanylmethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester To an ice-cooled solution of c / s- (3,5-bis-trifluoromethyl-benzyl) - (6,7-dimethoxy-2-methylsulfanylmethyl-1, 2,3,4-tetrahydro-quinolin-4-) il) -amine (example 112B) (120 mg) and pyridine (0.50 ml) in dichloromethane (30 ml), ethyl chloroformate (0.5 ml) was added. The solution was stirred at 0 ° C for 30 minutes and then at room temperature for 18 hours. The reaction was quenched with water and the mixture was extracted twice with ethyl acetate. The combined extracts were dried over magnesium sulfate, filtered and concentrated. The residue was chromatographed with 25% ethyl acetate / hexanes to yield the title product (100 mg). MS m / z 636.3 (M +); 1 H NMR (CDCl 3) d 2.1 (s, 3 H), 3.8 (s, 3 H), 3.9 (s, 3 H), 6.4 (s, 1 H), 7.0 (s, 1 H).

EXAMPLE 113 Isopropyl ester of c / s-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2- (2-hydroxymethyl-cyclopropyl) -6-trifluoromethyl-3-4-dihydro-2H-quinoline- 1 -carboxylic To a solution of isopropyl ester of c / s-4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2- (2-ethoxycarbonyl-cyclopropyl) -6-trifluoromethyl] -3 acid , 4-dihydro-2H-quinoline-1-carboxylic acid (example 53) (100 mg, 0.14 mmol) in refluxing methanol (40 ml), sodium borohydride (1.0 g) was added in portions and the resulting mixture was heated reflux for an additional 30 minutes. The cooled reaction was concentrated and the residue was partitioned between ethyl acetate and 2N HCl. The aqueous layer was back extracted with ethyl acetate and the combined extracts were dried (MgSO4), filtered and concentrated. The residue was chromatographed with 15-20% ethyl acetate / hexane to yield the title product (55 mg). MS m / z 657.2 (M +); 1 H NMR (CDCl 3) d 3.8 (s, 3 H), 3.9 (q, 1 H), 7.1 (s, 1 H), 7.5 (s, 1 H), 7.5 (s, 2 H), 7.7 (s, 1 H). Examples 114-122 were prepared in an optically enriched form by resolution of the corresponding indicated racemate, or an intermediate in their synthesis, using the procedures described in the specification.

EXAMPLE 114 4 (S) - [(3,5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino-2 (S) -sopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester.

Enantiomer of the title product of example 20.

EXAMPLE 115 4 (S) - [(3,5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2 (S) -cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester Enantiomer of the title product of example 10.

EXAMPLE 116 4- (S) - [(3,5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2 (S) -cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H- tert -butyl ester quinoline-1 -carboxylic Enantiomer of the title product of example 107D. ^^ ^ ^^^ g ^^^^ gg ^^^^^^^^^^^ & ^^^^^^^^^^^^^^^^^^^^^ EXAMPLE 117 4 (S) - [(3,5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2 (S) -cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid propyl ester Enantiomer of the title product of example 63.

EXAMPLE 118 4 (S) - [(3,5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2- (R) -ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester Enantiomer of the product of the title of example 15.

EXAMPLE 119 4 (S) - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2 (S) -cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-ethyl ester ethyl ester carboxylic Enantiomer of the title product of example 78. r & & , And J & afc - * - EXAMPLE 120 4 (S) - [(3,5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2 (R) -ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline- ethyl ester ethyl ester 1 -carboxylic Enantiomer of the title product of Example 7F.

EXAMPLE 121 4 (S) - [(3,5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2 (R) -ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid propyl ester Enantiomer of the title product of example 79.

Example 122 4 (S) - [(3,5-Bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2 (R) -ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester Enantiomer of example 84. 7-r ~ r. - &JB? -. - «- - ^ - ^ - ^ AA: ^ 1_j ^^^^^^^^^^^ _ | Mll ^^^^^ fe ^^^^^^^^^ g ^^^^^^

Claims

NOVELTY OF THE INVENTION

.- A compound of formula 1
Formula I a prodrug thereof to a pharmaceutically acceptable salt of said compound or said prodrug; wherein R1 is hydrogen, Y, W-X or W-Y; where W is a carbonyl, thiocarbonyl, sulfinyl or sulfonyl, X is -O-Y, -S-Y, -N (H) -Y or -N- (Y) 2; where Y, for each case, is independently Z or a linear or branched carbon chain, from one to ten members, fully saturated, partially unsaturated or totally unsaturated, where the carbons other than the connecting carbon can be optionally replaced with one or two selected heteroatoms independently between oxygen, sulfur and nitrogen, and said carbon is optionally mono-, di- or tri- substituted independently with halo, said carbon is optionally mono-substituted with hydroxy, said carbon is optionally mono-substituted with oxo, said sulfur is optionally mono-or di-substituted with oxo, said nitrogen is optionally mono or disubstituted with oxo, and said carbon chain is optionally mono-substituted with Z; where Z is a partially saturated, fully saturated fully unsaturated three to eight member ring optionally having one to four heteroatoms independently selected from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two condensed rings of three to six members, partially saturated, fully saturated or totally unsaturated, taken independently, optionally having from one to four heteroatoms independently selected from nitrogen, sulfur and oxygen; wherein said substituent Z is optionally mono-, di- or tri-substituted independently with halo, alkenyl (dd), alkyl (dd), hydroxy, alkoxy (dd), alkylthio (d-C4), amino, nitro, cyano, oxo , carboxy, alkoxycarbonyl (d- d), mono-N- or di-N, N-alkylamino (dd), wherein said alkyl substituent (dd) is optionally mono-, di- or tri-substituted independently with halo, hydroxy, alkoxy (d-Ce). (C 1 -C 4) alkylthio, amino, nitro, cyano, oxo, carboxy, alkoxycarbonyl (Ci-d), mono-N- or di-N, N-alkylamino (dd), and said alkyl substituent (dd) is also optionally substituted with one to nine fluorine atoms; R2 is a linear or branched carbon chain, from one to six members, partially saturated, fully saturated or totally unsaturated, in which the carbons other than the connecting carbon can optionally be replaced with one or two heteroatoms independently selected from oxygen, sulfur and nitrogen , where said atoms of carbon are optionally mono-, di- or tri-substituted independently with halo, said carbon is optionally mono-substituted with oxo, said carbon is optionally mono-substituted with hydroxy, said sulfur is optionally mono- or di-substituted with oxo, said nitrogen is optionally mono- or di-substituted with oxo; or said R2 is a three to seven member ring partially saturated, fully saturated or completely unsaturated having optionally one or two heteroatoms independently selected from oxygen, sulfur and nitrogen, wherein said ring R4 is optionally linked through an alkyl group ( C? -C4); wherein said ring R2 is optionally mono-, di- or tri substituted independently with halo, alkenyl (dd), alkyl (C? -d), hydroxy, alkoxy (C-? -d), alkylthioid-d), amino nitro, cyano, oxo, carboxy, alkoxycarbonyl (CrCe), mono-N- or di-N, N-alkylamino (dd) wherein said alkyl substituent (dd) is optionally mono-, di- or tri-substituted independently with halo, hydroxy, alkoxy (dd), alkylthio (dC), oxo or alkyloxycarbonyl (dd); with the proviso that R2 is not methyl; R3 is hydrogen or Q; where Q is a linear or branched carbon chain of one to six members fully saturated, partially unsaturated or totally unsaturated, in which the carbons other than the connecting carbon can be optionally replaced with a heteroatom selected from oxygen, sulfur and nitrogen, and said carbon is optionally mono-, di- or tri- substituted independently with halo, said carbon is optionally mono-substituted with hydroxy, said carbon being optionally mono- substituted with oxo, said sulfur is optionally mono- or di-substituted with oxo, said nitrogen is optionally mono- or di-substituted with oxo, and said carbon chain is optionally mono-substituted with V; where V is a three to eight member ring partially saturated, totally saturated or totally unsaturated having optionally one to four heteroatoms independently selected from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two condensed rings of three to six partially saturated, fully saturated or totally unsaturated, taken independently, which optionally have one 10 to three heteroatoms independently selected from nitrogen, sulfur and oxygen; wherein said substituent V is optionally mono-di-, tri-, or tetra-substituted independently with halo, alkyl (dd), alkenyl (dd), hydroxy, alkoxy (dd), alkylthio (C? -C), amino, nitro , cyano, oxo, carboxamoyl, mono-N or di-N, N-alkylcarboxamoyl (dd), carboxy,
Alkoxycarbonyl (dd), mono-N or di-N, N-alkylamino (dd) wherein said alkyl (dd) or alkenyl (dd) substituent is optionally mono-, di- or tri-substituted independently with hydroxy, alkoxy (dd) ), alkylthio (d-d), amino, nitro, cyano, oxo, carboxy, alkoxycarbonyl (Crd), mono-N- or di- N, N-aqluylamino (dd), and said alkyl (dd) or alkenyl substituents ( C2-20 d) are also optionally substituted with one to nine fluorine atoms; R4 is Q1 or V1; where Q1 is a carbon chain of one to six members, linear or branched, fully saturated, partially unsaturated or totally unsaturated, in which the carbons other than the connecting carbon can optionally substituted with a heteroatom selected from oxygen, sulfur and nitrogen and said carbon is optionally mono-, di- or tri-substituted independently with halo, said carbon is optionally mono-substituted with hydroxy, said carbon is optionally mono-substituted with oxo, said sulfur is optionally mono- or di-substituted with oxo, said nitrogen is optionally mono- or di-substituted with oxo and said carbon chain is optionally mono-substituted with V1; where V1 is a three to six member ring partially saturated, fully saturated or completely unsaturated having one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein said substituent V1 is optionally mono-, di-, tri- or tetra-substituted independently with halo, alkyl (dd), alkoxy (dd), amino, nitro, cyano, alkoxycarbonyl (dd), mono-N- or di- N, N-alkylamino (dd), wherein said alkyl substituent (dd) is optionally mono-substituted with oxo, and said alkyl substituent (dd) is also optionally substituted with one to nine fluorine atoms; where R3 must contain V or R4 must contain V1; R5, R6, R7 and R8 are independently hydrogen, a bond, nitro or halo, where said bond is substituted with T or a straight or branched carbon chain, (C1-C12), partially saturated, fully saturated or totally unsaturated, where the carbon it can optionally be replaced with one or two heteroatoms independently selected from oxygen, sulfur and nitrogen, where said carbon atoms are optionally mono-, di- or tri-substituted "- - -> - r. .. ^ * .- ^.. ^ .. .. feÉi &a ^^ independently with halo, said carbon is optionally mono-substituted with hydroxy, said carbon is optionally mono -substituted with oxo, said sulfur is optionally mono- or di-substituted with oxo, said nitrogen is optionally mono- or di-substituted with oxo, and said carbon chain is optionally mono-substituted with T, where T is a ring of three to eight members partially saturated, fully saturated or completely unsaturated having optionally one to four heteroatoms independently selected from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two condensed rings of three to six members
Partially saturated, fully saturated or totally unsaturated, taken independently, optionally having from one to four heteroatoms independently selected from nitrogen, sulfur and oxygen; wherein said substituent T is optionally mono-, di- or tri- substituted independently with halo, alkyl (d-d), alkenyl (d-d),
Hydroxy, alkoxy (dd), alkylthio (dd), amino, nitro, cyano, oxo, carboxy, alkoxycarbonyl (dd), mono-N- or di-N, N-alkylamino (dd) wherein said alkyl substituent (dd) is optionally mono-, di- or tri-substituted independently with hydroxy, alkoxy (dd), alkylthio (C? -C4), amino, nitro, cyano, oxo, carboxy, alkoxycarbonyl (dd), mono-N- or di- N, N-alkylamino (d-20 Ce) and said alkyl substituent (dd) is also optionally substituted with one to nine fluorine atoms; and wherein R5 and R6, or R6 and R7, and / or R7 and R8 may also be taken together and may form at least one ring of four to eight members which is optionally saturated or totally unsaturated having optionally from one to three heteroatoms independently selected from hydrogen, sulfur and oxygen; wherein said ring or rings formed by R5 and R6, or R6 and R7, and / or R7 and R8 are optionally mono-, di or tri- substituted independently with halo, alkyl (Crd), alkylsulfonyl (CrC), alkenyl (dd) , hydroxy, alkoxy (dd), (C 1 -C 4) alkylthio, amino, nitro, cyano, oxo, carboxy, alkoxycarbonyl (dd), mono-N- or di-N, N-alkylamino (dd) wherein said alkyl substituent ( dd) is optionally mono-, di- or tri-substituted independently with hydroxy, alkoxy (dd), alkylthio (dd), amino, nitro, cyano, oxo, carboxy, alkoxycarbonyl (dd), mono-N- or di-N , N-alkylamino (dd) and said alkyl substituent (dd), is also optionally substituted with one to nine fluorine atoms; with the proviso that when R 2 is carboxyl or alkylcarboxyl, then R is not hydrogen. 2. The compound according to claim 1, wherein R2 is beta; nitrogen C4 is beta; R1 is W-X; W is carbonyl, thiocarbonyl or -SO2-; X is -O-Y-, S-Y-, N (H) -Y- or -N- (Y) 2-; And, for each case, it is independently Z or alkyl (d-d), said alkyl (d-d) being optionally substituted with one to nine fluorine or hydroxy atoms, or said alkyl (d-d) being optionally mono-substituted with Z; where Z is a three to six member ring partially saturated, fully saturated or fully unsaturated having optionally one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein said substituent Z is optionally mono-, di- or tri-substituted
+? E ¿Ji «> > ..! v »- - iimí s ^? ^ ii ^^ Í3 ~ ^ á ^ íS ^ 7i ^^^^^^^^^ independently with halo, alkyl (dd), alkoxy (d-C4), alkylthio (d-) C4), nitro, cyano, oxo or alkyloxycarbonyl (dd), said (C1-C4) alkyl being optionally substituted with one to nine fluorine atoms; R2 is a linear or branched partially saturated, fully saturated or fully unsaturated one to four membered carbon chain in which the carbons other than the connecting atom can optionally be replaced with a heteroatom independently selected from oxygen, sulfur and nitrogen, wherein said atoms carbon are optionally mono-, di- or tri-substituted independently with halo, said carbon is optionally mono-substituted with oxo, said carbon is optionally mono-substituted with hydroxy, said sulfur is optionally mono- or disubstituted with oxo, said nitrogen being optionally mono- or di-substituted with oxo; or said R2 is a three to five member ring partially saturated, fully saturated or completely unsaturated, optionally having a heteroatom independently selected from oxygen, sulfur and nitrogen; wherein said ring R2 is optionally mono-, di- or tri-substituted independently with halo, hydroxy, alkoxy (d-d) or alkoxycarbonyl (d-d); R3 is Q-V where Q is (C1-C4) alkyl and V is a partially saturated five to six member ring, fully saturated or totally unsaturated having optionally one to three heteroatoms independently selected from oxygen, sulfur and nitrogen, wherein said ring V is optionally mono-, di-, tri- or tetra-substituted independently with halo, alkyl (dd), hydroxy, alkoxy (d-C4), nitro cyano or oxo and wherein said alkyl substituent (dd) optionally has one or nine fluorine atoms; R 4 is alkyl (d-d); each of R6 and R7 is independently H, halo, T or alkyl (d-d), said alkyl (d-d) optionally having from one to nine fluorine atoms or said alkyl (d-d) being optionally mono-substituted with T; where T is a partially saturated, or fully unsaturated, five or six member ring having optionally one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein said substituent T is optionally mono-, di or tri-substituted independently with halo, alkyl (dd), hydroxy, alkoxy (dd), alkylthio (dd), amino, oxo, carboxy, alkyloxycarbonyl (dd), mono.N- or di-N, N-alkylamino (dd), wherein said alkyl substituent (dd) optionally has from one to nine fluorine atoms; and R5 and R8 are H; or a pharmaceutically acceptable salt thereof. 3. The compound according to claim 2, wherein W is carbonyl; X is O-Y where Y is alkyl (d-d), said alkyl substituent (d-d) being optionally substituted with one to nine fluorine or hydroxy atoms; Q is (C 1 -C 4) alkyl and V is phenyl, pyridinyl or pyrimidinyl; wherein said ring V is optionally mono-, di or tri-substituted independently with halo, alkyl (dd), hydroxy, alkoxy (dd), nitro, cyano or oxo, wherein said alkyl substituent (dd) optionally has from one to nine atoms of fluorine; R2 is a straight or branched carbon chain (C1-C4) fully saturated; or said R2 is a ring of three to five members totally saturated; wherein said chain or ring R is optionally mono ^, di- or tri-substituted independently with halo; and each of R6 and R7 are independently hydrogen, halo or alkyl (d-d), said alkyl (d-d) optionally having from one to nine fluorine atoms; or a pharmaceutically acceptable salt thereof. 4. The compound according to claim 3, wherein Q is methyl and V is phenyl or pyridinyl; wherein said ring V is optionally mono-, di- or tri-substituted independently with halo, alkyl (d-d) or nitro, wherein said alkyl (d-d) optionally has one to five fluorine atoms, or a pharmaceutically acceptable salt thereof. 5. The compound according to claim 1, wherein said compound is [2S, 4S] 4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-isopropyl isopropyl ester. -6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid; [2S.4S] 4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -6-chloro-2-cyclopropyl-3,4-dihydro-2H-quinoline-1 isopropyl ester -carboxylic; [2S.4S] 2-Cyclopropyl-4 - [(3,5-dichloro-benzyl) -methoxycarbonyl-amino] -6-trifluoromethyl-3,4-dihydro-2H-quinoline- 1 -carboxylic; [2S, 4S] 4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-tert-butyl ester -1-carboxylic; [2S.4S] 4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl] amino] -2-cyclopropyl-6-trifluoromethyl-3,4-dihydroxypropionate 2H-quinoline-1-carboxylic acid; or [2S, 4S] 4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-cyclobutyl-6-trifluoromethyl-2-isopropyl ester • - - - - - j- - ^^^ jH «M ^^ liMtf.tA. ^. ^ Jat * 'M" 3,4-dihydro-2H-quinoline-1-carboxylic acid; or a pharmaceutically acceptable salt of said compounds. 6. The compound according to claim 1, wherein said compound is [2S.4S] 4- [1- (3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2- isopropyl ester. -ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid; [2S.4S] 4- [1- (3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-methoxymethyl-6-trifluoromethyl-3,4-dihydro isopropyl ester -2H- quinoline-1 -carboxylic; 2-hydroxy-ethyl ester of [2R, 4S] 4 - [(3,5-bis-trifluoromethyl) -benzyl) -methoxycarbonyl-amino] -2-ethyl-6-trifluoromethyl-3,4- dihydro-2H-quinoline-1-carboxylic acid; [2S.4S] 4 - [(3,5-bistrifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro ethyl ester -2H-quinoline-1-carboxylic acid; [2R.4S] 4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H ethyl ester -quinoline-1-carboxylic acid; [2S, 4S] 4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline propyl ester -1-carboxylic; or [2S.4S] 4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H- propyl ester quinol-1-carboxylic acid; or a pharmaceutically acceptable salt of said compounds. 7. The compound according to claim 4, wherein Y is sopropyl; R2 is isopropyl; R3 is 3,5-bis-trifluoromethylphenylmethyl; R4 is methyl; R6 is trifluoromethyl; and R7 is H, or a pharmaceutically acceptable salt thereof.
8. - The compound according to claim 4, wherein Y is isopropyl; R2 is cyclopropyl; R3 is 3,5-bis-trifluoromethylphenylmethyl; R4 is methyl; R6 is chlorine; and R7 is H, or a pharmaceutically acceptable salt thereof.
9. The compound according to claim 4, wherein Y is sopropyl R2 is cyclopropyl; R3 is 3,5-dichlorophenylmethyl; R4 is methyl; R6 is trifluoromethyl; and R7 is H, or a pharmaceutically acceptable salt thereof.
10. The compound according to claim 4, wherein Y is tert-butyl; R2 is cyclopropyl; R3 is 3,5-bis-trifluoromethylphenylmethyl; R4 is methyl; R6 is trifluoromethyl; and R7 is H, or a pharmaceutically acceptable salt thereof.
11. The compound according to claim 4, wherein And it is isopropyl; R2 is cyclopropyl; R3 is 3,5-bis-trifluoromethylphenylmethyl; R4 is methyl; R6 is trifluoromethyl; and R7 is H, or a pharmaceutically acceptable salt thereof.
12. The compound according to claim 4, wherein And it is sopropilo; R2 is cyclobutyl; R3 is 3,5-bis-trifluoromethylphenylmethyl; R4 is methyl; R6 is trifluoromethyl; and R7 is H, or a pharmaceutically acceptable salt thereof.
13. The compound according to claim 4, wherein Y is isopropyl; R2 is ethyl; R3 is 3,5-bis-trifluoromethylphenylmethyl; R4 is methyl; R6 is trifluoromethyl; and R7 is H, or a pharmaceutically acceptable salt thereof.
14. The compound according to claim 4, wherein Y is isopropyl; R2 is methoxymethyl; R3.es 3,5-bis-trifluoromethylphenylmethyl; R4 is methyl; R6 is trifluoromethyl; and Rt is H, or a pharmaceutically acceptable salt thereof.
15. The compound according to claim 4, wherein Y is 2-hydroxyethyl; R2 is ethyl; R3 is 3,5-bis-trifluoromethylphenylmethyl; R4 is methyl; R6 is trifluoromethyl; and R7 is H, or a pharmaceutically acceptable salt thereof.
16. The compound according to claim 4, wherein Y is ethyl; R2 is cyclopropyl; R3 is 3,5-bis-trifluoromethylphenylmethyl; R4 is methyl; R6 is trifluoromethyl; and R7 is H, or a pharmaceutically acceptable salt thereof.
17. The compound according to claim 4, wherein Y is ethyl; R2 is ethyl; R3 is 3,5-bis-trifluoromethylphenylmethyl; R4 is methyl; R6 is trifluoromethyl; and R7 is H, or a pharmaceutically acceptable salt thereof.
18. The compound according to claim 4, wherein Y is n-propyl; R2 is cyclopropyl; R3 is 3,5-bis-trifluoromethylphenylmethyl; R4 is methyl; R6 is trifluoromethyl; and R7 is H, or a pharmaceutically acceptable salt thereof.
19. The compound according to claim 4, wherein Y is n-propyl; R2 is ethyl; R3 is 3,5-bis-trifluoromethylphenylmethyl; R4 is methyl; ^ A ^ ^^^^^^^^^^^^^^^^ ^^^^^^^^^^^^^^^^ g jj g ^^^^^ R6 is trifluoromethyl; and R7 is H, or a pharmaceutically acceptable salt thereof.
20. The compound selected from the group consisting of [2S, 4S] 4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-isopropyl-6-isopropyl ester. -trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid; [2S.4S] 4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -6-chloro-2-cyclopropyl-3,4-dihydro-2H- acid soproxylic acid ester quinone-1-carboxylic acid; [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-tert-butyl ester -1-carboxylic; [2S.4S] 4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 isopropyl ester -carboxylic; [2S.4S] 4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-cyclobutyl-6-trifluoromethyl-3,4-dihydroxypropionate 2H-quinoline-1 carboxylic acid; [2R.4S] 4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H isopropyl ester -quinoline-1-carboxylic acid; [2S, 4S] 4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-methoxymethyl-6-trifluoromethyl-3,4-dihydro-2H-quinol isopropyl ester Na-1-carboxylic acid; 2-hydroxy-ethyl ester of [2R, 4S] 4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-ethyl-6-trifluoromethyl-3,4 -dihydro-2H-quinoline-1-carboxylic acid; acid ethyl ester [2S, 4S] 4 - [(3,5-bis-trifluoromethyl-benzyl) methoxycarbonyl-amino] -2-cyclopropyl-6-tr¡fluorometil-3,4- fo ^^^^^^^^^^^ ^^ ¡^^^ fe ^^ j ^ - ^ j & dihydro-2H-quinoline-1-carboxylic acid; [2R.4S] 4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-etl-6-trifluoromethyl-3,4-dihydro-2H-quinoline ethyl ester -1-carboxylic; [2S.4S] 4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline propyl ester -1-carboxylic; and [2R.4S] 4 - [(3,5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H- propyl ester quinoline-1-carboxylic acid; or a pharmaceutically acceptable salt thereof.
21. The compound according to claim 1, wherein R2 is beta; the nitrogen of C4 is beta; R1 is W-Z; W is carbonyl, thiocarbonyl or sulfonyl; X is -OY-, -SY-, N (H) -Y- or N- (Y) 2-1 and, for each case, is independently Z or (C 1 -C 4) alkyl, optionally having said alkyl (dd) from one to nine fluorine atoms or said alkyl (dd) being mono-substituted with Z optionally; where Z is a three to six member ring partially saturated, fully saturated or fully unsaturated having optionally one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein said substituent Z is optionally mono-, di- or tri-substituted independently with halo, alkyl (dd), alkoxy (dd), alkylthio (dd), nitro, cyano, oxo or alkoxycarbonyl (dd), said alkyl substituent ( dd) optionally substituted with one or nine fluorine atoms; R2 is a linear or branched, partially saturated, fully saturated or totally unsaturated carbon chain of one to four members, where the carbons other than the connecting carbon ^. ^. ^. ^^ ... «faith. ^ ... - ... Atoa | g¡yffi ^^ can optionally be replaced with a heteroatom independently selected from oxygen, sulfur and nitrogen, where said carbon atoms are optionally mono-, di- or tri-substituted independently with halo, said The carbon is optionally mono-substituted with oxo, said carbon is optionally mono-substituted with hydroxy, said sulfur is optionally mono- or di-substituted with oxo, said nitrogen being optionally mono- or di-substituted with oxo; or said R2 is a three to five member ring partially saturated, fully saturated or totally unsaturated optionally having a heteroatom independently selected from oxygen, sulfur and nitrogen; wherein said ring R2 is optionally mono-, di- or tri-substituted independently with halo, hydroxy, alkoxy (d-d) or alkoxycarbonyl (d-d); R3 is Q-V, where Q is (C1-C4) alkyl and V is a five to six member ring partially saturated, fully saturated or totally unsaturated, optionally having from one to three heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein said ring V is optionally mono-, di-, tri- or tetra-substituted independently with halo, alkyl (dd), hydroxy, alkoxy (dd), nitro, cyano or oxo, wherein said alkyl substituent (dd) optionally has one to nine fluorine atoms; R 4 is alkyl (d-d); and R5 and R6, or R6 and R7, or R7 and R8 are taken together and form a ring that is a ring of five to six members that is partially saturated or totally unsaturated having optionally one or two heteroatoms independently selected from nitrogen, sulfur and oxygen; where said ring formed by R5 and R6, or R6 and R7 or R7 and R8 is optionally mono-, di- or tri- substituted independently with halo, alkyl (dd), alkylsulfonyl (C1-C4), alkenyl (dd), hydroxy, alkoxy ( CrC4), (C 1 -C 4) alkylthio, amino, nitro, cyano, oxo, carboxy, alkoxycarbonyl (C 1 -C 4), mono-N- or di-N, N-alkylamino (C 1 -C 4), wherein said alkyl substituent (C1-C4), is optionally mono-, di- or tri- substituted independently with hydroxy, (C1-C4) alkoxy, (C1-C4) alkylthio, amino, nitro, cyano, oxo, carboxy, alkoxycarbonyl (C1-C4) ), mono-N- or di-N, N-alkylamino (C 1 -C 4) or said alkyl substituent (C 1 -C 4) optionally has from one to nine fluorine atoms; with the proviso that R5, R6, R7 and / or R8, as 10 may be the case, that they do not form the ring, are hydrogens; or a pharmaceutically acceptable salt thereof.
22. The compound according to claim 1, wherein R2 is beta; the nitrogen of C4 is beta; R1 is W-Y, W is carbonyl, thiocarbonyl or sulfonyl; Y is alkyl (d-d), optionally having said alkyl (d-d) 15 of one to nine fluorine atoms or said alkyl (d-d) being optionally mono-substituted with Z; where Z is a three to six member ring partially saturated, fully saturated or totally unsaturated having optionally one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein said substituent Z is Optionally mono-, di- or tri-substituted independently with halo, (C 1 -C 4) alkyl, alkoxy (dd), (C 1 -C 4) alkylthio, nitro, cyano, oxo or alkoxycarbonyl (d-), said substituent being alkyl (CrC) optionally substituted with one to nine fluorine atoms; R2 is a carbon chain of one to four linear or branched partially saturated, fully saturated or fully unsaturated members, wherein the carbons other than the connecting carbon may optionally be replaced with a heteroatom independently selected from oxygen, sulfur and nitrogen, where said carbon atoms are optionally mono-, di- - or tri-substituted independently with halo, said carbon is optionally mono-substituted with oxo, said carbon is optionally mono-substituted with hydroxy, said sulfur is optionally mono- or di-substituted with oxo, said nitrogen being optionally mono- or di- -replaced with oxo; or said R2 is a three to five member ring partially saturated, fully saturated or fully unsaturated optionally having a heteroatom independently selected from oxygen, sulfur and nitrogen; wherein said ring R2 is optionally mono-, di- or tri-substituted independently with halo, hydroxy, alkoxy (d-d) or alkoxycarbonyl (d-d); R3 is Q-V, where Q is alkyl (d-d) and V is a partially saturated, fully saturated or fully unsaturated five to six member ring optionally having one to three heteroatoms selected independently from oxygen, sulfur and nitrogen; wherein said ring V is optionally mono-, di-, tri- or tetra-substituted independently with halo, alkyl (dd), hydroxy, alkoxy (dd), nitro, cyano or oxo, wherein said alkyl substituent (dd), optionally has from one to nine fluorine atoms; R4 is alkyl (C? -C4); each of R6 and R7 is independently alkyl (d-d), or alkoxy (Crd), said substituent optionally having alkoxy (d-d) or alkyl (C Ce) of , »One to nine fluorine atoms or standalone substituent alkoxy (d-d) or alkyl (d-d) optionally substituted by T; where T is a partially saturated, fully saturated or fully unsaturated five or six member ring optionally having one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein said substituent T is opaquely mono-, di- or tri-substituted independently with halo, alkyl (d-d), hydroxy, alkoxy (d-d), alkylthio (d-d), amino, oxo, carboxy, alkyloxycarbonyl (C-i-d), mono-N- or di-N, N-alkylamino (d-d), wherein said alkyl substituent (d-d) optionally has from one to nine fluorine atoms; or R6 and R7 are taken together and form a ring which is a partially or fully unsaturated five or six member ring optionally having one or two heteroatoms independently selected from nitrogen, sulfur and oxygen; wherein said ring formed by R6 and R7 is optionally mono-, di- or tri-substituted independently with halo, alkyl (Cid), alkylsulfonyl (dd), alkenyl (dd), hydroxy, alkoxy (dd), alkylthio (C1-C4) ), amino, nitro, cyano, oxo, carboxy, alkyloxycarbonyl (dd), mono-N- or di-N, N-alkylamino (C 1 -C 4), wherein said (C 1 -C 4) alkyl substituent, optionally has one to nine fluorine atoms; R5 and R8 are H; or a pharmaceutically acceptable salt thereof.
23. The compound according to claim 1, wherein R2 is beta; the nitrogen of C4 is beta; R1 is Y; Y is alkenyl (dd) or alkyl (dd), optionally having said alkenyl (dd) or alkyl (Cr d), from one to nine fluorine atoms or optionally said alkenyl (dd) or alkyl (CrCe) mono-substituted with Z; where Z is a three to six member ring partially saturated, fully saturated or totally unsaturated having optionally one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein said substituent Z is optionally mono-, di- or tri- substituted independently with halo, alkyl (dd), alkoxy (dd), alkylthio (dd), nitro, cyano, oxo or alkyloxycarbonyl (dd), said alkyl substituent ( dd) optionally substituted with one to nine fluorine atoms; R2 is a linear or branched partially saturated, fully saturated or fully unsaturated, one to four carbon chain in which carbons other than the connecting carbon can optionally be replaced with a heteroatom independently selected from oxygen, sulfur and nitrogen, where said carbon atoms are optionally mono-, di-, or tri-substituted independently with halo, said carbon is optionally mono-substituted with oxo, said carbon is optionally mono-substituted with hydroxy, said sulfur is optionally mono- or disubstituted with oxo said nitrogen is optionally mono- or di-substituted with oxo; or said R2 is a three to five member ring partially saturated, fully saturated or totally unsaturated optionally having a heteroatom independently selected from oxygen, sulfur and nitrogen; wherein said ring R2 is optionally mono-, di- or tri-substituted independently with halo, hydroxy, alkoxy (d-d) or ¿^^^^^ ¿^^? ¿^ Ll ^^^^ f ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ^^^^^^^^^^^^^^^^^^^^ alkoxycarbonyl (d-d); R3 is Q-V, where Q is alkyl (d-d) and V is a partially saturated, fully saturated or fully unsaturated five to six member ring optionally having one to three heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein said ring V is optionally mono-di-, tri- or tetra-substituted independently with halo, alkyl (dd), hydroxy, alkoxy (dd), nitro, cyano or oxo, wherein said alkyl substituent (dd) optionally has one to nine fluorine atoms; R 4 is alkyl (d-d); each of R6 and R7 are independently alkyl (dd) or alkoxy (Crd), said alkyl (dd) or alkoxy (dd) substituent optionally having from one to nine fluorine atoms or said substituent being alkoxy (dd) or alkyl (dd) ) optionally mono-substituted with T; where T is a partially saturated, fully saturated or fully unsaturated five to six member ring optionally having one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein said substituent T is optionally mono-, di- or tri-substituted independently with halo, alkyl (dd), hydroxy, alkoxy (dd), alkylthio (dd), amino, oxo, carboxy, alkoxycarbonyl (dd), mono-N - or di-N, N-alkylamino (dd), wherein said alkyl substituent (dd) optionally has from one to nine fluorine atoms; or R6 and R7 are taken together and form a ring that is a partially saturated or fully unsaturated five to six member ring optionally having one or two heteroatoms independently selected from nitrogen, sulfur and oxygen; wherein said ring formed by R6 and R7 is optionally mono-, di-, or tri-substituted independently with halo, alkyl (dd), alkylsulfonyl (dd), alkenyl (d-C4), hydroxy, alkoxy (CrC4), alkylthio ( dd), amino, nitro, cyano, oxo, carboxy, alkyloxycarbonyl (dd), mono-N- or di-N, N-alkylamino (dd), wherein said alkyl substituent (dd) optionally has from one to nine fluorine atoms; R5 and R8 are H, or a pharmaceutically acceptable salt thereof.
24. The compound according to claim 1, wherein R2 is beta; the nitrogen of C4 is beta; R1 is Z; Z is a three to six member ring partially saturated, fully saturated or totally unsaturated having optionally one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein said substituent Z is optionally mono-, di- or tri- substituted independently with halo, alkyl (dd), alkoxy (dd), alkylthio (dd), nitro, cyano, oxo or alkoxycarbonyl (dd), said alkyl substituent ( dd) optionally of one nine fluorine atoms; R2 is a carbon chain of one to four members, linear or branched, partially saturated, fully saturated or totally unsaturated, in which the carbons other than the connecting carbon can optionally be replaced with a heteroatom independently selected from oxygen, sulfur and nitrogen, wherein said carbon atoms are optionally mono-, di-, or tri-substituted independently with halo, said carbon is optionally mono-substituted with oxo, said carbon being optionally mono-substituted with hydroxy, said sulfur is optionally mono- or disubstituted with oxo, said nitrogen being optionally mono- or di-substituted with oxo; or said R2 is a three to five member ring partially saturated, fully saturated or totally unsaturated having optionally a heteroatom independently selected from oxygen, sulfur and nitrogen; wherein said ring R2 is optionally mono-, di- or tri-substituted independently with halo, hydroxy, alkoxy (d-d) or alkoxycarbonyl (d-d); R3 is Q-V, where Q is alkyl (d-d) and V is a five to six member ring partially saturated, fully saturated or - fully unsaturated having optionally one to three heteroatoms independently selected from oxygen, sulfur and nitrogen, wherein said ring V is optionally mono-, di-, tri- or tetra-substituted independently with halo, alkyl (dd), hydroxy , alkoxy (Crd), nitro, cyano or oxo, wherein said alkyl substituent (dd) optionally has 15 one to nine fluorine atoms; R 4 is alkyl (d-d); each of R6 and R7 are independently alkyl (CrCe) or alkoxy (Crd), said alkyl (dd) or alkoxy (dd) substituent optionally having from one to nine fluorine atoms or said substituent being alkoxy (dd) or alkyl (dd) optionally mono-substituted with T; where T is a ring of five to six 20 members partially saturated, fully saturated or totally unsaturated optionally having one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein said substituent T is optionally mono-, di- or tri-substituted ,? «• Ktfflwtini. -'- T -i-l- it-n- T * -» ~ * ¿- »- > - • - -. - - &"£, ^ .. Ajá¡ = ¡¡¡¡¡¡¡^^^ independently with halo, alkyl (dd), hydroxy, alkoxy (dd), alkylthio (dd), amino, oxo, carboxy, alkoxycarbonyl (dd) ), mono-N- or di-N-, N-alkylamino (dd), wherein said alkyl substituent (dd) optionally has one to nine fluorine atoms; or R6 and R7 are taken together and form a ring which is a five or six member ring partially saturated or totally unsaturated having optionally one or two heteroatoms independently selected from nitrogen, sulfur and oxygen; wherein said ring formed by R6 and R7 is optionally mono-, di-, or tri-substituted independently with halo, alkyl (d-d), alkylsulfonyl 10 (dd), (C2-d) alkenyl, hydroxy, alkoxy (dd), alkylthio (dd), amino, nitro, cyano, oxo, carboxy, alkyloxycarbonyl (dd), mono-N- or di-N, N- alkylamino (dd), wherein said alkyl substituent (dd) optionally has from one to nine fluorine atoms; R5 and R8 are H, or a pharmaceutically acceptable salt thereof.
25. The compound according to claim 1, wherein R2 is beta; the nitrogen of C4 is beta; R is W-Z; W is carbonyl, thiocarbonyl or sulfonyl; Z is a three to six member ring partially saturated, fully saturated or totally unsaturated having optionally one or two heteroatoms independently selected from oxygen, sulfur and 20 nitrogen; wherein said substituent Z is optionally mono-, di- or tri- substituted independently with halo, alkyl (dd), alkoxy (-d), alkylthio (Crd), nitro, cyano, oxo or alkoxycarbonyl (dd), said alkyl substituent having (dd) optionally from one to nine fluorine atoms; R2 is a carbon chain of one to four members, linear or branched, partially saturated, fully saturated or totally unsaturated, in which the carbons other than the connecting carbon can optionally be replaced with a heteroatom independently selected from oxygen, sulfur and nitrogen, wherein said carbon atoms are optionally mono-, di-, or tri-substituted independently with halo, said carbon is optionally mono-substituted with oxo, said carbon is optionally mono-substituted with hydroxy, said sulfur is optionally mono- or di- substituted with oxo, said nitrogen is optionally mono- or di- ~ 10 substituted with oxo; or said R2 is a three to five member ring partially saturated, fully saturated or totally unsaturated, optionally having a heteroatom independently selected from oxygen, sulfur and nitrogen; wherein said ring R2 is optionally mono-, di- or tri-substituted independently with halo, hydroxy, alkoxy (CrCe) or alkoxycarbonyl (d-d); R3 is Q-V, where Q is alkyl (d-d) and V is a five to six member ring partially saturated, fully saturated or fully unsaturated having optionally from one to three heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein said ring V is optionally mono-di-, tri- or tetra-substituted independently with halo, alkyl (CrCe), hydroxy, alkoxy (dd), nitro, cyano or oxo, wherein said alkyl substituent (dd) optionally has one to nine fluorine atoms; R 4 is alkyl (d-d); each of R6 and R7 are independently alkyl (d-d) or alkoxy (d-d), optionally having ? = í_- ¿^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ j ^^^^^^^^^ said alkyl (dd) or alkoxy (dd) substituent of one to nine fluorine atoms or said substituent being alkoxy (dd) or alkyl (dd) optionally mono-substituted with T; where T is a partially saturated, saturated or fully unsaturated five or six member ring having optionally one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein said substituent T is optionally mono-, di- or tri-substituted independently with halo, alkyl (dd), hydroxy, alkoxy (dd), alkylthio (C 1 -C 4), amino, oxo, carboxy, alkoxycarbonyl (dd), mono -N- or di-N-, N-10 alkylamino (dd), wherein said alkyl substituent (dd) optionally has one to nine fluorine atoms; or R6 and R7 are taken together and form a ring that is a partially saturated or fully unsaturated five to six member ring optionally having one or two heteroatoms independently selected from nitrogen, sulfur 15 and oxygen; wherein said ring formed by R6 and R7 is optionally mono-, di-, or tri-substituted independently with halo, alkyl (dd), alkylsulfonyl (C1-C4), alkenyl (dd), hydroxy, alkoxy (dd), alkylthio ( CrC), amino, nitro, cyano, oxo, carboxy, alkyloxycarbonyl (dd), mono-N- or di-N, N-alkylamino (dd), wherein said alkyl substituent (dd) optionally has one to 20 nine fluorine atoms; R5 and R8 are H, or a pharmaceutically acceptable salt thereof.
26. The compound according to claim 1, wherein R2 is beta; the nitrogen of C4 is beta; R1 is W-Z; W is carbonyl, thiocarbonyl ^^^^^^^^^^^^^^^^^^^^^^^^ * rt¡? ^^^^^^^^^^^^^^^^^^^^^ or sulfonyl; X is -O-Y-, S-Y-, N (H) -Y- # -N- (Y) 2-; And, for each case, it is independently Z or alkyl (d-d), said alkyl (d-d) optionally having one to nine fluorine atoms or said alkyl (d-d) ring being optionally mono-substituted with Z; where Z is a three to five six member ring partially saturated, fully saturated or fully unsaturated optionally having one to two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein said substituent Z is optionally mono-, di- or tri- substituted independently with halo, alkyl (d-d), alkoxy (d-d), alkylthio (d-d), nitro, cyano, oxo or 10 alkoxycarbonyl (d-d), said alkyl substituent (d-d) being optionally substituted with one to nine fluorine atoms; R2 is a carbon chain of one to four members, linear or branched, partially saturated, fully saturated or totally unsaturated, in which the carbons other than the connecting carbon can optionally be replaced with an 15 heteroatom independently selected from oxygen, sulfur and nitrogen, where said carbon atoms are optionally mono-, di-, or tri-substituted independently with halo, said carbon being optionally mono-substituted with oxo, said carbon being optionally mono-substituted with hydroxy, said sulfur is optionally mono- or di-substituted with oxo, said nitrogen being optionally mono-substituted or disubstituted with oxo; or said R2 is a three to five member ring partially saturated, fully saturated or totally unsaturated, optionally having a heteroatom independently selected from oxygen, sulfur and nitrogen; wherein said ring R2 is optionally mono-, di- or tri-substituted independently with halo, hydroxy, alkoxy (d-d) or alkoxycarbonyl (d-d); R3 is Q-V, where Q is alkyl (d-d) and V is a five- or six-member partially saturated, fully saturated or fully unsaturated ring optionally having one to three heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein said ring V is optionally mono-di-, tri- or tetra-substituted independently with halo, alkyl (d-d), hydroxy, alkoxy (CrCe), nitro, cyano or oxo, wherein said alkyl substituent (d-d) optionally has 10 one to nine fluorine atoms; R 4 is alkyl (d-d); at least one of R6 and R7 is alkoxy (d-d) and at least one of R6 and R7 is alkyl (d-d), said alkyl (d-d) or alkoxy (d-d) substituent optionally having from one to nine fluorine atoms; or said alkoxy (d-d) or alkyl (d-d) substituent being optionally mono-substituted with T; where T is a ring of five to Six members partially saturated, fully saturated or completely unsaturated optionally having one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein said substituent T is optionally mono-, di- or tri-substituted independently with halo, alkyl (d-d), hydroxy, alkoxy (d-d), alkylthio 20 (d-d), amino, oxo, carboxy, alkoxycarbonyl (d-d), mono-N- or di-N-, N-alkylamino (d-d), wherein said alkyl substituent (d-d) optionally has one to nine fluorine atoms; or R5 and R8 are H, or a pharmaceutically acceptable salt thereof.
27. - The use of a compound as claimed in claim 1, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug for the manufacture of a medicament for the treatment of atherosclerosis, peripheral vascular disease, dyslipidemia, hyperbetalipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial hypercholesterolemia, cardiovascular disorders, angina, cardiac ischemia, stroke, myocardial infarction, reperfusion injury, angioplastic resteinosis, hypertension, vascular complications of diabetes, obesity or endotoxemia in a mammal (including a human being, both male and female) .
28.- The use as claimed in claim 27, in which atherosclerosis is treated.
29. The use as claimed in claim 27, in which peripheral vascular disease is treated.
30. The use as claimed in claim 27, in which dyslipidemia is treated.
31. The use as claimed in claim 27, in which hyperbetalipoproteinemia is treated.
32. The use as claimed in claim 27, in which hypoalphalipoproteinemia is treated.
33. The use as claimed in claim 27, in which hypercholesterolemia is treated. ..... . .M? KjfH &Aí * _ * ^. . ^. - - "- *" - - * fa ^ aS * MMa * a «? a-. .....
34. - The use as claimed in claim 27, wherein the hypertriglyceridemia is treated.
35.- The use as claimed in claim 27, in which cardiovascular disorders are treated. 5. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or said prodrug, and a pharmaceutically acceptable carrier. 1 10 37.- The pharmaceutical composition for the treatment of atherosclerosis, peripheral vascular disease, dyslipidemia, hyperbetalipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial hypercholesterolemia, cardiovascular disorders, angina, cardiac ischemia, stroke, myocardial infarction, Reperfusion, angioplastic resteinosis, hypertension, vascular complications of diabetes, obesity or endotoxemia in a mammal, comprising a therapeutically effective amount of a compound of claim 1, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or said prodrug and a pharmaceutically vehicle 20 acceptable. 38.- The pharmaceutical composition for the treatment of atherosclerosis in a mammal, comprising an amount for treating atherosclerosis of a compound of claim 1, a prodrug of the same, or a pharmaceutically acceptable salt of said compound or of said prodrug and a pharmaceutically acceptable carrier. 39.- The combination pharmaceutical composition comprising: a therapeutically effective amount of a composition comprising: a first compound, said first compound being a compound of claim 1, a prodrug thereof or a pharmaceutically acceptable salt of said compound or of said prodrug; a second compound, said second compound being an inhibitor of HMG-CoA reductase, an inhibitor of MTP / ApoB secretion, an activator 10 of PPAR, a bile acid reuptake inhibitor, an inhibitor of the I absorption of cholesterol, an inhibitor of cholesterol synthesis, a fibrate, niacin, an ion exchange resin, an antioxidant, an ACAT inhibitor or a bile acid complexor; and a pharmaceutical vehicle. 40.- The pharmaceutical composition of combination of agreement 15 with claim 39, wherein the second compound is an inhibitor of HMG-CoA reductase or an inhibitor of MTP / Apo B secretion. 41.- The combination pharmaceutical composition according to claim 39, in the that the second compound is lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin or rivastatin. The use of a) a first compound, said first compound being a compound of claim 1, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug; in combination with b) a second compound, being said second compound an inhibitor of HMG-CoA reductase, an inhibitor of MTP / ApoB secretion, an inhibitor of cholesterol absorption, an inhibitor of cholesterol synthesis, a fibrate, niacin, an ion exchange resin, an antioxidant , an ACAT inhibitor or a bile acid complexer for the manufacture of a medicament for the treatment of atherosclerosis in a mammal. 43.- The use as claimed in claim 42, wherein the second compound is an inhibitor of HMG-CoA reductase or an inhibitor of MTP / Apo B secretion. 44.- Use as the one It is claimed in claim 42, wherein the second compound is lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin or rivastatin. 45.- A team that includes: a. a first compound, said first compound being a compound according to claim 1, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or said prodrug and a pharmaceutically acceptable carrier, in a first unit dosage form; b. a second compound, said second compound being an inhibitor of HMG CoA reductase, an inhibitor of MTP / Apo B secretion, an inhibitor of cholesterol absorption, an inhibitor of cholesterol synthesis, a fibrate, niacin, a resin ion exchange, an antioxidant, an ACAT inhibitor or a bile acid complex and an acceptable vehicle in a second unit dosage form; and c. means for containing said first and second forms of dosificacjójppunitaria, where the quantities of 71 | * f first and second compounds produce a therapeutic effect. 46. The equipment according to claim 45, wherein said second compound is an inhibitor of HMG-CoA reductase or an inhibitor of MTP / Apo B secretion. 47. The equipment according to claim 45 , wherein said second compound is lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin or rivastatin. ,. ^^^ * ^^ »..aawitej. ^ .: